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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 were10 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.

Objective To assess the utility of cardiovascular disease (CVD) risk scores compared to age or years since menopause for prediction of CVD events in the WHI clinical trials. Methods Briefly, in the randomized clinical trial 27,347 postmenopausal women age 50 to 79 years entered from 1993 to 1998. Women with a uterus (16,608) were randomized to receive daily oral conjugated equine estrogen (CEE) (0.625 mg) plus medroxyprogesterone acetate (2.5 mg) (5.7 years or placebo), while women with a hysterectomy (10,739) were randomized to receive daily oral CEE (0.625 mg) alone or placebo (7.2 y). CVD risk scores were assessed at baseline and CVD events were adjudicated throughout the follow-up period to the end of the main study phase and to the end of cumulative follow-up. The median follow-up time after the start of the randomized clinical trial to the end of the main study phase was 8.2 years. The median follow-up time to the end of cumulative follow-up was 17.6 years. We compared The American Heart Association/American College of Cardiology (AHA/ACC) and Framingham Heart Study risk scores to age or years since menopause all obtained at baseline to predict subsequent CVD events. The absolute event rates, hazard ratios, and C-statistics (Uno Concordance from Cox proportional models) were compared. Results Overall, the hazard ratios for CVD events were highest with calculated CVD scores calculated at trial onset both at the end of the main study (ranging from 2.02 to 10.8 for Q2-Q5, compared to Q1) and at cumulative follow-up (ranging from 1.76 to 8.86 for Q2-Q5, compared to Q1). While older age and years since menopause at baseline were also associated with higher CVD event rates, better risk prediction was accomplished by using CVD risk scores. The Framingham Heart Study BMI score had the highest C-statistic at the end of the main study (0.711) and after 17.6 years through the end of follow-up (0.689). Conclusions CVD risk scores can help identify postmenopausal women at higher risk for CVD beyond age or time since menopause. Risk scoring that better estimates vascular aging may facilitate CVD risk prevention. When performed prior to initiation of menopausal hormone therapy, scores can better inform HT risk/benefit discussions.

This study evaluated whether vasomotor symptom (VMS) severity and number of moderate/severe menopausal symptoms (nMS) were associated with health outcomes, and whether calcium and vitamin D (CaD) modified the risks.The Women's Health Initiative CaD study was a double blind, randomized, placebo-controlled trial, which tested 400 IU of 25-hydroxyvitamin-D and 1,000 mg of calcium per day in women aged 50 to 79 years. This study included 20,050 women (median follow-up of 7 y). The outcomes included hip fracture, colorectal cancer, invasive breast cancer, all-cause mortality, coronary heart disease, stroke, cardiovascular death, and total cardiovascular disease (CVD). MS included: hot flashes, night sweats, dizziness, heart racing, tremors, feeling restless, feeling tired, difficulty concentrating, forgetfulness, mood swings, vaginal dryness, breast tenderness, migraine, and waking up several times at night. Associations between VMS severity and nMS with outcomes were tested.No association between VMS severity and any outcome were found. In contrast, nMS was associated with higher stroke (hazard ratio [HR] 1.40 95% confidence interval [CI] 1.04-1.89 for ≥ 2 MS vs none; HR 1.20 95% CI 0.89-1.63 for 1 MS vs none, P trend = 0.03) and total CVD (HR 1.35, 95% CI, 1.18-1.54 for ≥ 2 MS vs none; HR 0.99, 95% CI, 0.87-1.14 for 1 MS vs none P trend0.001). CaD did not modify any association.Severity of VMS was not associated with any outcome. Having ≥2 moderate or severe MS was associated with an increased risk for CVD. The number of moderate/severe MS may be a marker for higher CVD risk. : Video Summary:http://links.lww.com/MENO/A669.Video Summary:http://links.lww.com/MENO/A669.

OBJECTIVE The Women's Health Initiative (WHI) assessed oral conjugated equine estrogens (CEE) taken with or without medroxyprogesterone acetate (MPA) for prevention of chronic disease in postmenopausal women aged 50-79 years. METHODS Women with an intact uterus (n = 16,608) were randomized to CEE+ MPA therapy or placebo for a median of 5.6 years; women with hysterectomy (n = 10,739) were randomized to CEE-alone therapy or placebo for a median of 7.2 years. Both cohorts have been followed for 18 years. RESULTS In the overall study population (mean age, 63 y), neither estrogen-progestin therapy (EPT) nor estrogen-only therapy prevented coronary heart disease or led to a favorable balance of chronic-disease benefits and risks. Subgroup analyses, however, suggest that timing of hormone therapy (HT) initiation influences the relation between HT and coronary risk, as well as its overall benefit-risk balance, with more favorable effects in women who are younger (age < 60 year) or recently menopausal (within 10 year) than in women who are older or further past the menopausal transition. In younger women who entered the trial of estrogen-only therapy with oophorectomy, the intervention was associated with a significant 32% reduction in all-cause mortality over long-term follow-up. CONCLUSIONS WHI findings indicate important differences in HT-related clinical outcomes by age and time since menopause. Systemic HT has an acceptable safety profile for menopause management when initiated among healthy women who are younger (or recently menopausal) and not at elevated risk for cardiovascular disease or breast cancer. Initiation of treatment in older women who are distant from menopause onset, however, should be avoided. Other HT formulations and routes of delivery warrant further study.(WHI clinicaltrials.gov identifier: NCT00000611).

Author(s): Shikany, James M; Manson, JoAnn E; Shadyab, Aladdin H; Garcia, Lorena; Lewis, Cora E; Neuhouser, Marian L; Tinker, Lesley F; Beasley, Jeannette M; Beresford, Shirley AA; Zaslavsky, Oleg; Vitolins, Mara Z; Sealy-Jefferson, Shawnita; Bae, Sejong | Abstract: ObjectiveThis analysis examined whether specific social, physical, and financial factors were associated with diet quality among older, community-dwelling women.MethodsThis cross-sectional analysis was conducted in a subset of 6,094 community-dwelling Women's Health Initiative participants who completed a food frequency questionnaire, administered from 2012 to 2013, and a self-administered supplemental questionnaire, administered approximately 1 year later. The supplemental questionnaire included five questions assessing social, physical, and financial factors related to eating. Diet quality was assessed with the Healthy Eating Index-2010 (HEI-2010; range of 0-100; higher score indicates a higher quality diet). The total HEI-2010 score was calculated by summing individual scores representing the intake of nine adequacy components (beneficial food groups) and three moderation components (food groups to limit). Associations of responses to the five questions on the supplemental questionnaire with HEI-2010 scores were examined with multiple linear regression, adjusting for relevant covariates.ResultsMean ± standard deviation age of participants was 78.8 ± 6.7 years. Reporting eating fewer than two meals per day, having dental or other mouth problems causing problems with eating, and not always being able to shop, cook, or feed oneself were associated with statistically significantly lower HEI-2010 scores, compared with those not reporting these issues, after multivariable adjustment: 5.37, 2.98, and 2.39 lower scores, respectively (all P values l0.0001). Reporting eating alone most of the time and not always having enough money to buy food were not associated with HEI-2010 scores.ConclusionsAmong older, community-dwelling women, eating fewer than two meals per day, dental and other mouth problems, and diminished ability to shop for food, prepare meals, and feed oneself were associated with lower diet quality. These are potential targets for interventions to improve diet quality in older women. : Video Summary:http://links.lww.com/MENO/A561.

Objective: The aim of the study was to propose a unifying theory for the role of estrogen in postmenopausal women through examples in basic science, randomized controlled trials, observational studies, and clinical practice. Methods: Review and evaluation of the literature relating to estrogen. Discussion: The role of hormone therapy and ubiquitous estrogen receptors after reproductive senescence gains insight from basic science models. Observational studies and individualized patient care in clinical practice may show outcomes that are not reproduced in randomized clinical trials. The understanding gained from the timing hypothesis for atherosclerosis, the critical window theory in neurosciences, randomized controlled trials, and numerous genomic and nongenomic actions of estrogen discovered in basic science provides new explanations to clinical challenges that practitioners face. Consequences of a hypo-estrogenemic duration in women's lives are poorly understood. The Study of Women Across the Nation suggests its magnitude is greater than was previously acknowledged. We propose that the healthy user bias was the result of surgical treatment (hysterectomy with oophorectomy) for many gynecological maladies followed by pharmacological and physiological doses of estrogen to optimize patient quality of life. The past decade of research has begun to demonstrate the role of estrogen in homeostasis. Conclusions: The theory of eu-estrogenemia provides a robust framework to unify the timing hypothesis, critical window theory, randomized controlled trials, the basic science of estrogen receptors, and clinical observations of patients over the past five decades.

Data in humans and nonhuman primates have suggested a possible synergistic effect of vitamin D and calcium (CaD) and estrogen on the cardiovascular disease (CVD) risk factors. Using randomized trial data we explored whether the effect of menopausal hormone therapy (HT) on CVD events is modified by CaD supplementation.A prospective, randomized, double-blind, placebo-controlled trial was implemented among postmenopausal women in the Women's Health Initiative. A total of 27,347 women were randomized to the HT trials (0.625 mg/d of conjugated equine estrogens [CEE] alone for women without a uterus vs placebo; or 0.625 mg of CEE in addition to 2.5 mg of medroxyprogesterone acetate daily [CEE + MPA] for women with a uterus vs placebo). After 1 year, 16,089 women in the HT trial were randomized to the CaD trial and received either 1,000 mg of elemental calcium carbonate and 400 IU of vitamin D3 daily or placebo. The mean (SD) duration of follow-up after CaD randomization was 6.2 (1.3) years for the CEE trial and 4.6 (1.1) years for the CEE + MPA trial. CVD and venous thromboembolism events evaluated in this subgroup analysis included coronary heart disease, stroke, pulmonary embolism, all-cause mortality, plus select secondary endpoints (total myocardial infarction, coronary revascularization, deep venous thrombosis, cardiovascular death, and all CVD events). Time-to-event methods were used and models were fit with a Cox proportional hazards regression model.In the CEE trial, CaD significantly modified the effect of CEE on stroke (P interaction = 0.04). In the CaD-placebo group, CEE's effect on stroke was harmful (hazard ratio [95% confidence interval] = 2.19[1.34-3.58]); however, it was neutral in the CaD-supplement group (hazard ratio [95% confidence interval] = 1.07[0.66-1.73]). We did not observe significant CEE-CaD interactions for coronary heart disease, total CVD events, or any of the remaining endpoints. In the CEE + MPA trial, there was no evidence that the effect of CEE + MPA on any of CVD endpoints was modified by CaD supplementation.CaD did not consistently modify the effect of CEE therapy or CEE + MPA therapy on CVD events. However, the increased risk of stroke due to CEE therapy appears to be mitigated by CaD supplementation. In contrast, CaD supplementation did not influence the risk of stroke due to CEE + MPA.

Previous studies have shown social support to be inversely associated with cardiovascular disease (CVD) in men, whereas fewer studies have assessed the relationship in women. The purpose of this study was to evaluate the relationship between perceived social support and cardiovascular outcomes among postmenopausal women enrolled in the Women's Health Initiative Observational Study.We examined the relationships between perceived social support and (1) incident coronary heart disease (CHD), (2) total CVD, and (3) all-cause mortality. Participants were Women's Health Initiative Observational Study women, ages 50 to 79 years, enrolled between 1993 and 1998 and followed for up to 10.8 years. Social support was ascertained at baseline via nine questions measuring the following functional support components: emotional/informational, tangible, positive social interaction, and affectionate support.Among women with prior CVD (n = 17,351) and no prior CVD (n = 73,421), unadjusted hazard ratios ranged from 0.83 to 0.93 per standard deviation increment of social support. Adjustment for potential confounders, such as smoking and physical activity levels, eliminated the statistical significance of the associations with CHD and CVD. However, for all-cause mortality and among women free of baseline CVD, the association was modest but remained statistically significant after this adjustment (hazard ratio = 0.95 [95% confidence interval, 0.91-0.98]). No statistically significant association was observed among women with a history of CVD.After controlling for potential confounding variables, higher perceived social support is not associated with incident CHD or CVD. However, among women free of CVD at baseline, perceived social support is associated with a slightly lower risk of all-cause mortality.

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

To determine the association between use of vaginal estrogen and risk of a global index event (GIE), defined as time to first occurrence of coronary heart disease (CHD), invasive breast cancer, stroke, pulmonary embolism, hip fracture, colorectal cancer, endometrial cancer, or death from any cause.For this prospective observational cohort study, we used data from participants of the Women's Health Initiative Observational Study, who were recruited at 40 US clinical centers, aged 50 to 79 years at baseline and did not use systemic estrogen therapy during follow-up (n = 45,663, median follow-up 7.2 years). We collected data regarding incident CHD, invasive breast cancer, stroke, pulmonary embolism, hip fracture, colorectal cancer, endometrial cancer, death, and self-reported use of vaginal estrogen (cream, tablet). We used Cox proportional-hazards regression models to adjust for covariates.Among women with an intact uterus, the risks of stroke, invasive breast cancer, colorectal cancer, endometrial cancer, and pulmonary embolism/deep vein thrombosis were not significantly different between vaginal estrogen users and nonusers, whereas the risks of CHD, fracture, all-cause mortality, and GIE were lower in users than in nonusers (GIE adjusted hazard ratio 0.68, 95% confidence interval 0.55-0.86). Among hysterectomized women, the risks of each of the individual GIE components and of the overall GIE were not significantly different in users versus nonusers of vaginal estrogen (GIE adjusted hazard ratio 0.94, 95% confidence interval 0.70-1.26).The risks of cardiovascular disease and cancer were not elevated among postmenopausal women using vaginal estrogens, providing reassurance about the safety of treatment.

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.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.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.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.

The aim of the study was to understand the association between women's reproductive history and their risk of developing type 2 diabetes. We hypothesized that characteristics signifying lower cumulative endogenous estrogen exposure would be associated with increased risk.Prospective cohort analysis of 124,379 postmenopausal women aged 50 to 79 years from the Women's Health Initiative (WHI). We determined age of menarche and final menstrual period, and history of irregular menses from questionnaires at baseline, and calculated reproductive length from age of menarche and final menstrual period. Presence of new onset type 2 diabetes was from self-report. Using multivariable Cox proportional hazards models, we assessed associations between reproductive variables and incidence of type 2 diabetes.In age-adjusted models, women with the shortest (30 y) reproductive periods had a 37% (95% CI, 30-45) greater risk of developing type 2 diabetes than women with medium-length reproductive periods (36-40 y). Women with the longest (45+ y) reproductive periods had a 23% (95% CI, 12-37) higher risk than women with medium-length periods. These associations were attenuated after full adjustment (HR 1.07 [1.01, 1.14] for shortest and HR 1.09 [0.99, 1.22] for longest, compared with medium duration). Those with a final menstrual period before age 45 and after age 55 had an increased risk of diabetes (HR 1.04; 95% CI, 0.99-1.09 and HR 1.08; 95% CI, 1.01-1.14, respectively) compared to those with age of final menstrual period between 46 and 55 years. Timing of menarche and cycle regularity was not associated with risk after full adjustment.Reproductive history may be associated with type 2 diabetes risk. Women with shorter and longer reproductive periods may benefit from lifestyle counseling to prevent type 2 diabetes.

Objective: In the years after the 2002 publication of results from the Women's Health Initiative study, there has been a reluctance to prescribe hormone therapy to symptomatic postmenopausal women and confusion over its duration and method of prescription. The main concerns are the risks of cardiovascular events and breast cancer. However, local vaginal estrogen (VE) may provide benefits without systemic effects. Methods: This study investigates the use and effects of VE on quality of life and urogenital morbidity among women who stopped hormone therapy after the Women's Health Initiative and compares them with women who continued hormone therapy. Three groups were compared: group 1, women who have remained on HT/ET; group 2, women who have resumed HT/ET after stopping for at least 6 months, and group 3, women who have stopped HT/ET and have not resumed. Results: Overall, ever use and present use of VE were most prevalent in women who reported dyspareunia (ever, P = 0.003; present, P = 0.005) and vaginal dryness (ever, P = 0.001; present, P = 0.004). VE use was significantly more probable for women in group 3 than for women in the other groups (group 3 [3.5%] vs group 1 [17.7%] and group 2 [16.7%]; P = 0.002). Women in group 3 who used VE reported significantly higher sexual quality of life (using the sexual domain of the Utian Quality of Life Scale) compared with women in group 3 who did not use VE (P = 0.007). There was no difference in the incidence of urinary tract infections between the three groups (group 1, 22.9%; group 2, 26.3%; group 3, 25.5%). The percentage of women who were either married or living in a marriage-like relationship did not differ between the three groups (group 1, 68.4%; group 2, 78.6%; group 3, 78.8%). Conclusions: Women who report dyspareunia and vaginal dryness are more likely to use VE. Women who do not use systemic therapy but use VE score significantly higher on the sexual quality-of-life scale than women not using VE.

Objective This study aims to estimate the effects of bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy and estrogen therapy on vaginal prolapse. Methods A retrospective analysis of the Women's Health Initiative estrogen-alone trial was performed. Women who retained their ovaries were compared with women who had BSO at the time of hysterectomy for the presence of cystocele or rectocele at entry into the study. Based on BSO and hormone therapy (HT) status, participants were categorized into groups. We hypothesized that BSO and prolonged hypoestrogenemia may be associated with an increased risk of prolapse. Univariate and multivariate analyses were used to determine the effects of BSO and HT status on cystocele and rectocele. Results Of 10,739 participants in the estrogen-alone trial, 8,879 women were included in the analysis. Older age, higher parity, higher body mass index, higher waist-to-hip ratio, and non-African-American race/ethnicity were associated with increased odds of developing cystocele or rectocele. Women who retained their ovaries had higher rates of cystocele or rectocele at screening (39%) compared with all women who had BSO (31-36%; odds ratio, 1.18; 95% CI, 1.04-1.33). After controlling for multiple variables, our analysis showed that women who retained their ovaries had higher odds of developing cystocele or rectocele compared with women who had BSO and no subsequent HT (odds ratio, 1.23; 95% CI, 1.07-1.41). All other comparisons were nonsignificant. Conclusions BSO at the time of hysterectomy is not associated with increased risk of cystocele or rectocele. BSO and no subsequent HT may even have a protective effect against cystocele or rectocele.

The author considers hypothetical comparisons between oral conjugated equine estrogens and transdermal estradiol and between oral medroxyprogesterone acetate and oral micronized progesterone for their effects on four primary outcomes of the Women's Health Initiative (WHI): cardiovascular disease risk, cerebrovascular disease risk, venous thromboembolism risk, and breast cancer risk. Although the discussion in this article focuses on transdermal estradiol delivered through patches, gels, or lotions, it could be broadened to include all forms of nonoral estrogen administration. After a brief review of the WHI and a survey of the relevant literature in which the safety of these various hormone therapies is assessed or compared, the author uses statistical methods to ascertain the attributable risk of venous thromboembolism for transdermal estradiol versus oral hormone therapy and imputes those risks into the WHI primary outcomes.

OBJECTIVE After we demonstrated a substantial drop in postmenopausal hormone therapy (HT) in France after 2002, we sought to compare health characteristics assessed before menopause and reasons for beginning treatment among women who started postmenopausal HT before and after this year. METHODS Among participants of the GAZEL (GAZ and ELectricite) cohort of employees of the French national power company, we studied 1,229 women who reached menopause before 2002 and 562 women who reached menopause after 2002. We analyzed HT use among these newly postmenopausal women before and after 2002 and its relations to self-rated health, simple and troublesome hot flushes, and various other symptoms before menopause. RESULTS After 2002, compared with before 2002, women starting HT were more likely to have reported troublesome hot flushes before menopause (odds ratio, 2.3; 95% CI, 1.0-5.4). The groups of new HT users did not differ significantly except for health characteristics. Significantly higher proportions of women starting HT reported using it for hot flushes (68.1% vs 52.9%, P = 0.02) and sleep disorders (11.1% vs 2.8%, P = 0.001) and a significantly lower proportion of women starting HT reported using it for osteoporosis prevention (12.5% vs 43.9%, P < 0.001) after 2002 than before 2002. CONCLUSIONS After 2002, HT tended to be prescribed for more severe hot flushes, but almost one third of prescriptions were still written for reasons not linked to hot flushes. Doctors seem to be following recommendations to not use HT as a first-line treatment of osteoporosis.

Research comparing hormone therapy (HT) doses, regimens, and routes of delivery in relation to cardiovascular disease (CVD) outcomes has been limited. This study directly compared different estrogen doses, routes of delivery, and HT formulations in postmenopausal women in relation to the risk of coronary heart disease (CHD), stroke, CVD mortality, total CVD, and all-cause mortality.The Women's Health Initiative Observational Study is a multicenter prospective cohort study that was conducted at 40 US sites. Analyses included 93,676 postmenopausal women aged 50 to 79 years at study entry who were recruited from September 1994 to December 1998, with annual follow-up through August 14, 2009.The mean follow-up was 10.4 years. In direct comparisons, oral estradiol was associated with lower hazard ratios (HRs) for stroke than oral conjugated equine estrogens (CEE; HR, 0.64; 95% CI, 0.40-1.02), but statistical power was limited. Similarly, transdermal estradiol was associated with a moderate but nonsignificantly lower risk of CHD compared with oral CEE (HR, 0.63; 95% CI, 0.37-1.06). For other outcomes, comparisons revealed no appreciable differences by estrogen doses, formulations, or routes of delivery. Absolute risks of CVD events and all-cause mortality were markedly lower in younger women compared with older women.In direct comparisons, various HT doses and regimens are associated with similar rates of cardiovascular events and all-cause mortality. However, oral estradiol may be associated with a lower risk of stroke, and transdermal estradiol may be associated with a lower risk of CHD, compared with conventional-dose oral CEE. Additional research is needed to confirm these hypotheses.

This study aims to test the added value of calcium and vitamin D (CaD) in fracture prevention among women taking postmenopausal hormone therapy (HT).This is a prospective, partial-factorial, randomized, controlled, double-blind trial among Women's Health Initiative postmenopausal participants aged 50 to 79 years at 40 centers in the United States with a mean follow-up of 7.2 years. A total of 27,347 women were randomized to HT (0.625 mg of conjugated estrogens alone, or 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate daily), and 36,282 women were randomized to 1,000 mg of elemental calcium (carbonate) plus 400 IU of vitamin D3 daily, each compared with placebo. A total of 16,089 women participated in both arms. The predefined outcomes were adjudicated hip fractures and measured bone mineral density.Interaction between HT and CaD on hip fracture (P interaction = 0.01) was shown. The effect of CaD was stronger among women assigned to HT (hazard ratio [HR], 0.59; 95% CI, 0.38-0.93) than among women assigned to placebo (HR, 1.20; 95% CI, 0.85-1.69). The effect of HT on hip fracture was stronger among women assigned to active CaD (HR, 0.43; 95% CI, 0.28-0.66) than among women assigned to placebo (HR, 0.87; 95% CI, 0.60-1.26). CaD supplementation enhanced the antifracture effect of HT at all levels of personal calcium intake. There was no interaction between HT and CaD on change in hip or spine bone mineral density.Postmenopausal women at normal risk for hip fracture who are on CaD supplementation experience significantly reduced incident hip fractures beyond HT alone at all levels of personal baseline total calcium intake.

International audience; This study aims to investigate venous thromboembolism (VTE) risk in relation to age at menopause, age at menarche, parity, bilateral oophorectomy, and time since menopause, as well as any interaction with randomized hormone therapy (HT) assignment, among postmenopausal women. Using pooled data from the Women's Health Initiative HT clinical trials including 27,035 postmenopausal women aged 50 to 79 years who had no history of VTE, we assessed the risk of VTE in relation to age at menopause, age at menarche, parity, bilateral oophorectomy, and time since menopause by Cox proportional hazards models. Linear trends, quadratic relationships, and interactions of reproductive life characteristics with HT on VTE risk were systematically tested. During follow-up, 426 women reported a first VTE, including 294 non-procedure-related events. No apparent interaction of reproductive life characteristics with HT assignment on VTE risk was detected, and there was not a significant association between VTE and age at menarche, age at menopause, parity, oophorectomy, or time since menopause. However, analyses restricted to non-procedure-related VTE showed a U-shaped relationship between age at menopause and thrombotic risk that persisted after multivariable analysis (P < 0.01). Compared with women aged 40 to 49 years at menopause, those who had early menopause (age 55 y) had a significantly increased VTE risk (hazard ratio [95% CI]: 1.8 [1.2-2.7] and 1.5 [1.0-2.4], respectively). Reproductive life characteristics have little association with VTE and do not seem to influence the effect of HT on thrombotic risk among postmenopausal women. Nevertheless, early and late onset of menopause might be newly identified risk factors for non-procedure-related VTE.

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

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).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.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 (P0.001). 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 (P0.001). 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).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.

The aim of this study was to examine the association between fracture and pelvic organ prolapse (POP) in postmenopausal women enrolled in the Women's Health Initiative Estrogen Plus Progestin trial.POP was assessed as cystocele, rectocele, or uterine prolapse and was graded as either "absent to mild" or "moderate to severe." Cox proportional hazard analyses (adjusting for age, body mass index, race, asthma, emphysema, thyroid disease, family history of fracture, regular menses, age at menopause, nulliparity, history of hormone therapy [HT], history of falls, socioeconomic status, calcium, and vitamin D supplementation and physical activity) explored the relationships between moderate to severe POP and incident bone fractures.Moderate- to severe-grade POP was identified in almost 8% of women (n = 1,192). During a follow-up duration of 7.41 (2.18) years (mean [SD]), 2,156 incident fractures were observed; the most common fracture site was the lower arm (n = 615; 28.51%) followed by the hip (n = 205; 9.51%). Adjusted analyses confirmed moderate to severe POP (of any type) as an independent risk factor for incident hip fractures (hazard ratio [HR], 1.83; 95% CI, 1.16-2.89; P = 0.010). On analyses stratified by assigned treatment (HT vs placebo), moderate to severe rectocele emerged as an independent predictor of incident spine (HR, 2.61; 95% CI, 1.04-6.56; P = 0.042) and lower arm fractures (HR, 1.87; 95% CI, 1.06-3.29; P = 0.030) in the placebo group.We identify moderate to severe POP (any type) in postmenopausal women as a risk factor for hip fracture; moderate to severe rectocele holds an additional risk of spine and lower arm fractures in women not taking HT.

The current evaluation of the benefit/risk ratio associated with menopausal hormone therapy (MHT) use is largely based on clinical trials which investigated the effects of oral treatments. Would MHT with transdermal estrogens be associated with a more favourable benefit/risk ratio? We reviewed the available epidemiologic evidence on that question. Epidemiologic studies were considered if they provided risk estimates of conditions which carry an important weight among menopausal women, and for which epidemiologic evidence of a possible link with MHT use is convincing: cardiovascular diseases, breast cancer, diabetes, colorectal cancer and hip fracture. We did not include studies with only surrogate measures. We found that the available information on the potential impact of the route of administration of MHT on the risk of our selected outcomes is limited. To date, epidemiologic data suggest that it has no impact on the risk of breast cancer and hip fracture. Results on the risk of coronary heart disease and colorectal cancer are inconsistent. Studies on stroke and diabetes risk are too few to allow meaningful conclusions. There is a suggestion that transdermal MHT may be less deleterious than oral MHT regarding venous thromboembolism which needs to be confirmed. The issue of the route of administration of MHT should remain an active area of research as part of an attempt to identify treatment modalities that would have the least potential for exerting adverse effects.

Coronary artery calcified plaque is a marker for atheromatous plaque burden and predicts future risk of cardiovascular events. The relationship between calcium plus vitamin D (calcium/D) supplementation and coronary artery calcium (CAC) has not been previously assessed in a randomized trial setting. We compared CAC scores after trial completion between women randomized to calcium/vitamin D supplementation and women randomized to placebo.In an ancillary substudy of women randomized to calcium carbonate (1,000 mg of elemental calcium daily) plus vitamin D3 (400 IU daily) or placebo, nested within the Women's Health Initiative trial of estrogen among women who underwent hysterectomy, we measured CAC with cardiac CT in 754 women aged 50 to 59 years at randomization. Imaging for CAC was performed at 28 of 40 centers after a mean of 7 years of treatment, and scans were read centrally. CAC scores were measured by a central reading center with masking to randomization assignments.Posttrial CAC measurements were similar in women randomized to calcium/D supplementation and those receiving placebo. The mean CAC score was 91.6 for women receiving calcium/D and 100.5 for women receiving placebo (rank test P value = 0.74). After adjustment for coronary risk factors, multivariate odds ratios for increasing CAC score cutpoints (CAC0,or =10, andor =100) for calcium/D versus placebo were 0.92 (95% CI, 0.64-1.34), 1.29 (0.88-1.87), and 0.90 (0.56-1.44), respectively. Corresponding odds ratios among women with a 50% or higher adherence to study pills and for higher levels of CAC (300) were similar.Treatment with moderate doses of calcium plus vitamin D3 did not seem to alter coronary artery calcified plaque burden among postmenopausal women. Whether higher or lower doses would affect this outcome remains uncertain.

Objective No guidelines or randomized trials address best practices for hormone therapy (HT) discontinuation. Methods We conducted a survey study to explore HT discontinuation practices at Group Health and Harvard Vanguard, large integrated health systems in the Northwest and Northeast United States, focusing on differences between specialties and study site. Results The response rate to the written questionnaire (mailed between December 2005 and May 2006) was 78.5% (736/928); this article reports the results for 483 eligible physicians. To discontinue oral HT, most physicians (91%) advised tapering, not immediate cessation (8%), and most (60%) suggested decreasing both dose and days per week. Almost 60% of physicians reported no experience with tapering patches. Harvard Vanguard physicians were more likely than Group Health physicians to encourage discontinuing HT and less likely to recommend resuming HT when a woman's symptoms returned after discontinuing HT. Physicians were most strongly influenced by their own experience (48%), advice from colleagues (25%), and the woman's preference (19%) when choosing a discontinuation strategy; only 2% relied on research evidence. Physicians endorsed various approaches to manage symptoms after HT discontinuation, most often behavioral changes (44%) and increased exercise (37%), and these approaches were more often endorsed by Harvard Vanguard physicians and obstetrician/gynecologists than Group Health physicians or family practitioners or internists. Conclusions Two health plans in the Northwestern and Northeastern United States have no standard protocol for HT discontinuation. Physicians customized approaches, influenced by their location, colleagues, and specialty. Research is needed to guide approaches to HT discontinuation.

Impairments in physical function, such as decreased muscle strength and balance, increase sharply with age.1 Declines in physical function are associated with increased risk of disability, especially among older women.2,3 Prior research suggests that estrogen depletion in women, related to hormonal transitions of menopause, causes physiological changes that damage the musculoskeletal system, thus causing subsequent decreases in function.4,5 The mechanisms by which estrogen influences muscle function remain unknown, but studies have established that estrogen and estrogen receptors in the skeletal muscle cells of women4 regulate carbohydrate and lipid metabolism. Moreover, recent data suggest that higher endogenous estrogen levels and lower sex hormone–binding globulin concentrations were associated with muscle strength in 75-year-old women. These parameters were associated with lower rates of fall-related limb fractures even after adjusting for bone mineral density.5 The literature on connections between hormone therapy (HT) and physical function is complex because of inconsistent use of definitions and measurement of physical function, different classifications of HT use, and study design effects. Results from cohort studies examining the role of HT on physical function are not consistent, with some studies reporting improved physical function associated with HT,6 some reporting decrements,7 and others reporting no association.8 In randomized controlled trials (RCTs) examining the effects of HT on physical function, results have also been inconclusive.9–12 However, these trials relied on self-reported physical function, rather than on objective measures,9–11 or failed to differentiate between unopposed estrogen and estrogen + progestin.12 Identification of factors that affect changes in physical function can provide information useful for forecasting disability burden and related outcomes. Furthermore, evidence regarding the association between HT and physical function could inform our understanding of the musculoskeletal impact of hormone depletion associated with the menopausal transition and help physicians counsel women about the effects of HT. This study investigated the association between HT and changes in performance-based measures of physical function as part of the Women’s Health Initiative (WHI).

Objective: The aim of this study was to assess the impact of the scientific evidence reported by Women's Health Initiative (WHI) trial on hormone therapy (HT) use in a 10-year follow-up retrospective cohort of women participating in a breast cancer screening program. Methods: Between 1998 and 2007, a retrospective cohort of participants in a population-based breast cancer screening program in the city of Barcelona (Catalonia, Spain) was assessed. The study population consisted of 50,918 women. Trends in current HT use and the annual rate of new users were analyzed by age group. Results: From 1998, successive annual increases were found in the prevalence levels of HT use in all age groups. In 2002, the prevalence peaked at 11% in 50- to 54-year-olds and at 10.1 % in 55- to 59-year-olds, followed by a sudden reversal and a progressive decrease. In 2007, 5 years after the publication of the WHI trial, the HT use decreased by 89.1% in 50- to 54-year-olds, 87.5% in 55- to 59-year-olds, 84.6% in 60- to 64-year-olds, and 66.0% in 65- to 69-year-olds. The percentage of new users also fell substantially after 2002. Conclusions: HT use decreased during the 5 years after the publication of the WHI. This reduction was especially marked in the first 2 years, when the decrease in new treatments exceeded the number of continuations. In the following 3 years, the decrease was approximately equal in both groups.

Objective: Surgical menopause has been associated with an increased risk of coronary heart disease events. In this study, we aimed to determine the associations between coronary artery calcium (CAC) and hysterectomy, oophorectomy, and hormone therapy use with a focus on the duration of menopause for which there was no hormone therapy use. Design: In a substudy of the Women's Health Initiative placebo-controlled trial of conjugated equine estrogens (0.625 mg/d), we measured CAC by computed tomography 1.3 years after the trial was stopped. Participants included 1,064 women with previous hysterectomy, aged 50 to 59 years at baseline. The mean trial period was 7.4 years. Imaging was performed at a mean of 1.3 years after the trial was stopped. Results: Mean age was 55.1 years at randomization and 64.8 years at CAC measurement. In the overall cohort, there were no significant associations between bilateral oophorectomy, years since hysterectomy, years since hysterectomy without taking hormone therapy (HT), years since bilateral oophorectomy, and years of HT use before Women's Health Initiative enrollment and the presence of CAC. However, there was a significant interaction between bilateral oophorectomy and prerandomization HT use for the presence of any CAC (P = 0.05). When multivariable analyses were restricted to women who reported no previous HT use, those with bilateral oophorectomy had an odds ratio of 2.0 (95% CI: 1.2-3.4) for any CAC compared with women with no history of oophorectomy, whereas among women with unilateral or partial oophorectomy, the odds of any CAC was 1.7 (95% CI: 1.0-2.8). Among women with bilateral oophorectomy, HT use within 5 years of oophorectomy was associated with a lower prevalence of CAC. Conclusions: Among women with previous hysterectomy, subclinical coronary artery disease was more prevalent among those with oophorectomy and no prerandomization HT use, independent of traditional cardiovascular disease risk factors. The results suggest that factors related to oophorectomy and the absence of estrogen treatment in oophorectomized women may be related to coronary heart disease.

OBJECTIVE Testing a hypothesis that pelvic organ prolapse (POP) is a focal manifestation of disordered connective tissue, we evaluated whether there is an association between POP and history of fracture. DESIGN This was a case-control study. Baseline data were from postmenopausal women aged 60 years or older enrolled in the Women's Health Initiative Estrogen Plus Progestin trial. Distinct variants (cystocele, rectocele, and uterovaginal) and severity (mild, moderate, or severe) of POP were recognized. A history of "fracture after age 55" was considered as the event of interest. RESULTS Moderate to severe POP was identified in 9% of 11,096 participants aged 60 years or older. Women with moderate to severe rectocele were significantly more likely to report fracture (odds ratio: 1.37, 95% CI: 1.06-1.77, P = 0.02) compared with those with absent to mild prolapse. Of the subset of participants who underwent bone mineral density assessment, those with moderate to severe prolapse demonstrated significantly lower whole-body bone mineral density ([beta] = -0.03, SE 0.02); this difference was of borderline significance (P = 0.05) compared with that for participants with absent to mild POP. Multivariate logistic regression analysis confirmed an independent association between moderate to severe rectocele and fracture (odds ratio: 1.45, 95% CI: 1.08-1.95, P = 0.01). CONCLUSIONS We demonstrate a relationship between moderate to severe POP and low bone mineral density in postmenopausal women enrolled in the Women's Health Initiative Estrogen Plus Progestin trial. Our findings of an association between clinically significant (moderate to severe) POP, specifically rectocele, and a history of fracture suggest that suboptimal collagen status purported to associate with POP may also involve bone collagen and hence translate into skeletal compromise.

Objective Findings from the Women's Health Initiative (WHI) failed to confirm previous expectations about the net benefits of menopausal hormone therapy and have resulted in reduced use of these medications. The aim of this study was to evaluate women's awareness and knowledge concerning the risks and benefits of hormone therapy. Design A nationally representative survey was completed for a sample of 781 women (ages 40-60 y, mean 49 y) drawn from the Knowledge Networks Internet panel 24 months after publication of the first WHI findings, in June 2004. Responses were weighted to reflect the demographics of the US population. The main outcome measures were awareness of WHI and knowledge of its findings. An aggregate score was constructed to assess women's knowledge of the impact of hormone therapy on seven key disease outcomes. Logistic regression determined the independent predictors of (1) WHI awareness and (2) a positive aggregate knowledge score, reflecting appropriate responses about risks and benefits. Results Only 29% of women were aware of the WHI results. Only 40% of women had a positive aggregate knowledge score. Aside from awareness of WHI and independent of other factors, knowledge scores were lower for African American women (odds ratio, 0.4; 95% CI: 0.2-0.6) and among women with less education (odds ratio, 0.5; 95% CI: 0.3-0.9). Knowledge was greatest for breast cancer and osteoporosis outcomes and most limited for colorectal cancer and memory loss. Conclusion Surveyed women had limited awareness and knowledge of the WHI results, suggesting limited diffusion. Targeting younger, less educated, and African American women is warranted.

Objective: There has been a significant shift in the use of hormone therapy (HT) among nonminority women since the publication of results of the Women's Health Initiative (WHI). Little is known about how the WHI results affected minority populations. This survey measured patterns of HT use among inner city women after publication of the WHI results, identified factors involved in the decision to continue or discontinue HT, and characterized the symptom burden and the experience of women who attempted to discontinue HT. Design: We conducted a cross-sectional survey of 101 English- and Spanish-speaking women in an inner city general internal medicine clinic from August 2003 to April 2004. All women had been taking HT at the time of the publication of the WHI results. The survey included questions on patient-reported experience with HT, symptoms of menopause, and use of alternative treatments. Results: Overall, 101 of 142 (71%) eligible women agreed to participate. The mean age of participants was 60 years; 43% were African American and 46% were Hispanic. The mean duration of HT use was 9.6 years. Three quarters (74%) had heard about the WHI findings, and 87% had attempted to stop taking HT after their publication. The most common reason for attempting to stop HT was concern about an increased risk of cancer or a general increase in risk to health. Of those who stopped HT, the vast majority (85%) reported vasomotor symptoms, and 26% restarted HT, mostly to treat those symptoms. Conclusions: Nearly all minority women in this small sample attempted to stop HT use after the results of the WHI were published. Restarting HT for treatment of symptoms was common.

Objective: The purpose of this representative, nationwide telephone survey was to collect information about postmenopausal hormone therapy (HT) use in relation to women's knowledge about the Women's Health Initiative Randomized Controlled Trial 2002 (WHI-RCT) in Germany. Design: During July 2003, telephone interviews were conducted with randomly selected women aged 45 to 60 years (N = 10,030; response 59.9%; completed interviews n = 6,007). They were asked about information sources regarding the WHI-RCT, and use of HT in conjunction with it. Results: Most women stated that they knew about the WHI-RCT (88.6%), and those with high educational status appeared to have more information than those with middle or low educational status. Among informed women (uninformed excluded), 46.6% continued, 25.7% stopped, and 14.2% ceased use of HT before the WHI-RCT. The prevalence of lifetime use of HT was higher in West Germany (37.4%) than in East Germany (29.2%), the highest prevalence of use was in the group aged 55 to 59 years. The most common reason to continue HT was the benefit risk assessment by physicians (58%); the most common reason to stop HT were women's perceptions that the risks of HT exceeded the benefits (56%). If information was solely given by physicians, women were more likely to continue HT (60.4%), compared with mass media (46.1%), as a source of information. Conclusions: The survey demonstrates the impact of the WHI-RCT in Germany, and shows that both the media and advice given by physicians were important. Women who continued to use HT did so largely because of their physician's advice. Women who discontinued were mainly those who had a negative subjective perception about risk of HT.

OBJECTIVE: To assess the effect of the publication of the Women's Health Initiative (WHI) study on patients' and physicians' attitudes in relation to hormone therapy (HT). DESIGN: A survey focused on the degree of knowledge and on the reactions to the WHI study was administered to 600 women allocated in two groups according to their socioeconomic status, high (HSES) or low (LSES). Additionally, 283 physicians were surveyed to determine their attitudes regarding HT after the publication of the WHI study. The rates of HT prescription before and after publication of the study were compared. RESULTS: Among patients, HT use and knowledge of the WHI study were less common among women of lower socioeconomic status (LSES 16.7% v HSES 47.3%, and LSES 15.7% v HSES 67.3%; P < 0.0001). Of the women in the LSES group who were HT users and had knowledge on the subject of the WHI study (n = 30), 56.7% contacted their physicians and 6.6% abandoned HT. These rates were similar for women in the HSES group. Among physicians, 97.2% of physicians referred to being aware of the WHI study, and 64.7% modified their clinical approach. The main changes were that 21.5% applied more rigorous risk/benefit assessment, 20.1% lowered hormone dosage, 18.8% decreased continuous-combined therapy use, 12.1% shortened the duration of HT, 7.7% abandoned medroxyprogesterone or conjugated estrogen use, and 5.0% increased the use of transdermal estrogens, tibolone, or other alternatives. As for prescriptions, after the publication of the WHI study, there was an 8.6% drop in the rate of HT prescriptions. This decrease was more pronounced for prescriptions based on conjugated equine estrogen and medroxyprogesterone acetate. In contrast, prescription of transdermal estrogens and tibolone increased 5.2% and 16%, respectively. CONCLUSIONS: There was a significant change in physicians' and patients' attitudes toward HT after publication of the WHI study.