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Objective: While the deleterious associations of surgical menopause after bilateral oophorectomy with cardiovascular disease are documented, less is specifically known concerning subclinical atherosclerosis progression., Methods: We used data from 590 healthy postmenopausal women randomized to hormone therapy or placebo in the Early versus Late Intervention Trial with Estradiol (ELITE), which was conducted from July 2005 to February 2013. Subclinical atherosclerosis progression was measured as annual rate of change in carotid artery intima-media thickness (CIMT) over a median 4.8 years. Mixed-effects linear models assessed the association of hysterectomy and bilateral oophorectomy compared with natural menopause with CIMT progression adjusted for age and treatment assignment. We also tested modifying associations by age at or years since oophorectomy or hysterectomy., Results: Among 590 postmenopausal women, 79 (13.4%) underwent hysterectomy with bilateral oophorectomy and 35 (5.9%) underwent hysterectomy with ovarian conservation, a median of 14.3 years before trial randomization. Compared with natural menopause, women who underwent hysterectomy with and without bilateral oophorectomy had higher fasting plasma triglycerides while women who underwent bilateral oophorectomy had lower plasma testosterone. The CIMT progression rate in bilaterally oophorectomized women was 2.2 μm/y greater than natural menopause ( P = 0.08); specifically, compared with natural menopause, the associations were significantly greater in postmenopausal women who were older than 50 years at the time of bilateral oophorectomy ( P = 0.014) and in postmenopausal women who underwent bilateral oophorectomy more than 15 years before randomization ( P = 0.015). Moreover, the CIMT progression rate in hysterectomized women with ovarian conservation was 4.6 μm/y greater than natural menopause ( P = 0.015); in particular, compared with natural menopause, the association was significantly greater in postmenopausal women who underwent hysterectomy with ovarian conservation more than 15 years before randomization ( P = 0.018)., Conclusions: Hysterectomy with bilateral oophorectomy and ovarian conservation were associated with greater subclinical atherosclerosis progression relative to natural menopause. The associations were stronger for later age and longer time since oophorectomy/hysterectomy. Further research should continue to examine long-term atherosclerosis outcomes related to oophorectomy/hysterectomy., Competing Interests: Financial disclosures/conflicts of interest: None reported., (Copyright © 2023 by The North American Menopause Society.)

Objective: To identify factors associated with serum estradiol (E2) levels among healthy postmenopausal women using hormone therapy (HT)., Methods: This is an unplanned post hoc analysis of data from ELITE (Early versus Late Intervention Trial with Estradiol), a randomized controlled trial of 1 mg oral E2 with or without vaginal progesterone in healthy early compared with late (<6 years compared with 10 or more years since menopause) postmenopausal women. We included results from visits when women reported at least 80% compliance with HT. Mixed-effects linear models identified factors associated with serum E2 levels while participants were taking HT, assessed every 6 months over a median follow-up of 4.8 years and adjusted for baseline E2 level, visit, and reduced E2 dose. Possible correlates evaluated included demographics, clinical characteristics, medication use, and biomarkers of liver and kidney metabolic function., Results: The analysis included 2,160 E2 measurements in 275 postmenopausal women. Mean±SD age was 55.4±3.9 vs 64.4±5.5 years, and mean±SD time since menopause was 3.6±1.8 vs 16.0±5.6 years for early vs late postmenopausal women. Adjusted for pretreatment E2 level, visit, and reduced dose indicator, higher serum E2 levels were associated with higher body mass index (BMI), higher weight, surgical menopause, alcohol use, and antihypertensive medication use. Current and past smoking and antifungal medication use were associated with lower serum E2 levels. In the multivariable model, higher BMI and alcohol use were associated with higher serum E2 levels, whereas current and past smoking were associated with lower serum E2 levels. These factors were similar between early and late postmenopausal women., Conclusion: Factors associated with serum E2 levels among postmenopausal women taking HT include BMI, alcohol use, and smoking. As serum E2 levels relate to HT effect, achievement of desirable E2 levels may be maximized through personalized intervention., Clinical Trial Registration: ClinicalTrials.gov, NCT00114517.

Background and Aims: In almost all countries, incidence rates of liver cancer (LC) are 100%-200% higher in males than in females. However, this difference is predominantly driven by hepatocellular carcinoma (HCC), which accounts for 75% of LC cases. Intrahepatic cholangiocarcinoma (ICC) accounts for 12% of cases and has rates only 30% higher in males. Hormones are hypothesized to underlie observed sex differences. We investigated whether prediagnostic circulating hormone and sex hormone binding globulin (SHBG) levels were associated with LC risk, overall and by histology, by leveraging resources from five prospective cohorts., Approach and Results: Seven sex steroid hormones and SHBG were quantitated using gas chromatography/tandem mass spectrometry and competitive electrochemiluminescence immunoassay, respectively, from baseline serum/plasma samples of 191 postmenopausal female LC cases (HCC, n = 83; ICC, n = 56) and 426 controls, matched on sex, cohort, age, race/ethnicity, and blood collection date. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between a one-unit increase in log 2 hormone value (approximate doubling of circulating concentration) and LC were calculated using multivariable-adjusted conditional logistic regression. A doubling in the concentration of 4-androstenedione (4-dione) was associated with a 50% decreased LC risk (OR = 0.50; 95% CI = 0.30-0.82), whereas SHBG was associated with a 31% increased risk (OR = 1.31; 95% CI = 1.05-1.63). Examining histology, a doubling of estradiol was associated with a 40% increased risk of ICC (OR = 1.40; 95% CI = 1.05-1.89), but not HCC (OR = 1.12; 95% CI = 0.81-1.54)., Conclusions: This study provides evidence that higher levels of 4-dione may be associated with lower, and SHBG with higher, LC risk in women. However, this study does not support the hypothesis that higher estrogen levels decrease LC risk. Indeed, estradiol may be associated with an increased ICC risk., (© 2020 by the American Association for the Study of Liver Diseases.)

Objective: Pelvic organ prolapse (POP) affects a significant percentage of women and contributes to major healthcare costs both in the United States and worldwide. This review examines the current understanding of the role of sex steroid hormones (estrogens, androgens, and progesterone) in POP in premenopausal, perimenopausal, and postmenopausal women., Methods: We reviewed the relevant studies on POP related to estrogens, androgens, and progesterone in both animal models and humans., Results: Estrogen has a profound influence on the synthesis and metabolism of pelvic connective tissues, and may have the ability to both prevent POP and improve prognosis if used therapeutically. There is limited research regarding the role of androgens and progesterone and their receptors in POP and results so far have been contradictory, warranting further study to determine whether changes in androgen and progesterone receptor expression are a cause or effect of POP., Conclusions: Because of the role that estrogen plays in maintaining the integrity of pelvic floor connective tissues, we propose that rigorous and well-controlled studies are needed on the role of exogenous estrogen administration as a form of POP prevention. : Video Summary:http://links.lww.com/MENO/A583.

Objective: Vasomotor flushing (hot flushes) is a common menopausal symptom experienced by most women going through the menopausal transition; flushing continues for a variable period in postmenopause. Primarily due to lack of ovarian estrogen, other biomarkers of hot flushes have not been clearly identified. We examined the relationship of hot flushes with ghrelin and adipokines., Methods: Baseline data from two clinical trials, the Women's Isoflavone Soy Health (WISH) trial and Early versus Late Intervention Trial of Estrogen (ELITE), were used in this post hoc cross-sectional study. Both WISH and ELITE had similar study designs, inclusion criteria, and data collection processes. Study participants were healthy postmenopausal women not taking estrogen-based hormone therapy, free of cardiovascular disease, or any other chronic diseases. Both trials used the same hot flush diary in which participants recorded the number of daily hot flushes by severity over a month on average. Serum concentrations of ghrelin, leptin, adiponectin, and resistin were assessed in stored fasting blood samples using highly specific radioimmunoassay. In this analysis, self-reported flushing experience was tested for an association with leptin, adiponectin, resistin, and ghrelin concentrations using logistic regression and mean comparisons., Results: A total of 898 postmenopausal women from the ELITE and WISH trials contributed to this analysis. Mean (SD) age was 60.4 (7.0) years, body mass index (BMI) 27 (5.3) kg/m, 67% were white, and 47% were within 10 years of menopause. Reported flushing was significantly associated with younger age, lower education, lower BMI, being married, and more recent menopause. Adjusted for these factors other than BMI, women in the highest quartile of ghrelin had significantly greater likelihood of experiencing hot flushes (OR [95% CI] = 1.84 [1.21-2.85]) compared to women in the lowest quartile. The association was more pronounced among overweight or obese women (OR [95% CI] = 2.36 [1.28-4.35]) compared to those with normal BMI (1.24 [0.54, 2.86]; interaction P value = 0.46). The association between ghrelin and hot flushes was similar among early (within 10 y) and late (over 10 y) postmenopausal women. Blood levels of adiponectin and resistin were not associated with hot flushes., Conclusions: Higher concentrations of ghrelin were associated with greater likelihood of hot flushes in both early- and late-postmenopausal women. Leptin, adiponectin, and resistin levels were not associated with hot flushes in postmenopausal women.

Objective: In the REPLENISH trial, women receiving TX-001HR-an oral, softgel capsule, combining 17β-estradiol (E2) and progesterone (E2 mg/P4 mg 1/100, 0.5/100), had significantly improved vasomotor symptoms, while having their endometrium protected from hyperplasia. The objective here was to describe P4 levels sufficient to counteract the potential endometrial effects of 1 or 0.5 mg oral E2 with TX-001HR., Methods: In REPLENISH (phase 3; NCT01942668), serum P4, E2, and estrone (E1) levels were characterized in postmenopausal women treated with TX-001HR (E2 mg/P4 mg: 1/100, 0.5/100, [0.5/50, 0.25/50 and placebo not reported here]) at baseline, week 12, and month 12 for P4, and at baseline, weeks 4 and 12, and months 6, 9, and 12 for E2 and E1. In a phase 1 study, pharmacokinetic parameters were assessed after 7 daily doses of oral E2 mg/P4 mg (1/100 and 0.5/100)., Results: In REPLENISH (n = 1,835), mean P4 levels were 0.39 to 0.55 ng/mL with 100-mg P4 doses; E2 levels were 42.3 to 45.6 pg/mL and 23.0 to 27.4 pg/mL for the 1-mg and 0.5-mg E2 doses, respectively; E1 levels were 214 to 242 pg/mL and 114 to 129 pg/mL for the 1-mg and 0.5-mg E2 doses. In the phase 1 study (n = 40; day 7), mean Cavg for P4 was 0.66 ng/mL with 100-mg P4 doses; E2 was 38.1 pg/mL and 29.2 pg/mL for 1 mg and 0.5 mg E2, respectively; and E1 was 211 and 106 pg/mL for 1 mg and 0.5 mg E2. All three analytes reached steady state within 7 days; accumulation ratios were 1.36 to 1.94., Conclusions: P4 levels observed with TX-001HR were similar in the phase 1 and 3 studies, and were associated with no endometrial hyperplasia with either E2 daily dose over 1 year in the REPLENISH phase 3 study, which showed significant improvements in menopausal vasomotor symptoms.

Objective: This study aimed to determine the effect of oophorectomy on baseline serum levels of androgens and estrogens in premenopausal and postmenopausal women., Methods: Fourteen premenopausal and 10 postmenopausal women underwent total hysterectomy and bilateral oophorectomy for benign disease of the uterus. Serum levels of dehydroepiandrosterone sulfate (DHEAS), androstenedione (A), testosterone (T), dihydrotestosterone (DHT), 5α-androstane-3α,17β-diol-17β-glucuronide (3α-diol G), estrone (E 1 ), estradiol (E 2 ), and sex hormone-binding globulin (SHBG) were measured by highly specific immunoassays prior to surgery and 2 weeks afterward. Free T and free E 2 were calculated. Differences were determined between preoperative (preop) and postoperative (postop) samples, and between premenopausal and postmenopausal women., Results: In premenopausal women, postop levels of total and free T, DHT, and total and free E 2 decreased significantly from preop. Postop levels of DHEAS, A, 3α-diol G, and SHBG were decreased, but not significantly different from preop. In postmenopausal women, postop levels of total and free T and total and free E 2 decreased significantly from preop, but there was little change in the other compounds. Significant differences in the mean change from baseline between premenopausal and postmenopausal women were observed only for E 1 and total and free E 2 ., Conclusion: The significant decrease in serum T in postmenopausal women following oophorectomy adds to the evidence that the postmenopausal ovary continues to produce T.

Purpose: The comparability between serum, plasma, and urinary measurements of estrogen metabolites via liquid chromatography-tandem mass spectrometry (LC-MS/MS) has not been largely explored, and it is unclear if urinary LC-MS/MS measurements are suitable surrogates of circulating levels., Methods: Serum, plasma (EDTA and heparin), and urinary estrogen/estrogen metabolite levels were measured via LC-MS/MS in paired samples from 64 healthy volunteers (18 men, 20 premenopausal women, 26 postmenopausal women). Geometric means and Spearman correlation coefficients were used to compare individual and combined pathway levels of estrogens/estrogen metabolites across biologic matrices by sex/menopausal status., Results: Measured concentrations of estrogens/estrogen metabolites across blood matrices were almost identical (percent differences < 4.8%). Parent estrogen concentrations measured in serum and urine were moderately correlated in postmenopausal women (estrone: r = 0.69, estradiol: r = 0.69). Correlations were similar comparing unconjugated serum estradiol to urinary estrone (r = 0.76) and urinary estradiol (r = 0.65) in postmenopausal women but were moderate to low in premenopausal women (r = 0.60, 0.40, respectively)/men (r = 0.33, 0.53, respectively). Comparing metabolite ratios, proportionally higher concentrations of 16-pathway metabolites were measured in urine versus serum across sex/menopausal status groups (e.g., postmenopausal women: 50.3% 16-pathway metabolites/total in urine versus 35.3% in serum)., Conclusions: There is strong agreement between estrogen/estrogen metabolites measurements in serum, heparin plasma, and EDTA plasma. Individual estrogen metabolite concentrations were moderately correlated between urine and serum, but were not well correlated when evaluating pathway- or relative estrogen concentrations. Differences between serum and urine are likely explained by differences in metabolism and/or excretion.

Background parenchymal enhancement (BPE) is the degree to which normal breast tissue enhances on contrast-enhanced magnetic resonance imaging (MRI). MRI-density is a volumetric measure of breast density that is highly correlated with mammographic density, an established breast cancer risk factor. Endogenous estrogen concentrations are positively associated with postmenopausal breast cancer risk and BPE has been shown to be sensitive to hormonal exposures. The objective of our study was to examine the relationship between BPE and MRI-density and serum hormone concentrations in postmenopausal women. This was a study of cancer-free postmenopausal women undergoing contrast-enhanced breast MRI (N = 118). At the time of MRI all women completed a self-administered questionnaire and blood samples were collected for hormone analyses. Serum concentrations of estrone (E1), estradiol (E2) and bioavailable E2 were examined by category of BPE and MRI-density. Compared to women with "minimal" BPE, those who had "marked" BPE had significantly higher serum concentrations of E1, E2 and bioavailable E2 (90% increase, p trend across all categories = 0.001; 150% increase, p trend  = 0.001; and 158% increase, p trend  = 0.001, respectively). These associations were only affected to a minor extent by adjustment for BMI and other variables. After adjustment for BMI, no significant associations between MRI-density and serum E1, E2 and bioavailable E2 were observed. Serum estrogen concentrations were significantly positively associated with BPE. Our study provides further evidence of the hormone-sensitive nature of BPE, indicating a potential role for BPE as an imaging marker of endogenous and exogenous hormonal exposures in the breast., (© 2018 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Circulating melatonin is a good candidate biomarker for studies of circadian rhythms and circadian disruption. However, epidemiologic studies on circulating melatonin are limited because melatonin is secreted at night, yet most epidemiologic studies collect blood during the day when melatonin levels are very low, and assays are lacking that are ultrasensitive to detect low levels of melatonin reliably., Objective: To assess the performance of a refined radioimmunoassay in measuring morning melatonin among women., Methods: We used morning serum samples from 47 postmenopausal women ages 48-80 years without a history of breast cancer who participated in the San Francisco Bay Area Breast Cancer Study, including 19 women who had duplicate measurements. The coefficient of variation (CV) and intraclass coefficient (ICC) were estimated using the random effect model., Results: Reproducibility for the assay was satisfactory, with a CV of 11.2% and an ICC of 98.9%; correlation between the replicate samples was also high (R = 0.96). In the 47 women, serum melatonin levels ranged from 0.6 to 62.6 pg/ml, with a median of 7.0 pg/ml., Conclusion: Our results suggest that it is possible to reliably measure melatonin in postmenopausal women in morning serum samples in large epidemiologic studies to evaluate the role of melatonin in cancer etiology or prognosis.

Purpose: Epigenetic mechanisms may help to explain the complex and heterogeneous relation between sex hormones and cancer. Few studies have investigated the effects of sex hormones on epigenetic markers related to cancer risk such as levels of methylation within repetitive DNA elements. Our objective was to describe the association between endogenous sex hormone exposure and levels of LINE-1 and Alu methylation in healthy postmenopausal women., Methods: We nested a cross-sectional study within the Alberta Physical Activity and Breast Cancer Prevention Trial (2003-2006). Study participants consisted of healthy postmenopausal women who had never been diagnosed with cancer (n = 289). Sex hormone exposures included serum concentrations of estradiol, estrone, testosterone, androstenedione, and sex hormone-binding globulin. We estimated the participants' lifetime number of menstrual cycles (LNMC) as a proxy for cumulative exposure to ovarian sex hormones. Buffy coat samples were assessed for DNA methylation. Linear regression was used to model the associations of interest and to control for confounding., Results: Both estradiol and estrone had a significant positive dose-response association with LINE-1 methylation. LNMC was associated with both LINE-1 and Alu methylation. Specifically, LNMC had a non-linear "U-shaped" association with LINE-1 methylation regardless of folate intake and a negative linear association with Alu methylation, but only amongst low folate consumers. Androgen exposure was not associated with either outcome., Conclusion: Current and cumulative estrogen exposure was associated with repetitive element DNA methylation in a group of healthy postmenopausal women. LINE-1 and Alu methylation may be epigenetic mechanisms through which estrogen exposure impacts cancer risk.

Objective: To better understand the pathogenesis of inflammatory-related diseases after menopause, we studied the adiposity-independent association between endogenous sex hormones and C-reactive protein (CRP), a biomarker of inflammation., Methods: We conducted a secondary, cross-sectional analysis of baseline data from the Alberta Physical Activity and Breast Cancer Prevention Trial (2003-2007), including 319 healthy, postmenopausal women not using hormone therapy. Multivariable linear regression models related serum CRP levels to estrogens, androgens, and sex hormone-binding globulin (SHBG), all on the natural logarithmic scale. Models were adjusted for age, lipids, medication, and former menopausal hormone therapy use, and also for adiposity (body mass index [BMI], per cent body fat [via whole-body dual x-ray absorptiometry], or intra-abdominal fat area [via computed tomography])., Results: Without adiposity adjustment, estrone, total estradiol, and free estradiol were significantly positively associated with CRP, whereas SHBG was significantly inversely associated with CRP. Of all adiposity measures, adjustment for BMI caused the greatest attenuation of CRP-estrogen associations; only free estradiol (β = 0.24, 95% confidence interval [CI] 0.06, 0.43) and SHBG (β = -0.37, 95% CI -0.60, -0.13) associations remained significant. Inverse associations between CRP-total testosterone became stronger with BMI adjustment (β = -0.20, 95% CI -0.40, -0.01). Differential associations across categories of BMI, former hormone therapy use, and years since menopause were suggestive, but not statistically significant (Pheterogeneity > 0.05)., Conclusions: Prospective and systems epidemiological studies are needed to understand whether or not the cross-sectional associations we observed, independent of adiposity, between CRP-SHBG, CRP-total testosterone, and CRP-free estradiol, are causal.

Objective: Studies have linked vasomotor symptoms (VMS) to markers of cardiovascular disease (CVD) risk, yet few have considered clinical cardiovascular events. Data suggest that associations may depend upon the age that symptoms occur. We examined associations between VMS and cardiovascular events and endothelial function, considering age of symptom onset., Methods: The Women's Ischemia Syndrome Evaluation enrolled women referred for coronary angiography for suspected myocardial ischemia. A total of 254 women aged more than 50 years, postmenopausal, with both ovaries, not taking hormone therapy underwent a baseline evaluation, were followed annually (median = 6.0 y), and the National Death Index was searched to ascertain CVD mortality (median = 9.3 y). A subset of participants underwent brachial artery ultrasound for flow-mediated dilation (FMD). Receiver-operating curve analysis was used to determine vasomotor symptom groups (symptoms beginning < age 42 [early onset], beginning ≥42 [later onset], never) which were examined in relation to cardiovascular events and FMD in Cox proportional hazard and linear regression models., Results: Women reporting early onset VMS (HR = 3.35, 95% CI = 1.23-7.86, P = 0.005) and women who never had VMS (HR = 2.17, 95% CI = 1.02-4.62, P = 0.05) had higher CVD mortality than women with later onset symptoms (multivariable models). Women with early onset VMS had lower FMD than women with later onset symptoms (b = -4.31, SE = 2.10, P = 0.04, multivariable)., Conclusions: Women with signs and symptoms of ischemia who had VMS beginning early in midlife had higher CVD mortality and reduced endothelial function relative to women with later onset symptoms. Future research should evaluate the vascular phenotype of women with early midlife VMS., Competing Interests: G Braunstein is a consultant for Merck (Merck Manual), Takada Pharmaceuticals, Amgen, Allergan, Synagena, Sanofi, and Johnson and Johnson. G Braunstein owns stock in Pfizer and is a part-time employee of Pathway Genomics. F Stanczyk has consulted with Merck & Co., Agile Therapeutics, TherapeuticsMD, and Abbvie. For the remaining authors none were declared.

Background: Postmenopausal obesity is associated with increased circulating levels of androgens and estrogens and elevated breast cancer risk. Crown-like structures (CLS; microscopic foci of dying adipocytes surrounded by macrophages) are proposed to represent sites of increased aromatization of androgens to estrogens. Accordingly, we examined relationships between CLS and sex-steroid hormones in breast adipose tissue and serum from postmenopausal breast cancer patients., Methods: Formalin-fixed paraffin embedded benign breast tissues collected for research from postmenopausal women (n = 83) diagnosed with invasive breast cancer in the Polish Breast Cancer Study (PBCS) were evaluated. Tissues were immunohistochemically stained for CD68 to determine the presence of CLS per unit area of adipose tissue. Relationships were assessed between CD68 density and CLS and previously reported sex-steroid hormones quantified using radioimmunoassays in serum taken at the time of diagnosis and in fresh frozen adipose tissue taken at the time of surgery. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the relationships between hormones (in tertiles) and CLS., Results: CLS were observed in 36% of benign breast tissues, with a higher frequency among obese versus lean women (54% versus 17%, p = 0.03). Detection of CLS was not related to individual hormone levels or breast tumor pathology characteristics. However, detection of CLS was associated with hormone ratios. Compared with women in the highest tertile of estrone:androstenedione ratio in fat, those in the lowest tertile were less likely to have CLS (OR 0.12, 95% CI 0.03-0.59). A similar pattern was observed with estradiol:testosterone ratio in serum and CLS (lowest versus highest tertile, OR 0.18, 95% CI 0.04-0.72)., Conclusions: CLS were more frequently identified in the breast fat of obese women and were associated with increased ratios of select estrogens:androgens in the blood and tissues, but not with individual hormones. Additional studies on CLS, tissue and blood hormone levels, and breast cancer risk are needed to understand and confirm these findings.

Background: Women with polycystic ovary syndrome (PCOS) have greater cardiac risk factor clustering but the link with mortality is incompletely described., Objective: To evaluate outcomes in 295 postmenopausal women enrolled in the National Institutes of Health-National Heart, Lung, and Blood Institute (NIH-NHLBI) sponsored Women's Ischemia Syndrome Evaluation (WISE) study according to clinical features of PCOS., Materials and Methods: A total of 25/295 (8%) women had clinical features of PCOS defined by a premenopausal history of irregular menses and current biochemical evidence of hyperandrogenemia, defined as the top quartile of androstenedione (≥701 pg/mL), testosterone (≥30.9 ng/dL), or free testosterone (≥4.5 pg/mL). Cox proportional hazard model estimated death (n = 80)., Results: Women with clinical features of PCOS had an earlier menopause (p = 0.01), were more often smokers (p < 0.04), and trended toward more angiographic coronary artery disease (CAD) (p = 0.07) than women without these features. Cumulative 10-year mortality was 28% for women with (n = 25) versus 27% without clinical features of PCOS (n = 270) (p = 0.85). PCOS was not a significant predictor (p = NS) in prognostic models including diabetes, waist circumference, hypertension, and angiographic CAD., Conclusion: From this longer-term follow up of a relatively small cohort of postmenopausal women with suspected ischemia, the prevalence of PCOS is similar to the general population, and clinical features of PCOS are not associated with CAD or mortality. These findings question whether identification of clinical features of PCOS in postmenopausal women who already have known cardiovascular disease provides any additional opportunity for risk factor intervention.

Background: Data suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later. However, the hypothesis that the cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation (the hormone-timing hypothesis) has not been tested., Methods: A total of 643 healthy postmenopausal women were stratified according to time since menopause (<6 years [early postmenopause] or ≥10 years [late postmenopause]) and were randomly assigned to receive either oral 17β-estradiol (1 mg per day, plus progesterone [45 mg] vaginal gel administered sequentially [i.e., once daily for 10 days of each 30-day cycle] for women with a uterus) or placebo (plus sequential placebo vaginal gel for women with a uterus). The primary outcome was the rate of change in carotid-artery intima-media thickness (CIMT), which was measured every 6 months. Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography (CT), which was performed when participants completed the randomly assigned regimen., Results: After a median of 5 years, the effect of estradiol, with or without progesterone, on CIMT progression differed between the early and late postmenopause strata (P=0.007 for the interaction). Among women who were less than 6 years past menopause at the time of randomization, the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group (P=0.008). Among women who were 10 or more years past menopause at the time of randomization, the rates of CIMT progression in the placebo and estradiol groups were similar (0.0088 and 0.0100 mm per year, respectively; P=0.29). CT measures of coronary-artery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum., Conclusions: Oral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum. (Funded by the National Institute on Aging, National Institutes of Health; ELITE ClinicalTrials.gov number, NCT00114517.).

Objective: This review examines the etiology and pathophysiology of dry eye disease in postmenopausal women, and describes the steroid reproductive hormone influences that may contribute to its development., Methods: We have reviewed the relevant studies on dry eye disease related to hormonal status and hormone therapy (HT) in both animal models and humans., Results: Although both low and high estrogen levels have been associated with symptoms of dry eye disease, low androgen levels are a more consistent factor in its etiology. Postmenopausal HT with estrogen or estrogen plus progestogen has shown a limited benefit for dry eye symptoms and may even result in progression of meibomian gland dysfunction, decreased tear film break up time, and tear flow reduction. However, systemic or local androgen treatment has shown promising results in improving dry eye symptoms., Conclusions: Because of the high incidence of dry eye among postmenopausal women that may be related to the hormonal treatment, we propose that a multidisciplinary approach should be considered between gynecologists and ophthalmologists in management of this disorder.

Exercise dose comparison trials with biomarker outcomes can identify the amount of exercise required to reduce breast cancer risk and also strengthen the causal inference between physical activity and breast cancer. The Breast Cancer and Exercise Trial in Alberta (BETA) tested whether or not greater changes in estradiol (E2), estrone, and sex hormone-binding globulin (SHBG) concentrations can be achieved in postmenopausal women randomized to 12 months of HIGH (300 min/week) vs MODERATE (150 min/week) volumes of aerobic exercise. BETA included 400 inactive postmenopausal women aged 50-74 years with BMI of 22-40 kg/m(2). Blood was drawn at baseline and 6 and 12 months. Adiposity, physical fitness, diet, and total physical activity were assessed at baseline and 12 months. Intention-to-treat analyses were performed using linear mixed models. At full prescription, women exercised more in the HIGH vs MODERATE group (median min/week (quartiles 1,3): 253 (157 289) vs 137 (111 150); P<0.0001). Twelve-month changes in estrogens and SHBG were <10% on average for both groups. No group differences were found for E2, estrone, SHBG or free E2 changes (treatment effect ratios (95% CI) from linear mixed models: 1.00 (0.96-1.06), 1.02 (0.98-1.05), 0.99 (0.96-1.02), 1.01 (0.95, 1.06), respectively, representing the HIGH:MODERATE ratio of geometric mean biomarker levels over 12 months; n=382). In per-protocol analyses, borderline significantly greater decreases in total and free E2 occurred in the HIGH group. Overall, no dose effect was observed for women randomized to 300 vs 150 min/week of moderate to vigorous intensity exercise who actually performed a median of 253 vs 137 min/week. For total and free E2, the lack of differential effect may be due to modest adherence in the higher dose group., (© 2015 Society for Endocrinology.)

Background: Postmenopausal hormone therapy use has been associated with lower colorectal cancer risk in observational studies. However, the role of endogenous sex hormones in colorectal cancer development in postmenopausal women is uncertain., Methods: The relation of colorectal cancer risk with circulating levels of estradiol, estrone, free (bioactive) estradiol, progesterone and sex hormone-binding globulin (SHBG) was determined in a nested case-control study of 1203 postmenopausal women (401 case patients and 802 age and race/ethnicity-matched control patients) enrolled in the Women's Health Initiative Clinical Trial (WHI-CT) who were not assigned to the estrogen-alone or combined estrogen plus progestin intervention groups. We used multivariable-adjusted conditional logistic regression models that included established colorectal cancer risk factors. All statistical tests were two-sided., Results: Comparing extreme quartiles, estrone (odds ratio [OR]q4-q1 = 0.44, 95% confidence interval [CI] = 0.28 to 0.68, P trend = .001), free estradiol (ORq4-q1 = 0.43, 95% CI = 0.27 to 0.69, P trend ≤ .0001), and total estradiol (ORq4-q1 = 0.58, 95% CI = 0.38 to 0.90, P trend = .08) were inversely associated with colorectal cancer risk. SHBG levels were positively associated with colorectal cancer development (OR[q4-q1] = 2.30, 95% CI = 1.51 to 3.51, P trend ≤ .0001); this association strengthened after further adjustment for estradiol and estrone (ORq4-q1 = 2.50, 95% CI = 1.59 to 3.92, P trend < .0001). Progesterone was not associated with colorectal cancer risk., Conclusion: Endogenous estrogen levels were inversely, and SHBG levels positively, associated with colorectal cancer risk, even after control for several colorectal cancer risk factors. These results suggest that endogenous estrogens may confer protection against colorectal tumorigenesis among postmenopausal women., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Context: Sex hormones, adipokines, and ghrelin have been implicated in central control of appetite, energy homeostasis, maintenance of fat mass, and inflammation. Women tend to gain weight after menopause and adipose tissue is a major source of sex steroid postmenopause. Understanding the dynamics of these analytes are of particular importance in postmenopausal women, who are at greater risk for cardiometabolic diseases., Objectives: This study sought to evaluate the associations of adipokines and ghrelin with sex hormone concentrations in postmenopausal women., Design: We conducted a cross-sectional analysis of baseline clinical trial data., Setting: The parent trial was conducted at a university clinical research facility., Participants: Baseline data from 634 postmenopausal women participating in the Early vs Late Intervention Trial with Estradiol (ELITE). PARTICIPANTS had no history of chronic illness in the past 5 years and were not taking exogenous hormone therapy., Main Outcome Measures: Serum levels of estrone (E1), total estradiol (E2), free estradiol (FE2), free testosterone (FT), total testosterone (T), and sex hormone-binding globulin (SHBG)., Results: Adjusted for age, race, time since menopause, and body mass index (BMI), leptin concentrations were significantly positively associated with E1, E2, FE2, and FT and inversely associated with SHBG levels. Only the associations of adiponectin with FE2 (inverse) and SHBG (positive) remained significant after controlling for BMI. The inverse associations of adiponectin with E1, E2, and FT were substantially mediated by BMI. Associations of ghrelin with E1, E2, FE2, and SHBG were not independent of BMI. Waist-to-hip circumference ratio was not a mediator in any of the associations., Conclusions: In postmenopausal women, leptin and adiponectin concentrations are substantially correlated with sex hormone and SHBG concentrations regardless of obesity status.

Background: Exercise has favorable effects on biomarkers associated with a lower risk of breast cancer, however it is unclear if higher doses of exercise provide additional effects. No clinical trial has systematically examined how different exercise volumes influence the mechanisms underlying breast cancer etiology. The Breast Cancer and Exercise Trial in Alberta (BETA) - a follow-up study to the Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial - is examining how a one-year, high versus moderate volume aerobic exercise intervention influences several biomechanisms hypothesized to influence breast cancer risk in a group of postmenopausal women. Secondary aims are to compare intervention effects on psychosocial and quality of life outcomes as well as understand exercise adherence at 12 and 24 months, and maintenance of all study outcomes at 24 months., Methods/design: The BETA Trial is a two-center, two-armed randomized controlled exercise intervention trial conducted in 400 previously inactive, postmenopausal women aged 50-74 years, in Alberta, Canada. Participants were randomly assigned to a one-year aerobic exercise intervention of either high volume (300 minutes/week) or moderate volume (150 minutes/week). Blood draws and accelerometry were performed at baseline, six and 12 months. Baseline and 12-month measurements were taken of adiposity (including dual energy X-ray absorptiometry and computed tomography scans), physical fitness, dietary intake, self-reported physical activity and sedentary behavior, quality of life, perceived stress, happiness, sleep, and determinants of exercise adherence. Exercise maintenance was assessed and all study measurements were repeated at 24 months. Blood will be analyzed for endogenous estrogens, insulin resistance indicators, and inflammatory markers., Discussion: The BETA Trial will compare the impact of a high versus moderate volume of aerobic exercise on a variety of biological, physiological, and psychological outcomes of relevance to postmenopausal women. A tightly controlled exercise intervention and objective outcome measurements are methodological strengths. The BETA Trial will inform future prevention initiatives by assessing adherence to a high volume of exercise over 12 months by postmenopausal women, and the ability of these women to maintain activity over the longer-term. The ultimate objective is to inform public health guidelines for reducing breast cancer risk through physical activity., Clinical Trials Registration Number: NCT01435005.

Medroxyprogesterone acetate (MPA) has been in clinical use for over 30 years, and was generally considered to be safe until the results of long-term studies of postmenopausal hormone therapy (HT) using treatment with conjugated equine estrogens (CEE) combined with MPA and CEE alone suggested that MPA, and perhaps other progestogens, may play a role in the increased risk of breast cancer and cardiovascular diseases. This review examines critically the safety of MPA in terms of breast cancer and cardiovascular disease risk, and its effects on brain function. Research into mechanisms by which MPA might cause adverse effects in these areas, combined with the available clinical evidence, suggests a small increase in relative risk for breast cancer and stroke, and a decline in cognitive function, in older women using MPA with an estrogen for postmenopausal HT. However, short-term (less than 5 years) use of MPA with an estrogen in the years immediately after the onset of menopause for the management of vasomotor symptoms does not appear to be associated with any increased risk of these disorders., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Variations in the hormonal milieu after menopause may influence neural processes concerned with cognition, cognitive aging, and mood, but findings are inconsistent. In particular, cognitive effects of estradiol may vary with time since menopause, but this prediction has not been assessed directly using serum hormone concentrations. We studied 643 healthy postmenopausal women not using hormone therapy who were recruited into early (<6 y after menopause) and late (10+ y after menopause) groups. Women were administered a comprehensive neuropsychological battery and assessed with the Center for Epidemiologic Studies Depression Scale. They provided serum for free estradiol, estrone, progesterone, free testosterone, and sex hormone binding globulin measurements. Cognitive outcomes were standardized composite measures of verbal episodic memory, executive functions, and global cognition. Covariate-adjusted linear regression analyses were conducted for each hormone separately and after adjustment for other hormone levels. Endogenous sex steroid levels were unassociated with cognitive composites, but sex hormone binding globulin was positively associated with verbal memory. Results for early and late groups did not differ significantly, although progesterone concentrations were significantly positively associated with verbal memory and global cognition in early group women. Hormone concentrations were not significantly related to mood. Results fail to support the hypothesis that temporal proximity to menopause modifies the relation between endogenous serum levels of estradiol and verbal memory, executive functions, or global cognition. Physiological variations in endogenous postmenopausal levels of sex steroid hormones are not substantially related to these aspects of cognition or mood; positive associations for progesterone and sex hormone binding globulin merit additional study.

Objective: This study aims to investigate the distribution of progesterone in venous whole blood, venous serum, fingertip capillary blood, and saliva after its topical application in both cream and gel formulations., Methods: Ten postmenopausal women were randomized to receive 80 mg of progesterone cream or gel applied daily for 14 days, crossing over after a 14-day washout. On the last day of each treatment period, venous blood, fingertip capillary blood, and saliva were sampled frequently for 24 hours after the final application., Results: After progesterone cream or gel application, serum progesterone levels rose gradually, reaching a peak at 9 and 8 hours, respectively; AUC(0-24) h was significantly higher with cream (12.39 vs 8.32 ng h mL(-1), P = 0.0391). Whole venous blood levels followed a pattern similar to that of serum but were considerably lower. Saliva progesterone showed a peak at 1 and 6 hours after cream and gel application, respectively, and C(max) was comparable with cream and gel. Saliva AUC(0-24) h was substantially higher than the corresponding area under the curve for serum or whole blood but did not differ significantly by delivery method (39.02 and 58.37 ng h mL(-1), P = 0.69). In capillary blood, C(max) was reached at the same time (8 h) and was similar with both formulations; AUC(0-24) h was also similar with both formulations (1,056 ng h mL(-1) for cream and 999 ng h mL(-1) for gel) but was dramatically higher than the corresponding areas under the curve for venous serum and whole blood., Conclusions: After application of topical progesterone, saliva and capillary blood levels are approximately 10-fold and 100-fold greater, respectively, than those seen in serum or whole blood. High capillary blood and saliva levels indicate high absorption and transport of progesterone to tissues. Reliance on serum levels of progesterone for monitoring topical dose could lead to underestimation of tissue levels and consequent overdose.

A relation between the breast cancer risk factors, insulin-like growth factor-I (IGF-I) and mammographic density, is biologically plausible, but results from cross-sectional epidemiologic studies have been mixed. Our objective was to examine the relation in a longitudinal manner, that is, between the change in circulating IGF-I concentrations and the change in mammographic measures over one year. Data from an exercise intervention trial conducted in 302 postmenopausal women ages 50 to 74 years were used. Blood drawn at baseline and postintervention was assessed for IGF-I and its binding protein (IGFBP-3) by direct chemiluminscent immunoassay. Area and volumetric measurements of mammographic dense fibroglandular and nondense fatty tissue were made. Statistical analyses were based on multiple linear regression. A one SD (20.2 ng/mL) change in IGF-I over one year was associated with small changes in percent dense area [mean: 0.8%; 95% confidence interval (CI), 0.1-1.4] and dense area (mean: 1.2 cm(2); 95% CI, 0.2-2.1). Change in IGFBP-3 was also associated with percent and absolute dense area. Absolute and percent dense volume, and mammographic measures representing fatty tissue (nondense area and volume) were not associated with changes in IGF-I and IGFBP-3. Longitudinal associations may be more detectable than cross-sectional associations due to the absence of confounding by invariant personal factors. Absolute and percent dense area, measures that are related to breast cancer risk, may be affected by IGF-I. Confirmation should be sought in further longitudinal studies in which larger changes in the IGF system are evoked., (©2013 AACR.)

Although grapefruit intake leads to elevated serum estrogen levels when hormones are taken orally, there are no published data on the effect on endogenous levels. We conducted a pilot dietary intervention study among healthy postmenopausal volunteers to test whole grapefruit, 2 juices, and 1 grapefruit soda. Fifty-nine participants were recruited through the Love/Avon Army of Women. The study consisted of a 3-wk run-in, 2 wk of grapefruit intake, and a 1-wk wash-out. Eight fasting blood samples were collected. An additional 5 samples drawn at 1, 2, 4, 8, and 10 hr after grapefruit intake were collected during an acute-phase study for 10 women. Serum assays for estrone (E1), estradiol (E2), estrone-3-sulfate (E1S), dehydroepiandrosterone sulfate, and sex hormone-binding globulin were conducted. Whole grapefruit intake had significant effects on endogenous E1S. Peak effects were seen at 8 hr, increasing by 26% from baseline. No changes in mean E1 or E2 with whole fruit intake were observed. In contrast, fresh juice, bottled juice, and soda intake all had significant lowering effects on E2. The findings suggest an important interaction between grapefruit intake and endogenous estrogen levels. Because endogenous estrogen levels are associated with breast cancer risk, further research is warranted.

Purpose: Estrogens and androgens are elevated in obesity and associated with increased postmenopausal breast cancer risk, but the effect of weight loss on these biomarkers is unknown. We evaluated the individual and combined effects of a reduced-calorie weight loss diet and exercise on serum sex hormones in overweight and obese postmenopausal women., Patients and Methods: We conducted a single-blind, 12-month, randomized controlled trial from 2005 to 2009. Participants (age 50 to 75 years; body mass index > 25.0 kg/m(2), exercising < 100 minutes/wk) were randomly assigned using a computer-generated sequence to (1) reduced-calorie weight loss diet ("diet"; n = 118), (2) moderate- to vigorous-intensity aerobic exercise ("exercise"; n = 117), (3) combined reduced-calorie weight loss diet and moderate- to vigorous-intensity aerobic exercise ("diet + exercise"; n = 117), or (4) control (n = 87). Outcomes were estrone concentration (primary) and estradiol, free estradiol, total testosterone, free testosterone, androstenedione, and sex hormone-binding globulin (SHBG) concentrations (secondary)., Results: Mean age and body mass index were 58 years and 30.9 kg/m(2), respectively. Compared with controls, estrone decreased 9.6% (P = .001) with diet, 5.5% (P = .01) with exercise, and 11.1% (P < .001) with diet + exercise. Estradiol decreased 16.2% (P < .001) with diet, 4.9% (P = .10) with exercise, and 20.3% (P < .001) with diet + exercise. SHBG increased 22.4% (P < .001) with diet and 25.8% (P < .001) with diet + exercise. Free estradiol decreased 21.4% (P < .001) with diet and 26.0% (P < .001) with diet + exercise. Free testosterone decreased 10.0% (P < .001) with diet and 15.6% (P < .001) with diet + exercise. Greater weight loss produced stronger effects on estrogens and SHBG., Conclusion: Weight loss significantly lowered serum estrogens and free testosterone, supporting weight loss for risk reduction through lowering exposure to breast cancer biomarkers.

Gonadal hormones may influence cognitive function. Postmenopausal midlife women in the population-based Melbourne Women's Midlife Health Project cohort were administered a comprehensive battery of neuropsychological tests on two occasions 2 years apart. Participants (n = 148, mean age 60 years) had undergone natural menopause and were not using hormone therapy. Estrone, total and free estradiol, and total and free testosterone levels were measured at time of the first testing. Principal-component analysis identified four cognitive factors. In multiple linear regression analyses, better semantic memory performance was associated with higher total (p = 0.02) and free (p = 0.03) estradiol levels and a lower ratio of testosterone to estradiol (p = 0.007). There were trends for associations between better verbal episodic memory and lower total testosterone (p = 0.08) and lower testosterone/estradiol ratio (p = 0.06). Lower free testosterone levels were associated with greater 2-year improvement on verbal episodic memory (p = 0.04); higher testosterone/estradiol predicted greater semantic memory improvement (p = 0.03). In postmenopausal midlife women, endogenous estradiol and testosterone levels and the testosterone/estradiol ratio are associated with semantic memory and verbal episodic memory abilities., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Gonadal hormones may influence cognitive function. Postmenopausal midlife women in the population-based Melbourne Women's Midlife Health Project cohort were administered a comprehensive battery of neuropsychological tests on two occasions 2 years apart. Participants (n = 148, mean age 60 years) had undergone natural menopause and were not using hormone therapy. Estrone, total and free estradiol, and total and free testosterone levels were measured at time of the first testing. Principal-component analysis identified four cognitive factors. In multiple linear regression analyses, better semantic memory performance was associated with higher total (p = 0.02) and free (p = 0.03) estradiol levels and a lower ratio of testosterone to estradiol (p = 0.007). There were trends for associations between better verbal episodic memory and lower total testosterone (p = 0.08) and lower testosterone/estradiol ratio (p = 0.06). Lower free testosterone levels were associated with greater 2-year improvement on verbal episodic memory (p = 0.04); higher testosterone/estradiol predicted greater semantic memory improvement (p = 0.03). In postmenopausal midlife women, endogenous estradiol and testosterone levels and the testosterone/estradiol ratio are associated with semantic memory and verbal episodic memory abilities., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: Estrogen plus progestin therapy (EPT) in postmenopausal women increases breast cancer risk and mammographic density to a higher extent than does estrogen therapy alone. Data from the randomized placebo-controlled Postmenopausal Estrogen/Progestinv Interventions trial showed that EPT-induced increases in serum estrone and estrone sulfate levels were positively correlated with increases in mammographic density. Here, after adjusting for serum estrone and estrone sulfate levels, we investigated the roles of posttreatment serum progestogen increase and of progesterone receptor gene (PGR) genetic variations on changes in mammographic density., Methods: We measured the percent mammographic density and serum progestogen levels in 280 Postmenopausal Estrogen/Progestin Interventions trial participants randomized to EPT treatment. Analyses of genetic variations in PGR were limited to 260 white women for whom we successfully obtained PGR genotypes. We used linear regression analyses to determine how an increase in progestogen levels and PGR genetic variation influenced mammographic density change after EPT., Results: The increase in posttreatment serum progestogen level was positively associated with greater increases in mammographic density after adjustment for covariates (P trend = 0.044). Compared with women in the lowest quartile of serum progestogen level, women in the highest quartile experienced a 3.5% greater increase in mammographic density (P = 0.046). We did not find a strong indication that genetic variation in PGR was associated with mammographic density increase or modified the association with serum progestogen; however, confidence in these null findings is constrained by our small sample size., Conclusions: Our results suggest that higher serum progestogen levels resulting from EPT treatment lead to greater increases in mammographic density.

Objective: To identify factors that mediate or moderate the effects of exercise on postmenopausal sex hormone concentrations., Methods: Postmenopausal women were randomized to 12 months of aerobic exercise for 200 min/week (n = 160) or to a control group (n = 160). Intention-to-treat analyses were performed using general linear models with sex hormone concentrations at 6 and 12 months as the outcome. Mediation by adiposity and insulin was investigated by examining changes in effect estimates after adjustment for changes in these factors over 12 months. Moderation was studied as the interaction between group assignment and eight baseline characteristics., Results: Intervention effects on sex hormone-binding globulin (SHBG) and estradiol changes were attenuated with adjustment for change in overall body fat, while there was less attenuation adjusting for intra-abdominal fat change. Intervention effects on SHBG levels were unaffected by adjustment for insulin change. Significant interactions were identified between treatment and physical fitness (for SHBG and testosterone) and age (for testosterone), implying subgroup differences in intervention effect., Conclusions: Our data suggest that overall fat loss partially mediated exercise-induced changes in estradiol and SHBG concentrations. No previous RCT in postmenopausal women has studied moderators of exercise-induced sex hormone changes; therefore, future studies are needed to corroborate our results.

Objective: Postmenopausal changes in the hormonal milieu in women with or without hormone therapy are hypothesized to be the pathway for a number of menopause-associated modifications in physiology and disease risk. Physical activity may modify these changes in women's hormone profiles. The crucial yet complex relationship between physical activity and physiologic and pharmacologic sex hormone levels in postmenopausal women has not been investigated sufficiently., Methods: Using structured recall, physical activity was assessed longitudinally during a period of 2 years in 194 postmenopausal women (90 randomized to 1 mg 17β-estradiol treatment daily and 104 randomized to placebo) in the Estrogen in the Prevention of Atherosclerosis Trial. The levels of physical activity were correlated with the serum sex hormone and the serum hormone-binding globulin levels in each treatment group., Results: Among the placebo-treated women, total energy expenditure was positively associated with sex hormone-binding globulin (SHBG; P < 0.001) and inversely associated with testosterones (total, bioavailable, or free) and androstenedione (P < 0.001 for all), as well as with estradiol (P = 0.02). In estradiol-treated women, estradiol levels were inversely associated with total energy expenditure (P = 0.002) and weekly hours spent in moderate or more vigorous physical activity (P = 0.001)., Conclusions: Physical activity is associated with lower serum levels of estradiol in both hormone therapy-treated and untreated women. In placebo-treated women only, physical activity is associated with reduced androgen levels and elevated SHBG levels.

Physical activity is a known modifiable lifestyle means for reducing postmenopausal breast cancer risk, but the biologic mechanisms are not well understood. Metabolic factors may be involved. In this study, we aimed to determine the effects of exercise on insulin resistance (IR) indicators, IGF1, and adipokines in postmenopausal women. The Alberta Physical Activity and Breast Cancer Prevention Trial was a two-armed randomized controlled trial in postmenopausal, inactive, cancer-free women. A year-long aerobic exercise intervention of 225  min/week (n=160) was compared with a control group asked to maintain usual activity levels (n=160). Baseline, 6- and 12-month serum levels of insulin, glucose, IGF1, IGF-binding protein 3 (IGFBP3), adiponectin, and leptin were assayed, and after data collection, homeostasis model assessment of IR (HOMA-IR) scores were calculated. Intention-to-treat analyses were performed using linear mixed models. The treatment effect ratio (TER) of exercisers to controls was calculated. Data were available on 308 (96.3%) women at 6 months and 310 (96.9%) women at 12 months. Across the study period, statistically significant reductions in insulin (TER=0.87, 95% confidence interval (95% CI)=0.81-0.93), HOMA-IR (TER=0.86, 95% CI=0.80-0.93), and leptin (TER=0.82, 95% CI=0.78-0.87), and an increase in the adiponectin/leptin ratio (TER=1.21, 95% CI=1.13-1.28) were observed in the exercise group compared with the control group. No significant differences were observed for glucose, IGF1, IGFBP3, adiponectin or the IGF1/IGFBP3 ratio. Previously inactive postmenopausal women who engaged in a moderate-to-vigorous intensity exercise program experienced changes in insulin, HOMA-IR, leptin, and adiponectin/leptin that might decrease the risk for postmenopausal breast cancer.

Context: It has been proposed that because dehydroepiandrosterone (DHEA) and its sulfate, DHEAS, are important precursors for estrogen and androgen production, treatment with DHEA is a physiologically based strategy for the alleviation of hormone deficiency symptoms in postmenopausal women. We have summarized the physiology of DHEA in women and reviewed the findings from randomized controlled trials (RCT) of the effects of DHEA therapy in postmenopausal women with normal adrenal function., Evidence Acquisition: We reviewed the medical literature for key papers investigating DHEA physiology and RCT of the use of DHEA in postmenopausal women through November 2010. The focus was on sexual function, well-being, metabolic parameters, and cognition as study endpoints., Evidence Synthesis: Although cross-sectional studies have indicated a link between low DHEA levels and impaired sexual function, well-being, and cognitive performance in postmenopausal women, placebo-controlled RCT do not show benefits of oral DHEA for any of these outcomes or favorable effects on lipids and carbohydrate metabolism., Conclusions: Taken together, findings from this review of the published literature of studies do not support the use of DHEA in postmenopausal women at this time.

It is controversial to what extent endogenous gonadal hormone exposures influence executive functions in midlife women. Participants in the population-based Melbourne Women's Midlife Health Project were administered a battery of neuropsychological tests on two occasions 2 years apart. Tests of executive functions were the Trail Making Test (Part B), Tower of London (administered at baseline only), Symbol Digit Modalities Test, Digit Span Backward, and Letter-Number Sequencing. Estrone, free estradiol, and free testosterone levels were measured at the time of the first testing, and analyses were restricted to 147 women aged 56-64 years who had recently undergone natural menopause (mean age of menopause 53 years) and were not using hormone therapy. In multiple linear regression analyses, 2 of 20 baseline associations were significant at an alpha level of 0.05. Estrone concentrations were positively associated with Tower of London performance (p=0.02), and the ratio of free testosterone to free estradiol was positively associated with scores on the Symbol Digit Modalities Test score (p=0.04). No hormone measure was significantly predictive of 2-year change in executive functions performance. Significance levels in these exploratory analyses were unadjusted for multiple comparisons, and observed associations could be due to unique psychometric properties of these particular tasks or due to chance. Sex hormone binding globulin concentrations were unrelated to executive function scores. In recently postmenopausal women not receiving hormone therapy, serum concentrations of estrone, estradiol and testosterone, and the testosterone/estradiol ratio are not strongly associated with executive functions., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The use of breast density as an intermediate or predictive marker of breast cancer risk is limited by an incomplete understanding of the etiology of breast density. High blood levels of endogenous estrogens and androgens are associated with increased risk of breast cancer among postmenopausal women. We sought to examine whether these hormones are also associated with breast density. The Wisconsin Breast Density Study enrolled 257 postmenopausal women, ages 55-70 years, with no history of postmenopausal hormone use, from mammography clinics in Madison, Wisconsin. Subjects provided a blood sample for sex hormone analysis, and breast density was measured from subjects' screening mammograms using a computer-assisted thresholding method. Numerous sex hormones were associated with breast density in age-adjusted analyses. However, further adjustment for body mass index and other potentially confounding factors substantially attenuated or eliminated these associations. In the fully adjusted model, there remained a positive association between percent breast density and serum progesterone (P=0.03), with percent density rising from 11.9% (95% CI: 9.8, 14.1%) among women in the lowest quartile of serum progesterone to 15.4% (12.9, 18.2%) among women in the highest quartile. There was also a positive association between sex hormone binding globulin and percent breast density (P=0.06). In contrast, there were no independent associations between percent breast density and estradiol (total, free, or bioavailable), estrone, estrone sulfate, or testosterone (total, free, or bioavailable). These results suggest that breast density has a hormonal etiology; however, it may differ in important ways from that of breast cancer risk., (© Springer Science+Business Media, LLC 2010)

Context: Dehydroepiandrosterone sulfate (DHEA-S), a major circulating sex steroid prohormone, declines with age. Low levels have been associated with increased cardiovascular disease (CVD) risk and all-cause mortality, although these results have not been consistently replicated, particularly in women., Objective: Our objective was to examine the association of circulating DHEA-S levels, CVD, and mortality risk among postmenopausal women with suspected myocardial ischemia., Design: In the Women's Ischemia Syndrome Evaluation, 270 postmenopausal women underwent coronary angiography and blood hormone levels for suspected ischemia and were followed annually. The primary outcome of interest was CVD mortality; secondary analyses included all-cause mortality and nonfatal CVD events (myocardial infarction, stroke, and congestive heart failure) and angiographic obstructive coronary artery disease (CAD)., Results: Women in the lowest DHEA-S tertile had higher CVD mortality (17% 6-yr mortality rate vs. 8%; log-rank P = 0.011), and all-cause mortality (21 vs. 10%; P = 0.011) compared with women with higher DHEA-S levels. The increased CVD mortality risk [hazard ratio (HR) = 2.55; 95% confidence interval (CI) = 1.19-5.45] remained unchanged after adjustment for multiple CVD risk factors (HR = 2.43; 95% CI = 1.06-5.56) but became nonsignificant when further adjusting for the presence or severity of angiographic obstructive CAD (HR = 1.99; 95% CI = 0.87-4.59). Results were similar for all-cause mortality. Lower DHEA-S levels were only marginally but not independently associated with obstructive CAD., Conclusions: Among postmenopausal women with coronary risk factors undergoing coronary angiography for suspected myocardial ischemia, lower DHEA-S levels were linked with higher CVD mortality and all-cause mortality. Our study provides valuable feasibility data useful for future investigations and possible mechanistic pathways.

Aim: The type of estrogen and progestin as well as their doses, route and regimens of administration may each affect the benefit-risk profile of postmenopausal hormone therapy. The aim of this study was to evaluate the endometrial effect of progesterone released continuously from a vaginal ring, combined with transdermal estradiol in postmenopausal women., Method: Forty-four postmenopausal women participated in a randomized, double-blind, dose-finding study evaluating two hormonal treatments, combining 50 microg/day of estradiol delivered by transdermal patches and either 0.5-g or 1-g progesterone vaginal rings (PVR) given for 12 weeks. The effect on the endometrium was assessed by histology and the detection of the proliferative marker Ki-67. We also measured the serum concentration of estradiol and progesterone, the tissue concentration of progesterone and the immunolocalization of estradiol and progesterone receptors in the endometrium., Results: Endometrial thickness was increased after both treatments, although endometrial histology appeared atrophic in most biopsies. A circulating dose-response of serum progesterone levels was observed from the first to the 12th week of PVR use. In the high-progesterone-dose group, the scarce presence of Ki-67 and hormone receptors reflected the predominant action of progesterone in endometrial glands and stroma, in parallel with a lower tissue concentration of progesterone in this group., Conclusion: The PVR appears to be a promising method of administering natural progesterone to postmenopausal women treated with estrogen. Estradiol levels corrected the menopausal symptoms, as expected, and the presence of atrophic endometrium in the majority of women indicated that both doses of progesterone oppose the stimulatory estradiol effects, although the percentage of proliferative tissue was not negligible in both groups.

Objective: The role of testosterone in the regulation of metabolic and physiological function in men is well defined, but its role in women remains enigmatic. Thus, the present study sought to assess the contribution of endogenous circulating androgens to the regulation of metabolic function, body morphometry, and physical function in normal naturally postmenopausal women., Methods: Using a cross-sectional design, we measured serum androgens in a cohort of 29 naturally postmenopausal women and correlated the results with metabolic, morphometric, and functional outcome parameters. These included insulin sensitivity, whole-body fat and lean body mass, visceral/abdominal fat areasm and aerobic capacity., Results: Higher serum testosterone levels were related to greater maximal aerobic capacity and reduced adiposity. Additionally, higher serum dihydrotestosterone, dehydroepiandrosterone sulfate, androstenedione, and androstenetriol glucuronidate levels were correlated to greater insulin sensitivity., Conclusion: In naturally postmenopausal women, endogenous androgens may play a role in the maintenance of beneficial patterns of metabolic, morphometric, and functional parameters.

Objective: Hormone therapy has been shown to reduce markers of vascular inflammation in . C-reactive protein (CRP), a marker of generalized inflammation, is raised by oral estradiol therapy (ET). It is not known how sex hormone concentrations relate to the markers of inflammation in postmenopausal women taking or not taking hormone therapy., Methods: This observational study includes postmenopausal women participating in the Estrogen in the Prevention of Atherosclerosis Trial. Multiple measures of serum sex hormone and sex hormone-binding globulin(SHBG) levels from 107 postmenopausal women taking oral ET and 109 taking placebo for 2 years were correlated with markers of inflammation over the same time period using generalized estimating equations., Results: Levels of soluble intercellular adhesion molecule-1 were significantly inversely associated with estrone(P = 0.05), total and free estradiol (P = 0.008 and 0.02, respectively), and SHBG (P = 0.03) only among oral ET users. Serum homocysteine levels were also inversely associated with estrone (P = 0.001) and total and free estradiol (P = 0.0006 and 0.0009, respectively) in ET-treated women only. No such associations were observed among women taking placebo. CRP was positively associated with estrogens and SHBG among women taking oral ET but inversely associated with SHBG among the placebo group., Conclusions: The inverse associations of estrogens with soluble intercellular adhesion molecule-1 and homocysteine support an anti-inflammatory property of estrogen, which was observed only at pharmacological levels in postmenopausal women. The positive associations between estrogens and CRP in the ET-treated women can be explained by the first-pass hepatic effect rather than a proinflammatory response.

To add to the existing evidence that comes mostly from White populations, we conducted a nested case-control study to examine the association between sex hormones and breast cancer risk within the Multiethnic Cohort that includes Japanese American, White, Native Hawaiian, African American, and Latina women. Of the postmenopausal women for whom we had a plasma sample, 132 developed breast cancer during follow-up. Two controls per case, matched on study area (Hawaii, Los Angeles), ethnicity/race, birth year, date and time of blood draw and time fasting, were randomly selected from the women who had not developed breast cancer. Levels of estradiol (E(2)), estrone (E(1)), androstenedione, dehydroepiandrosterone (DHEA), and testosterone were quantified by RIA after organic extraction and Celite column partition chromatography. E(1) sulfate, DHEA sulfate (DHEAS), and sex hormone-binding globulin (SHBG) were quantified by direct immunoassays. Based on conditional logistic regression, the sex hormones were positively associated and SHBG was negatively associated with breast cancer risk. All associations, except those with DHEAS and testosterone showed a significant linear trend. The odds ratio (OR) associated with a doubling of E(2) levels was 2.26 (95% confidence interval (CI) 1.58-3.25), and the OR associated with a doubling of testosterone levels was 1.34 (95% CI 0.98-1.82). The associations in Japanese American women, who constituted 54% of our sample, were similar to or nonsignificantly stronger than in the overall group. This study provides the best evidence to date that the association between sex hormones and breast cancer risk is generalizable to an ethnically diverse population.

Objective: Hormone therapy (HT) increases the risk of venous thrombosis and stroke. Risk of venous thrombosis and stroke is higher in older, overweight, and obese women using HT. However, the impact of age and obesity on estrogen concentrations among HT users is not well defined., Method: We measured serum levels of estrone, total and free estradiol, and SHBG in 180 postmenopausal women participating in the Estrogen in the Prevention of Atherosclerosis Trial (EPAT), 91 receiving estradiol therapy (ET) and 89 taking placebo, every 6 months over 2 yr. Mean on-trial levels of estrogens and SHBG were compared across age, body mass index (BMI), and waist to hip ratio categories among ET users and placebo separately., Results: Among the ET users, total (P = 0.01) and free estradiol (P = 0.002) were significantly directly associated with BMI adjusted for age. SHBG was inversely related to waist to hip ratio adjusted for age (P = 0.005). Age was not associated with any of the estrogen or SHBG concentrations in ET or placebo groups. BMI was positively associated with estrone concentrations among older but not younger ET users (P for interaction = 0.03)., Conclusion: Overweight and obese women using ET attain greater concentrations of estrogen compared to women with normal BMI, whereas ET users with abdominal obesity attain lower SHBG levels. Obese older women using ET have the highest concentration of estrone. It may be useful to consider age and obesity when prescribing HT to minimize the risk of venous thrombosis or stroke in postmenopausal women. Further research regarding relationships among circulating hormone levels and risk for these conditions is required to substantiate this conclusion.

Objective: Some postmenopausal women use over-the-counter dehydroepiandrosterone because of its purported beneficial effects. Although without major inherent androgenic activity, it is metabolized to potent androgens and estrogens. We investigated the pharmacokinetics of dehydroepiandrosterone and its relevant metabolites after prolonged treatment of postmenopausal women with 25 mg/d of dehydroepiandrosterone., Methods: Twenty healthy postmenopausal women were randomized to either 25 mg/d of dehydroepiandrosterone or placebo for 6 months. Frequent blood samples were obtained over 24 hours on day 1 and after 3 and 6 months., Results: Mean baseline androgen levels at day 1 and month 3 in the treated group (seven evaluable women) were the following: dehydroepiandrosterone, 1.82 and 3.56 ng/mL; dehydroepiandrosterone sulfate, 0.96 and 3.37 microg/mL; 5-androstene-3beta,17beta-diol, 0.32 and 0.66 ng/mL; androstenedione, 0.50 and 0.86 ng/mL; testosterone, 17.9 and 28.7 ng/dL; dihydrotestosterone, 6.91 and 17.4 ng/dL; and 3alpha-androstanediol glucuronide, 2.66 and 10.7 ng/mL, respectively; these increases were significant. Small changes (-6% to 16%) were observed from month 3 to month 6. Nonsignificant increases were observed in baseline estrone and estradiol levels and in Cmax and AUC0-24h values for the androgens and estrogens from day 1 to months 3 and 6 of treatment. Sex hormone-binding globulin levels were unchanged, but free testosterone increased significantly from day 1 to month 3. Baseline hormone levels did not increase in the placebo group (six evaluable women). Changes in baseline values over time differed significantly between the groups for all hormones except estrone and estradiol., Conclusions: In postmenopausal women treated orally with a commonly available dose of dehydroepiandrosterone, the daily exposure (AUC) of dehydroepiandrosterone and its principal androgenic metabolites was found to be similar during 6 months of treatment despite increased serum baseline concentrations of these androgens.

Context: Because androgens are obligatory precursors of estrogens, it is reasonable to assume that their serum concentrations would exhibit positive correlations. If so, then epidemiologic studies that examine the association between androgens and pathological processes should adjust the results for the independent effect of estrogens., Objective: The objective of the study was to examine the interrelationships among testosterone (T), androstenedione, estradiol (E2), estrone, and SHBG in postmenopausal women., Design: This was a cross-sectional study of women participating in the National Heart, Blood, and Lung Institute-sponsored Women's Ischemia Syndrome Evaluation study., Setting: The study was conducted at four academic medical centers., Patients: A total of 284 postmenopausal women with chest pain symptoms or suspected myocardial ischemia., Main Outcome Measures: Post hoc analysis of the relationships among sex steroid hormones with insulin resistance, body mass index (BMI), and presence or absence of coronary artery disease as determined by coronary angiography., Results: BMI was significantly associated with insulin resistance, total E2, free E2, bioavailable E2, and free T. Highly significant correlations were found for total T, free T, and androstenedione with total E2, free E2, bioavailable E2, and estrone and persisted after adjustment for BMI and insulin resistance. A significant relationship was present between total and free T and the presence of coronary artery disease after adjustment for the effect of E2., Conclusions: Serum levels of androgens and estrogens track closely in postmenopausal women referred for coronary angiography for suspected myocardial ischemia. Epidemiological studies that relate sex steroid hormones to physiological or pathological processes need to control for the independent effect of both estrogens and androgens.

IGF-1 levels increased, and IGF-2 and IGFBP-3 levels remained unchanged, in postmenopausal women following oophorectomy. The increase in IGF-1 likely results from decreased ovarian steroidogenic precursors resulting from removal of the hormonally active ovary. This finding raises concerns, given the association between increased IGF-1 and elevated colon cancer risk, and adds to the literature suggesting a potential benefit from ovarian preservation.

In postmenopausal women, levels of estrogens, androgens, and perhaps prolactin have been related to risk of breast and other hormonal cancers in women. However, the determinants of these hormone concentrations have not been firmly established. Associations among various demographic, menstrual, and reproductive factors, medication use and endogenous sex hormone concentrations (estradiol, free estradiol, estrone, estrone sulfate, testosterone, free testosterone, sex hormone binding globulin, androstenedione, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), dihydrotestosterone, and prolactin) were evaluated in a cross-sectional analysis from a simple random sample of 274 postmenopausal women selected from the Women's Health Initiative Dietary Modification Trial. In multiple regression analyses on log-transformed hormones, the concentrations of DHEA, and DHEAS were negatively and statistically significantly associated with age (both beta=-0.03, P<0.001, respectively). Estradiol, estrone, DHEA, and free testosterone concentrations were higher in African-American than in non-Hispanic White women, but after multivariate adjustment the associations were statistically significant only for free testosterone (beta=0.38, P=0.01). Women who had a history of bilateral oophorectomy had a mean 35% lower testosterone concentration compared with women with at least one ovary remaining (beta=-0.43, P=0.002), and lower free testosterone (beta=-0.42, P=0.04) after multivariate adjustment. Women who reported regular use of NSAIDs had higher DHEA concentrations (beta=0.20, P=0.04) and lower prolactin concentrations (beta=-0.18, P=0.02) compared with non-users. These results suggest that while age, oophorectomy status, and NSAID use may be associated with selected sex hormone concentrations, few menstrual or reproductive factors affect endogenous sex hormones in the postmenopausal period.

Objective: To compare serum 17beta-estradiol (E2), estrone (E1), estrone sulfate, follicle-stimulating hormone, luteinizing hormone, sex hormone-binding globulin, vaginal pH, and the vaginal maturation indices in women using a low-dose transdermal patch releasing 14 microg of E2 per day and a vaginal ring releasing 7.5 microg of E2 per day., Design: Twenty-four postmenopausal women were randomly assigned to either the patch (n = 12) or the ring (n = 12) for a 12-week study period. Serum E2, E1, estrone sulfate, follicle-stimulating hormone, luteinizing hormone, and sex hormone-binding globulin were measured by immunoassay at baseline and 6 and 12 weeks. Vaginal pH was determined at baseline and 6 and 12 weeks. Vaginal cytologic examinations for vaginal maturation index were done at baseline and 12 weeks., Results: Twenty women completed the study. The patch significantly increased serum E1 and E2 levels at 6 and 12 weeks (P < 0.01); there was no significant increase in serum E1 and E2 levels with the ring. Both the patch and the ring significantly reduced vaginal pH at 6 (P < 0.001) and 12 (P < 0.001) weeks and significantly reduced the percentage of vaginal parabasal cells at 12 weeks with no significant difference between the two groups. Both preparations increased the proportion of superficial cells; the increase was significant only with the patch (P = 0.04)., Conclusions: A transdermal E2 skin patch releasing 14 microg of E2 per day had an effect on vaginal pH and vaginal maturation indices similar to that of a vaginal E2 ring releasing 7.5 microg of E2 per day. Therefore, this patch is likely to relieve symptoms of vulvovaginal atrophy.