Oocyte mitochondrial function and reproduction

Abstract: PURPOSE OF REVIEW: Mitochondria are cellular organelles that are required for energy production. Emerging evidence demonstrates their role in oocyte development and reproduction. In this review, we examine recent animal and clinical studies on the role of mitochondria in fertility. We also analyse the impact of assisted reproductive techniques (ARTs) on mitochondrial function and discuss the future clinical implications of mitochondrial nutrients and mitochondrial replacement. RECENT FINDINGS: Mitochondria affect all aspects of mammalian reproduction. They are essential for optimal oocyte maturation, fertilization and embryonic development. Mitochondrial dysfunction causes a decrease in oocyte quality and interferes with embryonic development. ART procedures affect mitochondrial function, while mitochondrial nutrients may increase mitochondrial performance in oocytes. New mitochondrial replacement procedures using mitochondria obtained from polar bodies or from the patient's own oogonial stem cells are promising and may address concerns related to the induction of high-levels of heteroplasmy, which could potentially result in negative long-term health effects. SUMMARY: Optimal energy production is required for oocyte and embryo development, and mitochondrial abnormalities have devastating reproductive consequences. Improvement of oocyte mitochondrial function via intake of compounds that boost mitochondrial activity may have clinical benefits, and mitochondrial replacement could potentially be used for the prevention of mitochondrial diseases.

Current opinion in obstetrics & gynecology


Impact of Luteal Phase Defect on Ectopic Pregnancy Risk

Abstract:
Introduction: Luteal phase deficiency (LPD), while commonly observed and managed in stimulated in-vitro fertilisation cycles, is a more contentious phenomenon in natural cycles. The challenge arises in the definition and diagnosis of LPD. Controversy regarding the clinical significance of LPD is due in part to the lack of a reliable test to diagnose the disorder.2 Jones first described LPD based on temperature criteria, urinary pregnanediol studies and histological appearance of the endometrium in 1949. 3 In current practice, timing of the luteal phase from which an evaluation of its length and hormonal parameters can be made are problematic. Ovulation and thereby the length of the luteal phase can reliably and reproducibly be determined by teaching women to identify their Peak Symptom Day (PSD) of cervical mucus (the last day of any mucus discharge that is clear, stretchy, or lubricative). 4 There is an abrupt and dramatic change in the characteristic fertile pattern of pre-ovulatory mucus that is due to the effects of progesterone post-ovulation. Correlation with ultrasound and hormonal evaluation indicates that the mucus observation occurs within 2 days of ovulation. Using such a fertility awareness based method, the American Academy of Fertility Care Professionals has defined a luteal phase deficiency as a deficiency in the length of the luteal phase, or a deficiency of the hormones progesterone and oestradiol that occurs during the luteal phase. Method: Women presenting with infertility or recurrent miscarriages to the Fertility Assessment and Research Clinic of the Mater Mothers' Hospital (Brisbane, Australia) were instructed in the Sympto-Thermal Method. This allowed for accurate documentation of ovulation and the luteal phase. Luteal phase hormone levels were collected 5, 7 and 9 days after ovulation. Women were allocated a luteal phase status using the definition below for luteal phase defect. This data is part of the recruitment phase of the Pregnancy Achieving Trials (Mater Health Services HREC no. 1618M).

Results: By the definition above, a luteal phase deficiency exists in 36% (100) of 279 infertile couples who presented to our clinic, in preparation for involvement in the Pregnancy Achieving Trials. Of 16 infertile women who had previously experienced both a miscarriage and an ectopic pregnancy, 75% (12) met the criteria for a luteal phase deficiency.

Discussion: Ectopic pregnancy is known to be associated with infectious history, smoking, age, previous spontaneous miscarriage, history of infertility, previous use of an intrauterine device and prior history of medical termination of pregnancy (mifepristone + misoprostol). Previous research has suggested an association between luteal phase defect (LPD) and ectopic pregnancy in subfertile couples." All stimulated cycles of in-vitro fertilisation have abnormal luteal phases.' There exists a high rate of ectopic pregnancy among women undergoing in-vitro fertilization. The high proportion of ectopic pregnancies among women who fall pregnant on progestogen-only contraceptives also suggests an hormonal association." Women who are heavy smokers, another risk factor associated with ectopic pregnancy, has been shown to have lower urinary progesterone metabolite levels in the luteal phase compared with non-smokers. 10

Conclusion: There appears to be an association between prior miscarriage, prior ectopic pregnancy and luteal phase deficiency in subfertile couples. Could luteal phase deficiency, an hormonal disorder, be useful in the definition of ectopic pregnancy risk?


Clinical Effectiveness of Modified Laparoscopic Fimbrioplasty for the Treatment of Minimal Endometriosis and Unexplained Infertility

Abstract: Objective. To study the reproductive outcomes of modified laparoscopic fimbrioplasty (MLF), a surgical technique designed to increase the working surface area of the fimbriated end of the fallopian tube. We postulated that an improvement in fimbrial function through MLF will improve reproductive outcomes. Design. Retrospective cohort study. Setting. Academic tertiary-care medical center. Patients. Women with minimal endometriosis or unexplained infertility, who underwent MLF during diagnostic laparoscopy (n = 50) or diagnostic laparoscopy alone (n = 87). Intervention. MLF involved gentle, circumferential dilatation of the fimbria and lysis of fimbrial adhesions bridging the fimbrial folds. Main Outcome Measures. The primary outcome was pregnancy rate and the secondary outcome was time to pregnancy. Results. The pregnancy rate for the MLF group was 40.0%, compared to 28.7% for the control group. The average time to pregnancy for the MLF group was 13 weeks, compared to 18 weeks for the control group. The pregnancy rate in the MLF group was significantly higher for patients ≤35 ys (51.5% versus 28.8%), but not for those >35 ys (17.6% versus 28.6%). Conclusion. MLF was associated with a significant increase in pregnancy rate for patients ≤35 ys.


Executive Summary of Hormonal Physiology of Childbearing: Evidence and Implications for Women, Babies, and Maternity Care

Abstract: This report synthesizes evidence about innate hormonally mediated physiologic processes in women and fetuses/newborns during childbearing, and possible impacts of common maternity care practices and interventions on these processes, focusing on four hormone systems that are consequential for childbearing. Core hormonal physiology principles reveal profound interconnections between mothers and babies, among hormone systems, and from pregnancy through to the postpartum and newborn periods. Overall, consistent and coherent evidence from physiologic understandings and human and animal studies finds that the innate hormonal physiology of childbearing has significant benefits for mothers and babies. Such hormonally-mediated benefits may extend into the future through optimization of breastfeeding and maternal-infant attachment. A growing body of research finds that common maternity care interventions may disturb hormonal processes, reduce their benefits, and create new challenges. Developmental and epigenetic effects are biologically plausible but poorly studied. The perspective of hormonal physiology adds new considerations for benefit-harm assessments in maternity care, and suggests new research priorities, including consistently measuring crucial hormonally mediated outcomes that are frequently overlooked. Current understanding suggests that safely avoiding unneeded maternity care interventions would be wise, as supported by the Precautionary Principle. Promoting, supporting, and protecting physiologic childbearing, as far as safely possible in each situation, is a low-technology health and wellness approach to the care of childbearing women and their fetuses/newborns that is applicable in almost all maternity care settings.


What we know about primary dysmenorrhea today: a critical review

Abstract:
BACKGROUND: Primary dysmenorrhea, or painful menstruation in the absence of pelvic pathology, is a common, and often debilitating, gynecological condition that affects between 45 and 95% of menstruating women. Despite the high prevalence, dysmenorrhea is often poorly treated, and even disregarded, by health professionals, pain researchers, and the women themselves, who may accept it as a normal part of the menstrual cycle. This review reports on current knowledge, particularly with regards to the impact and consequences of recurrent menstrual pain on pain sensitivity, mood, quality of life and sleep in women with primary dysmenorrhea.

METHODS: Comprehensive literature searches on primary dysmenorrhea were performed using the electronic databases PubMed, Google Scholar and the Cochrane Library. Full-text manuscripts published between the years 1944 and 2015 were reviewed for relevancy and reference lists were cross-checked for additional relevant studies. In combination with the word 'dysmenorrhea' one or more of the following search terms were used to obtain articles published in peer-reviewed journals only: pain, risk factors, etiology, experimental pain, clinical pain, adenomyosis, chronic pain, women, menstrual cycle, hyperalgesia, pain threshold, pain tolerance, pain sensitivity, pain reactivity, pain perception, central sensitization, quality of life, sleep, treatment, non-steroidal anti-inflammatory drugs.

RESULTS: Women with dysmenorrhea, compared with women without dysmenorrhea, have greater sensitivity to experimental pain both within and outside areas of referred menstrual pain. Importantly, the enhanced pain sensitivity is evident even in phases of the menstrual cycle when women are not experiencing menstrual pain, illustrating that long-term differences in pain perception extend outside of the painful menstruation phase. This enhanced pain sensitivity may increase susceptibility to other chronic pain conditions in later life; dysmenorrhea is a risk factor for fibromyalgia. Further, dysmenorrheic pain has an immediate negative impact on quality of life, for up to a few days every month. Women with primary dysmenorrhea have a significantly reduced quality of life, poorer mood and poorer sleep quality during menstruation compared with their pain-free follicular phase, and compared with the menstruation phase of pain-free control women. The prescribed first-line therapy for menstrual pain remains non-steroidal anti-inflammatory drugs, which are effective in relieving daytime and night-time pain.

CONCLUSION: Further study is needed to determine whether effectively blocking dysmenorrheic pain ameliorates risk for the development of chronic pain disorders and to explore whether it is possible to prevent the development-and not just treat-severe dysmenorrheic pain in adolescent girls. In conclusion, we demonstrate the extensive multi-factorial impact of dysmenorrhea and we encourage and direct researchers to necessary future studies.


Perceived stress, reproductive hormones, and ovulatory function: a prospective cohort study

K A Ahrens

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Catherine J. Vladutiu

University of North Carolina at Chapel Hill

Jean Wactawski-Wende

Department of Epidemiology and Environmental Health, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY.


DIR Jahrbuch 2014 (Deutsches IVF-Register Annual Report 2014)

Abstract: Annual report (Jahrbuch) of the Deutsches IVF-Register (DIR) for treatment year 2014. DIR is the German national IVF/ICSI registry, founded 1982 — the oldest continuously operating ART registry. Voluntary professional-society database with high de-facto coverage of German fertility centres. Reports cycles, transfers, pregnancies and clinical outcomes by treatment type (IVF, ICSI, frozen embryo transfer, donor). German-language registry document. Used as a Phase B historical-archive source for the ART Registry Comparison study (cross-registry classification by reporting completeness on 7 framework dimensions).


Effect of Lepidium meyenii Walp. on Semen Parameters and Serum Hormone Levels in Healthy Adult Men: A Double-Blind, Randomized, Placebo-Controlled Pilot Study

Abstract: Background/Aims. Products of Lepidium meyenii Walp. (maca) are touted worldwide as an alimentary supplement to enhance fertility and restore hormonal balance. Enhancing properties of maca on semen parameters in animals were previously reported by various authors, but we present to the best of our knowledge the first double-blind, randomized, placebo-controlled pilot trial in men. The aim of this study was to evaluate the effects of maca on semen parameters and serum hormone levels in healthy adult men. Methods. A group of 20 volunteers aged 20-40 years was supplied by milled hypocotyl of maca or placebo (1.75 g/day) for 12 weeks. Negative controls of semen were compared to the samples after 6 and 12 weeks of maca administration; negative blood controls were compared to the samples after 12 weeks of treatment. Results. Sperm concentration and motility showed rising trends compared to placebo even though levels of hormones did not change significantly after 12 weeks of trial. Conclusion. Our results indicate that maca possesses fertility enhancing properties in men. As long as men prefer to use alimentary supplement to enhance fertility rather than prescribed medication or any medical intervention, it is worth continuing to assess its possible benefits.

Evidence-based complementary and alternative medicine : eCAM


HFEA Fertility Trends and Figures 2013

HFEA Fertility Trends and Figures 2013

Human Fertilisation and Embryology Authority


Progesterone Accelerates the Completion of Sperm Capacitation and Activates CatSper Channel in Spermatozoa from the Rhesus Macaque

Abstract: During transit through the female reproductive tract, mammalian spermatozoa are exposed to increasing concentrations of progesterone (P4) released by the cumulus oophorus. P4 triggers massive calcium influx into human sperm through activation of the sperm-specific calcium channel CatSper. These properties of human spermatozoa are thought to be unique since CatSper is not progesterone sensitive in rodent sperm. Here, by performing patch clamp recording from spermatozoa from rhesus macaque for the first time, we report that they express P4-sensitive CatSper channel identically to human sperm and react to P4 by inducing responsiveness to zona pellucida, unlike human sperm, which respond directly to P4. We have also determined the physiologic levels of P4 capable of inducing capacitation-associated changes in macaque sperm. Progesterone (1 μM) induced up to a 3-fold increase in the percentage of sperm undergoing the zona pellucida-induced acrosome reaction with the lowest threshold as low as 10 nM of P4. Submicromolar levels of P4 induced a dose-dependent increase in curvilinear velocity and lateral head displacement, while sperm protein tyrosine phosphorylation was not altered. Macaque spermatozoa exposed to 10 μM of P4 developed fully hyperactivated motility. Similar to human sperm, on approaching cumulus mass and binding to zona pellucida, macaque spermatozoa display hyperactivation and undergo an acrosome reaction that coincides with the rise in the sperm intracellular calcium. Taken together, these data indicate that P4 accelerates the completion of capacitation and provides evidence of spermatozoa "priming" as they move into a gradient of progesterone in search for the oocyte.


Abstract: 10.1016/j.fertnstert.2014.11.004. Epub 2014 Dec 13. International committee for monitoring assisted reproductive technologies: world report on assisted reproductive technologies, 2007. Ishihara O(1), Adamson GD(2), Dyer S(3), de Mouzon J(4), Nygren KG(5), Sullivan EA(6), Zegers-Hochschild F(7), Mansour R(8). (1)Department of Obstetrics and Gynaecology, Saitama Medical University, Moroyama, Japan. Electronic address: osamishr@saitama-med.ac.jp. (2)Palo Alto Medical Foundation Fertility Physicians of North California, San Jose, California. (3)Department of Obstetrics & Gynaecology, Groote Schuur Hopsital and Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. (4)National Institute for Health and Medical Research, Gynecology, Obstetrics and Reproductive Medicine Unit, Cochin-Saint Vincent de Paul University Hospital, Paris, France. (5)Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden. (6)Faculty of Health, University of Technology, Sydney, Sydney, New South Wales, Australia. (7)Clinica las Condes and Program of Ethics and Public Policies in Human Reproduction, University Diego Portales, Santiago, Chile. (8)Egyptian In Vitro Fertilization-Embryo Transfer Center, Cairo, Egypt. OBJECTIVE: To analyze information on assisted reproductive technology (ART) performed worldwide, and trends in outcomes over successive years. DESIGN: Cross-sectional survey on access, efficiency, and safety of ART procedures performed in 55 countries during 2007. SETTING: Not applicable. PATIENT(S): Infertile women and men undergoing ART globally. INTERVENTION(S): Collection and analysis of international ART data. MAIN OUTCOME MEASURE(S): Number of cycles performed, by country and region, including pregnancies, single and multiple birth rates, and perinatal mortality. RESULT(S): Overall, >1,251,881 procedures with ART were reported, and resulted in 229,442 reported babies born. The availability of ART varied by country, from 12 to 4,140 treatments per million population. Of all aspiration cycles, 65.2% (400,617 of 614,540) were intracytoplasmic sperm injection. The overall delivery rate per fresh aspiration was 20.3%, and for frozen-embryo transfer (FET), 18.4%, with a cumulative delivery rate of 25.8%. With wide regional variations, single-embryo transfer represented 23.4% of fresh transfers, and the proportion of deliveries with twins and triplets from fresh transfers was 22.3% and 1.2%, respectively. The perinatal mortality rate was 19.9 per 1,000 births for fresh in vitro fertilization using intracytoplasmic sperm injection, and 9.6 per 1,000 for FET. The proportion of women aged ≥40 years increased to 19.8% from 15.5% in 2006. CONCLUSION(S): The international trend toward <3 transferred embryos continued, as did the wider uptake of FET. This was achieved without compromising delivery rates. The application of ART for women aged >40 years was a major component of ART services in some regions and countries. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.


Dmitry M. Kissin

Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, CDC

Abstract:
Assisted Reproductive Technology Surveillance -
United States, 2013. Sunderam S, Kissin DM, Crawford SB, Folger SG, Jamieson DJ, Warner L, Barfield WD; Centers for Disease Control and Prevention (CDC). PROBLEM/CONDITION: Since the first U.S. infant conceived with assisted reproductive technology (ART) was born in 1981, both the use of ART and the number of fertility clinics providing ART services have increased steadily in the United States. ART includes fertility treatments in which eggs or embryos are handled in the laboratory (i.e., in vitro fertilization [IVF] and related procedures). Women who undergo ART procedures are more likely than women who conceive naturally to deliver multiple-birth infants. Multiple births pose substantial risks to both mothers and infants, including obstetric complications, preterm delivery, and low birthweight infants. This report provides state-specific information for the United States (including Puerto Rico) on ART procedures performed in 2013 and compares infant outcomes that occurred in 2013 (resulting from ART procedures performed in 2012 and 2013) with outcomes for all infants born in the United States in 2013. REPORTING PERIOD COVERED: 2013. DESCRIPTION OF SYSTEM: In 1996, CDC began collecting data on ART procedures performed in fertility clinics in the United States as mandated by the Fertility Clinic Success Rate and Certification Act of 1992 (FCSRCA) (Public Law 102-493). Data are collected through the National ART Surveillance System (NASS), a web-based data collection system developed by CDC. This report includes data from 52 reporting areas (the 50 states, the District of Columbia [DC], and Puerto Rico). RESULTS: In 2013, a total of 160,521 ART procedures (range: 109 in Wyoming to 20,299 in California) with the intent to transfer at least one embryo were performed in 467 U.S. fertility clinics and were reported to CDC. These procedures resulted in 53,252 live-birth deliveries (range: 47 in Alaska to 6,979 in California) and 66,691 infants (range: 61 in Alaska to 8,649 in California). Nationally, the total number of ART procedures performed per million women of reproductive age (15-44 years), a proxy measure of the ART usage rate, was 2,521 (range: 352 in Puerto Rico to 7,688 in DC). ART use exceeded the national rate in 13 reporting areas (California, Connecticut, Delaware, Hawaii, Illinois, Maryland, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Virginia, and DC). Nationally, among ART transfer procedures in patients using fresh embryos from their own eggs, the average number of embryos transferred increased with increasing age of the woman (1.8 among women aged <35 years, 2.0 among women aged 35-37 years, and 2.5 among women aged >37 years). Among women aged <35 years, who typically are considered to be good candidates for elective single embryo transfer (eSET) procedures, the national eSET rate was 21.4% (range: 4.0% in Idaho to 77.5% in Delaware). In 2013, ART contributed to 1.6% of all infants born in the United States (range: 0.2% in Puerto Rico to 4.8% in Massachusetts) and 18.7% of all multiple-birth infants (range: 4.5% in Puerto Rico to 35.7% in Massachusetts), including 18.5% of all twin infants (range: 4.5% in Mississippi to 35.3% in Massachusetts) and 25.2% of all triplet and higher-order infants (range: 0% in several reporting areas to 51.5% in New Jersey). Multiple-birth deliveries were higher among infants conceived with ART (41.1%; range: 20.4% in Delaware to 61.6% in Wyoming) than among all infants born in the total birth population (only 3.5%; range: 1.8% in Puerto Rico to 4.5% in Massachusetts and New Jersey). Approximately 39% of ART-conceived infants were twin infants, and 2% were triplet and higher-order infants. ART-conceived twins accounted for approximately 95.4% of all ART-conceived infants born in multiple deliveries. Nationally, infants conceived with ART contributed to 5.8% of all low birthweight (<2,500 grams) infants (range: 0.9% in Puerto Rico to 15.1% in Massachusetts). Among ART-conceived infants, 29.1% were low birthweight (range: 18.3% in Delaware to 42.6% in Louisiana), compared with 8.0% among all infants (range: 5.8% in Alaska to 11.5% in Mississippi). ART-conceived infants contributed to 4.6% of all preterm (<37 weeks) infants (range: 0.6% in Puerto Rico to 13.3% in Massachusetts). Preterm birth rates were higher among infants conceived with ART (33.6%; range: 22.3% in DC to 50.7% in Louisiana) than among all infants born in the total birth population (11.4%; range: 8.8% in California to 16.6% in Mississippi). The percentage of ART-conceived infants who were low birthweight was 9.0% (range: 5.1% in Mississippi to 19.7% in Puerto Rico) among singletons and 56.3% (range: 48.3% in Maine to 72.4% in Puerto Rico) among twins; the corresponding percentages among all infants born were 6.3% for singletons (range: 4.6% in Alaska to 9.6% in Mississippi and Puerto Rico) and 55.3% for twins (range: 43.6% in Alas

Morbidity and mortality weekly report. Surveillance summaries (Washington, D.C. : 2002)


Assisted Reproductive Technology Surveillance — United States, 2012

Abstract:
Sunderam S, Kissin DM, Crawford SB, Folger SG, Jamieson DJ, Warner L, Barfield
WD; Centers for Disease Control and Prevention (CDC).


"It just happens": a qualitative study exploring low-income women's perspectives on pregnancy intention and planning

Aletha Y Akers

Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Womens Hospital and University of Pittsburgh, Pittsburgh, PA.

Said Ibrahim

VA Center for Health Equity, Research, and Promotion, Philadelphia VA Medical Center, Philadelphia, PA; Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia,...

Abstract:
OBJECTIVE: Unintended pregnancy is common and disproportionately occurs among low-income women. We conducted a qualitative study with low-income women to better typologize pregnancy intention, understand the relationship between pregnancy intention and contraceptive use, and identify the contextual factors that shape pregnancy intention and contraceptive behavior.

STUDY DESIGN: Semistructured interviews were conducted with low-income, African-American and white women aged 18-45 recruited from reproductive health clinics in Pittsburgh, PA, to explore factors that influence women's pregnancy-related behaviors. Narratives were analyzed using content analysis and the constant comparison method.

RESULTS: Among the 66 participants (36 African-American and 30 white), we identified several factors that may impede our public health goal of increasing the proportion of pregnancies that are consciously desired and planned. First, women do not always perceive that they have reproductive control and therefore do not necessarily formulate clear pregnancy intentions. Second, the benefits of a planned pregnancy may not be evident. Third, because preconception intention and planning do not necessarily occur, decisions about the acceptability of a pregnancy are often determined after the pregnancy has already occurred. Finally, even when women express a desire to avoid pregnancy, their contraceptive behaviors are not necessarily congruent with their desires. We also identified several clinically relevant and potentially modifiable factors that help to explain this intention-behavior discrepancy, including women's perceptions of low fecundity and their experiences with male partner contraceptive sabotage.

CONCLUSION: Our findings suggest that the current conceptual framework that views pregnancy-related behaviors from a strict planned behavior perspective may be limited, particularly among low-income populations.

IMPLICATIONS: This study identified several cognitive and interpersonal pathways to unintended pregnancy among low-income women in Pittsburgh, PA, including perceptions of low reproductive control, perceptions of low fecundity and male partner reproductive coercion.


Health and disease in children born after assistive reproductive therapies (ART

A G Sutcliffe

Royal Free and University College Medical School, Department of Paediatrics and Child Health, Royal Free Campus, NW3 2PF, London, UK. icsi@rfc.ucl.ac.uk

Abstract: In vitro fertilisation (IVF) and other assisted reproductive therapies (ART) offer hope to subfertile couples worldwide. At least 5 million ART children have been born to date. Their health is an issue that is increasingly relevant: first, to those children and young adults themselves; second, to couples considering fertility treatment; and third, to the general population as ART has progressed from experimental treatment to routine practice. Many concerns about the potential risks to these children have been voiced with varying degrees of supportive evidence. This article summarises some key long-term data. Current evidence suggests that ART does increase risk of: higher order pregnancy (with its inherent pre- and perinatal risks); prematurity and low birth weight; congenital malformations in particular of the male urogenital system; imprinting disorders. Reassuringly, evidence points away from an increased overall cancer risk or differences in neurodevelopmental outcomes. Many unknowns remain, including future fertility and cardiovascular risks and risk of cerebral palsy.


Depressive symptoms and their relationship with endogenous reproductive hormones and sporadic anovulation in premenopausal women

Enrique F Schisterman

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Jean Wactawski-Wende

Department of Epidemiology and Environmental Health, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY.

Abstract:
Purpose: To determine whether depressive symptoms are associated with ovulation or reproductive hormone concentrations in eumenorrheic women without a reported diagnosis of clinical depression.

Methods: A prospective cohort of 248 regularly menstruating women, aged 18 to 44 years (27.3 ± 8.2) were evaluated for depressive symptoms at baseline using the 20-item Center for Epidemiological Studies Depression (CES-D) scale and categorized dichotomously (<16, no depressive symptoms [92%] vs. ≥ 16, depressive symptoms [8%]). Serum concentrations of estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone were measured up to eight times per cycle for up to two menstrual cycles. Linear mixed models estimated associations between depressive symptoms and hormone concentrations, whereas generalized linear mixed models assessed their relationship with sporadic anovulation.

Results: No significant associations were identified between depressive symptoms and reproductive hormone levels (all P > .05) or the odds of sporadic anovulation (adjusted odds ratio, 1.1; 95% confidence interval, [0.02-5.0]), after adjusting for age, race, body mass index, perceived stress level, and alcohol consumption.

Conclusions: Despite reported associations between mental health and menstrual cycle dysfunction, depressive symptoms were not associated with reproductive hormone concentrations or sporadic anovulation in this cohort of regularly menstruating women with no recent (within 1 year) self-reported history of clinical depression.


Between Advanced Medical Technology and Prayer: Infertility Treatment in Post-socialist Poland*

Abstract: In Poland, invitro fertilisation technology (IVF) has been in use for over 25 years, garnering success and social approval. However, in 2007, a heated debate erupted on the moral, legal and economic aspects of IVF. A growing chorus of emphatic Catholic voices calls for IVF to be banned. This paper focuses on 'naprotechnology', a new actor and a fresh card in Poland's IVF debate. This method of treating infertility in accordance with the teachings of the Catholic Church is promoted as a cheaper and more effective alternative to IVF. Naprotechnology is primarily based on close observation of the female fertility cycle, but also involves pharmacological or surgical treatments. Most Polish gynecologists specialising in infertility treatments are strongly critical of the method, which is seldom referenced in international medical literature. Nonetheless, naprotechnology has considerable exposure in major Polish media outlets. The method has been debated in the Polish Parliament and is promoted by many politicians. The author argues that, despite the possible perception of naprotechnology as an emancipating force, it is in fact a form of a colonisation of the female body and strengthens traditional gender imagery and modern forms of discipline (control, confession, body regimes).


Treating morning sickness in the United States--changes in prescribing are needed

Abstract: Presently, 97.7% of prescriptions for the treatment of nausea and vomiting in pregnancy in the United States are with medications not labeled for use in pregnancy, not indicated for nausea and vomiting in pregnancy, and not classified as safe in pregnancy by the Food and Drug Administration. The use of ondansetron for nausea and vomiting in pregnancy has increased from 50,000 monthly prescriptions in 2008 to 110,000 at the end of 2013, despite unresolved issues regarding fetal safety and Food and Drug Administration warnings about serious dysrhythmias. In April 2013, the Food and Drug Administration approved the combination of doxylamine and pyridoxine, specifically for nausea and vomiting in pregnancy symptoms. Now that a safe and effective drug is available in the United States, there is no reason for women to be exposed to a drug of unproven maternal and fetal safety.

American journal of obstetrics and gynecology


Is There a Relationship between Mood Disorders and Dysmenorrhea?

Abstract:
Objective: Menstrual problems are common among adolescent females. Mood changes are related to menstrual problems (menorrhagia, dysmenorrhea, and abnormal menstrual cycle length). The aim of this study was to determine the relationship between depressive symptoms, anxiety, and premenstrual syndrome (PMS) with dysmenorrhea in adolescent girls.

Methods: A total of 159 adolescent girls (aged 13-19 y) with regular menstrual cycles presenting to the gynecology clinic with any complaints were included in the study during April-May 2013. All of the participants filled up the sociodemographic data collection form, FACES Pain Rating Scale, Beck anxiety inventory (BAI), Beck depression inventory (BDI), and a questionnaire form on criteria for PMS. Mann-Whitney U and chi-square tests were used to analyze the data.

Results: The prevalence of dysmenorrhea was 67.9%. The mean BAI and BDI scores of the patients were 13.64 ± 12.81 and 11.88 ± 10.83, respectively. Statistically significant differences were observed between patients and control groups on the BAI and BDI scoring (P < .05). At least 1 of the symptoms of the PMS was detected in all of the participants and 29 (18.2%) of them were diagnosed as premenstrual dysphoric disorder (PMDD). The mean BAI score of the patients with PMS and PMDD were 9.65 ± 9.28 and 21.31 ± 15.75, respectively. The mean BDI score of the patients with PMS and PMDD were 8.39 ± 8.62 and 19.1 ± 11.85, respectively. Statistically significant differences were observed between PMS/PMDD and BAI/BDI scoring (P = .00).

Conclusion: Adolescent girls with dysmenorrhea have an increased risk of depression and anxiety. These results of our study are significant in emphasizing the importance of a multidisciplinary approach to primary dysmenorrhea follow-up and treatment.

Journal of Pediatric and Adolescent Gynecology


Is Postpartum Depression a Disease of Modern Civilization?

Abstract: Access to calorie-dense foods, medicine, and other comforts has made modern humans healthier than our prehistoric ancestors in many respects. However, the epidemics of obesity, diabetes, and cardiovascular disease suggest that there are also drawbacks to modern living. Here, we address the question of whether the dramatic cultural changes that have occurred over the past century have inflated rates of postpartum depression, adding postpartum depression to the list of "diseases of modern civilization." We review evidence from cross-cultural, epidemiological, and experimental studies documenting associations between postpartum depression and modern patterns of early weaning, diets deficient in essential fatty acids, low levels of physical activity, low levels of sun exposure, and isolation from kin support networks, all of which mark significant divergences from lifestyles believed to have been typical throughout human evolutionary history. This "mismatch hypothesis" of postpartum depression integrates research across diverse research areas and generates novel predictions.

Current directions in psychological science


'Fertility Awareness-Based Methods' and subfertility: a systematic review

A Meier

Faculty of Medicine and Life Sciences, Hasselt University, Martelarenlaan 42, 3500 Hasselt, Belgium.

W Ombelet

Genk Institute for Fertility Technology, Department of Obstetrics and Gynaecology, Ziekenhuis Oost-Limburg, Schiepse Bos 6, 3600 Genk, Belgium. ; Faculty of Medicine and Life Sciences, Hasselt Univ...

Abstract: Fertility awareness based methods (FABMs) can be used to ameliorate the likelihood to conceive. A literature search was performed to evaluate the relationship of cervical mucus monitoring (CMM) and the day-specific -pregnancy rate, in case of subfertility. A MEDLINE search revealed a total of 3331 articles. After excluding articles based on their relevance, 10 studies and were selected. The observed studies demonstrated that the cervical mucus monitoring (CMM) can identify the days with the highest pregnancy rate. According to the literature, the quality of the vaginal discharge correlates well with the cycle-specific probability of pregnancy in normally fertile couples but less in subfertile couples. The results indicate an urgent need for more prospective randomised trials and -prospective cohort studies on CMM in a subfertile population to evaluate the effectiveness of CMM in the subfertile couple.


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

Vancouver Hospital and Health Sciences Centre

Christopher S Kovacs

Memorial University of Newfoundland, St John’s, NL, Canada

Jonathan D Adachi

McMaster University, Hamilton, ON, Canada

William D Leslie

University of Manitoba, Winnipeg, MB, Canada

Brian C Lentle

Department of RadiologyUniversity of British ColumbiaVancouverBCCanada

Abstract:
Background: 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.

Methods: 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.

Results: 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).

Interpretation: There are sex differences in the predominant sites and age-gradients of fracture. In older men, competing mortality exceeds cumulative fracture risk.


Favorable effects of vitamin D supplementation on pregnancy outcomes in gestational diabetes: a double blind randomized controlled clinical trial

Abstract: Gestational diabetes mellitus (GDM) has been recognized as a significant risk factor for unfavorable pregnancy outcomes. Prevalence of vitamin D deficiency is highly prevalent among women with GDM. This study was designed to assess the effect of vitamin D supplementation on pregnancy outcomes of pregnant women with GDM who were not on oral hypoglycemic agents. This randomized controlled clinical trial was performed among 45 pregnant women diagnosed with GDM at 24-28 weeks' gestation. Subjects were randomly assigned to consume either vitamin D supplements (cholecalciferol) or placebo. Individuals in the vitamin D group (n=22) received 50 000 IU vitamin D3 pearl 2 times during the study: at study baseline and day 21 of intervention and those in placebo group (n=23) received 2 placebos at the mentioned times. Fasting blood samples were taken at baseline to measure fasting plasma glucose. Participants underwent a 3-h oral glucose tolerance tests (OGTT) and the blood samples were collected at time 60, 120, and 180 min to measure plasma glucose levels. Newborn's weight, height, head circumference, Apgar score, and hyperbilirubinemia were determined. Taking vitamin D supplements, compared with placebo, resulted in improved pregnancy outcomes; such that those in the vitamin D group had no case of polyhydramnios, while 17.4% of subjects in placebo group had this condition (p=0.04). In addition, newborn's hyperbilirubinemia was significantly lower in vitamin D group than that in placebo group (27.3% vs. 60.9%, p=0.02). In conclusion, vitamin D supplementation for 6 weeks among pregnant women with GDM resulted in decreased maternal polyhydramnios and infant hyperbilirubinemia compared with placebo. Clinical trial registration number www.irct.ir:IRCT201305115623N7.

Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et  Metabolisme


Neonatal survival after prolonged preterm premature rupture of membranes before 24 weeks of gestation

Abstract:
OBJECTIVE: To evaluate neonatal survival after prolonged preterm premature rupture of membranes (PROM) in the era of antenatal corticosteroids, surfactant, and inhaled nitric oxide.

METHODS: A single-center retrospective cohort study of neonates born from 2002-2011 after prolonged (1 week or more) preterm (less than 24 weeks of gestation) rupture of membranes was performed. The primary outcome was survival to discharge. Neonates whose membranes ruptured less than 24 hours before delivery (n=116) were matched (2:1) on gestational age at birth, sex, and antenatal corticosteroid exposure with neonates whose membranes ruptured 1 week or more before delivery (n=58). Analysis used conditional logistic regression for categorical data and Wilcoxon signed rank test for continuous data.

RESULTS: The prolonged preterm PROM exposed and unexposed cohorts had survival rates of 90% and 95%, respectively, although underpowered to assess the statistical significance (P=.313). Exposed neonates were more likely have pulmonary hypoplasia (26/58 exposed, 1/114 unexposed, P<.001), pulmonary hypertension (21/56 exposed, 10/112 unexposed, P<.001), and pulmonary air leak (21/58 exposed, 14/114 unexposed, P<.001). Gestational age at rupture (20.4 weeks exposed, 22.3 weeks unexposed, P=.189), length of rupture (3.7 weeks exposed, 6.4 weeks unexposed, P=.717), and lowest maximal vertical pocket before 24 weeks of gestation (0 cm exposed, 1.4 cm unexposed, P=.114) did not discriminate between survivors and nonsurvivors after exposure to prolonged preterm PROM.

CONCLUSION: With antenatal steroid exposure and aggressive pulmonary management, survival to discharge after prolonged preterm PROM was 90%. Pulmonary morbidities were common. Of note, the data were limited to women who remained pregnant 1 week or longer after rupture of membranes.


Chapter 19: Targeted Hormone Assessment of the Menstrual Cycle

Arlete Fernandes

Universidade Estadual de Campinas (UNICAMP)

Thomas W Hilgers

Pope Paul VI Institute for the Study of Human Reproduction, Omaha, Nebraska.

The Medical and Surgical Practice of NaProTECHNOLOGY


Letrozole or clomiphene for infertility in the polycystic ovary syndrome

Eunice Kennedy Shriver NICHD Reproductive Medicine Network

Richard S Legro

Penn State Milton S. Hershey Medical Center


Is a foetus developing in a sterile environment?

T M Wassenaar

Molecular Microbiology and Genomics Consultants (Germany)

Abstract: Novel findings in microbiology question the long-standing paradigm that a healthy pregnancy implies a sterile uterus. It now seems that the placenta is frequently colonized with bacteria, and a placental microbiome has been identified. Recent literature findings are summarized here, and an attempt is made to separate pathological bacterial presence from a naturally occurring microbiome.


Diagnosing and managing low serum testosterone

Abstract: Measuring testosterone levels became easier in the 1970s, and it wasn't long before levels were being checked in men across all age groups. At that time, several authors reported an age-associated decline of serum testosterone levels beginning in the fourth or fifth decades of life. Other studies found that the decline in testosterone with age might be more related to comorbidities that develop in many aging men. Aggressive marketing campaigns by pharmaceutical companies have led to increased awareness of this topic, and primary care physicians are seeing more patients who are concerned about "low T." Unfortunately, testosterone replacement therapy has not been straightforward. Many men with low testosterone levels have no symptoms, and many men with symptoms who receive treatment and reach goal testosterone levels have no improvement in their symptoms. The actual prevalence of hypogonadism has been estimated to be 39% in men aged 45 years or older presenting to primary care offices in the United States. As the US population ages, this number is likely to increase. This article, targeted to primary care physicians, reviews the concept of late-onset hypogonadism, describes how to determine the patients who might benefit from therapy, and offers recommendations regarding the workup and initiation of treatment.

Proceedings (Baylor University. Medical Center)


World Endometriosis Research Foundation Endometriosis Phenome and Biobanking  Harmonisation Project: IV. Tissue collection, processing, and storage in  endometriosis research

Fassbender A, Rahmioglu N, Vitonis AF, Viganò P, Giudice LC, D'Hooghe TM, Hummelshoj L, Adamson GD, Becker CM, Missmer SA, Zondervan KT

Abstract:
Objective: To harmonize standard operating procedures (SOPs) and standardize the recording of associated data for collection, processing, and storage of human tissues relevant to endometriosis.
Design: An international collaboration involving 34 clinical/academic centers and three industry collaborators from 16 countries on five continents.
Setting: In 2013, two workshops were conducted followed by global consultation, bringing together 54 leaders in endometriosis research and sample processing from around the world. PATIENT(S): None. INTERVENTION(S): Consensus SOPs were based on: 1) systematic comparison of SOPs from 24 global centers collecting tissue samples from women with and without endometriosis on a medium or large scale (publication on >100 cases); 2) literature evidence where available, or consultation with laboratory experts otherwise; and 3) several global consultation rounds. MAIN OUTCOME MEASURE(S): Standard recommended and minimum required SOPs for tissue collection, processing, and storage in endometriosis research. RESULT(S): We developed "recommended standard" and "minimum required" SOPs for the collection, processing, and storage of ectopic and eutopic endometrium, peritoneum, and myometrium, and a biospecimen data collection form necessary for interpretation of sample-derived results. CONCLUSION(S): The EPHect SOPs allow endometriosis research centers to decrease variability in tissue-based results, facilitating between-center comparisons and collaborations. The procedures are also relevant to research into other gynecologic conditions involving endometrium, myometrium, and peritoneum. The consensus SOPs are based on the best available evidence; areas with limited evidence are identified as requiring further pilot studies. The SOPs will be reviewed based on investigator feedback and through systematic triannual follow-up. Updated versions will be made available at: http://endometriosisfoundation.org/ephect.


World Endometriosis Research Foundation Endometriosis Phenome and Biobanking  Harmonization Project: II. Clinical and covariate phenotype data collection in  endometriosis research

Vitonis AF, Vincent K, Rahmioglu N, Fassbender A, Buck Louis GM, Hummelshoj L, Giudice LC, Stratton P, Adamson GD, Becker CM, Zondervan KT, Missmer SA

Abstract:
Objective: To harmonize the collection of nonsurgical clinical and epidemiologic data relevant to endometriosis research, allowing large-scale collaboration.
Design: An international collaboration involving 34 clinical/academic centers and three industry collaborators from 16 countries on five continents.
Setting: In 2013, two workshops followed by global consultation, bringing together 54 leaders in endometriosis research.

Patients: None. INTERVENTION(S): Development of a self-administered endometriosis patient questionnaire (EPQ), based on [1] systematic comparison of questionnaires from eight centers that collect data from endometriosis cases (and controls/comparison women) on a medium to large scale (publication on >100 cases); [2] literature evidence; and [3] several global consultation rounds. MAIN OUTCOME MEASURE(S): Standard recommended and minimum required questionnaires to capture detailed clinical and covariate data. RESULT(S): The standard recommended (EPHect EPQ-S) and minimum required (EPHect EPQ-M) questionnaires contain questions on pelvic pain, subfertility and menstrual/reproductive history, hormone/medication use, medical history, and personal information. CONCLUSION(S): The EPQ captures the basic set of patient characteristics and exposures considered by the WERF EPHect Working Group to be most critical for the advancement of endometriosis research, but is also relevant to other female conditions with similar risk factors and/or symptomatology. The instruments will be reviewed based on feedback from investigators, and-after a first review after 1 year-triannually through systematic follow-up surveys. Updated versions will be made available through http://endometriosisfoundation.org/ephect.


How Humanae vitae has advanced reproductive health

Abstract: By encouraging doctors and scientists to improve the regulation of births through the observation of natural fertility rhythms, Humanae vitae promoted the development of natural family planning (NFP). The study of NFP has lead to NFP-based methodologies in reproductive healthcare that are promoting advances in treatment of infertility, miscarriage, and a number of reproductive health disorders. In contrast, the contraceptive mentality has stunted the development of reproductive healthcare. Humanae vitae has provided a great gift to science and reproductive healthcare that all Catholics should be proud of.


billingsMentor: Adapting natural family planning to information technology and  relieving the user of unnecessary tasks

Abstract: BillingsMentor is an automated Web-based service for the Billings Method of natural family planning in which the guidance and interpretation previously communicated from teacher to student is provided by programmed algorithms. There are two functions: (1) to instruct the client to generate proper descriptions of her fertility symptoms; and (2) to interpret the symptoms efficiently according to the Billings Method and to communicate the results to the client. The efficiency of billingsMentor was tested by using the historical records of students who were under the guidance of a teacher to emulate their experience under the guidance of billingsMentor. The results indicate that billingsMentor performs as well as the teacher/student in recognizing the peak of fertility but it is slightly less efficient than the teacher/student in establishing the basic infertile pattern. Advantages that arise from adapting natural family planning to information technology are discussed.


Hormonal contraception, thrombosis and age

Abstract: Introduction: This paper reviews the risk of thrombosis with use of different types of hormonal contraception in women of different ages. AREAS COVERED: Combined hormonal contraceptives with desogestrel, gestodene, drospirenone or cyproterone acetate (high-risk products) confer a sixfold increased risk of venous thromboembolism as compared with nonusers, and about twice the risk as compared with users of products with norethisterone, levonorgestrel or norgestimate (low-risk products). Transdermal patches and vaginal ring belong to high-risk products. The risk of thrombotic stroke and myocardial infarction is increased 50 - 100% with use of combined products, with little difference in risk between different progestins. Progestin-only products do not confer any increased risk of venous or arterial thrombosis, except for progestin depot, which may double the risk of venous thrombosis. EXPERT Opinion: First choice in women below 35 years should be a combined low-risk pill, that is, with a second-generation progestin, with the lowest compliable dose of estrogen. Young women with risk factors of thrombosis such as age above 35 years, genetic predispositions, adiposity, polycystic ovary syndrome, diabetes, smoking, hypertension or migraine with aura should not use high-risk products, but should primarily consider progestin-only products, and be careful to use low-risk combined products.


Impact of instruction in the Creighton model fertilitycare system on time to pregnancy in couples of proven fecundity: results of a randomised trial

Abstract:
BACKGROUND: The Creighton Model FertilityCare System (CrMS) teaches women to identify days when intercourse is likely to result in pregnancy. We sought to assess the impact of the CrMS on time to pregnancy (TTP), via per-cycle pregnancy rates (fecundability).

METHODS: We conducted a parallel randomised trial at the University of Utah School of Medicine, 2003-06. Women ages 18-35 years, in a relationship of proven fertility, who desired to conceive, were block-randomised and stratified for age, with allocation concealment by opaque sequentially numbered sealed envelopes. The control group received the advice to have intercourse 2-3 times per week, and the intervention group received CrMS instruction. All women were asked to begin trying to conceive starting the second cycle in the study and were followed actively up to seven cycles, without blinding of research personnel. We calculated descriptive statistics and fecundability, and estimated Cox models for TTP. (Clinicaltrials.gov NCT00161395).

RESULTS: There were 143 women randomised: 71 to the control group (all analysed) and 72 to the CrMS group (69 analysed). The adjusted hazard ratio for the influence of CrMS on TTP was 0.86 [95% confidence interval (CI): 0.53, 1.38]. Fecundability in cycles with intent to conceive was 31% in controls and 36% with CrMS (P = 0.32). By the first cycle, fecundability was 17% in controls, and 4% with CrMS (P = 0.02). No adverse events were reported.

CONCLUSIONS: We found no significant impact of CrMS on TTP or fecundability, but fewer of the women receiving CrMS conceived by the first cycle.


Air bubble saline infused sonography (SIS) is equivalent to hysterosalpingogram (HSG) in assessment of tubal patency


Ethical Problems in the Use of Hormonal Contraception

Abstract: The development of hormonal contraception introduced a new era in medical practice, marked by the suppression of female fertility by interventions in the hormonal system. The interventions are very grave, as sex hormones are of existential importance both to preserve human life and to preserve the human species. This article conducts an ethical evaluation of the use of hormonal contraception through two ethical theories: natural law theory and virtue ethics. Based on philosophical reflection, the author examines what effects hormonal contraception has on primary goods and whether its use is congruent with the cardinal virtues. National Catholic Bioethics Quarterly 14.3 (Autumn 2014): 491–524.

The national Catholic bioethics quarterly


The laparoscopic management of endometriosis in patients with pelvic pain

Abstract: Endometriosis, an underdiagnosed and undertreated condition, affects 1 in 10 women and is associated with pain and infertility. Preoperative evaluation should include testing and management of other causes of pelvic pain. Ultrasonography can aid in surgical planning. Hormonal suppression improves symptoms, but should not be used to diagnose endometriosis, and is not shown to be effective in preventing disease recurrence nor in improving fertility. The goal of surgical management should be optimal removal or treatment of disease and should include measures for adhesion prevention. Rates of recurrence of endometriosis depend on the surgical completeness of removing the disease.

Obstetrics and Gynecology Clinics of North America


World Endometriosis Research Foundation Endometriosis Phenome and Biobanking  Harmonisation Project: I. Surgical phenotype data collection in endometriosis  research

Becker CM, Laufer MR, Stratton P, Hummelshoj L, Missmer SA, Zondervan KT, Adamson GD

Abstract:
Objective: To standardize the recording of surgical phenotypic information on endometriosis and related sample collections obtained at laparoscopy, allowing large-scale collaborative research into the condition.
Design: An international collaboration involving 34 clinical/academic centers and three industry collaborators from 16 countries.
Setting: Two workshops were conducted in 2013, bringing together 54 clinical, academic, and industry leaders in endometriosis research and management worldwide. PATIENT(S): None. INTERVENTION(S): A postsurgical scoring sheet containing general and gynecological patient and procedural information, extent of disease, the location and type of endometriotic lesion, and any other findings was developed during several rounds of review. Comments and any systematic surgical data collection tools used in the reviewers' centers were incorporated. MAIN OUTCOME MEASURE(S): The development of a standard recommended (SSF) and minimum required (MSF) form to collect data on the surgical phenotype of endometriosis. RESULT(S): SSF and MSF include detailed descriptions of lesions, modes of procedures and sample collection, comorbidities, and potential residual disease at the end of surgery, along with previously published instruments such as the revised American Society for Reproductive Medicine and Endometriosis Fertility Index classification tools for comparison and validation. CONCLUSION(S): This is the first multicenter, international collaboration between academic centers and industry addressing standardization of phenotypic data collection for a specific disease. The Endometriosis Phenome and Biobanking Harmonisation Project SSF and MSF are essential tools to increase our understanding of the pathogenesis of endometriosis by allowing large-scale collaborative research into the condition.


50 years of hormonal contraception-time to find out, what it does to our brain

Abstract: Hormonal contraceptives are on the market for more than 50 years and used by 100 million women worldwide. However, while endogenous steroids have been convincingly associated with change in brain structure, function and cognitive performance, the effects of synthetic steroids contained in hormonal contraceptives on brain and cognition have barely been investigated. In this article we summarize the sparse findings, describing brain structural, functional and behavioral findings from the literature and suggest that synthetic steroids may contribute to masculinizing as well as feminizing effects on brain and behavior. We try to identify methodological challenges, explain, how results on endogenous steroids may transfer into research on hormonal contraceptives and point out factors that need to be controlled in the study of hormonal contraceptive dependent effects. We conclude that there is a strong need for more systematic studies, especially on brain structural, functional and cognitive changes due to hormonal contraceptive use. The hormonal contraceptive pill is the major tool for population control. Hence, such behavioral changes could cause a shift in society dynamics and should not stay unattended.


Recent oral contraceptive use by formulation and breast cancer risk among women 20 to 49 years of age

Diana S M Buist

Group Health Research Institute, Group Health Cooperative, Seattle, Washington. Department of Epidemiology, University of Washington, Seattle, Washington.

William E Barlow

Division of Public Health Sciences, 2Division of Human Biology, Fred Hutchinson Cancer Research Center; Departments of 3Epidemiology, 4Biostatistics, and 5Pathology, University of Washington, Seatt...

Abstract: Previous studies of oral contraceptives and breast cancer indicate that recent use slightly increases risk, but most studies relied on self-reported use and did not examine contemporary oral contraceptive formulations. This nested case-control study was among female enrollees in a large U.S. integrated health care delivery system. Cases were 1,102 women ages 20 to 49 years diagnosed with invasive breast cancer from 1990 to 2009. Controls were randomly sampled from enrollment records (n = 21,952) and matched to cases on age, year, enrollment length, and medical chart availability. Detailed oral contraceptive use information was ascertained from electronic pharmacy records and analyzed using conditional logistic regression, ORs, and 95% confidence intervals (CI). Recent oral contraceptive use (within the prior year) was associated with an increased breast cancer risk (OR, 1.5; 95% CI, 1.3-1.9) relative to never or former OC use. The association was stronger for estrogen receptor-positive (ER(+); OR, 1.7; 95% CI, 1.3-2.1) than estrogen receptor-negative (ER(-)) disease (OR, 1.2, 95% CI, 0.8-1.8), although not statistically significantly different (P = 0.15). Recent use of oral contraceptives involving high-dose estrogen (OR, 2.7; 95% CI, 1.1-6.2), ethynodiol diacetate (OR, 2.6; 95% CI, 1.4-4.7), or triphasic dosing with an average of 0.75 mg of norethindrone (OR, 3.1; 95% CI, 1.9-5.1; Pheterogeneity compared with using other oral contraceptives = 0.004) was associated with particularly elevated risks, whereas other types, including low-dose estrogen oral contraceptives, were not (OR, 1.0; 95% CI, 0.6-1.7). Our results suggest that recent use of contemporary oral contraceptives is associated with an increased breast cancer risk, which may vary by formulation. If confirmed, consideration of the breast cancer risk associated with different oral contraceptive types could impact discussions weighing recognized health benefits and potential risks.


The effects of hormonal contraceptives on glycemic regulation

Abstract: A number of side effects have been linked to the use of hormonal contraceptives, among others, alterations in glucose levels. Hence, the objective of this mini-review is to show the main effects of hormonal contraceptive intake on glycemic regulation. First, the most relevant studies on this topic are described, then the mechanisms that might be accountable for this glycemic regulation impairment as exerted by hormonal contraceptives are discussed. Finally, we briefly discuss the ethical responsibility of health professionals to inform about the potential risks on glycemic homeostasis regarding hormonal contraceptive intake.


The impact of assisted reproductive technologies on intra-uterine growth and birth defects in singletons

Abstract: Pooled odds ratios from meta-analyses of infants born following assisted reproductive technologies (ART) compared with non-ART singletons show increases in low birth weight, preterm birth, small for gestational age, and birth defects. Although there have been small reductions in recent data, odds associated with these outcomes are still higher for ART singletons. Both ART procedures and underlying infertility contribute to these increased risks. Outcomes appear better for frozen-thawed compared with fresh embryo transfers, but are poorer than for non-ART infants. There is a concerning increase in large-for-gestational-age infants born following frozen-thawed embryo transfer and limited data on the effects of embryo vitrification used instead of slow-freezing techniques. Using large datasets, we now need to investigate risks of individual birth defects and disentangle the inter-related effects of different types of infertility and the multiple aspects of ART. Greater understanding of the causes of adverse ART outcomes and identification of modifiable risk factors may lead to further reductions in the disparities in outcome between ART and non-ART infants.


Biological variability in serum anti-Müllerian hormone throughout the menstrual cycle in ovulatory and sporadic anovulatory cycles in eumenorrheic women

M. R. Danaher

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), MSC 751...

Jean Wactawski-Wende

Department of Epidemiology and Environmental Health, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY.

Abstract:
Study Question: Does serum anti-Müllerian hormone (AMH) vary significantly throughout both ovulatory and sporadic anovulatory menstrual cycles in healthy premenopausal women?

Summary Answer: Serum AMH levels vary statistically significantly across the menstrual cycle in both ovulatory and sporadic anovulatory cycles of healthy eumenorrheic women.

What Is Known Already: Studies to date evaluating serum AMH levels throughout the menstrual cycle have conflicting results regarding intra-woman cyclicity. No previous studies have evaluated an association between AMH and sporadic anovulation.

STUDY DESIGN, SIZE, Duration: We conducted a prospective cohort study of 259 regularly menstruating women recruited between 2005 and 2007. PARTICIPANTS/MATERIALS, SETTING,

Methods: Women aged 18-44 years were followed for one (n = 9) or two (n = 250) menstrual cycles. Anovulatory cycles were defined as any cycle with peak progesterone concentration ≤5 ng/ml and no serum LH peak on the mid or late luteal visits. Serum AMH was measured at up to eight-time points throughout each cycle.

Main Results and the Role of Chance: Geometric mean AMH levels were observed to vary across the menstrual cycle (P < 0.01) with the highest levels observed during the mid-follicular phase at 2.06 ng/ml, decreasing around the time of ovulation to 1.79 ng/ml and increasing thereafter to 1.93 (mid-follicular versus ovulation, P < 0.01; ovulation versus late luteal, P = 0.01; mid-follicular versus late luteal, P = 0.05). Patterns were similar across all age groups and during ovulatory and anovulatory cycles, with higher levels of AMH observed among women with one or more anovulatory cycles (P = 0.03).

LIMITATIONS, Reasons for Caution: Ovulatory status was not verified by direct visualization. AMH was analyzed using the original Generation II enzymatically amplified two-site immunoassay, which has been shown to be susceptible to assay interference. Thus, absolute levels should be interpreted with caution, however, patterns and associations remain consistent and any potential bias would be non-differential. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrates a significant variation in serum AMH levels across the menstrual cycle regardless of ovulatory status. This variability, although statistically significant, is not large enough to warrant a change in current clinical practice to time AMH measurements to cycle day/phase.

Study Funding/competing Interests: This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD (Contracts # HHSN275200403394C, HHSN275201100002I Task 1 HHSN27500001). The authors have no conflicts of interest to declare.


Assessment of anovulation in eumenorrheic women: comparison of ovulation detection algorithms

Brian W Whitcomb

Department of Biostatistics & Epidemiology, University of Massachusetts Amherst, 715 N Pleasant Street, Amherst, MA, USA.

Audrey J Gaskins

Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, Georgia. Electronic address: Audrey.jane.gaskins@emory.edu.

Abstract:
Objective: To compare previously used algorithms to identify anovulatory menstrual cycles in women self-reporting regular menses.
Design: Prospective cohort study.
Setting: Western New York. PATIENT(S): Two hundred fifty-nine healthy, regularly menstruating women followed for one (n=9) or two (n=250) menstrual cycles (2005-2007). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Prevalence of sporadic anovulatory cycles identified using 11 previously defined algorithms that use E2, P, and LH concentrations. RESULT(S): Algorithms based on serum LH, E2, and P levels detected a prevalence of anovulation across the study period of 5.5%-12.8% (concordant classification for 91.7%-97.4% of cycles). The prevalence of anovulatory cycles varied from 3.4% to 18.6% using algorithms based on urinary LH alone or with the primary E2 metabolite, estrone-3-glucuronide, levels. CONCLUSION(S): The prevalence of anovulatory cycles among healthy women varied by algorithm. Mid-cycle LH surge urine-based algorithms used in over-the-counter fertility monitors tended to classify a higher proportion of anovulatory cycles compared with luteal-phase P serum-based algorithms. Our study demonstrates that algorithms based on the LH surge, or in conjunction with estrone-3-glucuronide, potentially estimate a higher percentage of anovulatory episodes. Addition of measurements of postovulatory serum P or urine pregnanediol may aid in detecting ovulation.


Melatonin and the circadian system: contributions to successful female reproduction

Abstract:
OBJECTIVE: To summarize the role of melatonin and circadian rhythms in determining optimal female reproductive physiology, especially at the peripheral level.

DESIGN: Databases were searched for the related English-language literature published up to March 1, 2014. Only papers in peer-reviewed journals are cited.

SETTING: Not applicable.

PATIENT(S): Not applicable.

INTERVENTION(S): Melatonin treatment, alterations of the normal light:dark cycle and light exposure at night.

MAIN OUTCOME MEASURE(S): Melatonin levels in the blood and in the ovarian follicular fluid and melatonin synthesis, oxidative damage and circadian rhythm disturbances in peripheral reproductive organs.

RESULT(S): The central circadian regulatory system is located in the suprachiasmatic nucleus (SCN). The output of this master clock is synchronized to 24 hours by the prevailing light-dark cycle. The SCN regulates rhythms in peripheral cells via the autonomic nervous system and it sends a neural message to the pineal gland where it controls the cyclic production of melatonin; after its release, the melatonin rhythm strengthens peripheral oscillators. Melatonin is also produced in the peripheral reproductive organs, including granulosa cells, the cumulus oophorus, and the oocyte. These cells, along with the blood, may contribute melatonin to the follicular fluid, which has melatonin levels higher than those in the blood. Melatonin is a powerful free radical scavenger and protects the oocyte from oxidative stress, especially at the time of ovulation. The cyclic levels of melatonin in the blood pass through the placenta and aid in the organization of the fetal SCN. In the absence of this synchronizing effect, the offspring may exhibit neurobehavioral deficits. Also, melatonin protects the developing fetus from oxidative stress. Melatonin produced in the placenta likewise may preserve the optimal function of this organ.

CONCLUSION(S): Both stable circadian rhythms and cyclic melatonin availability are critical for optimal ovarian physiology and placental function. Because light exposure after darkness onset at night disrupts the master circadian clock and suppresses elevated nocturnal melatonin levels, light at night should be avoided.


Anti-inflammatory effects of progesterone in lipopolysaccharide-stimulated BV-2 microglia

Abstract: Female sex is associated with improved outcome in experimental brain injury models, such as traumatic brain injury, ischemic stroke, and intracerebral hemorrhage. This implies female gonadal steroids may be neuroprotective. A mechanism for this may involve modulation of post-injury neuroinflammation. As the resident immunomodulatory cells in central nervous system, microglia are activated during acute brain injury and produce inflammatory mediators which contribute to secondary injury including proinflammatory cytokines, and nitric oxide. In this study, the authors examined the anti-inflammatory effects of progesterone on lipopolysaccharide-stimulated BV-2 microglia, characterizing progesterone's suppression of microglial inflammatory mediator production.


The role of the cervix in fertility: is it time for a reappraisal?

Abstract: Knowledge regarding the role of the cervix in fertility has expanded considerably over the past 20 years and in this article, we propose that it is now time for its function to be reappraised. First, we review the anatomy of the cervix and the vaginal ecosystem that it inhabits. Then, we examine the physiology and the role of the cervical mucus. The ongoing mystery of the exact mechanism of the sperm-cervical mucus interaction is reviewed and the key players that may unlock this mystery in the future are discussed. The soluble and cellular biomarkers of the lower female genital tract which are slowly being defined by contemporary research are reviewed. Attempts to standardize these markers, in this milieu, are hindered by the changes that may be attributed to endogenous or exogenous factors such as: age, hormonal changes during the menstrual cycle, ectropion, infection, smoking and exposure to semen during sexual intercourse. We review what is known about the immunology of the cervix. With the widespread use of large loop excision of the transformation zone (LLETZ) for treatment of cervical intraepithelial neoplasia, the anatomy of the cervix is changing for many women. While LLETZ surgery has had very positive effects in the fight against cervical cancer, we debate the impact it could have on a woman's fertility.


Characteristics of hyperparathyroid states in the Canadian multicentre  osteoporosis study (CaMos) and relationship to skeletal markers

Christopher S Kovacs

Memorial University of Newfoundland, St John’s, NL, Canada

Jonathan D Adachi

McMaster University, Hamilton, ON, Canada

Jerilynn C Prior

Vancouver Hospital and Health Sciences Centre

Abstract:
Context: PTH is an essential regulator of mineral metabolism; PTH hypersecretion may result in hyperparathyroidism including normocalcaemic, primary and secondary hyperparathyroidism.

Objective: To examine the characteristics of participants with hyperparathyroid states and the relationship to bone mineral density (BMD). DESIGN AND

Participants: A cross-sectional study of 1872 community-dwelling men and women aged 35+ years (mostly Caucasian) with available serum PTH from Year 10 Canadian Multicentre Osteoporosis Study follow-up (2005-07). PTH was determined using a second-generation chemiluminescence immunoassay.

OUTCOME MEASURES: L1-L4, femoral neck and total hip BMD.

Results: We established a PTH reference range (2·7-10·2 pmol/l) based on healthy participants (i.e. normal serum calcium, serum 25-hydroxyvitamin D, kidney function and body mass index, who were nonusers of antiresorptives, glucocorticoids and diuretics and not diagnosed with diabetes or thyroid disease). Participants with PTH levels in the upper reference range (5·6-10·2 pmol/l), representing a prevalence of 10·7%, had lower femoral neck and total hip BMD, by 0·030 g/cm(2) [95% confidence interval: 0·009; 0·051] and 0·025 g/cm(2) (0·001; 0·049), respectively, than those with levels 2·7-5·6 pmol/l. Participants with normocalcaemic and secondary hyperparathyroidism also had lower total hip BMD than those with levels 2·7-5·6 pmol/l, and CaMos prevalences of normocalcaemic, primary and secondary hyperparathyroidism were 3·3%, 1·4% and 5·2%, respectively.

Conclusion: We found reduced BMD in participants with accepted hyperparathyroid states but also a notable proportion of other participants that might benefit from having lower PTH levels.


Cancer risk in women using the levonorgestrel-releasing intrauterine system in  Finland

Eero Pukkala

Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Unioninkatu 22, 00130, Helsinki, Finland.

Abstract:
Objective: To examine the association between premenopausal use of the levonorgestrel-releasing intrauterine system and cancer incidence in Finland with a special focus on endometrial adenocarcinoma.

Methods: All Finnish women aged 30-49 years using a levonorgestrel-releasing intrauterine system for treatment of menorrhagia in 1994-2007 (n=93,843) were identified from the National Reimbursement Registry and linked to the Finnish Cancer Registry data. The incidence of cancers in levonorgestrel-releasing intrauterine system users was compared with that in the general population.

Results: A total of 2,781 cancer cases were detected in levonorgestrel-releasing intrauterine system users during the follow-up of 855,324 women-years. The standardized incidence ratio (observed-to-expected ratio) for endometrial adenocarcinoma was 0.50 (95% confidence interval [CI] 0.35-0.70; 34 observed compared with 68 expected cases) after the first levonorgestrel-releasing intrauterine system purchase and 0.25 (95% CI 0.05-0.73; three observed compared with 12 expected cases) after two purchases. The standardized incidence ratio for ovarian cancer was 0.60 (95% CI 0.45-0.76; 59 observed compared with 99 expected cases), for pancreatic cancer 0.50 (95% CI 0.28-0.81; 15 observed compared with 30 expected cases), and for lung cancer 0.68 (95% CI 0.49-0.91; 43 observed compared with 63 expected cases). The standardized incidence ratio for breast cancer among all levonorgestrel-releasing intrauterine system users was 1.19 (95% CI 1.13-1.25; 1,542 observed compared with 1,292 expected cases).

Conclusion: The levonorgestrel-releasing intrauterine system may have a protective effect against endometrial malignant transformation. Using the levonorgestrel-releasing intrauterine system for treatment of menorrhagia during reproductive years was associated with a lower incidence of endometrial, ovarian, pancreatic, and lung cancers than expected. Levonorgestrel-releasing intrauterine system use was associated with a higher than expected incidence of breast cancer. LEVEL OF EVIDENCE: II.


Infertility and impaired fecundity in the United States, 1982-2010: data from the National Survey of Family Growth

Abstract:
OBJECTIVES: This report presents nationally representative estimates and trends for infertility and impaired fecundity-two measures of fertility problems-among women aged 15-44 in the United States. Data are also presented on a measure of infertility among men aged 15-44.

METHODS: Data for this report come primarily from the 2006-2010 National Survey of Family Growth (NSFG), which consisted of 22,682 interviews with men and women aged 15-44, conducted from June 2006 through June 2010. The response rate for women in the 2006-2010 NSFG was 78%, and for men was 75%. Selected trends are shown based on prior NSFG years.

RESULTS: The percentage of married women aged 15-44 who were infertile fell from 8.5% in 1982 (2.4 million women) to 6.0% (1.5 million) in 2006-2010. Impaired fecundity among married women aged 15-44 increased from 11% in 1982 to 15% in 2002, but decreased to 12% in 2006-2010. Among all women, 11% had impaired fecundity in 2006-2010. Both infertility and impaired fecundity remain closely associated with age for nulliparous women. Among married, nulliparous women aged 35-44, the percentage infertile declined from 44% in 1982 to 27% in 2006-2010, reflecting greater delays in childbearing over this period. Among married women in 2006-2010, non-Hispanic black women were more likely to be infertile than non-Hispanic white women. Some form of infertility (either subfertility or nonsurgical sterility) was reported by 9.4% of men aged 15-44 and 12% of men aged 25-44 in 2006-2010, similar to levels seen in 2002.


Processed meat intake is unfavorably and fish intake favorably associated with semen quality indicators among men attending a fertility clinic

Abstract: Emerging literature suggests that men's diets may affect spermatogenesis as reflected in semen quality indicators, but literature on the relation between meat intake and semen quality is limited. Our objective was to prospectively examine the relation between meat intake and indicators of semen quality. Men in subfertile couples presenting for evaluation at the Massachusetts General Hospital Fertility Center were invited to participate in an ongoing study of environmental factors and fertility. A total of 155 men completed a validated food-frequency questionnaire and subsequently provided 338 semen samples over an 18-mo period from 2007-2012. We used linear mixed regression models to examine the relation between meat intake and semen quality indicators (total sperm count, sperm concentration, progressive motility, morphology, and semen volume) while adjusting for potential confounders and accounting for within-person variability across repeat semen samples. Among the 155 men (median age: 36.1 y; 83% white, non-Hispanic), processed meat intake was inversely related to sperm morphology. Men in the highest quartile of processed meat intake had, on average, 1.7 percentage units (95% CI: -3.3, -0.04) fewer morphologically normal sperm than men in the lowest quartile of intake (P-trend = 0.02). Fish intake was related to higher sperm count and percentage of morphologically normal sperm. The adjusted mean total sperm count increased from 102 million (95% CI: 80, 131) in the lowest quartile to 168 million (95% CI: 136, 207) sperm in the highest quartile of fish intake (P-trend = 0.005). Similarly, the adjusted mean percentages of morphologically normal sperm for men in increasing quartiles of fish intake were 5.9 (95% CI: 5.0, 6.8), 5.3 (95% CI: 4.4, 6.3), 6.3 (95% CI: 5.2, 7.4), and 7.5 (95% CI: 6.5, 8.5) (P-trend = 0.01). Consuming fish may have a positive impact on sperm counts and morphology, particularly when consumed instead of processed red meats.


Light Elimination Therapy for the Treatment of Infertility (LET)

Abstract: Infertility remains a common and often unresolved condition afflicting certain couples. Numerous animal studies have demonstrated that alterations in the light-dark cycle can affect reproduction as mediated by the pineal gland and its hormone, melatonin. To examine whether a similar disruption could affect human fertility, a pilot study was conducted with infertile women enrolled in a Natural Family Planning program.


Sexual activity, endogenous reproductive hormones and ovulation in premenopausal women

Sunni L Mumford

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Jean Wactawski-Wende

Department of Epidemiology and Environmental Health, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY.

Abstract: We investigated whether sexual activity was associated with reproductive function in the BioCycle Study, a prospective cohort study that followed 259 regularly menstruating women aged 18 to 44years for one (n=9) or two (n=250) menstrual cycles in 2005-2007. Women were not attempting pregnancy nor using hormonal contraceptives. History of ever having been sexually active was assessed at baseline and frequency of sexual activity, defined as vaginal-penile intercourse, was self-reported daily throughout the study. Serum concentrations of estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone, and testosterone were measured up to 8times/cycle. Sporadic anovulation was identified using peak progesterone concentration. Linear mixed models were used to estimate associations between sexual activity and reproductive hormone concentrations and generalized linear models were used to estimate associations with sporadic anovulation. Models were adjusted for age, race, body mass index, perceived stress, and alcohol consumption and accounted for repeated measures within women. Elevated concentrations of estrogen (+14.6%, P<.01), luteal progesterone (+41.0%, P<.01) and mid-cycle LH (+23.4%, P<.01), but not FSH (P=.33) or testosterone (P=.37), were observed in sexually active women compared with sexually inactive women (no prior and no study-period sexual activity); sexually active women had lower odds of sporadic anovulation (adjusted odds ratio=0.34, 95% confidence interval: 0.16-0.73). Among sexually active women, frequency of sexual activity was not associated with hormones or sporadic anovulation (all P>.23). Findings from our study suggest that ever having been sexually active is associated with improved reproductive function, even after controlling for factors such as age.


Cervical cancer precursors and hormonal contraceptive use in HIV-positive women: application of a causal model and semi-parametric estimation methods

May Maloba

FACES, Family AIDS Care and Education Services, Kisumu, Kenya.

Abstract:
Objective: To demonstrate the application of causal inference methods to observational data in the obstetrics and gynecology field, particularly causal modeling and semi-parametric estimation.

Background: Human immunodeficiency virus (HIV)-positive women are at increased risk for cervical cancer and its treatable precursors. Determining whether potential risk factors such as hormonal contraception are true causes is critical for informing public health strategies as longevity increases among HIV-positive women in developing countries.

Methods: We developed a causal model of the factors related to combined oral contraceptive (COC) use and cervical intraepithelial neoplasia 2 or greater (CIN2+) and modified the model to fit the observed data, drawn from women in a cervical cancer screening program at HIV clinics in Kenya. Assumptions required for substantiation of a causal relationship were assessed. We estimated the population-level association using semi-parametric methods: g-computation, inverse probability of treatment weighting, and targeted maximum likelihood estimation.

Results: We identified 2 plausible causal paths from COC use to CIN2+: via HPV infection and via increased disease progression. Study data enabled estimation of the latter only with strong assumptions of no unmeasured confounding. Of 2,519 women under 50 screened per protocol, 219 (8.7%) were diagnosed with CIN2+. Marginal modeling suggested a 2.9% (95% confidence interval 0.1%, 6.9%) increase in prevalence of CIN2+ if all women under 50 were exposed to COC; the significance of this association was sensitive to method of estimation and exposure misclassification.

Conclusion: Use of causal modeling enabled clear representation of the causal relationship of interest and the assumptions required to estimate that relationship from the observed data. Semi-parametric estimation methods provided flexibility and reduced reliance on correct model form. Although selected results suggest an increased prevalence of CIN2+ associated with COC, evidence is insufficient to conclude causality. Priority areas for future studies to better satisfy causal criteria are identified.


Prospectively measured 10-year changes in health-related quality of life and  comparison with cross-sectional estimates in a population-based cohort of adult  women and men

Abstract:
Purpose: To prospectively assess changes in health-related quality of life (HRQOL) over 10 years, by age and sex, and to compare measured within-person change to estimates of change based on cross-sectional data.

Methods: Participants in the Canadian Multicentre Osteoporosis Study completed the 36-item short form (SF-36) in 1995/1997 and 2005/2007. Mean within-person changes for domain and summary components were calculated for men and women separately, stratified by 10-year age groups. Projected changes based on published ageand sex-stratified cross-sectional data were also calculated. Mean differences between the two methods were then estimated, along with the 95 % credible intervals of the differences.

Results: Data were available for 5,569/9,423 (59.1 %) of the original cohort. Prospectively collected 10-year changes suggested that the four physically oriented domains declined in all but the youngest group of men and women, with declines in the elderly men exceeding 25 points. The four mentally oriented domains tended to improve over time, only showing substantial declines in vitality and role emotional in older women, and all four domains in older men. Cross-sectional estimates identified a similar pattern of change but with a smaller magnitude, particularly in men. Correspondence between the two methods was generally high.

Conclusions: Changes in HRQOL may be minimal over much of the life span, but physically oriented HRQOL can decline substantially after middle age. Although clinically relevant declines were more evident in prospectively collected data, differences in 10-year age increments of cross-sectional data may be a reasonable proxy for longitudinal changes, at least in those under 65 years of age. Results provide additional insight into the natural progression of HRQOL in the general population.

Quality of Life Research : an International Journal of Quality of Life Aspects of  Treatment, Care and Rehabilitation


Fractures are increased and bisphosphonate use decreased in individuals with insulin-dependent diabetes: a 10 year cohort study

Abstract:
Background: Individuals with diabetes have been found previously to be at increased risk of non-traumatic fracture. However, it is unclear if these individuals are being identified and treated for osteoporosis.

Methods: 7753 Canadians over 50 years of age were followed prospectively for 10 years. 606/7753 (7.8%) of had diabetes; 98 were insulin-dependent and 508 were not. Using a cox proportional hazards model, we assessed the association between diabetes status and incident non-traumatic fracture. Using logistic regression we identified factors associated with bisphosphonate use over the 10 year period of study.

Results: Mean (SD) age of participants was 66.7(9.4) years and 72% were female. Those with diabetes had higher BMD T-scores at baseline, with a mean (SD) femoral neck T-Score of -0.97 (1.06), compared to -1.24 (0.99) in the general cohort. The adjusted hazard ratio (HR) for incident non-traumatic fracture in individuals with insulin-dependent diabetes over the 10 year study period was 2.50 (95% confidence interval [CI] 1.60, 3.90; p < 0.001). Despite this increased fracture rate, individuals with diabetes (insulin-dependent or non-insulin-dependent) were less likely to be on bisphosphonate therapy at any point over 10 years of prospective follow up compared to other CaMos subjects (odds ratio [OR]: 0.59; 95% CI 0.46-0.75, p < 0.001).

Conclusions: Despite the increased risk of non-traumatic fracture associated with insulin-dependent diabetes, we that found individuals with diabetes are less likely to be treated with a bisphosphonate than those without diabetes. These findings point to a possible care gap in the treatment of non-traumatic fractures in individuals with diabetes in Canada.


Coenzyme Q10 Supplementation and Oocyte Aneuploidy in Women Undergoing IVF-ICSI Treatment

Navid Esfandiari

Toronto Centre for Advanced Reproductive Technology, Toronto, Ontario, Canada. ; Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Toron...

Abstract:
BACKGROUND: The age-related reduction in live-birth rate is attributed to a high rate of aneuploidy and follicle depletion. We showed in an animal model that treatment with Coenzyme Q10 (CoQ10) markedly improved reproductive outcome. The aim of this study was to compare the post-meiotic oocyte aneuploidy rate in in vitro fertilization (IVF) and intra cytoplasmic sperm injection (ICSI) patients treated with CoQ10 or placebo.
METHODS: We conducted a double blind placebo controlled randomized trial that included IVF-ICSI patients 35-43 years of age. The patients were treated with either 600 mg of CoQ10 or an equivalent number of placebo caps. We compared the post-meiotic aneuploidy rate using polar body biopsy (PBBX) and comparative genomic hybridization (CGH). According to the power calculation, 27 patients were needed for each arm.
RESULTS: Owing to safety concerns regarding the effects of polar body biopsy on embryo quality and implantation, the study was terminated before reaching the target number of participants. A total of 39 patients were evaluated and randomized (17 CoQ10, 22 placebo), 27 were given the study medication (12 CoQ10, 15 placebo), and 24 completed an IVF-ICSI cycle including PBBX and embryo transfer (10 CoQ10, 14 placebo). Average age, base line follicle stimulating hormone (FSH), peak estradiol and progesterone serum level, as well as the total number of human menopausal gonadotropin (hMG) units-did not differ between the groups. The rate of aneuploidy was 46.5% in the CoQ10 group compared to 62.8% in the control. Clinical pregnancy rate was 33% for the CoQ10 group and 26.7% for the control group.
CONCLUSION: No significant differences in outcome were detected between the CoQ10 and placebo groups. However, the final study was underpowered to detect a difference in the rate of aneuploidy.

Clinical medicine insights. Reproductive health


Levonorgestrel in cases of rape: How does it work?

Abstract: The Ethical and Religious Directives for Catholic Health Care Services allows the use of an emergency contraceptive for a woman who has been raped, as a defense against her attacker's sperm, provided the drug prevents fertilization and does not act against a conceived human life. Catholic emergency rooms around the country have been pressured to provide Plan B (LNG-EC) to patients seeking help after a sexual assault. Catholic bioethicists have supported the use of this drug based on their interpretation of the scientific literature regarding its mechanism of action. This paper presents a review of the mechanisms of action of LNG-EC when given during the fertile window, showing a high probability that it acts against human life rather than preventing fertilization, and proposes another class of drugs as a possible alternative.


Practical resource for creating a Catholic living will

Abstract: Dear Editor, I read with interest the recent issue of the Linacre dedicated to geriatrics and end-of-life care. This is such a timely topic! With the implementation of Obamacare – which is government-run health care funded at the rate of economic inflation, not the more rapidly increasing healthcare inflation – there will be ever-increasing healthcare rationing. This will lead to escalating pressure to withhold life-preserving treatment (including food and water) especially to vulnerable populations including the elderly, the disabled, and the poor. As a result, end-of-life documents are already incredibly important and will become ever moreso. The article by Dr. Morrow articulates several key principles that should be present in an end-of-life document that adheres to Catholic principles – one that recognizes and respects the inherent dignity for human life for its own sake, one that ensure ordinary care and comfort care, and one that is “personalized” by appointing a healthcare proxy who understands and can implement your wishes according to the situation at hand. While there are several end-of-life document templates available, most do not adhere to the principles outlined in Dr. Morrow's article. A practical, easy-to-use resource for developing an end-of-life document that adheres firmly to the principles outlined in Dr. Morrow's article is the Will To Life Project developed by the National Right To Life Committee. From this website, one can download a legally valid document for any of the fifty states. While creating a Catholic end-of-life document can be daunting, this resource provides a practical starting point and a template anyone can complete. For more information, check out: http://www.nrlc.org/medethics/willtolive/.


The impact of assisted reproductive technologies on genomic imprinting and imprinting disorders

Abstract:
Purpose of reviewGenomic imprinting refers to preferential allele-specific gene expression. DNA methylation-based molecular mechanisms regulate establishment and maintenance of parental imprints during early embryo development and gametogenesis. Because of the coincident timing, a potential association between assisted reproductive technology (ART) procedures and imprinting defects has been investigated in various studies. In this review, we provide an overview of genomic imprinting and present a summary of the relevant clinical data.

Recent findings: ART procedures affect DNA methylation pattern, parental imprinting status, and imprinted gene expression in the mouse embryo. In humans, several case series suggested an association between ART and imprinting disorders, with a three-fold to six-fold higher prevalence of ART use among children born with Beckwith-Wiedemann syndrome compared to the general population. However, more recent studies failed to support these findings and could not demonstrate an association between imprinting disorders and ARTs, independent of subfertility.

Summary: ART procedures may affect methylation status of imprinted regions in the DNA, leading to imprinting disorders. Although the low prevalence of imprinting disorders makes it challenging to perform conclusive clinical trials, further studies in large registries are required to determine the real impact of ARTs on their occurrence.

Current Opinion in Obstetrics & Gynecology