Margery Gass

ContextDespite decades of use and considerable research, the role of estrogen alone in preventing chronic diseases in postmenopausal women remains uncertain.ObjectiveTo assess the effects on major disease incidence rates of the most commonly used postmenopausal hormone therapy in the United States.Design, Setting, and ParticipantsA randomized, double-blind, placebo-controlled disease prevention trial (the estrogen-alone component of the Women's Health Initiative [WHI]) conducted in 40 US clinical centers beginning in 1993. Enrolled were 10 739 postmenopausal women, aged 50-79 years, with prior hysterectomy, including 23% of minority race/ethnicity.InterventionWomen were randomly assigned to receive either 0.625 mg/d of conjugated equine estrogen (CEE) or placebo.Main Outcome MeasuresThe primary outcome was coronary heart disease (CHD) incidence (nonfatal myocardial infarction or CHD death). Invasive breast cancer incidence was the primary safety outcome. A global index of risks and benefits, including these primary outcomes plus stroke, pulmonary embolism (PE), colorectal cancer, hip fracture, and deaths from other causes, was used for summarizing overall effects.ResultsIn February 2004, after reviewing data through November 30, 2003, the National Institutes of Health (NIH) decided to end the intervention phase of the trial early. Estimated hazard ratios (HRs) (95% confidence intervals [CIs]) for CEE vs placebo for the major clinical outcomes available through February 29, 2004 (average follow-up 6.8 years), were: CHD, 0.91 (0.75-1.12) with 376 cases; breast cancer, 0.77 (0.59-1.01) with 218 cases; stroke, 1.39 (1.10-1.77) with 276 cases; PE, 1.34 (0.87-2.06) with 85 cases; colorectal cancer, 1.08 (0.75-1.55) with 119 cases; and hip fracture, 0.61 (0.41-0.91) with 102 cases. Corresponding results for composite outcomes were: total cardiovascular disease, 1.12 (1.01-1.24); total cancer, 0.93 (0.81-1.07); total fractures, 0.70 (0.63-0.79); total mortality, 1.04 (0.88-1.22), and the global index, 1.01 (0.91-1.12). For the outcomes significantly affected by CEE, there was an absolute excess risk of 12 additional strokes per 10 000 person-years and an absolute risk reduction of 6 fewer hip fractures per 10 000 person-years. The estimated excess risk for all monitored events in the global index was a nonsignificant 2 events per 10 000 person-years.ConclusionsThe use of CEE increases the risk of stroke, decreases the risk of hip fracture, and does not affect CHD incidence in postmenopausal women with prior hysterectomy over an average of 6.8 years. A possible reduction in breast cancer risk requires further investigation. The burden of incident disease events was equivalent in the CEE and placebo groups, indicating no overall benefit. Thus, CEE should not be recommended for chronic disease prevention in postmenopausal women.

The Women's Health Initiative trial of combined estrogen plus progestin was stopped early when overall health risks, including invasive breast cancer, exceeded benefits. Outstanding issues not previously addressed include characteristics of breast cancers observed among women using hormones and whether diagnosis may be influenced by hormone effects on mammography.To determine the relationship among estrogen plus progestin use, breast cancer characteristics, and mammography recommendations.Following a comprehensive breast cancer risk assessment, 16 608 postmenopausal women aged 50 to 79 years with an intact uterus were randomly assigned to receive combined conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo from 1993 to 1998 at 40 clinical centers. Screening mammography and clinical breast examinations were performed at baseline and yearly thereafter.Breast cancer number and characteristics, and frequency of abnormal mammograms by estrogen plus progestin exposure.In intent-to-treat analyses, estrogen plus progestin increased total (245 vs 185 cases; hazard ratio [HR], 1.24; weighted P<.001) and invasive (199 vs 150 cases; HR, 1.24; weighted P =.003) breast cancers compared with placebo. The invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology and grade but were larger (mean [SD], 1.7 cm [1.1] vs 1.5 cm [0.9], respectively; P =.04) and were at more advanced stage (regional/metastatic 25.4% vs 16.0%, respectively; P =.04) compared with those diagnosed in the placebo group. After 1 year, the percentage of women with abnormal mammograms was substantially greater in the estrogen plus progestin group (716 [9.4%] of 7656) compared with placebo group (398 [5.4%] of 7310; P<.001), a pattern which continued for the study duration.Relatively short-term combined estrogen plus progestin use increases incident breast cancers, which are diagnosed at a more advanced stage compared with placebo use, and also substantially increases the percentage of women with abnormal mammograms. These results suggest estrogen plus progestin may stimulate breast cancer growth and hinder breast cancer diagnosis.

The efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal.

Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention.To report a comprehensive, integrated overview of findings from the 2 Women's Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up.A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers.Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010.Primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death.During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10,000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials.Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women.clinicaltrials.gov Identifier: NCT00000611.

Multiple epidemiologic studies and some trials have linked diet with cardiovascular disease (CVD) prevention, but long-term intervention data are needed.To test the hypothesis that a dietary intervention, intended to be low in fat and high in vegetables, fruits, and grains to reduce cancer, would reduce CVD risk.Randomized controlled trial of 48,835 postmenopausal women aged 50 to 79 years, of diverse backgrounds and ethnicities, who participated in the Women's Health Initiative Dietary Modification Trial. Women were randomly assigned to an intervention (19,541 [40%]) or comparison group (29,294 [60%]) in a free-living setting. Study enrollment occurred between 1993 and 1998 in 40 US clinical centers; mean follow-up in this analysis was 8.1 years.Intensive behavior modification in group and individual sessions designed to reduce total fat intake to 20% of calories and increase intakes of vegetables/fruits to 5 servings/d and grains to at least 6 servings/d. The comparison group received diet-related education materials.Fatal and nonfatal coronary heart disease (CHD), fatal and nonfatal stroke, and CVD (composite of CHD and stroke).By year 6, mean fat intake decreased by 8.2% of energy intake in the intervention vs the comparison group, with small decreases in saturated (2.9%), monounsaturated (3.3%), and polyunsaturated (1.5%) fat; increases occurred in intakes of vegetables/fruits (1.1 servings/d) and grains (0.5 serving/d). Low-density lipoprotein cholesterol levels, diastolic blood pressure, and factor VIIc levels were significantly reduced by 3.55 mg/dL, 0.31 mm Hg, and 4.29%, respectively; levels of high-density lipoprotein cholesterol, triglycerides, glucose, and insulin did not significantly differ in the intervention vs comparison groups. The numbers who developed CHD, stroke, and CVD (annualized incidence rates) were 1000 (0.63%), 434 (0.28%), and 1357 (0.86%) in the intervention and 1549 (0.65%), 642 (0.27%), and 2088 (0.88%) in the comparison group. The diet had no significant effects on incidence of CHD (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.90-1.06), stroke (HR, 1.02; 95% CI, 0.90-1.15), or CVD (HR, 0.98; 95% CI, 0.92-1.05). Excluding participants with baseline CVD (3.4%), the HRs (95% CIs) for CHD and stroke were 0.94 (0.86-1.02) and 1.02 (0.90-1.17), respectively. Trends toward greater reductions in CHD risk were observed in those with lower intakes of saturated fat or trans fat or higher intakes of vegetables/fruits.Over a mean of 8.1 years, a dietary intervention that reduced total fat intake and increased intakes of vegetables, fruits, and grains did not significantly reduce the risk of CHD, stroke, or CVD in postmenopausal women and achieved only modest effects on CVD risk factors, suggesting that more focused diet and lifestyle interventions may be needed to improve risk factors and reduce CVD risk.ClinicalTrials.gov Identifier: NCT00000611.

Higher intake of calcium and vitamin D has been associated with a reduced risk of colorectal cancer in epidemiologic studies and polyp recurrence in polyp-prevention trials. However, randomized-trial evidence that calcium with vitamin D supplementation is beneficial in the primary prevention of colorectal cancer is lacking.We conducted a randomized, double-blind, placebo-controlled trial involving 36,282 postmenopausal women from 40 Women's Health Initiative centers: 18,176 women received 500 mg of elemental calcium as calcium carbonate with 200 IU of vitamin D3 [corrected] twice daily (1000 mg of elemental calcium and 400 IU of vitamin D3) and 18,106 received a matching placebo for an average of 7.0 years. The incidence of pathologically confirmed colorectal cancer was the designated secondary outcome. Baseline levels of serum 25-hydroxyvitamin D were assessed in a nested case-control study.The incidence of invasive colorectal cancer did not differ significantly between women assigned to calcium plus vitamin D supplementation and those assigned to placebo (168 and 154 cases; hazard ratio, 1.08; 95 percent confidence interval, 0.86 to 1.34; P=0.51), and the tumor characteristics were similar in the two groups. The frequency of colorectal-cancer screening and abdominal symptoms was similar in the two groups. There were no significant treatment interactions with baseline characteristics.Daily supplementation of calcium with vitamin D for seven years had no effect on the incidence of colorectal cancer among postmenopausal women. The long latency associated with the development of colorectal cancer, along with the seven-year duration of the trial, may have contributed to this null finding. Ongoing follow-up will assess the longer-term effect of this intervention. (ClinicalTrials.gov number, NCT00000611.).

The aim of this article is to summarize the recommended updates to the 2001 Stages of Reproductive Aging Workshop (STRAW) criteria. The 2011 STRAW + 10 reviewed advances in understanding of the critical changes in hypothalamic-pituitary-ovarian function that occur before and after the final menstrual period.Scientists from five countries and multiple disciplines evaluated data from cohort studies of midlife women and in the context of chronic illness and endocrine disorders on change in menstrual, endocrine, and ovarian markers of reproductive aging including antimüllerian hormone, inhibin-B, follicle-stimulating hormone, and antral follicle count. Modifications were adopted by consensus.STRAW + 10 simplified bleeding criteria for the early and late menopausal transition, recommended modifications to criteria for the late reproductive stage (Stage -3) and the early postmenopause stage (Stage +1), provided information on the duration of the late transition (Stage -1) and early postmenopause (Stage +1), and recommended application regardless of women's age, ethnicity, body size, or lifestyle characteristics.STRAW + 10 provides a more comprehensive basis for assessing reproductive aging in research and clinical contexts. Application of the STRAW + 10 staging system should improve comparability of studies of midlife women and facilitate clinical decision making. Nonetheless, important knowledge gaps persist, and seven research priorities are identified.

Observational studies have suggested that postmenopausal hormone treatment may improve cognitive function, but data from randomized clinical trials have been sparse and inconclusive. The Women's Health Initiative Memory Study (WHIMS) is an ancillary study of the Women's Health Initiative (WHI) hormone therapy trials. On July 8, 2002, the estrogen plus progestin therapy in the WHI trial was discontinued because of certain increased health risks for women.To determine whether estrogen plus progestin therapy protects global cognitive function in older postmenopausal women.A randomized, double-blind, placebo-controlled clinical trial, WHIMS is an ancillary study of geographically diverse, community-dwelling women aged 65 years or older from 39 of 40 clinical centers within the WHI estrogen plus progestin trial that started in June 1995. Of 4894 eligible postmenopausal women aged 65 years or older and free of probable dementia at baseline, 4532 (92.6%) were enrolled in the estrogen plus progestin component of WHIMS. A total of 4381 participants (96.7%) provided at least 1 valid cognitive function score between June 1995 and July 8, 2002.Participants received either 1 daily tablet containing 0.625 mg of conjugated equine estrogen with 2.5 mg of medroxyprogesterone acetate (n = 2145) or matching placebo (n = 2236).Global cognitive function measured annually with the Modified Mini-Mental State Examination.The Modified Mini-Mental State Examination mean total scores in both groups increased slightly over time (mean follow-up of 4.2 years). Women in the estrogen plus progestin group had smaller average increases in total scores compared with women receiving placebo (P =.03), but these differences were not clinically important. Removing women by censoring them after adjudicated dementia, mild cognitive impairment, or stroke, and nonadherence to study protocol, did not alter the findings. Prior hormone therapy use and duration of prior use did not affect the interpretation of the results, nor did timing of prior hormone therapy initiation with respect to the final menstrual period. More women in the estrogen plus progestin group had a substantial and clinically important decline (> or =2 SDs) in Modified Mini-Mental State Examination total score (6.7%) compared with the placebo group (4.8%) (P =.008).Among postmenopausal women aged 65 years or older, estrogen plus progestin did not improve cognitive function when compared with placebo. While most women receiving estrogen plus progestin did not experience clinically relevant adverse effects on cognition compared with placebo, a small increased risk of clinically meaningful cognitive decline occurred in the estrogen plus progestin group.

Objective:The aim of this article is to summarize the recommended updates to the 2001 Stages of Reproductive Aging Workshop (STRAW) criteria. The 2011 STRAW + 10 reviewed advances in understanding of the critical changes in hypothalamic-pituitary-ovarian function that occur before and after the final menstrual period.

A LOWfat dietary pattern can reduce breast cancer risk has existed for decades.Supported by early rodent experiments, 1 country-to-country comparisons linked higher dietary fat intake to breast cancer risk. 2 However, case-control and cohort studies have had mixed results.A metaanalysis 3 of 12 international case-See also pp 643, 655, and 691. ContextThe hypothesis that a low-fat dietary pattern can reduce breast cancer risk has existed for decades but has never been tested in a controlled intervention trial.Objective To assess the effects of undertaking a low-fat dietary pattern on breast cancer incidence.Design and Setting A randomized, controlled, primary prevention trial conducted at 40 US clinical centers from 1993 to 2005.Participants A total of 48 835 postmenopausal women, aged 50 to 79 years, without prior breast cancer, including 18.6% of minority race/ethnicity, were enrolled.Interventions Women were randomly assigned to the dietary modification intervention group (40% [n = 19 541]) or the comparison group (60% [n = 29 294]).The intervention was designed to promote dietary change with the goals of reducing intake of total fat to 20% of energy and increasing consumption of vegetables and fruit to at least 5 servings daily and grains to at least 6 servings daily.Comparison group participants were not asked to make dietary changes. Main Outcome Measure Invasive breast cancer incidence.Results Dietary fat intake was significantly lower in the dietary modification intervention group compared with the comparison group.The difference between groups in change from baseline for percentage of energy from fat varied from 10.7% at year 1 to 8.1% at year 6.Vegetable and fruit consumption was higher in the intervention group by at least 1 serving per day and a smaller, more transient difference was found for grain consumption.The number of women who developed invasive breast cancer (annualized incidence rate) over the 8.1-year average follow-up period was 655 (0.42%) in the intervention group and 1072 (0.45%) in the comparison group (hazard ratio, 0.91; 95% confidence interval, 0.83-1.01for the comparison between the 2 groups).Secondary analyses suggest a lower hazard ratio among adherent women, provide greater evidence of risk reduction among women having a high-fat diet at baseline, and suggest a dietary effect that varies by hormone receptor characteristics of the tumor.Conclusions Among postmenopausal women, a low-fat dietary pattern did not result in a statistically significant reduction in invasive breast cancer risk over an 8.1year average follow-up period.However, the nonsignificant trends observed suggesting reduced risk associated with a low-fat dietary pattern indicate that longer, planned, nonintervention follow-up may yield a more definitive comparison.

Calcified plaque in the coronary arteries is a marker for atheromatous-plaque burden and is predictive of future risk of cardiovascular events. We examined the relationship between estrogen therapy and coronary-artery calcium in the context of a randomized clinical trial.In our ancillary substudy of the Women's Health Initiative trial of conjugated equine estrogens (0.625 mg per day) as compared with placebo in women who had undergone hysterectomy, we performed computed tomography of the heart in 1064 women aged 50 to 59 years at randomization. Imaging was conducted at 28 of 40 centers after a mean of 7.4 years of treatment and 1.3 years after the trial was completed (8.7 years after randomization). Coronary-artery calcium (or Agatston) scores were measured at a central reading center without knowledge of randomization status.The mean coronary-artery calcium score after trial completion was lower among women receiving estrogen (83.1) than among those receiving placebo (123.1) (P=0.02 by rank test). After adjustment for coronary risk factors, the multivariate odds ratios for coronary-artery calcium scores of more than 0, 10 or more, and 100 or more in the group receiving estrogen as compared with placebo were 0.78 (95% confidence interval, 0.58 to 1.04), 0.74 (0.55 to 0.99), and 0.69 (0.48 to 0.98), respectively. The corresponding odds ratios among women with at least 80% adherence to the study estrogen or placebo were 0.64 (P=0.01), 0.55 (P<0.001), and 0.46 (P=0.001). For coronary-artery calcium scores of more than 300 (vs. <10), the multivariate odds ratio was 0.58 (P=0.03) in an intention-to-treat analysis and 0.39 (P=0.004) among women with at least 80% adherence.Among women 50 to 59 years old at enrollment, the calcified-plaque burden in the coronary arteries after trial completion was lower in women assigned to estrogen than in those assigned to placebo. However, estrogen has complex biologic effects and may influence the risk of cardiovascular events and other outcomes through multiple pathways. (ClinicalTrials.gov number, NCT00000611.)

AbstractObjectiveThe aim of this article is to summarize the recommended updates to the 2001 Stages of Reproductive Aging Workshop (STRAW) criteria. The 2011 STRAW + 10 reviewed advances in understanding of the critical changes in hypothalamic-pituitary-ovarian function that occur before and after t

Background In 2012, the Board of Directors of the International Society for the Study of Women’s Sexual Health (ISSWSH) and the Board of Trustees of The North American Menopause Society (NAMS) acknowledged the need to review current terminology associated with genitourinary tract symptoms related to menopause. Methods The 2 societies cosponsored a terminology consensus conference, which was held in May 2013. Results and Conclusions Members of the consensus conference agreed that the term genitourinary syndrome of menopause (GSM) is a medically more accurate, all-encompassing, and publicly acceptable term than vulvovaginal atrophy. GSM is defined as a collection of symptoms and signs associated with a decrease in estrogen and other sex steroids involving changes to the labia majora/minora, clitoris, vestibule/introitus, vagina, urethra and bladder. The syndrome may include but is not limited to genital symptoms of dryness, burning, and irritation; sexual symptoms of lack of lubrication, discomfort or pain, and impaired function; and urinary symptoms of urgency, dysuria and recurrent urinary tract infections. Women may present with some or all of the signs and symptoms, which must be bothersome and should not be better accounted for by another diagnosis. The term was presented and discussed at the annual meeting of each society. The respective Boards of NAMS and ISSWSH formally endorsed the new terminology—genitourinary syndrome of menopause (GSM)—in 2014.

<h3>Context</h3>In the Women's Health Initiative randomized, placebo-controlled trial of estrogen plus progestin, after a mean intervention time of 5.6 (SD, 1.3) years (range, 3.7-8.6 years) and a mean follow-up of 7.9 (SD, 1.4) years, breast cancer incidence was increased among women who received combined hormone therapy. Breast cancer mortality among participants in the trial has not been previously reported.<h3>Objective</h3>To determine the effects of therapy with estrogen plus progestin on cumulative breast cancer incidence and mortality after a total mean follow-up of 11.0 (SD, 2.7) years, through August 14, 2009.<h3>Design, Setting, and Participants</h3>A total of 16 608 postmenopausal women aged 50 to 79 years with no prior hysterectomy from 40 US clinical centers were randomly assigned to receive combined conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo pill. After the original trial completion date (March 31, 2005), reconsent was required for continued follow-up for breast cancer incidence and was obtained from 12 788 (83%) of the surviving participants.<h3>Main Outcome Measures</h3>Invasive breast cancer incidence and breast cancer mortality.<h3>Results</h3>In intention-to-treat analyses including all randomized participants and censoring those not consenting to additional follow-up on March 31, 2005, estrogen plus progestin was associated with more invasive breast cancers compared with placebo (385 cases [0.42% per year] vs 293 cases [0.34% per year]; hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.07-1.46; P = .004). Breast cancers in the estrogen-plus-progestin group were similar in histology and grade to breast cancers in the placebo group but were more likely to be node-positive (81 [23.7%] vs 43 [16.2%], respectively; HR, 1.78; 95% CI, 1.23-2.58; P = .03). There were more deaths directly attributed to breast cancer (25 deaths [0.03% per year] vs 12 deaths [0.01% per year]; HR, 1.96; 95% CI, 1.00-4.04; P = .049) as well as more deaths from all causes occurring after a breast cancer diagnosis (51 deaths [0.05% per year] vs 31 deaths [0.03% per year]; HR, 1.57; 95% CI, 1.01-2.48; P = .045) among women who received estrogen plus progestin compared with women in the placebo group.<h3>Conclusions</h3>Estrogen plus progestin was associated with greater breast cancer incidence, and the cancers are more commonly node-positive. Breast cancer mortality also appears to be increased with combined use of estrogen plus progestin.<h3>Trial Registration</h3>clinicaltrials.gov Identifier: NCT00000611

Following the release of the 2002 report of the Women's Health Initiative (WHI) trial of estrogen plus progestin, the use of menopausal hormone therapy in the United States decreased substantially. Subsequently, the incidence of breast cancer also dropped, suggesting a cause-and-effect relation between hormone treatment and breast cancer. However, the cause of this decrease remains controversial.

The efficacy and safety of testosterone treatment for hypoactive sexual desire disorder in postmenopausal women not receiving estrogen therapy are unknown.We conducted a double-blind, placebo-controlled, 52-week trial in which 814 women with hypoactive sexual desire disorder were randomly assigned to receive a patch delivering 150 or 300 microg of testosterone per day or placebo. Efficacy was measured to week 24; safety was evaluated over a period of 52 weeks, with a subgroup of participants followed for an additional year. The primary end point was the change from baseline to week 24 in the 4-week frequency of satisfying sexual episodes.At 24 weeks, the increase in the 4-week frequency of satisfying sexual episodes was significantly greater in the group receiving 300 microg of testosterone per day than in the placebo group (an increase of 2.1 episodes vs. 0.7, P<0.001) but not in the group receiving 150 microg per day (1.2 episodes, P=0.11). As compared with placebo, both doses of testosterone were associated with significant increases in desire (300 microg per day, P<0.001; 150 microg per day, P=0.04) and decreases in distress (300 microg per day, P<0.001; 150 microg per day, P=0.04). The rate of androgenic adverse events - primarily unwanted hair growth - was higher in the group receiving 300 microg of testosterone per day than in the placebo group (30.0% vs. 23.1%). Breast cancer was diagnosed in four women who received testosterone (as compared with none who received placebo); one of the four received the diagnosis in the first 4 months of the study period, and one, in retrospect, had symptoms before undergoing randomization.In postmenopausal women not receiving estrogen therapy, treatment with a patch delivering 300 microg of testosterone per day resulted in a modest but meaningful improvement in sexual function. The long-term effects of testosterone, including effects on the breast, remain uncertain. (ClinicalTrials.gov number, NCT00131495.)

Observational studies and polyp recurrence trials are not conclusive regarding the effects of a low-fat dietary pattern on risk of colorectal cancer, necessitating a primary prevention trial.To evaluate the effects of a low-fat eating pattern on risk of colorectal cancer in postmenopausal women.The Women's Health Initiative Dietary Modification Trial, a randomized controlled trial conducted in 48,835 postmenopausal women aged 50 to 79 years recruited between 1993 and 1998 from 40 clinical centers throughout the United States.Participants were randomly assigned to the dietary modification intervention (n = 19,541; 40%) or the comparison group (n = 29,294; 60%). The intensive behavioral modification program aimed to motivate and support reductions in dietary fat, to increase consumption of vegetables and fruits, and to increase grain servings by using group sessions, self-monitoring techniques, and other tailored and targeted strategies. Women in the comparison group continued their usual eating pattern.Invasive colorectal cancer incidence.A total of 480 incident cases of invasive colorectal cancer occurred during a mean follow-up of 8.1 (SD, 1.7) years. Intervention group participants significantly reduced their percentage of energy from fat by 10.7% more than did the comparison group at 1 year, and this difference between groups was mostly maintained (8.1% at year 6). Statistically significant increases in vegetable, fruit, and grain servings were also made. Despite these dietary changes, there was no evidence that the intervention reduced the risk of invasive colorectal cancer during the follow-up period. There were 201 women with invasive colorectal cancer (0.13% per year) in the intervention group and 279 (0.12% per year) in the comparison group (hazard ratio, 1.08; 95% confidence interval, 0.90-1.29). Secondary analyses suggested potential interactions with baseline aspirin use and combined estrogen-progestin use status (P = .01 for each). Colorectal examination rates, although not protocol defined, were comparable between the intervention and comparison groups. Similar results were seen in analyses adjusting for adherence to the intervention.In this study, a low-fat dietary pattern intervention did not reduce the risk of colorectal cancer in postmenopausal women during 8.1 years of follow-up.ClinicalTrials.gov Identifier: NCT00000611.

The aim of this article is to summarize the recommended updates to the 2001 Stages of Reproductive Aging Workshop (STRAW) criteria. The 2011 STRAW +10 reviewed advances in understanding of the critical changes in hypothalamic-pituitary-ovarian function that occur before and after the final menstrual period.Scientists from five countries and multiple disciplines evaluated data from cohort studies of midlife women and in the context of chronic illness and endocrine disorders on change in menstrual, endocrine, and ovarian markers of reproductive aging including antimüllerian hormone, inhibin-B, follicle-stimulating hormone, and antral follicle count. Modifications were adopted by consensus.STRAW +10 simplified bleeding criteria for the early and late menopausal transition, recommended modifications to criteria for the late reproductive stage (Stage -3) and the early postmenopause stage (Stage +1), provided information on the duration of the late transition (Stage -1) and early postmenopause (Stage +1), and recommended application regardless of women's age, ethnicity, body size, or lifestyle characteristics.STRAW +10 provides a more comprehensive basis for assessing reproductive aging in research and clinical contexts. Application of the STRAW +10 staging system should improve comparability of studies of midlife women and facilitate clinical decision making. Nonetheless, important knowledge gaps persist, and seven research priorities are identified.

By contrast with many observational studies, women in the Women's Health Initiative (WHI) trial who were randomly allocated to receive oestrogen alone had a lower incidence of invasive breast cancer than did those who received placebo. We aimed to assess the influence of oestrogen use on longer term breast cancer incidence and mortality in extended follow-up of this cohort.Between 1993 and 1998, the WHI enrolled 10,739 postmenopausal women from 40 US clinical centres into a randomised, double-masked, placebo-controlled trial. Women aged 50-79 years who had undergone hysterectomy and had expected 3-year survival and mammography clearance were randomly allocated by a computerised, permuted block algorithm, stratified by age group and centre, to receive oral conjugated equine oestrogen (0·625 mg per day; n=5310) or matched placebo (n=5429). The trial intervention was terminated early on Feb 29, 2004, because of an adverse effect on stroke. Follow-up continued until planned termination (March 31, 2005). Consent was sought for extended surveillance from the 9786 living participants in active follow-up, of whom 7645 agreed. Using data from this extended follow-up (to Aug 14, 2009), we assessed long-term effects of oestrogen use on invasive breast cancer incidence, tumour characteristics, and mortality. We used Cox regression models to estimate hazard ratios (HRs) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00000611.After a median follow-up of 11·8 years (IQR 9·1-12·9), the use of oestrogen for a median of 5·9 years (2·5-7·3) was associated with lower incidence of invasive breast cancer (151 cases, 0·27% per year) compared with placebo (199 cases, 0·35% per year; HR 0·77, 95% CI 0·62-0·95; p=0·02) with no difference (p=0·76) between intervention phase (0·79, 0·61-1·02) and post-intervention phase effects (0·75, 0·51-1·09). In subgroup analyses, we noted breast cancer risk reduction with oestrogen use was concentrated in women without benign breast disease (p=0·01) or a family history of breast cancer (p=0·02). In the oestrogen group, fewer women died from breast cancer (six deaths, 0·009% per year) compared with controls (16 deaths, 0·024% per year; HR 0·37, 95% CI 0·13-0·91; p=0·03). Fewer women in the oestrogen group died from any cause after a breast cancer diagnosis (30 deaths, 0·046% per year) than did controls (50 deaths, 0·076%; HR 0·62, 95% CI 0·39-0·97; p=0·04).Our findings provide reassurance for women with hysterectomy seeking relief of climacteric symptoms in terms of the effects of oestrogen use for about 5 years on breast cancer incidence and mortality. However, our data do not support use of oestrogen for breast cancer risk reduction because any noted benefit probably does not apply to populations at increased risk of such cancer.US National Heart, Lung, and Blood Institute; Wyeth.

In Brief OBJECTIVE: To compare efficacy and safety of desvenlafaxine succinate (desvenlafaxine) with placebo for the treatment of vasomotor symptoms. METHODS: This randomized, double-blind, placebo-controlled trial enrolled 707 healthy, postmenopausal women experiencing 50 or more moderate-to-severe hot flushes per week. Participants randomly received desvenlafaxine 50, 100, 150, or 200 mg or placebo daily. Trial duration was 52 weeks. Primary outcomes were change from baseline in average daily number of moderate-to-severe hot flushes and in daily hot flush severity score at weeks 4 and 12. RESULTS: Six hundred twenty women with an average of 11 moderate-to-severe hot flushes per day at baseline completed at least one on-therapy evaluation for primary efficacy end points; 519 participants completed 12 weeks of treatment, and 368 completed the study. Desvenlafaxine 100 mg/d achieved a significantly greater reduction compared with placebo in average daily number of hot flushes at weeks 4 (P=.013) and 12 (P=.005), reaching a 64% decrease from baseline at week 12, and the 75% responder rate was significantly higher for desvenlafaxine 100 mg (50%) compared with placebo (29%; P=.003; number needed to treat=4.7) at week 12. Average daily severity of hot flushes was significantly lower in the desvenlafaxine 100-mg group compared with placebo at week 12 (P=.020). Desvenlafaxine-treated women reported significantly more treatment-emergent adverse events than placebo-treated women during the first week of therapy only. CONCLUSION: Desvenlafaxine is an effective nonhormonal treatment for vasomotor symptoms in postmenopausal women. Its tolerability profile is consistent with that of other serotonin-norepinephrine reuptake inhibitors. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00421031 LEVEL OF EVIDENCE: I Desvenlafaxine is an effective nonhormonal treatment for the relief of vasomotor symptoms in postmenopausal women.

Osteoporosis is a skeletal disorder characterized by compromised bone strength, which predisposes a person to increased risk of fracture. In the United States, 26% of women aged > or =65 years and >50% of women aged > or =85 years have osteoporosis. Over 1.5 million fractures per year are attributable to osteoporosis; these fractures result in 500,000 hospitalizations, 800,000 emergency room visits, 2.6 million physician visits, 180,000 nursing home placements, and 12 billion dollars to 18 billion dollars in direct healthcare costs each year. Fracture also results in loss of function and has a negative impact on psychological status. In recognition of the importance of bone health, the US Surgeon General has, for the first time, issued a comprehensive report on bone health and treatment. The report recommends a pyramidal approach to osteoporosis treatment that includes calcium and vitamin D supplementation, physical activity, and fall prevention as the first line in fracture prevention. The second level consists of treating secondary causes of osteoporosis; the third and top level consists of pharmacotherapy. Pharmacotherapeutic interventions (e.g., bisphosphonates, selective estrogen receptor modulators, calcitonin, and teriparatide) in women with postmenopausal osteoporosis provide substantial reduction in fracture risk over and above risk reduction with calcium and vitamin D supplementation alone. Despite the effectiveness of therapy, most patients who receive treatment do not remain on treatment for >1 year. An important approach to reducing the rate of fractures is first to target our treatments to patients at high risk for fracture and then to develop strategies to improve treatment continuation rates.

Background In the post-intervention period of the Women's Health Initiative (WHI) trial, women assigned to treatment with oestrogen plus progestin had a higher risk of cancer than did those assigned to placebo. Results also suggested that the combined hormone therapy might increase mortality from lung cancer. To assess whether such an association exists, we undertook a post-hoc analysis of lung cancers diagnosed in the trial over the entire follow-up period. Methods The WHI study was a randomised, double-blind, placebo-controlled trial undertaken in 40 centres in the USA. 16 608 postmenopausal women aged 50–79 years with an intact uterus were randomly assigned by a computerised, stratified, permuted block algorithm to receive a once-daily tablet of 0·625 mg conjugated equine oestrogen plus 2·5 mg medroxyprogesterone acetate (n=8506) or matching placebo (n=8102). We assessed incidence and mortality rates for all lung cancer, small-cell lung cancer, and non-small-cell lung cancer by use of data from treatment and post-intervention follow-up periods. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00000611. Findings After a mean of 5·6 years (SD 1·3) of treatment and 2·4 years (0·4) of additional follow-up, 109 women in the combined hormone therapy group had been diagnosed with lung cancer compared with 85 in the placebo group (incidence per year 0·16% vs 0·13%; hazard ratio [HR] 1·23, 95% CI 0·92–1·63, p=0·16). 96 women assigned to combined therapy had non-small-cell lung cancer compared with 72 assigned to placebo (0·14% vs 0·11%; HR 1·28, 0·94–1·73, p=0·12). More women died from lung cancer in the combined hormone therapy group than in the placebo group (73 vs 40 deaths; 0·11% vs 0·06%; HR 1·71, 1·16–2·52, p=0·01), mainly as a result of a higher number of deaths from non-small-cell lung cancer in the combined therapy group (62 vs 31 deaths; 0·09% vs 0·05%; HR 1·87, 1·22–2·88, p=0·004). Incidence and mortality rates of small-cell lung cancer were similar between groups. Interpretation Although treatment with oestrogen plus progestin in postmenopausal women did not increase incidence of lung cancer, it increased the number of deaths from lung cancer, in particular deaths from non-small-cell lung cancer. These findings should be incorporated into risk–benefit discussions with women considering combined hormone therapy, especially those with a high risk of lung cancer. Funding National Heart, Lung and Blood Institute, National Institutes of Health.

Shifren, Jan L. MD, NCMP; Gass, Margery L.S. MD, NCMP for the NAMS Recommendations for Clinical Care of Midlife Women Working Group

<h3>Objective</h3> To evaluate the effects of a tissue-selective estrogen complex (TSEC) composed of bazedoxifene/conjugated estrogens (BZA/CE) on menopausal symptoms, metabolic parameters, and overall safety. <h3>Design</h3> Multicenter, double-blind, placebo- and active-controlled phase 3 trial (Selective estrogens, Menopause, And Response to Therapy [SMART]-1). <h3>Setting</h3> Outpatient clinical. <h3>Patient(s)</h3> Healthy, postmenopausal women (n = 3,397) age 40 to 75 with an intact uterus. <h3>Intervention(s)</h3> Single tablets of BZA (10, 20, or 40 mg), each with CE (0.625 or 0.45 mg); raloxifene 60 mg; or placebo taken daily for 2 years. <h3>Main Outcome Measure(s)</h3> Hot flushes, breast pain, vaginal atrophy, metabolic parameters, and adverse events. <h3>Result(s)</h3> BZA (20 mg)/CE (0.625 or 0.45 mg) significantly reduced the frequency and severity of hot flushes and improved measures of vaginal atrophy compared with placebo. At week 12, the daily number of hot flushes decreased by 51.7% to 85.7% with all BZA/CE doses vs. 17.1% for placebo. BZA/CE improved lipid parameters and homocysteine levels, did not significantly change carbohydrate metabolism, and had only minor effects on some coagulation parameters. The incidences of breast pain and adverse events were similar between BZA/CE and placebo. <h3>Conclusion</h3> The TSEC composed of BZA (20 mg)/CE (0.625 or 0.45 mg) is an effective and safe treatment for menopausal symptoms.

The following Consensus Statement is endorsed by The American Society for Reproductive Medicine, The Asia Pacific Menopause Federation, The Endocrine Society, The European Menopause and Andropause Society, The International Menopause Society, The International Osteoporosis Foundation and The North American Menopause Society.

<h3>Importance</h3> The influence of menopausal hormone therapy on breast cancer remains unsettled with discordant findings from observational studies and randomized clinical trials. <h3>Objective</h3> To assess the association of prior randomized use of estrogen plus progestin or prior randomized use of estrogen alone with breast cancer incidence and mortality in the Women’s Health Initiative clinical trials. <h3>Design, Setting, and Participants</h3> Long-term follow-up of 2 placebo-controlled randomized clinical trials that involved 27 347 postmenopausal women aged 50 through 79 years with no prior breast cancer and negative baseline screening mammogram. Women were enrolled at 40 US centers from 1993 to 1998 with follow-up through December 31, 2017. <h3>Interventions</h3> In the trial involving 16 608 women with a uterus, 8506 were randomized to receive 0.625 mg/d of conjugated equine estrogen (CEE) plus 2.5 mg/d of medroxyprogesterone acetate (MPA) and 8102, placebo. In the trial involving 10 739 women with prior hysterectomy, 5310 were randomized to receive 0.625 mg/d of CEE alone and 5429, placebo. The CEE-plus-MPA trial was stopped in 2002 after 5.6 years’ median intervention duration, and the CEE-only trial was stopped in 2004 after 7.2 years’ median intervention duration. <h3>Main Outcomes and Measures</h3> The primary outcome was breast cancer incidence (protocol prespecified primary monitoring outcome for harm) and secondary outcomes were deaths from breast cancer and deaths after breast cancer. <h3>Results</h3> Among 27 347 postmenopausal women who were randomized in both trials (baseline mean [SD] age, 63.4 years [7.2 years]), after more than 20 years of median cumulative follow-up, mortality information was available for more than 98%. CEE alone compared with placebo among 10 739 women with a prior hysterectomy was associated with statistically significantly lower breast cancer incidence with 238 cases (annualized rate, 0.30%) vs 296 cases (annualized rate, 0.37%; hazard ratio [HR], 0.78; 95% CI, 0.65-0.93;<i>P</i> = .005) and was associated with statistically significantly lower breast cancer mortality with 30 deaths (annualized mortality rate, 0.031%) vs 46 deaths (annualized mortality rate, 0.046%; HR, 0.60; 95% CI, 0.37-0.97;<i>P</i> = .04). In contrast, CEE plus MPA compared with placebo among 16 608 women with a uterus was associated with statistically significantly higher breast cancer incidence with 584 cases (annualized rate, 0.45%) vs 447 cases (annualized rate, 0.36%; HR, 1.28; 95% CI, 1.13-1.45;<i>P</i> &lt; .001) and no significant difference in breast cancer mortality with 71 deaths (annualized mortality rate, 0.045%) vs 53 deaths (annualized mortality rate, 0.035%; HR, 1.35; 95% CI, 0.94-1.95;<i>P</i>= .11). <h3>Conclusions and Relevance</h3> In this long-term follow-up study of 2 randomized trials, prior randomized use of CEE alone, compared with placebo, among women who had a previous hysterectomy, was significantly associated with lower breast cancer incidence and lower breast cancer mortality, whereas prior randomized use of CEE plus MPA, compared with placebo, among women who had an intact uterus, was significantly associated with a higher breast cancer incidence but no significant difference in breast cancer mortality.

In 2012, the Board of Directors of the International Society for the Study of Women's Sexual Health (ISSWSH) and the Board of Trustees of The North American Menopause Society (NAMS) acknowledged the need to review current terminology associated with genitourinary tract symptoms related to menopause.The two societies cosponsored a terminology consensus conference, which was held in May 2013.Members of the consensus conference agreed that the term genitourinary syndrome of menopause (GSM) is a medically more accurate, all-encompassing, and publicly acceptable term than vulvovaginal atrophy. GSM is defined as a collection of symptoms and signs associated with a decrease in estrogen and other sex steroids involving changes to the labia majora/minora, clitoris, vestibule/introitus, vagina, urethra and bladder. The syndrome may include but is not limited to genital symptoms of dryness, burning, and irritation; sexual symptoms of lack of lubrication, discomfort or pain, and impaired function; and urinary symptoms of urgency, dysuria and recurrent urinary tract infections. Women may present with some or all of the signs and symptoms, which must be bothersome and should not be better accounted for by another diagnosis. The term was presented and discussed at the annual meeting of each society. The respective Boards of NAMS and ISSWSH formally endorsed the new terminology - genitourinary syndrome of menopause (GSM) - in 2014.

Background In 2012, the Board of Directors of the International Society for the Study of Women's Sexual Health (ISSWSH) and the Board of Trustees of The North American Menopause Society (NAMS) acknowledged the need to review current terminology associated with genitourinary tract symptoms related to menopause. Methods The 2 societies cosponsored a terminology consensus conference, which was held in May 2013. Results and conclusion Members of the consensus conference agreed that the term genitourinary syndrome of menopause (GSM) is a medically more accurate, all-encompassing, and publicly acceptable term than vulvovaginal atrophy. GSM is defined as a collection of symptoms and signs associated with a decrease in estrogen and other sex steroids involving changes to the labia majora/minora, clitoris, vestibule/introitus, vagina, urethra and bladder. The syndrome may include but is not limited to genital symptoms of dryness, burning, and irritation; sexual symptoms of lack of lubrication, discomfort or pain, and impaired function; and urinary symptoms of urgency, dysuria and recurrent urinary tract infections. Women may present with some or all of the signs and symptoms, which must be bothersome and should not be better accounted for by another diagnosis. The term was presented and discussed at the annual meeting of each society. The respective Boards of NAMS and ISSWSH formally endorsed the new terminology—genitourinary syndrome of menopause (GSM)—in 2014.

Breast cancer and its treatment may compromise bone health. We tested the hypothesis in the Women's Health Initiative Observational Study that postmenopausal survivors of breast cancer have a higher risk for fractures compared with women who have no cancer history.A prospective cohort (5.1 years' follow-up) study design was used. Breast cancer survivors were women who reported a history of breast cancer (n = 5298). A reference group included women who had no cancer history at baseline (n = 80 848). Fracture occurrence was ascertained from annual self-reports. Hip fractures were confirmed by reviewing medical records.After adjustment for age, weight, ethnicity, and geographic region of enrollment, the hazard ratios (HRs) of breast cancer survivors to women in the reference group were 0.93 (95% confidence interval [CI], 0.64-1.33) for hip; 1.36 (95% CI, 1.16-1.59) for forearm or wrist; 1.31 (95% CI, 1.19-1.43) for eligible fractures other than hip, vertebral, and forearm or wrist; and 1.31 (95% CI, 1.21-1.41) for these fractures combined. The increased risk for clinical vertebral fracture was statistically significant only among survivors who had a breast cancer diagnosis before age 55 years (HR, 1.78; 95% CI, 1.28-2.46). After adjusting for factors related to hormone levels, risk of fall, fracture history, medication use, comorbidity, and lifestyle, the increased risk for all fractures studied among survivors was reduced to 15% (HR, 1.15; 95% CI, 1.05-1.25).Postmenopausal survivors of breast cancer are at increased risk for clinical fractures. Preventions and therapeutic interventions are needed to reduce fracture risk in this large and growing population.

<h3>Background</h3> Postmenopausal hormone therapy has been associated with a 2- to 3-fold increased risk of venous thromboembolism (VT) (including deep vein thrombosis and pulmonary embolism) in observational studies and secondary prevention clinical trials. Clinical trial data on the effects of estrogen alone on VT are limited. <h3>Methods</h3> The Women's Health Initiative estrogen trial enrolled 10 739 women aged 50 to 79 years without a uterus. Participants were randomly assigned to receive conjugated equine estrogen (0.625 mg/d) or placebo. <h3>Results</h3> During a mean of 7.1 years, VT occurred in 111 women randomly assigned to receive estrogen (3.0 per 1000 person-years) and 86 randomly assigned to receive placebo (2.2 per 1000 person-years; hazard ratio, 1.32; 95% confidence interval, 0.99-1.75). Deep venous thrombosis was reported in 85 women randomly assigned to receive estrogen (2.3 per 1000 person-years) and 59 randomly assigned to receive placebo (1.5 per 1000 person-years; hazard ratio, 1.47; 95% confidence interval, 1.06-2.06). The VT risk was highest in the first 2 years. There were no significant interactions between estrogen use and age, body mass index, or most other VT risk factors. Comparison of Women's Health Initiative VT findings for estrogen and previous Women's Health Initiative findings for estrogen plus progestin showed that the hazard ratios for estrogen plus progestin were significantly higher than those for estrogen alone (<i>P</i> = .03), even after adjusting for VT risk factors. <h3>Conclusion</h3> An early increased VT risk is associated with use of estrogen, especially within the first 2 years, but this risk increase is less than that for estrogen plus progestin.

<h3>Objective</h3> The aim of this article is to summarize the recommended updates to the 2001 Stages of Reproductive Aging Workshop (STRAW) criteria. The 2011 STRAW + 10 reviewed advances in understanding of the critical changes in hypothalamic-pituitary-ovarian function that occur before and after the final menstrual period. <h3>Method(s)</h3> Scientists from five countries and multiple disciplines evaluated data from cohort studies of midlife women and in the context of chronic illness and endocrine disorders on change in menstrual, endocrine, and ovarian markers of reproductive aging including antimüllerian hormone, inhibin-B, follicle-stimulating hormone, and antral follicle count. Modifications were adopted by consensus. <h3>Result(s)</h3> STRAW + 10 simplified bleeding criteria for the early and late menopausal transition, recommended modifications to criteria for the late reproductive stage (Stage −3) and the early postmenopause stage (Stage +1), provided information on the duration of the late transition (Stage −1) and early postmenopause (Stage +1), and recommended application regardless of women's age, ethnicity, body size, or lifestyle characteristics. <h3>Conclusion(s)</h3> STRAW + 10 provides a more comprehensive basis for assessing reproductive aging in research and clinical contexts. Application of the STRAW + 10 staging system should improve comparability of studies of midlife women and facilitate clinical decision making. Nonetheless, important knowledge gaps persist, and seven research priorities are identified.

We studied 41 young and middle-aged adults who developed innumerable, small, round, uniformly sized, yellow, subretinal nodules that were often arranged in clusters throughout the posterior fundus. Angiographically, they fluoresced discretely during the early arteriovenous phase. In middle or later life 17 of these patients developed visual loss caused by vitelliform retinal detachment in the macula of one or both eyes. Spontaneous resolution of the detachment and retention of good visual acuity occurred frequently. We found evidence indicating that the multiple, small, subretinal nodules are probably focal areas of pigment epithelial attenuation overlying nodular thickenings of the basement membrane of the pigment epithelium. The term basal laminar drusen would distinguish these nodules from those of typical drusen, which are caused by focal detachments of attenuated pigment epithelium and its usually normal-thickness basement membrane from the inner collagenous zone of Bruch's membrane.

Background: The Women's Health Initiative (WHI) randomized clinical trial (RCT) of calcium plus vitamin D (CaD) supplements found a 17% excess in urinary tract stone incidence in the supplemented group. This study evaluated whether this risk is modified by participant characteristics.

Cognitive function and physical performance are associated, but the common sequence of cognitive and physical decline remains unclear.In the Women's Health Initiative Memory Study (WHIMS) clinical trial, we examined associations at baseline and over a 6-year follow-up period between the Modified Mini-Mental State (3MS) Examination and three physical performance measures (PPMs): gait speed (meters/second), chair stands (number of stands in 15 seconds), and grip strength (kilograms). Using mixed models, we examined the baseline 3MS as predictor of change in PPM, change in the 3MS as predictor of change in PPM, and baseline PPM as predictors of 3MS change.Among 1,793 women (mean age = 70.3 years, 89% white, and mean 3MS score = 95.1), PPM were weakly correlated with 3MS-gait speed: r = .06, p = .02; chair stands: r = .09, p < .001; and grip strength: r = .10, p < .001. Baseline 3MS score was associated with subsequent PPM decline after adjustment for demographics, comorbid conditions, medications, and lifestyle factors. For every SD (4.2 points) higher 3MS score, 0.04 SD (0.04 m/s) less gait speed and 0.05 SD (0.29 kg) less grip strength decline is expected over 6 years (p </= .01 both). Changes in 3MS and PPM were associated, particularly with chair stands and grip strength (p < .003 both). Baseline PPMs were not associated with subsequent 3MS change.Baseline global cognitive function and change in global cognitive function were associated with physical performance change, but baseline physical performance was not associated with cognitive change in this cohort. These analyses support the hypothesis that cognitive decline on average precedes or co-occurs with physical performance decline.

The following Consensus Statement is endorsed by The American Society for Reproductive Medicine, The Asia Pacific Menopause Federation, The Endocrine Society, The European Menopause and Andropause Society, The International Menopause Society, The International Osteoporosis Foundation and The North American Menopause Society. The past 10 years saw much confusion regarding the use of menopausal hormone therapy (MHT). New evidence challenged previously accepted clinical guidelines, especially on aspects of safety and disease prevention. This led to many women unnecessarily being denied the use of MHT. Detailed revised guidelines were published and regularly updated by the major regional menopause societies. The confusion was initially escalated by significant differences amongst published guidelines. In recent revisions, the differences have become much less. In view of this, The International Menopause Society took the initiative to arrange a round-table discussion, in November 2012, between representatives of the major regional menopause societies to reach consensus on core recommendations regarding MHT. The aim was to produce a short document in bullet-point style, only containing the points of consensus. It is acknowledged that, in view of the global variance of disease and regulatory restrictions, these core recommendations do not replace the more detailed and fully referenced recommendations prepared by individual national and regional societies. This document serves to emphasize international consensus regarding MHT and is aimed at empowering women and health-care practitioners in the appropriate use of MHT.•MHT is the most effective treatment for vasomotor symptoms associated with menopause at any age, but benefits are more likely to outweigh risks for symptomatic women before the age of 60 years or within 10 years after menopause.•MHT is effective and appropriate for the prevention of osteoporosis-related fractures in at-risk women before age 60 years or within 10 years after menopause.•Randomized clinical trials and observational data as well as meta-analyses provide evidence that standard-dose estrogen-alone MHT may decrease coronary heart disease and all-cause mortality in women younger than 60 years of age and within 10 years of menopause. Data on estrogen plus progestogen MHT in this population show a similar trend for mortality but in most randomized clinical trials no significant increase or decrease in coronary heart disease has been found.•Local low-dose estrogen therapy is preferred for women whose symptoms are limited to vaginal dryness or associated discomfort with intercourse.•Estrogen as a single systemic agent is appropriate in women after hysterectomy but additional progestogen is required in the presence of a uterus.•The option of MHT is an individual decision in terms of quality of life and health priorities as well as personal risk factors such as age, time since menopause and the risk of venous thromboembolism, stroke, ischemic heart disease and breast cancer.•The risk of venous thromboembolism and ischemic stroke increases with oral MHT but the absolute risk is rare below age 60 years. Observational studies point to a lower risk with transdermal therapy.•The risk of breast cancer in women over 50 years associated with MHT is a complex issue. The increased risk of breast cancer is primarily associated with the addition of a progestogen to estrogen therapy and related to the duration of use. The risk of breast cancer attributable to MHT is small and the risk decreases after treatment is stopped.•The dose and duration of MHT should be consistent with treatment goals and safety issues and should be individualized.•In women with premature ovarian insufficiency, systemic MHT is recommended at least until the average age of the natural menopause.•The use of custom-compounded bioidentical hormone therapy is not recommended.•Current safety data do not support the use of MHT in breast cancer survivors. These core recommendations will be reviewed in the future as new evidence becomes available. The International Menopause Society: Tobie J. de Villiers, President (MediClinic Panorama and Department of Obstetrics and Gynecology, Stellenbosch University, Cape Town, South Africa); David F. Archer, Treasurer (Jones Institute, Eastern Virginia Medical School, Norfolk, VA, USA); Rodney J. Baber, General Secretary (Sydney Medical School, The University of Sydney, NSW, Australia); Mary Ann Lumsden, Board member (Reproductive & Maternal Medicine, School of Medicine, University of Glasgow, Glasgow, UK); Amos Pines, Director of Education and Development (Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel); The Asia Pacific Menopause Federation: Christopher J. Haines, Honorary Secretary (Department of Obstetrics and Gynecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR); The American Society for Reproductive Medicine: Rogerio A. Lobo, Past President (Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA); The International Osteoporosis Foundation: Dominique D. Pierroz, Science Manager University of Geneva (Switzerland); The European Menopause and Andropause Society: Margaret Rees, President (Reader Emeritus, University of Oxford, UK); Florence Tremollières, Board member (Centre de Menopause, Hopital Paule de Viguier, Toulouse, France); The Endocrine Society: Janet E. Hall, Past President (Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA); The North American Menopause Society: Margery L. S. Gass, Executive Director (Department of Surgery, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, OH, USA). The meeting of the Consensus Panel was supported by the participating societies only.

The terminology for the genitourinary tract symptoms related to menopause was vulvovaginal atrophy, which does not accurately describe the symptoms nor is a term that resonates well with patients.In 2012, the Board of Directors of the International Society for the Study of Women's Sexual Health (ISSWSH) and the Board of Trustees of The North American Menopause Society (NAMS) acknowledged the need to review current terminology associated with genitourinary tract symptoms related to menopause.The two societies cosponsored a terminology consensus conference, which was held in May 2013.The development of a new terminology that more accurately described the genitourinary tract symptoms related to menopause.Members of the consensus conference agreed that the term genitourinary syndrome of menopause (GSM) is a medically more accurate, all-encompassing, and publicly acceptable term than vulvovaginal atrophy. GSM is defined as a collection of symptoms and signs associated with a decrease in estrogen and other sex steroids involving changes to the labia majora/minora, clitoris, vestibule/introitus, vagina, urethra, and bladder. The syndrome may include but is not limited to genital symptoms of dryness, burning, and irritation; sexual symptoms of lack of lubrication, discomfort or pain, and impaired function; and urinary symptoms of urgency, dysuria, and recurrent urinary tract infections. Women may present with some or all of the signs and symptoms, which must be bothersome and should not be better accounted for by another diagnosis.The term GSM was presented and discussed at the annual meeting of each society. The respective Boards of NAMS and ISSWSH formally endorsed the new terminology--genitourinary syndrome of menopause--in 2014.

Abstract Background: Although endometrial cancer is clearly influenced by hormonal factors, few epidemiologic studies have investigated the role of endogenous estrogens or especially estrogen metabolites. Methods: We conducted a nested case–control study within the Women's Health Initiative Observational Study (WHI-OS), a cohort of 93,676 postmenopausal women recruited between 1993 and 1998. Using baseline serum samples from women who were non-current hormone users with intact uteri, we measured 15 estrogens/estrogen metabolites via HPLC/MS-MS among 313 incident endometrial cancer cases (271 type I, 42 type II) and 354 matched controls, deriving adjusted ORs and 95% confidence intervals (CI) for overall and subtype-specific endometrial cancer risk. Results: Parent estrogens (estrone and estradiol) were positively related to endometrial cancer risk, with the highest risk observed for unconjugated estradiol (OR 5th vs. 1st quintile = 6.19; 95% CI, 2.95–13.03, Ptrend = 0.0001). Nearly all metabolites were significantly associated with elevated risks, with some attenuation after adjustment for unconjugated estradiol (residual risks of 2- to 3-fold). Body mass index (kg/m2, BMI) relations were somewhat reduced after adjustment for estrogen levels. The association with unconjugated estradiol was stronger for type I than type II tumors (Phet = 0.01). Conclusions: Parent estrogens as well as individual metabolites appeared to exert generalized uterotropic activity, particularly for type I tumors. The effects of obesity on risk were only partially explained by estrogens. Impact: These findings enhance our understanding of estrogen mechanisms involved in endometrial carcinogenesis but also highlight the need for studying additional markers that may underlie the effects on risk of certain risk factors, for example, obesity. Cancer Epidemiol Biomarkers Prev; 25(7); 1081–9. ©2016 AACR.

In three patients (two women, 73 and 74 years old, and one man, 74 years old), a pigment epithelial rip occurred near the edge of a hypopigmented, partly organized choroidal neovascular membrane at the time of its treatment with krypton red photocoagulation. In all three cases, final visual acuity was 20/200.

In the Women's Health Initiative (WHI) randomized controlled trial, use of estrogen plus progestin increased lung cancer mortality. We conducted post hoc analyses in the WHI trial evaluating estrogen alone to determine whether use of conjugated equine estrogen without progestin had a similar adverse influence on lung cancer.The WHI study is a randomized, double-blind, placebo-controlled trial conducted in 40 centers in the United States. A total of 10 739 postmenopausal women aged 50-79 years who had a previous hysterectomy were randomly assigned to receive a once-daily 0.625-mg tablet of conjugated equine estrogen (n = 5310) or matching placebo (n = 5429). Incidence and mortality rates for all lung cancers, small cell lung cancers, and non-small cell lung cancers in the two randomization groups were compared by use of hazard ratios (HRs) and 95% confidence intervals (CIs) that were estimated from Cox proportional hazards regression analyses. Analyses were by intention to treat, and all statistical tests were two-sided.After a mean of 7.9 years (standard deviation = 1.8 years) of follow-up, 61 women in the hormone therapy group were diagnosed with lung cancer compared with 54 in the placebo group (incidence of lung cancer per year = 0.15% vs 0.13%, respectively; HR of incidence = 1.17, 95% CI = 0.81 to 1.69, P = .39). Non-small cell lung cancers were of comparable number, stage, and grade in both groups. Deaths from lung cancer did not differ between the two groups (34 vs 33 deaths in estrogen and placebo groups, respectively; HR of death = 1.07, 95% CI = 0.66 to 1.72, P = .79).Unlike use of estrogen plus progestin, which increased deaths from lung cancer, use of conjugated equine estrogen alone did not increase incidence or death from lung cancer.

Objective: The aim of this study was to determine the patterns and predictors of sexual activity in the Hormone Therapy (HT) Trials of the Women's Health Initiative (WHI). Methods: Sexual activity questions were administered to 27,347 women ages 50 to 79 years at baseline and at year 1 and to a random 8.6% subsample at years 3 and 6. The associations with demographic and health characteristics were determined. Results: Sexual activity at baseline was 60.7%, 44.9%, and 28.2% in the 50- to 59-, 60- to 69-, and 70- to 79-year-old age groups, respectively. Most of the participants were satisfied with their current sexual activity (63.2%). Of those dissatisfied, 57% preferred more sexual activity. Vaginal atrophy correlated with sexual inactivity at baseline (P < 0.001). The correlates associated with stopping sexual activity at year 1 included poor/fair self-rated health, lack of satisfaction with quality of life, depression, and loss of partner (P < 0.001). The strongest predictor of sexual activity at year 1 was sexual activity at baseline (odds ratio, 96.71; 95% CI, 81.90-114.20). A subset analysis of women adherent with HT or placebo at years 3 and 6 suggested that HT was associated with a higher percentage of participants reporting sexual activity (P = 0.01). Conclusions: Most women in the WHI HT Trials were satisfied with their sexual activity. Of those who were dissatisfied, the majority preferred more, rather than less, sexual activity. Vaginal atrophy at baseline correlated with sexual inactivity, and sexual activity at baseline was the strongest identified predictor of sexual activity at year 1. HT use was not predictive of ongoing sexual activity in the intent-to-treat analysis. This report further characterizes the participants in the WHI HT trials and reveals the complexity of factors related to the prevalence of sexual activity and satisfaction.

In the Women's Health Initiative (WHI) trial of calcium plus vitamin D (CaD), we examined the treatment effect on incidence and mortality for all invasive cancers. Postmenopausal women (N = 36,282) were randomized to 1,000 mg of elemental calcium with 400 IU vitamin D3 or placebo. Cox models estimated risk of cancer incidence and mortality. After 7.0 yr, 1,306 invasive cancers were diagnosed in the supplement and 1,333 in the placebo group [hazard ratio (HR) = 0.98; CI = 0.90, 1.05, unweighted P = 0.54]. Mortality did not differ between supplement (315, annualized% = .26) and placebo [(347, 0.28%; P = 0.17; HR = 0.90 (0.77, 1.05)]. Significant treatment interactions on incident cancer were found for family history of cancer, personal total intake of vitamin D, smoking, and WHI dietary trial randomized group. Calcium/vitamin D supplementation did not reduce invasive cancer incidence or mortality. Supplementation lowered cancer risk in the WHI healthy diet trial arm and in women without a first-degree relative with cancer. The interactions are only suggestive given multiple testing considerations. The low vitamin D dose provided, limited adherence, and lack of serum 25(OH)D values should be considered when interpreting these findings.

The US Preventive Services Task Force (USPSTF) recommends osteoporosis screening for women younger than 65 years whose 10-year predicted risk of major osteoporotic fracture is ≥ 9.3%. For identifying screening candidates among women aged 50 to 64 years, it is uncertain how the USPSTF strategy compares with the Osteoporosis Self-Assessment Tool (OST) and the Simple Calculated Osteoporosis Risk Estimate (SCORE). We examined data (1994 to 2012) from 5165 Women's Health Initiative participants aged 50 to 64 years. For the USPSTF (Fracture Risk Assessment Tool [FRAX] major fracture risk ≥ 9.3% calculated without bone mineral density [BMD]), OST (score <2), and SCORE (score >7) strategies, we assessed sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) to discriminate between those with and without femoral neck (FN) T-score ≤-2.5. Sensitivity, specificity, and AUC for identifying FN T-score ≤-2.5 were 34.1%, 85.8%, and 0.60 for USPSTF (FRAX); 74.0%, 70.8%, and 0.72 for SCORE; and 79.8%, 66.3%, and 0.73 for OST. The USPSTF strategy identified about one-third of women aged 50 to 64 years with FN T-scores ≤-2.5. Among women aged 50 to 64 years, the USPSTF strategy was modestly better than chance alone and inferior to conventional SCORE and OST strategies in discriminating between women with and without FN T-score ≤-2.5.

OVERVIEW The Menopause Decision-Support Algorithm (Fig. 1) and companion MenoPro iPhone/iPad app, developed in collaboration with The North American Menopause Society (NAMS), are designed to help clinicians decide which patients are candidates for pharmacologic treatment of menopausal symptoms, understand what the treatment options are, and gain experience deciding among the options. Menopausal symptoms vary dramatically among women.1,2 Some women are good candidates for hormonal treatments and others, due to their personal preferences or risk factor profiles, are not appropriate candidates and should consider non-hormonal options. One of the most complex health care decisions facing women in mid-life is whether to use prescription medications for menopausal symptom management, and the array of pharmacologic options has expanded markedly in recent years.2,3 The new MenoPro app, which can be downloaded free of charge on a mobile phone or tablet device, helps clinicians and patients work together to “personalize” treatment decisions, based on risk stratification4-9 and the patient’s personal preferences. The mobile app has two modes, one for clinicians and a companion mode for patients, to facilitate shared decision making and patient-centered care.FIG. 1: Algorithm for menopausal symptom management and hormonal/non-hormonal therapy decision making. Algorithm footnotes appear at the end of the article.The algorithm and MenoPro mobile app address options for “moderate to severe” hot flashes and/or night sweats (defined as bothersome enough to interfere with daily activities, impair quality of life, and/or interrupt sleep), as well as genitourinary symptoms (including vaginal dryness or pain with intercourse or other sexual activities). Convenient links provide information about treatment options, formulations and doses, and contraindications to therapy. The app calculates an atherosclerotic cardiovascular disease (CVD) risk score for each patient,10 which is relevant to the decision regarding initiation of systemic menopausal hormone therapy (HT). Women at high risk of, or with significant concern about, breast cancer should be informed about availability of non hormonal therapies. Once the clinician becomes familiar with the algorithm, personalized decision-making for most patients will require only 2-3 minutes, and the app provides a summary at the end that can be printed out or directly emailed to the patient. The tool can be used for women with menopausal symptoms who are ages ≥45 years old. The algorithm can also be used for women who have had removal of both ovaries, regardless of age. Women below age 45 or those who are not clearly menopausal, as well as women who have had endometrial ablation, progestin-releasing intrauterine device/system, or hysterectomy without removal of ovaries, may need additional clinical evaluation before applying this algorithm (evaluation may include hCG, FSH, TSH, prolactin, and other tests).3 The algorithm encourages all patients to try lifestyle modifications for at least 3 months before beginning HT or other pharmacologic therapies. For information on lifestyle modifications, cognitive behavioral therapy, and/or alternative remedies, clinicians may want to print out the materials for the patient at the below link (or send the link by email via the app): http://www.menopause.org/docs/for-women/mnflashes.pdf. Women at high risk of osteoporotic fracture and unable to tolerate standard preventive medications may also be candidates for HT (NAMS Hormone Therapy Position Statement: http://www.menopause.org/docs/default-document-library/psht12.pdf?sfvrsn=2).2 The algorithm also addresses considerations relevant to decisions about duration of treatment, including balancing risks of breast cancer, cardiovascular disease, and osteoporosis.1-3 Each step of the algorithm should be reassessed at least once every 12 months or if health status changes. BACKGROUND Women have an increasing number of options, both hormonal and non-hormonal, for the management of menopausal symptoms.1-3 A major deterrent to treatment, however, is the complexity of the decision-making process and the lack of information about available options. This new algorithm and mobile app for menopausal symptom management incorporate state-of-the-science evidence and research to clarify and streamline the decision-making process for both patients and clinicians. Menopausal HT continues to have an important clinical role in the management of vasomotor and other menopausal symptoms, but it has complex biological effects. The rational use of HT requires balancing the potential benefits and risks of treatment. Although findings from the Women’s Health Initiative (WHI) and other randomized clinical trials have helped to clarify the benefits and risks of HT and provided insights to improve decision making,4-7 current options include lower doses and transdermal formulations that may further minimize risks. Available research suggests that risk stratification based on clinical characteristics of the patient has utility in identifying those for whom benefits of HT are likely to outweigh the risks.4-9 Age and time since menopause are strong predictors of health outcomes on HT, and the absolute risks of adverse events are much lower in younger than older women (see Fig. 2).4 Differences by age have been particularly apparent for estrogen alone among women with hysterectomy.4,5 In addition, women at higher baseline cardiovascular risk, due to dyslipidemia, metabolic syndrome, or other cardiometabolic risk factors, have greater risk of adverse vascular outcomes on HT than women at lower risk.2-7 These findings, based on proximity to menopause, underlying cardiovascular risk, and other personal risk factors, have been incorporated into the decision-making process used in this algorithm. Women who are not candidates for, or do not choose to take, HT can be evaluated for non-hormonal treatments. The use of risk stratification and personalized risk assessment offers promise for improved safety and a more favorable benefit:risk profile for both hormonal and non-hormonal treatments.FIG. 2: WHI hormone therapy trials: absolute risks (cases per 10,000 person-years) for outcomes in the intervention phases of the estrogen-progestin and estrogen-alone trials, by age group. Data are from reference 4.DECISION-MAKING PROCESS AND TREATMENT OPTIONS The key elements of the algorithm (Fig. 1) include assessment of whether the patient has moderate to severe vasomotor symptoms (the primary indication for initiating systemic HT); eliciting the patient’s personal preference regarding treatment; evaluating the patient for the presence of any contraindications to systemic HT, as well as the patient’s time since menopause onset and baseline risks of CVD and breast cancer; reviewing the benefits and risks of treatment with the patient (giving more emphasis to absolute than to relative measures of effect) (Fig. 2); and, if HT is initiated, regularly reviewing the patient’s need for continued treatment. If hormonal treatment is chosen, lower doses may be effective for many women, and the transdermal route may be preferable to oral for patients with metabolic syndrome or other significant CVD risk factors. In appropriate patients, a tissue-selective estrogen complex, such as conjugated estrogens combined with bazedoxifene (a selective estrogen receptor modulator) may be an option. A similar process is followed for non-hormonal treatments in women who are not candidates for, or who choose not to take, hormonal therapy. Paroxetine 7.5 mg/d is an FDA-approved non-hormonal medication for vasomotor symptoms; a wide range of other selective serotonin reuptake inhibitors or serotonin/norepinephrine reuptake inhibitors, as well as gabapentin, pregabalin, and clonidine, can be considered. For patients who do not have moderate or severe hot flashes but have significant genitourinary symptoms (vaginal dryness or pain with intercourse/sexual activities) without adequate response to vaginal lubricants and/or moisturizers, low-dose vaginal estrogen is an option. Ospemifene can also be considered for women without contraindications and who prefer a non-estrogen oral treatment. Clinicians should check product labeling for a comprehensive listing of contraindications and cautions for any medications prescribed. Whether or not to initiate systemic HT to prevent osteoporosis is controversial, but if done, current guidelines from NAMS recommend that treatment be limited to women at high risk of osteoporotic fracture who cannot tolerate alternate osteoporosis therapies.2 CONCLUSIONS Risk stratification can be used to identify appropriate candidates for pharmacologic treatment of menopausal symptoms and to facilitate a safer and more personalized approach to clinical decision making. Recent research has advanced our understanding of the benefits and risks of available treatment options and enhanced the ability of both clinicians and patients to make informed choices about treatment. JoAnn E. Manson, MD, DrPH, NCMP1 Jeffrey M. Ames, BS, MEng2 Marla Shapiro, MD, NCMP3 Margery L.S. Gass, MD, NCMP4 Jan L. Shifren, MD, NCMP1 Cynthia A. Stuenkel, MD, NCMP5 JoAnn V. Pinkerton, MD, NCMP6 Andrew M. Kaunitz, MD, NCMP7 Diane T. Pace, PhD, FNP-BC, NCMP8 Risa Kagan, MD, NCMP9 Peter F. Schnatz, DO, NCMP10 Sheryl A. Kingsberg, PhD4 James H. Liu, MD4 Hadine Joffe, MD, MSc1 Gloria Richard-Davis, MD11 Steven R. Goldstein, MD, NCMP12 Isaac Schiff, MD1 Wulf H. Utian, MB, Bch, PhD, DSc (Med)4 Disclaimer: This Application is intended for informational purposes only and is not intended as a substitute for professional medical judgment, diagnosis, or treatment. Users of the app are asked to read and accept an End User License Agreement, available on the app. Financial disclosure/conflicts of interest: JEM, JMA, JLS, MLSG, PFS, IS, and WHU report no disclosures. MS is a consultant/advisory board member for Amgen, Merck, Pfizer and serves on the speakers’ bureau for Amgen, Merck, Novo Nordisk, and Pfizer. CAS has served as a consultant to Pfizer. JVP is a consultant (fees to the University of Virginia) for Pfizer Inc, TherapeuticsMD, Noven, NovoNordisk, and Shionogi. AMK is a consultant/advisory board member for Actavis, Bayer, Teva, and has received grant support from Bayer, Endoceutics, Noven, Teva, and TherapeuticsMD. DTP is a consultant/advisory board member for Hologic and Pfizer. RK is a consultant for Amgen and Merck, is a consultant for and has received payment for lectures/service on speakers’ bureaus for, Pfizer, Novo Nordisk, Noven, and Shionogi, and receives research support from TherapeuticsMD (fees to Sutter Research Institution). SAK serves as a consultant/advisory board member for Apricus, Novo Nordisk, Pfizer, Shionogi, Teva, Trimel Biopharm, and Viveve. JL is on advisory board for Noven, Pfizer, and Shionogi. HJ receives grant support from Cephalon/Teva and serves as a consultant to Noven and on an advisory board for Merck. GRD is a consultant/advisory board member for Pfizer. SRG is a consultant to, and has received payment for lectures/service on speakers’ bureaus for, Shionogi, Pfizer, Noven, and JDS Therapeutics, and is a consultant and has received payment for service for Smith and Nephew.

Abstract Objective: The aim of the present study was to investigate associations between reproductive factors and survival to age 90 years. Methods: This was a prospective study of postmenopausal women from the Women's Health Initiative recruited from 1993 to 1998 and followed until the last outcomes evaluation on August 29, 2014. Participants included 16,251 women born on or before August 29, 1924 for whom survival to age 90 during follow-up was ascertained. Women were classified as having survived to age 90 (exceptional longevity) or died before age 90. Multivariable logistic regression models were used to evaluate associations of ages at menarche and menopause (natural or surgical) and reproductive lifespan with longevity, adjusting for demographic, lifestyle, and reproductive characteristics. Results: Participants were on average aged 74.7 years (range, 69-81 y) at baseline. Of 16,251 women, 8,892 (55%) survived to age 90. Women aged at least 12 years at menarche had modestly increased odds of longevity (odds ratio [OR], 1.09; 95% CI, 1.00-1.19). There was a significant trend toward increased longevity for later age at menopause (natural or surgical; P trend = 0.01), with ORs (95% CIs) of 1.19 (1.04-1.36) and 1.18 (1.02-1.36) for 50 to 54 and at least 55 compared with less than 40 years, respectively. Later age at natural menopause as a separate exposure was also significantly associated with increased longevity ( P trend = 0.02). Longer reproductive lifespan was significantly associated with increased longevity ( P trend = 0.008). The odds of longevity were 13% (OR 1.13; 95% CI, 1.03-1.25) higher in women with more than 40 compared with less than 33 reproductive years. Conclusions: Reproductive characteristics were associated with late-age survival in older women.

This commentary summarizes the activities of several clinicians and researchers to encourage modifications to the labeling of low-dose vaginal estrogen. Motivated by concerns of practicing clinicians that the boxed warning on the labels and package inserts for these products overstate potential risks and thus adversely affect patient care, leaders in the field are spearheading an effort to encourage consideration of alternative labeling, as discussed below. The members of the Working Group on Women’s Health and Well-Being in Menopause have affiliations with a number of medical societies, including The North American Menopause Society, the American College of Obstetricians and Gynecologists, the Endocrine Society, the American Society for Reproductive Medicine, the International Society for the Study of Women’s Sexual Health, and other professional organizations. We appreciated the opportunity to share our concerns, literature review, and proposal for alternative labeling with members of the US Food and Drug Administration (FDA) Division of Bone, Reproductive, and Urologic Products via a teleconference earlier this year. We encourage further consideration of our rationale and proposal by both the FDA and the pharmaceutical companies that own these products. Overview of the proposal for label change Vulvovaginal atrophy (VVA; also known as genitourinary syndrome of menopause) is a common and progressive condition that adversely affects the health and quality of life of many postmenopausal women.1 Symptomatic VVA is a growing problem because of the confluence of several factors, including the burgeoning population of older postmenopausal women and the declining use of systemic menopausal hormone therapy since the initial report of the Women’s Health Initiative (WHI).2,3 Our view is that an additional factor—the boxed warning on the package label for low-dose vaginal estrogen—discourages clinicians from prescribing the product and women from taking it even after purchase. The boxed warning, which reflects estrogen class labeling, states “WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER, and PROBABLE DEMENTIA” and is based on extrapolations of data from clinical trials of systemic hormone therapy such as the WHI, which involved substantially higher levels of exposure. We believe that the boxed warning is not evidence-based and harms women by discouraging the use of a highly effective local treatment of a common condition with medical risks and adverse effects on quality of life. We contend that the boxed warning for low-dose vaginal estrogen products is unjustified based on several lines of reasoning described below, including the following: (a) the dramatic differences in blood hormone levels achieved by low-dose vaginal estrogen (eg, Vagifem tablets [estradiol 10 μg], Estring [releasing estradiol 7.5 μg/d], or comparable low-dose vaginal estrogen cream formulations) versus conventional systemic estrogen therapy; (b) absence of randomized trial evidence or consistent observational evidence linking low-dose vaginal estrogen to cancer, cardiovascular disease, dementia, or any of the other conditions highlighted in the boxed warning; and (c) absence of evidence that changes in blood hormone levels—of the small magnitude achieved with these products—increase risk of these conditions. As a result of the boxed warning, a large number of older women with symptomatic VVA and genitourinary symptoms are being undertreated and do not receive the substantial benefits that these medications could provide. We believe that women would be better served by a modified label that more closely reflects the safety profile of low-dose vaginal estrogen and would actually enhance safety by emphasizing the key information that women and clinicians need to know about the products. Our proposal is to state in the package labeling, in regular text and font, that estrogen and estrogen-progestin given systemically, in higher doses, have been linked to the health conditions currently noted in the boxed warning, but that the relevance to low-dose vaginal estrogen remains unknown, given minimal increase in serum estrogen levels with low-dose vaginal estrogen products. We recommend bolding the phrase “report any vaginal bleeding or spotting right away while using ______.” We also recommend adding in bold “Women with a history of cancer of the breast or uterus (womb), or other hormone-sensitive cancers, are encouraged to consult their oncologist before using this product.” We believe that these label changes will, paradoxically, enhance patient safety because the relevant information and cautions will stand out and be highly visible, rather than being obscured by extraneous and alarming bolded and boxed statements that lack proven relevance to the product. Thus, the proposed label change would serve the purpose of informing women of previous research and addressing safety issues while stating that the relevance of past research findings on systemic hormone therapy to low-dose vaginal estrogen is unknown. The specific suggested wording of our proposed label change is provided at the end of this commentary. Prevalence of VVA (Genitourinary Syndrome of Menopause) and the impact on women’s health and quality of life VVA symptoms, such as vaginal dryness, lack of lubrication, pain or spotting with intercourse, and burning with urination, affect 20% to 45% of midlife and older women.4,5 In contrast to vasomotor symptoms, which tend to improve across time irrespective of treatment, VVA is usually progressive and unlikely to resolve without intervention. VVA symptoms can have a significantly adverse effect on a woman’s sexual health and quality of life. In an online survey conducted in six countries, an estimated 45% of postmenopausal women reported experiencing vaginal symptoms.6 The largest survey of US women, REVIVE (Real Women’s Views of Treatment Options for Menopausal Vaginal Changes), included 3,046 women with VVA symptoms.7 In this study, 85% of women with partners reported “some loss of intimacy,” 59% indicated that VVA symptoms detracted from enjoyment of sex, 47% of women with partners reported that VVA interfered with their relationship, and 27% reported that VVA had a negative effect on their general enjoyment of life. Similar results were found in the VIVA (Vaginal Health: Insights, Views & Attitudes) survey.6 Aging and diminished estrogen levels are major contributors to VVA, atrophic vaginitis, and recurrent urinary tract infections.1,8 Efficacy of treatment and impact of product labeling/boxed warning As emphasized in the 2013 North American Menopause Society VVA position statement,1 the primary goal of treating symptomatic VVA is to alleviate symptoms. First-line therapies include nonhormonal lubricants and long-acting vaginal moisturizers, as well as low-dose vaginal estrogen in those remaining symptomatic, assuming no contraindications.1 For women with moderate to severe dyspareunia related to VVA who prefer nonvaginal therapy, transdermal or oral systemic hormone therapy and the oral estrogen agonist/antagonist ospemifene are options. Women with significant vasomotor symptoms may choose systemic (oral or transdermal) hormone therapy, which will also treat VVA if present. Low-dose vaginal estrogen, however, is the preferred mode of treatment when vaginal symptoms are the only complaint.1 Low-dose vaginal estrogen products can provide sufficient local estrogen effect to relieve symptoms, decrease vaginal pH, and increase maturation of the vaginal and urethral epithelia, with minimal systemic absorption.1,9-11 These products have been shown to be at least as effective as systemic oral estrogen therapy in relieving VVA symptoms, with 80% to 90% of women reporting a favorable response compared with 75% of women using oral estrogen.9,10 A 2006 Cochrane review of 19 efficacy trials reported that all local estrogen products tested had similar efficacy in alleviating symptoms.11 Therapeutic benefit of vaginal estrogen has also been observed with conditions other than VVA, such as recurrent urinary tract infections12,13 and overactive bladder.14,15 Although systemic hormone therapy has been associated with an increase in stress incontinence,8,16 the low-dose estradiol ring has been approved for the treatment of dysuria and urinary urgency. VVA has been linked to considerable impairment of quality of life; nonetheless, clinical studies demonstrate that a substantial proportion of women are undertreated.1 Moreover, in our collective clinical experience and in those of the professional colleagues we represent, among women who seek treatment and/or receive prescriptions for low-dose vaginal estrogen, a substantial proportion ultimately choose not to use the product or discontinue use because of concerns and alarm about the boxed warning in the package insert. Testimonials by working group members during the teleconference with the FDA highlighted the adverse impact of VVA on women’s lives, including their physical, sexual, and emotional health; clinical experience with the marked efficacy of treatment; and the deleterious effect of the boxed warning on women’s health by discouraging clinician colleagues from prescribing, and women from using, these highly effective low-dose vaginal estrogen products. Specifically, several clinicians reported that many women who have purchased the low-dose vaginal estrogen products, often at significant financial cost, ended up not using them after reading the boxed warning. Comparative blood concentrations of estrogens associated with low-dose vaginal estrogen versus systemic estrogens versus no treatment “Low-dose” vaginal estrogen refers to products such as Estring (vaginal ring releasing estradiol 7.5 μg/d), Vagifem (10-μg tablets two times a week), and comparable low doses of vaginal creams (eg, Estrace [estradiol]) or Premarin [conjugated estrogens]).17 These products are considered to have a more favorable risk profile than commonly used doses of systemic estrogen therapy because they lead to small, if any, increases in serum estrogen concentrations.1,18-23 When low-dose vaginal estrogen is used as directed, reported serum estrogen levels fall generally within the average postmenopausal range (below 20 pg/mL).1,18 Reported estradiol levels ranged from 5 to 10 pg/mL with use of the vaginal ring (releasing estradiol approximately 7.5 μg/d)19-21 and from 3 to 11 pg/mL with use of the 10-μg vaginal tablet.22,23 In contrast, use of 0.2 mg (200 μg) of estradiol cream led to serum levels of 80 pg/mL.24 However, a small pilot study showed that using one twentieth of the dose of estradiol cream (a 10-μg dose) was associated with full efficacy in genitourinary tissues, whereas circulating estradiol levels measured using a highly sensitive assay remained within the postmenopausal range of 3 to 10 pg/mL.22 Conjugated estrogens cream at a dose of 0.3 mg produced no change in serum estradiol levels,25 but conjugated estrogens products contain multiple estrogenic compounds, and plasma estradiol levels may not fully reflect estrogenic activity. Among women treated with 0.3 mg of vaginal conjugated equine estrogens three times a week for 6 months, the serum estrone levels were 61.6 pg/mL compared with 55.6 pg/mL at baseline.25 It is instructive to compare the serum estrogen concentrations of women on low-dose vaginal estrogen with the endogenous estrogen levels in untreated premenopausal and postmenopausal women, as well as with the hormone concentrations of postmenopausal women treated with systemic estrogen. Among untreated women in the Melbourne Women’s Midlife Health Project, the average serum estradiol levels were 78 pg/mL (range, 39-158 pg/mL) 4 years before the final menstrual period, 31 pg/mL (range, 23-42 pg/mL) at the time of the final menstrual period, and 10 pg/mL (range, 8-11 pg/mL) 2 years after menopause.26 Among postmenopausal women treated with systemic estrogen, serum estrogen concentrations increase markedly. For example, in a 12-week trial of oral estradiol 1 mg/day, the average estradiol level on treatment was 164 pg/mL (range, 86-243 pg/mL), representing a 9.5-fold increase from baseline menopausal levels.27 Among women in the Kronos Early Estrogen Prevention Study (average age, 53 y; all within 3 y of their final menstrual period), estradiol levels after treatment with a transdermal patch containing estradiol 50 μg/day were more than three times higher than baseline levels; among women treated with oral conjugated estrogens 0.45 mg/day, estrone levels were more than twice as high as baseline levels.28 Thus, treatment with systemic estrogen leads to substantial increases in blood hormone levels compared with baseline, whereas serum hormone levels among women treated with low-dose vaginal estrogen remain within the reference postmenopausal range. Low-dose vaginal estrogen and the endometrium Endometrial tissue response is an extremely sensitive bioassay for estrogenic action and reflects the integration of serum estrogen levels with duration of estrogenic exposure. Three different low-dose vaginal estrogen therapies have been evaluated, and their endometrial effects have been assessed via either transvaginal ultrasound–measured endometrial thickness or endometrial biopsy. The largest trial to date is a randomized double-blind controlled study of 1,612 postmenopausal women in which vaginal estradiol tablets were administered at a dose of 25 μg/day for 2 weeks, followed by a dose of 25 μg two times a week for 12 months. This study demonstrated no increases in serum estradiol levels at 4 and 12 months compared with baseline levels: (mean [SD], 15.7 [2.3] pg/mL {baseline} vs 15.5 [2.5] pg/mL {12 mo}).29 Vaginal ultrasound–determined endometrial thickness remained essentially unchanged after 12 months of therapy (mean [SD], 3.1 [0.4] mm {baseline} vs 2.9 [0.5] mm {12 mo}).29 There was no change in uterine volume or enlargement of preexisting myomas across 12 months. In a separate study of a vaginal estradiol tablet 10 μg/day, endometrial biopsies were performed in 297 women after 12 months of treatment; 183 women had endometrial tissue that was atrophic or inactive, whereas 111 women had no tissue or had insufficient tissue for diagnosis. There was one case of complex hyperplasia without atypia.30 Similar findings have been reported in a trial of estradiol vaginal cream given at a dose of 10 μg/day for 3 weeks then 10 μg two times a week. Endometrial thickness remained stable at less than 5 mm during the 12-week treatment.22 Moreover, in a randomized study of a low-dose vaginal estradiol ring delivering estradiol 7.5 μg/day, estradiol levels increased less than 1 pg/mL above baseline (P = 0.59) and endometrial lining thickness at 12 months was similar to baseline, with a mean (SD) change of −0.14 (0.53) mm (P = 0.54).21 If low-dose vaginal estrogens have either regional or systemic effects beyond their local action, one would expect to observe endometrial proliferation, as determined by either transvaginal ultrasound–measured endometrial thickness or endometrial biopsy. Collectively, these studies demonstrate that low-dose vaginal estrogen therapy, including assessments of three different estradiol preparations at 12 months of evaluation, does not seem to have significant endometrial impact beyond the local vaginal estrogenic effects. Higher dosing, long-term use, and use by women with comorbidities may carry higher risks. Low-dose vaginal estrogen and breast-related outcomes Assessment of the potential biologic effects of low-dose vaginal estrogen on breast tissue can be approached by considering three separate endpoints: mammographic breast density, breast cancer, and breast pain. Although we could find no studies examining the endpoint of breast density in relation to low-dose vaginal estrogens, a 2-year placebo-controlled randomized trial examining a transdermal preparation delivering estradiol 14 μg/day showed no difference in breast density at 2 years compared with placebo.31 Regarding breast cancer, a large-scale observational study of Finnish women, including 18,314 users of vaginal estrogen, indicated no increase in the risk of breast cancer associated with vaginal estrogen use.32 Moreover, no increased risk would be expected based on the results of the unopposed estrogen arm of the WHI.33,34 With 7.2 years of oral conjugated equine estrogens (0.625 mg/d), the hazard ratios (95% CIs) were 0.79 (0.61-1.02) for the intervention phase and 0.79 (0.65-0.97) for the 13-year cumulative follow-up phase,34 suggesting no increased risk of breast cancer with unopposed conjugated equine estrogens across this time frame. Evidence that this finding applies to other formulations of estrogen remains inconclusive. However, one would not expect that an even lower dose of unopposed estrogen given vaginally, and with minimal systemic absorption, would have an adverse effect on breast cancer risk. Regarding breast pain, this symptom has been reported with intermediate doses of vaginal estrogen. However, in a study of low-dose vaginal estrogen (Estring), only 1 of 108 women complained of breast pain while the ring was in place.13 Reports on the use of 10 μg of low-dose vaginal estrogen make no mention of breast pain.35 Based on these collective findings, it is improbable that these products exert important biologic effects on the breast. Special considerations for women with a history of breast cancer Despite the reassuring evidence mentioned previously, women with a history of breast cancer warrant special consideration. The clinical relevance of even very small increases in circulating estrogen levels with low-dose vaginal estrogen products in women with breast cancer remains unclear. Aromatase inhibitors (AIs), which block 95% of estrogen synthesis, are typically associated with circulating estradiol levels lower than 1 pg/mL.36 Thus, as would be expected, vaginal administration of low-dose estrogen will lead to higher-than-baseline serum estradiol levels in women receiving AI therapy.37 As any rise above baseline serum estradiol levels may affect AI efficacy, the use of any hormone therapy product in women with breast cancer warrants special caution, especially in view of sparse research on the safety of these products in breast cancer patients. In one case-control study, women receiving endocrine treatment (such as tamoxifen or AIs) for breast cancer did not have higher rates of recurrence with local estrogen use compared with nonuse,38 but vaginal estrogen treatment by ring or tablet did increase circulating estrogen levels, at least initially.39 For systemic hormone therapy, inconsistent results for breast cancer recurrence have been found in randomized trials and observational studies.40 Patients with breast cancer who have symptomatic VVA and do not respond to nonhormonal therapies are encouraged to discuss the risks and benefits of low-dose vaginal estrogen therapy with their oncologist. Oral ospemifene has not been tested in women at high risk for breast cancer or with a history of breast cancer; thus, no recommendations can be given for its use in this population. Low-dose vaginal estrogen and cardiovascular, cerebrovascular, cognitive, and other outcomes Compared with oral systemic estrogen and estrogen-progestin, as studied in the WHI and forming the basis for the boxed warning, low-dose vaginal estrogen has lower systemic absorption and, similar to transdermal estradiol formulations, avoids “first-pass” liver metabolism and effects on hepatic enzymes.1,41,42 Lower-dose transdermal estradiol has been shown to have less risk of venous thromboembolism (VTE)42 and possibly stroke43; thus, the significantly lower systemic absorption of low-dose vaginal estrogen makes it even less likely to increase risk of VTE and other cardiovascular events than oral systemic estrogen.42,43 The increased risks of coronary heart disease, stroke, and VTE, which have been reported with oral systemic hormone therapy,1,42,43 have not been reported with low-dose vaginal estrogen therapy.1 Moreover, long-term follow-up of women in the WHI trial of unopposed estrogen44 showed no increased risk of coronary events or all-cause mortality, indicating that low-dose vaginal estrogen is unlikely to affect these outcomes. The 2006 Cochrane review of VVA did not find evidence of an increased risk of VTE with low-dose estrogen,11 but data for women at high risk for these events are lacking. An increase in probable dementia was observed in the WHI among women aged 65 years or older who were treated with oral systemic estrogen-progestin therapy (equivocal results for systemic oral estrogen alone); there is no evidence that the minimal absorption of low-dose vaginal estrogen preparations would have the potential to affect dementia risk among women in any age group or would have biologic plausibility to do so. Effects of endogenous estrogen concentrations within the reference postmenopausal range The main source of endogenous estrogen in postmenopausal women is the peripheral conversion of steroid precursors via the aromatase enzyme located primarily in peripheral adipose and muscle tissues.45 Obesity itself is a risk factor for breast and endometrial cancers and cardiometabolic disorders.45,46 Pathways implicated in the association of obesity with these disorders include insulin resistance, hyperinsulinemia, growth factors, and inflammation,45,46 in addition to elevation of sex steroid hormones. Central adiposity is further associated with dyslipidemia, type 2 diabetes, and higher levels of inflammatory cytokines, which likely also contribute to cardiovascular disease. Thus, observational studies linking endogenous estrogen concentrations within the postmenopausal range to cardiometabolic disorders or cancer have potential for confounding by the abovementioned factors and are not viewed as a concern for the use of low-dose vaginal estrogen products. Conclusions and proposed label changes Based on these data, we submit that revisiting the labeling of low-dose vaginal estrogen to include the changes below would enhance women’s safety and improve their health and well-being. As discussed previously, the boxed warning on these products is based on extrapolations of data from trials of systemic estrogen or combination estrogen-progestin hormone therapy, which involve substantially higher levels of exposure. It is noteworthy that there are dramatic differences in estrogen blood levels achieved with low-dose vaginal estrogen therapies compared with systemic estrogen administration. Our view is that the highly visible boxed warning on low-dose vaginal estrogen is unsubstantiated and not evidence-based and is harming women by discouraging the use of effective treatments that would provide substantial benefits to postmenopausal women with symptomatic VVA. We believe that women would be better served by a modified label that more closely reflects the safety profile of low-dose vaginal estrogen and could ultimately enhance safety by emphasizing the key information that women and clinicians need to know about the products. Our proposal, as noted above, is to mention in the product labeling, in regular text and font, that estrogen and estrogen-progestin given systemically, in higher doses, have been linked to the health conditions currently included in the boxed warning, but that the relevance to low-dose vaginal estrogen remains unknown, given minimal increase in serum estrogen levels with low-dose vaginal estrogen products. We recommend bolding the phrase “report any vaginal bleeding or spotting right away while using ______.” We also recommend adding in bold “Women with a history of cancer of the breast or uterus (womb), or other hormone-sensitive cancers, are encouraged to consult their oncologist before using this product.” This label change would serve the purpose of informing women of previous research and addressing safety issues while stating that the relevance of past research findings on systemic hormone therapy to the current vaginal products is unknown. Regarding other statements in the boxed warning, we propose the following (all would be listed in regular and unbolded font, except as noted; none of the text would be boxed): What is the most important information I should know about _____? Instead of: Using estrogen alone may increase your chance of getting cancer of the uterus (womb). Report any unusual vaginal bleeding right away while you are using ______. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find the cause. Change to: Using higher doses of estrogen alone is associated with an increased chance of getting cancer of the uterus (womb), but the relevance of these findings to low-dose vaginal estrogen is unknown. Nonetheless, report any vaginal bleeding or spotting right away while you are using ______. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any vaginal bleeding or spotting to find the cause. Include: Do not use estrogen alone to prevent heart disease, heart attacks, strokes, or dementia (decline of brain function). Comment: Include this in regular unbolded font, not boxed. Instead of: Using estrogen alone may increase your chances of getting strokes or blood clots. Change to: Using higher doses of estrogen may increase your chances of getting strokes or blood clots, but the relevance of these findings to low-dose vaginal estrogen, which leads to minimal increase in blood estrogen levels, is unknown. Instead of: Using estrogen alone may increase your chance of getting dementia, based on a study of women aged 65 years or older. Change to: Using higher doses of estrogen may increase your chance of getting dementia, based on a study of women aged 65 years or older, but the relevance of these findings to low-dose vaginal estrogen, which leads to minimal increase in blood estrogen levels, is unknown. Instead of: Using estrogens with progestins may increase your chance of getting breast cancer. Change to: Using estrogens with progestins may increase your chance of getting breast cancer, but the relevance of these findings to low-dose vaginal estrogen without progestins is unknown. Add in bold: Women with a history of cancer of the breast or uterus (womb), or other hormone-sensitive cancers, are encouraged to consult their oncologist before using this product. Include the statement below in regular unbolded font: You and your healthcare provider should talk regularly about whether you still need treatment with _______. We believe that these label modifications will improve women’s health. JoAnn E. Manson, MD, DrPH, NCMP 1 Steven R. Goldstein, MD, NCMP2 Risa Kagan, MD, NCMP3 Andrew M. Kaunitz, MD, NCMP4 James H. Liu, MD5 JoAnn V. Pinkerton, MD, NCMP6 Robert W. Rebar, MD7 Peter F. Schnatz, DO, NCMP8 Jan L. Shifren, MD, NCMP1 Cynthia A. Stuenkel, MD, NCMP9 Margery L.S. Gass, MD, NCMP5 Wulf H. Utian, MB Bch, PhD, DSc(Med)5 for the Working Group on Women’s Health and Well-Being in Menopause Financial disclosure/conflicts of interest J.E.M., R.W.R., P.F.S., J.L.S., M.L.S.G., and W.H.U. report no disclosures. S.R.G. is a consultant to, and has received payment for lectures/service on speakers’ bureaus for, Shionogi and Pfizer. R.K. is a consultant to, and has received payment for lectures/service on speakers’ bureaus for, Pfizer, Novo Nordisk, Noven, and Shionogi. A.M.K. serves on advisory boards for Actavis. J.H.L. is on the Advisory board for Noven, Pfizer, and Shionogi. J.V.P. is a consultant (fees to the University of Virginia) for Pfizer, Novo Nordisk, and Shionogi. C.A.S. has served as a consultant to Pfizer. All authors are current or past members of the NAMS Board of Trustees.

The effect of obesity on late-age survival in women without disease or disability is unknown.To investigate whether higher baseline body mass index and waist circumference affect women's survival to 85 years of age without major chronic disease (coronary disease, stroke, cancer, diabetes mellitus, or hip fracture) and mobility disability.Examination of 36,611 women from the Women's Health Initiative observational study and clinical trial programs who could have reached 85 years or older if they survived to the last outcomes evaluation on September 17, 2012. Recruitment was from 40 US clinical centers from October 1993 through December 1998. Multinomial logistic regression models were used to estimate odds ratios and 95% CIs for the association of baseline body mass index and waist circumference with the outcomes, adjusting for demographic, behavioral, and health characteristics.Mutually exclusive classifications: (1) survived without major chronic disease and without mobility disability (healthy); (2) survived with 1 or more major chronic disease at baseline but without new disease or disability (prevalent diseased); (3) survived and developed 1 or more major chronic disease but not disability during study follow-up (incident diseased); (4) survived and developed mobility disability with or without disease (disabled); and (5) did not survive (died).Mean (SD) baseline age was 72.4 (3.0) years (range, 66-81 years). The distribution of women classified as healthy, prevalent diseased, incident diseased, disabled, and died was 19.0%, 14.7%, 23.2%, 18.3%, and 24.8%, respectively. Compared with healthy-weight women, underweight and obese women were more likely to die before 85 years of age. Overweight and obese women had higher risks of incident disease and mobility disability. Disability risks were striking. Relative to healthy-weight women, adjusted odds ratios (95% CIs) of mobility disability were 1.6 (1.5-1.8) for overweight women and 3.2 (2.9-3.6), 6.6 (5.4-8.1), and 6.7 (4.8-9.2) for class I, II, and III obesity, respectively. Waist circumference greater than 88 cm was also associated with higher risk of earlier death, incident disease, and mobility disability.Overall and abdominal obesity were important and potentially modifiable factors associated with dying or developing mobility disability and major chronic disease before 85 years of age in older women.

Abstract BACKGROUND Breast cancer diagnosis and treatment may put women at higher risk for osteoporosis in later life. METHODS In a subgroup of participants in the Women's Health Initiative Observational Study, authors of the current study investigated differences in bone mineral density (BMD, measured by dual‐energy x‐ray absorptiometry) between breast cancer survivors ( n = 209) and a noncancer reference group ( n = 5759). RESULTS In comparison to the reference group, breast cancer survivors had significantly lower total body BMD value (0.989 vs. 1.013 g/cm 2 , P = 0.001) and total hip BMD value (0.823 vs. 0.845 g/cm 2 , P = 0.02) at baseline after adjustment for age, race/ethnicity, years since menopause, and clinical center. These lower BMD levels were largely explained by lower usage of hormone therapy (HT) among survivors: after additional statistical adjustment for HT, hip BMD values were 0.834 versus 0.844 g/cm 2 ( P = 0.26), and total body values were 1.005 versus 1.013 g/cm 2 ( P = 0.33) for survivors and reference women, respectively. More than 77% of survivors with osteoporosis were undiagnosed by their healthcare providers, and this was similar to the undiagnosed rate in the reference group (85.7%). Longitudinally, breast cancer survivors in this study did not demonstrate an accelerated rate of bone loss compared with the reference population. CONCLUSIONS Associated with lower HT usage, postmenopausal survivors of breast cancer were more likely to have low BMD in comparison to other women of the same age; and many of these survivors with osteoporosis were undiagnosed. Cancer 2005. © 2005 American Cancer Society.

To compare effects of 52 weeks' treatment with either raloxifene 60 mg/day alone (RLX) or in combination with 17beta-estradiol 1 mg/day (RLX + E) on vasomotor symptoms (n = 83) and endometrial safety (n = 123) in postmenopausal women who transitioned from estrogen-progestin therapy.In this randomized, double-blind clinical trial, the frequency of vasomotor symptoms, hot flashes, and night sweats was assessed for up to 52 weeks. Endometrial thickness was assessed by transvaginal ultrasonography at baseline and at 12 and 52 weeks. An exit endometrial biopsy was performed at study completion or early termination.The frequency of vasomotor symptoms, hot flashes, and night sweats was unchanged from baseline with RLX but was significantly reduced in women treated with RLX + E, from baseline (all P < 0.001) and the RLX group at 6, 12, 24, 36, and 52 weeks (all P < 0.01). Women in the RLX + E group had significantly increased endometrial thickness (0.74 +/- 0.28 mm, mean +/- SEM) at 52 weeks, from baseline and RLX (P < 0.05), with no statistically significant changes in women treated with RLX. Two women, both in the RLX + E group, had endometrial hyperplasia (one with atypia) on the exit biopsy.In women transitioning from estrogen-progestin therapy, occurrence of vasomotor symptoms was unchanged from baseline with RLX treatment, but these symptoms were significantly reduced with combined RLX + E therapy. Signs of endometrial stimulation were observed in the RLX + E group. Further studies using different estrogen doses and preparations are needed before concomitant use of raloxifene with systemic estrogens can be recommended.

Antiepileptic drugs (AEDs) are used increasingly in clinical practice to treat a number of conditions. However, the relationship between the use of these medications, particularly the newer AEDs, and fracture risk has not been well characterized. We used data from the Women's Health Initiative (WHI) to determine the relationship bewteen the use of AEDs and falls, fractures, and bone mineral density (BMD) over an average of 7.7 years of follow-up. We included 138,667 women (1,385 users of AEDs and 137,282 nonusers) aged 50 to 79 years in this longitudinal cohort analyses. After adjustment for covariates, use of AEDs was positively associated with total fractures [hazard ratio (HR) = 1.44, 95% confidence interval (CI) 1.30-1.61], all site-specific fractures including the hip (HR = 1.51, 95% CI 1.05-2.17), clinical vertebral fractures (HR = 1.60, 95% CI 1.20-2.12), lower arm or wrist fractures (HR = 1.40, 95% CI 1.11-1.76), and other clinical fractures (HR = 1.46, 95% CI 1.29-1.65) and two or more falls (HR = 1.62, 95% CI 1.50-1.74) but not with baseline BMD or changes in BMD (p > or = .064 for all sites). Use of more than one and use of enzyme-inducing AEDs were significantly associated with total fractures (HR = 1.55, 95% CI 1.15-2.09 and HR = 1.36, 95% CI 1.09-1.69, respectively). We conclude that in clinical practice, postmenopausal women who use AEDs should be considered at increased risk for fracture, and attention to fall prevention may be particularly important in these women.

In Brief Objective: The aim of this study was to assess vasomotor and other menopausal symptoms before starting estrogens or placebo, 1 year later, again at trial closure, and after stopping estrogens or placebo. The role of baseline symptoms and age was examined, as was the frequency and determinants of hormone use and symptom management strategies after discontinuing conjugated equine estrogens (CEE) or placebo. Methods: Intent-to-treat analyses of 10,739 postmenopausal women before and 1 year after randomization to CEE or placebo at 40 clinical centers and a cohort analysis of participants (n = 3,496) who continued taking assigned study pills up to trial closure and completed symptom surveys shortly before (mean, 7.4 ± 1.1 y from baseline) and after (mean, 306 ± 55 d after trial closure) stopping pills were performed. Generalized linear regression modeled vasomotor symptoms, vaginal dryness, breast tenderness, pain/stiffness, and mood swings as a function of treatment assignment and baseline symptoms, before and after stopping study pills. Results: Approximately one third of participants reported at least one moderate to severe symptom at baseline. Fewer symptoms were reported with increasing age, except joint pain/stiffness, which was similar among age groups. At 1 year, hot flashes, night sweats, and vaginal dryness were reduced by CEE, whereas breast tenderness was increased. Breast tenderness was also significantly higher in the CEE group at trial closure. After stopping, vasomotor symptoms were reported by significantly more women who had reported symptoms at baseline, compared with those who had not, and by significantly more participants assigned to CEE (9.8%) versus placebo (3.2%); however, among women with no moderate or severe symptoms at baseline, more than five times as many reported hot flashes after stopping CEE (7.2%) versus placebo (1.5%). Conclusions: CEE significantly reduced vasomotor symptoms and vaginal dryness in women with baseline symptoms but increased breast tenderness. The likelihood of experiencing symptoms was significantly higher after stopping CEE than placebo regardless of baseline symptom status. These potential effects should be considered before initiating CEE to relieve menopausal symptoms. This study shows that conjugated equine estrogens (CEE) significantly reduced vasomotor symptoms and vaginal dryness in women with baseline symptoms but increased breast tenderness. The likelihood of experiencing symptoms was significantly higher after stopping CEE than placebo regardless of baseline symptom status. These potential effects should be considered before initiating CEE to relieve menopausal symptoms.

A national survey was conducted to determine the extent of use of compounded hormone therapy (C-HT) and to characterize the differences between C-HT users and users of hormone therapy approved by the US Food and Drug Administration (FDA-HT users).This Internet survey enrolled 3,725 women aged 40 to 84 years who were postmenopausal or experiencing the menopause transition. The sample was weighted slightly by age, region, education, and race to reflect population attributes based on US Census data.Overall, 9% of women were current users of HT, and 28% of all respondents were ever-users of HT. C-HT users represented 31% of ever-users of HT, 35% of current users of HT, and 41% of ever-users aged 40 to 49 years. Approximately 13% of ever-users indicated current or past use of testosterone. The most cited reason for using HT was vasomotor symptoms (∼70%). Nonapproved indications for using HT were selected more often by C-HT users. There were four reports of endometrial cancer among the 326 C-HT users compared with none reported among the 738 FDA-HT users. Significance was not determined because of small numbers.This survey indicates substantial use of C-HT across the country and the possibility of higher rates of endometrial side effects with such products. There is a need for standardized data collection on the extent of use of compounded hormones and their potential risks.

Hormonal and reproductive factors contribute to the development of ovarian cancer, but few studies have examined associations between circulating estrogens and estrogen metabolites and ovarian cancer risk. We evaluated whether serum estrogens and estrogen metabolite levels are associated with ovarian cancer risk among postmenopausal women in a nested case-control study in the Women's Health Initiative (WHI) Observational Study (OS).We selected all 169 eligible epithelial ovarian cancer cases and 412 matched controls from women enrolled in WHI-OS who were not using menopausal hormones at baseline. Baseline levels of 15 estrogens and estrogen metabolites were measured via liquid chromatography/tandem mass spectrometry. Associations with ovarian cancer risk overall and stratified by histologic subtype (serous/nonserous) were analyzed using logistic regression. The mean time from serum collection to cancer diagnosis was 6.9 years.Overall, we observed modest ovarian cancer risk associations among women with higher levels of estrone [OR (95% confidence interval) quintile (Q)5 vs. Q1: 1.54 (0.82-2.90), Ptrend = 0.05], as well as 2- and 4-methoxyestrone metabolites [2.03 (1.06-3.88), Ptrend = 0.02; 1.86 (0.98-3.56), Ptrend = 0.01, respectively]. Associations of estrogens and estrogen metabolites varied substantially by histologic subtype. Associations with serous tumors were universally null, while estrone [2.65 (1.09-6.45), Ptrend = 0.01, Pheterogeneity = 0.04], unconjugated estradiol [2.72 (1.04-7.14), Ptrend = 0.03, Pheterogeneity = 0.02] and many of the 2-, 4-, and 16-pathway metabolites were positively associated with nonserous tumors.Our study provides novel molecular data showing an association of the parent estrogens and several estrogen metabolites with nonserous ovarian cancers.These findings further support the heterogeneous etiology of ovarian cancer. Cancer Epidemiol Biomarkers Prev; 25(4); 648-56. ©2016 AACR.

The United States Preventive Services Task Force (USPSTF) recommends osteoporosis screening for women younger than 65 years whose 10-year predicted risk of major osteoporotic fracture (MOF) is at least 9.3% using the Fracture Risk Assessment Tool. In postmenopausal women age 50-64 years old, it is uncertain how the USPSTF screening strategy compares with the Osteoporosis Self-Assessment Tool and the Simple Calculated Osteoporosis Risk Estimate (SCORE) in discriminating women who will and will not experience MOF.This study aimed to assess the sensitivity, specificity, and area under the receiver operating characteristic curve of the three strategies for discrimination of incident MOF over 10 years of follow-up among postmenopausal women age 50-64 years.This was a prospective study conducted between 1993-2008 at 40 US Centers.We analyzed data from participants of the Women's Health Initiative Observational Study and Clinical Trials, age 50-64 years, not taking osteoporosis medication (n = 62 492).The main outcome was 10-year (observed) incidence of MOF.For identifying women with incident MOF, sensitivity of the strategies ranged from 25.8-39.8%, specificity ranged from 60.7-65.8%, and AUC values ranged from 0.52-0.56. The sensitivity of the USPSTF strategy for identifying incident MOF ranged from 4.7% (3.3-6.0) among women age 50-54 years to 37.3% (35.4-39.1) for women age 60-64 years. Adjusting the thresholds to improve sensitivity resulted in decreased specificity.Our findings do not support use of the USPSTF strategy, Osteoporosis Self-Assessment Tool, or SCORE to identify younger postmenopausal women who are at higher risk of fracture. Our findings suggest that fracture prediction in younger postmenopausal women requires assessment of risk factors not included in currently available strategies.

Endometrial cancer (EC) is the most common gynecologic cancer in the USA. Over the last decade, the incidence rate has been increasing, with a larger increase among blacks. The aim of this study was to compare risk factors for EC in black and white women. Data from seven cohort and four case–control studies were pooled. Unconditional logistic regression was used to estimate adjusted odds ratios (OR) and 95 % confidence intervals for each risk factor in blacks and whites separately. Data were pooled for 2,011 black women (516 cases and 1,495 controls) and 19,297 white women (5,693 cases and 13,604 controls). BMI ≥ 30 was associated with an approximate threefold increase in risk of EC in both black and white women (ORblack 2.93, 95 % CI 2.11, 4.07 and ORwhite 2.99, 95 % CI 2.74, 3.26). Diabetes was associated with a 30–40 % increase in risk among both groups. Increasing parity was associated with decreasing risk of EC in blacks and whites (p value = 0.02 and <0.001, respectively). Current and former smoking was associated with decreased risk of EC among all women. Both black and white women who used oral contraceptives for 10 +years were also at reduced risk of EC (OR 0.49, 95 % CI 0.27, 0.88 and OR 0.69, 95 % CI 0.58, 0.83, respectively). Previous history of hypertension was not associated with EC risk in either group. The major known risk factors for EC exert similar effects on black and white women. Differences in the incidence rates between the two populations may be due to differences in the prevalence of risk factors.

Objectives. To examine associations of maternal age at childbirth and parity with survival to age 90 years (longevity). Methods. We performed a prospective study among a multiethnic cohort of postmenopausal US women in the Women’s Health Initiative recruited from 1993 to 1998 and followed through August 29, 2014. We adjusted associations with longevity for demographic, lifestyle, reproductive, and health-related characteristics. Results. Among 20 248 women (mean age at baseline, 74.6 years), 10 909 (54%) survived to age 90 years. The odds of longevity were significantly higher in women with later age at first childbirth (adjusted odds ratio = 1.11; 95% confidence interval = 1.02, 1.21 for age 25 years or older vs younger than 25 years; P for trend = .04). Among parous women, the relationship between parity and longevity was significant among White but not Black women. White women with 2 to 4 term pregnancies compared with 1 term pregnancy had higher odds of longevity. Conclusions. Reproductive events were associated with longevity among women. Future studies are needed to determine whether factors such as socioeconomic status explain associations between reproductive events and longevity.

In the Women's Health Initiative (WHI) estrogen plus progestin trial, after 5.6 years' intervention and 8 years' median follow-up, more women died from lung cancer in the hormone therapy group (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.16-2.52; P = .01). Now after 14 years' median follow-up, we reexamined combined hormone therapy effects on lung cancer mortality.In the WHI placebo-controlled trial, 16,608 postmenopausal women aged 50 to 79 years and with an intact uterus were randomly assigned to once-daily 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate (n = 8506) or placebo (n = 8102). Incidence and mortality rates for lung cancer were assessed from multivariant proportional hazard models.After 14 years' cumulative follow-up, there were 219 lung cancers (0.19% per year) in the estrogen plus progestin group and 184 (0.17%) in the placebo group (HR, 1.12; 95% CI, 0.92-1.37; P = .24). While there were more deaths from lung cancer with combined hormone therapy (153 [0.13%] vs. 132 [0.12%], respectively), the difference was not statistically significant (HR, 1.09; 95% CI, 0.87-1.38; P = .45). The statistically significant increase in deaths from lung cancer observed during intervention in women assigned to estrogen plus progestin was attenuated after discontinuation of study pills (linear trend over time, P = .042).The increased risk of death from lung cancer observed during estrogen plus progestin use was attenuated after discontinuation of combined hormone therapy.

Women with history of pregnancy loss (PL) have higher burden of cardiovascular disease (CVD) later in life, yet it is unclear whether this is attributable to an association with established CVD risk factors (RFs). We examined whether PL is associated with CVD RFs and biomarkers in parous postmenopausal women in the Women's Health Initiative, and whether the association between PL and CVD RFs accounted for the association between PL and incident CVD. Linear and logistic regressions were used to estimate associations between baseline history of PL and CVD RFs. Cox proportional hazards regression models were used to estimate the associations between baseline history of PL and incident CVD after adjustment for baseline RFs. Of 79,121 women, 27,272 (35%) had experienced PL. History of PL was associated with higher body mass index (p < 0.0001), hypertension (p < 0.0001), diabetes (p = 0.003), depression (p < 0.0001), and lower income (p < 0.0001), physical activity (p = 0.01), poorer diet (p < 0.0001), smoking (p < 0.0001), and alcohol use (p < 0.0001). After adjustment for CVD RFs, PL was significantly associated with incident CVD over mean follow up of 16 years (hazard ratio 1.11, 95% confidence interval 1.06 to 1.16). In conclusion, several CVD RFs are associated with PL, but they do not entirely account for the association between PL and incident CVD. Women with history of pregnancy loss (PL) have higher burden of cardiovascular disease (CVD) later in life, yet it is unclear whether this is attributable to an association with established CVD risk factors (RFs). We examined whether PL is associated with CVD RFs and biomarkers in parous postmenopausal women in the Women's Health Initiative, and whether the association between PL and CVD RFs accounted for the association between PL and incident CVD. Linear and logistic regressions were used to estimate associations between baseline history of PL and CVD RFs. Cox proportional hazards regression models were used to estimate the associations between baseline history of PL and incident CVD after adjustment for baseline RFs. Of 79,121 women, 27,272 (35%) had experienced PL. History of PL was associated with higher body mass index (p < 0.0001), hypertension (p < 0.0001), diabetes (p = 0.003), depression (p < 0.0001), and lower income (p < 0.0001), physical activity (p = 0.01), poorer diet (p < 0.0001), smoking (p < 0.0001), and alcohol use (p < 0.0001). After adjustment for CVD RFs, PL was significantly associated with incident CVD over mean follow up of 16 years (hazard ratio 1.11, 95% confidence interval 1.06 to 1.16). In conclusion, several CVD RFs are associated with PL, but they do not entirely account for the association between PL and incident CVD.

Abstract The health benefits and risks of menopausal hormone therapy among women aged 50–59 years are examined in the Women’s Health Initiative randomized, placebo-controlled trials using long-term follow-up data and a parsimonious statistical model that leverages data from older participants to increase precision. These trials enrolled 27,347 healthy postmenopausal women aged 50–79 years at 40 US clinical centers during 1993–1998, including 10,739 post-hysterectomy participants in a trial of conjugated equine estrogens and 16,608 participants with a uterus in the trial of these estrogens plus medroxyprogesterone acetate. Over a (median) 18-year follow-up period (1993–2016), risk for a global index (defined as the earliest of coronary heart disease, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and all-cause mortality) was reduced with conjugated equine estrogens with a hazard ratio of 0.82 (95% confidence interval: 0.71, 0.95), and with nominally significant reductions for coronary heart disease, breast cancer, hip fracture, and all-cause mortality. Corresponding global index hazard ratio estimates of 1.06 (95% confidence interval: 0.95, 1.19) were nonsignificant for combined estrogens plus progestin, but increased breast cancer risk and reduced endometrial cancer risk were observed. These results, among women 50–59 years of age, substantially agree with the worldwide observational literature, with the exception of breast cancer for estrogens alone.

Thirty-one patients had senile macular disease with serous detachments of the retinal pigment epithelium without evidence of choroidal neovascularization. Of these 31 patients the natural history of 24 eyes was compared with 21 eyes treated with photocoagulation. Eight patients with bilateral detachments had treatment applied to one eye. There was no conclusive evidence that photocoagulation alters the natural course of this condition.

A 23-year-old man developed a rapid-onset, large, dense scotoma that was associated with a peculiar gray intraretinal ring corresponding to the edge of the scotoma and normal fluorescein angiographic findings. This disorder may represent a variant of acute zonal occult outer retinopathy.We studied one patient by ophthalmoscopic examination and fluorescein angiography.The patient experienced a short period of concentric enlargement of the scotoma and narrowing of the retinal vessels within the ring, followed by stabilization of the scotoma and slow progressive depigmentation and intraretinal migration of the retinal pigment epithelium within the zone of visual loss. The cause of this disorder, which affects primarily the outer retina, was not determined.We speculate that this disorder is part of the spectrum of acute zonal occult outer retinopathy and that the gray border, which separates the normal from the abnormal retina, represents an immune ring phenomenon.

In Brief Objective: To explore the bone turnover marker profile during the menstrual cycle of premenopausal women. Design: This was a noninterventional study. Levels of bone turnover markers, including serum C-terminal telopeptide of type I collagen (sCTX), bone-specific alkaline phosphatase, osteocalcin, procollagen type 1 N propeptide, and urinary N-terminal telopeptide of type I collagen, were measured in blood and urine samples during one menstrual cycle. Levels were expressed as raw test results and percent change from serum luteinizing hormone peak. Differences in mean levels of bone turnover markers between menstrual phases and subphases were examined. Results: Fifty-five women comprised the per-protocol population. Mean sCTX values were 0.48 ng/mL during the follicular phase (FP), 0.47 ng/mL at serum luteinizing hormone peak, and 0.43 ng/mL during the luteal phase (LP). Additionally, the mean percent change from luteinizing hormone peak varied from +4.35% during the FP to −5.11% during the LP (P = 0.0014). Mean sCTX levels during the early and through mid FP were significantly higher than levels during the mid and late LP. The pattern for urinary N-terminal telopeptide of type I collagen was similar to that of sCTX but not statistically significant. There was a statistically significant tendency for procollagen type I N propeptide levels to be lower during the FP relative to the LP. Levels of osteocalcin and bone-specific alkaline phosphatase did not vary significantly during the menstrual cycle. Conclusions: Levels of some bone turnover markers varied during the menstrual cycle. A statistically significant change in sCTX (9.46%) occurred between the FP and LP of the menstrual cycle. This noninterventional study explored the profile of bone turnover markers during the menstrual cycle of premenopausal women. Serum C-terminal telopeptide of type I collagen, urinary N-terminal telopeptide of type I collagen, and procollagen type I N propeptide varied during the menstrual cycle, with a statistically significant change in serum C-terminal telopeptide of type I collagen (9.46%) observed between the follicular phase and luteal phase.

Stuenkel, Cynthia A. MD, NCMP; Gass, Margery L.S. MD, NCMP; Manson, JoAnn E. MD, DrPH, NCMP; Lobo, Rogerio A. MD; Pal, Lubna MBBS, MRCOG, MSc, NCMP; Rebar, Robert W. MD; Hall, Janet E. MD Author Information

Paradoxically, a breast cancer risk reduction with conjugated equine estrogens (CEE) and a risk elevation with CEE plus medroxyprogesterone acetate (CEE + MPA) were observed in the Women's Health Initiative (WHI) randomized controlled trials. The effects of hormone therapy on serum sex hormone levels, and on the association between baseline sex hormones and disease risk, may help explain these divergent breast cancer findings.Serum sex hormone concentrations were measured for 348 breast cancer cases in the CEE + MPA trial and for 235 cases in the CEE trial along with corresponding pair-matched controls, nested within the WHI trials of healthy postmenopausal women. Association and mediation analyses, to examine the extent to which sex hormone levels and changes can explain the breast cancer findings, were conducted using logistic regression.Following CEE treatment, breast cancer risk was associated with higher concentrations of baseline serum estrogens, and with lower concentrations of sex hormone binding globulin. However, following CEE + MPA, there was no association of breast cancer risk with baseline sex hormone levels. The sex hormone changes from baseline to year 1 provided an explanation for much of the reduced breast cancer risk with CEE. Specifically, the treatment odds ratio (95% confidence interval) increased from 0.71 (0.43, 1.15) to 0.92 (0.41, 2.09) when the year 1 measures were included in the logistic regression analysis. In comparison, the CEE + MPA odds ratio was essentially unchanged when these year 1 measures were included.Breast cancer risk remains low following CEE use among women having favorable baseline sex hormone profiles, but CEE + MPA evidently produces a breast cancer risk for all women similar to that for women having an unfavorable baseline sex hormone profile. These patterns could reflect breast ductal epithelial cell stimulation by CEE + MPA that is substantially avoided with CEE, in conjunction with relatively more favorable effects of either regimen following a sustained period of estrogen deprivation. These findings may have implications for other hormone therapy formulations and routes of delivery.clinicaltrials.gov identifier: NCT00000611.

In Brief Objective: First, to identify treatment satisfaction thresholds for interpreting treatment-related changes in vasomotor symptoms, and, second, to determine the doses of desvenlafaxine (DVS) (administered as desvenlafaxine succinate) that effectively provide relief of vasomotor symptoms considered important by menopausal women. Design: Efficacy and treatment satisfaction were assessed in 620 postmenopausal women with moderate to severe vasomotor symptoms participating in a double-blind, placebo-controlled trial and randomly assigned to placebo or 50, 100, 150, or 200 mg DVS. Number and severity of hot flushes and number of nighttime awakenings were recorded in daily diaries for 12 weeks of treatment. At week 12, responses to the Menopause Symptoms Treatment Satisfaction Questionnaire were compared with efficacy results. Results: Greater percentages of participants in the DVS groups reported being "satisfied" or "extremely satisfied" with daytime and nighttime control of hot flushes compared with placebo. The treatment satisfaction threshold, defined as the difference between the average reduction in vasomotor symptoms for women who were "neutral" versus "satisfied," was 1.64 for moderate to severe hot flushes and 0.42 for nighttime awakenings. Statistically significant reductions with 100, 150, and 200 mg DVS exceeded treatment satisfaction threshold results for at least one of these thresholds, and results with 100 mg DVS compared with placebo exceeded both treatment satisfaction thresholds. Conclusions: Among menopausal women with moderate to severe vasomotor symptoms, the treatment satisfaction thresholds that were meaningful to participants were 1.64 fewer moderate to severe hot flushes per day and 0.42 fewer nighttime awakenings per night. A dose of 100 mg DVS met both of these important vasomotor symptom change thresholds. This article addresses two important challenges in vasomotor symptom relief. First, it estimates a meaningful treatment satisfaction threshold for the reduction in the number and severity of hot flushes and nighttime awakenings for postmenopausal women with moderate to severe vasomotor symptoms, and, second, it suggests that a nonhormonal therapy (100 mg desvenlafaxine) can achieve these vasomotor symptom change thresholds in a double-blind, placebo-controlled trial

DiscussYou can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/gassm-womens-health-initiative/This year marks the 10th anniversary of the 2002 presentation of the results of the Women's Health Initiative hormone trials. Amidst the debate that ensued, the one consistent theme was that “even the experts don't agree.” Much has been learned and is still being unraveled regarding the safety and efficacy of hormone therapy from previous and ongoing studies. In response to the many women and clinicians seeking answers, our goal is to reassure both symptomatic women and their providers that experts do indeed agree on key points regarding the safety and role of hormone therapy in menopause management based on the scientific evidence of the last 10 years. We believe that women deserve to know the facts that can inform their decision to use or not to use hormone therapy.OverviewSystemic hormone therapy is an acceptable option for relatively young (up to age 59 or within 10 years of menopause) and healthy women who are bothered by moderate to severe menopausal symptoms. Individualization is key in the decision to use hormone therapy. Consideration should be given to the woman's quality-of-life priorities as well as her personal risk factors such as age, time since menopause, and her risk of blood clots, heart disease, stroke, and breast cancer.Symptom Relief BenefitsSystemic hormone therapy is the most effective treatment for most menopausal symptoms, including vasomotor symptoms and vaginal atrophy. Estrogen therapy as a single agent is sufficient in women who have undergone hysterectomy.Progestogen therapy is required to prevent endometrial cancer when estrogen is used systemically in women with a uterus.Local estrogen therapy is effective and preferred for women whose symptoms are limited to vaginal dryness or discomfort with intercourse; low-dose vaginal estrogen therapy is recommended in this setting.Hormone therapy risksVascular RisksBoth estrogen therapy and estrogen with progestogen therapy increase the risk of venous thromboembolic events—deep vein thrombosis and pulmonary emboli. Although the risks of venous thromboembolic events and ischemic stroke increase with either estrogen therapy or estrogen and progestogen therapy, the risk is rare in the 50- to 59-year-old age group.Breast CancerAn increased risk of breast cancer is seen with 5 years or more of continuous estrogen with progestogen therapy, possibly earlier with continuous use since menopause. The risk is real but not great, and the risk decreases after hormone therapy is discontinued. Use of estrogen alone for a mean of 7 years in the Women's Health Initiative did not increase the risk of breast cancer.Duration of therapyThe lowest dose of hormone therapy should be used for the shortest amount of time to manage menopausal symptoms. Although fewer than 5 years is recommended for estrogen with progestogen therapy, duration should be individualized.For estrogen therapy alone, more flexibility in duration of therapy may be possible. There are reports of increased risk of breast cancer after 10 to 15 years of use in large observational studies with estrogen alone.Additional informationIn observational studies, both transdermal estrogen therapy and low-dose oral estrogen therapy have been associated with lower risks of venous thromboembolic events and stroke than standard doses of oral estrogen, but comparison randomized clinical trials are not yet available.Many options for Food and Drug Administration–approved bioidentical hormone therapy (estradiol and progesterone) are available. Evidence is lacking that custom compounded bioidentical hormone therapy is safe or effective. Many medical organizations and societies agree in recommending against the use of custom compounded hormone therapy for menopause management, particularly given concerns regarding content, purity, and labeling. There is a lack of safety data supporting the use of estrogen or estrogen with progestogen therapy in breast cancer survivors. Nonhormonal therapies should be the first approach in managing menopausal symptoms in breast cancer survivors.ConclusionLeading medical societies devoted to the care of menopausal women agree that the decision to initiate hormone therapy should be for the indication of treatment of menopause-related symptoms. Although research is ongoing and these recommendations may be modified over time, there is no question that hormone therapy has an important role in managing symptoms for women during the menopausal transition and in early menopause. DiscussYou can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/gassm-womens-health-initiative/ DiscussYou can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/gassm-womens-health-initiative/ DiscussYou can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/gassm-womens-health-initiative/ You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/gassm-womens-health-initiative/ This year marks the 10th anniversary of the 2002 presentation of the results of the Women's Health Initiative hormone trials. Amidst the debate that ensued, the one consistent theme was that “even the experts don't agree.” Much has been learned and is still being unraveled regarding the safety and efficacy of hormone therapy from previous and ongoing studies. In response to the many women and clinicians seeking answers, our goal is to reassure both symptomatic women and their providers that experts do indeed agree on key points regarding the safety and role of hormone therapy in menopause management based on the scientific evidence of the last 10 years. We believe that women deserve to know the facts that can inform their decision to use or not to use hormone therapy. OverviewSystemic hormone therapy is an acceptable option for relatively young (up to age 59 or within 10 years of menopause) and healthy women who are bothered by moderate to severe menopausal symptoms. Individualization is key in the decision to use hormone therapy. Consideration should be given to the woman's quality-of-life priorities as well as her personal risk factors such as age, time since menopause, and her risk of blood clots, heart disease, stroke, and breast cancer.Symptom Relief BenefitsSystemic hormone therapy is the most effective treatment for most menopausal symptoms, including vasomotor symptoms and vaginal atrophy. Estrogen therapy as a single agent is sufficient in women who have undergone hysterectomy.Progestogen therapy is required to prevent endometrial cancer when estrogen is used systemically in women with a uterus.Local estrogen therapy is effective and preferred for women whose symptoms are limited to vaginal dryness or discomfort with intercourse; low-dose vaginal estrogen therapy is recommended in this setting. Systemic hormone therapy is an acceptable option for relatively young (up to age 59 or within 10 years of menopause) and healthy women who are bothered by moderate to severe menopausal symptoms. Individualization is key in the decision to use hormone therapy. Consideration should be given to the woman's quality-of-life priorities as well as her personal risk factors such as age, time since menopause, and her risk of blood clots, heart disease, stroke, and breast cancer. Symptom Relief BenefitsSystemic hormone therapy is the most effective treatment for most menopausal symptoms, including vasomotor symptoms and vaginal atrophy. Estrogen therapy as a single agent is sufficient in women who have undergone hysterectomy.Progestogen therapy is required to prevent endometrial cancer when estrogen is used systemically in women with a uterus.Local estrogen therapy is effective and preferred for women whose symptoms are limited to vaginal dryness or discomfort with intercourse; low-dose vaginal estrogen therapy is recommended in this setting. Systemic hormone therapy is the most effective treatment for most menopausal symptoms, including vasomotor symptoms and vaginal atrophy. Estrogen therapy as a single agent is sufficient in women who have undergone hysterectomy. Progestogen therapy is required to prevent endometrial cancer when estrogen is used systemically in women with a uterus. Local estrogen therapy is effective and preferred for women whose symptoms are limited to vaginal dryness or discomfort with intercourse; low-dose vaginal estrogen therapy is recommended in this setting. Hormone therapy risksVascular RisksBoth estrogen therapy and estrogen with progestogen therapy increase the risk of venous thromboembolic events—deep vein thrombosis and pulmonary emboli. Although the risks of venous thromboembolic events and ischemic stroke increase with either estrogen therapy or estrogen and progestogen therapy, the risk is rare in the 50- to 59-year-old age group.Breast CancerAn increased risk of breast cancer is seen with 5 years or more of continuous estrogen with progestogen therapy, possibly earlier with continuous use since menopause. The risk is real but not great, and the risk decreases after hormone therapy is discontinued. Use of estrogen alone for a mean of 7 years in the Women's Health Initiative did not increase the risk of breast cancer. Vascular RisksBoth estrogen therapy and estrogen with progestogen therapy increase the risk of venous thromboembolic events—deep vein thrombosis and pulmonary emboli. Although the risks of venous thromboembolic events and ischemic stroke increase with either estrogen therapy or estrogen and progestogen therapy, the risk is rare in the 50- to 59-year-old age group. Both estrogen therapy and estrogen with progestogen therapy increase the risk of venous thromboembolic events—deep vein thrombosis and pulmonary emboli. Although the risks of venous thromboembolic events and ischemic stroke increase with either estrogen therapy or estrogen and progestogen therapy, the risk is rare in the 50- to 59-year-old age group. Breast CancerAn increased risk of breast cancer is seen with 5 years or more of continuous estrogen with progestogen therapy, possibly earlier with continuous use since menopause. The risk is real but not great, and the risk decreases after hormone therapy is discontinued. Use of estrogen alone for a mean of 7 years in the Women's Health Initiative did not increase the risk of breast cancer. An increased risk of breast cancer is seen with 5 years or more of continuous estrogen with progestogen therapy, possibly earlier with continuous use since menopause. The risk is real but not great, and the risk decreases after hormone therapy is discontinued. Use of estrogen alone for a mean of 7 years in the Women's Health Initiative did not increase the risk of breast cancer. Duration of therapyThe lowest dose of hormone therapy should be used for the shortest amount of time to manage menopausal symptoms. Although fewer than 5 years is recommended for estrogen with progestogen therapy, duration should be individualized.For estrogen therapy alone, more flexibility in duration of therapy may be possible. There are reports of increased risk of breast cancer after 10 to 15 years of use in large observational studies with estrogen alone. The lowest dose of hormone therapy should be used for the shortest amount of time to manage menopausal symptoms. Although fewer than 5 years is recommended for estrogen with progestogen therapy, duration should be individualized. For estrogen therapy alone, more flexibility in duration of therapy may be possible. There are reports of increased risk of breast cancer after 10 to 15 years of use in large observational studies with estrogen alone. Additional informationIn observational studies, both transdermal estrogen therapy and low-dose oral estrogen therapy have been associated with lower risks of venous thromboembolic events and stroke than standard doses of oral estrogen, but comparison randomized clinical trials are not yet available.Many options for Food and Drug Administration–approved bioidentical hormone therapy (estradiol and progesterone) are available. Evidence is lacking that custom compounded bioidentical hormone therapy is safe or effective. Many medical organizations and societies agree in recommending against the use of custom compounded hormone therapy for menopause management, particularly given concerns regarding content, purity, and labeling. There is a lack of safety data supporting the use of estrogen or estrogen with progestogen therapy in breast cancer survivors. Nonhormonal therapies should be the first approach in managing menopausal symptoms in breast cancer survivors. In observational studies, both transdermal estrogen therapy and low-dose oral estrogen therapy have been associated with lower risks of venous thromboembolic events and stroke than standard doses of oral estrogen, but comparison randomized clinical trials are not yet available. Many options for Food and Drug Administration–approved bioidentical hormone therapy (estradiol and progesterone) are available. Evidence is lacking that custom compounded bioidentical hormone therapy is safe or effective. Many medical organizations and societies agree in recommending against the use of custom compounded hormone therapy for menopause management, particularly given concerns regarding content, purity, and labeling. There is a lack of safety data supporting the use of estrogen or estrogen with progestogen therapy in breast cancer survivors. Nonhormonal therapies should be the first approach in managing menopausal symptoms in breast cancer survivors. ConclusionLeading medical societies devoted to the care of menopausal women agree that the decision to initiate hormone therapy should be for the indication of treatment of menopause-related symptoms. Although research is ongoing and these recommendations may be modified over time, there is no question that hormone therapy has an important role in managing symptoms for women during the menopausal transition and in early menopause. Leading medical societies devoted to the care of menopausal women agree that the decision to initiate hormone therapy should be for the indication of treatment of menopause-related symptoms. Although research is ongoing and these recommendations may be modified over time, there is no question that hormone therapy has an important role in managing symptoms for women during the menopausal transition and in early menopause.

Objective This study aims to estimate the incidence of first hip or clinical vertebral fracture or major osteoporotic (hip, clinical vertebral, proximal humerus, or wrist) fracture in postmenopausal women undergoing their first bone mineral density (BMD) test before age 65 years. Methods We studied 4,068 postmenopausal women, aged 50 to 64 years without hip or clinical vertebral fracture or antifracture treatment at baseline, who were participating in the Women’s Health Initiative BMD cohort study. BMD tests were performed between October 1993 and April 2005, with fracture follow-up through 2012. Outcomes were the time for 1% of women to sustain a hip or clinical vertebral fracture and the time for 3% of women to sustain a major osteoporotic fracture before initiating treatment, adjusting for clinical risk factors and accounting for competing risks. Women without osteoporosis and women with osteoporosis on their first BMD test were analyzed separately. Results During a maximum of 11.2 years of concurrent BMD and fracture follow-up, the adjusted estimated time for 1% of women to have a hip or clinical vertebral fracture was 12.8 years (95% CI, 8.0-20.4) for women aged 50 to 54 years without baseline osteoporosis, 7.6 years (95% CI, 4.8-12.1) for women aged 60 to 64 years without baseline osteoporosis, and 3.0 years (95% CI, 1.3-7.1) for all women aged 50 to 64 years with baseline osteoporosis. Results for major osteoporotic fracture were similar. Conclusions Because of very low rates of major osteoporotic fracture, postmenopausal women aged 50 to 64 years without osteoporosis on their first BMD test are unlikely to benefit from frequent rescreening before age 65 years.

The aim of this study was to examine the association between common menopausal symptoms (MS) and long-term cardiovascular disease (CVD) and all-cause mortality.In an observational cohort of 80,278 postmenopausal women with no known CVD at baseline from the Women's Health Initiative, we assessed individual MS severity (mild vs none; moderate/severe vs none) for night sweats, hot flashes, waking up several times at night, joint pain or stiffness, headaches or migraines, vaginal or genital dryness, heart racing or skipping beats, breast tenderness, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating. Outcomes included total CVD events (primary) and all-cause mortality (secondary). Associations between specific MS, their severity, and outcomes were assessed during a median of 8.2 years of follow-up. All results were multivariable adjusted, and individual associations were Bonferroni corrected to adjust for multiple comparisons. A machine learning approach (least absolute shrinkage and selection operator) was used to select the most parsimonious set of MS most predictive of CVD and all-cause mortality.The severity of night sweats, waking up several times at night, joint pain or stiffness, heart racing or skipping beats, dizziness, feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating were each significantly associated with total CVD. The largest hazard ratio (HR) for total CVD was found for moderate or severe heart racing or skipping beats (HR, 1.55; 95% confidence interval [CI], 1.29-1.86). The individual severities of heart racing or skipping beats, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating were associated with increased all-cause mortality. Moderate or severe dizziness had the largest HR (1.58; 95% CI, 1.24-2.01). Multiple symptom modeling via least absolute shrinkage and selection operator selected dizziness, heart racing, feeling tired, and joint pain as most predictive of CVD, whereas dizziness, tremors, and feeling tired were most predictive of all-cause mortality.Among postmenopausal women with no known CVD at baseline, the severity of specific individual MS was significantly associated with incident CVD and mortality. Consideration of severe MS may enhance sex-specific CVD risk predication in future cohorts, but caution should be applied as severe MS could also indicate other health conditions.

Abstract Background Lynch syndrome represents one of the most common cancer predispositions worldwide and is caused by germline pathogenic variants (PV) in DNA mismatch repair (MMR) genes. We repeatedly identified a PV in the MMR gene PMS2 , c.1831dup, accounting for 27% of all Swiss PMS2 PV index patients identified. Notably, 2/18 index patients had been diagnosed with colorectal cancer (CRC) before age 30. Methods In this study, we investigated if this PV could (i) represent a founder variant by haplotype analysis and (ii) be associated with a more severe clinical phenotype. Results Haplotype analysis identified a shared common region of about 0.7 Mb/1.3 cM in 13 (81%) out of 16 index patients. Genotype–phenotype correlations, combining data from the 18 Swiss and 18 literature‐derived PMS2 c.1831dup PV index patients and comparing them to 43 Swiss index patients carrying other PMS2 PVs, indicate that the PMS2 c.1831dup variant may be associated with earlier (&lt;50 y) age at CRC diagnosis (55% vs. 29%, respectively; p = 0.047). Notably, 30% (9/30) of cancers from c.1831dup carriers displayed atypical MMR protein expression patterns on immunohistochemistry. Conclusion Our results suggest that the PMS2 c.1831dup PV represents a, probably ancient, founder mutation and is possibly associated with an earlier CRC diagnosis compared to other PMS2 PVs.

The Board of Trustees of The North American Menopause Society (NAMS) developed this manuscript with assistance from an Editorial Board composed of J. Christopher Gallagher, MD (Chair); Bruce Ettinger, MD; Margery L. S. Gass, MD; Risa Kagan, MD; Betsy L. McClung, RN, MN; Michael R. McClung, MD; and James A. Simon, MD. It was edited, modified, and subsequently approved by the NAMS Board of Trustees in November 2001. Received November 21, 2001. Address correspondence and reprint requests to NAMS, P.O. Box 94527, Cleveland, OH 44101, USA.

Vasomotor symptoms (VMS), including hot flashes and night sweats, are common among postmenopausal women and are associated with reduced health related quality of life (HRQOL).To determine whether Veterans are more likely to report VMS than non-Veterans, and whether the association of VMS with HRQOL varies by Veteran status.We used data from the Women's Health Initiative Observational Study, including self-reported baseline VMS presence and severity, and HRQOL at follow-up Year 3 (RAND Short Form 36-Item Health Survey). Employing generalized linear models we estimated whether Veteran status was associated with any VMS. We estimated the association between any VMS and HRQOL using linear regression, stratified by Veteran status. Interaction terms were added separately to determine whether the association varied by baseline depression, obesity, or smoking status.The final analyses included 77,153 postmenopausal women (2,004 Veterans). After adjustment, Veterans were no more likely than non-Veterans to report any VMS at baseline (relative risk [RR] 0.97, 95% confidence interval [CI] 0.90-1.04) or moderate to severe VMS (RR 1.03, 95% CI 0.89-1.18). Any VMS was associated with decreased HRQOL at Year 3, particularly among Veterans (mean difference range: Veterans -2.7 to -4.6, p-values < .001; non-Veterans -2.2 to -2.6, 95% CI -0.13 to -0.09, p values < .001). Baseline depression and obesity, but not smoking, amplified the negative association between VMS and HRQOL.Multicondition care models for postmenopausal Veteran and non-Veteran women are needed that incorporate management strategies for VMS, weight, and depression.

In Brief Objective: To determine the effects of lower doses of conjugated estrogens (CE) alone or in combination with medroxyprogesterone acetate (MPA) on body weight and to evaluate the influence of body mass index (BMI) on the effect of lower-dose CE or CE/MPA on vasomotor symptoms, vaginal atrophy, bone mineral density (BMD), endometrial safety, and side effects such as endometrial bleeding and breast pain. Design: In this large clinical trial [the Women's Health, Osteoporosis, Progestin, Estrogen (Women's HOPE) study], 2,673 healthy, postmenopausal women with intact uteri were randomized for 1 year of CE 0.625, CE 0.625/MPA 2.5, CE 0.45, CE 0.45/MPA 2.5, CE 0.45/MPA 1.5, CE 0.3, CE 0.3/MPA 1.5 (all doses mg/d), or placebo. Weight, BMI, number and severity of hot flushes, vaginal atrophy (as determined by the vaginal maturation index), bleeding profiles, breast pain, and endometrial biopsies were evaluated. A subset of 822 women was randomized into a 2-year substudy to evaluate changes in BMD with lower-dose CE or CE/MPA regimens. Results: After 1 year of treatment, a small but significant (P < 0.05) gain in body weight from baseline was observed in all arms of the study, the largest increase in body weight occurring in the placebo group [1.15 ± 0.21 (SE) kg]. Body mass index had no significant effect on changes from baseline for vasomotor symptoms, bleeding patterns, vaginal atrophy, BMD, endometrial safety, or breast pain when analyzed both by analysis of covariance with baseline BMI as covariate or when participants were grouped into BMI less than 25 kg/m2 and BMI of 25 kg/m2 or greater. In placebo-treated women, vaginal atrophy was significantly greater (P < 0.05) in women with a BMI less than 25 kg/m2 compared with a BMI of 25 kg/m2 or greater. Conclusions: Lower- and standard-dose regimens of CE or CE/MPA are not associated with greater weight gain than placebo. In addition, BMI does not seem to influence effects of these regimens on vasomotor symptoms, vaginal atrophy, bleeding profiles, BMD, endometrial safety, or breast pain. Lower- and standard-dose regimens of CE or CE/MPA are not associated with greater weight gain than placebo. Body mass index does not seem to influence effects of these regimens on vasomotor symptoms, vaginal atrophy, bleeding profiles, BMD, endometrial safety, or breast pain.

Cynthia A. Stuenkel, M.D., N.C.M.P., Margery L. S. Gass, M.D., N.C.M.P., JoAnn E. Manson, M.D., Dr.PH., N.C.M.P., Rogerio A. Lobo, M.D., Lubna Pal, M.B.B.S., M.R.C.O.G., M.Sc., N.C.M.P., Robert W. Rebar, M.D., and Janet E. Hall, M.D. a Clinical Professor of Medicine, Endocrinology and Metabolism, University of California, San Diego, California; b Executive Director, The North American Menopause Society, Consultant, Cleveland Clinic Center for Specialized Women's Health, Clinical Professor, Department of Reproductive Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio; c Professor of Medicine and the Michael and Lee Bell Professor of Women's Health, Harvard Medical School, Chief of Preventive Medicine, Co-Director, Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital, Boston, Massachusetts; d Professor, Department of Obstetrics and Gynecology, Columbia University, New York, New York; e Associate Professor, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, Director, Program for Polycystic Ovarian Syndrome, Director, Program for Reproductive Aging and Bone Health, New Haven, Connecticut; f Executive Director, American Society for Reproductive Medicine, Birmingham, Alabama; and g Professor, Department of Medicine, Harvard Medical School, Boston, Massachusetts

Menopausal hormone therapy (MHT) use induces alterations in circulating estrogens/estrogen metabolites, which may contribute to the altered risk of reproductive tract cancers among current users. Thus, the current study assessed associations between circulating estrogens/estrogen metabolites and ovarian and endometrial cancer risk among MHT users. We conducted a nested case–control study among postmenopausal women using MHT at baseline in the Women’s Health Initiative Observational Study (179 ovarian cancers, 396 controls; 230 endometrial cancers, 253 controls). Multivariable logistic regression was utilized to estimate odds ratios and 95% confidence intervals overall and by subtype. Estrogen/estrogen metabolite levels were not associated with overall or serous ovarian cancer risk, examined separately. However, unconjugated estradiol was positively associated with non-serous ovarian cancer risk [quintile 5 vs. quintile 1: 3.01 (1.17–7.73); p-trend = 0.03; p-het < 0.01]. Endometrial cancer risk was unrelated to estrogen/estrogen metabolite levels among women who took combined estrogen/progestin therapy (EPT). These findings provide novel evidence that may support a heterogeneous hormonal etiology across ovarian cancer subtypes. Circulating estrogens did not influence endometrial cancer risk among women with EPT-induced high-estrogen levels. Larger studies are needed to delineate the relationship between ovarian/endometrial cancer subtypes and estrogen levels in the context of MHT use.

Today, 42% of Americans use alternative nonprescription therapies to treat medical conditions; 46% of nonprescription alternative use for principal medical conditions is done without consulting either a medical doctor or a nonphysician practitioner of alternative therapy. Many nontraditional alternatives are used to treat the hot flashes and somatic complaints of menopause, for which options such as hormone replacement therapy and other prescription and over-the-counter drugs are also available. To date, no one agent treats all menopausal symptoms as effectively as estrogen. Selective estrogen-receptor modulators can help prevent osteoporosis but do not relieve menopausal symptoms. However, some women are unwilling or unable to take hormone replacement therapy, and some decide to discontinue therapy. Evidence supporting the use of some nonprescription alternatives for conditions related to menopause is limited. Patients need to be aware of the potential for drug interactions when these alternative therapies are used concomitantly with prescription drugs. The current evidence to support use of hormone replacement therapy, selective estrogen-receptor modulators, and nontraditional alternatives is reviewed here. (Am J Obstet Gynecol 2001;185:S47-56.)

Gass, Margery L.S. MD, FACOG, NCMP; Maki, Pauline M. PhD; Shifren, Jan L. MD, FACOG, NCMP; Schnatz, Peter F. DO, FACOG, FACP, NCMP; Kaunitz, Andrew M. MD, FACOG, NCMP; Shapiro, Marla MDCM, CCFP, MHSc, FRCP(C), FCFP, NCMP; Sievert, Lynnette Leidy BSN, PhD Author Information

This review summarizes and updates data presented at recent annual Southern Medical Association conferences on postmenopausal osteoporosis. As part of any osteoporosis treatment program, it is important to maintain adequate calcium and 25-hydroxyvitamin D levels either through diet or supplementation. Among the available pharmacologic therapies, the bisphosphonates alendronate and risedronate have demonstrated the most robust fracture risk reductions-approximately 40 to 50% reduction in vertebral fracture risk, 30 to 40% in nonvertebral fracture risk, and 40 to 60% in hip fracture risk. Ibandronate, a new bisphosphonate, has demonstrated efficacy in reducing vertebral fracture risk. Salmon calcitonin nasal spray and raloxifene demonstrated significant reductions in vertebral fracture risk in pivotal studies. Teriparatide significantly reduced vertebral and nonvertebral fracture risk. Drugs on the horizon include strontium ranelate, which has been shown to reduce vertebral and nonvertebral fracture risk, and zoledronic acid, an injectable bisphosphonate that increased bone density with once-yearly administration.

Gass, Margery L.S. MD, NCMP; Manson, JoAnn MD, DrPH, NCMP; Stuenkel, Cynthia MD, NCMP; Cosman, Felicia MD; Grodstein, Francine ScD; Jordan, V. Craig OBE, PhD, DSc, FMedSci; Karas, Richard MD, PhD; Kaunitz, Andrew M. MD; Maki, Pauline PhD; Schmidt, Peter J. MD; Shifren, Jan MD, NCMP; Utian, Wulf H. MD, PhD, DSc(Med) Author Information

Women’s military roles, exposures, and associated health outcomes have changed over time. However, mortality risk—within military generations or compared with non-Veteran women—has not been assessed. Using data from the Women’s Health Initiative (WHI), we examined all-cause and cause-specific mortality by Veteran status and military generation among older women. WHI participants (3,719 Veterans; 141,802 non-Veterans), followed for a mean of 15.2 years, were categorized into pre-Vietnam or Vietnam/after generations based on their birth cohort. We used cox proportional hazards models to examine the association between Veteran status and mortality by generation. After adjusting for sociodemographic characteristics and WHI study arm, all-cause mortality hazard rate ratios (HRs) for Veterans relative to non-Veterans were 1.16 (95% CI: 1.09–1.23) for pre-Vietnam and 1.16 (95% CI: 0.99–1.36) for Vietnam/after generations. With additional adjustment for health behaviors and risk factors, this excess mortality rate persisted for pre-Vietnam but attenuated for Vietnam/after generations. After further adjustment for medical morbidities, across both generations, Veterans and non-Veterans had similar all-cause mortality rates. Relative to non-Veterans, adjusting for sociodemographics and WHI study arm, pre-Vietnam generation Veterans had higher cancer, cardiovascular, and trauma-related morality rates; Vietnam/after generation Veterans had the highest trauma-related mortality rates (HR = 2.93, 1.64–5.23). Veterans’ higher all-cause mortality rates were limited to the pre-Vietnam generation, consistent with diminution of the healthy soldier effect over the life course. Mechanisms underlying Vietnam/after generation Veteran trauma-related mortality should be elucidated. Efforts to modify salient health risk behaviors specific to each military generation are needed.

Dual-outcome intention-to-treat hazard rate analyses have potential to complement single-outcome analyses for the evaluation of treatments or exposures in relation to multivariate time-to-response outcomes. Here we consider pairs formed from important clinical outcomes to obtain further insight into influences of menopausal hormone therapy on chronic disease. As part of the Women's Health Initiative, randomized, placebo-controlled hormone therapy trials of conjugated equine estrogens (CEE) among posthysterectomy participants and of these same estrogens plus medroxyprogesterone acetate (MPA) among participants with an intact uterus were carried out at 40 US clinical centers (1993-2016). These data provide the context for analyses covering the trial intervention periods and a nearly 20-year (median) cumulative duration of follow-up. The rates of multiple outcome pairs were significantly influenced by hormone therapy, especially over cumulative follow-up, providing potential clinical and mechanistic insights. For example, among women randomized to either regimen, hazard ratios for pairs defined by fracture during intervention followed by death from any cause were reduced and hazard ratios for pairs defined by gallbladder disease followed by death were increased, though these findings may primarily reflect single-outcome associations. In comparison, hazard ratios for diabetes followed by death were reduced with CEE but not with CEE + MPA, and those for hypertension followed by death were increased with CEE + MPA but not with CEE.

This article updates clinicians on the use of menopausal hormone therapy (HT) by reviewing key recommendations and observations from the North American Menopause Society's (NAMS) 2007 position statement on HT use in peri- and postmenopausal women and then summarizing and interpreting three new reports from the Women's Health Initiative released after the NAMS statement.

BackgroundClinical practice guidelines recommend use of fracture risk scores for screening and pharmacologic treatment decisions. The timing of occurrence of treatment-level (according to 2014 National Osteoporosis Foundation guidelines) or screening-level (according to 2011 US Preventive Services Task Force guidelines) fracture risk scores has not been estimated in postmenopausal women.MethodsWe conducted a retrospective competing risk analysis of new occurrence of treatment-level and screening-level fracture risk scores in postmenopausal women aged 50 years and older, prior to receipt of pharmacologic treatment and prior to first hip or clinical vertebral fracture.ResultsIn 54,280 postmenopausal women aged 50 to 64 years without a bone mineral density test, the time for 10% to develop a treatment-level FRAX score could not be estimated accurately because of rare incidence of treatment-level scores. In 6096 women who had FRAX scores calculated with bone mineral density, the estimated unadjusted time to treatment-level FRAX ranged from 7.6 years (95% confidence interval [CI], 6.6-8.7) for those aged 65 to 69, to 5.1 years (95% CI, 3.5-7.5) for those aged 75 to 79 at baseline. Of 17,967 women aged 50 to 64 with a screening-level FRAX at baseline, 100 (0.6%) experienced a hip or clinical vertebral fracture by age 65 years.ConclusionsPostmenopausal women with sub-threshold fracture risk scores at baseline were unlikely to develop a treatment-level FRAX score between ages 50 and 64 years. After age 65, the increased incidence of treatment-level fracture risk scores, osteoporosis, and major osteoporotic fracture supports more frequent consideration of FRAX and bone mineral density testing.

Abstract Objective: To assess the impact of discontinuing oral hormone therapy (HT) on sexual activity, vaginal symptoms, and sexual activity components among participants in the estrogen-progestin therapy (EPT) and estrogen therapy (ET) trial of the Women's Health Initiative. Methods: Surveys were sent postintervention to those who were still taking study pills and agreed to continue in the study when the trials were stopped. Comparisons between former HT and placebo users were accomplished with chi-square tests for categorical variables and t tests for continuous variables. Results: In all, 13,902 women with mean age at survey 69.9 years (EPT trial, women with intact uterus) and 71.7 years (ET trial, women with history of hysterectomy) responded. Prevalence of sexual activity postintervention was not significantly different between former EPT and placebo users (36.0% vs 34.2%; P = 0.37). Sexual activity of former ET users was 5.6% higher than placebo users (27.6% vs 22.0%; P = 0.001). The majority of sexually active women overall maintained orgasmic capacity and sexual satisfaction. Former EPT users were 10% to 12% more likely than former placebo users to report decreased desire, arousal, intercourse, climax, and satisfaction with sexual activity, and also increased dryness and dyspareunia upon discontinuing study drugs ( P &lt; 0.001). Former ET users were more likely than placebo users to report rare to no desire or arousal postintervention ( P &lt; 0.001). Conclusions: Postintervention ET trial participants formerly assigned to ET were significantly more likely to report sexual activity than those formerly assigned to placebo. Women who discontinued EPT were significantly more likely to report negative vaginal and sex-related effects.

to examine the association of parental longevity with healthy survival to age 90 years.this was a prospective study among a racially and ethnically diverse cohort of 22,735 postmenopausal women from the Women's Health Initiative recruited from 1993 to 1998 and followed through 2017. Women reported maternal and paternal ages at death and current age of alive parents. Parental survival categories were <70, 70-79 (reference), 80-89 and ≥90 years (longevity). Healthy ageing was defined as reaching age 90 without major chronic conditions (coronary heart disease, stroke, diabetes, cancer, or hip fracture) or physical limitations.women whose mothers survived to ≥90 years were more likely to attain healthy ageing (OR, 1.25; 95% CI, 1.11-1.42) and less likely to die before age 90 (OR, 0.75; 95% CI, 0.68-0.83). Women whose fathers survived to ≥90 years did not have significantly increased odds of healthy ageing but showed 21% (OR, 0.79; 95% CI, 0.70-0.90) decreased odds of death before age 90. Women whose mother and father both lived to 90 had the strongest odds of healthy ageing (OR, 1.38; 95% CI, 1.09-1.75) and decreased odds of death (OR, 0.68; 95% CI, 0.54-0.85). The proportion of healthy survivors was highest among women whose mother and father lived to 90 (28.6%), followed by those whose mother only lived to 90 (23.2%).parental longevity predicted healthy ageing in a national cohort of postmenopausal women, supporting the view that genetic, environmental, and behavioral factors transmitted across generations may influence ageing outcomes among offspring.

Most studies suggest that hysterectomies are more common in African American women than in other ethnic groups. To assess this ethnic surgical disparity in a novel way, our main goal was to determine whether admixture (the proportion of sub-Saharan African or European origin in individuals) is associated with hysterectomy frequency in African American women in the Women's Health Initiative.In this retrospective study, we used ancestry informative single nucleotide polymorphisms to estimate admixture proportions in >10,000 African American women from the Women's Health Initiative. Logistic regression models were used to assess the association between admixture and self-reported history of hysterectomy with and without controls for relevant covariates. Multinomial logistic regression models were used to assess the association between admixture and self-reported age of hysterectomy. We also considered other potential risk factors (adiposity, hypertension, and education) for hysterectomy accounting for admixture.African admixture was a strong risk factor after the adjustment for multiple covariates (odds ratio, 1.85; P < .0001). The admixture risk for hysterectomy was highest for those procedures that were performed in the 35-39 age range (odds ratio, 3.08; P < .0001) and least evident in oldest ages (≥45 years old). Our analyses also suggest that adiposity, hypertension, and education were associated independently with hysterectomy in this population group.These results suggest that higher African admixture is associated with higher frequencies of hysterectomy and that genetic studies that specifically target African American women and diseases that are associated with hysterectomy may be especially useful in understanding the pathogenesis and underlying cause of this disparity in health outcome.

The Women’s Health Initiative (WHI) was a placebo-controlled randomized study that investigated the benefits and risks of 2 menopausal hormone regimens in healthy normal postmenopausal women. The present report provides a comprehensive, integrated overview of findings from the intervention and extended postintervention phases of 2 WHI trials: one used conjugated equine estrogens (CEEs) plus medroxyprogesterone acetate (MPA), and the other used CEEs alone. Between 1993 and 1998, 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. Women with an intact uterus were randomized to receive a regimen of CEEs (0.625 mg/d) plus MPA (2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy were randomized to receive CEEs alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention phase of the CEEs plus MPA trial lasted a median of 5.6 years, and that of the CEEs alone trial lasted a median of 7.2 years with 13 years of cumulative follow-up until September 30, 2010. Primary efficacy and safety outcomes for both trials were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index of other health outcomes included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death. Benefits in the CEEs plus MPA intervention phase included decreased hip fractures, diabetes, and vasomotor symptoms. During the intervention phase in the CEEs plus MPA group, there were 196 CHD cases versus 159 for placebo (hazard ratio [HR], 1.18; 95% confidence interval [CI], 0.95–1.45), and 206 invasive breast cancer cases versus 155 for placebo (HR, 1.24; 95% CI, 1.01–1.53). Moreover, risks increased for stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence. Among women in the CEEs plus MPA group, most risks and benefits dissipated after intervention, but there was persisting elevation in risk of breast cancer (434 cases vs 323 for placebo; HR, 1.28; 95% CI, 1.11–1.48). During the intervention phase in the CEEs alone group, risks and benefits were more balanced; there were 204 CHD cases versus 222 cases for placebo (HR, 0.94; 95% CI, 0.78–1.14) and 104 cases of invasive breast cancer compared with 135 for placebo (HR, 0.79; 95% CI, 0.61–1.02). Moreover, during cumulative follow-up, 168 cases of breast cancer were diagnosed in the CEEs alone group compared with 216 for the placebo; the HR was 0.79, with a 95% CI of 0.65 to 0.97. Other outcomes in this group were similar to the CEEs plus MPA group. All-cause mortality was not affected with either regimen. Younger women (aged 50–59 years) in the CEEs alone group had more favorable results during the intervention phase than older women for all-cause mortality, myocardial infarction, and the global index. Compared with placebo, absolute risks of adverse events in the CEEs plus MPA group assessed using global index data were lower in younger women: women aged 50 to 69 years had 12 more adverse events per 10,000 person-years, whereas those aged 70 to 79 years had 38 more. In the CEEs alone group, women aged 50 to 59 years had 19 fewer adverse events per 10,000 person-years, and women aged 70 to 79 years had 51 more adverse events. In both trials, results of quality-of-life outcomes were mixed. These findings do not support the use of CEEs plus MPA or CEEs alone in postmenopausal women for prevention of chronic disease. However, hormonal treatment may be beneficial in generally healthy women during early menopause for management of moderate to severe menopausal symptoms.

Abstract Objective: The aim of the study was to examine the association of long-term oral bisphosphonate use, compared with short-term use, with fracture risk among postmenopausal women with breast cancer. Methods: We studied 887 postmenopausal women who were enrolled to the Women's Health Initiative from 1993 to 1998, diagnosed with breast cancer after enrollment, and reported current oral bisphosphonate use of 2 years or more on a medication inventory administered in 2008 to 2009. The outcome of any clinical fracture was ascertained by self-report on an annual study form; a subset of fractures was confirmed with medical records. Women were followed from completion of the medication inventory until 2014. The association between duration of bisphosphonate use reported on the medication inventory and fracture was estimated using multivariate Cox proportional hazards survival models that compared 4 to 7 years and 8 or more years of bisphosphonate use with 2 to 3 years of use. Results: On average, women were 76 years of age and were followed for 3.7 (SD 1.1) years. There were 142 clinical fractures. In the multivariate-adjusted analysis for fracture risk factors, 8 or more years of bisphosphonate use was associated with higher risk of fracture compared with 2 to 3 years of use (hazard ratio, 1.67 [95% CI, 1.06-2.62]). There was no significant association of 4 to 7 years of use with fracture. Conclusions: Bisphosphonate use of 8 or more years was associated with higher risk of any clinical fracture compared with 2 to 3 years of use. Our findings raise concern about potential harm or decreased effectiveness of long-term bisphosphonate use on fracture risk. The findings warrant confirmatory studies.

Physical activity and macronutrient intake, important contributors to energy balance, may be independently associated with female urinary incontinence (UI).We evaluated the association of baseline self-reported physical activity and macronutrient intake, via food frequency questionnaire, with incident UI subtypes after 3 years among 19 741 postmenopausal women in the Women's Health Initiative Observational Study. Odds ratios (ORs) for incident urgency, stress, and mixed UI were calculated using multivariable logistic regression.Women who reported total physical activity (metabolic equivalent task [MET]-hours/week) ≥30 versus <0.1 were 16% less likely to develop urgency UI (OR = 0.84; 95% CI 0.70, 1.00) and 34% less likely for mixed UI (OR = 0.66; 95% CI 0.46, 0.95), although linear trends were no longer statistically significant after adjusting for baseline weight and weight change (p trend = .15 and .16, respectively). The association between physical activity and incident stress UI was less consistent. Higher uncalibrated protein intake was associated with increased odds of incident urgency UI (≥19.4% vs <14.1% of energy intake OR = 1.14; 95% CI 0.99, 1.30; p trend = .02), while CIs were wide and included 1.0 for calibrated protein intake. Other macronutrients were not associated with urgency UI and macronutrient intake was not associated with incident stress or mixed UI (p trend > .05 for all).Among postmenopausal women, higher physical activity was associated with lower risk of incident urgency and mixed UI, but not stress UI, independent of baseline weight and weight change. Higher protein intake was associated with increased risk of urgency UI, but no associations were observed between other macronutrient and UI subtypes.

Women attending public seminars on the topic of menopause and hormone replacement therapy (HRT) were asked to complete questionnaires regarding their use of HRT. Of the 139 women who had used HRT, 110 were current users with an average age of 53.9 years (range 35–72) and an average duration of use of 5.4 years (28% < 1 year). Twenty-nine women with an average age of 58.6 years (range 46–80) had previously used HRT and discontinued it. Their average duration of use was 5.1 years (41% < 1 year). Forty-five percent of past users reported they felt better not using HRT. The remainder reported concerns about safety (52%), bloating and weight gain (40%), problems with bleeding (28%), and breast concerns (34%) including one breast cancer. Continued use of HRT was strongly associated with feeling better on HRT. Only 34% of past users felt better on HRT whereas 74% of current users felt better on HRT. The 5% of current users who felt worse on HRT were motivated to continue for reasons of vaginal dryness, osteoporosis, hot flushes, and cardiovascular protection. Hysterectomy was associated with initiation of HRT but was not associated with continued use of HRT. Continued use of HRT was not associated with difficulty of menopause, but it was associated with age of menopause. We conclude that women who have had a hysterectomy are more apt to initiate HRT and that those who feel better on HRT are most apt to continue using it.

Using data from the Women's Health Initiative Observational Study (WHI-OS), to determine the role of estrogen formulation, dose, route of delivery, and its combination with different progestogens on the risk for hypertension in the WHI-OS.After excluding women with diagnosed hypertension, receiving antihypertensive medication, presenting with elevated blood pressure ( ≥ 140/90), and those not taking menopausal hormone therapy at baseline, 19,986 women remained eligible for the analyses. Using hierarchal modeling, proportional hazard rate calculation, and linear and logistic regression analyses, we evaluated incident treated hypertension and mean systolic and diastolic blood pressure changes at 3 years. Multivariable models were adjusted for age, race/ethnicity, education, smoking, physical activity, body mass index, history of treated diabetes, history of prescription medicines for high cholesterol, alcohol intake, hysterectomy, and bilateral oophorectomy.At 3 years, and compared with conjugated estrogens (CEE) with or without a progestin, the odds for newly treated hypertension were lower in women who used transdermal estradiol (0.85, 95% CI, 0.73-1.00) or oral estrone sulphate dominant preparations (0.83, 0.72-0.96). The odds of incident treated hypertension after 3 years did not vary according to dose of estrogen. The mean measured systolic blood pressure was minimally lower with transdermal estradiol (-1.20, 95% CI, -1.97 to -0.44) mm Hg and other oral Estrone dominant preparations (-0.83, 95% CI, -1.51 to -0.16) mm Hg at 3 years. For a given estrogen type, the magnitudes of the hazard ratio were similar for estrogen-alone compared with estrogen plus a progestogen. For women 10 or more years past menopause when they entered, the HR for incident self-reported treated hypertension was 1.26 (95% CI, 1.09-1.46) with higher dose CEE compared with 0.625 mg CEE. It was 0.87 (95% CI, 0.68-1.13) when given to women who were < 10 years after menopause when they entered the WHI-OS.The risk of treated hypertension differed by formulation, dose, and years since menopause.Video Summary : http://links.lww.com/MENO/A795 .

Reanalysis of the Women's Health Initiative (WHI) data regarding prior oral contraceptive use and the effect on cardiovascular disease reveals no evidence of a delayed benefit or harm. The WHI database was not designed to answer this question.

To determine whether statin treatment is associated with increased risk of haemorrhagic stroke (HS) in older women. A secondary objective was to evaluate HS risk in users of combined statin and antiplatelet treatment.Observational study: secondary data analysis from the Women's Health Initiative (WHI) clinical trials.Women were recruited from 40 participating sites.Cohort of 68,132 women followed through 2005 (parent study) and for an additional 5 years in the extension study.Statin use was assessed at baseline and at follow-up visits (1, 3, 6 and 9 years). Women brought medications in original containers for inventory. Strokes were ascertained semiannually and centrally adjudicated. Risk of HS by statin use (time-varying covariate, with the 'no use' category as the referent) was estimated from Cox proportional hazard regression models adjusted for age (model 1); risk factors for HS (model 2); and possible confounders by indication (model 3). Prespecified subgroup analyses were conducted by use of antiplatelet medications.Final models included 67,882 women (mean age, 63±7 years). Over a mean follow-up of 12 years, incidence rates of HS were 6.4/10,000 person-years among statin users and 5.0/10,000 person-years among non-users (p=0.11). The unadjusted risk of HS in statin users was 1.21 (CI 0.96 to 1.53); after adjusting for age and HS risk factors the HR was 0.98 (CI 0.76 to 1.26). Risk of HS was higher among women on statins and antiplatelet agents versus women on antiplatelet medications alone (HR=1.59; CI 1.03 to 2.47); p for interaction=0.011.This retrospective analysis did not show an association between statin use and HS risk among older women. HS risk was higher among women taking statins with antiplatelet agents. These findings warrant further investigation, given potential implications for clinical decision-making.

Previous studies have failed to document positive effects of a low-fat diet on the risk of colorectal cancer. The risk was examined in relation to the dietary pattern in the Women’s Health Initiative Dietary Modification Trial. This randomized, controlled trial enrolled 48,835 postmenopausal women 50 to 79 years of age seen at 40 clinical centers throughout the United States in the years 1993–1998. The interventional diet called for at least 5 daily servings of vegetables and fruits and at least 6 servings of grains with the goal of lowering total fat to 20% of energy intake. An intensive behavioral intervention entailed 18 group sessions in the first year and, subsequently, quarterly sessions led by specially trained and certified nutritionists. Dietary goals were individualized on the basis of height. Motivational interviewing was part of the program. Forty percent of participants were assigned to the intervention and 60% to a comparison group of women who were given dietary guidelines but were not asked to change their diets. The 2 groups had similar risk profiles for colorectal cancer. During a mean follow-up interval of 8.1 years, the reduction in percentage of energy from fat was approximately 70% of that planned. Fewer than one third of women met the goal after 12 months and only 14% at year 6. Consumption of saturated fat did decline, and women in the intervention group did eat more fruits, vegetables, and grains. Dietary intake of folate and plasma carotenoid levels increased significantly, whereas serum cholesterol levels declined. Rates of invasive colorectal cancer were 0.13% per year in the intervention group and 0.12% in the comparison group. The hazard ratio (HR) was 1.08, with a 95% confidence interval (CI) of 0.90–1.29. The cumulative hazard of colorectal cancer was very similar in the 2 management groups, and no time trend for invasive colorectal cancer was evident. Outcomes were similar in the 2 groups, and there were no significant differences in total cancer incidence, total cancer mortality, or total mortality. Tumor characteristics were similar in the 2 groups. Annualized incidence rates of self-reported colonic polyps or adenomas were lower in the intervention group (HR, 0.91; 95% CI, 0.87–0.95). The risk of colon cancer increased with advancing age, but intervention did not interact with age at baseline. This large trial gave no evidence that, when taken by midlife to late-life postmenopausal women, a low-fat diet decreases the risk of colorectal cancer over 8 years of observation.