Demographic, Reproductive, and Medical Risk Factors for Intrauterine Device Expulsion.

OBJECTIVE: To explore to what extent intrauterine device (IUD) expulsion is associated with demographic and clinical risk factors. METHODS: The APEX-IUD (Association of Perforation and Expulsion of IntraUterine Devices) study was a U.S. cohort study using electronic health records from three integrated health care systems (Kaiser Permanente Northern California, Southern California, and Washington) and a health care information exchange (Regenstrief Institute). These analyses included individuals aged 50 years or younger with IUD insertions from 2001 to 2018. Intrauterine device expulsion cumulative incidence and incidence rates were estimated. Using Cox regression models, hazard ratios with 95% CIs were estimated before and after adjustment for risk factors of interest (age, race and ethnicity, parity, body mass index [BMI], heavy menstrual bleeding, and dysmenorrhea) and potential confounders. RESULTS: In total, 228,834 individuals with IUD insertion and no delivery in the previous 52 weeks were identified (184,733 [80.7%] with levonorgestrel-releasing intrauterine system). Diagnosis of heavy menstrual bleeding-particularly a diagnosis in both recent and past periods-was the strongest risk factor for IUD expulsion. Categories with the highest risk of IUD expulsion within each risk factor included individuals diagnosed with overweight, obesity, and morbid obesity; those in younger age groups, especially among those aged 24 years or younger; and in those with parity of four or more. Non-Hispanic White individuals had the lowest incidence and risk, and after adjustment, Asian or Pacific Islander individuals had the highest risk. Dysmenorrhea was not independently associated with expulsion risk when adjusting for heavy menstrual bleeding. CONCLUSION: Most risk factors for expulsion identified in this study appear consistent with known physiologic factors that affect uterine anatomy and physiology (age, BMI, heavy menstrual bleeding, parity). The increased risk of IUD expulsion among individuals of color warrants further investigation. Intrauterine devices are an effective long-term contraceptive; expulsion is uncommon, but patients should be counseled accordingly. FUNDING SOURCE: Bayer AG. CLINICAL TRIAL REGISTRATION: EU PAS register, EUPAS33461.

Association between intrauterine device type and risk of perforation and device expulsion: results from the Association of Perforation and Expulsion of Intrauterine Device study.

BACKGROUND: Intrauterine devices, including levonorgestrel-releasing and copper devices, are highly effective long-acting reversible contraceptives. The potential risks associated with intrauterine devices are low and include uterine perforation and device expulsion. OBJECTIVE: This study aimed to evaluate the risk of perforation and expulsion associated with levonorgestrel-releasing devices vs copper devices in clinical practice in the United States. STUDY DESIGN: The Association of Perforation and Expulsion of Intrauterine Device study was a retrospective cohort study of women aged ≤50 years with an intrauterine device insertion during 2001 to 2018 and information on intrauterine device type and patient and medical characteristics. Of note, 4 research sites with access to electronic health records contributed data for the study: 3 Kaiser Permanente-integrated healthcare systems (Northern California, Southern California, and Washington) and 1 healthcare system using data from a healthcare information exchange in Indiana (Regenstrief Institute). Perforation was classified as any extension of the device into or through the myometrium. Expulsion was classified as complete (not visible in the uterus or abdomen or patient reported) or partial (any portion in the cervix or malpositioned). We estimated the crude incidence rates and crude cumulative incidence by intrauterine device type. The risks of perforation and expulsion associated with levonorgestrel-releasing intrauterine devices vs copper intrauterine devices were estimated using Cox proportional-hazards regression with propensity score overlap weighting to adjust for confounders. RESULTS: Among 322,898 women included in this analysis, the incidence rates of perforation per 1000 person-years were 1.64 (95% confidence interval, 1.53-1.76) for levonorgestrel-releasing intrauterine devices and 1.27 (95% confidence interval, 1.08-1.48) for copper intrauterine devices; 1-year and 5-year crude cumulative incidence was 0.22% (95% confidence interval, 0.20-0.24) and 0.63% (95% confidence interval, 0.57-0.68) for levonorgestrel-releasing intrauterine devices and 0.16% (95% confidence interval, 0.13-0.20) and 0.55% (95% confidence interval, 0.44-0.68) for copper intrauterine devices, respectively. The incidence rates of expulsion per 1000 person-years were 13.95 (95% confidence interval, 13.63-14.28) for levonorgestrel-releasing intrauterine devices and 14.08 (95% confidence interval, 13.44-14.75) for copper intrauterine devices; 1-year and 5-year crude cumulative incidence was 2.30% (95% confidence interval, 2.24-2.36) and 4.52% (95% confidence interval, 4.40-4.65) for levonorgestrel-releasing intrauterine devices and 2.30% (95% confidence interval, 2.18-2.44) and 4.82 (95% confidence interval, 4.56-5.10) for copper intrauterine devices, respectively. Comparing levonorgestrel-releasing intrauterine devices with copper intrauterine devices, the adjusted hazard ratios were 1.49 (95% confidence intervals, 1.25-1.78) for perforation and 0.69 (95% confidence intervals, 0.65-0.73) for expulsion. CONCLUSION: After adjusting for potential confounders, levonorgestrel-releasing intrauterine devices were associated with an increased risk of uterine perforation and a decreased risk of expulsion relative to copper intrauterine devices. Given that the absolute numbers of these events are low in both groups, these differences may not be clinically meaningful.

Association between menorrhagia and risk of intrauterine device-related uterine perforation and device expulsion: results from the Association of Uterine Perforation and Expulsion of Intrauterine Device study.

BACKGROUND: Intrauterine devices are effective instruments for contraception, and 1 levonorgestrel-releasing device is also indicated for the treatment of heavy menstrual bleeding (menorrhagia). OBJECTIVE: To compare the incidence of intrauterine device expulsion and uterine perforation in women with and without a diagnosis of menorrhagia within the first 12 months before device insertion STUDY DESIGN: This was a retrospective cohort study conducted in 3 integrated healthcare systems (Kaiser Permanente Northern California, Southern California, and Washington) and a healthcare information exchange (Regenstrief Institute) in the United States using electronic health records. Nonpostpartum women aged ≤50 years with intrauterine device (eg, levonorgestrel or copper) insertions from 2001 to 2018 and without a delivery in the previous 12 months were studied in this analysis. Recent menorrhagia diagnosis (ie, recorded ≤12 months before insertion) was ascertained from the International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification codes. The study outcomes, viz, device expulsion and device-related uterine perforation (complete or partial), were ascertained from electronic medical records and validated in the data sources. The cumulative incidence and crude incidence rates with 95% confidence intervals were estimated. Cox proportional hazards models estimated the crude and adjusted hazard ratios using propensity score overlap weighting (13-16 variables) and 95% confidence intervals. RESULTS: Among 228,834 nonpostpartum women, the mean age was 33.1 years, 44.4% of them were White, and 31,600 (13.8%) had a recent menorrhagia diagnosis. Most women had a levonorgestrel-releasing device (96.4% of those with and 78.2% of those without a menorrhagia diagnosis). Women with a menorrhagia diagnosis were likely to be older, obese, and have dysmenorrhea or fibroids. Women with a menorrhagia diagnosis had a higher intrauterine device-expulsion rate (40.01 vs 10.92 per 1000 person-years) than those without, especially evident in the first few months after insertion. Women with a menorrhagia diagnosis had a higher cumulative incidence (95% confidence interval) of expulsion (7.00% [6.70-7.32] at 1 year and 12.03% [11.52-12.55] at 5 years) vs those without (1.77% [1.70-1.84] at 1 year and 3.69% [3.56-3.83] at 5 years). The risk of expulsion was increased for women with a menorrhagia diagnosis vs for those without (adjusted hazard ratio, 2.84 [95% confidence interval, 2.66-3.03]). The perforation rate was low overall (<1/1000 person-years) but higher in women with a diagnosis of menorrhagia vs in those without (0.98 vs 0.63 per 1000 person-years). The cumulative incidence (95% confidence interval) of uterine perforation was slightly higher for women with a menorrhagia diagnosis (0.09% [0.06-0.14] at 1 year and 0.39% [0.29-0.53] at 5 years) than those without it (0.07% [0.06-0.08] at 1 year and 0.28% [0.24-0.33] at 5 years). The risk of perforation was slightly increased in women with a menorrhagia diagnosis vs in those without (adjusted hazard ratio, 1.53; 95% confidence interval, 1.10-2.13). CONCLUSION: The risk of expulsion is significantly higher in women with a recent diagnosis of menorrhagia. Patient education and counseling regarding the potential expulsion risk is recommended at insertion. The absolute risk of perforation for women with a recent diagnosis of menorrhagia is very low. The increased expulsion and perforation rates observed are likely because of causal factors of menorrhagia.

MsFLASH analysis of diurnal salivary cortisol and palpitations in peri- and postmenopausal women.

OBJECTIVE: To evaluate the relationship between diurnal salivary cortisol patterns and distress from heart palpitations in midlife women. METHODS: We analyzed baseline data from 293 women who were eligible for a 3 × 2 factorial trial of exercise or yoga versus routine activity, and omega-3 fish oil versus placebo for vasomotor symptoms. Women self-collected salivary cortisol using swabs at four time points over 2 consecutive days and reported distress from heart racing or pounding during the past 2 weeks using a single item. Sample description and covariate data included demographics, clinical data, vasomotor symptom frequency from daily diaries, medication use, and validated questionnaires on depression, stress, and insomnia (Patient Health Questionnaire-8, Perceived Stress Scale, and Insomnia Severity index). Data were analyzed using descriptive statistics, chi-square and t tests, and repeated measure linear regression models. RESULTS: Participants were on average 54.6 (SD = 3.6) years old, most were White (67%) postmenopausal (84%), and 26% reported distress related to palpitations. In adjusted models, the morning (wake plus 30-min) geometric mean daily salivary cortisol concentrations were significantly more blunted in those with distress from palpitations compared with those without distress (P ≤ 0.03). When all covariates were controlled, distress from palpitations was the sole significant predictor of wake plus 30-minute cortisol (-0.25 [-0.45 to -0.04], P = 0.02). CONCLUSIONS: Palpitations among midlife women may be associated with blunted morning cortisol, and this relationship is not explained by demographics, clinical variables, vasomotor symptoms, medications, depression, stress, or insomnia.

Effects of pharmacologic and nonpharmacologic interventions on menopause-related quality of life: a pooled analysis of individual participant data from four MsFLASH trials.

OBJECTIVE: The Menopause Strategies: Finding Lasting Answers for Symptoms and Health network conducted three randomized clinical trials (RCTs) testing six interventions treating vasomotor symptoms (VMS), and also collected menopause-related quality of life (QOL) measures. A fourth RCT assessed an intervention for insomnia symptoms among women with VMS. We describe these seven interventions' effects on menopause-related QOL relative to control in women with VMS. METHODS: We pooled individual-level data from 1,005 peri- and postmenopausal women with 14 or more VMS/week across the four RCTs. Interventions included escitalopram 10 to 20 mg/d; yoga/aerobic exercise; 1.8 g/d omega-3-fatty acids; oral 17-beta-estradiol 0.5 mg/d; venlafaxine XR 75 mg/d; and cognitive behavioral therapy for insomnia (CBT-I). Outcomes measures were the Menopause-specific Quality of Life scale and its subscales. RESULTS: Significant improvements in total Menopause-specific Quality of Life from baseline were observed with estradiol, escitalopram, CBT-I, and yoga, with mean decreases of 0.3 to 0.5 points relative to control. The largest improvement in the vasomotor subscale was observed with estradiol (-1.2 points), with more modest but significant effects seen with escitalopram, yoga, and CBT-I. Significant improvements in the psychosocial subscale were observed for escitalopram, venlafaxine, and CBT-I. For the physical subscale, the greatest improvement was observed for CBT-I and exercise, whereas for the sexual subscale, the greatest improvement was observed for CBT-I, with yoga and estradiol demonstrating smaller effects. CONCLUSIONS: These results suggest that for menopause-related QOL, women have a variety of treatment strategies to choose from and can select an approach based on most bothersome symptoms and individual preferences.

Effects of Pharmacologic and Nonpharmacologic Interventions on Insomnia Symptoms and Self-reported Sleep Quality in Women With Hot Flashes: A Pooled Analysis of Individual Participant Data From Four MsFLASH Trials.

Study Objectives: The Menopause Strategies: Finding Lasting Answers for Symptoms and Health network conducted three randomized clinical trials (RCTs) testing six interventions treating vasomotor symptoms (VMS), and also collected self-reported sleep outcomes. A fourth RCT assessed an intervention for insomnia symptoms among women with VMS. We describe these seven interventions' effects relative to control in women with comparably severe insomnia symptoms and VMS. Methods: We analyzed pooled individual-level data from 546 peri- and postmenopausal women with Insomnia Severity Index (ISI) ≥ 12, and ≥14 bothersome VMS/week across the four RCTs. Interventions included the following: escitalopram 10-20 mg/day; yoga; aerobic exercise; 1.8 g/day omega-3 fatty acids; oral 17-beta-estradiol 0.5-mg/day; venlafaxine XR 75-mg/day; and cognitive behavioral therapy for insomnia (CBT-I). Outcome measures were ISI and Pittsburgh Sleep Quality Index (PSQI) over 8-12 weeks of treatment. Results: CBT-I produced the greatest reduction in ISI from baseline relative to control at -5.2 points (95% CI -7.0 to -3.4). Effects on ISI were similar for exercise at -2.1 and venlafaxine at -2.3 points. Comparably small decreases in ISI were observed with escitalopram, yoga, and estradiol. The largest reduction in PSQI from baseline was with CBT-I at -2.7 points (-3.9 to -1.5), although PSQI decreases of 1.2 to 1.6 points were significantly better than control with escitalopram, exercise, yoga, estradiol, and venlafaxine. Omega-3 supplements did not improve insomnia symptoms. Conclusions: This study's findings support current recommendations for CBT-I as a first line treatment in healthy midlife women with insomnia symptoms and moderately bothersome VMS.

Effects of Yoga and Aerobic Exercise on Actigraphic Sleep Parameters in Menopausal Women with Hot Flashes.

STUDY OBJECTIVES: To determine effects of yoga and aerobic exercise compared with usual activity on objective assessments of sleep in midlife women. METHODS: Secondary analyses of a randomized controlled trial in the Menopause Strategies: Finding Lasting Answers for Symptoms and Health (MsFLASH) network conducted among 186 late transition and postmenopausal women aged 40-62 y with hot flashes. Women were randomized to 12 w of yoga, supervised aerobic exercise, or usual activity. The mean and coefficient of variation (CV) of change in actigraph sleep measures from each intervention group were compared to the usual activity group using linear regression models. RESULTS: Baseline values of the primary sleep measures for the entire sample were mean total sleep time (TST) = 407.5 ± 56.7 min; mean wake after sleep onset (WASO) = 54.6 ± 21.8 min; mean CV for WASO = 37.7 ± 18.7 and mean CV for number of long awakenings > 5 min = 81.5 ± 46.9. Changes in the actigraphic sleep outcomes from baseline to weeks 11-12 were small, and none differed between groups. In an exploratory analysis, women with baseline Pittsburgh Sleep Quality Index higher than 8 had significantly reduced TST-CV following yoga compared with usual activity. CONCLUSIONS: This study adds to the currently scant literature on objective sleep outcomes from yoga and aerobic exercise interventions for this population. Although small effects on self-reported sleep quality were previously reported, the interventions had no statistically significant effects on actigraph measures, except for potentially improved sleep stability with yoga in women with poor self-reported sleep quality.

A yoga & exercise randomized controlled trial for vasomotor symptoms: Effects on heart rate variability.

OBJECTIVES: Heart rate variability (HRV) reflects the integration of the parasympathetic nervous system with the rest of the body. Studies on the effects of yoga and exercise on HRV have been mixed but suggest that exercise increases HRV. We conducted a secondary analysis of the effect of yoga and exercise on HRV based on a randomized clinical trial of treatments for vasomotor symptoms in peri/post-menopausal women. DESIGN: Randomized clinical trial of behavioral interventions in women with vasomotor symptoms (n=335), 40-62 years old from three clinical study sites. INTERVENTIONS: 12-weeks of a yoga program, designed specifically for mid-life women, or a supervised aerobic exercise-training program with specific intensity and energy expenditure goals, compared to a usual activity group. MAIN OUTCOME MEASURES: Time and frequency domain HRV measured at baseline and at 12 weeks for 15min using Holter monitors. RESULTS: Women had a median of 7.6 vasomotor symptoms per 24h. Time and frequency domain HRV measures did not change significantly in either of the intervention groups compared to the change in the usual activity group. HRV results did not differ when the analyses were restricted to post-menopausal women. CONCLUSIONS: Although yoga and exercise have been shown to increase parasympathetic-mediated HRV in other populations, neither intervention increased HRV in middle-aged women with vasomotor symptoms. Mixed results in previous research may be due to sample differences. Yoga and exercise likely improve short-term health in middle-aged women through mechanisms other than HRV.

Pooled Analysis of Six Pharmacologic and Nonpharmacologic Interventions for Vasomotor Symptoms.

OBJECTIVE: To 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. METHODS: An 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. RESULTS: The 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. CONCLUSION: These 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 REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00894543 (MsFLASH 01), NCT01178892 (MsFLASH 02), and NCT01418209 (MsFLASH 03).

Recent oral contraceptive use by formulation and breast cancer risk among women 20 to 49 years of age.

Previous studies of oral contraceptives and breast cancer indicate that recent use slightly increases risk, but most studies relied on self-reported use and did not examine contemporary oral contraceptive formulations. This nested case-control study was among female enrollees in a large U.S. integrated health care delivery system. Cases were 1,102 women ages 20 to 49 years diagnosed with invasive breast cancer from 1990 to 2009. Controls were randomly sampled from enrollment records (n = 21,952) and matched to cases on age, year, enrollment length, and medical chart availability. Detailed oral contraceptive use information was ascertained from electronic pharmacy records and analyzed using conditional logistic regression, ORs, and 95% confidence intervals (CI). Recent oral contraceptive use (within the prior year) was associated with an increased breast cancer risk (OR, 1.5; 95% CI, 1.3-1.9) relative to never or former OC use. The association was stronger for estrogen receptor-positive (ER(+); OR, 1.7; 95% CI, 1.3-2.1) than estrogen receptor-negative (ER(-)) disease (OR, 1.2, 95% CI, 0.8-1.8), although not statistically significantly different (P = 0.15). Recent use of oral contraceptives involving high-dose estrogen (OR, 2.7; 95% CI, 1.1-6.2), ethynodiol diacetate (OR, 2.6; 95% CI, 1.4-4.7), or triphasic dosing with an average of 0.75 mg of norethindrone (OR, 3.1; 95% CI, 1.9-5.1; Pheterogeneity compared with using other oral contraceptives = 0.004) was associated with particularly elevated risks, whereas other types, including low-dose estrogen oral contraceptives, were not (OR, 1.0; 95% CI, 0.6-1.7). Our results suggest that recent use of contemporary oral contraceptives is associated with an increased breast cancer risk, which may vary by formulation. If confirmed, consideration of the breast cancer risk associated with different oral contraceptive types could impact discussions weighing recognized health benefits and potential risks.

Menopausal quality of life: RCT of yoga, exercise, and omega-3 supplements.

OBJECTIVE: The 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 DESIGN: We 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). RESULTS: Among 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). CONCLUSION: All 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.

Methods for the design of vasomotor symptom trials: the menopausal strategies: finding lasting answers to symptoms and health network.

OBJECTIVE: This report describes the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health network and methodological issues addressed in designing and implementing vasomotor symptom trials. METHODS: Established in response to a National Institutes of Health request for applications, the network was charged with conducting rapid throughput randomized trials of novel and understudied available interventions postulated to alleviate vasomotor and other menopausal symptoms. Included are descriptions of and rationale for criteria used for interventions and study selection, common eligibility and exclusion criteria, common primary and secondary outcome measures, consideration of placebo response, establishment of a biorepository, trial duration, screening and recruitment, statistical methods, and quality control. All trial designs are presented, including the following: (1) a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the effectiveness of the selective serotonin reuptake inhibitor escitalopram in reducing vasomotor symptom frequency and severity; (2) a two-by-three factorial design trial to test three different interventions (yoga, exercise, and ω-3 supplementation) for the improvement of vasomotor symptom frequency and bother; and (3) a three-arm comparative efficacy trial of the serotonin-norepinephrine reuptake inhibitor venlafaxine and low-dose oral estradiol versus placebo for reducing vasomotor symptom frequency. The network's structure and governance are also discussed. CONCLUSIONS: The methods used in and the lessons learned from the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health trials are shared to encourage and support the conduct of similar trials and to encourage collaborations with other researchers.

Efficacy of omega-3 for vasomotor symptoms treatment: a randomized controlled trial.

OBJECTIVE: This study aims to determine the efficacy and tolerability of omega-3 fatty acids in reducing vasomotor symptoms (VMS) frequency and bother in perimenopausal and postmenopausal women. METHODS: This study was a 12-week, three-by-two factorial, randomized controlled trial. Eligible women were randomized to a double-blind comparison of omega-3 (n = 177) or placebo (n = 178) capsules, and simultaneously to yoga (n = 107), aerobic exercise (n = 106), or their usual physical activity (n = 142). Participants received 1.8 g of omega-3 daily for 12 weeks. Each capsule contained ethyl eicosapentaenoic acid (425 mg), docosahexaenoic acid (100 mg), and other omega-3s (90 mg). Primary outcomes were VMS frequency and bother. Secondary outcomes included sleep quality (Pittsburgh Sleep Quality Index), insomnia symptoms (Insomnia Severity Index), depressive symptoms (Physician's Health Questionnaire-8), and anxiety (Generalized Anxiety Disorder-7). RESULTS: The mean baseline frequency of VMS per day was 7.6 (95% CI, 7.0 to 8.2). After 12 weeks, the reduction in VMS frequency with omega-3 (-2.5; 95% CI, -3.0 to -1.9) did not differ significantly from that with placebo (-2.7; 95% CI, -3.3 to -2.2), with a relative difference of 0.3 fewer hot flashes per day (95% CI, -0.5 to 1.0; P = 0.28). Changes in VMS bother at 12 weeks were also similar between groups, with no relative difference on a four-point scale (95% CI, -0.1 to 0.2; P = 0.36). Omega-3s compared with placebo showed no improvement in self-reported sleep or mood (P > 0.09 for all comparisons). CONCLUSIONS: Among healthy, sedentary perimenopausal and postmenopausal women, a 12-week treatment with omega-3 does not improve VMS frequency, VMS bother, sleep, or mood compared with placebo.

Efficacy of yoga for vasomotor symptoms: a randomized controlled trial.

OBJECTIVE: This study aims to determine the efficacy of yoga in alleviating vasomotor symptoms (VMS) frequency and bother. METHODS: This study was a three-by-two factorial, randomized controlled trial. Eligible women were randomized to yoga (n = 107), exercise (n = 106), or usual activity (n = 142), and were simultaneously randomized to a double-blind comparison of ω-3 fatty acid (n = 177) or placebo (n = 178) capsules. Yoga intervention consisted of 12 weekly 90-minute yoga classes with daily home practice. Primary outcomes were VMS frequency and bother assessed by daily diaries at baseline, 6 weeks, and 12 weeks. Secondary outcomes included insomnia symptoms (Insomnia Severity Index) at baseline and 12 weeks. RESULTS: Among 249 randomized women, 237 (95%) completed 12-week assessments. The mean baseline VMS frequency was 7.4 per day (95% CI, 6.6 to 8.1) in the yoga group and 8.0 per day (95% CI, 7.3 to 8.7) in the usual activity group. Intent-to-treat analyses included all participants with response data (n = 237). There was no difference between intervention groups in the change in VMS frequency from baseline to 6 and 12 weeks (mean difference [yoga--usual activity] from baseline at 6 wk, -0.3 [95% CI, -1.1 to 0.5]; mean difference [yoga--usual activity] from baseline at 12 wk, -0.3 [95% CI, -1.2 to 0.6]; P = 0.119 across both time points). Results were similar for VMS bother. At week 12, yoga was associated with an improvement in insomnia symptoms (mean difference [yoga - usual activity] in the change in Insomnia Severity Index, 1.3 [95% CI, -2.5 to -0.1]; P = 0.007). CONCLUSIONS: Among healthy women, 12 weeks of yoga class plus home practice, compared with usual activity, do not improve VMS frequency or bother but reduce insomnia symptoms.

Improving depression treatment for women: integrating a collaborative care depression intervention into OB-GYN care.

BACKGROUND: Women have higher rates of depression and often experience depression symptoms during critical reproductive periods, including adolescence, pregnancy, postpartum, and menopause. Collaborative care intervention models for mood disorders in patients receiving care in an OB-GYN clinic setting have not been evaluated. Study design and methodology for a randomized controlled trial of collaborative care depression management versus usual care in OB-GYN clinics and the details of the adapted collaborative care intervention and model implementation are described in this paper. METHODS: Women over age 18 years with clinically significant symptoms of depression, as measured by a Patient Health Questionnaire-9 (PHQ-9) score ≥10 and a clinical diagnosis of major depression or dysthymia, were randomized to the study intervention or to usual care and were followed for 18 months. The primary outcome assessed was change over time in the SCL-20 depression scale between baseline and 12 months. BASELINE RESULTS: Two hundred five women were randomized: 57% white, 20% African American, 9% Asian or Pacific Islander, 7% Hispanic, and 6% Native American. Mean age was 39 years. 4.6% were pregnant and 7.5% were within 12 months postpartum. The majority were single (52%), and 95% had at least the equivalent of a high school diploma. Almost all patients met DSM IV criteria for major depression (99%) and approximately 33% met criteria for dysthymia. CONCLUSIONS: An OB-GYN collaborative care team, including a social worker, a psychiatrist, and an OB-GYN physician, who met weekly and used an electronic tracking system for patients was the essential element of the proposed depression care treatment model described here. Further study of models that improve quality of depression care that are adapted to the unique OB-GYN setting is needed.

Design and methods of a multi-site, multi-behavioral treatment trial for menopausal symptoms: the MsFLASH experience.

BACKGROUND: Behavioral strategies are recommended for menopausal symptoms, but little evidence exists regarding efficacy. PURPOSE: Describe design and methodology of a randomized controlled 3 by 2 factorial trial of yoga, exercise and omega-3 fatty acids. METHODS: Women 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. RESULTS: Of 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% CONCLUSIONS: Conducting 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.

Self-reported changes in providers' hormone therapy prescribing and counseling practices after the Women's Health Initiative.

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.

Complex hyperplasia with and without atypia: clinical outcomes and implications of progestin therapy.

OBJECTIVE: Limited data exist to inform clinicians and patients as to the likelihood of long-term endometrial hyperplasia response to progestin therapy, especially for atypical hyperplasia. We evaluated women with complex and atypical endometrial hyperplasia, comparing those prescribed progestin with those not prescribed progestin. METHODS: This retrospective cohort study was conducted in 1985-2005 among women aged 18-88 years at an integrated health plan in Washington State. Women were ineligible if they achieved an outcome (endometrial carcinoma, hysterectomy, or both) within 8 weeks of hyperplasia diagnosis. Exposure was progestin use for at least 14 days by duration and recency. Outcomes included rate of 1) endometrial carcinoma, 2) hysterectomy, or 3) both. Analyses performed included Kaplan-Meier, incident rate ratios, and Cox proportional hazard ratios. RESULTS: One thousand four hundred forty-three eligible women were identified. One thousand two hundred one had complex (n=164 no progestin) and 242 had atypical (n=62 no progestin) hyperplasia. During follow-up, a median of 5.3 years (range 8 weeks to 20.8 years), 71 women were diagnosed with endometrial carcinoma (35 complex, 36 atypia) and 323 underwent hysterectomy (216 complex, 107 atypia). Among women with complex and atypical hyperplasia, rates of endometrial carcinoma among progestin users were 3.6 and 20.5 per 1,000 woman-years, respectively (compared with women who did not use progestin, 10.8 and 101.4). Among women with complex and atypical hyperplasia, rates of hysterectomy among progestin users were 23.3 and 61.4 per 1,000 woman-years, respectively (compared with women who did not use progestin, 55.1 and 297.3). CONCLUSION: Endometrial carcinoma risk is diminished approximately threefold to fivefold in women diagnosed with complex or atypical endometrial hyperplasia and dispensed progestin; hysterectomy risk is also decreased. LEVEL OF EVIDENCE: II.

Brief telephone intervention increases soy intake in peri- and postmenopausal US women: the Herbal Alternatives Trial (HALT).

OBJECTIVE: Effective dietary intervention strategies that can be widely disseminated and have the potential for sustainable dietary modifications are needed. The purpose of this study was to describe and evaluate the effectiveness of a telephone-based soy intervention. DESIGN: A randomized controlled trial comparing self-reported intake and serum measures of soy during a 1-year dietary soy (Soy) to fruit and vegetable (Placebo) intervention conducted in two of five arms from the Herbal Alternatives Trial between May 2001 and September 2004. SUBJECTS/SETTING: One hundred sixty-three peri- and postmenopausal women (mean age=52 years) consuming self-selected diets in the Pacific Northwest, United States. INTERVENTION: Five telephone contacts with a registered dietitian during a 12-month intervention with the goal to increase soy food consumption to two servings daily. MAIN OUTCOME MEASURES: Change from baseline in self-reported soy servings and serum isoflavone (daidzein and genistein) concentrations were estimated using analysis of variance and generalized estimating equations. Proportions of participants achieving the intervention goal were compared using chi(2) tests. RESULTS: Ninety-four percent (n=74) of participants in the Soy arm and 89% (n=75) in the Placebo arm completed the trial, and slightly more than one third (n=27) received five phone contacts. Mean (+/-standard deviation) intakes of soy were similar for the Soy and Placebo arms at baseline (0.6+/-1.0 vs 0.4+/-0.8 servings/day; P>0.05). At 12-month follow-up visit, mean+/-standard deviation servings of soy per day were 1.6+/-1.4 for the Soy intervention compared to 0.5+/-0.9 within the Placebo arm (P<0.001). There were concomitant increases in serum isoflavones at 3 and 6 months from baseline in the Soy arm only, with approximately twofold increases in both daidzein (mean=66.4 nmol/L, 95% confidence interval [CI]: 39.0 to 93.9 [mean 16.9 ng/mL, 95% CI: 9.9 to 23.8]) and genistein (mean=100.4 nmol/L, 95% CI: 60.9 to 139.9 [mean 27.1 ng/mL, 95% CI: 16.5 to 37.8]) concentrations. Mean weight changed by <1 kg during the 12-month period in each group and physical activity remained stable, suggesting that participants incorporated soy foods into their diet by substituting for non soy foods rather than adding them to their diet. CONCLUSIONS: A brief telephone-based intervention with a focused message delivered by a registered dietitian is a feasible approach for encouraging targeted dietary changes, such as an increase in soy intake among peri- and postmenopausal women.

Hormone therapy discontinuation: physician practices after the Women's Health Initiative.

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