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Importance: Estrogen therapy is the gold standard treatment for hot flashes and night sweats, but some women are unable or unwilling to use it because of associated risks. The serotonin-norepinephrine reuptake inhibitor venlafaxine hydrochloride is used widely as a nonhormonal treatment. While the clinical impression is that serotonin-norepinephrine reuptake inhibitors are less effective than estrogen, these medications have not been simultaneously evaluated in one clinical trial to date., Objective: To determine the efficacy and tolerability of low-dose oral 17β-estradiol and low-dose venlafaxine extended release in alleviating vasomotor symptoms (VMS)., Design, Setting, and Participants: In total, 339 perimenopausal and postmenopausal women with at least 2 bothersome VMS per day (mean, 8.1 per day) were recruited from the community to MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) clinical network sites between December 5, 2011, and October 15, 2012., Interventions: Participants were randomized to double-blind treatment with low-dose oral 17β-estradiol (0.5 mg/d) (n = 97), low-dose venlafaxine hydrochloride extended release (75 mg/d) (n = 96), or placebo (n = 146) for 8 weeks., Main Outcomes and Measures: The primary outcome was the mean daily frequency of VMS after 8 weeks of treatment. Secondary outcomes were VMS severity, bother, and interference with daily life. Intent-to-treat analyses compared the change in VMS frequency between each active intervention and placebo and between the 2 active treatments., Results: Compared with baseline, the mean VMS frequency at week 8 decreased to 3.9 (95% CI, 2.9-4.9) VMS per day (52.9% reduction) in the estradiol group, to 4.4 (95% CI, 3.5-5.3) VMS per day (47.6% reduction) in the venlafaxine group, and to 5.5 (95% CI, 4.7-6.3) VMS per day (28.6% reduction) in the placebo group. Estradiol reduced the frequency of symptoms by 2.3 more per day than placebo (P < .001), and venlafaxine reduced the frequency of symptoms by 1.8 more per day than placebo (P = .005). The results were consistent for VMS severity, bother, and interference. Low-dose estradiol reduced the frequency of symptoms by 0.6 more per day than venlafaxine (P = .09). Treatment satisfaction was highest (70.3%) for estradiol (P < .001 vs placebo), lowest (38.4%) for placebo, and intermediate (51.1%) for venlafaxine (P = .06 vs placebo). Both interventions were well tolerated., Conclusions and Relevance: Low-dose oral estradiol and venlafaxine are effective treatments for VMS in women during midlife. While the efficacy of low-dose estradiol may be slightly superior to that of venlafaxine, the difference is small and of uncertain clinical relevance., Trial Registration: clinicaltrials.gov Identifier: NCT01418209.

Background: Careful management of symptoms, particularly sleep and mood disturbances, may assist women in discontinuing hormone therapy (HT). We sought to describe characteristics associated with successful HT cessation in women who attempted to discontinue estrogen pills/patches with or without progestin., Methods: We invited 2,328 women, aged 45-70, enrolled January 1, 2005, to May 31, 2006, at Group Health in Washington State and Harvard Vanguard Medical Associates in Massachusetts, to participate in a telephone survey about HT practices. For the sample, we selected 2,090 women with estrogen dispensings (pharmacy data) during the study period, 200 women without HT dispensing after January 2005, and 240 women with no estrogen dispensings; 1,358 (58.3%) completed the survey. These analyses are based on survey responses., Results: Among 802 women who attempted HT discontinuation, the mean age was 50 years, 93% were postmenopausal, 90% were white, 30% had had a hysterectomy, and 75% experienced hot flashes after discontinuation. Those who did not succeed had greater trouble sleeping (74% vs. 57%) and mood disturbances (51% vs. 34%) than those who succeeded. In multivariable analyses, factors associated with successful discontinuation included doctor advice (odds ratio [OR] 2.62, 95% confidence interval [CI] 1.68-4.08), lack of symptom improvement (OR 4.21, CI 1.50-12.17), vaginal bleeding (OR 5.96, CI 1.44-24.6), and learning to cope with symptoms (OR 3.36, CI 2.21-5.11). Factors associated with unsuccessful HT discontinuation included trouble sleeping (OR 0.40, CI 0.26-0.61) and mood swings or depression (OR 0.63, CI 0.42-0.92)., Conclusions: Doctor advice is strongly associated with successful HT discontinuation. Symptom management, particularly sleep and mood disturbances, may help women discontinue HT.

Objective: Because hormone therapy use benefits sleep, sleep problems may occur after suspension. We tested the effects of short-term hormone therapy suspension on sleep problems., Methods: A total of 1,704 women aged 45 to 80 years at Group Health were randomized to suspend hormone therapy for 1 or 2 months or to continue using hormone therapy. This study included 1,405 women willing to suspend hormone therapy use who returned both baseline and follow-up questionnaires, administered within approximately 3 months of randomization. We used generalized linear models to examine the relationships between hormone therapy suspension and nine individual items from a modified General Sleep Disturbance Scale (number of days experienced in the past week) and an overall sleep quality index at follow-up. We tested whether age, hormone therapy type, or duration of use modified these relationships., Results: Suspension of hormone therapy for 1 or 2 months was associated with greater frequency of sleep problems for the overall sleep quality index and most individual sleep items. For example, the incident rate ratios for waking too early (95% CI) were 1.23 (1.10-1.38) for the women in the 1-month suspension group and 1.30 (1.17-1.45) for the 2-month suspension group, compared with women who continued the use of hormone therapy. Age and type of and duration of hormone therapy use did not modify these relationships., Conclusions: Short-term hormone therapy suspension was related to moderately greater frequency of sleep problems. Alternative forms of sleep management may benefit women who choose to discontinue hormone therapy use.

Background: Prescribing and counseling practices in hormone therapy (HT) since publication of the Women's Health Initiative (WHI) trials have changed. Our objective was to compare changes by practice field and region., Methods: Between December 2005 and May 2006, we mailed surveys to 938 practitioners from two large integrated health systems in the Northeastern and Northwestern United States. We received 736 responses and excluded 144 who do not prescribe/counsel about HT, leaving 592. Data included prescriber characteristics, knowledge about HT trials, and self-reported HT counseling and prescribing changes. We compared provider characteristics and HT counseling and prescribing by region and practice field (obstetrician/gynecology [OB/GYN] or primary care)., Results: Respondents included 79 OB/GYNs and 513 primary care providers. OB/GYNs were more likely, than primary care providers to consider themselves experts regarding the Heart and Estrogen/progestin Replacement Study (HERS) and WHI trials (30.4% vs. 8.2%, p < 0.001). The majority (87%) were cautious about HT use, especially primary care providers (p < 0.01 compared to OB/GYNs). Respondents reported prescribing less oral unopposed estrogen (64%) and combination estrogen/progestin (81%) post-WHI. OB/GYNs were less likely to report decreases in oral unopposed estrogen use (p = 0.006). Use of lower-dose and transdermal products (low-dose estrogen, vaginal estrogen, estradiol vaginal ring) increased, especially by OB/GYNs., Conclusions: Our study highlights numerous HT prescribing and counseling differences between primary care and OB/GYN providers. Reasons for these differences are unknown but may be related to self-reported WHI/HERS knowledge. HT formulations used in the WHI trials are being replaced by low-dose and alternate formulations. Studies to support this practice are needed.

Background: Breast density tends to decrease when women stop taking hormone therapy (HT). Some women find HT cessation difficult to tolerate, possibly because of fluctuations in endogenous hormone levels and vasomotor symptoms. We hypothesized that women with dense breasts might have lower tolerance for short-term HT suspension than do women with fatty breasts., Methods: As part of the Radiologic Evaluation And breast Density (READ) trial, we randomly assigned 881 women aged 45-80 with a prior screening (index) mammogram to suspend HT for 1 or 2 months before their next screening (study) mammogram. We measured continuous breast density on index mammograms using computer-assisted thresholding. At study mammograms, women indicated tolerance for stopping HT from 1 (extremely difficult) to 7 (very easy). Using linear regression, we evaluated the association between index breast density and tolerance after cessation, adjusting for age, body mass index (BMI), HT type, randomization group, and vasomotor symptoms., Results: A higher percentage of breast density was associated with lower unadjusted mean tolerance scores (tolerance 4.27, 95% confidence interval [CI] 3.77-4.77 for women with > or =50% density, and 4.73, 95% CI 4.45-5.01 for women with <10% density, not a statistically significant difference). In adjusted analyses, neither percent breast density nor dense breast area was associated with tolerance for HT suspension., Conclusions: Although HT use affects breast density, tolerance for suspending HT is not associated with breast density. Women with dense breasts have the greatest potential for decreases in density after HT cessation; they should tolerate stopping HT as well as women with fatty breasts.

Objective: Some healthcare providers recommend hormone therapy (HT) cessation before mammography to improve performance. Our objective was to evaluate characteristics of women willing to consider HT cessation before screening mammography., Methods: We performed a randomized clinical trial, the Radiological Evaluation and Breast Density study, within an integrated health plan (2004-2007). Women aged 45 to 80 years who used HT at their most recent screening (index) mammogram, who were due for a screening (study) mammogram, and who were still using HT were invited to participate. Randomization groups were: (1) no, (2) 1-month, or (3) 2-month cessation. Women's willingness to participate was evaluated by age, race, ethnicity, education, hysterectomy, type of HT (unopposed estrogen and estrogen plus progestin), duration of HT use, body mass index, breast cancer risk, and breast density., Results: A total of 5,861 women were invited to participate; 2,999 refused. An additional 169 women agreed to participate but withdrew before data collection. Compared with women who participated (n = 1,535), nonparticipants (n = 3,168; 2,999 + 169; 54%) were older, were less educated, and had lower body mass index (all P < 0.05). Among nonparticipants, 1,876 (59.2%) were unwilling to stop HT. Among estrogen-plus-progestin users, women with a first-degree relative with a history of breast cancer had lower odds of refusal than women without a family history of breast cancer (adjusted odds ratio, 0.71; 95% CI, 0.54-0.93)., Conclusions: Most women were unwilling to stop HT, even for a short period, when the intent was to improve mammographic accuracy, and even when informed that they could restart HT at any time during the 2-month study. Some factors predicted willingness to stop HT; the magnitude of the differences may not be clinically meaningful.

Objective: The aim of this study was to identify provider characteristics associated with hormone therapy prescribing., Methods: The study design is cross-sectional. In December 2005, we mailed surveys to providers practicing in two integrated healthcare delivery systems located in the northwestern and northeastern United States; 379 responded (74%) and 249 (49% of total) granted access to their automated data. Data included provider demographics, practice characteristics, and perceptions about hormone therapy. Provider-specific annual hormone therapy prescribing frequency was calculated as days supply of hormone therapy filled divided by the number of visits (among women aged 45-80 y). Factors associated with higher rates of hormone therapy prescribing were identified using bivariate and multivariate analyses., Results: We report results separately for primary care providers (internists and family practitioners) and obstetrician/gynecologists because significant correlates differed in these two groups. For both primary care providers and obstetrician/gynecologists, in multivariate analyses, hormone therapy prescribing varied by site (P < or = 0.002) and years at the healthcare organization (P < or = 0.01). For primary care providers only, higher hormone therapy prescribing was associated with reported expert knowledge of the hormone therapy trials (P < or = 0.001). For obstetrician/gynecologists, higher hormone therapy prescription was related to feeling well prepared to counsel women on hormone therapy (P < or = 0.007), believing that the risks of estrogen with progestogen had been exaggerated (P = 0.04), and seeing younger aged patients (P = 0.03)., Conclusions: After the release of the Women's Health Initiative findings and practicing under similar clinical guidelines, hormone therapy prescribing is associated with providers' confidence, practice location, and time with a healthcare organization.

Background: Without population-based evidence, some clinicians recommend short-term suspension of hormone therapy to improve the performance of mammography. Hormone therapy increases breast density, and abnormal screening mammograms are more common among women with denser breasts and among women using hormone therapy., Objective: To test whether 1 to 2 months of hormone therapy suspension before screening mammography decreases additional mammographic imaging (recall) in women age 45 to 80 years., Design: 3-group randomized, controlled trial., Setting: Integrated health plan in western Washington from 2004 to 2007., Patients: 1704 women age 45 to 80 years who used hormone therapy at their most recent screening (index) mammography, were due for screening (study) mammography, and were still using hormone therapy., Intervention: Block random assignment (by breast density and hormone therapy type) to no hormone therapy suspension (n = 567) or suspension for 1 month (n = 570) or 2 months (n = 567) before study mammography. One blinded expert radiologist interpreted all mammograms., Measurements: Recall was the primary outcome, and change in mammographic breast density (percentage and dense area) between the index and study mammograms was the secondary outcome., Results: Mammography recall rates were 11.3% (61 of 542 women in the no-suspension group), 12.3% (50 of 478 women in the 1-month suspension group), and 9.8% (44 of 451 women in the 2-month suspension group). No subgroups were identified in which brief suspension of hormone therapy resulted in decreased mammography recall. With suspension, decreases in percentage of breast density were orderly and statistically significant: 0.1% (no-suspension group), -0.9% (1-month suspension group), and -1.5% (2-month suspension group). Similar ordered decreases were observed for dense area. Women in the suspension groups experienced increased menopause symptoms., Limitations: Results can only be generalized to women age 45 to 80 years who have used hormone therapy for at least 1 year and will consider short-term suspension; most eligible women (61%) declined participation. Mammography recall was determined by 1 expert radiologist., Conclusion: Brief hormone therapy suspension was associated with small changes in breast density and did not affect recall rates. No evidence supports short-term hormone therapy suspension before mammography.

Background: The use of menopausal hormone therapy (HT) has significantly declined since the release of the Women's Health Initiative findings, but to what extent physicians' and women's concerns about breast cancer contributed to this change is unknown. Our study explored physicians' and women's beliefs about hormone therapy and breast cancer risk., Methods: We conducted qualitative in-depth interviews with 22 primary care physicians and 45 female patients at two large integrated health care delivery systems in Washington State and Massachusetts., Results: Concerns about breast cancer risk weighed into the decision-making process for physicians and women in initiating and continuing hormone therapy. For women, control of menopausal symptoms was important and possibly outweighed their concerns about the potential risks of breast cancer. Though concerned about its association with increasing breast cancer risk, physicians were willing to consider hormone therapy to manage women's menopausal symptoms but were frustrated about the lack of available non-hormone therapy alternatives. Most physicians and some women were aware of the Women's Health Initiative, and its findings appeared to influence their beliefs about hormone therapy and breast cancer risk, though doubts remained among both groups about the study findings and implications., Conclusions: Our qualitative study suggests that after the Women's Health Initiative, concerns about breast cancer risk weighed into decisions to initiate and continue hormone therapy for both physicians and women, but menopausal symptoms often directed use.

Purpose: We sought to examine the relationship between recent use of oral contraceptives and hormone therapy and endometrial hyperplasia (EH) risk., Methods: Cases comprised women diagnosed with complex EH (n = 289) or atypical EH (n = 173) between 1985 and 2003. One age-matched control was selected for each case; excluded were women with a prior hysterectomy or diagnosis of EH or endometrial cancer. Hormone use in the 6 months prior to the date of the case's first symptoms was ascertained using a pharmacy database and medical records. Odds ratios (OR) and 95% confidence intervals (CI) were calculated., Results: Three (1.1%) cases had used oral contraceptives, compared to 16 (6.0%) controls (OR = 0.2, 95% CI: 0.0-0.6). Fifty-one (16.8%) cases had taken estrogen-only hormone therapy, in contrast to two (0.7%) controls (OR = 37.6, 95% CI: 8.8-160.0). The risk of EH among estrogen plus progestin hormone users did not differ from that of non-users (OR = 0.7, 95% CI: 0.4-1.1)., Conclusions: This study suggests that previous findings of the association of estrogen-only hormone therapy with increased risk of EH and the lack of an association between estrogen plus progestin hormone therapy and EH risk are likely to apply to both complex EH and atypical EH. Further examination of the association between oral contraceptives and EH, with greater numbers of OC users, is warranted.

Objectives: To describe hormone therapy (HT) initiation after the 2002 publication of the Women's Health Initiative., Design: Observational cohort (1999-2003) of women ages 40 to 79 years, five health plans, used HT in July 2002 and subsequently discontinued or never used before August 2002., Results: Of discontinuers, 15.8% (3,203 of 20,205) reinitiated HT. Reinitiation was higher among estrogen users (23.8%) versus estrogen with progestin users (11.3%), and lower among those with diabetes (relative risk [RR]=0.68, 95% CI: 0.61-0.76), cardiovascular disease (RR=0.87, 95% CI: 0.83-0.92), and hyperlipidemia (RR=0.83, 95% CI: 0.79-0.88). Only 2.3% (2,072 of 90,261) of never users initiated (August 2002 to December 2003). First-time initiation was associated with cardiovascular disease (RR=1.17, 95% CI: 1.10-1.25) and hyperlipidemia (RR=1.24, 95% CI: 1.17-1.33) and was less common among those with diabetes (RR=0.70, 95% CI: 0.63-0.79)., Conclusions: After the Women's Health Initiative, a minority of women reinitiated or became first-time initiators of HT. Women with cardiovascular disease, diabetes, and hyperlipidemia were less likely to reinitiate; women with cardiovascular disease and hyperlipidemia were more likely to be first-time initiators.

Objective: Black cohosh (Actaea racemosa) is an herb commonly used to treat menopausal symptoms. Little is known about its effect on other physiologic parameters that could result in untoward events. This study examines the effect of black cohosh on lipids, fibrinogen, glucose and insulin., Methods: Three hundred and fifty-one, 45-55 years old, peri or post-menopausal women experiencing vasomotor symptoms participated in a 3-month, double blind trial with randomization to: (1) black cohosh (160 mg daily); (2) multibotanical including black cohosh (200 mg daily); (3) multibotanical plus soy diet counseling; (4) conjugated equine estrogen .625 mg, with or without medroxyprogesterone acetate 2.5mg daily, for women with or without a uterus, respectively; (5) placebo. Baseline and month 3 total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol (calculated), triglyceride, insulin, glucose, and fibrinogen serum concentrations were measured in 310 women. Baseline information was also collected on medical history, demographic characteristics, and diet., Results: There were no statistically significant differences in the adjusted mean change from baseline to 3 months between the herbal groups and placebo in total cholesterol, LDL, HDL, triglycerides, glucose, and insulin. Adjusted fibrinogen levels appear to increase in the multibotanical treatment group in comparison with the other herbal groups and placebo overall (P = .02), but there was no statistically significant difference in the pairwise test against placebo (P = .11)., Conclusions: Black cohosh containing therapies had no demonstrable effects on lipids, glucose, insulin or fibrinogen.

Background: Herbal supplements are widely used for vasomotor symptoms., Objective: To test the efficacy of 3 herbal regimens and hormone therapy for relief of vasomotor symptoms compared with placebo., Design: 1-year randomized, double-blind, placebo-controlled trial conducted from May 2001 to September 2004., Setting: Group Health, Washington State., Participants: 351 women age 45 to 55 years with 2 or more vasomotor symptoms per day; 52% of the women were in menopausal transition and 48% were postmenopausal., Measurements: Rate and intensity of vasomotor symptoms (1 = mild to 3 = severe), and Wiklund Vasomotor Symptom Subscale., Interventions: 1) Black cohosh, 160 mg daily; 2) multibotanical with black cohosh, 200 mg daily, and 9 other ingredients; 3) multibotanical plus dietary soy counseling; 4) conjugated equine estrogen, 0.625 mg daily, with or without medroxyprogesterone acetate, 2.5 mg daily; or 5) placebo., Results: Vasomotor symptoms per day, symptom intensity, Wiklund Vasomotor Symptom Subscale score did not differ between the herbal interventions and placebo at 3, 6, or 12 months or for the average over all the follow-up time points (P > 0.05 for all comparisons) with 1 exception: At 12 months, symptom intensity was significantly worse with the multibotanical plus soy intervention than with placebo (P = 0.016). The difference in vasomotor symptoms per day between placebo and any of the herbal treatments at any time point was less than 1 symptom per day; for the average over all the follow-up time points, the difference was less than 0.55 symptom per day. The difference for hormone therapy versus placebo was -4.06 vasomotor symptoms per day for the average over all the follow-up time points (95% CI, -5.93 to -2.19 symptoms per day; P < 0.001)., Limitations: The trial did not simulate the whole-person approach used by naturopathic physicians. Differences between treatment groups smaller than 1.5 Vasomotor symptoms per day cannot be ruled out., Conclusion: Black cohosh used in isolation, or as part of a multibotanical regimen, shows little potential as an important therapy for relief of vasomotor symptoms., Clinical Trials Registration Number: NCT00169299.

Objective: Determine the impact of fracture, coronary disease, and diabetes on changes in rates of discontinuation and initiation of estrogen therapy with (EPT) and without (ET) progestin, before (September 1, 1999 to June 30, 2002, baseline) versus 5 months after (follow-up) release of the Women's Health Initiative EPT trial results (WHI)., Design, Setting, and Participants: Observational cohort; 169,586 women 40 to 80 years old from 5 U.S. HMOs., Methods: We used pharmacy data to identify ET and EPT users. A woman was a user any month she filled > or =1 estrogen prescription and in subsequent months based upon the number of pills/patches dispensed. We used inpatient and outpatient claims to identify fracture January 1, 1999 to June 30, 2002 and pharmacy data to identify disease-based groups of medications for diabetes and cardiovascular disease., Measures: EPT/ET prevalence, initiation, and discontinuation rates., Results: Baseline to follow-up EPT and ET prevalence declined 45% and 22%, respectively, with no difference by comorbidity. Follow-up EPT initiation was half the baseline rate irrespective of comorbidity. Compared to baseline, follow-up EPT discontinuation rates increased among women with diabetes (relative risk [RR], 6.9; 95% confidence interval [CI], 5.6 to 8.4), cardiovascular disease (RR, 5.5; 95% CI, 4.9 to 6.2), fracture (RR, 3.8; 95% CI, 2.4 to 5.7), and no comorbidity (RR, 4.4; 95% CI, 3.9 to 4.9). The RRs for follow-up versus baseline EPT discontinuation were higher among women with diabetes (P<.01) and cardiovascular disease (P<.01) versus women without these comorbidities. ET discontinuation rates among these same groups were elevated 2- to 2.8-fold., Conclusions: Diabetes and cardiovascular disease were associated with higher EPT discontinuation rates post-WHI compared to women without comorbidity; comorbidity had little impact on changes in prevalence or initiation of ET/EPT after release of the WHI.

Background: We examined the impact of race, education, and household income on changes in rates of discontinuation and initiation of hormone therapy before and after release of the Women's Health Initiative estrogen plus progestin trial results., Methods: We conducted an observational cohort study of 221 378 women aged 40-80 years enrolled in five health maintenance organizations to estimate the prevalence and rates of discontinuation and initiation of estrogen plus progestin and estrogen only between September 1, 1999, to June 31, 2002 (baseline), and December 31, 2002 (follow-up). We identified the census block group for each participant by geocoding her 2003 residential address. We categorized women into racial, education, and income groups based on the distribution of these characteristics in her community from year 2000 census data and the distributions of these characteristics within her HMO., Results: There were significant differences in estrogen plus progestin and estrogen only prevalence by race, education level, and household income, and in estrogen plus progestin initiation by race and education level, but not by household income at follow-up. However, there were no differences by community race, education, or household income in change in the prevalence of either hormone therapy use at follow-up or in the rates of hormone therapy discontinuation or initiation from baseline to follow-up., Conclusions: Given the wide spread media attention to the Women's Health Initiative estrogen plus progestin trial results, our findings suggest comparable dissemination of this information across diverse socioeconomic groups.

Recent randomized trials have indicated that the risks of hormone therapy for menopausal women may outweigh the benefits. The purpose of this study was to describe how health plans responded to the findings of the Women's Health Initiative (WHI) estrogen plus progestin trial. We surveyed five health plans affiliated with the HMO Research Network and the Cancer Research Network to document the response of each plan to the WHI in terms of patient and provider education and guidelines. Every health plan issued responses within 3 months of WHI's termination in a variety of formats. Recommendations were relatively consistent across the organizations. Given the documented changes in hormone therapy use in these five health plans in the post-WHI era, we conclude that attempts on the part of each organization to educate patients and providers about the implications of the WHI may have contributed to the observed changes in hormone therapy use.

Information from the Women's Health Initiative (WHI) trial has given physicians valuable tools for counseling women aged 50 to 79 years about the short-term risks of hormone therapy (HT). Unanswered questions remain, particularly on the risks and benefits of discontinuing HT among long-term users. The decision to discontinue HT should be carefully considered, because stopping and re-starting after several months may "reset the clock" for risks associated with changes in hepatic protein synthesis. The current authors recommend low-dose transdermal hormonal formulations,but no large-scale randomized trials exist to confirm the veracity of this recommendation. It has been suggested that starting HT in the menopausal transition would alleviate the HT risks observed withWHI. Until additional data are available to counsel women in the menopausal transition, however, the conservative counseling approach is to apply those figures available from the WHI, particularly because women aged 50 to 59 years using estrogen-progestin therapy have an unfavorable risk-benefit ratio, similar to that seen in older women.

Objective: We sought to examine prescribing patterns (prevalence and rates of initiation and discontinuation) for estrogen plus progestin (hormone therapy [HT] and estrogen alone [ET]) in the United States in the 2 years before the published results of Women's Health Initiative's (WHI) HT trial's early termination and for 5 months after their release., Methods: We conducted an observational cohort study of 169,586 women aged 40-80 years who were enrolled in 5 health maintenance organizations in the United States to estimate the prevalence of HT and ET and discontinuation and initiation rates between September 1, 1999, to June 31, 2002 (baseline), and December 31, 2002 (follow-up). We used automated pharmacy data to identify all oral and transdermal estrogen and progestin dispensed during the study period., Results: The prevalence of HT declined 46% from baseline to follow-up (14.6% to 7.9%); ET use declined 28% during the same period (12.6% to 9.1%). The discontinuation of HT increased almost immediately, from 2.5% at baseline to 13.8% in October 2002. We saw an immediate decrease in HT and ET initiation rates, from 0.4% and 0.3% at baseline, respectively, to 0.2% for HT and ET at follow-up., Conclusion: The diffusion of the WHI HT trial results had an immediate impact on the discontinuation of HT and ET and is likely responsible for the 46% and 28% decline in the initiation of these respective therapies. Further exploration of why women continue to use HT and identification of methods for addressing reasons for continued use are indicated., Level of Evidence: II-2.

Objective: To evaluate the association between estrogen therapy and cardiovascular disease risk among women with type 2 diabetes., Research Design and Methods: A retrospective, case-cohort study was conducted among 6017 women aged 45-80 years with type 2 diabetes from 1 January 1986 to 31 December 1992 at the Group Health Cooperative in Washington state. Cardiovascular outcomes, including nonfatal myocardial infarction (n = 215), coronary revascularization (n = 253), and cardiovascular deaths (n = 229), were ascertained through 31 December 1998. Use of estrogen and progestin was derived from automated pharmacy records and modeled as a time-dependent variable. Median follow-up was 6.8 years. Multivariable-adjusted relative risk (RR) and 95% CI were calculated using Cox proportional hazard models for case-cohort analyses., Results: Current use of estrogen with (RR 0.43, 95% CI 0.22-0.85) or without (0.48, 0.30-0.78) progestin was associated with a decreased risk of cardiovascular events compared with never having used estrogen. Risk of cardiovascular events associated with a first episode of estrogen use (with or without progestin) of <25 months' duration (1.12, 0.49-2.54), first episode of use >or=25 months' duration (0.32, 0.06-1.70), and current use that was not the first episode of use (0.42, 0.42-0.67) indicated that recent initiation was not associated with an increase or decrease in risk., Conclusions: These results show an association of estrogen therapy, with or without progestin, with decreased risk of cardiovascular events among women with type 2 diabetes. This association should be further investigated in large randomized, controlled trials.

ObjectiveThe aim of this study was to identify provider characteristics associated with hormone therapy prescribing.MethodsThe study design is cross-sectional. In December 2005, we mailed surveys to providers practicing in two integrated healthcare delivery systems located in the northwestern and northeastern United States; 379 responded (74%) and 249 (49% of total) granted access to their automated data. Data included provider demographics, practice characteristics, and perceptions about hormone therapy. Provider-specific annual hormone therapy prescribing frequency was calculated as days supply of hormone therapy filled divided by the number of visits (among women aged 45-80 y). Factors associated with higher rates of hormone therapy prescribing were identified using bivariate and multivariate analyses.ResultsWe report results separately for primary care providers (internists and family practitioners) and obstetrician/gynecologists because significant correlates differed in these two groups. For both primary care providers and obstetrician/gynecologists, in multivariate analyses, hormone therapy prescribing varied by site (P < or = 0.002) and years at the healthcare organization (P < or = 0.01). For primary care providers only, higher hormone therapy prescribing was associated with reported expert knowledge of the hormone therapy trials (P < or = 0.001). For obstetrician/gynecologists, higher hormone therapy prescription was related to feeling well prepared to counsel women on hormone therapy (P < or = 0.007), believing that the risks of estrogen with progestogen had been exaggerated (P = 0.04), and seeing younger aged patients (P = 0.03).ConclusionsAfter the release of the Women's Health Initiative findings and practicing under similar clinical guidelines, hormone therapy prescribing is associated with providers' confidence, practice location, and time with a healthcare organization.

ObjectiveTo evaluate vaginal, endometrial, and reproductive hormone effects of three herbal regimens compared with placebo and hormone therapy (HT).DesignThis was a 1-year, randomized, double-blind, placebo-controlled trial of 351 women, ages 45 to 55, with two or more vasomotor symptoms per day. Women were randomly assigned to (1) black cohosh, (2) a multibotanical containing black cohosh, (3) the same multibotanical plus dietary soy counseling, (4) HT, or (5) placebo. Women were ineligible if they had used HT in the previous 3 months or menopausal herbal therapies in the previous month. Data on vaginal cytology and dryness were collected (at baseline and 3 and 12 mo). Daily menstrual diaries were maintained by 313 women with a uterus, and abnormal bleeding was evaluated. Serum estradiol, follicle-stimulating hormone, luteinizing hormone, and steroid hormone-binding globulin were assessed (baseline and 12 mo) among 133 postmenopausal women. Gynecologic outcomes of the five groups were compared.ResultsThe five groups did not vary in baseline vaginal cytology profiles, vaginal dryness, menstrual cyclicity, or hormone profiles. The HT group had a lower percentage of parabasal cells and vaginal dryness than the placebo group at 3 and 12 months (P < 0.05). Abnormal bleeding occurred in 53 of 313 (16.9%) women. There were no differences in frequency of abnormal bleeding between any of the herbal and placebo groups, whereas women in the HT group had a greater risk than those in the placebo group (P < 0.001). Among postmenopausal women, HT significantly decreased follicle-stimulating hormone and increased estradiol; none of the herbal interventions showed significant effects on any outcomes at any time point.ConclusionBlack cohosh, used alone or as part of a multibotanical product with or without soy dietary changes, had no effects on vaginal epithelium, endometrium, or reproductive hormones.

ObjectiveTo evaluate vaginal, endometrial, and reproductive hormone effects of three herbal regimens compared with placebo and hormone therapy (HT).DesignThis was a 1-year, randomized, double-blind, placebo-controlled trial of 351 women, ages 45 to 55, with two or more vasomotor symptoms per day. Women were randomly assigned to (1) black cohosh, (2) a multibotanical containing black cohosh, (3) the same multibotanical plus dietary soy counseling, (4) HT, or (5) placebo. Women were ineligible if they had used HT in the previous 3 months or menopausal herbal therapies in the previous month. Data on vaginal cytology and dryness were collected (at baseline and 3 and 12 mo). Daily menstrual diaries were maintained by 313 women with a uterus, and abnormal bleeding was evaluated. Serum estradiol, follicle-stimulating hormone, luteinizing hormone, and steroid hormone-binding globulin were assessed (baseline and 12 mo) among 133 postmenopausal women. Gynecologic outcomes of the five groups were compared.ResultsThe five groups did not vary in baseline vaginal cytology profiles, vaginal dryness, menstrual cyclicity, or hormone profiles. The HT group had a lower percentage of parabasal cells and vaginal dryness than the placebo group at 3 and 12 months (P < 0.05). Abnormal bleeding occurred in 53 of 313 (16.9%) women. There were no differences in frequency of abnormal bleeding between any of the herbal and placebo groups, whereas women in the HT group had a greater risk than those in the placebo group (P < 0.001). Among postmenopausal women, HT significantly decreased follicle-stimulating hormone and increased estradiol; none of the herbal interventions showed significant effects on any outcomes at any time point.ConclusionBlack cohosh, used alone or as part of a multibotanical product with or without soy dietary changes, had no effects on vaginal epithelium, endometrium, or reproductive hormones.

BackgroundThe landmark Women's Health Initiative (WHI) Postmenopausal Hormone Therapy Trial published in 2002 showed that the health risks of combination hormone therapy (HT) with estrogen and progestin outweighed the benefits in healthy postmenopausal women. Dissemination of results had a major impact on prescriptions for, and physician beliefs about HT. No study has fully examined the influence of the widely publicized WHI on physicians' practice and attitudes or their opinions of the scientific evidence regarding HT; in addition, little is known about how physicians assist women in their decisions regarding HT.Design and participantsWe conducted in-depth telephone interviews with family practitioners, internists, and gynecologists from integrated health care delivery systems in Washington State (n = 10 physicians) and Massachusetts (n = 12 physicians). Our objectives were to obtain qualitative information from these physicians to understand their perspectives on use of HT, the scientific evidence regarding its risks and benefits, and counseling strategies around HT use and discontinuation.ApproachWe used Template Analysis to code transcribed telephone interviews and identify themes.ResultsPhysicians were conflicted about the WHI results and its implications. Seven themes identified from in-depth interviews suggested that the WHI (1) was a ground-breaking study that changed clinical practice, including counseling; (2) was not applicable to the full range of patients seen in clinical practice; (3) raised concerns over the impact of publicized health information on women; (4) created uncertainty about the risks and benefits of HT; (5) called for the use of decision aids; (6) influenced discontinuation strategies; and (7) provided an opportunity to discuss healthy lifestyle options with patients. As a result of the WHI, physicians reported they no longer prescribe HT for prevention and were more likely to suggest discontinuation, although many felt women should be in charge of the HT decision.ConclusionsPhysicians varied in their opinions of HT and the scientific evidence (positive and negative). Whereas the WHI delineated the risks and benefits of HT, physicians reported that decision aids are needed to guide discussions with women about menopause and HT. Better guidance at the time of WHI study publication might have been valuable to ensure best practices.

ObjectiveEffectively communicating information about the complex decisions that face women at midlife, including whether to use hormone replacement therapy (HRT), is an ongoing challenge. Although numerous decision-making tools exist, few have been evaluated. The objective of this study was to examine women's use of a workbook designed to promote informed HRT decision-making.DesignWe developed a workbook to prepare women to discuss HRT, osteoporosis, heart disease, and breast cancer with their providers. To evaluate the workbook, women aged 45-65 years were randomly assigned to one of three groups: (1) workbook plus baseline and 6-month surveys, (2) workbook and 6-month survey, or (3) no workbook with both surveys. Results are based on the responses of 580 women in groups 1 and 2 (response rate, 84.2%).ResultsAt 6 months, 79% of women recalled receiving the workbook, of whom 51% read all or most of it, 35% skimmed or read part of it, and 14% did not read it. The percentages of women completing self-assessments were 55% osteoporosis; 56% heart disease; 58% breast cancer; 57% advantages and disadvantages of HRT; and 52% personal preferences about HRT. As a result of the workbook, 10% made an appointment with their providers, and 12% had a discussion about HRT with their providers. Use of the workbook was not associated with menopause symptoms, attitudes about or use of HRT, hysterectomy, or provider discussions about menopause and HRT.ConclusionThis simple approach of using a mailed workbook holds promise as a successful mechanism to prepare women to discuss HRT and other related health issues with their providers.

BackgroundCounseling women facing the decision to initiate, continue, or discontinue hormone replacement therapy represents a major challenge for providers. Women's attitudes deserve careful consideration in this context, because attitudes may influence hormone replacement therapy use and patients' satisfaction with decision-making. Little is known about factors that may explain different attitudes.MethodsTo evaluate the association between char acteristics of peri- and postmenopausal women and their attitudes toward hormone replacement therapy, we conducted a population-based, computer-assisted telephone survey of 1,076 randomly selected women, ages 50-80, at a staff-model health maintenance organization. Women with a positive or neutral attitude were compared to those with a negative attitude. We exam ined associations between attitudes and demographic and clinical characteristics, self-rated health status, physical function, personal and family history of condi tions affected by hormone replacement therapy, gyne cologic visits, provider characteristics, interactions with provider, and sources of information about hor mone replacement therapy.ResultsThe perception of being adequately informed about the benefits of hormone replacement therapy by one's provider was associated with a tripling of the likelihood of having a positive attitude toward hormone replacement therapy. Additional fac tors associated with positive attitudes included past hormone replacement therapy use, younger age, a higher level of physical functioning, and personal history of heart disease. Relationships between these vari ables and attitudes varied among current hormone replacement therapy users and nonusers.ConclusionsThe study findings reinforce the critical role of provider counseling in shaping women's atti tudes about hormone replacement therapy.

BackgroundHealth care provider encouragement for particular preventive behaviors is associated with patient adherence, but it is unclear whether a provider's overall prevention approach influences whether patients engage in recommended preventive measures. We examined whether older women who perceived that their health care provider encouraged a particular preventive behavior were more likely to follow that recommendation if they also perceived that the provider encouraged other preventive behaviors.Data and methodsThe sample included 1119 women aged 50 to 79 enrolled in a health maintenance organization. We examined associations of reported provider encouragement for post-menopausal hormone use, physical activity, fecal occult blood testing (FOBT), and flexible sigmoidoscopy with one another and with adherence to these measures according to recommended guidelines.ResultsAmong women reporting provider encouragement for physical activity, the likelihood of reporting regular physical activity was greater among women who reported encouragement for one other (odds ratio [OR]=1.99; confidence interval [CI]=1.35 to 2.95) and at least two other (OR=2. 38; 95% CI=1.62 to 3.48) preventive measures compared with women who reported no other encouragement. The likelihood of reporting adequate counseling for post-menopausal hormone use was greater among women reporting encouragement for at least two other preventive measures compared with those reporting no other encouragement. The likelihood of having had an FOBT or sigmoidoscopic examination was related to encouragement for those procedures, but not with greater encouragement for other preventive measures.ConclusionsPatient perceptions of a provider's overall preventive practice approach may influence whether patients engage in recommended preventive practices, particularly for lifestyle factors.

ObjectiveTo describe factors associated with initiation of hormone replacement therapy (HRT) by older women.DesignA cross-sectional study of 671 randomly selected women aged 65 to 80 who participated in a larger telephone survey on preventive health behaviors.SettingA large health maintenance organization (HMO) in Seattle, Washington.ParticipantsOf the 521 women who responded (78%), 51 had begun taking HRT at age 60 or older and were identified as initiators. Women who had never used HRT or past users who had begun HRT before age 60 were classified as noninitiators (n = 362). Current users who started HRT before age 60 (n = 108) were excluded.MeasurementsSources included the telephone survey, automated HMO pharmacy data, and HMO utilization and provider databases.ResultsInitiators were similar to noninitiators with respect to age, marital status, education, and health status. Initiators were more likely to have had a hysterectomy at age 60 or later than noninitiators. Sixty-two percent of the non-initiators said they had received no information about the benefits of HRT from their providers compared with 18% of initiators. HRT initiation was associated with belief in prevention benefits of HRT for fractures and cardiovascular disease and with reported encouragement from the physician to use HRT.ConclusionsOther than hysterectomy status, there were few sociodemographic or health characteristics that markedly distinguished older initiators from noninitiators. Our findings show the importance of physician counseling in an older woman's decision to initiate HRT.

The effects of estrogen replacement therapy on prognosis in women with established coronary disease remain uncertain. The authors conducted a retrospective cohort study of 726 women (mean age, 66.2 years) who survived first myocardial infarction to hospital discharge from 1980 through 1991, while enrolled at Group Health Cooperative of Puget Sound in western Washington State. Estrogen replacement therapy after myocardial infarction (122 women) was ascertained from computerized pharmacy records. Reinfarctions (n = 135) and deaths (n = 183) through 1993 were identified, and relative risks were calculated. The relative risk for reinfarction associated with current estrogen replacement therapy after myocardial infarction, adjusting for age and time since infarction, was 0.64 (95% confidence interval (CI) 0.32-1.30), and that for past estrogen replacement therapy was 0.90 (95% CI 0.62-1.31). The relative risk for all-cause mortality associated with current estrogen replacement therapy was 0.50 (95% CI 0.25-1.00), and that for past estrogen replacement therapy was 0.79 (95% CI 0.56-1.09). While estrogen users were less likely than nonusers to have a history of diabetes or congestive heart failure, adjustment for these and additional prognostic factors altered risk estimates only slightly. Estrogen replacement therapy after first myocardial infarction was not associated with increased risk of reinfarction or mortality. This study provides reassurance regarding the safety of estrogen replacement therapy after myocardial infarction in women.

The characteristics that differentiate long-term (≥10 years) hormone replacement therapy (HRT) users from short-term (<10 years) users and nonusers are not well documented. The epidemiology of long-term HRT use was investigated within a random samples survey of 703 women aged 50–80 years who were members of Group Health Cooperative (GHC) of Puget Sound. Women who had been menopausal for ≥10 years comprised the study population. Long-term HRT users (29.4 percent) were compared with short-term (28.1 percent) and never users (42.5 percent). The authors examined the association between duration of HRT use and demographic characteristics, personal and family medical history, menopausal symptoms, information used in decision making, attitudes toward HRT, provider encouragement to use HRT, and GHC utilization. Compared with never users, the strongest correlates of long-term HRT use were having a hysterectomy before or after menopause, positive attitudes espousing the benefits of HRTs, and perceived provider encouragement to use HRT. Long-term HRT use was not associated with educational attainment, ethnicity, body mass index, health status, physical activity, or family medical history. Correlates commonly associated with HRT use, such as higher education, greater physical activity and functioning, and lower chronic disease comorbidity, did not significantly distinguish long-term from short-term users. Am J Epidemiol 1999;149:275–81. [ABSTRACT FROM AUTHOR]

Objective: To evaluate sexual function in midlife women taking low-dose oral estradiol or venlafaxine for hot flushes.Methods: In an 8-week randomized controlled trial among women aged 40-62 years, sexual function was compared between 0.5 mg oral estradiol per day or 75 mg venlafaxine per day (both compared with a placebo). Measures included composite and six domain scores from the Female Sexual Function Index and sexually related personal distress.Results: Participants were aged 54.6 years (standard deviation [SD] 3.8) years, 59% white, with 8.1 (SD 5.3) daily hot flushes. Median composite baseline Female Sexual Function Index score was 16.3 (SD 11.9, n=256) for all women and 21.7 (SD 9.3, n=198) among sexually active women. Composite mean Female Sexual Function Index change from baseline to week 8 was 1.4 (95% confidence interval [CI] -0.4 to 3.2) for estradiol, 1.1 (95% CI -0.5 to 2.7) for venlafaxine, and -0.3 (95% CI -1.6 to 1.0) for placebo. Composite Female Sexual Function Index and sexually related distress change from baseline did not differ between estradiol and placebo (P=.38, P=.30) or venlafaxine and placebo (P=.79, P=.48). Among sexually active women, Female Sexual Function Index domain score change from baseline differences (active compared with placebo) in desire was 0.3 (95% CI 0.0-0.6) for estradiol, -0.6 (95% CI -1.2 to 0.0) in orgasm for venlafaxine, and 0.9 (95% CI 0.2-1.6) in penetration pain for venlafaxine. No women reported adverse events related to sexual dysfunction.Conclusion: Overall sexual function among nondepressed midlife women experiencing hot flushes did not change over 8 weeks with low-dose oral estradiol or venlafaxine (compared with placebo), although a subtle increase in desire (estradiol) and decreases in orgasm and pain (venlafaxine) may exist.Clinical Trial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01418209.Level Of Evidence: I. [ABSTRACT FROM AUTHOR]