Perimenopause/Menopause

Hot flashes? Night sweats? Progesterone can help reduce symptoms of menopause

Prior JC, 2025

Association between endometriosis and type and age of menopause: a pooled analysis of 279 948 women from five cohort studies

Chung HF et al., 2025·Hum Reprod

What is the association between endometriosis and the type and age of menopause? Women with endometriosis had a 7-fold increased risk of undergoing surgical menopause rather than natural menopause and were more likely to experience premature or early menopause, both surgically and naturally. Endometriosis is associated with reduced ovarian reserve, but evidence on its relationship with the type of menopause (surgical vs natural) and timing (especially premature and early menopause) is limited. Women with endometriosis are more likely to undergo hysterectomy and/or oophorectomy (either unilateral or bilateral), but the average age of these surgeries remains unclear. STUDY DESIGN, SIZE, The study analysed individual-level data from 279 948 women in five cohort studies conducted in the UK, Australia, Sweden, and Japan between 1996 and 2022. PARTICIPANTS/MATERIALS, SETTING, Women whose menopause type and age could not be determined due to premenopausal hysterectomy with ovarian preservation or use of menopausal hormone therapy were excluded. Endometriosis was identified through self-reports and administrative data. Surgical menopause was defined as premenopausal bilateral oophorectomy. Fine-Gray subdistribution hazard models estimated hazard ratios (HRs) for surgical and natural menopause. Age at menopause was determined by the ages at the final menstrual period or bilateral oophorectomy. Linear regression assessed mean differences in menopause age, while multinomial logistic regression estimated odds ratios (ORs) <40 (premature), 40-44 (early), 45-49, 50-51 (reference), 52-54, and ≥55 years. Spontaneous premature ovarian insufficiency (POI) was defined as natural menopause before age 40 years. MAIN Endometriosis was identified in 3.7% of women. By the end of follow-up, 7.9% had surgical menopause and 58.2% experienced natural menopause. Using a competing risk model, women with endometriosis had a 7-fold increased risk of surgical menopause (HR: 7.54, 95% CI 6.84, 8.32) and were less likely to experience natural menopause (HR: 0.40, 95% CI 0.33, 0.49). On average, surgical menopause occurred 1.6 years (19 months) earlier (β: -1.59, 95% CI -1.77, -1.42) in women with endometriosis. Among women who experienced natural menopause, it was 0.4 years (5 months) earlier (β: -0.37, 95% CI -0.46, -0.28) for those with endometriosis. Women with endometriosis were twice as likely to experience premature surgical menopause (<40 years) (OR: 2.11, 95% CI 2.02, 2.20) or 1.4 times more likely to develop spontaneous POI (OR: 1.36, 95% CI 1.17, 1.59). They were also at increased odds of early surgical and natural menopause (40-44 years). LIMITATIONS, This study could not differentiate between subtypes and stages of endometriosis or assess treatments for ovarian endometrioma, which may impact ovarian reserve. Self-reported menopause type and age could introduce recall bias. Given the consistent findings across individual studies, our results are likely to be generalizable to different populations, highlighting the need for tailored management of endometriosis to prevent medically induced or premature menopause. Long-term monitoring of women with endometriosis is recommended, given their elevated risk of surgical menopause and premature or early menopause, which are associated with adverse health outcomes in later life. STUDY FUNDING/COMPETING INTEREST(S): The InterLACE Consortium is funded by the Australian National Health and Medical Research Council project grant (APP1027196) and Centres of Research Excellence (APP1153420). G.D.M. is funded by the Australian National Health and Medical Research Council Leadership Fellowship (APP2009577). This research is funded in part by the Japan Society for the Promotion of Science (JSPS 19KK0235, 23KK0167). The authors have no conflict of interest. Where authors are identified as personnel of the International Agency for Research on Cancer or WHO, the authors alone are responsible for the views expressed in this article, and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer or WHO. N/A.

Validating At-Home Urinary Hormone Measurements in Postpartum and Perimenopause Fertility Transitions

Bouchard TP et al., 2025·Womens Health Rep (New Rochelle)

Measuring quantitative menstrual cycle hormones at home may help women better understand their postpartum and perimenopause fertility transitions, but these quantitative fertility monitors require validation. This study included 16 North American women, aged 28-51, during either the postpartum (n = 8, cycles = 18) or perimenopause (n = 8, cycles = 35) fertility transitions testing daily first-morning urine testing with both the Mira Monitor and ClearBlue Fertility Monitor (CBFM) along with menstrual cycle parameter tracking. The main outcome measures were a rise in estrone-3-glucuronide (E13G) and luteinizing hormone (LH) urine hormone values from the Mira monitor correlated to low, high, or peak values on the CBFM. Both in the postpartum and perimenopause transitions, the identification of the day of ovulation based on the LH surge on the Mira and CBFM monitors was highly correlated (R = 0.94 and 0.83, p < 0.001). The E13G levels on the Mira monitor were significantly higher for a CBFM reading of "High" compared with "Low" for both the postpartum and perimenopausal cycles (all p < 0.001). Similarly, the LH levels on the Mira monitor were significantly higher for a CBFM reading of "Peak" (LH surge) compared with "High" for both the postpartum and perimenopausal cycles (all p < 0.001). The LH surge and levels of E13G in urine identified on the quantitative Mira fertility monitor strongly correlate to the LH surge and the shift from low to high on the CBFM during the postpartum and perimenopause transitions.

Expanding our Human Sexual Horizons

Foote AD et al., 2025

Evidence-based guideline: premature ovarian insufficiency

Panay N et al., 2024·Hum Reprod Open

How should premature/primary ovarian insufficiency (POI) be diagnosed and managed based on the best available evidence from published literature?Summary answerThe current guideline provides 145 recommendations on symptoms, diagnosis, causation, sequelae, and treatment of POI. Premature ovarian insufficiency (POI) presents a significant challenge to women's health, with far-reaching implications, both physically and emotionally. The potential implications include adverse effects on quality of life; fertility; and bone, cardiovascular, and cognitive health. Although hormone therapy (HT) can mitigate some of these effects, many questions still remain regarding the optimal management of POI.Study design size durationThe guideline was developed according to the structured methodology for development of ESHRE guidelines. Key questions were determined by a group of experts and informed by a scoping survey of women and health care professionals. Literature searches and assessments were then performed. Papers published up to 30 January 2024 and written in English were included in the guideline. An integrity review was conducted for the randomized controlled trials (RCTs) on POI included in the guideline. Participants/materials setting methodsBased on the collected evidence, recommendations were formulated and discussed within the guideline development group until consensus was reached. Women with lived experience of POI informed the recommendations in general, and particularly on those on provision of care. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline development group and the ESHRE Executive Committee. s and the role of chanceNew data indicate a higher prevalence of POI, 3.5%, than was previously thought. This guideline aims to help health care professionals to apply best practice care for women with POI. The recent update of the POI guideline covers 40 clinical questions on diagnosis of the condition, the different sequelae, including bone, cardiovascular, neurological and sexual function, fertility and general well-being, and treatment options, including HT. The list of clinical questions was expanded from the previous iteration of the guideline (2015) based on the scoping survey and appreciation of emerging knowledge of POI. Questions were added on the role of anti-Müllerian hormone (AMH) in the diagnosis of POI, fertility preservation, muscle health, and specific considerations for HT in iatrogenic POI. Additionally, the topic on complementary treatments was extended with specific focus on non-hormonal treatments and lifestyle management options. Significant changes from the previous 2015 guideline include the recommendations that only one elevated FSH >25 IU is required for diagnosis of POI, and guidance that AMH testing, repeat FSH measurement, and/or AMH may be required where there is diagnostic uncertainty. Recommendations were also updated regarding genetic testing, estrogen doses and regimens, use of the combined oral contraceptive and testosterone therapy. Women with lived experience of POI informed the recommendations on provision of care. Limitations reasons for cautionThe guideline describes different management options, but it must be acknowledged that for most of these options, supporting evidence is limited for POI. s of the findingsThe guideline provides health care professionals with clear advice on best practice in POI care, based on the best evidence currently available. In addition, a list of research recommendations is provided to guide further studies in POI.Study funding/competing interestsThe guideline was developed and funded by ESHRE, American Society for Reproductive Medicine (ASRM), Centre for Research Excellence in Women's Health in Reproduction Life (CRE-WHiRL), and International Menopause Society (IMS), covering expenses associated with the guideline meetings, literature searches, and dissemination of the guideline. The guideline group members did not receive payments. N.P. declared grants from Bayer Pharma (research and consultancy) and NIHR-research POISE; consulting fees from Abbott, Astellas, Bayer, Besins, Lawley, Mithra, Theramex, Viatris; honoraria from Astellas, Bayer, Besins, Gedeon Richter, Theramex, Viatris; support for attending meetings and/or travel from Astellas, Bayer, Theramex, Viatris; President, International Menopause Society, Medical Advisory Committee member, British Menopause Society, Patron Daisy Network. A.J.V. declared grants from Amgen Australia, Australian NHMRC, and Australian MRFF; consulting fees from IQ Fertility; honoraria from the Australasian Menopause Society; participation on a Data Safety Monitoring Board or Advisory Board of Astellas; Board Member of the International Menopause Society (2020 to current) and Past president of the Australasian Menopause Society (2017-2019); R.A.A. declared grants from Roche (Research support, to institution), and participation on a Data Safety Monitoring Board of Bayer. M.C. declared grants from NHI; payments or honoraria from Up-to-Date (as editor/reviewer); Board Member of American Society of Reproductive Medicine, and of American Gynecological and Obstetrical Society. M.D. declared (NIHR-HTA NIHR133461; NIHR128757; Action GN2818) consulting fees from a small personal medical practice, support for attending meetings and/or travel from ESHRE, Bayer and UCLH special Trustees; Participation on the Advisory Board of the British Menopause Society, UKSTORE project, the Progress Educational Trust, and the Turner Syndrome Support Society UK; Leadership or fiduciary roles in the British Fertility Society (Trustee), Elizabeth Garrett Anderson Hospital Charity (chair of Trustees), and the Essex Wynter charitable trust (Trustee). C.E. declared being Chair of a SIG from the Royal Australian College of General Practitioners Integrative Medicine Specific Interest Group and Program Lead for Next Practice Western Sydney Integrative Health. C.H.G. declared grants from Novo Nordisk Foundation (Nos. NNF15OC0016474 and NNF20OC0060610), sygesikringen danmark (No 2022-0189), and the Independent Research Fund Denmark (Nos. 0134-00406 and 0134-00130B); consulting fees from Novo Nordisk, Merck, and Astra Zeneca. S.K. declared grants from Roche diagnostics. A.K. declared grants from NIH R01 5R01HD101475; consulting fees as Medical Reviewer for Flo and for Healthline; honoraria as Medical Consultant for Summus; support for attending meetings from the Reproductive Scientist Development Program; Society for Reproductive Investigation Council Member and Society for Assisted Reproduction Registry/Validation Chair; R.E.N. declared consulting fees from Astellas, Bayer Pharma, Besins Healthcare, Fidia, Theramex; honoraria from Abbott, Astellas, Exeltis, Fidia, Gedeon Richter, Merck & Co, Novo Nordisk, Shionogi Limited, Theramex, Viatris; payment for expert testimony from Vichy Laboratories; Participation in Data Safety Monitoring Board of Advisory board from Astellas and Bayer Healthcare; President elect of the International Menopause Society (IMS). H.T. declared a grant from NHMRC Centre for Research Excellence for women's health in reproductive life. A.B. declared being chair of the Daisy Network Charity. The other authors have no conflicts of interest to declare.DisclaimerThis guideline represents the views of ESHRE, ASRM, CRE-WHiRL, and IMS, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgement to each individual presentation, nor variations based on locality and facility type. The collaborating societies make no warranty, expressed or implied, regarding the clinical practice guidelines and specifically exclude any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.).

Evidence-based guideline: premature ovarian insufficiency(†)(‡)

Panay N et al., 2024·Climacteric

How should premature/primary ovarian insufficiency (POI) be diagnosed and managed, based on the best available evidence from published literature? The current guideline provides 145 recommendations on symptoms, diagnosis, causation, sequelae and treatment of POI. POI presents a significant challenge to women's health, with far-reaching implications, both physically and emotionally. The potential implications include adverse effects on quality of life, on fertility and on bone, cardiovascular and cognitive health. Although hormone therapy (HT) can mitigate some of these effects, many questions still remain regarding the optimal management of POI. STUDY DESIGN, SIZE, The guideline was developed according to the structured methodology for development of European Society of Human Reproduction and Embryology (ESHRE) guidelines. Key questions were determined by a group of experts and informed by a scoping survey of women and healthcare professionals. Literature searches and assessment were then performed. Papers published up to 30 January 2024 and written in English were included in the guideline. An integrity review was conducted for the randomized controlled trials on POI included in the guideline. PARTICIPANTS/MATERIALS, SETTING, Based on the collected evidence, recommendations were formulated and discussed within the guideline development group until consensus was reached. Women with lived experience of POI informed the recommendations in general, and particularly those on provision of care. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline development group and the ESHRE Executive Committee. MAIN New data indicate a higher prevalence of POI, 3.5%, than was previously thought. This guideline aims to help healthcare professionals apply best practice care for women with POI. The recent update of the POI guideline covers 40 clinical questions on diagnosis of the condition, the different sequelae, including bone, cardiovascular, neurological and sexual function, fertility and general well-being, and treatment options, including HT. The list of clinical questions was expanded from the previous iteration of the guideline (2015) based on the scoping survey and appreciation of emerging knowledge of POI. Questions were added on the role of anti-Müllerian hormone (AMH) in the diagnosis of POI, fertility preservation, muscle health and specific considerations for HT in iatrogenic POI. Additionally, the topic on complementary treatments was extended with specific focus on non-hormonal treatments and lifestyle management options. Significant changes from the previous 2015 guideline include the recommendations that only one elevated follicle stimulating hormone (FSH) >25 IU is required for diagnosis of POI and guidance that AMH testing, repeat FSH measurement and/or AMH may be required where there is diagnostic uncertainty. Recommendations were also updated regarding genetic testing, estrogen doses and regimens, use of the combined oral contraceptive and testosterone therapy. Women with lived experience of POI informed the recommendations on provision of care. LIMITATIONS, The guideline describes different management options, but it must be acknowledged that for most of these options, supporting evidence is limited for POI. The guideline provides healthcare professionals with clear advice on best practice in POI care, based on the best evidence currently available. In addition, a list of research recommendations is provided to guide further studies in POI.

Using anti-Müllerian hormone to predict premature ovarian insufficiency: a retrospective cross-sectional study

Huang Y et al., 2024·Front Endocrinol (Lausanne)

Premature ovarian insufficiency/failure (POI/POF) is a significant issue for women of reproductive age. Anti-Müllerian hormone (AMH) is a potential biomarker of ovarian reserve, but its clinical value in diagnosing and predicting POI/POF remains unclear. This study aimed to analyze the correlation between AMH and basal follicle-stimulating hormone (FSH) levels in women aged 18 to 40 and evaluate AMH's predictive value for POI/POF. A total of 21,143 participants aged 18-40 who visited the gynecology department or underwent physical examinations at the International Peace Maternity and Child Health Hospital in Shanghai, China, from July 2016 to June 2021 were enrolled. Demographic information and laboratory test results were collected, including age, FSH, AMH, E2 and test dates. Participants were grouped by FSH and AMH levels, and subgroup analyses were performed to investigate the relationship between these hormones and age. The AMH level associated with POI risk was evaluated using restricted cubic splines (RCS) and logistic regression. Clinical benefit was assessed by decision curve analysis (DCA). Participants with higher FSH levels had significantly lower median AMH levels and vice versa(p<0.001). At AMH ≥ 0.5 ng/mL, FSH levels were normal or slightly elevated with age. At AMH level below 0.5ng/ml,basal FSH increased significantly with age. At FSH <10 IU/L, AMH levels show a trend of rising and then decreasing with age, reaching a peak at approximately 25 years old and gradually decreasing with age. At FSH ≥10 IU/L, AMH levels show a gradual downward trend with age, and at FSH >40 IU/L, AMH levels remain very low to undetectable values. The RCS showed that the risk of POI/POF in the overall population sharply increased until serum AMH reached a low level (below 0.5ng/ml). DCA showed that a low AMH level had good clinical diagnostic utility in predicting POI/POF. Our analysis of a large dataset suggests that serum AMH levels are inversely correlated with FSH levels and that AMH is a good predictor of POI until it drops to a low level.

Recognizing Endometrial Cancer Risks in Perimenopausal and Postmenopausal Experiences: Insights From Community Qualitative Interviews and Workshop

Ibrahim M et al., 2024·J Obstet Gynaecol Can

To evaluate the experiences of perimenopausal and postmenopausal women in British Columbia, their perceptions of expected reproductive aging, and potential concerns about endometrial cancer (EC). We interviewed 31 midlife community women of diverse backgrounds and hosted a workshop for more in-depth discussion. We summarized relayed experiences and beliefs through a thematic and descriptive analysis of participant stories and workshop feedback. Participants demonstrated a somewhat simplistic understanding of midlife changes, facing this phase of life with a "tough-it-out" attitude rather than seeking medical help for arising symptoms. Awareness of EC and EC-specific risk factors, such as obesity, was low. Confusion between cervical and EC was common. Although abnormal bleeding was seen as potentially of concern, many opted to wait before seeking medical help. Workshop participants stressed the need to include awareness about EC in a broader conversation about perimenopause and menopause and suggested strategies for disseminating EC awareness. Community women in British Columbia demonstrated low awareness of EC-associated symptoms and risk factors. There is little information to help distinguish when perimenopausal abnormal uterine bleeding is of concern and when to seek help. This highlights the need to enhance knowledge of EC and its risk factors in perimenopause among the public and among health care providers.

Longitudinal Assessment of Bone Mineral Density in Women Living With and Without HIV Across Reproductive Phases

Swann SA et al., 2024·J Acquir Immune Defic Syndr

Women living with HIV commonly experience low areal bone mineral density (BMD), but whether this is affected by low ovarian hormonal states (prolonged amenorrhea or menopause) is unknown. We compared rates of BMD loss between women living with HIV and HIV-negative control women and investigated its association with low ovarian hormonal states. Women living with HIV were enrolled from Vancouver Canada and controls from 9 Canadian sites. This longitudinal analysis included age-matched women living with AntiRetrovirals and Markers of Aging cohort and controls in the population-based Canadian Multicentre Osteoporosis Study. Rate of change/year in BMD at the total hip and lumbar spine (L1-L4) between 3 and 5 years was compared between groups, adjusting for sociodemographic and clinical variables. Ninety-two women living with HIV (median [interquartile range] 49.5 [41.6-54.1] 24.1 [20.7-30.8] kg/m 2 ) and 278 controls (age: 49.0 [43.0-55.0] 25.8 [22.9-30.6] kg/m 2 ) were included. Total hip BMD loss was associated with HIV (β: -0.003 [95% CI: -0.006 to -0.0001] g/cm 2 /yr), menopause (β: -0.007 [-0.01 to -0.005] g/cm 2 /yr), and smoking (β: -0.003 [-0.006 to -0.0002] g/cm 2 /yr); BMD gain was linked with higher body mass index (β: 0.0002 [0.0007-0.0004] g/cm 2 /yr). Menopause was associated with losing L1-L4 BMD (β: -0.01 [-0.01 to -0.006] g/cm 2 /yr). Amenorrhea was not associated with BMD loss. HIV and menopause negatively influenced total hip BMD. These data suggest women living with HIV require hip BMD monitoring as they age.

Case Reports from Women Using a Quantitative Hormone Monitor to Track the Perimenopause Transition

Meyers M et al., 2023·Medicina (Kaunas)

The fertility tracking of menstrual cycles during perimenopause with a quantitative hormone monitor is a novel undertaking. Women in regular menstrual cycles have been tracking their fertility using different biomarkers since the 1960's. Presently, there are newer electronic hormonal devices used to track fertility that provide more exact and objective data to help delineate the fertile time frame of a woman's cycle. These devices measure quantitative levels of estrogen, the luteinizing hormone, progesterone, and follicle-stimulating hormone, all of which occur at varying levels during the menstrual cycle. As women advance toward menopause, their cycles vary in length, and their hormones fluctuate. In this retrospective analysis, forty-two women aged 40 to 50 tracked their cycles over time, and eight of these forty-two women used the quantitative hormonal device. With the use of this device, the perimenopausal period has revealed distinct hormonal cycle characteristics that are unique to this group of women. It is the purpose of this paper to discuss these cycle's characteristics during perimenopause, which were found with the use of the quantitative hormonal device.

Long-Term Change in Bone Mineral Density in Women Living With HIV: A 10-Year Prospective Controlled Cohort Study

Heather M Macdonald et al., 2023·JBMR Plus

Women living with HIV (WLWH) may be at higher risk for osteoporosis and fragility fractures. However, limited prospective data describe long-term trajectories of bone mineral density (BMD) in WLWH versus women without HIV. Thus, in this prospective study, we aimed to compare 10-year change in areal BMD (aBMD) between WLWH (n = 49; 36.8 ± 8.8 years; 96% pre/perimenopausal) and HIV-negative women (population-based controls; n = 49; 41.9 ± 9.2 years; 80% pre/perimenopausal). In an exploratory analysis, we compared fracture history between WLWH and controls. Outcomes were lumbar spine (L(1) to L(4)), total hip, and femoral neck aBMD at baseline and follow-up, which occurred at 13 and 10 years in WLWH and controls, respectively. We fit multivariable regression models to compare baseline and 10-year change in aBMD between groups, adjusting for osteoporosis risk factors. Within WLWH, we examined associations between aBMD and HIV-related factors, including combination antiretroviral therapy (cART) duration. WLWH were diagnosed 6.5 ± 3.7 years before baseline, 80% were on cART for 241 ± 142 weeks, and 49% had HIV plasma viral load <40 copies/mL. Before and after adjusting for osteoporosis risk factors, baseline and 10-year change in aBMD did not differ between WLWH and controls at any site. At baseline, more WLWH than controls reported a history of low-trauma fracture (30% versus 10%, p < 0.05) and major osteoporotic fracture (17% versus 4%, p < 0.05). During follow-up, the number of WLWH and controls with incident fragility fracture was not significantly different. Lifetime cART duration and tenofovir use were not associated with aBMD 10-year percent change. Higher CD4 count at baseline was positively associated with femoral neck aBMD 10-year percent change. Long-term aBMD change in this small WLWH cohort paralleled normal aging, with no evidence of influence from cART use; however, these results should be interpreted with caution given the small sample size. Larger cohort studies are needed to confirm these findings.

Former long-term use of combined hormonal contraception and glucose metabolism disorders in perimenopausal women: A prospective, population-based cohort study

Mosorin ME et al., 2023·Acta Obstet Gynecol Scand

Current use of combined hormonal contraceptives worsens glucose tolerance and increases the risk of type 2 diabetes mellitus at late fertile age, but the impact of their former use on the risk of glucose metabolism disorders is still controversial. This was a prospective, longitudinal birth cohort study with long-term follow-up consisting of 5889 women. The cohort population has been followed at birth, and at ages of 1, 14, 31 and 46. In total, 3280 (55.7%) women were clinically examined and 2780 also underwent a 2-h oral glucose tolerance test at age 46. Glucose metabolism indices were analyzed in former combined hormonal contraceptive users (n = 1371) and former progestin-only contraceptive users (n = 52) and in women with no history of hormonal contraceptive use (n = 253). Compared with women with no history of hormonal contraceptive use, those who formerly used combined hormonal contraceptives for over 10 years had an increased risk of prediabetes (odds ratio [OR] 3.9, 95% confidence interval [CI]: 1.6-9.2) but not of type 2 diabetes mellitus. Former progestin-only contraceptive use was not associated with any glucose metabolism disorders. The results persisted after adjusting for socioeconomic status, smoking, alcohol consumption, parity, body mass index and use of cholesterol-lowering medication. Former long-term use of combined hormonal contraceptives was associated with a significantly increased risk of prediabetes in perimenopausal women, which potentially indicates a need of screening for glucose metabolism disorders in these women.

Don't ignore perimenopause

Prior JC et al., 2023·CMAJ

We agree with Lega and colleagues[1][1] that menopausal hormone therapy (MHT) has been shown in randomized controlled trials (RCTs) to be effective and safe for treating problematic vasomotor symptoms related to menopause. We also agree that treating menopausal vasomotor symptoms is important to

Global prevalence of sexual dysfunction among women with metabolic syndrome: a systematic review and meta-analysis

Salari N et al., 2023·J Diabetes Metab Disord

Sexual dysfunction is a common disorder among women, especially during menopause. Metabolic syndrome is a multifactorial disease that, according to previous studies, there is a relationship between the metabolic syndrome and sexual dysfunction among women. The aim of this systematic review and meta-analysis is to obtain the prevalence of Female Sexual Dysfunction (FSD) among women with metabolic syndrome, and to analyze available related evidence. In this systematic review and meta-analysis, the keywords of MeSH, female sexual dysfunction, FSD, metabolic syndrome were searched in PubMed, Web of Science, Scopus, Science Direct and Google Scholar. The searches were conducted without a lower time limit and until May 2022. The prevalence of FSD among women with metabolic syndrome was found to be 39.3% (95% CI: 28.3-51.5). In the subgroup analysis and in the review of 4 studies, the prevalence of sexual dysfunction in postmenopausal women with metabolic syndrome was 49.8% (95% CI: 26.1-73.6). Analyzing the results of the meta-regression test in examining the effect of the three factors of sample size, year of the study, age, and BMI of the patients on the heterogeneity of the meta-analysis, showed that with the increase of the sample size, the prevalence of sexual dysfunction among women with metabolic syndrome decreases (p < 0.05). Moreover, the prevalence of sexual dysfunction among women with metabolic syndrome increases (p < 0.05) with the increase in the years of conducting studies and the mean of age of women with metabolic syndrome. Also, with increasing mean of BMI of female patients with metabolic syndrome, the prevalence of sexual dysfunction in these women also increases (p < 0.05). Female sexual dysfunction is a global health problem that can affect women's life to a great extent. Metabolic syndrome, which is a set of factors such as obesity, high blood pressure, and diabetes, affects sexual dysfunction in women. From this study, it can be concluded that there is a close relationship between metabolic syndrome and female sexual dysfunction.

Oral micronized progesterone for perimenopausal night sweats and hot flushes a Phase III Canada-wide randomized placebo-controlled 4 month trial

Prior JC et al., 2023·Sci Rep

This study tested progesterone for perimenopausal hot flush ± night sweat (vasomotor symptom, VMS) treatment. It was a double-blind, randomized trial of 300 mg oral micronized progesterone@bedtime versus placebo for 3-months (m) after a 1-m untreated baseline during 2012/1-2017/4. We randomized untreated, non-depressed, screenand baseline-eligible by VMS, perimenopausal women (with flow within 1-year), ages 35-58 (n = 189). Participants aged 50 (± SD = 4.6) were mostly White, educated, minimally overweight with 63% in late perimenopause; 93% participated remotely. The 1° outcome was 3rd-m VMS Score difference. Participants recorded VMS number and intensity (0-4 scale)/24 h on a VMS Calendar. Randomization required VMS (intensity 2-4/4) of sufficient frequency and/or ≥ 2/week night sweat awakenings. Baseline total VMS Score (SD) was 12.2 (11.3) without assignment difference. Third-m VMS Score did not differ by therapy (Rate Difference - 1.51). However, the 95% CI [- 3.97, 0.95] P = 0.222, did not exclude 3, a minimal clinically important difference. Women perceived progesterone caused decreased night sweats (P = 0.023) and improved sleep quality (P = 0.005); it decreased perimenopause-related life interference (P = 0.017) without increased depression. No serious adverse events occurred. Perimenopausal night sweats ± hot flushes are variable; this RCT was underpowered but could not exclude a minimal clinically important VMS benefit. Perceived night sweats and sleep quality significantly improved.

Age at Natural Menopause in Women Living with HIV: A Cross-Sectional Study Comparing Self-Reported and Biochemical Data

Shayda A Swann et al., 2023·Viruses

Early menopause (<45 years) has significant impacts on bone, cardiovascular, and cognitive health. Several studies have suggested earlier menopause for women living with HIV; however, the current literature is limited by reliance on self-report data. We determined age at menopause in women living with HIV and socio-demographically similar HIV-negative women based on both self-report of menopause status (no menses for ≥12 months) and biochemical confirmation (defined as above plus follicle-stimulating hormone level ≥ 25 IU/mL). Multivariable median regression models assessed factors associated with menopause age, controlling for relevant confounders. Overall, 91 women living with HIV and 98 HIV-negative women were categorized as menopausal by self-report, compared to 83 and 92 by biochemical confirmation. Age at menopause did not differ significantly between groups, whether based on self-report (median [IQR]: 49.0 [45.3 to 53.0] vs. 50.0 [46.0 to 53.0] years; p = 0.28) or biochemical confirmation (50.0 [46.0 to 53.0] vs. 51.0 [46.0 to 53.0] years; p = 0.54). In the multivariable model, no HIV-related or psychosocial variables were associated with earlier age at menopause (all p > 0.05). Overall, HIV status per se was not statistically associated with an earlier age at menopause, emphasizing the importance of comparing socio-demographically similar women in reproductive health and HIV research.

Sexual dysfunction among gynecologic cancer survivors in a population-based cohort study

Chang CP et al., 2022·Support Care Cancer

Treatment for gynecologic cancer is associated with sexual dysfunction, which may present during and/or after treatment. The aim of this study was to investigate the risk of sexual dysfunction among gynecologic cancer survivors compared to cancer-free women in a population-based cohort study. We identified a cohort of 4863 endometrial, ovarian, and cervical cancer survivors diagnosed between 1997 and 2012 in the Utah Cancer Registry. Up to five cancer-free women were matched to cancer survivors (N = 22,693). We used ICD-9 codes to identify sexual dysfunction. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for sexual dysfunction with adjustment for potential confounders. Approximately 6.6% of gynecologic cancer survivors had sexual dysfunction diagnoses 1-5 years after cancer diagnosis. Gynecologic cancer survivors had higher risks of overall sexual dysfunction (HR: 2.51, 95% CI: 2.16, 2.93), dyspareunia (HR: 3.27, 95% CI: 2.63, 4.06), and vaginal dryness (HR: 2.63, 95% CI: 2.21, 3.12) compared to a general population of women, 1-5 years after cancer diagnosis. Sexual dysfunction was associated with advance cancer stage (HR(Regional vs. Localized): 1.61, 95% CI: 1.19, 2.31), radiation therapy (HR: 1.73, 95% CI: 1.29, 2.31), and chemotherapy (HR: 1.80, 95% CI: 1.30, 2.50). This large cohort study confirms that there is an increased risk of sexual dysfunction among gynecologic cancer survivors when compared to the general population. Further investigation is needed to address the risk factors for sexual dysfunction and to improve patient-provider communication, diagnosis, documentation, and treatment of sexual dysfunction among gynecologic cancer survivors.

The importance of estradiol for body weight regulation in women

Vigil P et al., 2022·Front Endocrinol (Lausanne)

Obesity in women of reproductive age has a number of adverse metabolic effects, including Type II Diabetes (T2D), dyslipidemia, and cardiovascular disease. It is associated with increased menstrual irregularity, ovulatory dysfunction, development of insulin resistance and infertility. In women, estradiol is not only critical for reproductive function, but they also control food intake and energy expenditure. Food intake is known to change during the menstrual cycle in humans. This change in food intake is largely mediated by estradiol, which acts directly upon anorexigenic and orexigenic neurons, largely in the hypothalamus. Estradiol also acts indirectly with peripheral mediators such as glucagon like peptide-1 (GLP-1). Like estradiol, GLP-1 acts on receptors at the hypothalamus. This review describes the physiological and pathophysiological mechanisms governing the actions of estradiol during the menstrual cycle on food intake and energy expenditure and how estradiol acts with other weight-controlling molecules such as GLP-1. GLP-1 analogs have proven to be effective both to manage obesity and T2D in women. This review also highlights the relationship between steroid hormones and women's mental health. It explains how a decline or imbalance in estradiol levels affects insulin sensitivity in the brain. This can cause cerebral insulin resistance, which contributes to the development of conditions such as Parkinson's or Alzheimer's disease. The proper use of both estradiol and GLP-1 analogs can help to manage obesity and preserve an optimal mental health in women by reducing the mechanisms that trigger neurodegenerative disorders.

Metabolic dysregulation in patients with premature ovarian insufficiency revealed by integrated transcriptomic, methylomic and metabolomic analyses

Lu C et al., 2022·Clin Transl Med

Premature ovarian insufficiency (POI) is a disorder of ovarian function, which occurs in approximately 3.7% of women younger than 40 years of age.1 The aetiologies of most cases were unknown and usually manifest as isolated organ senescence at early stage of diagnosis, only with long-term consequences of increased risk of metabolic syndrome or disease.2 We tried to explore the essence of POI from multiple dimensions. First, we found that upregulated genes in POI patients' ovarian granulosa cells were mainly enriched in metabolic pathways. Then, we profiled metabolites in the patients' sera and identified some metabolites with changed levels, including fumarate, arachidonate and acetoacetate, and the combination of hyodeoxycholic acid (HDCA) and acetoacetate may be used as one of potential biomarkers for POI. In addition, we found genes with upregulated transcription levels and differential methylated levels were enriched in oxidative stress pathways, which can be also elucidated from abnormal metabolism.The transcriptomes of patient and control granulosa cells were profiled, and 3966 differentially expressed genes (DEGs) (fold change > 2, Padj < .05) were identified (Table S1). Gene ontology analyses found that downregulated DEGs were mainly related to extracellular matrix/structure organization and different types of junctions. The upregulated DEGs were enriched in various catabolic/metabolic/biosynthetic/processes (Figure 1A). KEGG (Kyoto Encyclopaedia of Genes and Genomes) analysis showed that cytokine–cytokine receptor interaction, PI3K-Akt-signalling pathway and MAPK-signalling pathway were enriched in the downregulated genes, whereas the metabolic pathway was the most enriched in the upregulated genes. Moreover, other pathways, such as amino acid degradation, synthesis, peroxisome and oxidative phosphorylation, were also enriched in upregulated DEGs (Figure 1B). Several previous studies present valuable information about metabolic features of POI, which mainly focus on total cholesterol, lipoprotein cholesterol and glucose metabolism.3-6 Elevated levels of free fatty acids in follicular fluid were also reported as a potential driver of human POI.7 However, many of these results were inconsistent and not so comprehensive, although they have been noteworthy. Therefore, we carried out metabolomic analyses on serum samples from POI patients and controls. The outlined demographic characteristics of all recruited patients and controls were shown (Table 1). Two cohorts were enrolled in the metabolomic analyses in this study (Figure 2A). In the discovery cohort, a total of 6 categories of 181 features were reliably detected. POI patients could be clearly distinguished from controls by conducting multivariate statistical analysis (Figure 2B). Sixty-two features with VIP (variable importance in projection) values greater than 1 were identified and considered as differential metabolites (DMets). Subsequently, 26 of the 63 DMets were found to be significantly different between POI patients and controls using univariate t test analysis (p < .05) (Figure 2C; Table S2). Next, 32 out of the 62 features were validated using the validation cohort (Table S3). The numbers of metabolites in the union and intersections of the DMets identified from the discovery and validation cohorts were 39 and 13, respectively. Pearson's correlation coefficient figure and heat map analysis of the 39 DMets are shown (Figure S1). Enrichment and pathway analysis of the 39 DMets are shown respectively (Figure 2D,E). Out of the 13 validated DMets, 5 (acetoacetate, glutamate, C22:1, arachidonate and succinate) and 4 (HDCA, C22:0, homocitrulline [Hcit] and fumarate) were increased and decreased in the sera of POI patients, respectively. In addition, ROS and LDH (lactic dehydrogenase) were increased, and NADH and ATP were decreased in patients (Figure 2F). Receiver-operating characteristic (ROC) analysis was performed and 8 metabolites had area under curve (AUCs) greater than .7. In addition, the top two combinations with the highest AUCs were NADH plus acetoacetate (.868) and HDCA plus acetoacetate (.955) (Figure 2G,H). Furthermore, we reanalysed the human granulosa cell whole-genome DNA methylation profiling data that we previously generated.7 A number of 536 genes were hypermethylated in their differentially methylated regions (DMRs), whereas 1583 genes with hypomethylated DMRs were identified (Table S4; Figure S2). Integrating our transcriptomic and methylomic data, we found that 240 differentially expressed and methylated genes (DEMGs) were mainly enriched in response to oxidative stress, response to chemical stress, reactive oxygen species and hydrogen peroxide (Table S5; Figure S3A,B). DNMT3, DNMT1, methylenetetrahydrofolate reductase) and 5-methyltetrahydrofolate–homocysteine methyltransferase reductase, involved in methionine cycle, were differently expressed in POI patients' granulosa cells (Figure S3C). We next conducted network analysis on these DEMGs and the metabolites we detected (Table S6; Figure S4). The top five DMets were ATP, arachidonate, serotonin, glutamate and citrate. Glutamine synthetase (GLUL) and FOS were revealed as the top two hub genes in terms of connectivity with metabolites. GLUL, which catalyses the ATP-dependent conversion of glutamate and ammonia to glutamine, is related to 9 metabolites and was significantly upregulated and hypomethylated in exonic regions and the 3′UTRs. In-line with this, metabolic profiling showed decreased ATP and increased glutamate in POI patients. FOS was related to 8 metabolites and significantly upregulated and hypomethylated in exonic and 3′UTR regions (Figure 3A). It was also recently reported as a hub gene in the gene regulatory network of antioxidant in aged monkeys and human ovaries.8 In addition, we searched the human metabolome database for the associated enzymes/proteins of the 39 DMets. Changes in the expression and methylation status of these genes were displayed using Cytoscape software (Table S7; Figure S4). Joint-pathway analysis of DEMGs and DMets showed pathways those were impacted (Figure 3B). All the previous analyses were summarized as a metabolic network composed of DMets and enzymes of DEMGs that may contribute to the aetiology of POI (Figure 3C). Genes for NMNAT, PAR3 and NAMPT, enzymes involved in the synthesis or consumption of nicotinamide adenine dinucleotide (NAD+), which were reported associated with POI or ovarian ageing,9, 10 were upregulated or downregulated DEGs. In summary, the integrated analyses of transcriptomic and methylomic data from granulosa cells of the human ovary and the metabolomic data from human sera have identified increased levels of acetoacetate and arachidonate and disturbances in the TCA (tricarboxylic acid) cycle, fatty acids, ketone bodies and antioxidative processes, all of which contribute to decreased levels of NADH and ATP, increased oxidative stress and eventually ovarian premature senescence. Our data not only yielded valuable fundamental insights into its pathological mechanism but also would aid in the development of new therapeutic targets for POI. The causal effect relationship between gene expression and metabolic changes warrants further investigation in the future. This work was supported by the National Natural Science Foundation of China (81971349 and 81300456 to Cuiling Lu) and National Key Research and Development Program of China (2018YFE0201100 to Chunsheng Han and 2016YFC1000302 to Xiumei Zhen). The authors declare that there is no conflict of interest. The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Metabolic Disorders in Menopause

Jeong HG et al., 2022·Metabolites

Menopause is an aging process and an important time equivalent to one-third of a woman's lifetime. Menopause significantly increases the risk of cardiometabolic diseases, such as obesity, type 2 diabetes, cardiovascular diseases, non-alcoholic liver disease (NAFLD)/metabolic associated fatty liver disease (MFFLD), and metabolic syndrome (MetS). Women experience a variety of symptoms in the perimenopausal period, and these symptoms are distressing for most women. Many factors worsen a woman's menopausal experience, and controlling these factors may be a strategy to improve postmenopausal women's health. This review aimed to confirm the association between menopause and metabolic diseases (especially MetS), including pathophysiology, definition, prevalence, diagnosis, management, and prevention.

The Effect of Menopause on Antipsychotic Response

González-Rodríguez A et al., 2022·Brain Sci

It has been hypothesized that, whenever estrogen levels decline, psychosis symptoms in women increase. At menopause, this (a) the loss of estrogen (mainly estradiol) can directly affect central neurotransmission, leading to increase in schizophrenia-related symptoms, and (b) the loss of estrogen can decrease the synthesis of enzymes that metabolize antipsychotic drugs, thus weakening their efficacy. The aim of this narrative review was to investigate the second possibility by searching PubMed and ClinicalTrials.gov for studies over the last two decades that investigated the metabolism of antipsychotics and their efficacy before and after menopause in women or that studied systemic and local estrogen level effects on the pharmacokinetics and pharmacodynamics of individual antipsychotic drugs. The evidence suggests that symptom level in women with schizophrenia rises after menopause for many reasons beyond hormones but, importantly, there is an estrogen-dependent loss of efficacy related to antipsychotic treatment. Effective clinical intervention is challenging; nevertheless, several promising routes forward are suggested.

Effect of the use of prediagnosis hormones on breast cancer prognosis: MCC-Spain study

Alonso-Molero J et al., 2022·Menopause

To extend knowledge about the long-term use of hormones in hormone therapy or oral contraception as prognostic factors in breast cancer. The MCC-Spain project is a cohort of 1,685 women with incident breast cancer recruited in Spain. Recruitment was carried out between 2007 and 2010, and the follow-up finished in December 2017. The impact of hormone therapy or oral contraception on breast cancer prognosis was analyzed considering year of birth and menopausal status (1,095 women [65%] were postmenopausal). Hazard ratios (HRs) were estimated using Cox regression models. Death by any cause was considered as the event, and hormone therapy or oral contraception were analyzed as regressors. Oral contraception use for less than 5 years shows an HR of 1.10 (95% CI, 0.75 to 1.62), whereas use for 5 or more years shows an HR of 1.46 (95% CI, 0.95 to 2.25), with a P trend of 0.01, showing a dose-dependent response. Regarding hormone therapy and restricting the analysis to postmenopausal women born between1940 and 1959, where most hormone therapy (consumption) is concentrated, the results did not show any trend. Concerning oral contraception use, our results demonstrate that their use is related to poor prognosis in breast cancer. However, research in this field is limited and controversial, indicating the need for more research in this area. Regarding hormone therapy consumption, our results indicate no association with better prognosis, which contradicts what has previously been published.

Resilience and psychosocial factors linked to symptom experience during the menopause transition for women living with HIV

Elizabeth M King et al., 2022·Menopause

Women living with HIV (WLWH) are commonly symptomatic during perimenopause and menopause (≥1 y without menstruation), however, little is known of risks for symptoms and their timing. We analyzed these unwanted experiences to inform care. WLWH (≥40 y) in the Canadian HIV Women's Sexual and Reproductive Health Cohort Study rated midlife experiences for seven symptoms and a symptom composite (from 0 to 21). Timing was i) perimenopause (flow in the last year), ii) 1-2 years from final menstrual period (FMP), iii) 2-5 years post-FMP; and iv) >5 years post-FMP. Resilience (standardized out of 100) was assessed based on Wagnild's Resilience Scale. Univariable/multivariable mixed effects linear regression assessed correlates of symptom intensity by composite score. Among 457 peri-/menopausal women mean age 54.7 (±6.6) over two time points (703 observations), 88% experienced ≥1 mild symptom; 75% were of moderate and 55% severe intensity. The most frequently reported symptoms were joint/muscle stiffness (67%), depressed mood (67%), and hot flashes (57%). After adjusting for reproductive phase, we found that women with greater resilience had fewer/lower intensity symptoms (symptom score 1.37 [2.30 to 0.44] lower; P = 0.004); those with depressive symptoms and recreational drug use (respectively) had more/higher intensity symptoms (scores 1.71 [0.61 to 2.82] [P = 0.002]; 2.89 [2.09 to 3.77] [P<0.001] higher). Symptoms were most intense in perimenopause and declined with increasing menopausal years (P = 0.03). WLWH experiences a high burden of midlife symptoms, decreased by resilience and most intense during perimenopause. Unwanted experiences were linked to psychosocial and behavioral factors. These data encourage HIV providers to adopt a bio-psychosocial approach to midlife management.

Where's the break? Critique of radiographic vertebral fracture diagnostic methods

J C Prior et al., 2021·Osteoporos Int

Menopausal hormone therapy for women living with HIV

Elizabeth Marie King et al., 2021·Lancet HIV

People living with HIV are ageing, and a growing number of women living with HIV are entering menopause. Women living with HIV commonly have bothersome vasomotor symptoms and onset of menopause at earlier ages; both factors go on to affect quality of life and systemic health. Vasomotor symptoms and early menopause are both indications for menopausal hormone therapy; however, current evidence suggests that this therapy is seldom offered to women living with HIV. Additionally, women living with HIV have several risks to bone health and are likely to benefit from the bone-strengthening effects of menopausal hormone therapy. We present an assessment of the benefits and risks of menopausal hormone therapy in the context of HIV care and propose a practical approach to its prescription. If considered in the appropriate clinical context with discussion of risks and benefits, menopausal hormone therapy might provide substantial benefits to symptomatic menopausal women living with HIV and improve health-related quality of life.

British Columbia CARMA-CHIWOS Collaboration (BCC3): protocol for a community-collaborative cohort study examining healthy ageing with and for women living with HIV

Shayda A Swann et al., 2021·BMJ Open

Women living with HIV (WLWH) experience accelerated ageing and an increased risk of age-associated diseases earlier in life, compared with women without HIV. This is likely due to a combination of viral factors, gender differences, hormonal imbalance and psychosocial and structural conditions. This interdisciplinary cohort study aims to understand how biological, clinical and sociostructural determinants of health interact to modulate healthy ageing in WLWH. Methods and analysisThe British AntiRetroviral therapy and Markers of Aging-Canadian HIV Women's Sexual and Reproductive Health Cohort Study (CARMA-CHIWOS) Collaboration (BCC3) study will enrol WLWH (n=350) and sociodemographically matched HIV-negative women (n=350) living in British Columbia. A subset of BCC3 participants will be past participants of CARMA, n≥1000 women and children living with and without HIV, 2008-2018 and/or CHIWOS, n=1422 WLWH, 2013-2018. Over two study visits, we will collect biological specimens for virus serologies, hormones and biological markers as well as administer a survey capturing demographic and sociostructural-behavioural factors. Sociodemographics, comorbidities, number and type of chronic/latent viral infections and hormonal irregularities will be compared between the two groups. Their association with biological markers and psychostructural and sociostructural factors will be investigated through multivariable regression and structural equation modelling. Retrospective longitudinal analyses will be conducted on data from past CARMA/CHIWOS participants. As BCC3 aims to follow participants as they age, this protocol will focus on the first study visits.Ethics and disseminationThis study has been approved by the University of British Columbia Children's and Women's Research Ethics Board (H19-00896). Results will be shared in peer-reviewed journals, conferences and at community events as well as at www.hivhearme.ca and @HIV_HEAR_me. WLWH are involved in study design, survey creation, participant recruitment, data collection and knowledge translation. A Community Advisory Board will advise the research team throughout the study.

Simulated effects of early menopausal bone mineral density preservation on long-term fracture risk: a feasibility study

E O Billington et al., 2021·Osteoporos Int

Prevention of early menopausal bone loss may reduce the future burden of osteoporosis. In this modelling exercise, an osteoporosis prevention strategy involving 5-year infusions of zoledronic acid, beginning early in menopause, reduced long-term fracture risk and the proportion of aging women with femoral neck densitometric osteoporosis. This strategy warrants further evaluation. Preventing early menopausal bone loss may substantially reduce the future burden of osteoporosis. We modelled the effects of infrequent zoledronic acid infusions on long-term fracture risk. Data from the Canadian Multicentre Osteoporosis Study (CaMos) were used to determine the expected natural history of femoral neck areal bone mineral density (BMD) and fracture risk (using FRAX®) from ages 50-80 for women with no antiresorptive drug exposures. We modelled the effects of three infusions of zoledronic acid (at ages 50, 55, 60) on long-term fracture risk, assuming this intervention would preserve BMD until age 65 years, followed by losses mirroring early menopausal BMD loss. At age 65, untreated women and zoledronic acid recipients had expected mean (SD) femoral neck T-scores of - 1.5(1.0) and - 0.8(1.0), 10-year major osteoporotic fracture (MOF) risks of 9.8%(5.0) and 8.0%(3.7) and hip fracture risks of 1.7%(2.4) and 0.8%(1.2), respectively. At age 80, untreated women and zoledronic acid recipients had expected femoral neck T-scores of - 1.9(0.9) and - 1.4(0.9), MOF risks of 17.9%(8.2) and 14.9%(6.4) and hip fracture risks of 6.3%(6.2) and 4.4%(4.5), respectively. The expected proportion of women with femoral neck T-score ≤ - 2.5 was 14.9% for untreated women and 3.8% for zoledronic acid recipients at age 65, increasing to 28.1% and 12.0%, respectively, at age 80. Numbers-needed-to-treat to prevent one case of densitometric osteoporosis were 9 at age 65 and 5 at age 80. Infrequent infusions of zoledronic acid, initiated early in menopause, are expected to reduce long-term fracture risk and result in a substantial reduction in the proportion of women with densitometric osteoporosis after age 65.

Current use of combined hormonal contraception is associated with glucose metabolism disorders in perimenopausal women

Mosorin ME et al., 2020·Eur J Endocrinol

The use of combined hormonal contraceptives (CHCs) worsens glucose tolerance, but the risk for glucose metabolism disorders remains controversial. The study is a prospective longitudinal population-based cohort study. The study was based on a cohort population that comprised 1879 women born in 1966. At age 46, the women answered a questionnaire on contraceptive use and underwent an oral glucose tolerance test. Glucose metabolism indices were evaluated in current CHC (n = 153), progestin-only contraceptive (POC, n = 842), and non-hormonal contraceptive users (n = 884). In the entire study population, current CHC use was significantly associated with prediabetes (OR: 2.0, 95% CI: 1.3-3.2) and type 2 diabetes (OR: 3.3, 95% CI: 1.1-9.7) compared to non-hormonal contraceptive use. After 5 years of use, the prediabetes risk increased 2.2-fold (95% CI: 1.3-3.7) and type 2 diabetes risk increased 4.5-fold (95% CI: 1.5-13.5). Compared with the current POC use, current CHC use was significantly associated with prediabetes (OR: 1.9, 95% CI: 1.2-3.0). Current POC use was not associated with any glucose metabolism disorders. The results prevailed after adjusting for BMI and socioeconomic status. CHC use in perimenopausal women was associated with a significantly increased risk of glucose metabolism disorders. This association should be considered in women with increased metabolic risk.

Supplementation of dehydroepiandrosterone (DHEA) in pre- and postmenopausal women - position statement of expert panel of Polish Menopause and Andropause Society

Rabijewski M et al., 2020·Ginekol Pol

Dehydroepiandrosterone (DHEA) concentration decreases with age, therefore, DHEA has been considered a hormone that reduces the symptoms associated with aging, so the usefulness of DHEA in premenopausal and postmenopausal women, and the options of hormone therapy have received a large amount of attention. The effectiveness of DHEA in the premenopausal women remains unclear, while in postmenopausal women with coexisting estrogens deficiency is controversial. Despite many years of study, the use of DHEA is still controversial, especially regarding its effectiveness. The aim of present article was to evaluate DHEA specific effects on metabolic parameters, bone mineral density, insulin resistance as well as the therapeutic potential of DHEA in preand postmenopausal women using measures of sexual activity, cognition and well-being. The summary of this article is the position statement of expert group of the Polish Menopause and Andropause Society regarding the efficacy and safety of DHEA supplementation in women. We concluded, that currently available clinical trials and meta-analyses indicate that DHEA supplementation is effective in women with adrenal insufficiency and chronically treated with exogenous glucocorticoids, postmenopausal women with low bone mineral density and/or osteoporosis, premenopausal women with sexual disorders and low libido, and in women with vulvovaginal atrophy due to menopause or genitourinary syndrome of menopause. Currently available clinical trials also suggest that DHEA supplementation is probably effective in postmenopausal women with hypoactive sexual disorders, infertile women with diminished ovarian reserve, women suffering from depression and anxiety, and women with obesity and insulin resistance. No serious adverse effects have been reported.

A Risk Assessment Tool for Predicting Fragility Fractures and Mortality in the Elderly

Thach Tran et al., 2020·J Bone Miner Res

Existing fracture risk assessment tools are not designed to predict fracture-associated consequences, possibly contributing to the current undermanagement of fragility fractures worldwide. We aimed to develop a risk assessment tool for predicting the conceptual risk of fragility fractures and its consequences. The study involved 8965 people aged ≥60 years from the Dubbo Osteoporosis Epidemiology Study and the Canadian Multicentre Osteoporosis Study. Incident fracture was identified from X-ray reports and questionnaires, and death was ascertained though contact with a family member or obituary review. We used a multistate model to quantify the effects of the predictors on the transition risks to an initial and subsequent incident fracture and mortality, accounting for their complex interrelationships, confounding effects, and death as a competing risk. There were 2364 initial fractures, 755 subsequent fractures, and 3300 deaths during a median follow-up of 13 years (interquartile range [IQR] 7-15). The prediction model included sex, age, bone mineral density, history of falls within 12 previous months, prior fracture after the age of 50 years, cardiovascular diseases, diabetes mellitus, chronic pulmonary diseases, hypertension, and cancer. The model accurately predicted fragility fractures up to 11 years of follow-up and post-fracture mortality up to 9 years, ranging from 7 years after hip fractures to 15 years after non-hip fractures. For example, a 70-year-old woman with a T-score of -1.5 and without other risk factors would have 10% chance of sustaining a fracture and an 8% risk of dying in 5 years. However, after an initial fracture, her risk of sustaining another fracture or dying doubles to 33%, ranging from 26% after a distal to 42% post hip fracture. A robust statistical technique was used to develop a prediction model for individualization of progression to fracture and its consequences, facilitating informed decision making about risk and thus treatment for individuals with different risk profiles.

Effects of progesterone therapy on serum sclerostin levels in healthy menopausal women: a 3-month randomized, placebo-controlled clinical trial

Yang YB et al., 2020·Osteoporos Int

Sclerostin, a natural hormone made in bone, suppresses bone formation. Sclerostin is also decreased by estrogen. Progesterone, estrogen's menstrual partner, stimulates bone formation. It is unclear whether progesterone influences sclerostin. This study showed that progesterone did not change sclerostin using serum remaining from a randomized progesterone hot flush therapy trial. Progesterone and sclerostin are both endogenous hormones acting through osteoblast-origin cells and promote or suppress bone formation, respectively. Estradiol suppresses sclerostin, but progesterone, its menstrual cycle partner hormone, has unclear sclerostin relationships. We postulated that progesterone therapy would influence serum sclerostin levels. We obtained sclerostin levels for an ethics-approved post hoc analysis. Fasting sclerostin was measured in all remaining sera from a previous 12-week randomized controlled trial (RCT) of oral micronized progesterone (progesterone) for menopausal (> 1 year after last flow) vasomotor symptoms (VMS). Women in the RCT took 300 mg progesterone at bedtime or placebo (1:1) in a trial showing progesterone significantly decreased VMS. Participants were healthy menopausal, primarily Caucasian (91.2%) community-dwelling women (± SD), 55.2 ± 4.6 years old with BMI 24.9 ± 2.9 kg/m(2). The baseline sclerostin level in 60 women was 28.41 ± 10.47 pmol/L. Baseline sclerostin was not correlated with the run-in VMS score (r = 0.143, P = 0.294). Paired baseline and 12-week RCT data for 52 women showed serum sclerostin levels did not change related to experimental therapy (P = 0.504). Changes in final sclerostin values adjusted for baseline were progesterone (- 1.07 ± 7.96 pmol/L) and placebo (- 2.64 ± 8.70 pmol/L). In observational data (n = 60), baseline sclerostin levels correlated with the General Framingham Cardiovascular (CVD) Risk score (r = - 0.398, P = 0.003) and self-reported health by SF-36 quality of life instrument (QoL, r = - 0.331, P = 0.016). Physiological oral micronized progesterone did not stimulate nor suppress serum sclerostin levels based on post hoc analysis of RCT data. Exploratory results, however, showed sclerostin negatively correlated with CVD risk and QoL. ClinicalTrials.gov #NCT0146469.

Combining Frailty and Trabecular Bone Score Did Not Improve Predictive Accuracy in Risk of Major Osteoporotic Fractures

Guowei Li et al., 2020·J Bone Miner Res

It is recognized that the trabecular bone score (TBS) provides skeletal information, and frailty measurement is significantly associated with increased risks of adverse health outcomes. Given the suboptimal predictive power in fracture risk assessment tools, we aimed to evaluate the combination of frailty and TBS regarding predictive accuracy for risk of major osteoporotic fracture (MOF). Data from the prospective longitudinal study of CaMos (Canadian Multicentre Osteoporosis Study) were used for this study. TBS values were estimated using lumbar spine (L1 to L4 ) dual-energy X-ray absorptiometry (DXA) images; frailty was evaluated by a frailty index (FI) of deficit accumulation. Outcome was time to first incident MOF during the follow-up. We used the Harrell's C-index to compare the model predictive accuracy. The Akaike information criterion, likelihood ratio test, and net reclassification improvement (NRI) were used to compare model performances between the model combining frailty and TBS (subsequently called "FI + TBS"), FI-alone, and TBS-alone models. We included 2730 participants (mean age 69 years; 70% women) for analyses (mean follow-up 7.5 years). There were 243 (8.90%) MOFs observed during follow-up. Participants with MOF had significantly higher FI (0.24 versus 0.20) and lower TBS (1.231 versus 1.285) than those without MOF. FI and TBS were significantly related with MOF risk in the model adjusted for FRAX with bone mineral density (BMD) hazard ratio (HR) = 1.26 (95% confidence interval [CI] 1.11-1.43) for per-SD increase in FI; HR = 1.38 (95% CI 1.21-1.59) for per-SD decrease in TBS; and these associations showed negligible attenuation (HR = 1.24 for per-SD increase in FI, and 1.35 for per-SD decrease in TBS) when combined in the same model. Although the model FI + TBS was a better fit to the data than FI-alone and TBS-alone, only minimal and nonsignificant enhancement of discrimination and NRI were observed in FI + TBS. To conclude, frailty and TBS are significantly and independently related to MOF risk. Larger studies are warranted to determine whether combining frailty and TBS can yield improved predictive accuracy for MOF risk.

Testing a theoretical model of imminent fracture risk in elderly women: an observational cohort analysis of the Canadian Multicentre Osteoporosis Study

A Papaioannou et al., 2020·Osteoporos Int

We examined the underlying relationship between fracture risk factors and their imminent risk. Results suggested that having past year fracture, worse past year general health, worse past year physical functioning, and lower past year BMD T-score directly predicted higher imminent fracture risk. Past year falls indirectly predicted imminent risk through physical functioning and general health. This study aimed to examine direct and indirect effects of several factors on imminent (1 year) fracture risk. Data from women age 65 and older from population-based Canadian Multicentre Osteoporosis Study were used. Predictors were identified from study years 5 and 10, and imminent fracture data (1-year fracture) came from years 6 and 11 (year 5 predicts year 6, year 10 predicts year 11). A structural equation model (SEM) was used to test the theoretical construct. General health and physical functioning were measured as latent variables using items from the 36-Item Short Form Health Survey (SF-36) and bone mineral density (BMD) T-score was a latent variable based on observed site-specific BMD data (spine L1-L4, femoral neck, total hip). Observed variables were fractures and falls. Model fit was evaluated using root mean square error of approximation (RMSEA), Tucker Lewis index (TLI), and comparative fit index (CFI). The analysis included 3298 women. Model fit tests showed that the SEM fit the data well; χ2(172) = 1122.10 < .001, RMSEA = .03, TLI = .99, CFI = .99. Results suggested that having past year fracture, worse past year general health, worse past year physical functioning, and lower past year BMD T-score directly predicted higher risk of fracture in the subsequent year (p < .001). Past year falls had a statistically significant but indirect effect on imminent fracture risk through physical functioning and general health (p < .001). We found several direct and indirect pathways that predicted imminent fracture risk in elderly women. Future studies should extend this work by developing risk scoring methods and defining imminent risk thresholds.

Author Correction: Oral micronized progesterone for perimenopausal night sweats and hot flushes a Phase III Canada-wide randomized placebo-controlled 4 month trial

Prior JC et al., 2020·SSRN Electronic Journal

Paradigm shift in pathophysiology of vasomotor symptoms: Effects of estradiol withdrawal and progesterone therapy

Yubo Fan et al., 2020·Drug Discovery Today: Disease Models

A Case Series on Natural Conceptions Resulting in Ongoing Pregnancies in Menopausal and Prematurely Menopausal Women Following Platelet-Rich Plasma Treatment

Pantos K et al., 2019·Cell Transplant

Since the introduction of autologous platelet-rich plasma (PRP) in medical practice, various studies have documented that implementing PRP can enhance healing and the anti-aging process, employing angiogenesis regeneration due to the multiple growth factors and cytokines involved. Numerous reports have shown promising results with the use of PRP in ovarian treatment, regarding ovarian regeneration and reactivation of folliculogenesis. This case series reports on two women with premature ovarian failure (POF) aged 40 and 27 years, respectively, and one menopausal woman aged 46 years. All patients presented with lack of menstrual cycle for over a year. The women reported previous failed in vitro fertilization (IVF) attempts, and, after rejecting the option of oocyte donation, they opted for the approach of autologous ovarian PRP treatment. Following PRP treatment, the three patients were invited to conceive naturally. The primary outcome was the restoration of menstruation following autologous ovarian PRP treatment, as well as an improvement in hormonal profile, a decrease in follicle-stimulating hormone (FSH) levels, and a concurrent increase in anti-Müllerian hormone (AMH) levels. Further to that, our patients achieved pregnancy through natural conception within 2-6 months following PRP treatment, resulting in currently ongoing complication-free clinical pregnancies - a first report in the literature for menopausal and POF patients. Implementation of PRP should be further investigated through randomized controlled trials (RCTs), as it may hold the key to successful treatment for a certain cohort of patients exploring reproductive treatment options following menopause.

Predictors of imminent non-vertebral fracture in elderly women with osteoporosis, low bone mass, or a history of fracture, based on data from the population-based Canadian Multicentre Osteoporosis Study (CaMos)

Jonathan D Adachi et al., 2019·Arch Osteoporos

Using data from the Canadian Multicentre Osteoporosis Study, several risk factors predictive of imminent (2-year) risk of low-trauma non-vertebral fracture among high-risk women were identified, including history of falls, history of low-trauma fracture, poorer physical function, and lower T score. Careful consideration should be given to targeting this population for therapy. Fracture risk assessment has focused on a long-term horizon and populations with a broad risk range. For elderly women with osteoporosis or low bone mass, or a history of fragility fractures ("high-risk women"), risk prediction over a shorter horizon may have greater clinical relevance. A repeated-observations design and data from the Canadian Multicentre Osteoporosis Study were employed. Study population comprised women aged ≥ 65 years with T score (total hip, femoral neck, spine) ≤ - 1.0 or prior fracture. Hazard ratios (HR) for predictors of low-trauma non-vertebral fracture during 2-year follow-up were estimated using multivariable shared frailty model. The study population included 3228 women who contributed 5004 observations; 4.8% experienced low-trauma non-vertebral fracture during the 2-year follow-up. In bivariate analyses, important risk factors included age, back pain, history of falls, history of low-trauma fracture, physical function, health status, and total hip T score. In multivariable analyses, only four independent falls in past 12 months (≥ 2 HR = 1.9; 1 HR = 1.5), low-trauma fracture in past 12 months (≥ 1 HR = 1.7), SF-36 physical component summary score (≤ 42.0: HR = 1.6), and total hip T score (≤ - 3.5: HR = 3.7; > - 3.5 to ≤ - 2.5: HR = 2.5; > - 2.5 to ≤ - 1: HR = 1.3). Imminent risk of low-trauma non-vertebral fracture is elevated among high-risk women with a history of falls or low-trauma fracture, poorer physical function, and lower T score. Careful consideration should be given to identifying and targeting this population for therapy.

Longitudinal assessment of health-related quality of life in osteoporosis: data from the population-based Canadian Multicentre Osteoporosis Study

W M Hopman et al., 2019·Osteoporos Int

Little is known about the association between health-related quality of life (HRQOL) and osteoporosis in the absence of fracture, and how HRQOL may change over time. This study provides evidence of substantially reduced HRQOL in women and men with self-reported and/or BMD-confirmed osteoporosis, even in the absence of fragility fracture. Fragility fractures have a detrimental effect on the health-related quality of life (HRQOL) of those with osteoporosis. Less is known about the association between HRQOL and osteoporosis in the absence of fracture. Canadian Multicentre Osteoporosis Study participants completed the SF-36, a detailed health questionnaire and measures of bone mineral density (BMD) at baseline and follow-up. We report the results of participants ≥ 50 years with 10-year follow-up. Self-reported osteoporosis at baseline and BMD-based osteoporosis at follow-up were ascertained. Multivariable linear regression models were developed for baseline SF-36 domains, component summaries, and change over time, adjusting for relevant baseline information. Baseline data were available for 5266 women and 2112 men. Women in the osteoporosis group had substantially lower SF-36 baseline scores, particularly in the physically oriented domains, than those without osteoporosis. A similar but attenuated pattern was evident for the men. After 10-year follow-up (2797 women and 1023 men), most domain scores dropped for women and men regardless of osteoporosis status, with the exception of mentally-oriented ones. In general, a fragility fracture was associated with lower SF-36 scores and larger declines over time. This study provides evidence of substantially reduced HRQOL in women and men with self-reported and/or BMD-confirmed osteoporosis, even in the absence of fragility fracture. HRQOL should be thoroughly investigated even prior to fracture, to develop appropriate interventions for all stages of the disease.

Can Menopause Prediction Be Improved With Multiple AMH Measurements? Results From the Prospective Doetinchem Cohort Study

de Kat AC et al., 2019·J Clin Endocrinol Metab

Anti-Müllerian hormone (AMH) levels are used worldwide as a screening tool for the duration of the female reproductive lifespan. Although AMH levels are associated with age at menopause, individual predictions of menopause with a single AMH measurement are unreliable. This study investigated whether individual AMH decline patterns can improve the prediction of menopause compared with a single measurement. The study population comprised 2434 premenopausal women from the population-based Doetinchem Cohort Study. Participants were followed up every 5 years for a total of 20 years, and AMH was measured in 6699 plasma samples with the picoAMH assay. Longitudinal statistical modeling was combined with time varying Cox modeling, to integrate multiple AMH measurements per woman. The mean age at menopause was 50 years, and 7.4% of the women who reached menopause during follow-up did so before age 45 years. For a 25-year-old, the AMH decline rate between ages 20 and 25 years increased the C-statistic of menopause prediction from 0.64 to 0.69. Beyond that age, the AMH decline rate did not improve predictions of menopause or early menopause. For women younger than age 30 years, for whom menopause prediction is arguably most relevant, the models underestimated the risk of early menopause. These results suggest that knowledge of the AMH decline rate does not improve the prediction of menopause. Based on the low discriminative ability and underestimation of the risk of early menopause, the use of AMH as a screening method for the timing of menopause cannot currently be advocated.

SUN-537 Progesterone Therapy and Serum Sclerostin Levels in Healthy Menopausal Women: A 3-month Randomized, Placebo Controlled Clinical Trial

Yang Y et al., 2019·Journal of the Endocrine Society

Sclerostin is an osteocyte-produced glycoprotein that inhibits the WNT/β-catenin pathway essential for bone formation. Sclerostin was postulated to relate to normal bone metabolism in 2001; we still have an incomplete understanding of its regulation. Estradiol, a bone antiresorptive ovarian steroid, inhibits sclerostin. Estrogen and progesterone act together in menstrual cycles and bone remodelling with progesterone exerting an anabolic effect. We hypothesized a relationship between progesterone and sclerostin because progesterone and estrogen are “partner” hormones in most tissues, and because progesterone and sclerostin modulate bone formation in opposite directions. Two observational menstrual cycle studies have reported sclerostin levels; neither documented changes across cycles nor in luteal phases during which progesterone levels are high(1)(,2). Some reports have also shown positive correlations between sclerostin and age and BMI. In this study, sclerostin was measured using an assay (MSD) of high sensitivity (LOD ± 1pg/mL), broad detection range (1-10 000 pg/mL), and intra/inter-assay precisions of 6% and 10% respectively(3). We collected fasting serum during a 3-month double blind randomized controlled trial (RCT) of 300 mg oral micronized progesterone vs placebo in symptomatic menopausal women; progesterone significantly decreased hot flushes/night sweats (vasomotor symptoms, VMS)(4). Statistical analysis showed sclerostin was not related to the 28-day baseline VMS Score (r=.18, p=.22). Pearson correlation coefficients were used to evaluate sclerostin vs baseline data and ANCOVA to analyze RCT results (alpha=0.05 significant, [SD]). The study’s purpose was to determine if sclerostin levels changed during a 3-month RCT of progesterone for VMS in healthy menopausal women(3). The primary outcome was sclerostin level in the 3(rd) month adjusted for baseline and randomization. Results showed the 52 participating women had a mean age of 55.2 (4.6) years, height 1.60 (0.07) m, weight 66.4 (8.6) kg, BMI 24.9 (2.9) kg/m(2) and were primarily Caucasian (91.2%). Baseline variables did not correlate with the baseline mean serum sclerostin level of 27.9 (10.2) pmol/L. Sclerostin had no statistically significant relationship with progesterone or placebo therapy during this RCT; mean changes were -1.07 and -2.60 pmol/L respectively. These data are the first evidence that progesterone neither increases nor decreases serum sclerostin levels. These data fit with the lack of menstrual cycle changes in sclerostin levels(1)(,2). That sclerostin did not correlate with age and BMI in this RCT is likely due to their low trial variance. A limitation of this study is the small sample size. However, it has considerable strength in its RCT design that can document causation. (1)Cidem M Gyn Obstetric Invest. 2012; (2)Liakou CG Endocrine 2016; (3)Van Lierop AH J Bone Miner Res 2011; (4)Hitchcock CL Menopause 2012.

Incident Fragility Fractures Have a Long-Term Negative Impact on Health-Related Quality of Life of Older People: The Canadian Multicentre Osteoporosis Study

Sayem Borhan et al., 2019·J Bone Miner Res

Although the short-term impact of incident fragility fractures on health-related quality of life (HRQL) of older people has been confirmed, we lack long-term evidence. We explored the impact of incident fragility fractures on HRQL, among people aged 50 years and older, using 10-year prospective data from the Canadian Multicentre Osteoporosis Study (CaMos). This study was based on data from 7753 (2187 men and 5566 women) participants of CaMos. The HRQL, measured through the Health Utility Index (HUI), was captured at baseline and year 10. The incident fragility fractures were recorded over 10 years of follow-up at spine, hip, rib, shoulder, pelvis, or forearm. Multivariable regression analysis was conducted to measure the mean difference, termed as deficit, in the HUI scores for participants with and without fractures. We examined the effects of single or multiple fragility fractures, time (fractures that occurred between year 1 to 5 and 6 to 10) and recovery to the prefracture level. Incident spine and hip fractures were associated with significant deficits (varied from -0.19 to -0.07) on the HUI scores. Hip and spine fractures were associated with negative impact on mobility, self-care, and ambulation. Fractures that occurred closer to the follow-up assessment were associated with significant impact on HRQL compared to fractures occurring a long time before it, except for hip fracture (deficits lasted 5 years or longer). Similarly, multiple hip (-0.14), spine (-0.16), and rib (-0.21) fractures significantly impacted the HRQL of women. Women with a hip fracture never recovered to their prefracture level score (OR = 0.41; 95% confidence interval [CI], 0.19 to 0.98). Our analysis suggests that single and multiple hip fractures as well as multiple spine and rib fractures strongly impact the HRQL of older people over a prolonged period of time.

Mortality risk reduction differs according to bisphosphonate class: a 15-year observational study

D Bliuc et al., 2019·Osteoporos Int

In this prospective cohort of 6120 participants aged 50+, nitrogen-bisphosphonates but not non-nitrogen bisphosphonates were associated with a significant 34% mortality risk reduction compared to non-treated propensity score matched controls. These findings open new avenues for research into mechanistic pathways. Emerging evidence suggests that bisphosphonates (BP), first-line treatment of osteoporosis, are associated with reduced risks for all-cause mortality. This study aimed to determine the association between different BP types and mortality risk in participants with or without a fracture. A prospective cohort study of users of different BPs matched to non-users by propensity score (age, gender, co-morbidities, fragility fracture status) and time to starting the BP medication from the population-based Canadian Multicentre Osteoporosis Study from nine Canadian centres followed from 1995 to 2013. Mortality risk for bisphosphonate users vs matched non-users was assessed using pairwise multivariable Cox proportional hazards models. There were 2048 women and 308 men on BP and 1970 women and 1794 men who did not receive medication for osteoporosis. The relationship between BP and mortality risk was explored in three separate 1:1 propensity score-matched cohorts of BP users and no treatment (etidronate, n = 599, alendronate, n = 498, and risedronate n = 213). Nitrogen BP (n-BP) (alendronate and risedronate) was associated with lower mortality risks [pairwise HR, 0.66 (95% CI, 0.48-0.91)] while the less potent non-n-BP, etidronate, was not [pairwise HR: 0.89 (95% CI, 0.66-1.20)]. A direct comparison between n-BP and etidronate (n = 340 pairs) also suggested a better survival for n-BP [paired HR, 0.47 (95%CI, (95% CI, 031-0.70)] for n-BP vs. etidronate]. Compared to no treatment, nitrogen but not non-nitrogen bisphosphonates appear to be associated with better survival.

Autologous Platelet-Rich Plasma Treatment Enables Pregnancy for a Woman in Premature Menopause

Sfakianoudis K et al., 2018·J Clin Med

This report presents the case of a woman aged 40 who has experienced premature menopause from the age of 35. Having rejected oocyte donation, she opted for intraovarian injection of autologous platelet-rich plasma with the aim to rejuvenate the ovarian tissue and enable the employment of her own gametes through in-vitro fertilization. Six weeks following the autologous platelet-rich plasma treatment, a significant reduction in the patient's follicle-stimulating hormone (FSH) levels were noted. A natural in-vitro fertilization cycle led to a biochemical pregnancy, resulting in a spontaneous abortion at the 5th week of pregnancy. This is the first report of a successful autologous platelet-rich plasma application leading to pregnancy in menopause. This report uniquely contributes to the medical knowledge and challenges current practice in the context of infertility. The efficiency and safety of this treatment with regard to the reproductive system merits further investigation.

Innovations in Women's Bone Health-Appreciating Important "Bone Variables" Besides Estrogen

Jerilynn C Prior, 2018·Int J Environ Res Public Health

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Progesterone for treatment of symptomatic menopausal women

Prior JC, 2018·Climacteric

This review's purpose is to highlight evidence that oral micronized progesterone (progesterone) is effective for hot flushes and night sweats (vasomotor symptoms, VMS), improves sleep and is likely safe in menopausal women (who are more than 1 year since last menstruation). Methods include randomized controlled clinical trials (RCT) supplemented with basic science, population and observational data as needed. The barrier to use of progesterone is lack of awareness that safety concerns with estrogen-including 'menopausal hormone therapy' (MHT) are not applicable to progesterone. In a single 3-month RCT, progesterone (300 mg at bedtime) was effective treatment of VMS in 133 healthy menopausal women. It caused an overall 55% VMS decrease, no withdrawal-related VMS rebound and a greater VMS decrease in 46 women with ≥50 moderate-intense VMS/week. Progesterone is equally or more effective than estradiol in improving cardiovascular endothelial function and caused no cardiovascular safety concerns in a 3-month RCT. An 8-year prospective cohort study (E3N) in more than 80 000 menopausal women showed progesterone prevented breast cancer in estrogen-treated women. Multiple RCTs confirm that progesterone (300 mg daily at bedtime) does not cause depression and improves deep sleep. In conclusion, progesterone effectively treats VMS, improves sleep and may be the only therapy that symptomatic women, who are menopausal at a normal age and without osteoporosis, need.

Steroid Hormones and Their Action in Women's Brains: The Importance of Hormonal Balance

Del Río JP et al., 2018·Front Public Health

Sex hormones significantly impact women's lives. Throughout the different stages of life, from menarche to menopause and all stages in between, women experience dramatic fluctuations in the levels of progesterone and estradiol, among other hormones. These fluctuations affect the body as a whole, including the central nervous system (CNS). In the CNS, sex hormones act via steroid receptors. They also have an effect on different neurotransmitters such as GABA, serotonin, dopamine, and glutamate. Additionally, studies show that sex hormones and their metabolites influence brain areas that regulate mood, behavior, and cognitive abilities. This review emphasizes the benefits a proper hormonal balance during the different stages of life has in the CNS. To achieve this goal, it is essential that hormone levels are evaluated considering a woman's age and ovulatory status, so that a correct diagnosis and treatment can be made. Knowledge of steroid hormone activity in the brain will give women and health providers an important tool for improving their health and well-being.

Women's Mid-Life Night Sweats and 2-Year Bone Mineral Density Changes: A Prospective, Observational Population-Based Investigation from the Canadian Multicentre Osteoporosis Study (CaMos)

Wong EMM et al., 2018·Int J Environ Res Public Health

Women's hot flushes and night sweats, collectively called vasomotor symptoms (VMS), are maximal (79%) in late perimenopause. The evidence describing whether VMS are associated with loss of areal bone mineral density (BMD) is mixed. We examined baseline and 2-year data for 1570 randomly selected women aged 43⁻63 in the Canadian Multicentre Osteoporosis Study (CaMos), a prospective Canada-wide study; we used linear regression to assess the relationship of night sweats (VMSn) with BMD and its changes. Clinically important VMSn occurred for 12.2%. Women with VMSn were slightly younger (54.5 vs. 55.3 years, p = 0.02) and less likely to use sex steroid therapies (39.8% vs. 51.4%, p < 0.05). BMD at the lumbar spine (L1-4), femoral neck (FN) and total hip (TH) were similar between those with/without VMSn. In adjusted models, we did not find a significant association between VMSn and 2-year change in L1-4, FN and TH BMD. Age, reproductive status, weight, sex steroid therapy and smoking status were associated with 2-year change in BMD. Incident fractures over 2 years also did not differ by VMSn. Our analyses were restricted to VMSn and may not truly capture the relationship between VMS and BMD. Additional research involving VMS, bone loss and fracture incidence is needed.

Premature Spinal Bone Loss in Women Living with HIV is Associated with Shorter Leukocyte Telomere Length

Shirin Kalyan et al., 2018·Int J Environ Res Public Health

With advances in combination antiretroviral therapy (cART), people living with HIV are now surviving to experience aging. Evidence suggests that individuals living with HIV are at greater risk for low bone mineral density (BMD), osteoporosis, and fractures. Better understanding of the pathophysiology of bone health in women living with HIV (WLWH) is important for treatment strategies. The goal of this study was to explore new biological factors linked to low BMD in WLWH. Standardized BMD measures of WLWH were compared to reference values from an unselected population of women from the same geographical region of the same age range. Linear regression analysis was used to assess relationships among health-related characteristics, cellular aging (measured by leukocyte telomere length; LTL), cART, and BMD of WLWH. WLWH (n = 73; mean age 43 ± 9 years) had lower BMD Z-scores at the lumbar spine (LS) (mean difference = -0.39, p p = 0.012) relative to controls (n = 290). WLWH between 50 and 60 years (n = 17) had lower Z-scores at the LS (p = 0.008) and TH (p = 0.027) compared to controls (n = 167). Among WLWH, LS BMD was significantly associated with LTL (R² = 0.09, p = 0.009) and BMI (R² = 0.06, p = 0.042). Spinal BMD was adversely affected in WLWH. Reduction of LTL was strongly associated with lower BMD and may relate to its pathophysiology and premature aging in WLWH.

Estrogen-progestin therapy causes a greater increase in spinal bone mineral density than estrogen therapy - a systematic review and meta-analysis of controlled trials with direct randomization

Prior JC et al., 2017·J Musculoskelet Neuronal Interact

To assess whether progesterone (P4) or osteoblast P4 receptor-acting progestin (P) contributed to estrogen (E) therapy-related increased areal bone mineral density (BMD) in randomized controlled trials (RCT) with direct randomization to estrogen (ET) or estrogen-progestin (EPT) therapy. Systematic literature searches in biomedical databases identified RCT with direct randomization and parallel estrogen doses that measured spinal BMD change/year. Cyclic P4/P was included in this random effects meta-analysis only if for ≥ half the number of E-days. Searches yielded 155 publications; five met inclusion criteria providing eight dose-parallel ET-EPT comparisons in 1058 women. Women averaged mid-50 years, ⟨five years into menopause and took conjugated equine E daily at 0.625 mg with/without 2.5 mg medroxyprogesterone acetate (MPA). The weighted mean EPT minus ET percentage difference in spinal BMD change was +0.68%/year (95% CI 0.38, 0.97%) (P=0.00001). This result was highly heterogeneous (I²=81%) but this may reflect the small number of studies. Estrogen with an osteoblast P4R-acting progestin (EPT) in these five published RCT provides Level 1 evidence that MPA caused significantly greater annual percent spinal BMD gains than the same dose of ET. These data have implications for management of vasomotor symptoms and potentially for osteoporosis treatment in menopausal women.

Premenopausal Osteoporosis

Prior JC, 2017·Endocrinol Metab Clin North Am

Most premenopausal women with low trauma fracture(s) or low bone mineral density have a secondary cause of osteoporosis or bone loss. Where possible, treatment of the underlying cause should be the focus of management. Premenopausal women with an ongoing cause of bone loss and those who have had, or continue to have, low trauma fractures may require pharmacologic intervention. Clinical trials provide evidence of benefits of bisphosphonates and teriparatide for bone mineral density in several types of premenopausal osteoporosis, but studies are small and do not provide evidence regarding fracture risk reduction.

Andropause and vulnerability in health: when do we start to educate men and health professionals?

Cortés ME et al., 2016·Rev Med Chil

Andropausia y ¿cuándo empezamos a educar a los hombres y a los profesionales de la

Dietary patterns in men and women are simultaneously determinants of altered glucose metabolism and bone metabolism

Lisa Langsetmo et al., 2016·Nutr Res

We hypothesized that diet would have direct effects on glucose metabolism with direct and indirect effects on bone metabolism in a cohort of Canadian adults. We assessed dietary patterns (Prudent [fruit, vegetables, whole grains, fish, and legumes] and Western [soft drinks, potato chips, French fries, meats, and desserts]) from a semiquantitative food frequency questionnaire. We used fasting blood samples to measure glucose, insulin, homeostatic model assessment insulin resistance (HOMA-IR), 25-hydroxyvitamin D (25OHD), parathyroid hormone, bone-specific alkaline phosphatase (a bone formation marker), and serum C-terminal telopeptide (CTX; a bone resorption marker). We used multivariate regression models adjusted for confounders and including/excluding body mass index. In a secondary analysis, we examined relationships through structural equations models. The Prudent diet was associated with favorable effects on glucose metabolism (lower insulin and HOMA-IR) and bone metabolism (lower CTX in women; higher 25OHD and lower parathyroid hormone in men). The Western diet was associated with deleterious effects on glucose metabolism (higher glucose, insulin, and HOMA-IR) and bone metabolism (higher bone-specific alkaline phosphatase and lower 25OHD in women; higher CTX in men). Body mass index adjustment moved point estimates toward the null, indicating partial mediation. The structural equation model confirmed the hypothesized linkage with strong effects of Prudent and Western diet on metabolic risk, and both direct and indirect effects of a Prudent diet on bone turnover. In summary, a Prudent diet was associated with lower metabolic risk with both primary and mediated effects on bone turnover, suggesting that it is a potential target for reducing fracture risk.

Endocrine abnormalities in HIV-infected women are associated with peak viral load - the Children and Women: AntiRetrovirals and Markers of Aging (CARMA) Cohort

Kristen M Sokalski et al., 2016·Clin Endocrinol (Oxf)

To investigate the prevalence of endocrine disturbances in a group of HIV-positive (HIV+) women and to identify factors affecting presence of these disorders. To examine specifically whether cellular ageing, as measured by leukocyte telomere length (LTL), is correlated with the presence of endocrine disturbance. A cross-sectional retrospective substudy of an ongoing prospective cohort study. Adult HIV+ (≥19 years) women enrolled in the CARMA (Children AntiRetrovirals and Markers of Aging) cohort study (N = 192). Prevalences of T2DM, glucose intolerance, dyslipidaemia, thyroid disorders, adrenal insufficiency, hypogonadism, primary ovarian insufficiency (POI), demographics, HIV and hepatitis C virus (HCV) infection status, baseline LTL, combined antiRetroviral therapy (cART) and substance exposures were collected. Statistical analysis included univariable followed by multivariable Poisson regression and step-wise reduction to refine the multivariable model. Prevalence of any endocrine abnormality was 58% (dyslipidaemia 43%, glucose intolerance/T2DM 13%, thyroid disorders 15%). In multivariable analysis, age was associated with number and type (any, glucose, lipid) of abnormality, while increasing body mass index (BMI) was associated with number of diagnoses and with glucose metabolism disorders. Interestingly, peak HIV pVL ≥100 000 copies/ml was associated with any abnormality, total number of disorders and presence of a thyroid disorder, while any disorder, glucose abnormalities and dyslipidaemia were negatively associated with alcohol use. LTL was not associated with number or type of endocrine abnormalities in this study. Further studies examining the relationship between duration and extent of exposure to HIV viraemia in relation to developing abnormal endocrine function are warranted.

Progesterone or progestin as menopausal ovarian hormone therapy: recent physiology-based clinical evidence

Prior JC, 2015·Curr Opin Endocrinol Diabetes Obes

Provide evidence-based recent data on oral micronized progesterone (OMP) and progestins in menopausal hormonal therapy (MHT). Medroxyprogesterone acetate (MPA) increases breast cancer acting through the glucocorticoid receptor; progestins in MHT increase thrombosis more than oral estrogens; MPA, but not OMP or other progestins, increase monocyte cell endothelium adhesion; MPA and estradiol (E2)/MPA have negative brain effects, whereas E2/progesterone (P4) has neuroregenerative brain effects. The 'window of opportunity' cardiovascular disease hypothesis is not supported by a randomized controlled trial showing that transdermal estradiol with sequential OMP in early menopause does not prevent increased carotid intimal media thickness; P4 in the cardiac electrical system opposes E2 effects and prevents sudden death/long QT syndrome; transdermal estradiol/OMP does not increase venous thromboembolism in observational data. P4 decreases breast cell proliferation and improves prognosis through P4 receptor alteration of estrogen receptor α genetic effects; OMP with conjugated equine estrogen (CEE)/estrogen (E)/E2 does not increase breast cancer in two prospective cohorts, one population-based. Endometrial cancer is increased in MHT of CEE/E/E2+cyclic OMP at 200 mg/day. New data show CEE/E/E2+MPA/P mechanisms for negative breast cancer, venous thromboembolism, cardiovascular system, and brain effects. OMP/P4 counterbalances CEE/E/E2-related negative effects on breast cancer and long QT syndrome. OMP effectively treats vasomotor symptoms and sleep disturbances, and could safely be used alone for symptomatic menopause.

Perimenopause and menopause as oestrogen deficiency while ignoring progesterone

Prior JC, 2015·Nat Rev Dis Primers

Body composition and resting metabolic rate of perimenopausal women using continuous progestogen contraception

Napolitano A et al., 2015·Eur J Contracept Reprod Health Care

The effect on body composition and in particular on fat mass (FM) of 12 months' use of a desogestrel (DSG)-only contraceptive pill or the levonorgestrel-releasing intrauterine system (LNG-IUS) was evaluated in women in the perimenopause. An observational study comprised 102 42 received a 75 μg DSG pill, 34 received the 52 mg LNG-IUS, and 26 received no treatment. Body composition, body weight and resting metabolic rate (RMR) were evaluated at baseline and again after 12 months. FM did not change in the control group (- 0.5 ± 1.6%) but significantly increased in the LNG-IUS group (+ 1.1 ± 2.9%; p = 0.02 vs. controls) and in the DSG group (+ 2.8 ± 3.5%; p = 0.0001 vs. controls; p = 0.02 vs. LNG-IUS). Women treated with DSG or the LNG-IUS showed a non-significant increase in body weight, body mass index and waist circumference. RMR did not significantly vary in the control group (- 3.8 ± 292.9 kJ/ 24 h) and tended to decrease but not significantly in the LNG-IUS (115.5 ± 531.8 kJ/ 24 h) and DSG groups (305.9 ± 556.9 kJ/24 h). The results of this preliminary study seem to indicate that in perimenopausal women continuous use of the DSG-only pill and to a lesser extent the LNG-IUS may favour FM accumulation.

Ten-year incident osteoporosis-related fractures in the population-based Canadian Multicentre Osteoporosis Study - comparing site and age-specific risks in women and men

Jerilynn C Prior et al., 2015·Bone

Population-based incident fracture data aid fracture prevention and therapy decisions. Our purpose was to describe 10-year site-specific cumulative fracture incidence by sex, age at baseline, and degree of trauma with/without consideration of competing mortality in the Canadian Multicentre Osteoporosis Study adult cohort. Incident fractures and mortality were identified by annual postal questionnaires to the participant or proxy respondent. Date, site and circumstance of fracture were gathered from structured interviews and medical records. Fracture analyses were stratified by sex and age at baseline and used both Kaplan-Meier and competing mortality methods. The baseline (1995-97) cohort included 6314 women and 2789 men (aged 25-84 years; mean±SD 62±12 and 59±14, respectively), with 4322 (68%) women and 1732 (62%) men followed to year-10. At least one incident fracture occurred for 930 women (14%) and 247 men (9%). Competing mortality exceeded fracture risk for men aged 65+years at baseline. Age was a strong predictor of incident fractures especially fragility fractures, with higher age gradients for women vs. men. Major osteoporotic fracture (MOF) (hip, clinical spine, forearm, humerus) accounted for 41-74% of fracture risk by sex/age strata; in women all MOF sites showed age-related increases but in men only hip was clearly age-related. The most common fractures were the forearm for women and the ribs for men. Hip fracture incidence was the highest for the 75-84 year baseline age-group with no significant difference between women 7.0% (95% CI 5.3, 8.9) and men 7.0% (95% CI 4.4, 10.3). There are sex differences in the predominant sites and age-gradients of fracture. In older men, competing mortality exceeds cumulative fracture risk.

Cohort efficacy study of natural family planning among perimenopause age women

Fehring RJ et al., 2014·J Obstet Gynecol Neonatal Nurs

To determine the efficacy of using natural family planning (NFP) methods to avoid unintended pregnancy among women of perimenopause age (i.e., age 40-55 years). A secondary analysis of subset data from two prospective observational cohort studies. A university based in-person and online NFP service program. One hundred and sixty couples who used either a website or an in-person NFP service to learn how to avoid pregnancy from January 2001 to November 2012. A prospective 12-month effectiveness study among 160 women (between ages 40-55) who used NFP to avoid pregnancy. The women used either a hormonal fertility monitor, cervical mucus monitoring, or both to estimate the fertile phase of their menstrual cycles. Survival analysis was used to determine the pregnancy rate over 12 months of use. There were a total of five unintended pregnancies among the participants. The typical use pregnancy rate was six per 100 women over 12 months. The monitor alone participants (n = 35) had a 12-month pregnancy rate of three, the participants (n = 73) who used mucus alone had a pregnancy rate of four, and the participants (n = 42) who used the fertility monitor plus mucus had a pregnancy rate of six. Natural family planning methods can be effective for older women to avoid an unintended pregnancy with correct use and adequate instructions. The pregnancy rate most likely was affected by diminished fertility and motivation to limit family size.

Choice of lumbar spine bone density reference database for fracture prediction in men and women: a population-based analysis

William D Leslie et al., 2014·J Clin Densitom

The diagnosis of osteoporosis in men is controversial, although most studies demonstrate similar fracture rates for men and women with the same level of hip bone mineral density (BMD). Whether this applies to the lumbar spine is currently uncertain and has important implications with respect to choice of reference population for T-score calculation and osteoporosis diagnosis. This question was specifically addressed in the population-based Canadian Multicentre Osteoporosis Study cohort of 4745 women and 1887 men ages 50+ yr at the time of baseline lumbar spine dual energy x-ray absorptiometry. In up to 10 yr of observation, incident clinical major osteoporotic fractures occurred in 110 men (5.8%) vs 543 women (11.4%) (p < 0.001). Mean lumbar spine BMD in men was greater than in women, both among those with and those without incident major osteoporotic fracture (p < 0.001). Men were at slightly lower risk for incident major osteoporotic fracture than women for an equivalent lumbar spine BMD (ageand BMD-adjusted rate ratio 0.75, 95% confidence interval 0.60-0.93, p = 0.008) with similar findings after adjustment for the World Health Organization fracture risk assessment clinical risk factors or competing mortality. No significant sex difference in the BMD relationship was seen for vertebral fractures (clinical or radiographic) or for all fractures. In summary, this large population-based longitudinal cohort study found similar or lower fracture risk for men vs women after adjustment for absolute lumbar spine BMD and additional covariates. The least complicated model for describing fracture risk is therefore to use the same reference lumbar spine data for generating T-scores in men and women.

Glucocorticoids predict 10-year fragility fracture risk in a population-based ambulatory cohort of men and women: Canadian Multicentre Osteoporosis Study (CaMos)

George Ioannidis et al., 2014·Arch Osteoporos

We determined the prospective 10-year association among incident fragility fractures and four glucocorticoid (GC) treatment groups (Never GC, Prior GC, Baseline GC, and Ever GC). Results showed that GC treatment is associated with increased 10-year incident fracture risk in ambulatory men and women across Canada. Using the Canadian Multicentre Osteoporosis Study dataset, we determined the prospective 10-year association between incident fragility fractures and GC treatment. We conducted a 10-year prospective observational cohort study at nine sites across Canada. A total of 9,263 ambulatory men and women 25 years of age and older were included in the analysis. Multivariable Cox proportional hazards analyses were conducted to determine the relationship among GC treatment groups in four levels that included Never GC, Prior GC, Baseline GC, and Ever GC (combined baseline and prior groups) and time to fracture. In each of the Never GC, Prior GC, Baseline GC, and Ever GC treatment groups, the number of participants were 8,832 (95.4 %), 303 (3.3 %), 128 (1.4 %), and 431 (4.7 %), respectively. Of the 9,263 individuals enrolled, incident fragility non-spine, hip, spine, and any fractures were experienced by a total of 896 (9.67 %), 157 (1.69 %), 130 (1.40 %), and 1,102 (11.90 %) over 10-years, respectively. For men and women combined, prior GC treatment was associated with a higher hazard ratio (HR) for time to incident non-vertebral (HR = 1.5, 95 % confidence interval [CI] = 1.1, 2.0), hip (HR = 2.1, 95 % CI = 1.1, 4.0), and any fracture (HR = 1.4, 95 % CI = 1.0, 1.8) compared with never GC treatment. GC treatment is associated with increased 10-year incident fracture risk; this highlights the importance of considering therapy to prevent GC-induced fractures for patients who are using GC for various medical conditions.

Progesterone therapy, endothelial function and cardiovascular risk factors: a 3-month randomized, placebo-controlled trial in healthy early postmenopausal women

Prior JC et al., 2014·PLoS One

Progesterone is effective treatment for hot flushes/night sweats. The cardiovascular effects of progesterone therapy are unknown but evidence suggests that premenopausal normal estradiol with also normal progesterone levels may provide later cardiovascular protection. We compared the effects of progesterone to placebo on endothelial function, weight, blood pressure, metabolism, lipids, inflammation and coagulation. We conducted a randomized, double-blind, 3-month placebo-controlled trial of progesterone (300 mg daily) among 133 healthy postmenopausal women in Vancouver, Canada from 2003-2009. Endothelial function by venous occlusion plethysmography was a planned primary outcome. Enrolled women were 1-11 y since last menstruation, not using hormones (for >6 months), non-smoking, without diabetes, hypertension, heart disease or their medications. Randomized (1∶1) women (55 ± 4 years, body mass index 25 ± 3) initially had normal blood pressure, fasting lipid, glucose and electrocardiogram results. Endothelial function (% forearm blood flow above saline) was not changed with progesterone (487 ± 189%, n = 18) compared with placebo (408 ± 278%, n = 16) (95% CI diff [-74 to 232], P = 0.30). Progesterone (n = 65) and placebo (n = 47) groups had similar changes in systolic and diastolic blood pressure, resting heart rate, weight, body mass index, waist circumference, total cholesterol, low-density lipoprotein cholesterol and triglyceride levels. High-density lipoprotein was lower (-0.14 mmol/L, P = 0.001) on progesterone compared with placebo. Fasting glucose, hs-C-reactive protein, albumin and D-dimer changes were all comparable to placebo. Framingham General Cardiovascular Risk Profile scores were initially low and remained low with progesterone therapy and not statistically different from placebo. Results indicate that progesterone has short-term cardiovascular safety. Endothelial function, weight, blood pressure, waist circumference, inflammation and coagulation were unchanged as were lipids except for HDL-C. The statistically significant decrease in HDL-C levels was not clinically important (based on lack of Cardiovascular Risk Profile change). ClinicalTrials.gov NCT00152438.

Oral contraceptives, hormone replacement therapy and breast cancer risk: a cohort study of 16 928 women 48 years and older

Thorbjarnardottir T et al., 2014·Acta Oncol

Findings on potential interactive effects of oral contraceptives (OCs) and hormone replacement therapy (HRT) on breast cancer risk have been inconsistent. We aimed to use population-based cohort data to determine whether former use of OCs affects breast cancer risk among HRT users, taking into account regimens of HRT, duration and currency of use. The cohort consisted of 16 928 Icelandic women who visited the Icelandic Cancer Detection Clinic in 1979-2006 and provided information on use of OCs and HRT when they were 48 years or older. By record linkage to the Icelandic Cancer Registry, all breast cancer diagnosed during follow-up was identified. Using Cox regression, hazard ratios (HRs) for breast cancer according to hormone use were estimated, adjusting for menstrual and reproductive risk factors. Also, interaction analyses were carried out. Breast cancer risk was significantly increased among ever users of combined estrogen and progestin (EP-HRT) preparations (HR=2.61; 95% CI 2.00-3.41) and not among users of estrogen-only regimens (E-only HRT) (HR=1.13; 95% CI 0.85-1.49). Ever users of both OCs and HRT had higher breast cancer risk than users of only one of the two (HR=2.19; 95% CI 1.67-2.87). After restricting the analysis to EP-HRT and focusing on long-term and current use, there was an indication of a negative interaction with ever OC use (p=0.06); HR=2.87; 95% CI 1.79-4.60 for never OC users and HR=2.24; 95% CI 1.51-3.34 for former OC users. After taking HRT regimen, duration and currency of use into account, the results of our population-based cohort study do not support the notion that former OC use increases breast cancer risk among HRT users, on the contrary there was an indication of a slightly lower risk in former OC users, restricted to current, long-term EP-HRT users.

A meta-analysis of the association of fracture risk and body mass index in women

Helena Johansson et al., 2014·J Bone Miner Res

Several recent studies suggest that obesity may be a risk factor for fracture. The aim of this study was to investigate the association between body mass index (BMI) and future fracture risk at different skeletal sites. In prospective cohorts from more than 25 countries, baseline data on BMI were available in 398,610 women with an average age of 63 (range, 20-105) years and follow up of 2.2 million person-years during which 30,280 osteoporotic fractures (6457 hip fractures) occurred. Femoral neck BMD was measured in 108,267 of these women. Obesity (BMI ≥ 30 kg/m(2) ) was present in 22%. A majority of osteoporotic fractures (81%) and hip fractures (87%) arose in non-obese women. Compared to a BMI of 25 kg/m(2) , the hazard ratio (HR) for osteoporotic fracture at a BMI of 35 kg/m(2) was 0.87 (95% confidence interval [CI], 0.85-0.90). When adjusted for bone mineral density (BMD), however, the same comparison showed that the HR for osteoporotic fracture was increased (HR, 1.16; 95% CI, 1.09-1.23). Low BMI is a risk factor for hip and all osteoporotic fracture, but is a protective factor for lower leg fracture, whereas high BMI is a risk factor for upper arm (humerus and elbow) fracture. When adjusted for BMD, low BMI remained a risk factor for hip fracture but was protective for osteoporotic fracture, tibia and fibula fracture, distal forearm fracture, and upper arm fracture. When adjusted for BMD, high BMI remained a risk factor for upper arm fracture but was also a risk factor for all osteoporotic fractures. The association between BMI and fracture risk is complex, differs across skeletal sites, and is modified by the interaction between BMI and BMD. At a population level, high BMI remains a protective factor for most sites of fragility fracture. The contribution of increasing population rates of obesity to apparent decreases in fracture rates should be explored.

Longitudinal changes in calcium and vitamin D intakes and relationship to bone mineral density in a prospective population-based study: the Canadian Multicentre Osteoporosis Study (CaMos)

Zhou W et al., 2013·J Musculoskelet Neuronal Interact

Our objective was to study changes in calcium and vitamin D intakes over time, and their cross-sectional and longitudinal associations with bone mineral density (BMD). We followed 9382 women and men aged ≥25 and 899 aged 16-24, for 10 and 2 years respectively. Calcium and vitamin D intakes increased over time in adults, but decreased in women aged 16-18. The increased intakes in adults were largely attributable to the increased use of calcium and/or vitamin D supplements. Both the percentage of supplement users and average dose among users increased over time. There was nevertheless a high prevalence of calcium and vitamin D intake below the estimated average requirement. At baseline, higher calcium and vitamin D intakes were associated with higher total hip and femoral neck BMD in young men, and cumulatively high levels of calcium and vitamin D intakes over time contributed to better BMD maintenance at lumbar spine and hip sites in adult women. Although total intakes, particularly of vitamin D, frequently fell below the Institute of Medicine recommendations despite an increase over time in supplement use, we found some positive associations between total calcium and vitamin D intake and bone health.

Fracture risk prediction: importance of age, BMD and spine fracture status

John H Krege et al., 2013·Bonekey Rep

Our purpose was to identify factors for a parsimonious fracture risk assessment model considering morphometric spine fracture status, femoral neck bone mineral density (BMD) and the World Health Organization (WHO) clinical risk factors. Using data from 2761 subjects from the Canadian Multicentre Osteoporosis Study (CaMos), a prospective, longitudinal cohort study of randomly selected community-dwelling men and women aged ⩾50 years, we previously reported that a logistic regression model considering age, BMD and spine fracture status provided as much predictive information as a model considering these factors plus the remaining WHO clinical risk factors. The current analysis assesses morphometric vertebral fracture and/or nonvertebral fragility fracture at 5 years using data from an additional 1964 CaMos subjects who have now completed 5 years of follow-up (total N=4725). Vertebral fractures were identified from lateral spine radiographs assessed using quantititative morphometry at baseline and end point. Nonvertebral fragility fractures were determined by questionnaire and confirmed using radiographs or medical records; fragility fracture was defined as occurring with minimal or no trauma. In this analysis, a model including age, BMD and spine fracture status provided a gradient of risk per s.d. (GR/s.d.) of 1.88 and captured most of the predictive information of a model including morphometric spine fracture status, BMD and all WHO clinical risk factors (GR/s.d. 1.92). For comparison, this model provided more information than a model considering BMD and the WHO clinical risk factors (GR/s.d. 1.74). These findings confirm the value of age, BMD and spine fracture status for predicting fracture risk.

Calcium and vitamin D intake and mortality: results from the Canadian Multicentre Osteoporosis Study (CaMos)

Lisa Langsetmo et al., 2013·J Clin Endocrinol Metab

Calcium and vitamin D are recommended for bone health, but there are concerns about adverse risks. Some clinical studies suggest that calcium intake may be cardioprotective, whereas others report increased risk associated with calcium supplements. Both low and high serum levels of 25-hydroxyvitamin D have been associated with increased mortality. The purpose of this study was to determine the association between total calcium and vitamin D intake and mortality and heterogeneity by source of intake. The Canadian Multicentre Osteoporosis Study cohort is a population-based longitudinal cohort with a 10-year follow-up (1995-2007). This study included randomly selected community-dwelling men and women. A total of 9033 participants with nonmissing calcium and vitamin D intake data and follow-up were studied. Total calcium intake (dairy, nondairy food, and supplements) and total vitamin D intake (milk, yogurt, and supplements) were recorded. The outcome variable was all-cause mortality. There were 1160 deaths during the 10-year period. For women only, we found a possible benefit of higher total calcium intake, with a hazard ratio of 0.95 (95% confidence interval, 0.89-1.01) per 500-mg increase in daily calcium intake and no evidence of heterogeneity by source; use of calcium supplements was also associated with reduced mortality, with hazard ratio of 0.78 (95% confidence interval, 0.66-0.92) for users vs nonusers with statistically significant reductions remaining among those with doses up to 1000 mg/d. These associations were not modified by levels of concurrent vitamin D intake. No definitive associations were found among men. Calcium supplements, up to 1000 mg/d, and increased dietary intake of calcium may be associated with reduced risk of mortality in women. We found no evidence of mortality benefit or harm associated with vitamin D intake.

Progesterone therapy increases free thyroxine levels--data from a randomized placebo-controlled 12-week hot flush trial

Sathi P et al., 2012·Clin Endocrinol (Oxf)

Thyroid hormones and progesterone both influence core temperature, metabolism and are crucial during pregnancy. Our objective was to discover whether progesterone therapy caused changes in thyroid physiology compared with placebo. Post hoc analysis from a randomized (1:1) placebo-controlled 12-week trial of oral micronized progesterone (Progesterone, 300 mg/d at bedtime) for hot flushes (vasomotor symptoms, VMS) conducted in an academic medical centre. Postmenopausal euthyroid, healthy (without cardiovascular diseases or risks) women, 1-11 years since last flow on no thyroid or ovarian hormone therapy with VMS participated. Primary outcomes were final and 12-week changes in TSH, FreeT3 and FreeT4 on progesterone vs placebo. Women with thyroid data (69 of 133 in original trial) were randomized to progesterone (n = 39) or placebo (n = 30)-baseline thyroid values were normal. There were no VMS-thyroid interactions-VMS Score (number × intensity) did not correlate with TSH, FreeT3 or FreeT4 (Spearman's -0.03 to -0.19, respectively; all P > 0.15). At 12 weeks on progesterone, TSH levels tended to be lower (1.7 mU) than on placebo (2.2), P = 0.06; FreeT4 levels were higher (16.4 pmol/l) than on placebo (15.3), P = 0.02. FreeT3 was unchanged throughout. Analysis of covariance showed a significant increase in FreeT4 on progesterone (+2.5 pmol/l; 1.9-3.0) vs on placebo (+1.7; 1.1-2.4) with 95% CI of difference = 0.8 pmol/l [0.0, 1.6], P = 0.04. Progesterone caused a significant FreeT4 increase that was discovered during this randomized controlled VMS trial. The clinical importance of this increased FreeT4 level remains to be documented. Registered at ClinialTrials.gov#NCT00152438.

Progesterone for hot flush and night sweat treatment--effectiveness for severe vasomotor symptoms and lack of withdrawal rebound

Prior JC et al., 2012·Gynecol Endocrinol

A controlled trial recently showed that oral micronized progesterone (Progesterone, 300 mg at h.s. daily) was effective for vasomotor symptoms (VMS) in 133 healthy early postmenopausal women. Here, we present subgroup data in women with severe VMS (50 VMS of moderate-severe intensity/wk) and also 1-mo withdrawal study outcomes. Women with severe VMS (n = 46) resembled the full cohort but experienced 10 VMS/d of 3 of 4 intensity. On therapy, the progesterone VMS number (#) decreased significantly more than placebo # to 5.5/day (d) versus 8/d (ANCOVA -2.0 95% CI: -3.5 to -0.4). Just after trial mid-point, a withdrawal substudy (D/C) was added--56 women were invited and 34 (61%) took part (progesterone 17; placebo 17). Those in the D/C cohort resembled the whole cohort. On stopping, VMS gradually increased--at D/C week 4, on progesterone, VMS daily # reached 78% and significantly less than baseline (-3.0 to -0.8) but placebo VMS # did not differ from run-in. In summary, progesterone is effective for severe VMS and does not cause a rebound increase in VMS when stopped. That progesterone may be used alone for severe VMS and unlike estrogen does not appear to cause a withdrawal rebound increases VMS treatment options.

Hot flushes and night sweats differ in associations with cardiovascular markers in healthy early postmenopausal women

Hitchcock CL et al., 2012·Menopause

The aim of this study was to evaluate the associations between vasomotor symptoms ([VMS] hot flushes or flashes and night sweats) and markers of cardiovascular risk. Healthy postmenopausal women in a randomized controlled trial of progesterone for VMS recorded VMS frequency in the Daily Menopause Diary for 28 days at baseline. Accepted risks for cardiovascular body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), blood pressure (BP), endothelial function by venous occlusion plethysmography, fasting lipids, glucose, high-sensitivity C-reactive protein, albumin, and D-dimer. Relationships between risk variables and VMS frequency (24 h, day and night) were assessed by univariate and multivariate robust regressions with adjustment for age and WHtR. Data were available for 145 healthy, nonsmoking women without heart disease, hypertension, or diabetes who were 1 to 11 years past their final menstruation and were aged 43 to 65 years, with a mean (SD) BMI of 25.0 (2.9) kg/m and WC of 79.1 (7.1) cm. Anthropometric variables (BMI, WC, and WHtR) were significantly negatively associated with total (24-h day) VMS frequency and with day VMS but not with night VMS frequency. Systolic BP decreased with greater 24-hour VMS frequency, and both systolic and diastolic BPs were inversely related to day but not night VMS frequency. Albumin was positively associated with night VMS frequency but not with day or 24-hour VMS frequency. Other variables showed little association with VMS frequency. Hot flushes, but not night sweats, were associated with lower cardiovascular risk factors in these healthy postmenopausal women. Future research should differentiate night sweats from hot flushes.

Oral micronized progesterone for vasomotor symptoms--a placebo-controlled randomized trial in healthy postmenopausal women

Hitchcock CL et al., 2012·Menopause

The aim of this study was to compare oral micronized progesterone (progesterone) with placebo as therapy for postmenopausal hot flushes and night sweats (vasomotor symptoms [VMS]). Healthy volunteer community women 1 to 10 years since final menstruation were recruited for a randomized double-blind placebo-controlled trial of progesterone (300 mg daily at bedtime) between 2003 and 2009 and were screened for clinical, physical, or laboratory evidence of cardiovascular risks (nonsmoking, moderate body mass index [<35 kg/m], normal lipids, electrocardiogram, nondiabetic). Women recorded daily frequency and severity (1-4) of VMS in the Daily Menopause Diary during run-in (4 wk) and intervention (12 wk). Average daily VMS score (day frequency × day severity + night frequency × night severity) during final 28 therapy days was the primary outcome, analyzed by therapy, with run-in score as covariate. Randomized participants were 133 healthy community women with VMS, ages 44 to 62 years, with a mean (SD) VMS score of 17.0 (10.4) at run-in (VMS frequency 6.8 [3.2] episodes/d). Women were randomized to progesterone (n = 75) or placebo (n = 58); analysis included all with VMS data at run-in and on therapy (n = 68 and 46, respectively). The VMS scores of women taking progesterone were better than placebo (mean adjusted difference, -4.3 (95% CI, -6.6 to -1.9), with mean reductions of 10.0 (95% CI, -12.0 to -8.1) and 4.4 (95% CI, -6.6 to -2.2) in the progesterone and placebo arms, respectively. Discontinuation with adverse events was 9% (progesterone, 8; placebo, 4), with no serious cases. Oral micronized progesterone is effective for treatment of hot flushes and night sweats in healthy women early in postmenopause.

Should risk of bone fragility restrict weight control for other health reasons in postmenopausal women?--A ten year prospective study

Sirola J et al., 2012·Maturitas

The aim of the present study was to investigate the health risks of excess body weight in the light of its protective effects on bone fragility. Femoral neck and lumbar spine dual X-ray absorptiometry was performed for 1970 Finnish women with a mean baseline age of 58.8 years (range 53.1-65.7 years) in 1994 and 2004. Women were categorized according to baseline BMI into normal <25 kg/m2, overweight 25-29.9 kg/m(2) and obese ≥30 kg/m(2). Weight change (kg) was categorized into tertiles. Co-morbidities, not allowed to be present at baseline, was based on self-reports. Osteoporosis was defined as femoral neck or spinal (L2-L4) T-score <-2.5 SD at 10-year follow-up or <-2.0 SD+low trauma energy follow-up fracture. Uniand multivariate logistic regression models were used to estimate the 10-year risk of incident health disorders. Adjustment for age, number of diseases, alcohol intake and smoking was used in the multivariate models. Obesity (Ob) and overweight (Ow) were related with higher 10-year risk of hypertension (OR=2.6 (Ob)/OR=1.7 (Ow), p<0.001), coronary artery disease (OR=1.6, p<0.05/OR=1.2, p=NS), diabetes (OR=11.7/OR=5.3, p<0.001), osteoarthritis (OR=1.4, p<0.05/OR=1.1, p=NS), chronic back pain (OR=1.6, p=0.007/OR=1.2, p=NS) and poor self-rated health (OR=2.4, p<0.05/OR=1.5, p=NS) and lower risk of osteoporosis (OR=0.13/OR=0.28, p<0.001). Weight change of less than +1 kg was associated 1.8 and 2.6 times lower 10-year risk of having hypertension and breast cancer than weight change over 6.2 kg. Among obese women the absolute risk increase of hypertension was 17%, of diabetes 12%, and absolute risk reduction of osteoporosis 14% in comparison to BMI <25 kg/m(2). Health related risks of high BMI outweigh its protective effects on bone. Weight gain increases the risk hypertension and breast cancer.

Acute effects of premenopausal hysterectomy with bilateral oophorectomy on serum lipids, hormonal values, inflammatory markers and metabolism

Kalyan S et al., 2011·Journal of Gynecologic Surgery

The aim of this study was to provide a clinical reference for the acute postoperative changes to lipids and inflammation following premenopausal hysterectomy with bilateral oophorectomy and compare them to normal reference values. The study design was a planned secondary analysis of data from a randomized double-blind trial comparing the effectiveness of two different hormone therapies for preventing post-oophorectomy bone loss and controlling vasomotor symptoms. These data were obtained on hospital discharge before randomization to treatment. Premenopausal women scheduled for a hysterectomy with bilateral oophorectomy for benign reasons were identified from preoperative lists and approached, prior to hospital discharge, to participate in this study. Postoperative data were compared with premenopausal reference intervals using Z scores. Thirty-three (33) women (mean age 45 ± 4.8 years) were studied an average of 7 days postsurgery. Hemoglobin, albumin, testosterone, and high-density lipoprotein values were decreased in comparison to the normal mean, having Z scores of −3.0, −2.5, −2.4, and −1.7, respectively. C-reactive protein levels were quite significantly elevated (Z score = 20.3). The high levels of inflammation and abnormal lipids postsurgical menopause are important considerations for physicians when planning subsequent treatment and care. (J GYNECOL SURG 27:9)

Progesterone for Symptomatic Perimenopause Treatment - Progesterone politics, physiology and potential for perimenopause

Prior JC, 2011·Facts Views Vis Obgyn

Perimenopause, women's normal midlife reproductive transition, is highly symptomatic for about 20% of women who are currently inaccurately counseled and inappropriately treated with oral contraceptives, menopausal hormone therapy or hysterectomy. About 80% of perimenopausal women experience vasomotor symptoms (VMS), 25% have menorrhagia, and about 10% experience mastalgia. The majority of women describe varying intensities of sleep, -coping or mood difficulties. Women are more symptomatic because common knowledge inaccurately says that estradiol (E2) levels are dropping/deficient. Evidence shows that with disturbed brain-ovary feedbacks, E2 levels average 26% higher and soar erratically - some women describe feeling pregnant! Also, ovulation and progesterone (P4) levels become insufficient or absent. The most symptomatic women have higher E2 and lower P4 levels. Because P4 and E2 complement/counterbalance each other's tissue effects, oral micronized P4 (OMP4 300 mg at -bedtime) is a physiological therapy for treatment-seeking, symptomatic perimenopausal women. Given cyclically (cycle d 14-27, or 14 on/off) in menstruating midlife women, OMP4 decreases cyclic VMS, improves sleep and premenstrual mastalgia. Menorrhagia is treated with ibuprofen 200mg/6h plus OMP4 cycle d 4-28. For insulin resistance, metformin plus cyclic or daily OMP4 decreases insulin resistance and weight gain. Non-responsive migraines need daily OMP4 plus usual therapies. VMS and insomnia in late perimenopause respond to daily OMP4. In summary, OMP4 is a physiology-based therapy that improves sleep, treats VMS, does not increase breast proliferation or cancer risk, increases bone formation and has beneficial cardiovascular effects. A

The endocrinology of perimenopause: need for a paradigm shift

Jerilynn C Prior et al., 2011·Front Biosci (Schol Ed)

Perimenopause, rather than a time of declining estrogen, is characterized by three major hormonal changes that may begin in regularly menstruating erratically higher estradiol levels, decreased progesterone levels (in normally ovulatory, short luteal phase or anovulatory cycles), and disturbed ovarian-pituitary-hypothalamic feedback relationships. Recent data show that approximately a third of all perimenopausal cycles have a major surge in estradiol occurring de novo during the luteal phase. This phenomenon, named "luteal out of phase (LOOP)" event, may explain a large proportion of symptoms and signs for symptomatic perimenopausal women. Large urinary hormone data-sets from women studied yearly over a number of years in the Study of Women Across the Nation (SWAN) and in the Tremin data will eventually provide a more clear prospective understanding of within-woman hormonal changes. Predicting menopause proximity with FSH or Inhibin B levels is documented to be ineffective. Anti-Mullerian hormone levels may prove predictive. Finally, there is an urgent need to change perimenopause understandings, language and therapies used for midlife women's symptoms to reflect these hormonal changes.

Independent external validation of nomograms for predicting risk of low-trauma fracture and hip fracture

Lisa Langsetmo et al., 2011·CMAJ

A set of nomograms based on the Dubbo Osteoporosis Epidemiology Study predicts the fiveand ten-year absolute risk of fracture using age, bone mineral density and history of falls and low-trauma fracture. We assessed the discrimination and calibration of these nomograms among participants in the Canadian Multicentre Osteoporosis Study. We included participants aged 55-95 years for whom bone mineral density measurement data and at least one year of follow-up data were available. Self-reported incident fractures were identified by yearly postal questionnaire or interview (years 3, 5 and 10). We included low-trauma fractures before year 10, except those of the skull, face, hands, ankles and feet. We used a Cox proportional hazards model. Among 4152 women, there were 583 fractures, with a mean follow-up time of 8.6 years. Among 1606 men, there were 116 fractures, with a mean follow-up time of 8.3 years. Increasing age, lower bone mineral density, prior fracture and prior falls were associated with increased risk of fracture. For low-trauma fractures, the concordance between predicted risk and fracture events (Harrell C) was 0.69 among women and 0.70 among men. For hip fractures, the concordance was 0.80 among women and 0.85 among men. The observed fracture risk was similar to the predicted risk in all quintiles of risk except the highest quintile of women, where it was lower. The net reclassification index (19.2%, 95% confidence interval [CI] 6.3% to 32.2%), favours the Dubbo nomogram over the current Canadian guidelines for men. The published nomograms provide good fracture-risk discrimination in a representative sample of the Canadian population.

Fragility fractures and the osteoporosis care gap in women: the Canadian Multicentre Osteoporosis Study

LA Fraser et al., 2011·Osteoporos Int

Canadian women over 50 years old were studied over a 10-year period to see if those who sustained a fracture (caused by minimal trauma) were receiving the recommended osteoporosis therapy. We found that approximately half of these women were not being treated, indicating a significant care gap in osteoporosis treatment. Prevalent fragility fracture strongly predicts future fracture. Previous studies have indicated that women with fragility fractures are not receiving the indicated treatment. We aimed to describe post fracture care in Canadian women using a large, population-based prospective cohort that began in 1995-1997. We followed 5,566 women over 50 years of age from across Canada over a period of 10 years in the Canadian Multicentre Osteoporosis Study. Information on medication use and incident clinical fragility fractures was obtained during a yearly questionnaire or interview and fractures were confirmed by radiographic/medical reports. Over the 10-year study period, 42-56% of women with yearly incident clinical fragility fractures were not treated with an osteoporosis medication. During year 1 of the study, 22% of the women who had experienced a fragility fracture were on treatment with a bisphosphonate and 26% were on hormone therapy (HT). We were not able to differentiate HT use for menopause symptoms vs osteoporosis. Use of bisphosphonate therapy increased over time; odds ratio (OR) for use at year 10 compared to use at year 1 was 3.65 (95% confidence interval (CI) 1.83-7.26). In contrast, HT use declined, with an OR of 0.07 (95%CI 0.02-0.24) at year 10 compared to year 1 of the study. In a large population-based cohort study, we found a therapeutic care gap in women with osteoporosis and fragility fractures. Although bisphosphonate therapy usage improved over time, a substantial gap remains.

Dietary patterns and incident low-trauma fractures in postmenopausal women and men aged ≥ 50 y: a population-based cohort study

Lisa Langsetmo et al., 2010·Am J Clin Nutr

Previous research has shown that dietary patterns are related to the risk of several adverse health outcomes, but the relation of these patterns to skeletal fragility is not well understood. Our objective was to determine the relation between dietary patterns and incident fracture and possible mediation of this relation by body mass index, bone mineral density, or falls. We performed a retrospective cohort study based on the Canadian Multicentre Osteoporosis Study-a randomly selected population-based cohort. We assessed dietary patterns by using self-administered food-frequency questionnaires in year 2 of the study (1997-1999). Our primary outcome was low-trauma fracture occurring before the 10th annual follow-up (2005-2007). We identified 2 dietary patterns by using factor analysis. The first factor (nutrient dense) was strongly associated with intake of fruit, vegetables, and whole grains. The second factor (energy dense) was strongly associated with intake of soft drinks, potato chips, French fries, meats, and desserts. The nutrient-dense factor was associated with a reduced risk of fracture per 1 SD in men overall [hazard ratio (HR): 0.83; 95% CI: 0.64, 1.08] and in women overall (HR: 0.86; 95% CI: 0.76, 0.98). An age trend (P = 0.03) was observed, which yielded an HR of 0.97 in younger women (age < 70 y) compared with an HR of 0.82 in older women (age ≥ 70 y). The associations were independent of body mass index, bone mineral density, falls, and demographic variables. The energy-dense pattern was not related to fracture. A diet high in vegetables, fruit, and whole grains may reduce the risk of low-trauma fracture, particularly in older women.

Determining whether women with osteopenic bone mineral density have low, moderate, or high clinical fracture risk

Lisa Langsetmo et al., 2010·Menopause

Most low-trauma fractures occur among women with osteopenic bone mineral density (BMD), a population considered to have moderate absolute fracture risk. Our purpose was to refine the fracture risk prediction in women with osteopenic BMD to determine the subgroups at lowest and highest risk. We included 2,588 women aged 50 to 90 years with osteopenic BMD (femoral neck BMD between -1 and -2.5) participating in the Canadian Multicentre Osteoporosis Study, an ongoing prospective cohort study of randomly selected Canadians. Baseline variables, in addition to known risk factors, age, and BMD, were considered for inclusion in a model for the prediction of 5-year absolute risk of low-trauma fracture. Models were derived using logistic regression and assessed by the Bayesian Information Criterion. We found an increased fracture risk among those with lower BMD (odds ratio [OR], 1.53; 95% CI, 1.06-2.21) for each decrease in femoral neck T score (eg, from -1 to -2), those with prior low-trauma fracture (OR, 2.06; 95% CI, 1.46-2.92), those with self-reported worse general health (OR, 1.35; 95% CI, 1.15-1.59) for each lower category (categories: excellent, very good, good, fair, poor), and those with height loss (OR, 1.44; 95% CI, 1.16-1.90) for each 5-cm difference between current and maximal height. The new model had yielded a better risk stratification than did a model with World Health Organization risk factors. Including risk factors such as general health and height loss can be used to provide a highly effective assessment of fracture risk among women with osteopenic BMD.

Cardiovascular and metabolic effects of medroxyprogesterone acetate versus conjugated equine estrogen after premenopausal hysterectomy with bilateral ovariectomy

Kalyan S et al., 2010·Pharmacotherapy

To compare the cardiovascular and metabolic effects of medroxyprogesterone acetate (MPA) with those of conjugated equine estrogen (CEE) as single-hormone therapies in women who underwent hysterectomy with bilateral ovariectomy. Secondary analysis of a 12-month, double-blind, randomized, parallel-therapy trial. Four teaching hospitals and one community hospital in Vancouver, Canada. Thirty-three healthy women who underwent premenopausal hysterectomy with bilateral ovariectomy. Subjects received either MPA 10 mg/day (18 women) or CEE 0.6 mg/day (15 women) for 12 months, started immediately after hysterectomy with bilateral ovariectomy. MAIN Lipid profiles (high-density lipoprotein cholesterol [HDL], total cholesterol, apolipoprotein B, and triglyceride levels), homeostatic measures (hemoglobin A(1c) and fasting blood glucose level), hormone levels (free and bioavailable testosterone, cortisol, sex hormone-binding globulin [SHBG], and dehydroepiandrosterone sulfate), inflammatory markers (C-reactive protein [CRP] and serum albumin levels), and anthropometric measures (body mass index [BMI], truncal fat, and total body fat) were assessed over the 12-month period. After 12 months, the women assigned to MPA had lesser increases in BMI (p=0.04), triglyceride (p=0.003), HDL (p<0.0005), SHBG (p<0.0005), total testosterone (p=0.003), and CRP values (p=0.01) and higher serum albumin levels (p<0.0005) compared with the women receiving CEE. Therapy with CEE, but not MPA, after surgical menopause appears to predispose healthy women to low-grade inflammation, as evidenced by its independent associations with elevated CRP and reduced albumin levels. In women treated with MPA, the favorable levels of inflammatory markers, BMI, and triglyceride levels need to be confirmed in larger controlled trials, as progesterone therapy may provide a safe and effective alternative to estrogen for vasomotor symptoms in women with surgical menopause.

Community pharmacists' therapeutic recommendations for heavy flow, androgen excess, fragility fractures and night sweats in menstruating women

Marks M et al., 2010·Can Pharm J

Physicians and menstruating women often ask pharmacists for recommendations about menstrual cycle–related problems. Progesterone and medroxyprogesterone may provide physiology-based treatment, but official indications in menstruating women in Canada are minimal. To describe pharmacists' responses to vignette-based questions about the treatment of common clinical problems in menstruating women and review evidence-based therapies. A pharmacist interviewer administered an 11-item questionnaire to a random sample of community pharmacists. Questions were based on clinical vignettes in adolescent, preand perimenopausal women and related to heavy flow, polycystic ovary syndrome, premenopausal osteoporosis, perimenopausal night sweats and side effects/contraindications for estrogens and progesterone/progestins. The participation rate was 58%, including equal numbers of male and female pharmacists. Seventy-two percent indicated that they would treat menorrhagia in an anemic 13-year-old with oral contraceptives — 21% would recommend ibuprofen and 86% iron. Half recommended that a 35-year-old smoker with heavy flow and acne stop oral contraceptives, but the other 50% recommended a switch to an oral contraceptive with cyproterone. For premenopausal osteoporosis, the majority recommended calcium and vitamin D, but 53% endorsed oral contraceptives — only 7% suggested cyclic medroxyprogesterone. For night sweats, the majority recommended progesterone/progestin in a regularly menstruating 42-year-old woman. Estrogens are contraindicated with past thrombosis and/or breast cancer family history, and they could cause nausea; 50% of pharmacists also attributed these adverse effects to progesterone/progestins. Community pharmacists vary widely in their treatment choices for common preand perimenopausal women's menstrual cycle–related problems. The evidence in support of most recommendations is minimal or lacking.

Estrogen therapy and risk of breast cancer in postmenopausal women: a case-control study and results of a multivariate analysis

Lumachi F et al., 2010·Menopause

Several randomized trials and observational studies show that the use of hormone therapy (HT) increases the risk of breast cancer (BC). The aim of this study was to assess the effects of exposure to both HT and oral contraceptives (OCs) on BC risk in postmenopausal women, all residing in the same metropolitan area. Data regarding a series of 238 consecutive postmenopausal women with infiltrating ductal carcinoma (cases) and 255 randomly selected age-matched healthy women (controls) were reviewed. Odds ratios for no breast-feeding and HT and OC use were 1.82 (95% CI, 1.20-2.77), 2.49 (95% CI, 1.73-3.58), and 2.06 (95% CI 1.14-3.70), respectively. Four independent variables (years between menarche and menopause, breast-feeding, OC use, and HT use) were included in the final multivariate analysis using logistic regression. The cumulative odds ratio calculated from the observed versus predicted values, obtained using the logistic regression function, was 4.55 (95% CI, 2.13-9.71), whereas the cumulative risk of common exposure to both OCs and HT was 2.77 (95% CI, 1.44-5.32). The logistic model correctly classified 67.5% (95% CI, 63.2-71.5) of cases. The receiver operating characteristic (ROC) curve of the complete logistic function showed a fair area of accuracy (0.77; 95% CI, 0.72-0.81). Our results show that the risk of common exposure to both OCs and HT increases in women with other risk factors. However, several parameters traditionally considered in epidemiological studies do not have the same weight in each local community, suggesting the need to create different models to correctly select the high-risk population.

Dietary patterns in Canadian men and women ages 25 and older: relationship to demographics, body mass index, and bone mineral density

Lisa Langsetmo et al., 2010·BMC Musculoskelet Disord

Previous research has shown that underlying dietary patterns are related to the risk of many different adverse health outcomes, but the relationship of these underlying patterns to skeletal fragility is not well understood. The objective of the study was to determine whether dietary patterns in men (ages 25-49, 50+) and women (pre-menopause, post-menopause) are related to femoral neck bone mineral density (BMD) independently of other lifestyle variables, and whether this relationship is mediated by body mass index. We performed an analysis of 1928 men and 4611 women participants in the Canadian Multicentre Osteoporosis Study, a randomly selected population-based longitudinal cohort. We determined dietary patterns based on the self-administered food frequency questionnaires in year 2 of the study (1997-99). Our primary outcome was BMD as measured by dual x-ray absorptiometry in year 5 of the study (2000-02). We identified two underlying dietary patterns using factor analysis and then derived factor scores. The first factor (nutrient dense) was most strongly associated with intake of fruits, vegetables, and whole grains. The second factor (energy dense) was most strongly associated with intake of soft drinks, potato chips and French fries, certain meats (hamburger, hot dog, lunch meat, bacon, and sausage), and certain desserts (doughnuts, chocolate, ice cream). The energy dense factor was associated with higher body mass index independent of other demographic and lifestyle factors, and body mass index was a strong independent predictor of BMD. Surprisingly, we did not find a similar positive association between diet and BMD. In fact, when adjusted for body mass index, each standard deviation increase in the energy dense score was associated with a BMD decrease of 0.009 (95% CI: 0.002, 0.016) g/cm(2) for men 50+ years old and 0.004 (95% CI: 0.000, 0.008) g/cm(2) for postmenopausal women. In contrast, for men 25-49 years old, each standard deviation increase in the nutrient dense score, adjusted for body mass index, was associated with a BMD increase of 0.012 (95% CI: 0.002, 0.022) g/cm(2). In summary, we found no consistent relationship between diet and BMD despite finding a positive association between a diet high in energy dense foods and higher body mass index and a strong correlation between body mass index and BMD. Our data suggest that some factor related to the energy dense dietary pattern may partially offset the advantages of higher body mass index with regard to bone health.

Repeat low-trauma fractures occur frequently among men and women who have osteopenic BMD

Langsetmo L et al., 2009·J Bone Miner Res

Fracture risk assessment based solely on BMD has limitations. Additional risk factors include the presence of a previous low-trauma fracture. We sought to quantify the fracture burden attributable to first versus repeat fracture. We studied 2179 men and 5269 women, 50-90 yr of age, participating in the Canadian Multicentre Osteoporosis Study (CaMos). We included all low-trauma fractures that occurred over 8 yr of follow-up and classified these as either first or repeat clinical low-trauma fracture based on lifetime fracture history. Analyses were further stratified by sex, age, BMD risk categories (normal, osteopenia, osteoporosis), and vertebral deformity status. There were 128 fractures in men and 577 fractures in women. About 25% of fractures in men and 40% in women were repeat fractures. Just over one half of first fractures occurred in those with osteopenic BMD (58% in men, 54% in women). Just under one half of repeat fractures also occurred in those with osteopenic BMD (42% in men, 47% in women). The incidence of repeat fracture was, in most cases, nearly double, but sometimes nearly quadruple, the incidence of first fracture within a given BMD risk category in both men and women. Repeat fractures contribute substantially to overall fracture burden, and the contribution is independent of BMD. Furthermore, those with a combination of prior low-trauma fracture and another risk factor were at especially high risk of future fracture.

Relation between fractures and mortality: results from the Canadian Multicentre Osteoporosis Study

George Ioannidis et al., 2009·CMAJ

Fractures have largely been assessed by their impact on quality of life or health care costs. We conducted this study to evaluate the relation between fractures and mortality. A total of 7753 randomly selected people (2187 men and 5566 women) aged 50 years and older from across Canada participated in a 5-year observational cohort study. Incident fractures were identified on the basis of validated self-report and were classified by type (vertebral, pelvic, forearm or wrist, rib, hip and "other"). We subdivided fracture groups by the year in which the fracture occurred during follow-up; those occurring in the fourth and fifth years were grouped together. We examined the relation between the time of the incident fracture and death. Compared with participants who had no fracture during follow-up, those who had a vertebral fracture in the second year were at increased risk of death (adjusted hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.1-6.6); also at risk were those who had a hip fracture during the first year (adjusted HR 3.2, 95% CI 1.4-7.4). Among women, the risk of death was increased for those with a vertebral fracture during the first year (adjusted HR 3.7, 95% CI 1.1-12.8) or the second year of follow-up (adjusted HR 3.2, 95% CI 1.2-8.1). The risk of death was also increased among women with hip fracture during the first year of follow-up (adjusted HR 3.0, 95% CI 1.0-8.7). Vertebral and hip fractures are associated with an increased risk of death. Interventions that reduce the incidence of these fractures need to be implemented to improve survival.

Vertebral fracture status and the World Health Organization risk factors for predicting osteoporotic fracture risk

Peiqi Chen et al., 2008·J Bone Miner Res

Vertebral fractures are the most common osteoporotic fracture, and patients with prevalent vertebral fractures have a greater risk of future fractures. However, radiographically determined vertebral fractures are not identified as a distinct risk factor in the World Health Organization (WHO) fracture risk assessment tool. The objective of this study was to evaluate and compare potential risk factors including morphometric spine fracture status and the WHO risk factors for predicting 5-yr fracture risk. We hypothesized that spine fracture status provides prognostic information in addition to consideration of the WHO risk factors alone. A randomly selected, population-based community cohort of 2761 noninstitutionalized men and women > or =50 yr of age living within 50 km of one of nine regional centers was enrolled in the Canadian Multicentre Osteoporosis Study (CaMOS), a prospective and longitudinal cohort study following subjects for 5 yr. Prevalent and incident spine fractures were identified from lateral spine radiographs. Incident nonvertebral fragility fractures were determined by an annual, mailed fracture questionnaire with validation, and nonvertebral fragility fracture was defined by investigators as a fracture with minimal trauma. A model considering the WHO risk factors plus spine fracture status provided greater prognostic information regarding future fracture risk than a model considering the WHO risk factors alone. In univariate analyses, age, BMD, and spine fracture status had the highest gradient of risk. A model considering these three risk factors captured almost all of the predictive information provided by a model considering spine fracture status plus the WHO risk factors and provided greater predictive information than a model considering the WHO risk factors alone. The use of spine fracture status along with age and BMD predicted future fracture risk with greater simplicity and higher prognostic accuracy than consideration of the risk factors included in the WHO tool.

Association between change in BMD and fragility fracture in women and men

Claudie Berger et al., 2008·J Bone Miner Res

Our objective was to estimate the relationship between longitudinal change in BMD and fragility fractures. We studied 3635 women and 1417 men 50-85 yr of age in the Canadian Multicentre Osteoporosis Study who had at least two BMD measurements (lumbar spine, femoral neck, total hip, and trochanter) within the first 5 yr of the study and fragility fractures (any, main, forearm/wrist, ribs, hip) within the first 7 yr. Multiple logistic regression was used to model the relationship between baseline BMD, BMD change, and fragility fractures. We found that, among nonusers of antiresorptives, independent of baseline BMD, a decrease of 0.01 g/cm(2)/yr in total hip BMD was associated with an increased risk of fragility fracture with ORs of 1.15 (95% CI: 1.01; 1.32) in women and 1.34 (95% CI: 1.02; 1.78) in men. The risk of fragility fractures in subgroups such as fast losers and those with osteopenia was better estimated by models that included BMD change than by models that included baseline BMD but excluded BMD change. Although the association between baseline BMD and fragility fractures was similar in users and nonusers of antiresorptives, the association was stronger in nonusers compared with users. These results show that BMD change in both men and women is an independent risk factor for fragility fractures and also predicts fracture risk in those with osteopenia. The results suggest that BMD change should be included with other variables in a comprehensive fracture prediction model to capture its contribution to osteoporotic fracture risk.

The impact of incident fractures on health-related quality of life: 5 years of data from the Canadian Multicentre Osteoporosis Study

A Papaioannou et al., 2008·Osteoporos Int

Using prospective data from the Canadian Multicentre Osteoporosis Study (CaMos), we compared health utilities index (HUI) scores after 5 years of follow-up among participants (50 years and older) with and without incident clinical fractures. Incident fractures had a negative impact on HUI scores over time. This study examined change in health-related quality of life (HRQL) in those with and without incident clinical fractures as measured by the HUI. The study cohort was 4,820 women and 1,783 men (50 years and older) from the CaMos. The HUI was administered at baseline and year 5. Participants were sub-divided into incident fracture groups (hip, rib, spine, forearm, pelvis, other) and were compared with those without these fractures. The effects of both time and fracture type on HUI scores were examined in multivariable regression analyses. Men and women with hip fractures, compared to those without, had lower HUI measures that ranged from -0.05 to -0.25. Both women and men with spine fractures had significant deficits on the pain attributes (-0.07 to -0.12). In women, self-care (-0.06), mobility and ambulation (-0.05) were also negatively impacted. Women with rib fractures had deficits similar to women with spine fractures, and these effects persisted over time. In men, rib fractures did not significantly affect HUI scores. Pelvic and forearm fractures did not substantially influence HUI scores. The HUI was a sensitive measure of HRQL change over time. These results will inform economic analyses evaluating osteoporosis therapies.

Effectiveness of antiresorptives for the prevention of nonvertebral low-trauma fractures in a population-based cohort of women

L A Langsetmo et al., 2008·Osteoporos Int

Observational studies are needed to quantify real-life effectiveness of antiresorptive therapy in the prevention of clinical fractures. Antiresorptive therapies were associated with an overall 32% reduction in low-trauma nonvertebral fracture risk among women 50 and older. Effectiveness may be lower among older women and those without risk factors. Randomized controlled trials have shown that antiresorptive therapies reduce the risk of fracture in selected populations, but further study is needed to quantify their real-life effectiveness. The study objective was to determine the association between antiresorptive use and low-trauma nonvertebral fracture in women 50 and older. The design was a retrospective nested case-control study (density-based sampling) within the Canadian Multicentre Osteoporosis Study. There were 5,979 eligible women with 453 cases and 1,304 matched controls. The current use of antiresorptives was associated with a decreased risk of fracture with OR = 0.68, 95% CI: 0.52-0.91; where OR is the adjusted odds ratio and CI is the confidence interval. Subgroup analysis yielded OR = 0.61, 95% CI: 0.42-0.89 for ages 50-74; OR = 0.76, 95% CI: 0.50-1.17 for ages 75+; OR = 0.58, 95% CI: 0.40-0.83 for those with a major risk factor; and OR = 0.92; 95% CI: 0.59-1.42 for those without a major risk factor. Major risk factors were prevalent low-trauma fracture, vertebral deformity (grade 2+), and BMD T-score < or = -2.5. Antiresorptive therapy is associated with a clinically important reduction in low-trauma nonvertebral fracture risk among community-dwelling women aged 50 and older. Antiresorptive therapy may be less effective for women 75 and older and women without major risk factors.

Change in bone mineral density as a function of age in women and men and association with the use of antiresorptive agents

Berger C et al., 2008·CMAJ

Measurement of bone mineral density is the most common method of diagnosing and assessing osteoporosis. We sought to estimate the average rate of change in bone mineral density as a function of age among Canadians aged 25-85, stratified by sex and use of antiresorptive agents. We examined a longitudinal cohort of 9423 participants. We measured the bone mineral density in the lumbar spine, total hip and femoral neck at baseline in 1995-1997, and at 3-year (participants aged 40-60 years only) and 5-year follow-up visits. We used the measurements to compute individual rates of change. Bone loss in all 3 skeletal sites began among women at age 40-44. Bone loss was particularly rapid in the total hip and was greatest among women aged 50-54 who were transitioning from premenopause to postmenopause, with a change from baseline of -6.8% (95% confidence interval [CI] -7.5% to -4.9%) over 5 years. The rate of decline, particularly in the total hip, increased again among women older than 70 years. Bone loss in all 3 skeletal sites began at an earlier age (25-39) among men than among women. The rate of decline of bone density in the total hip was nearly constant among men 35 and older and then increased among men older than 65. Use of antiresorptive agents was associated with attenuated bone loss in both sexes among participants aged 50-79. The period of accelerated loss of bone mineral density in the hip bones occurring among women and men older than 65 may be an important contributor to the increased incidence of hip fracture among patients in that age group. The extent of bone loss that we observed in both sexes indicates that, in the absence of additional risk factors or therapy, repeat testing of bone mineral density to diagnose osteoporosis could be delayed to every 5 years.

Premature ovarian failure and dehydroepiandrosterone

Mamas L et al., 2008·Fertil Steril

In the light of similarities between premenstrual syndrome and toxaemia, and the fact that treatment of the former with progesterone not only relieved the symptoms (Greene and Dalton, 1953) but also prevented the development of edema, hypertension, and albumin

Dual-Energy X-Ray Absorptiometry Technical issues: the 2007 ISCD Official Positions

Christine Simonelli et al., 2008·J Clin Densitom

At the 2007 Position Development Conference, the Dual-Energy X-ray Absorptiometry Technical Task Force investigated three major areas of bone density testing. Although bone mineral density (BMD) testing in men had previously been reviewed at the 2005 Position Development Conference, we reviewed the most recent data in men to develop appropriate indications for bone density testing in men. We continue to recommend screening at age 70 and discuss the clinical risk factors that may be an appropriate indication for earlier BMD testing. Menopausal transition (perimenopause) was considered an important time to consider BMD evaluation because bone loss may be significant prior to menopause. However, because fracture risk is inherently low in women of this age without other risk factors, screening BMD testing is not appropriate. We discuss the risk factors that are strong indicators of fracture risk that may be increased during the menopause transition. The presence of these risk factors are appropriate indications for BMD testing with applicability of WHO diagnostic categorization. The issue of establishing a high threshold for BMD was investigated thoroughly and the current literature was reviewed. Despite the fact there is agreement that all BMD values greater than T-score -1.0 are not normal, it was felt that because of the paucity of sensitivity data and confounding factors such as high body mass index, an upper threshold could not be established or recommended at this time. This was felt to be an important area for further research.

A pilot study of the feasibility of long-term human bone balance during perimenopause using a 41Ca tracer

Hui S et al., 2007·Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms

Medroxyprogesterone and conjugated oestrogen are equivalent for hot flushes: a 1-year randomized double-blind trial following premenopausal ovariectomy

Prior JC et al., 2007·Clin Sci (Lond)

Oestrogen therapy is the gold standard treatment for hot flushes/night sweats, but it and oestrogen/progestin are not suitable for all women. MPA (medroxyprogesterone acetate) reduces hot flushes, but its effectiveness compared with oestrogen is unknown. In the present study, oral oestrogen [CEE (conjugated equine oestrogen)] and MPA were compared for their effects on hot flushes in a planned analysis of a secondary outcome for a 1-year randomized double-blind parallel group controlled trial in an urban academic medical centre. Participants were healthy menstruating women prior to hysterectomy/ovariectomy for benign disease. A total of 41 women {age, 45 (5) years [value is mean (S.D.)]} were enrolled; 38 women were included in this analysis of daily identical capsules containing CEE (0.6 mg/day) or MPA (10 mg/day). Demographic variables did not differ at baseline. Daily data provided the number of night and day flushes compared by group. The vasomotor symptom day-to-day intensity change was assessed by therapy assignment. Hot flushes/night sweats were well controlled in both groups, one occurred on average every third day and every fourth night. Mean/day daytime occurrences were 0.363 and 0.187 with CEE and MPA respectively, but were not significantly different (P=0.156). Night sweats also did not differ significantly (P=0.766). Therapies were statistically equivalent (within one event/24 h) in the control of vasomotor symptoms. Day-to-day hot flush intensity decreased with MPA and tended to remain stable with CEE (P<0.001). In conclusion, this analysis demonstrates that MPA and CEE are equivalent and effective in the control of the number of hot flushes/night sweats immediately following premenopausal ovariectomy.

Reproductive and menopausal factors and risk of systemic lupus erythematosus in women

Costenbader KH et al., 2007·Arthritis Rheum

Systemic lupus erythematosus (SLE) occurs predominantly in women, and hormones may play a role in its etiology. This study was carried out to examine associations between female reproductive and menopausal factors and the development of SLE. A cohort of 238,308 women was prospectively examined. Subjects were older women (ages 30-55 years at start) and younger women (ages 25-42 years at start) from the Nurses' Health Study (NHS) and NHSII cohorts. Incident SLE diagnosed between 1976 and 2003 was confirmed by medical record review. The relative risk (RR) of SLE was estimated separately in each cohort using Cox proportional hazards models, and then pooled using meta-analysis random effects models. Two hundred sixty-two incident cases of SLE were confirmed among the women. In multivariable models adjusted for reproductive and other risk factors, age<or=10 years at menarche (pooled RR 2.1, 95% confidence interval [95% CI] 1.4-3.2), oral contraceptive use (pooled RR 1.5, 95% CI 1.1-2.1), and use of postmenopausal hormones (RR 1.9, 95% CI 1.2-3.1) significantly increased the risk of SLE. An elevation of SLE risk was observed among postmenopausal women primarily after surgical menopause (RR 2.3, 95% CI 1.2-4.5), and also among women with earlier age at natural menopause (P for trend<0.05). Menstrual irregularity was associated with an increased risk of SLE among women in the younger (NHSII) cohort. Age at first birth, parity, and total duration of breastfeeding were not associated with SLE. Early age at menarche, oral contraceptive use, early age at menopause, surgical menopause, and postmenopausal use of hormones were each associated with an increased risk of SLE. These associations may point to the mechanisms underlying the pathogenesis of SLE.

Hormone replacement therapy and breast cancer in former users of oral contraceptives--The Norwegian Women and Cancer study

Lund E et al., 2007·Int J Cancer

Combined estrogen-progestin menopausal therapy (HRT) and combined estrogen-progestin contraceptives (OC) both increase breast cancer risk during current use and a few years after. We investigated risk of breast cancer in women who were users of HRT dependant on former history of OC use in a large, national population-based cohort study, the Norwegian Women and Cancer study (NOWAC). Exposure information was collected through postal questionnaires. Based on follow-up of 30,118 postmenopausal women by linkage to national registers of cancer, deaths, and emigration we revealed 540 incident breast cancer cases between 1996 and 2004. Compared to never users of either drugs current use of HRT gave a significant (p = 0.002) higher risk of breast cancer in former OC users, RR = 2.45 (95% CI 1.92-3.12), than among never users of OCs, RR = 1.67 (1.32-2.12). Relative risk of current use of HRT was similar for estrogen only and combinations with progestin added in ever users of OCs. The increased risk of breast cancer in current HRT users with a history of former OC use could have potential great impact on postmenopausal breast cancer risk as the proportion of postmenopausal women with former OC use will continue to increase.

Effectiveness of ERr 731 in the management of symptomatic perimenopause: clinical significance

Prior JC et al., 2007·Menopause

Prior, Jerilynn C. MD, FRCPC1; Klauss, Vanadin Seifert MD2; Kalyan, Shirin PhD1; Pride, Sheila MD, FRSCPC3

Walking the talk: Doing science with perimenopausal women and their health care providers

Prior JC et al., 2007·World Bank eBooks

No AccessOther Health Study28 Jun 2021Walking the TalkReimagining Primary Health Care After COVID-19Authors/Editors: //doi.org/10.1596/35842SectionsAboutPDF (22.7 MB) ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked The world has waited long enough for high-performing primary health care (PHC). It's time to deliver. Forty years ago, leaders embraced the promise of health for all through PHC. That vision has inspired generations. But for nearly half a century, countries have struggled to walk the talk on PHC. We have not built health systems anchored in strong PHC where they were needed most. Today, COVID-19 (coronavirus) has brought the reckoning for that shared failure—but also the chance to do the job right at last. The pandemic has shown policy makers and ordinary citizens why health systems matter and what happens when they fail. By doing so, it has also created a oncein-a-generation chance for structural health-system change. Bold reforms now can prepare health systems for future crises and bring goals like universal health coverage (UHC) within reach. PHC holds the key to these transformations. But to fulfill that promise, the walk has to finally match the talk. This report charts an agenda toward reimagined, fit-for-purpose PHC. It asks three questions about health-systems "Why?", "What?", and "How?" Since PHC has been around for decades, why write a thick report about it now? The answer is that the characteristics of high-performing PHC are exactly those that are most critical for managing the pressures coming to bear on health systems in the post-COVID world. The challenges include future infectious outbreaks and other emergent threats, but also long-term structural trends that are reshaping the environments in which systems operate in non-crisis times. This report highlights three sets of megatrends that will increasingly affect health demographic and epidemiological shifts; changes in technology; and citizens' evolving expectations for health care. Previous bookNext book FiguresreferencesRecommendeddetails June 2021 Copyright & Permissions Related TopicsHealth Nutrition and Population KeywordsCORONAVIRUSCOVID-19ACCOUNTABILITYHEALTH CARE REFORM PDF DownloadLoading ...

Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy (IARC Monograph Vol 91)

International Agency for Research on Cancer, 2007

FSH and bone--important physiology or not?

Prior JC, 2006·Trends Mol Med

For many years, osteoporosis in women was equated with estrogen deficiency. The recent articles by Zaidi and colleagues offer a new challenge to the estrogen-deficiency-osteoporosis hypothesis by showing that follicle-stimulating hormone (FSH) stimulates osteoclastic bone resorption perhaps through tumor necrosis factor-alpha (TNF-alpha). These authors, however, neglected to mention bone abnormalities and high testosterone levels that were previously shown in FSH-receptor knockout and other modified mice. It is also possible that they have overemphasized potential relationships of these new data with human bone loss. Despite these fascinating data, the paradigm of FSH causing hypogonadal bone loss is not yet ready to displace the estrogen-deficiency-osteoporosis paradigm, although that model already faces considerable challenge.

Perimenopause lost—reframing the end of menstruation

Prior et al., 2006·Journal of Reproductive and Infant Psychology

Ordinary women and official statements confuse and conflate perimenopause—the long, complex, life phase of higher and chaotic estrogen levels—with the low and stable estrogen levels of menopause. This paints both perimenopause and menopause with an inaccurate ‘estrogen deficiency’ brush. Menopause is the hormonal, and (except for hot flushes) the experiential opposite of perimenopause. This feminist analysis is from my perspective as physician‐scientist who experienced a perimenopause that was scientifically enlightening, but personally agonizing. Denial of perimenopausal and menopausal differences causes perimenopause to be ‘lost’ (1) we may assume that perimenopause is chronic rather than ending in a largely asymptomatic menopause; (2) societal taboos isolate us, depriving us of solidarity with perimenopause ‘survivors’; (3) we are told we have dropping estrogen levels when our experiences, like pregnancy dreams, tell us the opposite; (4) gynaecology treats heavy flow with estrogen despite higher perimenopausal estrogen levels; (5) feminists ignore hormonal changes and attribute perimenopausal symptoms to (real) stresses of inferior social status and ageing; and (6) many of us thus become menopausal without the unique, self‐actualization experience that perimenopause has the potential to provide. Thus perimenopause—a valuable transition into knowing and standing up for ourselves—becomes lost.

The effect of cyclooxygenase-2 inhibitors on bone mineral density: results from the Canadian Multicentre Osteoporosis Study

Richards JB et al., 2006·Osteoporos Int

The use of cyclooxygenase-2 (COX-2) inhibitors has been demonstrated to not only impair load-induced bone formation but also prevent menopause-associated bone loss. We hypothesized that COX-2 inhibitor use would be associated with increased bone mineral density (BMD) in postmenopausal women not using estrogen therapy and, conversely, with decreased BMD in men. The Canadian Multicentre Osteoporosis Study is a longitudinal, randomly selected, population-based community cohort. We present data from men (n=2,004) and postmenopausal women age 65 and older (n=2,776) who underwent a BMD measurement and structured interview in the 5th year of the study. The outcome measure was percent difference in BMD (g/cm(2)). Daily COX-2 inhibitor use was reported by 394 subjects. In men, daily use of COX-2 inhibitors was associated with a lower BMD at all hip sites, with a percent difference of -3.1% [95% confidence interval (CI), -6.0, -0.3] between users and nonusers at total hip. In postmenopausal women not using estrogen replacement therapy, daily COX-2 inhibitor use was associated with higher BMD at most sites [percent +3.0% (95% CI, 0.3, 5.8)]. These effects appeared to be dose-dependent. COX-2 inhibitor use was associated with a lower BMD in men and, on the other hand, with a higher BMD in postmenopausal women not using estrogen replacement therapy. Men who have used COX-2 inhibitors may wish to seek BMD measurement to assess their fracture risk. However, COX-2 inhibitors may have utility in postmenopausal women if bone-selective analogs can be developed.

Unsuccessful attempt to demonstrate progesterone's bone formation actions

Prior JC et al., 2006·Am J Obstet Gynecol

Progestogen-only contraception and bone mineral density: a systematic review

Curtis KM et al., 2006·Contraception

Questions have been raised about the effects of progestogen-only contraceptive use on bone health, particularly among young women who have not yet reached peak bone mass and perimenopausal women who may be starting to lose bone mass. We conducted a systematic review that evaluated the association between progestogen-only contraceptive use and fracture risk or bone mineral density (BMD). We identified 39 articles from MEDLINE and EMBASE, published through July 2005. One study reported that depot medroxyprogesterone acetate (DMPA) users were more likely to experience stress fractures than nonusers; this association was not statistically significant after controlling for baseline bone density. In cross-sectional studies, the mean BMD in DMPA users was usually below that of nonusers, but within 1 SD. In longitudinal studies, BMD generally decreased more over time among DMPA users than among nonusers, but women gained BMD upon discontinuation of DMPA. Limited evidence suggested that use of progestogen-only contraceptives other than DMPA did not affect BMD.

In vivo and in vitro estrogenic and progestagenic actions of Tibolone

Sadarangani A et al., 2005·Biol Res

Estrogen and progestin combination in hormone replacement therapy (HRT) increases the incidence of breast cancer, but decreases the endometrial cancer risk of unopposed estrogen. Therefore, a SERM such as Tibolone, that delivers the beneficial, but not the adverse side effects, of steroid hormones would be clinically advantageous. However, data from the Million Women Study suggests that Tibolone increases the risk of both breast and endometrial cancer. Herein, we assessed the estrogenic and progestagenic actions of Tibolone using transvaginal sonography studies and an in vitro model of breast (ZR-75, MCF7) and endometrial cancer (Ishikawa). The known cancer associated proteins (ER, EGFR, STATS, tissue factor and Bcl-xL) were selected for study. Transvaginal sonography demonstrated that postmenopausal women treated with Tibolone displayed a thinner endometrium than in the late proliferative phase, but had a phenotype characteristic of the secretory phase, thus demonstrating the estrogenic and progestagenic actions of this SERM. In vitro, Tibolone acted as an estrogen in downregulating ER and upregulating Bcl-xL, yet as progesterone, increasing STAT5 and tissue factor in breast cancer cells. The increase in tissue factor by Tibolone correlated with its coagulative potential. Interestingly, EGFR was up-regulated by progesterone in the breast and by estrogen in endometrial cells, while Tibolone increased protein levels in both cell types. In conclusion, this study further demonstrates the estrogenic and progestagenic nature of Tibolone. The pattern of regulation of known oncogenes in cells of breast and endometrial origin dictates caution and vigilance in the prescription of Tibolone and subsequent patient monitoring.

Prior oral contraception and postmenopausal fracture: a Women's Health Initiative observational cohort study

Barad D et al., 2005·Fertil Steril

To test for the possible association of past oral contraceptive (OC) use and incident fracture after menopause. A prospective cohort of 93,725 postmenopausal women. Forty Women's Health Initiative (WHI) clinical centers across the United States. PATIENT(S): Ethnically diverse 93,725 volunteer postmenopausal women, 50 to 79 years old. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The main outcome was self-reported incident first fracture assessed prospectively by annual questionnaire. RESULT(S): The adjusted relative hazard (HR) for fracture among past OC users was 1.07 (95% CI, 1.01-1.15). Among women without any postmenopausal hormone treatment, past OC use for < or =5 years led to an HR of 1.15 (95% CI, 1.04-1.27) and for past OC use >5 years led to an HR of 1.09 (95% CI, 0.97-1.23) compared with never users. CONCLUSION(S): This study does not support the idea that past OC use protects against later fracture.

Ovarian aging and the perimenopausal transition: the paradox of endogenous ovarian hyperstimulation

Prior JC, 2005·Endocrine

The purpose of this review is to put into a useful clinical context the changing over time of basic ovarian-pituitary-hypothalamic relationships during perimenopause. "Perimenopause" means changes in ovarian hormones, feedback relationships, and clinical experiences beginning in women ages 35-50 with regular flow and ending 1 yr after the final menstrual flow. A key observation must be explained--estradiol levels are increased in perimenopause. Inhibin B levels are lower and activin may be higher in midlife, menstruating women. These changes probably cause higher follicular phase FSH levels--"endogenous ovarian hyperstimulation" results. The positive estradiol feedback on LH is also disturbed--midcycle LH peaks and mid-luteal slow-frequency, high-amplitude LH pulses are less frequent. In addition to higher levels, estradiol receptors may increase in tissues of symptomatic women. Despite hyperstimulation of follicles, progesterone levels and luteal phase lengths are paradoxically decreased--reasons probably include LH peak disruptions and estrogen-stimulated greater corticotrophin-mediated reproductive suppression. In summary, disturbed feedback relationships causing higher and unpredictable estrogen and lower progesterone levels occur throughout perimenopause, especially during regular cycles. Prospective, population-based research is needed to systematically relate these feedback hormonal changes to clinical characteristics and to allow a diagnosis of perimenopause in regularly cycling midlife women.

Over-the-counter progesterone cream produces significant drug exposure compared to a food and drug administration-approved oral progesterone product

Hermann AC et al., 2005·J Clin Pharmacol

Progesterone products are available in prescription form as well as over-the-counter (OTC) topical preparations sold for "cosmetic" uses. In a randomized study design, the authors compared the drug exposure from an OTC progesterone cream to a Food and Drug Administration-approved oral preparation at the labeled daily doses recommended for each product. Twelve healthy postmenopausal women received 200-mg oral progesterone capsules once daily for 12 days or progesterone cream 40 mg twice daily for 12 days. At steady state (day 12 of each phase), whole-blood samples were collected over 24 hours (oral progesterone) or 12 hours (topical progesterone) and assayed for total progesterone concentration. No significant differences were found in dose-normalized 24-hour progesterone exposure comparing the cream to oral capsules (median AUC(0-24) 12.5 ng x h/mL vs 10.5 ng x h/mL, respectively; P = .81). In light of the potential risks associated with long-term progesterone use, the authors question whether topical progesterone products should be available OTC.

Risk factors associated with incident clinical vertebral and nonvertebral fractures in postmenopausal women: the Canadian Multicentre Osteoporosis Study (CaMos)

Alexandra Papaioannou et al., 2004·Osteoporos Int

Utilizing data from the Canadian Multicentre Osteoporosis Study (CaMos), we examined the association between potential risk factors and incident vertebral and nonvertebral fractures. A total of 5,143 postmenopausal women were enrolled. Information collected during the study included data from the CaMos baseline and annually mailed fracture questionnaires, the Short Form 36 (SF-36), the Health Utilities Index, and physical measurements. Participants were followed for 3 years. Postmenopausal women were classified into four groups according to their incident those without a new fracture; those with a new clinically recognized vertebral fracture; those with an incident nonvertebral fracture at the wrist, hip, humerus, pelvis, or ribs (main nonvertebral fracture group); and those with any new nonvertebral fracture (any-nonvertebral-fracture group). We performed multivariate Cox proportional hazard analysis using all possible risk factors to determine the association between risk factors and the time to the first minimal trauma fracture. Best predictive models were also determined using variables that were included in the full models. The Bayesian information criterion was used for model selection. For all analyses, relative risks and associated 95% confidence intervals were calculated. During the follow-up period, 34, 163, and 280 women developed a vertebral, a main nonvertebral, or any nonvertebral fracture, respectively. The best predictive models indicated that a five point lower quality of life as measured by the SF-36 physical component summary score was associated with relative risks of 1.21 (95% CI, 1.02 to 1.44), 1.17 (95% CI, 1.07 to 1.28), and 1.19 (95% CI, 1.11 to 1.27) for incident vertebral, main nonvertebral, and all nonvertebral fractures, respectively. In addition, for a one standard deviation (SD=0.12) lower femoral neck BMD, the relative risks for incident vertebral, main nonvertebral, and any nonvertebral fractures increased by 2.73 (95% CI, 1.74 to 4.28), 1.39 (95% CI, 1.06 to 1.82), and 1.34 (95% CI, 1.09 to 1.65), respectively. Furthermore, various anthropometric measures, disease conditions, and medications are associated with a new fracture. Identifying postmenopausal women at risk is important given that fracture prevention therapies are now available.

Osteoporosis: What a clinician expects to learn from a patient's bone density examination

Brian C Lentle et al., 2003·Radiology

Osteoporosis has lately become recognized as an important disease on two accounts. On one hand, demographic change has resulted in a greatly increased and increasing burden of morbidity and mortality due to osteoporotic fracturing. On the other hand, lifestyle changes and preventive measures have become recognized as important factors in prevention of both osteoporosis and osteoporotic fractures, while several effective drug treatments have recently become available to treat osteoporosis by increasing bone density and reducing fracture incidence. Because bone density is, with age, the best predictor of fracture risk, its measurement has become central to the care of those potentially at risk. When a clinician refers a person for a bone density examination, the clinician should be concerned less with an "imaging diagnosis" than with the requirement that the laboratory has procedures in place for rigorous quality assurance and precision measurements, as well as for education of the staff involved. Implementation of these measures and an understanding of their clinical relevance in diagnosis and follow-up, as well as communication with clinicians in this context, are more important than any diagnostic insight that might be provided by "interpreting" a bone density study.

The association between osteoporotic fractures and health-related quality of life as measured by the Health Utilities Index in the Canadian Multicentre Osteoporosis Study (CaMos)

J D Adachi et al., 2003·Osteoporos Int

Osteoporotic fractures can be a major cause of morbidity. It is important to determine the impact of fractures on health-related quality of life (HRQL). A total of 3,394 women and 1,122 men 50 years of age and older, who were recruited for the Canadian Multicentre Osteoporosis Study (CaMos), participated in this cross-sectional study. Minimal trauma fractures of the hip, pelvis, spine, lower body (included upper and lower leg, knee, ankle, and foot), upper body (included arm, elbow, sternum, shoulder, and clavicle), wrist and hand (included forearm, hand, and finger), and ribs were studied. Participants with subclinical vertebral deformities were also examined. The Health Utilities Index Mark II and III Systems were used to assess HRQL. Past osteoporotic fractures varied in prevalence from 1.2% (pelvis) to 27.8% (lower body) in women and 0.3% (pelvis) to 29.3% (wrist) in men. Multivariate linear regression analyses [parameter estimates and corresponding 95% confidence intervals (CI)] indicated that minimal trauma fractures were negatively associated with HRQL and that this relationship depends on fracture type and gender. The multi-attribute scores for the Mark II system were negatively related to hip (-0.05; 95% CI: -0.09, -0.01), lower body (-0.02; 95% CI: -0.03, -0.000), and subclinical vertebral fractures (-0.02; 95% CI: -0.03, -0.00) for women. The multi-attribute scores for the Mark III system were negatively related to hip (-0.09; 95% CI: -0.14, -0.03) and rib fractures (-0.06; 95% CI: -0.11, -0.00) for women, and rib fractures (-0.06; 95% CI: -0.12, -0.00) for men. In conclusion, this study demonstrates a negative association between osteoporotic fractures and quality of life in both women and men.

Cyclicity of breast tenderness and night-time vasomotor symptoms in mid-life women: information collected using the Daily Perimenopause Diary

Hale GE et al., 2003·Climacteric

The purpose was to explore cyclicity of breast tenderness and vasomotor symptoms in menstruating mid-life women using the Daily Perimenopause Diary. Untreated mid-life women from a convenience sample completed the Daily Perimenopause Diary for clinical (n = 14) or research (n = 10) assessments. Breast tenderness, sleep disturbance and day and night vasomotor intensity were rated on a 0-4 scale with vasomotor number as a count. Daily oral temperature data were analyzed using the Quantitative Basal Temperature algorithm to assess ovulation and estimate luteal phase length. Analysis of variance tested cyclicity using the mean of three 3-day windows (during flow, at mid-cycle and premenstrually). Ninety-eight complete flow-to-flow diaries (from 24 women, mean age 47 years, cycle length 27 +/- 6.4 (standard deviation) days) were available, with quantitative temperature data for 60 cycles in 16 women. Of assessed cycles, 90% were ovulatory; 25% had luteal phases < 10 days. Breast tenderness was maximal in the premenstrual window overall (p < 0.0001) and in the ovulatory subset. Night sweats were maximal premenstrually (p = 0.0035) except in anovulatory cycles. Daytime flushes were not cyclic (p = 0.1333) except in ovulatory cycles (p = 0.031). Daily Perimenopause Diaries from mid-life women show premenstrual increases in breast tenderness and night sweats.

2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada

JP Brown et al., 2002·CMAJ

To revise and expand the 1996 Osteoporosis Society of Canada clinical practice guidelines for the management of osteoporosis, incorporating recent advances in diagnosis, prevention and management of osteoporosis, and to identify and assess the evidence supporting the recommendations. All aspects of osteoporosis care and its fracture complications - including classification, diagnosis, management and methods for screening, as well as prevention and reducing fracture risk - were reviewed, revised as required and expressed as a set of recommendations. Strategies for identifying and evaluating those at high risk; the use of bone mineral density and biochemical markers in diagnosis and assessing response to management; recommendations regarding nutrition and physical activity; and the selection of pharmacologic therapy for the prevention and management of osteoporosis in men and women and for osteoporosis resulting from glucocorticoid treatment. All recommendations were developed using a justifiable and reproducible process involving an explicit method for the evaluation and citation of supporting evidence. All recommendations were reviewed by members of the Scientific Advisory Council of the Osteoporosis Society of Canada, an expert steering committee and others, including family physicians, dietitians, therapists and representatives of various medical specialties involved in osteoporosis care (geriatric medicine, rheumatology, endocrinology, obstetrics and gynecology, nephrology, radiology) as well as methodologists from across Canada. BENEFITS, Earlier diagnosis and prevention of fractures should decrease the medical, social and economic burdens of this disease. This document outlines detailed recommendations pertaining to all aspects of osteoporosis. Strategies for identifying those at increased risk (i.e., those with at least one major or 2 minor risk factors) and screening with central dual-energy x-ray absorptiometry at age 65 years are recommended. Bisphosphonates and raloxifene are first-line therapies in the prevention and treatment of postmenopausal osteoporosis. Estrogen and progestin/progesterone is a first-line therapy in the prevention and a second-line therapy in the treatment of postmenopausal osteoporosis. Nasal calcitonin is a second-line therapy in the treatment of postmenopausal osteoporosis. Although not yet approved for use in Canada, hPTH(1-34) is expected to be a first-line treatment for postmenopausal women with severe osteoporosis. Ipriflavone, vitamin K and fluoride are not recommended. Bisphosphonates are the first-line therapy for the prevention and treatment of osteoporosis in patients requiring prolonged glucocorticoid therapy and for men with osteoporosis. Nasal or parenteral calcitonin is a first-line treatment for pain associated with acute vertebral fractures. Impact-type exercise and age-appropriate calcium and vitamin D intake are recommended for the prevention of osteoporosis. All recommendations were graded according to the strength of the evidence; where the evidence was insufficient and recommendations were based on consensus opinion alone, this is indicated. These guidelines are viewed as a work in progress and will be updated periodically in response to advances in this field.

Hormonal and reproductive risk factors for development of systemic lupus erythematosus: results of a population-based, case-control study

Cooper GS et al., 2002·Arthritis Rheum

Estrogen and prolactin may accelerate the progression of murine systemic lupus erythematosus (SLE). In humans, 85% of lupus patients are women, which also suggests the importance of hormonal factors in disease pathogenesis. The purpose of this study was to examine hormonal and reproductive risk factors for lupus among women. This population-based, case-control study included 240 female SLE patients diagnosed between January 1, 1995 and July 31, 1999 who fulfilled the American College of Rheumatology classification criteria. Female controls (n = 321) were identified through driver's license records. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) as measures of association, adjusting for age, state, race, and education. Analyses were limited to exposures before diagnosis. Breast-feeding was associated with a decreased risk of developing SLE (OR 0.6, 95% CI 0.4-0.9), with a statistically significant trend for number of babies breast-fed and total weeks of breast-feeding. There were no associations with number of pregnancies or live births. Natural menopause occurred earlier in women with subsequent development of SLE compared with controls (P < 0.001). There was little association between SLE and current use or duration of use of hormone replacement therapy or oral contraceptives, and no association with previous use of fertility drugs. We found little evidence that estrogenor prolactin-related exposures are associated with an increased risk of lupus. The reduced risk observed among women who had breast-fed one or more babies should be examined in other studies. Early natural menopause, rather than decreasing risk of SLE because of reduced estrogen exposure, may be a marker of susceptibility to development of SLE.

Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: a randomized, controlled clinical trial

Van Patten CL et al., 2002·J Clin Oncol

Vasomotor symptoms, such as hot flashes and night sweats, in breast cancer survivors are often worsened by chemotherapy and tamoxifen, and/or the discontinuation of hormone replacement therapy at diagnosis. This study evaluated the acceptability and effectiveness of a soy beverage containing phytoestrogens as a treatment for hot flashes in postmenopausal women with breast cancer. A randomized, placebo-controlled, double-blind clinical trial was conducted in postmenopausal women with moderate hot flashes who were previously treated for early-stage breast cancer. Women were stratified for tamoxifen use and randomized to a soy beverage (n = 59) containing 90 mg of isoflavones or to a placebo rice beverage (n = 64). Women recorded the number and severity of hot flashes daily with a daily menopause diary for 4 weeks at baseline and for 12 weeks while consuming 500 mL of a soy or placebo beverage. There were no significant differences between the soy and placebo groups in the number of hot flashes or hot flash scores. However, presumably because of a strong placebo effect, both groups had significant reductions in hot flashes. Mild gastrointestinal side effects were experienced by both groups but occurred with greater frequency and severity with soy. The mean serum genistein concentration at 6 weeks was significantly higher in women who consumed soy (0.61 +/- 0.43 micromol/L) compared with placebo (0.43 +/- 0.37 micromol/L) (P =.02). Overall acceptability and compliance were high and similar in both groups. The soy beverage did not alleviate hot flashes in women with breast cancer any more than did a placebo. Future research into other compounds is recommended to identify safe and effective therapies for hot flashes in breast cancer survivors.

The ageing female reproductive axis II: ovulatory changes with perimenopause

Prior JC, 2002·Novartis Found Symp

Perimenopause, a complex physiological transition for midlife women, begins with changes in experiences many years before cycles become irregular, oestradiol levels decrease or follicle-stimulating hormone levels increase. Erratic and average higher oestradiol levels as well as shorter luteal phase lengths and lower progesterone levels occur during perimenopause. These ovarian changes may be causally related to lower inhibin production but the dynamic prospective inter-relationships within women are not well documented. This review will first define perimenopause and then explore the limited published data on ovulatory characteristics in perimenopause. In addition, it will report preliminary prospective observational data on menstrual cycles and ovulation in initially ovulatory women followed through the perimenopause. Prospective data suggest that ovulation disturbances begin early in perimenopause and increase with irregular cycles. Combined with higher oestradiol levels they may cause menorrhagia. It is not yet known whether disturbances of ovulation relate to bone loss in perimenopausal, as in premenopausal, women. It is also not known whether progesterone therapy can effectively counteract the end organ (breast, endometrial, brain) effects of higher/erratic oestradiol levels and effectively treat perimenopausal vasomotor and other symptoms.

Impact of progestins on estrogen-induced neuroprotection: synergy by progesterone and 19-norprogesterone and antagonism by medroxyprogesterone acetate

Nilsen J et al., 2001·Endocrinology

Estrogen replacement therapy is associated with improvement of cognitive deficits and reduced incidence of Alzheimer's disease. To compare the impact of therapeutically relevant progestins on estrogen-induced neuroprotection, we treated primary hippocampal neuron cultures with 17beta-E2 and progestin, alone and in combination, 48 h before glutamate insult. Estrogen, progesterone, and 19-norprogesterone, alone or in combination, protected against glutamate toxicity. In contrast, medroxyprogesterone acetate (MPA) failed to protect against glutamate toxicity. Not only was MPA an ineffective neuroprotectant but it attenuated the estrogen- induced neuroprotection when coadministered. We addressed the role of MAPK activation in neuroprotection by ovarian steroids. Estrogen and all three progestins tested, alone or in combination, activated MAPK, indicating another mechanism of protection. Bcl-2 expression has been shown to prevent cell death and is up-regulated by 17beta-E2. Progesterone and 19-norprogesterone, alone or in combination with estrogen, increased Bcl-2 expression. In contrast, MPA blocked estrogen-induced Bcl-2 expression when coadministered. These results may have important implications for the effective use of hormone replacement therapy in the maintenance of neuronal function during menopause and aging and for protection against neurodegenerative diseases such as Alzheimer's disease.

Perimenopausal bone loss: more than estrogen depletion

Prior JC et al., 2001·J Bone Miner Res

In their recent article, "Characterization of Perimenopausal Bone Loss," Recker and colleagues present unique longitudinal bone mineral density (BMD) and hormonal data.1 We acknowledge the work involved in recruiting, motivating, and continuing to follow 75 women each for an average of 8 years. The data from this study are an important contribution to our knowledge of bone changes through the natural perimenopausal transition. Unfortunately, these authors have chosen to reduce the complex endocrinological and physiological changes of perimenopause2 to one idea—"estrogen deprivation." Our first concern is that "estrogen deprivation" or "depletion" is not an adequate concept with which to explain the rapid bone loss during perimenopause. The author's own data show that 50% of spinal BMD loss has occurred by 6 months before the final menstrual period at which time estradiol levels are not lower than in the so called "estrogen replete" group. In this study, perimenopausal bone loss appears to begin approximately 3 years before the final menstrual flow, which is about the time when menstrual cycles become irregular.3 Several other studies also show accelerated rates of perimenopausal bone loss.2, 4, 5 During these later phases of perimenopause, estradiol levels can be very high and certainly are not consistently low.2, 6, 7 If estradiol levels are not low in perimenopause, how can we explain the rapid bone loss? First, estradiol levels vary widely.2 Perhaps, acute drops in estradiol levels (often from abnormally high values) cause increased bone resorption much like that which has been shown to occur within seven days of premenopausal ovariectomy.8 A second possibility is that perimenopause causes psychosocial stress.9 Social stress coupled with high estradiol levels in men have been experimentally shown to cause increased cortisol levels10 that are known to be negative for bone. Finally, ovulatory changes that increase as women progress through perimenopause,11 are associated with accelerated cancellous bone loss, despite normal estradiol levels and regular cycles in premenopausal women.12 Replacement of luteal phases with cyclic progestin in a double-blind randomized study in premenopausal women with abnormal cycles caused an important positive change in spinal BMD.13 As a mechanism to allow use of all of their data, the authors labeled "estrogen replete" those women who continued to menstruate as well as those who started hormone therapy before menopause. It seems odd to us to combine data from three women who have undergone ovariectomy and seven women on exogenous hormone therapy with 10 preor perimenopausal women. The estrogen deprivation hypothesis has led the authors to overlook important physiological differences within this group. We request that the data for the 10 untreated preor perimenopausal women be provided and that we be told whether or not they continued to menstruate regularly. In women's life cycle, low levels of estrogen are as natural for menopausal women as for toddlers. To label menopause as a hormone deficiency condition is to ignore the normal hormonal pattern of women's lives. Recker and colleagues suggest that "hormone replacement therapy" should "begin as early as 2 years before the last menstrual period." Although we acknowledge that vasomotor symptoms commonly begin in perimenopause and have a very negative impact on quality of life, we suggest that progesterone would be a more appropriate therapy. Progesterone is truly low at this phase of perimenopause11 and is effective for night sweats/hot flushes. We fear that prescription of estrogen to women in late perimenopause may have negative consequences in both the short and the long-term. In the short term, it may exacerbate symptoms such as breast tenderness, headaches, and fluid retention. In the long term, having experienced side effects from estrogen treatment these women may refuse it when they are menopausal, a time when it has the potential to be valuable therapy. In summary, this important study is flawed because it relies on a clearly inadequate "estrogen deprivation" concept as the sole explanation for differences found in the prospective data from midlife women.

Executive summary: Stages of Reproductive Aging Workshop (STRAW)

Soules MR et al., 2001·Fertil Steril

Oral contraceptive use and bone mineral density in premenopausal women: cross-sectional, population-based data from the Canadian Multicentre Osteoporosis Study

Prior JC et al., 2001·CMAJ

Positive and negative effects on bone mineral density (BMD) have been described as a result of the premenopausal use of oral contraceptives (OCs); increased fracture rates have also been reported. This study assessed the relation between OC use and BMD in a population-based, 9-centre, national sample of women aged 25-45 years. Premenopausal women who had been enrolled in the Canadian Multicentre Osteoporosis Study were classified as having ever been OC users (> or = 3 months) or as having never been OC users (0 to < 3 months). Data were obtained through extensive questionnaires and measuring of participants' weight, height and the BMD of lumbar vertebrae and the proximal femur. Of the sample of 524 women, whose mean age was 36.3 (standard deviation [SD] 5.9) years, 454 had used OCs; their mean age when they started using OCs was 19.8 (SD 3.5) years and the mean duration of use was 6.8 (SD 4.8) years. Women who had ever and those who had never used OCs showed no differences in age, age at menarche, parity, current calcium intake, exercise, body mass index (BMI), education, past irregular cycles or amenorrhea. OC users reported more alcohol and cigarette use and more use of medications to create regular cycles. Mean BMD values (adjusted for age, BMI and height) were 0.02-0.04 g/cm2 (that is, 2.3%-3.7%) lower in OC users, and were significantly lower in the spine and trochanter. The BMD of the spine in OC users was 1.03 (SD 0.12) g/cm2 versus 1.07 (SD 0.12) g/cm2 (95% confidence interval [CI] of difference -0.07 to -0.001) in those who had never used OCs. BMD was neither related to the duration of OC use nor to gynecological age at first use. Current and past users had similar BMD values. National, population-based data show lower BMD values for the trochanter and spine in premenopausal women who have used OCs compared with those who have never used OCs.

The influence of osteoporotic fractures on health-related quality of life in community-dwelling men and women across Canada

J D Adachi et al., 2001·Osteoporos Int

Health-related quality of life (HRQL) was examined in relation to prevalent fractures in 4816 community-dwelling Canadian men and women 50 years and older participating in the Canadian Multicentre Osteoporosis Study (CaMos). Fractures clinically recognized main fractures, subclinical vertebral fractures and fractures at other sites. Main fractures were divided and analyzed at the hip, spine, wrist/forearm, pelvis and rib sites. Baseline assessments of anthropometric data, medical history, therapeutic drug use, spinal radiographs and prevalent fractures were obtained from all participants. The SF-36 instrument was used as a tool to measure HRQL. A total of 652 (13.5%) main fractures were reported. Results indicated that hip, spine, wrist/forearm, pelvis and rib fractures had occurred in 78 (1.6%), 40 (0.8%), 390 (8.1%), 19 (0.4%) and 125 (2.6%) individuals, respectively (subjects may have had more than one main fracture). Subjects who had experienced a main prevalent fracture had lower HRQL scores compared with non-fractured participants. The largest differences were observed in the physical functioning (-4.0; 95% confidence intervals (CI): -6.0, -2.0) and role-physical functioning domains (-5.8; 95% CI: -9.5, -2.2). In women, the physical functioning domain was most influenced by hip (-14.9%; 95% CI: -20.9, -9.0) and pelvis (-18.1; 95% CI: -27.6, -8.6) fractures. In men, the role-physical domain was most affected by hip fractures (-35.7; 95% CI: -60.4, -11.1). Subjects who experienced subclinical vertebral fractures had lower HRQL scores than those without prevalent fractures. In conclusion, HRQL was lower in the physical functioning domain in women and the role-physical domain in men who sustained main fractures at the hip. Subclinical vertebral fractures exerted a moderate effect on HRQL.

Chronobiological basis of female-specific mood disorders

Parry BL et al., 2001·Neuropsychopharmacology

Women have twice the incidence of major depression compared with men. They are prone to develop episodes of depression during times of reproductive hormonal change at puberty, with use of oral contraceptives, during the premenstrual phase of the menstrual cycle, postpartum and during the perimenopause (see ). describes the variety of disturbances in biological rhythms observed in mood disorders. In this report, we describe the chronobiological disturbances observed in female-specific mood disorders, namely, premenstrual dysphoric disorder, pregnancy and postpartum depression and menopause. We hypothesize that changing reproductive hormones, by affecting the synchrony or coherence between components of the circadian system, may alter amplitude or phase (timing) relationships and thereby contribute to the development of mood disorders in predisposed individuals.

Results of a 10 week community based strength and balance training programme to reduce fall risk factors: a randomised controlled trial in 65-75 year old women with osteoporosis

N D Carter et al., 2001·Br J Sports Med

To test the efficacy of a community based 10 week exercise intervention to reduce fall risk factors in women with osteoporosis. Static balance was measured by computerised dynamic posturography (Equitest), dynamic balance by timed figure of eight run, and knee extension strength by dynamometry. Subjects were randomised to exercise intervention (twice weekly Osteofit classes for 10 weeks) or control groups. The outcome in 79 participants (39 exercise, 40 control) who were available for measurement 10 weeks after baseline measurement is reported. After confounding factors had been controlled for, the exercise group did not make significant gains compared with their control counterparts, although there were consistent trends toward greater improvement in all three primary outcome measures. Relative to the change in control subjects, the exercise group improved by 2.3% in static balance, 1.9% in dynamic balance, and 13.9% in knee extension strength. A 10 week community based physical activity intervention did not significantly reduce fall risk factors in women with osteoporosis. However, trends toward improvement in key independent risk factors for falling suggest that a study with greater power may show that these variables can be improved to a level that reaches statistical significance.

[Hormone replacement therapy of menopause, heart and blood vessels]

Kuttenn F et al., 2001·Arch Mal Coeur Vaiss

The incidence of coronary heart disease (CHD) is lower in premenopausal women than in men and post-menopausal women of the same age. The higher CHD rate after menopause is currently attributed many epidemiological (case-control and prospective) studies have reported a reduced risk (0.5-0.63) of CHD in post-menopausal women receiving hormone replacement therapy (HRT). Moreover, estrogens have multiple effects that would be expected to be cardioprotective, including favorable changes in lipids, endothelial function, vascular reactivity and blood flow. However, the observational studies are subject to several biases that could falsely elevate the women taking estrogens tend to be wealthier, more educated and healthier than untreated women. The american HERS (Heart and Estrogen-progestin Replacement Study; 2.763 women) is a large multicenter randomized study of secondary prevention, designed to evaluate the efficacy of HRT. Results are disappointing, since no reduced risk was observed, and the risk of CHD was even higher in women receiving 1.52 (CI 95%: 1.01-2.29). In HERS study, the treatments consisted of conjugated equine estrogens and the synthetic progestin medroxyprogesterone acetate (MPA) which are rarely used in Europe. Indeed, the effects of HRT are not equivalent depending on the dose, the route of administration, the type of progestogen. It should be emphasized that MPA, contrarily to progesterone, inhibits the beneficial effect of estrogens on lipids and experimental atherosclerosis. The route of administration estrogens alter hemostasis factors, and when orally administered, they have a first pass liver effect, which favors hypercoagulability. It is therefore urgent that Europeans undertake a European "HERS study" in order to investigate the possible beneficial effect of non oral estrogens (gel or patch) associated with natural progesterone.

Evaluation of decision rules for referring women for bone densitometry by dual-energy x-ray absorptiometry

SM Cadarette et al., 2001·JAMA

Identification of women with low bone mineral density (BMD) is an important strategy in reducing the incidence of osteoporotic fractures. However, screening all women is not recommended. To assess the diagnostic properties of 4 decision rules--Simple Calculated Osteoporosis Risk Estimation (SCORE), Osteoporosis Risk Assessment Instrument (ORAI), Age, Body Size, No Estrogen (ABONE), and body weight less than 70 kg (weight criterion)--for selecting women for dual-energy x-ray absorptiometry (DXA) testing and to compare results with recommendations made in the National Osteoporosis Foundation (NOF) practice guidelines. Analysis of data from the Canadian Multicentre Osteoporosis Study, a population-based community sample, collected from 9 study centers across Canada between February 1996 and September 1997. Postmenopausal women aged 45 years or older (N = 2365) without bone disease who had DXA data for the femoral neck, data to apply selection criteria, and who were not currently taking estrogens or who had been taking hormone replacement therapy for 5 or more years. Sensitivity, specificity, and area under the receiver operating characteristic (AUROC) curve of each of the 4 decision rules and the NOF guidelines for identifying women with a BMD T score of less than -1.0 SD, less than -2.0 SD, and no more than -2.5 SD at the femoral neck, and percentages of women recommended for testing, stratified by BMD level and age. The percent of women with a BMD T score less than -1, less than -2, and no more than -2.5 were 68.3%, 25.4%, and 10.0%, respectively. The AUROC curves were greatest using SCORE and ORAI. The sensitivity for identifying women with a BMD T score of less than -2.0 was 93.7% (95% confidence interval [CI], 91.8%-95.6%) using the NOF guidelines and was 97.5% (95% CI, 96.3%-98.8%), 94.2% (95% CI, 92.3%-96.1%), 79.1% (95% CI, 75.9%-82.3%), and 79.6% (95% CI, 76.4%-82.8%), respectively, using the SCORE, ORAI, ABONE, and weight criterion. However, the NOF guidelines also resulted in 74.4% (95% CI, 71.3%-77.6%) of women with a normal BMD (T score of -1.0 or higher) being tested compared with 69.2% (95% CI, 65.9%-72.5%), 56.3% (95% CI, 52.7%-59.8%), 35.8% (95% CI, 32.4%-39.2%), and 38.1% (95% CI, 34.6%-41.6%), respectively, using the 4 decision rules. Assessments suggest that ABONE and weight criterion are not useful case-finding approaches. The SCORE and ORAI decision rules are better than the NOF guidelines at targeting BMD testing in high-risk patients. The acceptability of these rules in clinical practice merits further investigation given their potential effect on the use of densitometry services.

Physiologic effects of lowering caloric intake in nonhuman primates and nonobese humans

S B Roberts et al., 2001·J Gerontol A Biol Sci Med Sci

Caloric restriction (CR) reduces the rate of aging and increases life span in all small animal species studied to date, but the effects of CR in humans remain uncertain. This review summarizes current knowledge of the effects of CR in nonhuman primates and humans. The results suggest that CR has a range of beneficial effects in nonhuman primates studied under laboratory conditions, and short-term markers of CR seen in animal models appear to occur in humans subject to CR also. However, the overall benefit of CR in human populations remains to be established, and studies in human populations are needed.

Estimation of the prevalence of low bone density in Canadian women and men using a population-specific DXA reference standard: the Canadian Multicentre Osteoporosis Study (CaMos)

A Tenenhouse et al., 2001·Osteoporos Int

The Canadian Multicentre Osteoporosis Study (CaMos) is a prospective cohort study which will measure the incidence and prevalence of osteoporosis and fractures, and the effect of putative risk factors, in a random sample of 10,061 women and men aged > or = 25 years recruited in approximately equal numbers in nine centers across Canada. In this paper we report the results of studies to establish peak bone mass (PBM) which would be appropriate reference data for use in Canada. These reference data are used to estimate the prevalence of osteoporosis and osteopenia in Canadian women and men aged > or = 50 years. Participants were recruited via randomly selected household telephone listings. Bone mineral density (BMD) of the lumbar spine and femoral neck were measured by dual-energy X-ray absorptiometry using Hologic QDR 1000 or 2000 or Lunar DPX densitometers. BMD results for lumbar spine and femoral neck were converted to a Hologic base. BMD of the lumbar spine in 578 women and 467 men was constant to age 39 years giving a PBM of 1.042 +/- 0.121 g/cm2 for women and 1.058 +/- 0.127 g/cm2 for men. BMD at the femoral neck declined from age 29 years. The mean femoral neck BMD between 25 and 29 years was taken as PBM and was found to be 0.857 +/- 0.125 g/cm2 for women and 0.910 +/- 0.125 g/cm2 for men. Prevalence of osteoporosis, as defined by WHO criteria, in Canadian women aged > or = 50 years was 12.1% at the lumbar spine and 7.9% at the femoral neck with a combined prevalence of 15.8%. In men it was 2.9% at the lumbar spine and 4.8% at the femoral neck with a combined prevalence of 6.6%.

Preserved forearm endothelial responses with acute exposure to progesterone: A randomized cross-over trial of 17-beta estradiol, progesterone, and 17-beta estradiol with progesterone in healthy menopausal women

Mather KJ et al., 2001·J Clin Endocrinol Metab

Regularly menstruating women are relatively protected from cardiovascular disease. Epidemiological and endothelial function studies attribute this protection to estradiol (E(2)), but both progesterone (P) and E(2) are normally present. A range of vascular effects of added progestins have been described, from neutral to detrimental, but the effects of P per se on endothelial function in humans have not been reported. We therefore investigated the acute effects of E(2), P, and E(2) combined with P, on endothelium-dependent and -independent forearm blood flow responses. Using venous occlusion plethysmography, forearm blood flow (FBF) was measured during acute brachial artery infusions, achieving physiologic levels of 17-beta-E(2), P, and 17-beta-E(2) with P in healthy menopausal women with no cardiovascular disease risk factors. Vehicle or hormones were infused, in random order, on 4 days, 1 week apart. Flow responses were measured during coinfusions of hormone with the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator sodium nitroprusside. Twenty-seven healthy menopausal women were studied, and all had normal baseline endothelial responses. Small ( approximately 15%), statistically nonsignificant increases in endothelium-dependent flow responses were seen after all acute hormone treatments. No impairment in response was seen with P alone or in combination with 17-beta-E(2). In healthy menopausal women without cardiovascular disease risk factors and without baseline defects in endothelial function, acute exposure to physiologic levels of 17-beta-E(2), P, and 17-beta-E(2) with P produced equivalent endothelium-dependent responses. These data suggest that P does not have detrimental vascular effects in humans.

Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women

Rosano GM et al., 2000·J Am Coll Cardiol

We sought to compare the effects of estrogen/transvaginal progesterone gel with estrogen/medroxyprogesterone acetate (MPA) on exercise-induced myocardial ischemia in postmenopausal women with coronary artery disease or previous myocardial infarction, or both. Estrogen therapy beneficially affects exercise-induced myocardial ischemia in postmenopausal women; however, women with an intact uterus also take progestin to protect against uterine malignancies. The effects of combination estrogen/progestin therapy on myocardial ischemia are unknown. Eighteen postmenopausal women (mean +/- SD age 59+/-7 years) were given 17-beta-estradiol in single-blinded manner for four weeks (1 mg/day for three weeks then 2 mg/day for one week). Estradiol (2 mg/day) was then continued, and the patients were randomized (double-blind) for 12 days to either transvaginal progesterone gel (90 mg on alternate days) and oral MPA placebo (10 mg/day), or vice versa. After another two weeks on estradiol alone, the patients crossed over to progestin treatment and repeated the protocol on the opposite treatment. Patients underwent treadmill exercise testing after each estradiol phase and at day 10 of each progestin phase. Exercise time to myocardial ischemia increased after the first estrogen phase as compared with baseline (mean difference with 95% confidence interval [CI]: 72 s [34 to 110], p = 0.001), and was increased by combination estradiol/progesterone therapy as compared with estradiol/MPA therapy (92 s [35 to 149], p = 0.001)). Two patients (11%) were withdrawn while taking estradiol/MPA owing to unstable angina. Combination estrogen/transvaginal progesterone gel increases exercise time to myocardial ischemia, as compared with estrogen/MPA. These results imply that the choice of progestin in women at higher cardiovascular risk requires careful consideration.

Randomized, Controlled Comparison of Transdermal Estradiol with Oral Conjugated Estrogens for the Relief of Hot Flashes

Parsey K et al., 2000

Effects of estrogen replacement on the progression of coronary-artery atherosclerosis

Herrington DM et al., 2000·N Engl J Med

Heart disease is a major cause of illness and death in women. To understand better the role of estrogen in the treatment and prevention of heart disease, more information is needed about its effects on coronary atherosclerosis and the extent to which concomitant progestin therapy may modify these effects. We randomly assigned a total of 309 women with angiographically verified coronary disease to receive 0.625 mg of conjugated estrogen per day, 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate per day, or placebo. The women were followed for a mean (+/-SD) of 3.2+/-0.6 years. Base-line and follow-up coronary angiograms were analyzed by quantitative coronary angiography. Estrogen and estrogen plus medroxyprogesterone acetate produced significant reductions in low-density lipoprotein cholesterol levels (9.4 percent and 16.5 percent, respectively) and significant increases in high-density lipoprotein cholesterol levels (18.8 percent and 14.2 percent, respectively); however, neither treatment altered the progression of coronary atherosclerosis. After adjustment for measurements at base line, the mean (+/-SE) minimal coronary-artery diameters at follow-up were 1.87+/-0.02 mm, 1.84+/-0.02 mm, and 1.87+/-0.02 mm in women assigned to estrogen, estrogen plus medroxyprogesterone acetate, and placebo, respectively. The differences between the values for the two active-treatment groups and the value for the placebo group were not significant. Analyses of several secondary angiographic outcomes and subgroups of women produced similar results. The rates of clinical cardiovascular events were also similar among the treatment groups. Neither estrogen alone nor estrogen plus medroxyprogesterone acetate affected the progression of coronary atherosclerosis in women with established disease. These results suggest that such women should not use estrogen replacement with an expectation of cardiovascular benefit.

Comparison of regimens containing oral micronized progesterone or medroxyprogesterone acetate on quality of life in postmenopausal women: a cross-sectional survey

Fitzpatrick LA et al., 2000·J Womens Health Gend Based Med

A cross-sectional survey was conducted to examine quality of life (QOL) related to physiological, somatic, and vasomotor effects of changing progestogen treatment from medroxyprogesterone acetate (MPA) to micronized progesterone in postmenopausal women. Eligible women (n = 176) were currently using hormone replacement therapy (HRT) containing micronized progesterone for 1-6 months and had previously received HRT containing MPA. QOL was assessed via telephone interview using the Greene Climacteric Scale and the Women's Health Questionnaire. When compared with the MPA-containing regimen, women using micronized progesterone-containing HRT experienced significant improvement in vasomotor symptoms, somatic complaints, and anxiety and depressive symptoms. Women reported improved perceptions of their patterns of vaginal bleeding and control of menopausal symptoms while on the micronized progesterone-containing regimen. Approximately 80% of women reported overall satisfaction with the micronized progesterone-containing regimen. A micronized progesterone-containing HRT regimen offers the potential for improved QOL as measured by improvement of menopause-associated symptoms.

Effects of gonadal steroids in women with a history of postpartum depression

Bloch M et al., 2000·Am J Psychiatry

Endocrine factors are purported to play a role in the etiology of postpartum depression, but direct evidence for this role is lacking. The authors investigated the possible role of changes in gonadal steroid levels in postpartum depression by simulating two hormonal conditions related to pregnancy and parturition in euthymic women with and without a history of postpartum depression. The supraphysiologic gonadal steroid levels of pregnancy and withdrawal from these high levels to a hypogonadal state were simulated by inducing hypogonadism in euthymic women-eight with and eight without a history of postpartum depression-with the gonadotropin-releasing hormone agonist leuprolide acetate, adding back supraphysiologic doses of estradiol and progesterone for 8 weeks, and then withdrawing both steroids under double-blind conditions. Outcome measures were daily symptom self-ratings and standardized subjective and objective cross-sectional mood rating scales. Five of the eight women with a history of postpartum depression (62.5%) and none of the eight women in the comparison group developed significant mood symptoms during the withdrawal period. Analysis of variance with repeated measures of daily and cross-sectional ratings of mood showed significant phase-by-group effects. These effects reflected significant increases in depressive symptoms in women with a history of postpartum depression but not in the comparison group after hormone withdrawal (and during the end of the hormone replacement phase), compared with baseline. The data provide direct evidence in support of the involvement of the reproductive hormones estrogen and progesterone in the development of postpartum depression in a subgroup of women. Further, they suggest that women with a history of postpartum depression are differentially sensitive to mood-destabilizing effects of gonadal steroids.

Efficacy and safety of oral estriol for managing postmenopausal symptoms

Takahashi K et al., 2000·Maturitas

to assess the therapeutic efficacy and safety of oral estriol for the treatment of climacteric symptoms in postmenopausal women. 68 postmenopausal women with climacteric symptoms received oral estriol, 2 mg/day, daily for 12 months. We evaluated the degree of climacteric complaints with estriol therapy; serum levels of gonadotropins, estradiol (E2) and lipids; biochemical markers of bone metabolism; blood pressure; and side effects both at baseline and during treatment. Climacteric symptoms were assessed according to the menopausal index (MI), a version of the Kupperman index that had been modified for Japanese women. oral estriol therapy significantly reduced total MI scores. The greatest relief was noted for hot flushes, night sweats, and insomnia. Estriol treatment significantly lowered serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) concentrations but did not affect any of the other parameters (lipids, bone, liver and blood pressure) during the study period. Slightly vaginal bleeding occurred in 14.3% of those who underwent natural menopausal women. Histologic evaluation of the endometrium and ultrasound assessment of the breasts following 12 months of estriol treatment found normal results in all women. Estriol is a safe and effective alternative for relieving climacteric symptoms in postmenopausal Japanese women.

The Changing Face of Breast Cancer: A Clinic Bulletin on Menopause

Archer DF, 2000·JAMA

"Natural" isomolecular hormone replacement: an evidence-based medicine approach

Drisko JA, 2000·Int J Pharm Compd

Is adolescent pregnancy associated with adverse perinatal outcome?

Orvos H et al., 1999·J Perinat Med

The number of teenage pregnancies has increased throughout the world and these pregnancies are reported in association with a higher rate of maternal and fetal complications. To evaluate the social surroundings; the results of ante-, intrapartum surveillance and perinatal outcome in adolescent pregnancies where mothers were below the age of 18. Between 1st January, 1991 and 31st December, 1996 there were 13,131 births at our department. During this period, 209 newborns were born of 207 adolescent mothers. We compared the data of adolescent mothers with the data of all mothers who delivered in Hungary during the study period. 39 (18.6%) from 209 newborns were delivered before 37th week of gestation, and 34 (16.3%) newborns showed signs of intrauterine growth retardation (IUGR). The rate of primiparous adolescent mothers was 72.0%, 131 (63.3%) were primigravidae, and 136 (65.7%) received adequate prenatal care. Maternal complications (pregnancy induced hypertension, threatened preterm delivery, gestational diabetes and pre-eclampsia) and adverse perinatal outcome (higher rate of IUGR and perinatal mortality) were found more frequently in adolescent pregnancies. As young maternal age is associated with an increased risk of unfavourable fetal outcome, teenage mothers need improved prenatal care and increased observation during labour. In addition, improvement of the social environment of adolescents and the prevention of teenage pregnancies should be recommended.

Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss

Leonetti HB et al., 1999·Obstet Gynecol

To determine effectiveness of transdermal progesterone cream for controlling vasomotor symptoms and preventing postmenopausal bone loss. We randomly assigned 102 healthy women within 5 years of menopause to transdermal progesterone cream or placebo. Study subjects and investigators were masked until data analysis was completed. An initial evaluation included complete history, physical examination, bone mineral density determination, and serum studies (TSH, FSH, lipid profile, and chemistry profile). Subjects were instructed to apply a quarter teaspoon of cream (containing 20 mg progesterone or placebo) to the skin daily. Each woman received daily multivitamins and 1200 mg of calcium and were seen every 4 months for review of symptoms. Bone scans and serum chemistries were repeated after 1 year. Thirty of the 43 (69%) in the treatment group and 26 of the 47 (55%) in the placebo group complained initially of vasomotor symptoms. Improvement or resolution of vasomotor symptoms, as determined by review of weekly symptom diaries, was noted in 25 of 30 (83%) treatment subjects and five of 26 (19%) placebo subjects (P < .001). However, the number of women who showed gain in bone mineral density exceeding 1.2% did not differ (alpha = .05, power of 80%). Although we found no protective effect on bone density after 1 year, we did see a significant improvement in vasomotor symptoms in the treated group.

The major metabolite of equilin, 4-hydroxyequilin, autoxidizes to an o-quinone which isomerizes to the potent cytotoxin 4-hydroxyequilenin-o-quinone

Zhang F et al., 1999·Chem Res Toxicol

The risk factors for women developing breast and endometrial cancers are all associated with a lifetime of estrogen exposure. Estrogen replacement therapy in particular has been correlated with a slight increased cancer risk. Previously, we showed that equilenin, a minor component of Premarin (Wyeth-Ayerst), was metabolized to highly cytotoxic quinoids which caused oxidative stress and alkylation of DNA in vitro [Bolton, J. L., Pisha, E., Zhang, F., and Qiu, S. (1998) Chem. Res. Toxicol. 11, 1113-1127]. In this study, we have compared the chemistry of the major catechol metabolite of equilin (4-hydroxyequilin), which is found in several estrogen replacement formulations, to the equilenin catechol (4-hydroxyequilenin). Unlike endogenous catechol estrogens, both equilin and equilenin were primarily converted by rat liver microsomes to 4-hydroxylated rather than 2-hydroxylated o-quinone GSH conjugates. With equilin, a small amount of 2-hydroxyequilin GSH quinoids were detected (4-hydroxyequilin:2-hydroxyequilin ratio of 6:1); however, no peaks corresponding to 2-hydroxyequilenin were observed in incubations with equilenin. These data suggest that unsaturation in the B ring alters the regiochemistry of P450-catalyzed hydroxylation from primarily 2-hydroxylation for endogenous estrogens to 4-hydroxylation for equine estrogens. 4-Hydroxyequilenin-o-quinone reacts with GSH to give two mono-GSH conjugates and one di-adduct. The behavior of 4-hydroxyequilin was found to be more complex than 4-hydroxyequilenin as conjugates resulting from 4-hydroxyequilenin were detected in addition to the 4-hydroxyequilin-GSH adducts. The mechanism of decomposition of 4-hydroxyequilin likely involves isomerization to a quinone methide which readily aromatizes to 4-hydroxyequilenin followed by autoxidation to 4-hydroxyequilenin-o-quinone. Similar results were obtained with 2-hydroxyequilin, although, in contrast to 4-hydroxyequilenin, 2-hydroxyequilenin does not autoxidize and the reaction stops at the catechol. Since 4-hydroxyequilin is converted to 4-hydroxyequilenin and 4-hydroxyequilenin-o-quinone, similar effects were observed for this equine catechol, including consumption of NAD(P)H likely by the 4-hydroxyequilenin-o-quinone, depletion of molecular oxygen by 4-hydroxyequilenin or its semiquinone radical, and alkylation of deoxynucleosides and DNA by 4-hydroxyequilenin quinoids. Finally, preliminary studies conducted with the human breast tumor cell line MCF-7 demonstrated that the cytotoxic effects of the catechol estrogens from estrone, equilin, and 2-hydroxyequilenin were similar, whereas 4-hydroxyequilenin was a much more potent cytotoxin ( approximately 30-fold). These results suggest that the catechol metabolites of equine estrogens have the ability to cause alkylation/redox damage in vivo primarily through formation of 4-hydroxyequilenin quinoids.

Research Notes: The Canadian Multicentre Osteoporosis Study (CaMos): Background, Rationale, Methods

N Kreiger et al., 1999·Can. J. Aging

Relatively little is known about the factors in Canada which lead to osteoporosis and its concomitant fractures. The Canadian Multicentre Osteoporosis Study (CaMos) is a prospective cohort study which will estimate the incidence and prevalence of declining bone mass and fractures. The impact of osteoporosis in Canada will be assessed, including regional variation and the effect of various risk factors. The study will provide information for developing prevention programs. The cohort has been drawn from a random population-based sample of non-institutionalized men and women 25 years old or more and living within 50 km. of nine cities in Canada. Through telephone interviews 9,423 participants have been recruited. All answered an extensive questionnaire, and had physical measurements related to bone quality taken. This paper details the CaMos baseline and five-year follow-up protocol.

Oral micronized progesterone

Driguez PD et al., 1999·Clin Ther

This review sought to examine the rationale for selecting an oral micronized progesterone formulation rather than a synthetic progestin for some of the main indications for progestogens. Unopposed estrogen use is associated with a high risk (relative risk, 2.1 to 5.7) of endometrial hyperplasia and adenocarcinoma, and it has been understood for some time that a progestogen must be added for at least 10 to 14 days per month to prevent these effects. However, the most commonly used synthetic progestins, norethisterone and medroxyprogesterone acetate, have been associated with metabolic and vascular side effects (eg, suppression of the vasodilating effect of estrogens) in both experimental and human controlled studies. All comparative studies to date conclude that the side effects of synthetic progestins can be minimized or eliminated through the use of natural progesterone, which is identical to the steroid produced by the corpus luteum. The inconvenience associated with the use of injectable, rectal, or vaginal formulations of natural progesterone can be circumvented by using orally administered micronized progesterone. The bioavailability of micronized progesterone is similar to that of other natural steroids, and interindividual and intraindividual variability of area under the curve is similar to that seen with synthetic progestins. A clear dose-ranging effect has been demonstrated, and long-term protection of the endometrium has been established. Micronized progesterone has been used widely in Europe since 1980 at dosages ranging from 300 mg/d (taken at bedtime) 10 days a month for women wishing regular monthly bleeding to 200 mg 14 days a month or 100 mg 25 days a month for women willing to remain amenorrheic. This therapy is well tolerated, with the only specific side effect being mild and transient drowsiness, an effect minimized by taking the drug at bedtime. The prospective, comparative Postmenopausal Estrogens/Progestin Intervention trial has recommended oral micronized progesterone as the first choice for opposing estrogen therapy in nonhysterectomized postmenopausal women.

Ambulatory--not office--blood pressures decline during hormone replacement therapy in healthy postmenopausal women

van Ittersum FJ et al., 1998·Am J Hypertens

Hormone replacement therapy (HRT, estrogen plus progestagen) in postmenopausal women has beneficial effects on the cardiovascular system. However, effects on blood pressure, determined with office measurements, remain controversial. We studied the effects of HRT in 29 healthy normotensive postmenopausal women (mean age 52.3 [3.8] years, median duration of amenorrhea 34.5 months), using ambulatory blood pressure monitoring at baseline and at 3 and 12 months of follow-up. Women an HRT group (N = 14), treated with 1 mg 17beta-estradiol once daily and 5 or 10 mg dydrogesterone once daily during the third and fourth week of every 4 weeks; and a control group (C-group, N = 15), which did not receive therapy. Blood pressures did not differ between the groups at baseline (HRT group 117.1 (9.2)/74.4 (6.6) mm Hg, C-group 113.8 (11.2)/71.3 (7.4) mm Hg). During the follow-up period, changes from baseline of office blood pressures did not differ significantly between the groups. However, changes (95% CI) of mean 24-h blood pressures differed significantly between the two groups after 1 a decrease of blood pressures was observed in the HRT group (delta systolic/delta diastolic = -5.54 [-8.86 to -2.21]/-4.23 [-6.66 to -1.80] mm Hg), whereas an increase was found in the C-group (+3.33 [-0.69 to +7.35]/+1.67 [-1.75 to +5.09] mm Hg; P [HRT v control group] = .001/.005). We conclude that HRT may have blood pressure lowering properties in healthy, normotensive postmenopausal women.

Randomized comparison of oral and transdermal hormone replacement on carotid and uterine artery resistance to blood flow

Cacciatore B et al., 1998·Obstet Gynecol

To compare the long-term effects of oral and transdermal hormone replacement therapy (HRT) on carotid and uterine vascular impedance. Sixty-three postmenopausal women were randomized to 1 year's treatment with oral or transdermal sequential combined HRT. Carotid and uterine artery pulsatility indices (PIs) were assessed by color Doppler at baseline, and after 2, 6, and 12 months of treatment. Fifty-eight women completed the trial, 27 in the oral and 31 in the transdermal group. In a subgroup of 30 women, we also performed Doppler measurements in the estrogen-progestin combined phase. The study had 90% power to detect a difference between treatment groups of 0.05 in the carotid artery and of 0.25 in uterine artery PI at the 5% significance level. The carotid PI decreased significantly (P < .001) and similarly during both regimens. This drop was already clearly detectable during the second month, from 0.97 (0.95, 1.01) (mean and 95% confidence intervals [CII) to 0.94 (0.91, 0.97) in the oral and from 0.98 (0.94, 1.00) to 0.92 (0.89, 0.95) in the transdermal group, but it continued up to 12 months (0.85 [0.82, 0.88], 13% of baseline values in the oral group and 0.84 [0.81, 0.871, 14% in the transdermal group). In the uterine arteries, the drop in PI was steeper and greater and reached its maximum at 6 months (39% and 40%, respectively). Drops in carotid and uterine PI correlated positively with baseline PI values, but were not affected by patient age, time from menopause, previous HRT and smoking. Addition of norethisterone acetate did not counteract drops in carotid and uterine PI in either group. Oral and transdermal sequential HRT are similarly effective at 1 year in reducing impedance to flow in carotid and uterine circulation. This long-term vascular effect might explain how HRT protects women from cardiovascular disease.

Estradiol-17beta reduces blood pressure and restores the normal amplitude of the circadian blood pressure rhythm in postmenopausal hypertension

Mercuro G et al., 1998·Am J Hypertens

After menopause, both systolic (SBP) and diastolic (DBP) blood pressure (BP) become higher in women than in men of the same age, suggesting that estrogen deficiency may influence the age-related increase in BP. We studied 30 postmenopausal women (mean age, 55 +/- 5.7 years; time from menopause, 2-5 years) affected by mild hypertension with no target-organ complications by means of 24-h BP monitoring. None of the group were undergoing estrogen replacement therapy or taking antihypertensive drugs. According to a randomized, double-blind protocol, subjects received patches of transdermal estradiol-17beta (E2) or a matched placebo, with crossover after a 7-day washout period. In 12 patients the 24-h peak-to-trough variation in SBP and DBP amounted to less than 10% (nondippers). Administration of E2 significantly decreased 24-h SBP and DBP in the whole cohort (P < .05). Furthermore, E2 restored the expected reduction in BP during nighttime in the nondipper subgroup. It is well known that estrogen replacement therapy protects against the development of both cardiovascular diseases and stroke. Our data suggest that this activity could be attributed, at least in part, to the activity of E2 in preserving physiologic circadian fluctuation of BP.

Perimenopause: the complex endocrinology of the menopausal transition

Prior JC, 1998·Endocr Rev

I. Introduction II. Defining the Perimenopause III. Classic Studies of the Perimenopause A. Historical studies B. Early reports of women’s experiences in the perimenopause C. Early prospective menstrual cycle interval and basal temperature documentation IV. Prospective Epidemiological Studies of the Perimenopause A. Manitoba Project on Women and Their Health in the Middle Years B. Massachusetts Women’s Health Study C. Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) Study V. Systematic Studies of the Endocrinology of the Perimenopause A. Cross-sectional (single-cycle) hormonal studies in the perimenopause B. Prospective ovarian hormonal levels in the perimenopause VI. Histological Studies of Ovarian Changes Across the Lifespan VII. Physiological Studies of Changing Ovarian Hormones in Women in Their Forties and Fifties A. Folliculogenesis and ovarian hyperstimulation for in vitro fertilization (IVF) B. Inhibin physiology in women over forty VIII. Hypotheses to Explain Perimenopausal Endocrinology A...

Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group

Hulley S et al., 1998·JAMA

Observational studies have found lower rates of coronary heart disease (CHD) in postmenopausal women who take estrogen than in women who do not, but this potential benefit has not been confirmed in clinical trials. To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease. Randomized, blinded, placebo-controlled secondary prevention trial. Outpatient and community settings at 20 US clinical centers. A total of 2763 women with coronary disease, younger than 80 years, and postmenopausal with an intact uterus. Mean age was 66.7 years. Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n = 1380) or a placebo of identical appearance (n = 1383). Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were taking it at the end of 1 year, and 75% at the end of 3 years. The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischemic attack, and peripheral arterial disease. All-cause mortality was also considered. Overall, there were no significant differences between groups in the primary 172 women in the hormone group and 176 women in the placebo group had MI or CHD death (relative hazard [RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The lack of an overall effect occurred despite a net 11% lower low-density lipoprotein cholesterol level and 10% higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each P<.001). Within the overall null effect, there was a statistically significant time trend, with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5. More women in the hormone group than in the placebo group experienced venous thromboembolic events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84 vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were no significant differences in several other end points for which power was limited, including fracture, cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38). During an average follow-up of 4.1 years, treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease. The treatment did increase the rate of thromboembolic events and gallbladder disease. Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the favorable pattern of CHD events after several years of therapy, it could be appropriate for women already receiving this treatment to continue.

Estradiol and progesterone regulate the proliferation of human breast epithelial cells

Foidart JM et al., 1998·Fertil Steril

To study the effects of estradiol and progesterone on the proliferation of normal human breast epithelial cells in vivo. Double-blind randomized study. Departments of gynecology and of cell biology at a university hospital. PATIENT(S): Forty postmenopausal women with untreated menopause and documented plasma FSH levels of >30 mIU/mL and estradiol levels of <20 pg/mL. INTERVENTION(S): Daily topical application to both breasts of a gel containing a placebo, estradiol, progesterone, or a combination of estradiol and progesterone during the 14 days preceding esthetic breast surgery or excision of a benign lesion. MAIN OUTCOME MEASURE(S): Plasma and breast tissue concentrations of estradiol and progesterone. Epithelial cell cycles were evaluated in normal breast tissue by counting mitoses and performing quantitative proliferating cell nuclear antigen immunolabeling analyses. RESULT(S): Increasing the estradiol concentration enhanced the number of cycling epithelial cells, whereas increasing the progesterone concentration significantly limited the number of cycling epithelial cells. CONCLUSION(S): Exposure to progesterone for 14 days reduced the estradiol-induced proliferation of normal breast epithelial cells in vivo.

Long-term effects of percutaneous estradiol on bone loss and bone metabolism in postmenopausal hysterectomized women

Devogelaer JP et al., 1998·Maturitas

To determine whether percutaneous estradiol (pE2) (1.5 mg/day) is able to counteract the postmenopausal bone loss in postmenopausal hysterectomized women, in a double-blind study versus oral estriol (E3) (2 mg/day). The bone mineral density of the lumbar spine (LS) and of the proximal femur (PF) was measured every 3 months by dual energy X-ray absorptiometry for 2 years in 43 hysterectomized postmenopausal women (21 in the E2 group and 22 in the E3 control group), and in a subset of patients for a 3rd year. The statistical analyses were performed on Macintosh using Stat View II. A significant bone loss of 1.2 (0.4%)% and of 1.3 (0.3)% per year was observed in the control group, respectively at LS and at PF, versus a significant gain of 1.2 (0.5)% per year in the treated group at the LS. No significant change at PF occurred in the treated group. In the 20 patients followed up for a 3rd year on pE2, an increase of 1.2 (0.9) and 2.5 (1.4)% at LS in the 12 former active group patients and the eight formerly control patients, respectively was seen. The same trend was observed at the proximal femur. pE2 (1.5 mg E2) is able to counteract the postmenopausal bone loss in hysterectomized women, whereas E3 (2 mg/day administered orally) is unable to maintain bone mass.

Plasma concentrations of progesterone are higher in the uterine artery than in the radial artery after vaginal administration of micronized progesterone in an oil-based solution to postmenopausal women

Cicinelli E et al., 1998·Fertil Steril

To verify the occurrence of preferential distribution of vaginally administered progesterone to the uterus compared with extrapelvic regions in vivo and in humans. Prospective clinical study. University medical school. PATIENT(S): Twenty postmenopausal women undergoing transabdominal hysterectomy for benign pathologies. INTERVENTION(S): Forty-five minutes before surgery, the women received a single vaginal administration of an oil-based micronized progesterone (100 mg) solution currently available on the market for IM use. During the operation, parallel blood samples were drawn from the uterine and radial arteries. MAIN OUTCOME MEASURE(S): Plasma levels of progesterone were measured by RIA. RESULT(S): Mean (+/- SD) plasma levels of progesterone were significantly higher in the uterine artery than in the radial artery (9.75 +/- 3.21 vs. 5.12 +/- 2.06 ng/mL, respectively). CONCLUSION(S): Vaginal administration allows a preferential distribution of progesterone to the uterus, which confirms the existence of the so-called "first uterine pass effect."

Premenopausal ovariectomy-related bone loss: a randomized, double-blind, one-year trial of conjugated estrogen or medroxyprogesterone acetate

Prior JC et al., 1998·J Bone Miner Res

The purpose of this study was to contrast the effects of conventional estrogen treatment with medroxyprogesterone on cancellous and cortical bone change in the first year following premenopausal ovariectomy. This 1-year double-blind randomized therapy trial was stratified by osteoporosis family history and performed in an academic medical center and community hospitals. Premenopausal women 45 +/- 5 years old, postovariectomy for benign diseases were provided 600 mg/day of calcium and randomized to daily therapy with conjugated equine estrogen (CEE, 0.6 mg) or medroxyprogesterone (MPA, 10 mg). The primary outcome variable was spinal quantitative computed tomography (QCT) bone density change over 1 year with additional outcomes of dual-energy X-ray absorptiometry (DXA) of proximal femur (FN), whole body (WB), and spine segment (WBS) and N-telopeptide, bone-specific alkaline phosphatase, and other bone marker, hormonal, and weight changes. Results in the 33 women completing the study, whose initial bone densities were normal (QCT 133 mg/cm3, femoral neck 0.94 g/cm2, whole body DXA 1.13 g/cm2), showed annual QCT loss during CEE therapy of -11.5 mg/cm3 (p < 0.0007) and MPA bone loss of -19.7 mg/cm3 (p < 0.0001). Losses were marginally greater on MPA than CEE (p = 0.04). Extremely high postovariectomy (5 days) and pretreatment resorption markers (> 3 SD above premenopausal normal levels) were significantly related to bone loss. Across the year, resorption decreased during CEE but increased on MPA treatment. Significant DXA bone losses were prevented by CEE treatment (-1.4% FN, -.4% WB, and -1.5% WBS, all NS). However, DXA bone loss was not prevented by MPA treatment (-5% FN, -2.8% WB, and -6.1% WBS, all p < 0.03). Average weight gain was significant (+ 3.2 +/- 4.0 kg) and greater on CEE than MPA (+ 4.7 vs. + 2.0 kg, p = 0.049). In conclusion, CEE therapy did not prevent significant 8% cancellous spinal bone loss in the first year following premenopausal ovariectomy, despite supplementation with 600 mg/day of calcium, good control of vasomotor symptoms, and nearly 5 kg of gain in weight. Significant DXA bone loss, however, was prevented by CEE, but not by MPA therapy. These unexpected results were statistically related to high bone resorption following ovariectomy, which CEE suppressed but MPA did not. Bone formation markers increased during MPA therapy but were unchanged during CEE therapy.

Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group

Women's Health Initiative Study Group, 1998·Control Clin Trials

The Women's Health Initiative (WHI) is a large and complex clinical investigation of strategies for the prevention and control of some of the most common causes of morbidity and mortality among postmenopausal women, including cancer, cardiovascular disease, and osteoporotic fractures. The WHI was initiated in 1992, with a planned completion date of 2007. Postmenopausal women ranging in age from 50 to 79 are enrolled at one of 40 WHI clinical centers nationwide into either a clinical trial (CT) that will include about 64,500 women or an observational study (OS) that will include about 100,000 women. The CT is designed to allow randomized controlled evaluation of a low-fat eating pattern, hypothesized to prevent breast cancer and colorectal cancer and, secondarily, coronary heart disease; hormone replacement therapy, hypothesized to reduce the risk of coronary heart disease and other cardiovascular diseases and, secondarily, to reduce the risk of hip and other fractures, with increased breast cancer risk as a possible adverse outcome; and calcium and vitamin D supplementation, hypothesized to prevent hip fractures and, secondarily, other fractures and colorectal cancer. Overall benefit-versus-risk assessment is a central focus in each of the three CT components. Women are screened for participation in one or both of the components--dietary modification (DM) or hormone replacement therapy (HRT)--of the CT, which will randomize 48,000 and 27,500 women, respectively. Women who prove to be ineligible for, or who are unwilling to enroll in, these CT components are invited to enroll in the OS. At their 1-year anniversary of randomization, CT women are invited to be further randomized into the calcium and vitamin D (CaD) trial component, which is projected to include 45,000 women. The average follow-up for women in either CT or OS is approximately 9 years. Concerted efforts are made to enroll women of racial and ethnic minority groups, with a target of 20% of overall enrollment in both the CT and OS. This article gives a brief description of the rationale for the interventions being studied in each of the CT components and for the inclusion of the OS component. Some detail is provided on specific study design choices, including eligibility criteria, recruitment strategy, and sample size, with attention to the partial factorial design of the CT. Some aspects of the CT monitoring approach are also outlined. The scientific and logistic complexity of the WHI implies particular leadership and management challenges. The WHI organization and committee structure employed to respond to these challenges is also briefly described.

Pharmacokinetics and pharmacodynamics of conjugated equine estrogens: chemistry and metabolism

Bhavnani BR, 1998·Proc Soc Exp Biol Med

Conjugated equine estrogens (Premarin), are used extensively for estrogen replacement therapy and prevention of osteoporosis and cardiovascular disease in postmenopausal women. Premarin contains at least 10 estrogens that are the sulfate esters of estrone, 17beta-estradiol, 17alpha-estradiol, and the equilin, 17beta-dihydroequilin, 17alpha-dihydroequilin, equilenin, 17beta-dihydroequilenin, 17alpha-dihydroequilenin, and delta-8-estrone. Bioassays and estrogen receptor binding studies indicate that all 10 estrogens are biologically active. Moreover, individual components, such as equilin sulfate, delta-8-estrone sulfate, 17beta-dihydroequilin sulfate and estrone sulfate, have potent estrogenic effects. Estrogen sulfates can be absorbed directly from the gastrointestinal tract; however, hydrolysis of the sulfates also occurs in the gastrointestinal tract, and the unconjugated estrogens formed are readily absorbed. After absorption, these estrogens are sulfated rapidly and circulate in this form. The pharmacokinetics of these estrogens indicate that the unconjugated estrogens are cleared from the circulation at a faster rate than their sulfate ester forms. In postmenopausal women, the 17-keto derivatives of these estrogens are metabolized to the more potent 17beta-reduced products. The extent of this activation is nearly 10 times higher with some ring B unsaturated estrogens. The 17beta-reduced metabolites are cleared from the blood at a slower rate than their corresponding 17-keto derivatives. In the human endometrium, equilin is metabolized to 2-hydroxy and 4-hydroxy equilin, with 2-hydroxylation being predominant. In contrast, 2-hydroxy and 4-hydroxy estradiol are formed in equal amounts. Similarly, 16alpha-hydroxylation occurs with both types of estrogens; however, with the ring B saturated estrogens, the 17-keto steroid 16alpha-hydroxy estrone was the major urinary metabolite, whereas with the ring B unsaturated estrogens, the 17beta-reduced steroids, such as 16alpha-hydroxy-17beta-dihydroequilin and 16alpha-hydroxy-17beta-dihydroequilenin, were the major metabolites. This difference in metabolism may be important as it has been suggested that 16alpha-hydroxy estrone (alpha-ketol structure) can form covalent adducts with macromolecules and that it may be oncogenic. These types of interactions will not occur with the 16alpha-hydroxylated-17beta-reduced metabolites of ring B unsaturated estrogens. Since all of the estrogens present in Premarin have estrogenic activity, the pharmacological effects of Premarin are a result of the sum of these individual activities. Therefore, preparations lacking some of these important components may not offer the same degree of beneficial effects as Premarin.

Metabolic changes induced by peroral oestrogen and transdermal oestradiol gel therapy

Karjalainen A et al., 1997·Br J Obstet Gynaecol

To investigate changes in plasma lipid and lipoprotein levels induced by peroral oestrogen replacement and transdermal oestradiol gel therapy. The effects of peroral oestradiol valerate tablets (2 mg) and placebo gel were compared with 1g transdermal oestradiol gel (1mg oestradiol) and placebo tablets in a randomised, double-blind, double-dummy study for 6 months. Department of Internal Medicine, University of Oulu and Oulu Deaconess Institute, Oulu, Finland. Seventy-nine hysterectomised, postmenopausal women, 39 women in the peroral oestrogen group and 40 in the gel group. Cholesterol and triglycerides in total plasma and in various lipoprotein fractions, and sex hormones. In the peroral oestrogen group total and LDL cholesterol were decreased and HDL cholesterol and triglycerides were increased. In the oestradiol gel group plasma total, LDL and VLDL cholesterol and the ratio of LDL/HDL cholesterol were significantly decreased, but no change in HDL cholesterol and triglycerides was observed. Overall the decrease in LDL levels was correlated with the increase in oestrogen levels. Both peroral and transdermal replacement therapy had beneficial effects on plasma lipids by lowering total and LDL cholesterol and LDL/HDL cholesterol ratio. These changes seem to be associated with changes in oestrogen levels.

Successful pregnancy in a 63-year-old woman

Paulson RJ et al., 1997·Fertil Steril

To report the occurrence of an unusual case of successful pregnancy achieved by oocyte donation in a woman > 60 years of age. Case report. University-based assisted reproductive technology program. PATIENT(S): Sixty-three-year old nulligravida, married for 16 years to her 60-year-old husband. Throughout her infertility treatment, the patient was believed to be 10 years younger, as she claimed. She revealed her true age of 63 only upon being referred for obstetric care at 13 weeks of gestational age. INTERVENTION(S): Oocyte donation, IVF, embryo cryopreservation, and ET. MAIN OUTCOME MEASURE(S): Attainment of pregnancy and subsequent delivery. RESULT(S): The patient underwent two cycles of oocyte donation. During the second attempt, the fresh transfer resulted in a clinical miscarriage at approximately 8 weeks of gestational age. A subsequent transfer of three frozen-thawed embryos resulted in an ongoing singleton gestation. The pregnancy was complicated by gestational diabetes (controlled by diet) and mild pregnancy-induced hypertension. Delivery by cesarean section at 38 weeks of gestational age resulted in the birth of a healthy female infant weighing 2,844 g with Apgar scores of 9 and 9. CONCLUSION(S): This case demonstrates that the uterus is capable of supporting nidation and subsequent gestation for many years beyond natural menopause. It shows that other aspects of human physiology are capable of adapting to the stresses and changes of pregnancy sufficiently well to achieve a normal birth at the age of 63 years. This case also exemplifies the difficulty in attempting to regulate the age of recipients in oocyte donation. As in other aspects of human life, when age limits are applied to the provision of certain services, human beings whose age falls outside of these limits become motivated to deceive the providers of those services to avail themselves of the services.

Physiologic estradiol replacement therapy and cardiac structure and function in normal postmenopausal women: a randomized, double-blind, placebo-controlled, crossover trial

Snabes MC et al., 1997·Obstet Gynecol

To assess the effect of estradiol (E2) replacement therapy on cardiac structure and function in healthy postmenopausal women. We conducted a randomized, double-blind, placebo-controlled, crossover study of 31 healthy postmenopausal female volunteer study subjects (55-65 years) using 12 weeks of micronized E2 replacement therapy (2 mg/day). Echocardiography and Doppler techniques were used to assess the cardiac effects of E2 at rest and during graded bicycle ergometry. Crossover analysis demonstrated no carryover effects of estrogen treatment (which increased serum E2 15-fold to 37.6 pmol/L) on the cardiac characteristics measured. Estradiol treatment did not affect measurements of systolic function, diastolic function, left ventricular mass, or pulmonary artery pressure at rest or during bicycle ergometry. Left ventricular end-diastolic volume at rest was slightly higher with E2 treatment (P = .03). However, this change was not reflected by changes in stroke volume, ejection fraction, or cardiac output. Estrogen replacement therapy, which results in physiologic serum concentrations, does not affect cardiac structure or function in normal postmenopausal women after 12 weeks of treatment.

Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm

Miyagawa K et al., 1997·Nat Med

Cardiovascular disease, the major cause of death in post-menopausal women, can be reduced by replacement of ovarian steroid hormones. To compare medroxyprogesterone with progesterone as the progestin in hormone replacement therapy from the standpoint of coronary artery vasospasm, we treated ovariectomized rhesus monkeys with physiological levels of estradiol-17 beta in combination with medroxyprogesterone or progesterone for four weeks. Coronary vasospasm in response to pathophysiological stimulation without injury showed that progesterone plus estradiol protected but medroxyprogesterone plus estradiol failed to protect, allowing vasospasm. We conclude that medroxyprogesterone in contrast to progesterone increases the risk of coronary vasospasm.

Prevention and management of osteoporosis: consensus statements from the Scientific Advisory Board of the Osteoporosis Society of Canada. 5. Physical activity as therapy for osteoporosis

J C Prior et al., 1996·CMAJ

To examine exercise as a therapy for people with osteoporosis. Immobilization, standing low-load and high-load physical activities. Risk of injury, quality of life, risk of falls and fractures, strength and posture and pain management. Relevant epidemiologic studies, clinical trials and reviews were examined, including the large-scale FICSIT trial in the United States, a prospective 4-year study of women enrolled in an exercise program in Toronto and the large-scale Study of Osteoporotic Fractures. Minimizing risk of injury and increasing quality of life were given a high value. BENEFITS, HARMS, Moderate physical activity in people with osteoporosis can reduce the risk of falls and fractures, decrease pain and improve fitness and overall quality of life. It may also stimulate bone gain and decrease bone loss. Its positive effects are an adjunct to other interventions, such as hormonal therapy. It may give patients the confidence to resume regular activity and can provide social interaction and support. During exercise programs, proper nutrition is necessary to prevent excessive weight loss and impaired immune function resulting from inadequate protein, vitamin and mineral intake. Immobilization should be avoided if possible in anyone with osteoporosis or at increased risk for osteoporosis. Regular, moderate physical activity is recommended for those with osteoporosis. Elderly people should be assessed for risk of falling to identify those in greatest need of an exercise program. Community group exercise programs are beneficial. Younger people with osteoporosis also need exercise that will preserve or improve bone mass, muscular strength, endurance and cardiovascular fitness. Weight loss as a result of physical activity should be avoided and adequate intake of protein, vitamins and minerals assured. Because the benefits of physical activity are independent of the effect of other therapies, physical activity is an essential adjunct to appropriate nutrition and other therapies. These recommendations were developed by the Scientific Advisory Board of the Osteoporosis Society of Canada at its 1995 Consensus Conference. They are in agreement with the position taken on osteoporosis and exercise by the United States Center for Disease Control and Prevention and the American College of Sports Medicine. Sponsors of the 1995 conference included the Dairy Farmers of Canada, Eli Lilly Canada, Inc., Hoffmann-La Roche Canada Ltd., Merck Frosst Canada Inc. and Procter & Gamble Pharmaceuticals Canada Inc.

Treatment of skin aging with topical estrogens

Schmidt JB et al., 1996·Int J Dermatol

The coincidence of climacteric symptoms and the beginning of skin aging suggests that estrogen deficiency may be a common and important factor in the perimenopausal woman. Often hormones have been considered important in endogenous aging of the skin, but their role has not been clearly defined. Therefore, we investigated, whether topical treatment of the skin with estrogen could reverse some of the changes in the aging skin. The effects of 0.01% estradiol and 0.3% estriol compounds were compared in 59 preclimacteric women with skim aging symptoms. Monthly determinations of estrodiol (E2), follicle-stimulating hormone (FSH), and prolactin (PRL) were done and the monthly clinical monitoring was supplemented by measurements of skin hydration by corneometry and profilometry. In 10 patients, skin biopsies were taken for immunohistochemical determination of collagen types I and III. After treatment for 6 months, elasticity and firmness of the skin had markedly improved and the wrinkle depth and pore sizes had decreased by 61 to 100% in both groups. Furthermore, skin moisture had increased and the measurement of wrinkles using skin profilometry, revealed significant, or even highly significant, decreases of wrinkle depth in the estradiol and the estriol groups, respectively. On immunohistochemistry, significant increases of Type III collagen labeling were combined with increased numbers of collagen fibers at the end of the treatment period. As to hormone levels, only those of PRL had increased significantly and no systemic hormonal side effects were noted.

Menstrual and reproductive factors and hip fractures in post menopausal women

Parazzini F et al., 1996·Maturitas

We analyzed the relationship between menstrual and reproductive history and risk of hip fractures in post-menopausal women using data from an Italian case-control study. Cases were 206 post-menopausal women admitted for fractures of the hip proximal femur to a network of teaching and general hospitals in Milan, Italy. The comparison group consisted of 590 post-menopausal women admitted to the same network of hospitals for acute, non-neoplastic, non-hormone-related conditions, other than traumatic or orthopedic disorders. Odds ratios (OR) of hip fracture were derived from unconditional multiple logistic regression. No relation emerged between risk of hip fractures and age at menarche, lifelong menstrual cycle pattern and age at menopause. In comparison with women with age at menopause > or = 53 years, the multivariate OR of hip fractures were 1.2, 1.1, 1.2 and 0.5 in women with menopause at 50-52, 45-49, 40-44 and before 40 years (X2(1) trend 0.21). In comparison with nulliparae, the estimated age-adjusted OR was 0.6 (95% confidence interval, CI, 0.4-0.9) for parous women, but the multivariate estimate was not significant (OR 0.8, 95% CI 0.6-1.3) and the multivariate trend in risk with number of births was not significant either. No relation emerged between hip fractures and age at first and last birth, and history of abortions. This study found no relevant influence of menstrual and reproductive factors on the risk of hip fractures in post-menopausal women. However, this is not in contrast with the observation of a short-term effect of menopause and more in general. female hormone levels on osteoporosis and hence on hip fractures.

Effect of estriol on bone loss in postmenopausal Japanese women: a multicenter prospective open study

Minaguchi H et al., 1996·J Obstet Gynaecol Res

To assess the effects of oral estriol on the bone mineral density (BMD) and bone metabolism in postmenopausal women. Seventy-five natural postmenopausal women with a BMD of more than 10% below the peak bone density were treated for 50 weeks with 2 mg/day estriol (E3) cyclically and 0.8 g/day of calcium lactate continuously. BMDs at L2-L4 were measured by dual energy X-ray absorptiometry (DXA). The BMD increased 1.79% (p < 0.01 vs. pretreatment) after 50 weeks, accompanied with decrease of biochemical markers of bone turnover. With regard to climacteric symptoms, Kupperman's menopausal index improved (p < 0.01 vs. pretreatment) after 5 weeks of treatment. As to the incidence of adverse events genital bleeding was observed in only 8.0% of the subjects. Endometrial histology and cytology showed neither abnormalities nor hyperplasia during and after the treatment. Estriol prevented postmenopausal bone loss and improved climacteric symptoms effectively with low incidence of genital bleeding.

Risk factors, falls, and fracture of the distal forearm in Manchester, UK

O'Neill TW et al., 1996·J Epidemiol Community Health

To determine the risk factors associated with fracture of the distal forearm, and to evaluate the influence of falls on these risks. This was a case-control study. Manchester, UK. The cases were 62 white women aged 45-82 years who had sustained a fracture of the distal forearm and had attended local hospitals. Two control groups were studied - 50 women who had fallen onto the hand but had not sustained a fracture (recruited from the same source as those with fracture) and 116 women randomly selected from primary care age and sex registers in the catchment area of the hospitals. Both cases and controls were sent a letter inviting them to take part in the study. Data were collected by questionnaire completed by an interviewer. Compared with the population control group, those with fracture were more likely to walk at a brisk pace (odds ratio (OR) = 3.5; 95% confidence interval (CI) 1.3, 9.6) though they had undertaken less physical activity at home or work on a daily basis throughout life (OR = 0.4; 95% CI 0.2, 0.9). The risk associated with brisk walking was less marked when the cases were compared with fall controls. Other lifestyle factors including calcium intake, smoking, and alcohol consumption were not associated with fracture. Analysis of gynaecological and hormonal factors suggested that compared with population controls, those with fracture of the distal forearm had had fewer fertile years (OR = 0.4; 95% CI 0.1, 0.9) and were less likely to have used oral contraceptives (OR = 0.3; 95% CI 0.1, 0.9). The data highlight the need for caution when advising middle aged and elderly subjects about exercise. Such advice should be combined with practical information about the prevention of falls. Hormonal factors seem to be additional determinants of fracture. Other lifestyle interventions seem unlikely to play an important part in preventing distal forearm fracture.

Effect of oral estradiol on Lp(a) and other lipoproteins in postmenopausal women. A randomized, double-blind, placebo-controlled, crossover study

Haines C et al., 1996·Arch Intern Med

Lp(a) lipoprotein level is an independent risk factor for premature coronary artery disease and cerebrovascular accident. Concentrations of this lipoprotein tend to increase after menopause. To determine whether oral estrogen was effective in lowering concentrations of Lp(a) lipoprotein in postmenopausal women. A double-blind, placebo-controlled, cross-over study was conducted during a 12-month period in 100 postmenopausal women who had undergone hysterectomy. They were group 1 received oral estradiol, 2 mg/d, for the first 6 months and placebo for the second, and group 2 received these treatments in the reverse order. After completion of the crossover study, the effect of prolonged administration of oral estradiol was examined by placing all patients on active treatment and repeating the lipoprotein measurements approximately 12 months later. No significant differences were noted between the two groups at the commencement of the study (median concentration of Lp[a] lipoprotein, 10.78 mg/dL [range, 2.2 to 108.5 mg/dL] in group 1 and 12.74 mg/dL [range, 0.8 to 98.1 mg/dL] in group 2). Crossover analysis showed a 9.62% reduction in values of Lp(a) lipoprotein with estradiol treatment compared with placebo during 12 months of treatment (P < .001). With prolonged treatment, the median concentration of Lp(a) lipoprotein for those in group 1 decreased from 8.12 mg/dL (range, 1.05 to 57.4 mg/dL) to 5.77 mg/dL (range, 0.84 to 75.39 mg/dL) (P < .001). In group 2, the median concentration decreased from 8.19 mg/dL (range, 2.52 to 99.82 mg/dL) to 7.07 mg/dL (range, 0.70 to 48.79 mg/dL), but this difference was not significant (P = .63). The results of this study confirm the beneficial effect of oral estradiol on the basic lipoprotein pattern and demonstrate that this treatment is effective in reducing concentrations of Lp(a) lipoprotein in postmenopausal women.

Low and conventional dose transdermal oestradiol are equally effective at preventing bone loss in spine and femur at all post-menopausal ages

Evans SF et al., 1996·Clin Endocrinol (Oxf)

We wished to appraise the effectiveness of hormone replacement therapy (HRT) in early (< 67 years) and late (> 67 years) post-menopausal women referred to a metabolic outpatient clinic for assessment of their bone status. Because older women often experience side-effects with conventional HRT, a low dose preparation (Estraderm 25) was also compared with conventional HRT (Estraderm 50). Since all patients were symptomatic, the investigation was open and not placebo controlled. Patients were offered HRT and told about the two dosages. If they wished to use HRT, allocation of dosage was made randomly unless there were reasons to use a specific dose. One hundred and ninety-six women were studied over 1 or 2 years with 80 reaching 3 years of treatment. Patients were divided into those under 67 years and those over 67 years at the start of treatment. Each group was further divided into those taking Estraderm 25 and those taking Estraderm 50 with norethisterone if appropriate. Bone mineral density (BMD) was measured (DXA, Hologic) at the lumbar spine and femoral neck at 0 year (196 patients), at 1 year (169 patients), at 2 years (139 patients) and at 3 years (80 patients). Patients losing bone were expressed as those whose 3 year BMD was lower than initial or as those whose BMD at 3 years had fallen by more than twice the coefficient of variation for that site (non-responders). In lumbar spine, BMD increased maximally in the first year in all groups and the gain was maintained after 3 years. The change was similar whether patients were divided by age or dosage. For those on Estraderm 25, mean change after 3 years was 8.1 +/- 6.8% and on Estraderm 50, 9.0 +/- 8.3% (combined 8.7 +/- 7.8%). Only 3.9% of patients were non-responders at the lumbar spine after 3 years. At femoral neck, changes were significant at 3 years only in the Estraderm 25 > 67 years and Estraderm 50 < 67 years groups and averaged 2.3 +/- 5.4% for all patients. At the femoral neck, 10.4% of patients were non-responders after 3 years. Percentage change of BMD over 3 years at lumbar spine correlated with that at the femoral neck (r = 0.56). Percentage change of BMD at lumbar spine over 3 years correlated with menopausal age (r = 0.295). No relation was found between dosage of Estraderm/kg body weight and response of BMD at either site. Transdermal oestrogen is effective at preventing bone loss in the spine at all post-menopausal ages and is capable of doing this in low dosage. Prevention of bone loss at the femoral neck is less certain and the average change in BMD over 3 years was significantly lower (P < 0.001) than in the lumbar spine. Use of Estraderm 50 is not associated with a greater response of bone mass and there was no evidence of an increasing BMD response as oestradiol dosage/kg body weight increased.

Epithelial Ovarian Cancer: Epidemiology, Screening, and Prevention in Menopausal Medicine (1996)

Bass KM, 1996

Estrogen acutely increases peripheral blood flow in postmenopausal women

Volterrani M et al., 1995·Am J Med

To test the acute effect of estrogen on peripheral blood flow and vascular resistance in postmenopausal women. Eleven normotensive, post-menopausal female volunteers (mean age 53 +/- 6 years) were studied. Six women were in natural menopause and 5 had had a hysterectomy (mean age of the menopause 49 +/- 3 years). We used a double-blind, randomized protocol to assess the acute response to sublingual estradiol-17 beta (1 mg) on the forearm resistance vessels, compared with sublingual placebo. Blood flow was measured by strain-gauge plethysmography, and mean peripheral vascular resistance was then calculated. Mean blood pressure was also measured. The mean blood flow induced by estradiol-17 beta after 40 minutes was significantly greater than that induced by placebo (3.9 +/- 0.5 mL/100 mL per minute versus 2.4 +/- 0.4 mL/100 mL per minute, respectively, P < 0.05). The forearm resistance was significantly reduced at 40 minutes after estradiol-17 beta compared with placebo (25.7 +/- 4.4 resistance units (RU) to 44.4 +/- 6.4 RU, respectively, P < 0.05). Mean blood pressure 40 minutes after the administration of estradiol-17 beta was no different when compared with placebo (91 +/- 1.5 mm Hg versus 90 +/- 2.5 mm Hg, respectively, P = NS). These results indicate that the acute administration of estradiol-17 beta affects blood flow in the peripheral vasculature in human subjects. The mechanism of this effect has not been determined, but it may explain some of the beneficial effects of estrogen on the vascular system and have future therapeutic potential in postmenopausal women.

Medroxyprogesterone increases basal temperature: a placebo-controlled crossover trial in postmenopausal women

Prior JC et al., 1995·Fertil Steril

To assess whether temperature is increased by medroxyprogesterone (MPA) and thus whether basal temperature records could be used to determine ovulation during cyclic MPA therapy. A 2-month double-blind placebo-controlled crossover trial in which oral basal temperature was measured daily. Normal human volunteers in an academic medical environment. Eleven postmenopausal women not taking gonadal hormones. Medroxyprogesterone acetate (10 mg/d) or placebo, calendar days 16 to 25, with crossover. Comparison of mean temperature days 17 to 26 during MPA versus placebo; comparison of differences between temperatures days 7 to 16 and 17 to 26 in MPA versus placebo months; and analysis for a significant monthly thermal shift. The mean temperatures during MPA treatment averaged 0.27 degrees C higher than during the placebo phase and showed a significant change from pretreatment to "treatment" phases during MPA but not during placebo cycles. Eight of the MPA and one of the placebo cycles showed a shift from lower to higher temperatures days 16 to 25. Medroxyprogesterone acetate has a physiological progesterone-like thermal effect. Therefore basal temperature data cannot reliably indicate ovulation during cyclic MPA administration.

Effects of Estrogen or Estrogen/Progestin Regimens on Heart Disease Risk Factors in Postmenopausal Women

Miller VT et al., 1995·JAMA

To assess pairwise differences between placebo, unopposed estrogen, and each of three estrogen/progestin regimens on selected heart disease risk factors in healthy postmenopausal women. A 3-year, multicenter, randomized, double-blind, placebo-controlled trial. A total of 875 healthy postmenopausal women aged 45 to 64 years who had no known contraindication to hormone therapy. Participants were randomly assigned in equal numbers (1) placebo; (2) conjugated equine estrogen (CEE), 0.625 mg/d; (3) CEE, 0.625 mg/d plus cyclic medroxyprogesterone acetate (MPA), 10 mg/d for 12 d/mo; (4) CEE, 0.625 mg/d plus consecutive MPA, 2.5 mg/d; or (5) CEE, 0.625 mg/d plus cyclic micronized progesterone (MP), 200 mg/d for 12 d/mo. Four endpoints were chosen to represent four biological systems related to the (1) high-density lipoprotein cholesterol (HDL-C), (2) systolic blood pressure, (3) serum insulin, and (4) fibrinogen. Analyses presented are by intention to treat. P values for primary endpoints are adjusted for multiple comparisons; 95% confidence intervals around estimated effects were calculated without this adjustment. Mean changes in HDL-C segregated treatment regimens into three (1) placebo (decrease of 0.03 mmol/L [1.2 mg/dL]); (2) MPA regimens (increases of 0.03 to 0.04 mmol/L [1.2 to 1.6 mg/dL]); and (3) CEE with cyclic MP (increase of 0.11 mmol/L [4.1 mg/dL]) and CEE alone (increase of 0.14 mmol/L [5.6 mg/dL]). Active treatments decreased mean low-density lipoprotein cholesterol (0.37 to 0.46 mmol/L [14.5 to 17.7 mg/dL]) and increased mean triglyceride (0.13 to 0.15 mmol/L [11.4 to 13.7 mg/dL]) compared with placebo. Placebo was associated with a significantly greater increase in mean fibrinogen than any active treatment (0.10 g/L compared with -0.02 to 0.06 g/L); differences among active treatments were not significant. Systolic blood pressure increased and postchallenge insulin levels decreased during the trial, but neither varied significantly by treatment assignment. Compared with other active treatments, unopposed estrogen was associated with a significantly increased risk of adenomatous or atypical hyperplasia (34% vs 1%) and of hysterectomy (6% vs 1%). No other adverse effect differed by treatment assignment or hysterectomy status. Estrogen alone or in combination with a progestin improves lipoproteins and lowers fibrinogen levels without detectable effects on postchallenge insulin or blood pressure. Unopposed estrogen is the optimal regimen for elevation of HDL-C, but the high rate of endometrial hyperplasia restricts use to women without a uterus. In women with a uterus, CEE with cyclic MP has the most favorable effect on HDL-C and no excess risk of endometrial hyperplasia.

Vascular responses to 17 beta-oestradiol in postmenopausal women

Riedel M et al., 1995·Eur J Clin Invest

The vascular responses to 17 beta-oestradiol were examined in 23 postmenopausal women (59 +/- 7 years [mean +/- SD]) using a placebo-controlled double-blind crossover design. All women received 1 mg 17 beta-oestradiol or placebo (P) sublingually on consecutive days in random order. Axial diameters and blood flow rates of the left common femoral arteries were determined before and 60-80 min after application of verum or placebo as well as 10-30 min after 10 mg isosorbide dinitrate (ISDN) with a quantitative duplex ultrasound technique. Oestradiol induced a vasodilation of femoral arteries (+6.4 +/- 4.1% of basal, P < 0.001 vs. basal and P), the vessel diameter was unchanged with placebo (+0.7 +/- 2.1%). The blood flow rate increased significantly after oestradiol application (+30 +/- 28%, P < 0.05 vs. basal and P), but not after placebo (+11 +/- 21%). Mean blood pressure and heart rate remained constant with both drugs. Despite its vasodilatory effect, ISDN significantly reduced the arterial blood flow after pretreatment with oestradiol and placebo, probably through cardiac preload reduction. In conclusion, 17 beta-oestradiol alters the vascular tone of systemic arteries resulting in a vasodilation and increase of blood flow. We suggest that these direct vascular actions may contribute to the preventive properties of oestrogens on cardiovascular diseases in postmenopausal women.

Effects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries in cynomolgus monkeys

Williams JK et al., 1994·J Am Coll Cardiol

We attempted to determine whether continuous and cyclic medroxyprogesterone acetate modulates the effects of estrogen on dilation of atherosclerotic coronary arteries in surgically postmenopausal female monkeys. Estrogen replacement in postmenopausal women preserves normal dilator responses of atherosclerotic coronary arteries. The effects of progestins on coronary artery reactivity have not been determined. Repeated quantitative coronary angiography was used to study the effects after 1 month of 1) no hormone replacement (control) or oral administration of 2) continuous conjugated equine estrogens, 3) cyclic high dose medroxyprogesterone acetate (MPA) given on days 16 to 26 of the month, 4) conjugated equine estrogens plus continuous low dose MPA, or 5) conjugated equine estrogens plus cyclic high dose MPA on endothelium-mediated dilation of atherosclerotic coronary arteries in 12 cynomolgus monkeys. Change in diameter of the left circumflex coronary artery was measured in response to intracoronary infusions of acetylcholine (10(-6) mol/liter per min) and nitroglycerin (15 micrograms/min). Coronary arteries constricted during no hormone treatment (-8 +/- 3% [mean +/- SEM]), dilated during conjugated equine estrogen treatment (+3 +/- 1%, p < 0.05 vs. control) and constricted during cyclic MPA treatment (-3 +/- 2%). Addition of cyclic or continuous MPA to the conjugated equine estrogen regimen inhibited acetylcholine responses by 50% (p < 0.05 vs. conjugated equine estrogens). There was no effect of treatment on vascular response to nitroglycerin (p > 0.05). Treatment with conjugated equine estrogens, but not MPA, augmented endothelium-mediated dilation of atherosclerotic coronary arteries. Addition of cyclic or continuous MPA to the conjugated equine estrogen regimen diminished endothelium-mediated dilation.

Calcium resorption from bone in a human studied by 41CA tracing

RR Johnson et al., 1994·Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms

The menstrual cycle: effects on bone in menopausal women

Barr SI et al., 1994·Adv Nutr Res

No adverse effects of medroxyprogesterone treatment without estrogen in postmenopausal women: double-blind, placebo-controlled, crossover trial

Prior JC et al., 1994·Obstet Gynecol

To determine whether cyclic medroxyprogesterone treatment given without estrogen causes adverse symptoms in postmenopausal women. This was a placebo-controlled, double-blind, crossover trial of 10 days/month of medroxyprogesterone and placebo treatments given during 2 consecutive months in random order. Participants recorded their physiologic and emotional experiences on a 0-4 scale using a daily diary form. Eleven postmenopausal women aged 43-63 completed the study. The subjects were not taking hormones. Height, weight, and serum estradiol concentration were measured once. In each woman, the sum of scores for the 10 days of medroxyprogesterone was compared to the sum of scores for the 10 days of placebo using nonparametric tests. No significant differences in scores were found between the 10 days on medroxyprogesterone and the 10 days on placebo. The median and range for the composite scores for premenstrual-like symptoms were 26 (20-67) during medroxyprogesterone and 25 (19-40) during placebo (P = .39). Medroxyprogesterone given alone does not cause adverse symptoms in postmenopausal women. Therefore, medroxyprogesterone therapy, by itself, cannot explain the side effects reported by postmenopausal women taking combined hormones.

Metabolic clearance rate of equilin sulfate and its conversion to plasma equilin, conjugated and unconjugated equilenin, 17 beta-dihydroequilin, and 17 beta-dihydroequilenin in normal postmenopausal women and men under steady state conditions

Bhavnani BR et al., 1993·J Clin Endocrinol Metab

The constant infusion of [3H]equilin sulfate ([3H]EqS) was used to estimate the MCR of equilin sulfate (EqS) and to measure the conversion of this estrogen to equilin (Eq), equilenin (Eqn), equilenin sulfate (EqnS), 17 beta-dihydroequilin (17 beta-Eq), 17 beta-dihydroequilin sulfate (17 beta-EqS), 17 beta-dihydroequilenin (17 beta-Eqn), and 17 beta-dihydroequilenin sulfate (17 beta-EqnS) in normal postmenopausal women and men. Infusion of [3H]EqS was started in five postmenopausal women and two men 30 min after a priming dose and continued at a constant rate of 12-15 microCi/h for 3 h. Blood samples were taken 15 min before the end of infusion, at the end of the infusion, and 15 min after the end of infusion. Unconjugated and sulfate-conjugated Eq, Eqn, 17 beta-Eq, and 17 beta-Eqn were isolated from plasma. The mean MCR of EqS was calculated to be 280 +/- 24 L/day or 170 +/- 18 L/day.m2. The mean conversion ratios for precursor EqS to product 17 beta-EqS, EqnS, 17 beta-EqnS, 17 beta-Eq, Eq, Eqn, and 17 beta-Eqn were 0.300, 0.190, 0.100, 0.020, 0.016, 0.008, and 0.004 respectively. In both the sulfate-conjugated and unconjugated forms, 17 beta-Eq was the most abundant metabolite formed. 17 beta-Eq estrogen is a potent uterotropic agent and has a much higher affinity for estrogen receptors than Eq. Its formation may be of importance in the overall biological activity of EqS present in conjugated equine estrogen preparations.

A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections

Raz R et al., 1993·N Engl J Med

Recurrent urinary tract infections are a problem for many postmenopausal women. Estrogen replacement restores atrophic mucosa, lowers vaginal pH, and may prevent urinary tract infections. We enrolled 93 postmenopausal women with a history of recurrent urinary tract infections in a randomized, double-blind, placebo-controlled trial of a topically applied intravaginal estriol cream. Midstream urine cultures were obtained at enrollment, monthly for eight months, and whenever urinary symptoms occurred. Vaginal cultures and pH measurements were obtained at entry and after one and eight months. The women were assigned to receive either estriol (n = 50) or placebo (n = 43), both administered intravaginally; 36 and 24, respectively, completed the eight months of follow-up. The incidence of urinary tract infection in the group given estriol was significantly reduced as compared with that in the group given placebo (0.5 vs. 5.9 episodes per patient-year, P < 0.001). Survival analysis showed that more of the women in the estriol group than in the placebo group remained free of urinary tract infection (P < 0.001). Lactobacilli were absent in all vaginal cultures before treatment and reappeared after one month in 22 of 36 estriol-treated women (61 percent) but in none of the 24 placebo recipients (P < 0.001). With estriol the mean vaginal pH declined from 5.5 to 3.8 (P < 0.001), whereas there was no significant change with placebo. The rate of vaginal colonization with Enterobacteriaceae fell from 67 percent to 31 percent in estriol recipients but was virtually unchanged (from 67 to 63 percent) in the placebo recipients (P < 0.005). Side effects were minor, but caused 10 estriol recipients (28 percent) and 4 placebo recipients (17 percent) to discontinue treatment. The intravaginal administration of estriol prevents recurrent urinary tract infection in postmenopausal women, probably by modifying the vaginal flora.

Osteoporosis risk factors, gynaecological history and fractures in perimenopausal women--the results of the baseline postal enquiry of the Kuopio Osteoporosis Risk Factor and Prevention Study

Tuppurainen M et al., 1993·Maturitas

The Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) Study examines the risk factors of osteoporosis, the relationship of risk factors to bone density and fractures, as well as the possibility to prevent bone loss by administering certain hormones. The baseline postal enquiry in 1989 was sent to all the 14,220 women aged 47-56 years residing in the Kuopio Province, Finland. The questionnaire included questions about their gynaecological history, physical exercise and smoking habits, calcium intake, body weight and height, history of bone fractures, health disorders, their current and previous use of drugs, as well as their willingness to participate in bone densitometry and in a clinical hormone trial. The response rate was 92.8%. In all, 56% reported some previous use of female hormones. Strong contraindications for oestrogen replacement therapy were found in 9.3% of the women. Almost half of the respondents reported lack of regular physical exercise, 11.9% were smokers, and 17.0% reported a calcium intake from milk products of less than 500 mg daily. The incidence of fractures increased steadily with age. The incidence of premenopausal fractures within the last 10 years was 7.65 per 1000 person/years and that of postmenopausal fractures was 17.40 per 1000 person/years (P = 0.000). The effect of menopause on fracture incidence was stronger than the effect of a 5-year age increase. Of the respondents, 84.4% were willing to participate in bone densitometry and 68.3% for long-term prevention of osteoporosis with oestrogen.

Beneficial effect of oestrogen on exercise-induced myocardial ischaemia in women with coronary artery disease

Rosano GM et al., 1993·Lancet

Oestradiol-17 beta causes relaxation of isolated coronary arteries and increases blood flow in several vascular beds in human beings and animals. Oestrogen replacement therapy is associated with a lower incidence of cardiovascular disease, but the acute effects of oestradiol-17 beta on myocardial ischaemia are unknown. We have studied the acute effect of sublingual oestradiol-17 beta on exercise-induced myocardial ischaemia in eleven women (mean age 58 [SD 8] years) with coronary artery disease. The women did two treadmill exercise tests on separate days; 40 min before the test they took sublingual oestradiol-17 beta (1 mg) or placebo, in random order. Plasma oestradiol-17 beta concentrations were confirmed to be higher after sublingual oestradiol-17 beta than after placebo (2531 [1192] vs 155 [168] pmol/L, p < 0.001). Oestradiol-17 beta increased both time to 1 mm ST depression (456 [214] vs 579 [191] s, p < 0.004; difference of medians 92 [95% CI 46-254]) and total exercise time (569 [249] vs 658 [193] s, p < 0.01; difference 54 [10-212]). Acute administration of oestradiol-17 beta therefore has a beneficial effect on myocardial ischaemia in women with coronary artery disease. This effect may be due to a direct coronary-relaxing effect, to peripheral vasodilation, or to a combination of these mechanisms. Oestradiol-17 beta may prove to be a useful adjunct to the treatment of angina in postmenopausal women with coronary heart disease.

Effect of transdermal 17 beta-estradiol and oral conjugated equine estrogens on biochemical parameters of bone resorption in natural menopause

Reginster JY et al., 1993·Calcif Tissue Int

To evaluate and compare the effects or oral and transdermal estrogen replacement therapy on biochemical markers of bone resorption in early postmenopausal women. Controlled, randomized group comparison. Outpatient clinic for menopausal women and research into osteoporosis. Sixty healthy women menopausal for less than 5 years and who had never received any medications interfering with bone metabolism. The 60 women were randomly allocated to 3 months therapy with either oral conjugated estrogens (0.625 mg/day) (n = 28) or transdermal estradiol (50 micrograms/day) (n = 32) in cyclical combination with medroxyprogesterone acetate (5 mg/day). Traditional (urinary calcium/creatinine and hydroxyproline/creatinine) and the new specific (urinary pyridinoline/creatinine and deoxypyridinoline/creatinine) markers of bone resorption were determined before and after 3 months of treatment. In both groups, circulating levels of estrone and estradiol were significantly (P < 0.001) increased during treatment. In women treated with oral conjugated equine estrogens, urinary calcium/creatinine and hydroxyproline/creatinine ratios were significantly (P < 0.05) reduced. Pyridinoline/creatinine ratio fell from 69.1 (4) [mean (SEM)] to 50 (4) mumol/mumol (P < 0.01) and deoxypyridinoline/creatinine ratio fell from 10.8 (1) [mean (SEM)] to 8.3 (0.8) mumol/mumol (P < 0.01). In the group treated with transdermal estradiol, urinary hydroxyproline/creatinine ratio was significantly (P < 0.05) reduced. Pyridinoline/creatinine ratio fell from 66.3 (4) [mean (SEM)] to 46.2 (3) mumol/mumol (P < 0.01) and deoxypyridinoline/creatinine ratio fell from 11.5 (1.5) [mean (SEM)] to 7.7 (0.6) mumol/mumol (P < 0.01). There were no differences between the evolution of the biochemical variables in the two groups. These results suggest that oral conjugated equine estrogens and transdermal estradiol, in the given doses, are equally effective in reducing postmenopausal bone resorption.

The absorption of oral micronized progesterone: the effect of food, dose proportionality, and comparison with intramuscular progesterone

Simon JA et al., 1993·Fertil Steril

To examine the effects of food ingestion and administered dose on the absorption of oral micronized P (Utrogestan; Besins-Iscovesco, Paris, France) and to compare the bioavailability of intramuscular versus oral routes of administration. Prospective, randomized, open label crossover protocol with 7 days between dosages. Academic institution. Fifteen normal postmenopausal women. All subjects participated [1] micronized P (200 mg) or placebo under fasting or nonfasting conditions once daily for 5 days; [2] micronized P (100, 200, or 300 mg) once daily under fasting conditions for 5 days; and [3] micronized P (200 mg) or intramuscular P (50 mg in oil) administered once daily for 2 days. Serum P concentrations were measured in all groups. Concomitant food ingestion increased the area under the serum P concentration versus time curve (AUC0 to 24) and the maximum serum P concentration (Cmax) without affecting time to maximum serum concentration (Tmax) (P < 0.05). Micronized P absorption and elimination were first-order processes and exhibited dose-independent pharmacokinetics between 100 and 300 mg. After intramuscular P, Cmax was higher and Tmax occurred later compared with the oral P preparation. Oral P had lower relative bioavailability (8.6%) than intramuscular P. Absorption of micronized P was enhanced twofold in the presence of food. Both absorption and elimination were dose-independent, dose proportionality being confirmed. Bioavailability of the oral P was approximately 10% compared with intramuscular P.

Relationship between carbohydrate metabolism and serum insulin-like growth factor system in postmenopausal women: comparison of endometrial cancer patients with healthy controls

Rutanen EM et al., 1993·J Clin Endocrinol Metab

Insulin is a major regulator of circulating insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1), suppressing the hepatic production of IGFBP-1. Postmenopausal age, obesity, hypertension, and impaired glucose tolerance, which are known risk factors for endometrial cancer, are all associated with hyperinsulinemia and insulin resistance. In this study, we investigated the relationship among serum insulin, glucose, insulin-like growth factors (IGF-I and IGF-II), and IGFBP-, -2, and -3 in 32 nondiabetic postmenopausal women with endometrial cancer and in 18 healthy controls. The mean fasting levels of glucose and insulin were higher, whereas the mean basal IGF-I, IGF-II, and IGFBP-3 levels were lower in the endometrial cancer patients than in the healthy control subjects. The mean fasting IGFBP-1 and IGFBP-2 levels did not differ between the groups, and no correlation was found between fasting insulin and IGFBP-1 concentrations or between insulin and IGFBP-2 concentrations in either of the study groups. During an oral glucose tolerance test, the mean glucose levels at 1 and 3 h as well as the mean insulin level at 3 h were significantly higher in the endometrial cancer patients than in the controls, and the area under the glucose curve was larger in the first group. An oral glucose load resulted in a similar fall in serum IGFBP-1 levels in endometrial cancer patients and controls (51% and 55% at 3 h). When the cancer patients were divided into two subgroups according to the body mass index (kilograms per m2), the obese group had higher glucose and insulin indices than the nonobese group. No difference was found by the same measures in healthy controls. The fasting serum IGFBP-1 levels tended to be lower in the obese than in the normal weight subjects, but the difference did not reach statistical significance. In summary, these results provide preliminary evidence that the inverse relation between fasting insulin and IGFBP-1, well established in children and young adults, disappears in elderly women, although short term suppression by insulin still occurs. Further, our data indicate that in addition to carbohydrate metabolism, postmenopausal women with endometrial cancer have alterations in their circulating IGF system compared to controls.

Oestriol in the prophylactic treatment of recurrent urinary tract infections in postmenopausal women

Kirkengen AL et al., 1992·Scand J Prim Health Care

A block randomized, double-blind, group-comparative, placebo-controlled study was conducted to assess the effect of oestriol on recurrent urinary tract infections in postmenopausal women. 40 women, median age 78 years (66-91), 20 in each group, were treated with oestriol three mg p.o. per day or corresponding placebo for four weeks, followed by one mg per day for eight weeks. The main response parameter was the number of urinary tract infections per week in the two treatment periods. Both oestriol and placebo reduced the number of infections per week significantly in both periods, compared with the pretreatment period. There was no difference between oestriol and placebo treatment in the first period. In the second period, however, oestriol treatment was significantly more effective than placebo (p = 0.05). Correspondingly, there was a significant difference between the two groups in the vaginal pH at the end of the study (p less than 0.05). We conclude that oestriol reduces recurrent urinary tract infections in postmenopausal women.

Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long-term follow-up focusing on natural history and circulating hormones

Dahlgren E et al., 1992·Fertil Steril

To determine if the hormonal imbalance in women with polycystic ovary syndrome (PCOS) continues into and after menopause and to analyze factors constituting an increased risk for developing metabolic disorders. The study was a transectional retrospective cohort follow-up of patients with PCOS. The women with PCOS were recruited from hospital clinics, and referents were randomized from a population study of women. Thirty-three women ages 40 to 59 years with ovarian histopathology typical of PCOS at wedge resection 22 to 31 years previously; 132 age-matched referents were analyzed. Clinical data were collected via a questionnaire supplemented with an interview in connection to a clinical examination that also included fasting venous sampling. Infertility, hirsutism, and oligomenorrhea were more common among the subjects with PCOS, but there was a considerable spontaneous restitution of cyclic regularity with time. Women with PCOS were more often hysterectomized and entered menopause later compared with referents. The hormone data show a typical profile for PCOS. Compared with referents women with PCOS showed marked increase in prevalence of central obesity, higher basal serum insulin concentrations, and a higher prevalence of diabetes mellitus and hypertension. Perimenopausal women with PCOS have an increased morbidity in hypertension and diabetes mellitus that adds to the classic symptoms, such as anovulation, hirsutism, and infertility.

Low-dosage micronized 17 beta-estradiol prevents bone loss in postmenopausal women

Ettinger B et al., 1992·Am J Obstet Gynecol

With the use of a double-blind, randomized, dose-ranging design, we tested during an 18-month period the degree of protection against postmenopausal bone loss afforded by micronized 17 beta-estradiol in dosages of 0.5, 1.0, and 2.0 mg. All subjects received supplementation to ensure a minimum of 1500 mg calcium daily. Fifty-one subjects completed at least 1 year of follow-up bone density measurements by quantitative computed tomography and by single- and dual-photon absorptiometry. In the placebo group spinal trabecular bone density decreased 4.9% annually (p less than 0.001), whereas in those taking micronized 17 beta-estradiol bone density tended to increase (annual increases of 0.3% in the 0.5 mg micronized 17 beta-estradiol group, 1.8% in the 1.0 mg micronized 17 beta-estradiol group, and 2.5% in the 2.0 mg micronized 17 beta-estradiol group). After completing the double-blind phase, 41 subjects completed an additional 18 months of follow-up while taking 1.0 mg micronized 17 beta-estradiol. During this time one third of the subjects were randomly assigned to discontinue calcium supplements. Among those who previously received placebo, trabecular bone density increased 4.3% annually, whereas among those who had used micronized 17 beta-estradiol, trabecular bone density response was inversely related to the dosage previously used. Additionally and independently, the level of calcium intake showed a statistically significant correlation with the change in spinal trabecular bone density (r = 0.37, p = 0.02). We conclude that micronized 17 beta-estradiol has a continuous skeletal dose-response effect in the range of 0.5 to 2.0 mg and that calcium intake positively modifies the skeletal response to 1.0 mg micronized 17 beta-estradiol.

Progesterone administration by nasal spray

Cicinelli E et al., 1991·Fertil Steril

The bioavailability and the clinical usefulness of the P administered by nasal spray were investigated. Ten healthy menopausal women received an IN spray administration (4 doses of an oleic P solution 20 mg/mL, corresponding to nearly 11.2 mg of P) and the circulating P levels were calculated. Sixty minutes after administration, the maximum concentration (CMax, 3.75 +/- 0.214 ng/mL) was reached. High P levels (greater than 2 ng/mL) lasted until 360 minutes, and the AUC 0 to 720 was 1,481.6 +/- 343 ng.h/mL. Progesterone administration by spray formulation has proven to be effective in reaching therapeutic levels and to be acceptable to patients and, probably, clinically safe.

Metabolism of [3H]equilin in normal and malignant human endometrium and in endometrial adenocarcinoma transplanted into nude mice

Bhavnani BR et al., 1991·J Steroid Biochem Mol Biol

One of the main components of conjugated equine estrogens is equilin sulfate and this estrogen in postmenopausal women is metabolized to 17 beta-dihydroequilin, 17 beta-dihydroequilenin and equilenin. To investigate the possibility that some of these estrogens may be formed directly in the target tissues, we studied the in vitro metabolism of [3H]equilin in various types of normal and malignant human endometrium, including adenocarcinoma grown in athymic nude mice. The results indicate that normal and neoplastic human endometrium can form the above three metabolites. The highest level of 17 beta-reduced products were isolated from the normal secretory endometrium. Equilenin was the most abundant metabolite isolated from both the normal and malignant endometrium. The formation of [3H]equilenin indicates the presence of a 6,8(9) steroid dehydrogenase-isomerase in the human endometrium. The formation of 17 beta-dihydroequilin in the endometrium may be of importance as this estrogen is 8 times more potent as a uterotrophic agent than equilin and estrone.

The contraceptive needs of midlife women

Jarrett ME et al., 1990·Nurse Pract

For those women who have not been contraceptively sterilized, midlife is a period of waning fertility. However, the occurrence of anovulatory menstrual cycles is unpredictable. Contraceptive methods also become increasingly contraindicated, both medically and physiologically. This article reviews the physiology of waning fertility and midlife contraceptive options, and discusses implications for helping women meet their contraceptive needs throughout the perimenopausal period.

Pharmacokinetics of oestrogens and progestogens

Kuhl H, 1990·Maturitas

There are large inter- and intra-individual variations in the serum concentrations of natural and synthetic sex steroids irrespective of the route of administration. Oral ingestion of steroids has a stronger effect on hepatic metabolism than parenteral administration, as the local concentration in liver sinusoids are 4-5 times higher during the first liver passage. Oestradiol and oestrone are interconvertible, dependent on the local concentrations in liver and target organs, and oestrone sulphate serves as a large reservoir. The oestrone/oestradiol ratio has no physiological significance, as oestrone is only a weak oestrogen. Oestrone is both a precursor and a metabolite of oestradiol. Oestriol is extensively conjugated after oral administration. Therefore, the oestriol serum levels are similar after oral intake of 10 mg and after vaginal application of 0.5 mg oestriol resulting in similar systemic effectiveness. Conjugated oestrogens can easily enter the hepatocytes but are hormonally active only after hydrolyzation into the parent steroids. Ethinylestradiol which exerts strong effects on hepatic metabolism and inhibits metabolizing enzymes, should not be used for hormone replacement therapy. Among the progestogens, the progesterone derivatives have less effects on liver metabolism than the norethisterone derivatives (13-methyl-gonanes and 13-ethyl-gonanes). The highly potent 13-ethyl-gonanes are effective at very low doses, because of a slow inactivation and elimination rate due to the ethinyl group.

Pharmacokinetics of estrogen

Stumpf PG, 1990·Obstet Gynecol

The main types of pharmacologic therapy used to treat the hormone deficiency of menopause are parenteral and oral administrations of estrogen. Parenteral administration results in predictable absorption without major intermediary metabolism, whereas all oral estrogens are subject to intestinal metabolism before entering the systemic circulation. Various options are available. Injectable estrogens, because of rapid absorption and metabolism, are impractical for long-term replacement therapy. The primary drawback to subcutaneous estradiol pellets is the surgical procedure required for their insertion and removal. Vaginal epithelium is an effective pathway for absorption of estrogen given by solution, tablet, or cream, although only the latter is currently approved for clinical use; relatively constant serum levels of estradiol can be obtained with vaginal rings. Transdermal patches provide controlled hormone levels for up to 3.5 days. Although oral conjugated equine estrogens have been used extensively, they introduce types of estrogen, such as equilin, that are not naturally found in humans and that can produce a pronounced hepatic response. Micronized estradiol, oral estrone, and other estrogens have been used as alternatives to equine estrogens. Clinicians should understand the pharmacokinetics of the various options for replacement therapy and select a course of treatment that is safe, effective, and convenient for the patient.

Sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites

Arafat ES et al., 1988·Am J Obstet Gynecol

Progesterone and its metabolites were measured in serum extracts by radioimmunoassay and gas chromatography-mass spectrometry, respectively, after ingestion of micronized progesterone by eight postmenopausal women. One subject received 400 mg of micronized progesterone orally that induced a hypnotic state that lasted for approximately 2 hours. Blood samples were drawn periodically from all subjects for measurement of progesterone and its metabolites in serum. Levels of serum progesterone and its metabolites increased significantly from baseline values and reached a peak between 2 and 6 hours after oral progesterone administration. Significant quantities of five compounds (progesterone, 5 alpha-pregnan-3 alpha-ol-20-one, 5 beta-pregnan-3 alpha-ol-20-one, 5 beta-pregnan-3 alpha,20 beta-diol, and 5 beta-pregnan-3 alpha-ol-11,20-dione) that have been reported to possess anesthetic qualities were identified. The sedative and hypnotic effects of oral administration of progesterone may be mediated through those compounds.

Hyperinsulinemia and stromal luteinization of the ovaries in postmenopausal women with endometrial cancer

Nagamani M et al., 1988·J Clin Endocrinol Metab

Ovarian secretion of testosterone and androstenedione is increased in postmenopausal women with endometrial cancer, and insulin stimulates ovarian stromal androgen synthesis in vitro. We undertook this study to investigate whether women with endometrial cancer have increased serum immunoreactive insulin levels. Ten postmenopausal women with endometrial carcinoma and 10 postmenopausal women without cancer who matched the cancer patients in age, years since menopause, and percentage of ideal body weight were studied. The women with endometrial cancer had significantly higher fasting serum insulin levels than the normal women [mean, 187 +/- 26 (+/- SE) vs. 55 +/- 11 pmol/L; P less than 0.01]. The cancer patients had significantly higher insulin responses after glucose administration than normal women (sum of 1, 2, and 3 h postglucose values, 5545 +/- 1526 vs. 1444 +/- 156 pmol/L; P less than 0.02), even though their glucose responses were similar. Nests of luteinized cells, which were positive for testosterone by immunoperoxidase staining, were found in the ovarian stroma of 8 of the women with endometrial cancer, but in only 1 of those without cancer (P less than 0.01). Specific high affinity insulin receptors were demonstrable in the stroma of the postmenopausal ovaries. These results suggest that the frequency of stromal luteinization is increased in women with endometrial cancer and that insulin may play a role in the pathogenesis of this luteinization.

Oral micronized progesterone. Bioavailability pharmacokinetics, pharmacological and therapeutic implications--a review

Sitruk-Ware R et al., 1987·Contraception

Progesterone (P), the natural hormone, binds to its specific receptors to induce specific progestational effects. In addition to this binding, P is able to interfere with the binding sites of other steroids. Therefore the natural hormone exhibits an anti-estrogenic activity, and anti-androgenic activity and also exerts anti-mineralocorticoid effects. For a long time progesterone could not be used in clinical applications because of a rapid liver inactivation after oral administration. An oral micronized preparation of progesterone is now available which produces adequate plasma and tissue levels of progesterone. The preparation reproduces the anti-estrogenic effect of the natural hormone on the endometrium at the dose of 200 mg daily. It also reproduces the anti-mineralocorticoid effect and has no androgenic action. No side effects have been reported as far as lipids profile, coagulation factors and blood pressure are concerned. Therefore oral micronized progesterone appears suitable for hormonal replacement therapy in various areas, essentially postmenopause therapy, premenstrual syndrome, correction of irregular cycles and pregnancy maintenance.

Absorption and metabolism of oral progesterone when administered twice daily

Padwick ML et al., 1986·Fertil Steril

The absorption, metabolism, and clearance of progesterone (P) from the peripheral circulation were investigated in five postmenopausal women after oral administration of 100 mg at 9:00 A.M. and 200 mg at 9:00 P.M. for 5 consecutive days. Mean peak plasma concentrations of P were observed 2 hours after ingestion of both the 100 and 200 mg doses and were 22.7 and 47.7 nmol/l, respectively. Of the three metabolites studied, the plasma concentrations of pregnanediol-3 alpha-glucuronide were most raised by treatment; those of 17-hydroxyprogesterone were least raised. Increases in the plasma levels of 20 alpha-dihydroprogesterone were more sustained than those of P, and the plasma concentrations remained elevated at approximately 20 nmol/l for at least 12 hours after P administration. We conclude that administration of oral P 100 mg in the morning and 200 mg at night increases the circulating concentrations of P and the biologically active metabolite 20 alpha-dihydroprogesterone, and that the duration of these increases is sufficient to evoke progestational responses in responsive end-organs.

Bioavailability of oral micronized progesterone

Maxson WS et al., 1985·Fertil Steril

Progesterone (P) has not been administered orally because of reportedly poor bioavailability and a rapid clearance rate. Unfortunately, the synthetic derivatives, although orally active, have a number of disadvantages and fail to mimic natural P completely. To investigate the bioavailability and short-term toxicity of oral micronized P, a standardized dose of 200 mg of micronized P was administered to nine healthy postmenopausal women and one male subject. Serial determinations of serum P concentrations demonstrated rapid absorption of P. Peak concentrations of P rose from a negligible baseline level to 17.0 +/- 4.9 ng/ml at an average of 2.8 +/- 0.35 hours after administration. The peak concentrations of P were equivalent to those observed in the midluteal phase in normal control cycles (14.1 +/- 2.7 ng/ml). All subjects exhibited significant elevation of P over baseline levels that persisted for at least 6 hours after the single oral dose and returned to initial levels by 24 hours. There was no significant change in estradiol, follicle-stimulating hormone, luteinizing hormone, cortisol, aldosterone, lipids, or hepatic enzymes during the 24-hour study interval.

Intravaginal administration of progesterone: enhanced absorption after estrogen treatment

Villanueva B et al., 1981·Fertil Steril

A progesterone solution was administered by intravaginal instillation, intramuscular injection, and sublingually to estrogen-deficient women, with or without estradiol (E2) replacement, and serum progesterone (P) concentrations were measured by radioimmunoassay. Intravaginal application to postmenopausal subjects receiving E2 gave 10 times baseline at 15 minutes and 30 to 40 times at 1 to 2 hours, with sustained levels, for 7 hours and decline to 10 times baseline at 24 hours. Intravaginal application to hypoestrogenic women gave similar results, but of much lower magnitude (highest value, 20 times baseline). Intramuscular injection, in contradistinction, showed gradually increasing levels over the study period, up to 30 times basal values at 24 hours. It contrast, sublingual application produced very modest serum increases, to approximately 10 times baseline within 2 hours and return to basal value at 24 hours. Since the most rapid and highest levels were observed by vaginal application to postmenopausal women receiving estrogen, and considering that the vagina has been similarly shown to be very effective for estrogen absorption, it is conceived that full hormone replacement could be accomplished in the deficient states by cyclic vaginal application of both steroids.

Estriol in the management of the menopause

Tzingounis VA et al., 1978·JAMA

Estriol was administered for a six-month period as estrogen replacement therapy to 52 symptomatic postmenopausal women. Assays of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrone, and estradiol were performed before and during therapy. During this period of administration, vaginal cytology, cervical mucus, and endometrial studies were performed. Clinical effectiveness was directly related to dosage (2 to 8 mg/day). Estriol (8 mg/day) failed to induce endometrial proliferation and proved a poor suppressor of FSH and LH. This agent's capacity to relieve vasomotor instability and improve vaginal maturation without notable side effects is sufficient reason to include this drug in the management of the postmenopausal syndrome.

Estriol, the forgotten estrogen?

Follingstad AH, 1978·JAMA

Circulating estradiol, estrone and gonadotropin levels following the administration of orally active 17beta-estradiol in postmenopausal women

Yen SS et al., 1975·J Clin Endocrinol Metab

Ingestion of a single tablet containing 2 mg micronized 17beta-estradiol (E-2) produced marked increases in the serum concentrations of E-2 and estrone (E-1) in 9 postmenopausal women. The rise in circulating E-2 became significant within 2 h, reached a maximum (110 pg/ML; 437% increase) at 5 h, and remained significantly elevated at 8 h posttreatment. By 24 h, the serum E-2 concentration was not significantly different than baseline. In contrast, a more rapid (within 1 h) and pronounced (4-fold) increase in the serum concentration of E-1 was observed. This rise continued until a peak (467 pg/ml; 2000%) was reached 6 h posttreatment. Thereafter, the serum E-1 concentration declined progressively but was still significantly elevated (140 pg/ml; P smaller than 0.01) 24 h after treatment. Serum concentrations of FSH AND LH were significantly decreased within 6 and 3 h, respectively and both gonadotropins remained significantly suppressed 24 h following the ingestion of E-2. The ratios of circulating E-1: E-2 reported herein (ca. 3-6) were much higher than those observed by other investigators following iv E-2 (I.E., smaller than 1). Thus the data indicate that micronized E-2 peros is readily absorbed and that during this process a significant portion of the hormone is converted to E-1 by the gstrointestinal tract. In addition, 2 mg oral E-2 exerts significant biologic activity as assessed by serum gonadotropin suppression.