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

K J Mather; Eric G Norman; Jerilynn C Prior; Thomas G Elliott

doi:10.1210/jcem.85.12.7011

Perimenopause and Menopause · Hormone Therapy

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

Mather KJ, Norman EG, Prior JC, Elliott TG

Published January 3, 2001 The Journal of Clinical Endocrinology and Metabolism, 85(12), 4644-4649

DOI 10.1210/jcem.85.12.7011 PMID 11134122

Abstract

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

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By this author

Luteal Phase · Luteal Phase Deficiency

The influence of the menstrual cycle on muscle injuries - a systematic review and meta-analysis

Guthardt Y et al., 2026 Sci Rep Free full text on PubMed Central

This systematic review and meta-analysis examined the relationship between menstrual cycle phases and the incidence of muscle injuries in female team sport athletes, following PRISMA 2020 and PERSiST guidelines. A comprehensive search was conducted in PubMed, Scopus, and SPORTDiscus from inception to mid-January 2024. Studies were included if they examined female team sport athletes of reproductive age with regular menstrual cycles and compared the occurrence of muscle injuries across at least two menstrual phases. Studies involving hormonal contraceptive use, medications affecting the menstrual cycle or musculoskeletal system, or menstrual dysfunction were excluded. Three studies met the inclusion criteria, involving 318 participants. Meta-analysis yielded a pooled Risk Ratio of 1.18 (95% CI: 0.75 to 1.86, p = 0.46) for injury risk between the luteal and follicular phases, suggesting no statistically significant association. However, the certainty of the cumulative evidence was rated as very low due to methodological limitations, including inconsistent phase classifications and reliance on imprecise methods for identifying menstrual phases. Consequently, no practical or clinical recommendations can be made at this time. Future research employing standardised, physiologically accurate methods for classifying and detecting menstrual cycle phases is necessary to better understand the potential links between hormonal fluctuations and injury risk.

Breast Health · Benign Breast Conditions

MON-154 Breast areolar diameter in healthy menstruating women—a single cycle cross-sectional study of associations with body size and ovulatory characteristics

Baaske AV et al., 2025 Journal of the Endocrine Society Free full text on PubMed Central

Tanner Breast Stage 3 (TB3, at menarche) and Tanner 5 (TB5, once ovulatory cycles established), despite being similar with an “upstanding” nipple, are different. Evidence suggests that steady and high ovulatory-level progesterone exposure accounts for the larger areolar diameter in TB5. Progesterone levels indicate whether the menstrual cycle is ovulatory and have crucial implications for women’s reproductive, metabolic, cardiovascular, and bone health. However, few data show average areolar diameter in regularly cycling women in whom SES, body size, and reproductive variables have been documented. As a step towards better understanding the role of areolar diameter in reflecting estradiol-progesterone balance, this study aims to document the average mean bilateral lateral areolar diameter (AD) in a cohort of regularly menstruating, premenopausal women in whom ovulation was documented in one cycle. We also aim to describe relationships between AD and demographic, anthropometric, and reproductive/ovulation variables. Women were eligible if aged 19-35 years with about month-apart cycles and no exogenous hormone use in the last 3-months. Participants completed one cycle with a daily Menstrual Cycle Diary© (cycle length, CL) and first morning temperatures for Quantitative Basal Temperature© (QBT©) ovulation analysis (normal luteal phase length ≥10 days). Questionnaires gathered SES, ethnic, general health, and reproductive characteristics. Bilateral horizontal areolar diameters were measured by a woman researcher with the participant supine in a warm room. From February 2020 to September 2022 (during the SARS-CoV-2 pandemic), 73 women from Metro Vancouver, British Columbia participated. Women were of median (min-max) age 30 (19-35) years, BMI 24.5 (17.1-41.4) and most identified as White (61.6%) with a median of 16 years of education. Median CL was 29 days (n=65) and QBT data showed 39.3% were normally ovulatory, 34.4% had short luteal phases and 26.2% were anovulatory. Median within-woman bilateral AD was 3.85 (2.35-8.00) cm. Left AD exceeded right (L 3.8 [2.3,8.2]; R 3.7 [ 2.4,7.8]; P=.003). Larger AD (≥3.85cm) was associated with greater body size (BMI r=.534), weight and waist circumference. However, earlier age at menarche (P=.02) was also significantly associated. No other reproductive variables (cycle length, luteal phase length, parity, ever use of CHC) were related to AD before body size adjustments. This study is the first to document, and describe demographic, anthropomorphic and reproductive associations with, AD in community dwelling, regularly cycling, premenopausal women. Future steps will determine the most influential of the anthropometric variables; adjustment for these will facilitate assessments of associations with ovulation related characteristics.

Breast Health · Benign Breast Conditions

SAT-128 Prospective 1-year Menstrual CycleBreast Tenderness and Swelling Experiences—data from healthy regularly cycling women initially proven normally ovulatory on two consecutive cycles

Wood M et al., 2025 Journal of the Endocrine Society Free full text on PubMed Central

Breast tenderness and swelling are associated with premenstrual symptoms but have not been well described in healthy, normally cycling women with known ovulatory status. There are documented negative health risks (in bone, the cardiovascular system and cancers) in association with ovulatory disturbances within normal-length cycles. Identifying breast changes across a predictable, month-apart cycle but with Subclinical Ovulatory Disturbances (SOD, short luteal phase [<10 days] and anovulation (with normal estradiol but lower or absent progesterone levels) could advance our understanding of menstrual cycle physiology, women’s health education and identification of those with chronic SOD who may benefit from cyclic progesterone therapy. Our objective was to determine whether within-woman breast tenderness and swelling experiences differed between normally ovulatory and ovulatory-disturbed cycles. In this 1-year prospective observational study, we examined daily breast tenderness (0-4) and swelling (1-5 change from usual = 3) experiences recorded via the Menstrual Cycle Diary© over ≥8 cycles (mean=13/woman) in 53 women. Ovulatory status was documented by the twice-validated Quantitative Basal Temperature© (QBT©) analysis. Cycle and ovulatory data were previously reported (Prior NEJM, 1990); Diary data were unreported. Participants were healthy, community-dwelling women, mean age 34 (32.4:35.5 years), BMI 22.0, primarily White, and about two-thirds were runners (for health or were marathon-training). Comparison of breast parameters in all normally ovulatory (n = 495) vs all SOD cycles (n = 199) (mean cycle length 28.1 [27.5-28.8 days]), showed significantly higher Breast Tenderness Score [intensity X days; 6.0 (range 1.0, 14.0) vs. 3.0 (0.0, 11.0) (P = .001)] and increased breast size [4.0 (2.0, 4.0) vs. 4.0 (0.0, 4.0) (P = .034]) in normally ovulatory cycles. However, in within-woman analysis (n = 47 women with both normally ovulatory and SOD cycles), breast tenderness/swelling did not significantly differ by ovulatory status. We plotted all ovulatory cycles (n=676) centred on ovulation; this revealed parallel timing of increases in breast tenderness and swelling in the late luteal phase. These 1-year prospective data documented that mild breast tenderness and swelling occurred before flow in cycles with normal ovulation; symptoms were less in SOD cycles. Breast changes were totally absent during the follicular phases.

Hormonal Agents · Progesterone and Progestins

"SUN-109 Feasibility of Cyclic Progesterone and Spironolactone for PCOS-specific Health-Related Quality of Life—a six-month, Phase II, single arm, single center, open-label study"

Nelson K et al., 2025 J Endocr Soc Free full text on PubMed Central

Polycystic ovary syndrome (PCOS) is an endocrine-metabolic disorder that significantly decreases health-related quality of life (HRQoL). Combined hormonal contraceptives (CHC) are standard-of-care for PCOS but do not mitigate the neuroendocrine cause nor women’s primary concerns. Treatment options need expansion. We hypothesized cyclic oral micronized progesterone (CyclicP4) and spironolactone (Sp) would improve HRQoL, decrease LH, and acne. This Phase II, open-label single-arm pilot study evaluated the 6-month cyclicP4 and Sp treatment feasibility and safety in androgenic PCOS. Our primary outcome was within-woman change in PCOS-HRQoL (PCOSQ). No sample size calculation was possible; 40 was considered feasible. Eligible women were 19-40 years with physician-diagnosed androgenic PCOS. Exclusion criteria included HbA1c > 6.4%, use of metformin or CHC in the last month. Participants received progesterone (300 mg/bedtime 14 days/month); spironolactone (200 mg/day) began in cycle two. Adherence was tracked daily (Menstrual Cycle Diary©) and by pill counts. Safety was assessed by post-study potassium (K+). Feasibility by women’s post-trial treatment intention. PCOSQ, serum LH, calculated bioavailable testosterone (cBAT), HbA1c, hsCRP, and AMH were measured at baseline and trial end. We also assessed perceived acne and sleep changes (-5 to +5), K+ and therapy intent at study end. Six-month change by paired t-test or Wilcoxon signed-rank assessed P < .05 as important. Of 109 expressing interest, 41 enrolled, 36 began therapy (5 did not), and 26 provided final questionnaire data (19 with complete lab data). Completing women were mean age 29 (SD 4.9) years, BMI 30.3 (8.1), 61.5% White and 73.1% with university degrees. Total PCOSQ scores within-woman increased from 3.5±1.0 to 4.9±1.1 (95% CI 3.1-3.8, 4.6-5.3; P<.0000001). Each PCOSQ domain significantly improved (at least P<.001) as did acne and sleep. Weight was unchanged but waist circumference decreased 1.1 cm (NS). LH, cBAT, and AMH each decreased: LH 10.0±5.4 to 8.5±5.2 IU/L (95% CI 7.6-12.3, 6.3-10.8; P<.4), cBAT 0.7±0.4 to 0.6±0.3 nmol/L (0.5-0.9, 0.5-0.8; P<.2), and AMH 10.5±6.5 to 9.7±5.7 ng/ml (7.4-13.7, 7.0-12.4; P<.4). hsCRP remained unchanged (2.8±3.3 to 2.7±3.6 mg/L; P<.8) as did HbA1c (5.2±0.3 to 5.2±0.3%; P<.0). K+ remained within the normal range (3.5-5.0 mmol/L) at final testing (mean 4.0). Two allergic responses to spironolactone and one frequent flow/religious practice led to discontinuation. Feasibility was confirmed and participants strongly preferred continuing therapy (median Likert score=6/7, P<.0001) CyclicP4 and Sp for 6-months was feasible and significantly improved HRQoL in a non-medicine-seeking community women cohort with androgenic PCOS. Though the small sample size limited generalizability, findings are promising. A larger randomized trial comparing CyclicP4 vs. CHC is warranted.

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Hormone Therapy · Benefits and Risks

Vascular responses to 17 beta-oestradiol in postmenopausal women

Riedel M et al., 1995 Eur J Clin Invest

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

Hormonal Agents · Progesterone and Progestins

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

Prior JC et al., 2014 PLoS One Free full text on PubMed Central

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

Hormonal Agents · Estrogen Preparations

Estrogen acutely increases peripheral blood flow in postmenopausal women

Volterrani M et al., 1995 Am J Med

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

Hormonal Agents · Progesterone and Progestins

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

Rosano GM et al., 2000 J Am Coll Cardiol

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

Perimenopause and Menopause › Hormone Therapy › Benefits and Risks · Reproductive Endocrinology › Ovarian Hormones › Progesterone

Jerilynn C Prior, Thomas G Elliott, Eric G Norman

J Prior, Tom Elliott, T Elliott, E Norman

PMID 11134122 11134122 DOI 10.1210/jcem.85.12.7011 10.1210/jcem.85.12.7011 Mather et al. 2001, Mather 2001

Cite this article

Mather, K. J., Norman, E. G., Prior, J. C., & Elliott, T. G. (2000). Preserved forearm endothelial responses with acute exposure to progesterone: A randomized cross-over trial of 17-beta estradiol, progesterone, and 17-beta estradiol with progesterone in healthy menopausal women. The Journal of clinical endocrinology and metabolism, 85(12), 4644-4649. https://doi.org/10.1210/jcem.85.12.7011

Keywords

Vasodilator Agents, Nitroprusside, Progesterone, Estradiol