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ImportanceEffective, practical, nonpharmacologic therapies are needed to treat menopause-related insomnia symptoms in primary and women's specialty care settings.ObjectiveTo evaluate the efficacy of telephone-based cognitive behavioral therapy for insomnia (CBT-I) vs menopause education control (MEC).Design, setting, and participantsA single-site, randomized clinical trial was conducted from September 1, 2013, to August 31, 2015, in western Washington State among 106 perimenopausal or postmenopausal women aged 40 to 65 years with moderate insomnia symptoms (Insomnia Severity Index [ISI] score, ≥12) and 2 or more daily hot flashes. Blinded assessments were conducted at baseline, 8, and 24 weeks postrandomization. An intent-to-treat analysis was conducted.InterventionsSix CBT-I or MEC telephone sessions in 8 weeks. Participants submitted weekly electronic sleep diaries and received group-specific written educational materials. The CBT-I sessions included sleep restriction, stimulus control, sleep hygiene education, cognitive restructuring, and behavioral homework; MEC sessions provided information about menopause and women's health.Main outcomes and measuresPrimary outcome was scores on the ISI (score range, 0-28; scores ≥15 indicate moderate to severe insomnia). Secondary outcome was scores on the Pittsburgh Sleep Quality Index (score range, 0-21; higher scores indicate worse sleep quality). Additional outcomes included sleep and hot flash diary variables and hot flash interference.ResultsAt 8 weeks, ISI scores had decreased 9.9 points among 53 women receiving CBT-I (mean [SD] age, 55.0 [3.5] years) and 4.7 points among 53 women receiving MEC (age, 54.7 [4.7] years), a mean between-group difference of 5.2 points (95% CI, -6.1 to -3.3; P

ObjectiveResearch has suggested that the autonomic nervous system (ANS) is involved in the experience of vasomotor symptoms (VMS) during menopause. We examined the relationship of VMS intensity and heart rate variability (HRV), a measure of ANS function.MethodsWomen (n = 282) were recruited from three American states for a clinical trial of yoga, exercise, and omega-3 fatty acid supplements for VMS. To be eligible, women had to report at least 14 VMS per week, with some being moderate to severe. Sitting electrocardiograms were recorded for 15 min using Holter monitors at both baseline and 12-week follow-up. Time and frequency domain HRV measures were calculated. Women completed daily diary measures of VMS frequency and intensity for 2 weeks at baseline and for 1 week at the follow-up assessment 12 weeks later. Multivariable linear regression was used to assess the relationship between VMS and baseline HRV measures and to compare change in HRV with change in VMS over the 12 weeks.ResultsBaseline HRV was not associated with either VMS frequency or intensity at baseline. Change in HRV was not associated with change in VMS frequency or intensity across the follow-up.InterpretationHeart rate variability (HRV) was not associated with basal VMS frequency or intensity in perimenopausal and postmenopausal women experiencing high levels of VMS. Autonomic function may be associated with the onset or presence of VMS, but not with the number or intensity of these symptoms.

ObjectiveTo describe the effects of six interventions for menopausal vasomotor symptoms relative to control in a pooled analysis, facilitating translation of the results for clinicians and symptomatic women. The Menopause Strategies: Finding Lasting Answers for Symptoms and Health network tested these interventions in three randomized clinical trials.MethodsAn analysis of pooled individual-level data from three randomized clinical trials is presented. Participants were 899 perimenopausal and postmenopausal women with at least 14 bothersome vasomotor symptoms per week. Interventions included 10-20 mg escitalopram per day, nonaerobic yoga, aerobic exercise, 1.8 g per day omega-3 fatty acid supplementation, 0.5 mg low-dose oral 17-beta-estradiol (E2) per day, and 75 mg low-dose venlafaxine XR per day. The main outcome measures were changes from baseline in mean daily vasomotor symptom frequency and bother during 8-12 weeks of treatment. Linear regression models estimated differences in outcomes between each intervention and corresponding control group adjusted for baseline characteristics. Models included trial-specific intercepts, effects of the baseline outcome measure, and time.ResultsThe 8-week reduction in vasomotor symptom frequency from baseline relative to placebo was similar for escitalopram at -1.4 per day (95% confidence interval [CI] -2.7 to -0.2), low-dose E2 at -2.4 (95% CI -3.4 to -1.3), and venlafaxine at -1.8 (95% CI -2.8 to -0.8); vasomotor symptom bother reduction was minimal and did not vary across these three pharmacologic interventions (mean -0.2 to -0.3 relative to placebo). No effects on vasomotor symptom frequency or bother were seen with aerobic exercise, yoga, or omega-3 supplements.ConclusionThese analyses suggest that escitalopram, low-dose E2, and venlafaxine provide comparable, modest reductions in vasomotor symptom frequency and bother among women with moderate hot flushes.Clinical trial registrationClinicalTrials.gov, www.clinicaltrials.gov, NCT00894543 (MsFLASH 01), NCT01178892 (MsFLASH 02), and NCT01418209 (MsFLASH 03).

Study objectivesDetermine effects of low-dose estradiol and low-dose venlafaxine on self-reported sleep measures in menopausal women with hot flashes.Design3-arm double-blind randomized trial. Participants assigned in a 2:2:3 ratio to 17β estradiol 0.5 mg/day (n = 97), venlafaxine XR 75 mg/day (n = 96), or placebo (n = 146) for 8 weeks.SettingAcademic research centers.Participants339 community-dwelling perimenopausal and postmenopausal women with ≥2 bothersome hot flashes per day.Measurements and resultsInsomnia symptoms (Insomnia Severity Index [ISI]) and sleep quality (Pittsburgh Sleep Quality Index [PSQI]) at baseline, week 4 and 8; 325 women (96%) provided ISI data and 312 women (92%) provided PSQI data at baseline and follow-up. At baseline, mean (SD) hot flash frequency was 8.1/day (5.3), mean ISI was 11.1 (6.0), and mean PSQI was 7.5 (3.4). Mean (95% CI) change from baseline in ISI at week 8 was -4.1 points (-5.3 to -3.0) with estradiol, -5.0 points (-6.1 to -3.9) with venlafaxine, and -3.0 points (-3.8 to -2.3) with placebo (P overall treatment effect vs. placebo 0.09 for estradiol and 0.007 for venlafaxine). Mean (95% CI) change from baseline in PSQI at week 8 was -2.2 points (-2.8 to -1.6) with estradiol, -2.3 points (-2.9 to -1.6) with venlafaxine, and -1.2 points (-1.7 to -0.8) with placebo (P overall treatment effect vs. placebo 0.04 for estradiol and 0.06 for venlafaxine).ConclusionsAmong perimenopausal and postmenopausal women with hot flashes, both low dose oral estradiol and low-dose venlafaxine compared with placebo modestly reduced insomnia symptoms and improved subjective sleep quality.Clinical trial registrationNCT01418209 at www.clinicaltrials.gov.

ObjectiveTo evaluate sexual function in midlife women taking low-dose oral estradiol or venlafaxine for hot flushes.MethodsIn 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.ResultsParticipants 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.ConclusionOverall 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 registrationClinicalTrials.gov, www.clinicaltrials.gov, NCT01418209.Level of evidenceI.

ImportanceEstrogen 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.ObjectiveTo 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 participantsIn 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.InterventionsParticipants 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 measuresThe 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.ResultsCompared 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

BackgroundCareful 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.MethodsWe 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.ResultsAmong 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).ConclusionsDoctor advice is strongly associated with successful HT discontinuation. Symptom management, particularly sleep and mood disturbances, may help women discontinue HT.

ObjectiveThis study aims to determine the efficacy of exercise training for alleviating vasomotor and other menopausal symptoms.MethodsLate perimenopausal and postmenopausal sedentary women with frequent vasomotor symptoms (VMS) participated in a randomized controlled trial conducted in three sites: 106 women randomized to exercise and 142 women randomized to usual activity. The exercise intervention consisted of individual facility-based aerobic exercise training three times per week for 12 weeks. VMS frequency and bother were recorded on daily diaries at baseline and on weeks 6 and 12. Intent-to-treat analyses compared between-group differences in changes in VMS frequency and bother, sleep symptoms (Insomnia Severity Index and Pittsburgh Sleep Quality Index), and mood (Patient Health Questionnaire-8 and Generalized Anxiety Disorder-7 questionnaire).ResultsAt the end of week 12, changes in VMS frequency in the exercise group (mean change, -2.4 VMS/d; 95% CI, -3.0 to -1.7) and VMS bother (mean change on a four-point scale, -0.5; 95% CI, -0.6 to -0.4) were not significantly different from those in the control group (-2.6 VMS/d; 95% CI, -3.2 to -2.0; P = 0.43; -0.5 points; 95% CI, -0.6 to -0.4; P = 0.75). The exercise group reported greater improvement in insomnia symptoms (P = 0.03), subjective sleep quality (P = 0.01), and depressive symptoms (P = 0.04), but differences were small and not statistically significant when P values were adjusted for multiple comparisons. Results were similar when considering treatment-adherent women only.ConclusionsThese findings provide strong evidence that 12 weeks of moderate-intensity aerobic exercise do not alleviate VMS but may result in small improvements in sleep quality, insomnia, and depression in midlife sedentary women.

ObjectiveThis study aims to determine the efficacy of exercise training for alleviating vasomotor and other menopausal symptoms.MethodsLate perimenopausal and postmenopausal sedentary women with frequent vasomotor symptoms (VMS) participated in a randomized controlled trial conducted in three sites: 106 women randomized to exercise and 142 women randomized to usual activity. The exercise intervention consisted of individual facility-based aerobic exercise training three times per week for 12 weeks. VMS frequency and bother were recorded on daily diaries at baseline and on weeks 6 and 12. Intent-to-treat analyses compared between-group differences in changes in VMS frequency and bother, sleep symptoms (Insomnia Severity Index and Pittsburgh Sleep Quality Index), and mood (Patient Health Questionnaire-8 and Generalized Anxiety Disorder-7 questionnaire).ResultsAt the end of week 12, changes in VMS frequency in the exercise group (mean change, -2.4 VMS/d; 95% CI, -3.0 to -1.7) and VMS bother (mean change on a four-point scale, -0.5; 95% CI, -0.6 to -0.4) were not significantly different from those in the control group (-2.6 VMS/d; 95% CI, -3.2 to -2.0; P = 0.43; -0.5 points; 95% CI, -0.6 to -0.4; P = 0.75). The exercise group reported greater improvement in insomnia symptoms (P = 0.03), subjective sleep quality (P = 0.01), and depressive symptoms (P = 0.04), but differences were small and not statistically significant when P values were adjusted for multiple comparisons. Results were similar when considering treatment-adherent women only.ConclusionsThese findings provide strong evidence that 12 weeks of moderate-intensity aerobic exercise do not alleviate VMS but may result in small improvements in sleep quality, insomnia, and depression in midlife sedentary women.

ObjectiveThe purpose of this study was to determine the efficacy of 3 nonhormonal therapies for the improvement of menopause-related quality of life in women with vasomotor symptoms.Study designWe conducted a 12-week 3 × 2 randomized, controlled, factorial design trial. Peri- and postmenopausal women, 40-62 years old, were assigned randomly to yoga (n = 107), exercise (n = 106), or usual activity (n = 142) and also assigned randomly to a double-blind comparison of omega-3 (n = 177) or placebo (n = 178) capsules. We performed the following interventions: (1) weekly 90-minute yoga classes with daily at-home practice, (2) individualized facility-based aerobic exercise training 3 times/week, and (3) 0.615 g omega-3 supplement, 3 times/day. The outcomes were assessed with the following scores: Menopausal Quality of Life Questionnaire (MENQOL) total and domain (vasomotor symptoms, psychosocial, physical and sexual).ResultsAmong 355 randomly assigned women who average age was 54.7 years, 338 women (95%) completed 12-week assessments. Mean baseline vasomotor symptoms frequency was 7.6/day, and the mean baseline total MENQOL score was 3.8 (range, 1-8 from better to worse) with no between-group differences. For yoga compared to usual activity, baseline to 12-week improvements were seen for MENQOL total -0.3 (95% confidence interval, -0.6 to 0; P = .02), vasomotor symptom domain (P = .02), and sexuality domain (P = .03) scores. For women who underwent exercise and omega-3 therapy compared with control subjects, improvements in baseline to 12-week total MENQOL scores were not observed. Exercise showed benefit in the MENQOL physical domain score at 12 weeks (P = .02).ConclusionAll women become menopausal, and many of them seek medical advice on ways to improve quality of life; little evidence-based information exists. We found that, among healthy sedentary menopausal women, yoga appears to improve menopausal quality of life; the clinical significance of our finding is uncertain because of the modest effect.

BackgroundBehavioral strategies are recommended for menopausal symptoms, but little evidence exists regarding efficacy.PurposeDescribe design and methodology of a randomized controlled 3 by 2 factorial trial of yoga, exercise and omega-3 fatty acids.MethodsWomen from three geographic areas with a weekly average of ≥14 hot flashes/night sweats, who met exclusion/inclusion criteria, were randomized to 12weeks of: 1) yoga classes and daily home practice; 2) supervised, facility-based aerobic exercise training; or 3) usual activity. Women in each arm were further randomized to either omega-3 supplement or placebo. Standardized training, on-going monitoring, and site visits were adopted to ensure consistency across sites and fidelity to the intervention. Participant adherence to the intervention protocol was monitored continuously, and retention was actively encouraged by staff. Information on adverse events was systematically collected.ResultsOf 7377 women who responded to mass mailings, 355 (4.8%) were randomized; mean age was 54.7 (sd=3.7), 26.2% were African American, 81.7% were post-menopausal, and mean baseline frequency of daily hot flashes/night sweats was 7.6 (sd=3.8). Adherence of ≥80% was 59% for yoga, 77% for exercise training, and 80% for study pills. Final week 12 data were collected from 95.2%ConclusionsConducting a multi-site, multi-behavioral randomized trial for menopausal symptoms is challenging but feasible. Benefits included cost-effective study design, centralized recruitment, and methodologic standardization.

ObjectiveTo evaluate the effects of escitalopram 10-20 mg/day on menopause-related quality of life and pain in healthy menopausal women with hot flashes.Study designA double-blind, placebo-controlled randomized trial of escitalopram 10-20mg/day vs. identical placebo was conducted among 205 women ages 40-62 years with an average of ≥4 daily hot flashes recruited at 4 clinical sites from July 2009 to June 2010.Main outcome measuresThe primary trial outcomes, reported previously, were the frequency and severity of vasomotor symptoms at 8 weeks. Here, we report on the pre-specified secondary endpoints of total and domain scores from the Menopause-Specific Quality of Life Questionnaire (MENQOL) and the pain intensity and interference scale (PEG).ResultsOutcome data were collected on 97% of randomized women and 87% of women took at least 70% of their study medication. Treatment with escitalopram resulted in significantly greater improvement in total MENQOL scores (mean difference at 8 weeks of -0.41; 95% confidence interval (CI) -0.71 to -0.11; p

ContextConcerns regarding the risks associated with estrogen and progesterone to manage menopausal symptoms have resulted in its declining use and increased interest in nonhormonal treatments with demonstrated efficacy for hot flashes.ObjectiveTo determine the efficacy and tolerability of 10 to 20 mg/d escitalopram, a selective serotonin reuptake inhibitor, in alleviating the frequency, severity, and bother of menopausal hot flashes.Design, setting, and patientsA multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel group trial that enrolled 205 women (95 African American; 102 white; 8 other) between July 2009 and June 2010.InterventionWomen received 10 to 20 mg/d of escitalopram or a matching placebo for 8 weeks.Main outcome measuresPrimary outcomes were the frequency and severity of hot flashes assessed by prospective daily diaries at weeks 4 and 8. Secondary outcomes were hot flash bother, recorded on daily diaries, and clinical improvement (defined as hot flash frequency ≥50% decrease from baseline).ResultsMean (SD) daily hot flash frequency was 9.78 (5.60) at baseline. In a modified intent-to-treat analysis that included all randomized participants who provided hot flash diary data, the mean difference in hot flash frequency reduction was 1.41 (95% CI, 0.13-2.69) fewer hot flashes per day at week 8 among women taking escitalopram (P < .001), with mean reductions of 4.60 (95% CI, 3.74-5.47) and 3.20 (95% CI, 2.24-4.15) hot flashes per day in the escitalopram and placebo groups, respectively. Fifty-five percent of women in the escitalopram group vs 36% in the placebo group reported a decrease of at least 50% in hot flash frequency (P = .009) at the 8-week follow-up. Reductions in hot flash severity scores were significantly greater in the escitalopram group (-0.52; 95% CI, -0.64 to -0.40 vs -0.30; 95% CI, -0.42 to -0.17 for placebo; P < .001). Race did not significantly modify the treatment effect (P = .62). Overall discontinuation due to adverse events was 4% (7 in the active group, 2 in the placebo group). Three weeks after treatment ended, women in the escitalopram group reported a mean 1.59 (95% CI, 0.55-2.63; P = .02) more hot flashes per day than women in the placebo group.ConclusionAmong healthy women, the use of escitalopram (10-20 mg/d) compared with placebo resulted in fewer and less severe menopausal hot flashes at 8 weeks of follow-up.Trial registrationclinicaltrials.gov Identifier: NCT00894543.

BackgroundPrescribing 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.MethodsBetween 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).ResultsRespondents 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

ObjectiveThe goal of this study was to assess whether menopausal symptoms were more common and/or more severe among women with depressive symptoms.MethodsA cross-sectional survey of 1358 women, ages 45-70, at two large integrated health plans (Seattle; Boston) was performed. Information on demographics, medical and reproductive history, medication use, menopausal experience and depressive symptoms (PHQ-8) were collected. Women taking HT were excluded. Logistic regression models adjusted for age and body mass index tested the associations between menopausal symptoms (hot flushes, night sweats, vaginal dryness and dyspareunia) and presence of moderate/severe depressive symptoms.Results770 women were included; 98 (12.7%) had moderate/severe depressive symptoms and 672 (87.3%) had no/mild depressive symptoms. Women with moderate/severe depressive symptoms were almost twice as likely to report recent vasomotor symptoms (hot flashes and or night sweats) vs. women with no/mild depressive symptoms (adjusted odds ratio (aOR) 1.67, 95%CI 1.04-2.68), and to report them as severe (aOR 1.63, 95%CI 0.95-2.83). A higher symptom burden was observed despite the fact that 20% of women with moderate/severe depressive symptoms (vs. 4.6% no/mild depressive symptoms) were using an SSRI or SNRI, medications known to improve vasomotor symptoms. The percentage of women with menopausal symptoms, and the percentage with severe vasomotor symptoms were linearly associated with the depressive symptom score.ConclusionsDepressive symptoms "amplified" the menopausal experience, or alternatively, severe vasomotor symptoms worsened depressive symptoms.

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.

ObjectiveThe objective of the study was to evaluate the association of depression, sleep disturbance, and menopausal symptoms with diminished libido.Study designData from a 2001-2002 baseline survey of 341 peri- and postmenopausal women, aged 45-55 years, participating in a randomized trial, was analyzed. Eligibility included at least 2 hot flashes and/or night sweats per day and no hormone therapy for at least the prior 3 months. The survey evaluated sexual function, depression, sleep, and vasomotor symptoms. We examined the association between these factors, using multivariate regression models.ResultsOf 341 women, 64% had diminished libido, 18% had moderate to severe depression, and 43% had poor sleep quality. Women averaged 4.6 hot flashes and 1.9 night sweats per day. Depressive symptoms (P = .003), poor sleep (P = .02), and night sweats (P = .04) were significantly associated with diminished libido.ConclusionFactors associated with diminished libido in midlife are complex but include depression, disturbed sleep, and night sweats, all common symptoms of the menopausal transition and early menopause.

ObjectiveBlack 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.MethodsThree 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.ResultsThere 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).ConclusionsBlack cohosh containing therapies had no demonstrable effects on lipids, glucose, insulin or fibrinogen.

BackgroundHerbal supplements are widely used for vasomotor symptoms.ObjectiveTo test the efficacy of 3 herbal regimens and hormone therapy for relief of vasomotor symptoms compared with placebo.Design1-year randomized, double-blind, placebo-controlled trial conducted from May 2001 to September 2004.SettingGroup Health, Washington State.Participants351 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.MeasurementsRate and intensity of vasomotor symptoms (1 = mild to 3 = severe), and Wiklund Vasomotor Symptom Subscale.Interventions1) 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.ResultsVasomotor 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).LimitationsThe 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.ConclusionBlack 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 numberNCT00169299.

We designed a randomized double-blind randomized trial to examine the short and long-term effects of alternative approaches commonly used to manage menopause symptoms. Women were randomly assigned to: (1) black cohosh 160 mg daily; (2) multibotanical (50 mg black cohosh, alfalfa, chaste tree, dong quai, false unicorn, licorice, oats, pomegranate, Siberian ginseng, boron) four capsules daily; (3) multibotanical plus telephone counseling to increase dietary soy; (4) conjugated equine estrogen 0.625 mg +/- 2.5 mg medroxyprogesterone acetate; or (5) placebo. Working with a skilled CAM provider helped us choose interventions that reflected naturopathic practices worthy of study. Mass mailing, with careful tracking and rapid responses to recruitment rates, was an effective and cost-effective recruitment strategy. Creativity was necessary to construct methods for blinding capsules and the dietary soy intervention. Independent testing of herbal products was vital to confirming their constituents. The Data and Safety and Monitoring Committee, and project officers at the funding agency, were critical partners in designing responses to unanticipated Women's Health Initiative findings published during the HALT trial. Careful monitoring of adverse events may provide much needed information about side effects of herbal products and supplements. Despite inherent challenges, the study of alternative therapies for menopause symptoms is a rewarding and important area deserving of further inquiry.

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 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.

ObjectivesThe purpose of this study was to compare hormone replacement therapy (HRT) prescribing frequency to provider characteristics, attitudes and beliefs about menopause and HRT.MethodsThere was a mailed survey of providers at a large staff-model HMO in Washington state. Participants included 250 family practice physicians, 22 gynecologists, and 13 women's health care specialists and nurse midwives (83% response rate). The primary outcome, "HRT prescribing frequency" (derived from automated pharmacy and visit data) was defined as: the total number of estrogen prescriptions written by the provider and filled by women aged 50-80 years during the 12 months prior to the survey, divided by the number of visits made to the provider by women aged 50-80 years during that same 12-month period. Covariates included provider characteristics and beliefs about menopause and HRT. Logistic regression was used to distinguish providers in the upper 40% versus the lower 60% of HRT prescribing frequency.ResultsControlling for age and practice type, HRT prescribing frequency was lower among men than women providers (odds ratio [OR] 0.38, 95% confidence interval [CI] 0.21-0.65), higher among providers who agreed (vs. disagreed or neutral) that a convincing scientific case has been made that HRT prevents heart disease (OR 2.66, 95% CI 1.53-4.61), and higher among those in the upper tertile vs. lower tertiles of an HRT encouragement scale (OR 2.50, 95% CI 1.29-4.85).ConclusionsFemale providers and providers with positive attitudes toward HRT are the most likely to prescribe it.

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.

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 ≥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. [ABSTRACT FROM AUTHOR]

Objective: Blood and urine concentrations of hormones are implicated in the etiology of some cancers. Small studies have assessed relationships between production of the daidzein metabolites equol and O-desmethylangolensin (ODMA) and hormones, but findings are unclear. We evaluated relationships between daidzein-metabolizing phenotypes and follicular phase concentrations of estrogens, androgens, sex hormone binding globulin (SHBG), and urinary estrogen metabolites in premenopausal women.Methods: Two-hundred women collected a first-void urine sample after a 3-day soy challenge, and 191 and 193 provided fasting blood and spot urine samples, respectively, during days 5-9 of their menstrual cycle. Soy challenge urines were analyzed for isoflavones; serum was analyzed for estrogens, androgens, and SHBG; spot urines were analyzed for 2-hydroxyestrone and 16alpha-hydroxyestrone. Data were log-transformed and multiple regression analyses were conducted to assess relationships between daidzein-metabolizing phenotypes and hormones and SHBG. Data from 187 and 189 women were included in analyses of serum and urine hormones, respectively.Results: 55 (27.5%) and 182 (91%) of the 200 women who provided a soy challenge urine sample were equol- and ODMA-producers (>87.5 ng/ml urine), respectively. In unadjusted analyses, equol-producers (n = 52) had lower free testosterone than equol non-producers (n = 137, p = 0.02). In adjusted analyses, there were no differences between producers and non-producers of either daidzein metabolite.Conclusions: In the absence of a soy intervention, we found no difference in serum or urine hormone concentrations between producers and non-producers of equol or ODMA. [ABSTRACT FROM AUTHOR]

Background: The 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 Participants: We 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.Approach: We used Template Analysis to code transcribed telephone interviews and identify themes.Results: Physicians 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.Conclusions: Physicians 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. [ABSTRACT FROM AUTHOR]

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 LIT 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 Will 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. [ABSTRACT FROM AUTHOR]

Background: Vulvovaginal symptoms, which include dryness, irritation, and pain with intercourse, are common among postmenopausal women and are associated with impaired sexual functioning and quality of life. Previous assessment of treatment strategies for these symptoms has been limited by a lack of sensitive patient-centered outcome measures that assess symptom impact on functional and quality-of-life domains.Objective: We aimed to (1) examine change in the impact of postmenopausal vulvovaginal symptoms on multiple aspects of well-being and functioning in relation to vaginal estradiol and moisturizer treatment and (2) guide meaningful interpretation of scores on a structured-item questionnaire measure of condition-specific impact.Study Design: Data were drawn from postmenopausal women who were enrolled in the Menopause Strategies: Finding Lasting Answers for Symptoms and Health Vaginal Health Trial (a 12-week, double-blind, placebo-controlled randomized trial of treatment for vulvovaginal symptoms) who were assigned to vaginal 10-μg estradiol tablet plus placebo gel (n=98), vaginal moisturizer plus placebo tablet (n=97), or dual placebo (n=94). At baseline and 12-week follow up, participants completed the Day-to-Day Impact of Vaginal Aging questionnaire to assess the impact of vaginal symptoms on 4 domains (activities of daily living, emotional well-being, sexual functioning, and body image), each on a 0-4 point scale. Day-to-Day Impact of Vaginal Aging sensitivity to change was assessed by the examination of the associations between change in Day-to-Day Impact of Vaginal Aging domain scores and vulvovaginal symptom severity from baseline to 12 weeks with analysis of covariance. Within-woman and between-group minimal clinically important improvement was assessed with the use of an anchor-based approach that relates change in Day-to-Day Impact of Vaginal Aging domain scores with self-reported benefit from treatment.Results: Participants in all treatment arms (n=289) demonstrated reduced impact of vulvovaginal symptoms on all domains of well-being and functioning as assessed by Day-to-Day Impact of Vaginal Aging at 12-week follow up, with no significant differences in improvement between women who were assigned to either estradiol tablet or vaginal moisturizer compared with placebo. For all Day-to-Day Impact of Vaginal Aging domains, mean impact scores were reduced when participants reported symptom improvement (-0.3 to -0.8 point change in Day-to-Day Impact of Vaginal Aging scores for <2-point symptom severity change vs -0.4 to -1.6 point change in Day-to-Day Impact of Vaginal Aging scores for 2+ point symptom severity change; all P<.001). Minimal clinically important change in Day-to-Day Impact of Vaginal Aging domain scale scores, which are anchored to self-reported meaningful benefit from treatment at 12 weeks, ranged from -0.4 to -1.3 (within-woman) and -0.2 to -0.7 (between-group). Observed change and minimal clinically important difference were largest for the sexual functioning domain.Conclusion: The impact of vulvovaginal symptoms on day-to-day activities, sexual function, emotional well-being, and body image may be improved with low-dose vaginal estradiol, moisturizer, or topical placebo. The Day-to-Day Impact of Vaginal Aging questionnaire demonstrates sensitivity to change with treatment of vulvovaginal symptoms, particularly Day-to-Day Impact of Vaginal Aging scales that focus on symptom impact on sexual functioning and body image. Minimal clinically important improvement in the impact of vulvovaginal symptoms as measured by the Day-to-Day Impact of Vaginal Aging can be defined with the use of these measures. [ABSTRACT FROM AUTHOR]

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. [Copyright &y& Elsevier]