Publications by authors named "Ellen W Freeman"

112 Publications

Lights on MsFLASH: a review of contributions.

Menopause 2020 04;27(4):473-484

Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.

Objective: The Menopause Strategies: Finding Lasting Answers for Symptoms and Health clinical trials network was funded by the National Institutes of Health to find new ways to alleviate the most common, bothersome menopausal symptoms by designing and conducting multiple concurrent clinical intervention studies, accommodating a wide scope of populations and intervention strategies.

Methods: Trials were conducted in Boston, Indianapolis, Minneapolis, Oakland, Philadelphia, and Seattle, with the Data Coordinating Center in Seattle, and were designed with standardized eligibility criteria and endpoints. Primary outcomes focused on vasomotor symptoms, sleep quality and insomnia symptoms, and vaginal symptoms. Secondary outcomes included quality of life, sexual function, and mood.

Results: We completed five randomized clinical trials and three ancillary studies, testing nine interventions in over 1,300 women and collecting nearly 16,000 bio-specimens. Escitalopram, venlafaxine hydrochloride extended release, and low-dose estradiol diminished hot flashes by approximately 50% as compared with a 30% decrease by placebo. No benefits on vasomotor symptoms were observed with yoga or exercise compared with usual activity, nor with omega-3 supplementation compared with placebo. Cognitive behavioral therapy for insomnia reduced self-reported insomnia symptoms and improved overall sleep quality compared with menopause education control. We did not find significant benefit from a vaginal estradiol tablet or a vaginal moisturizer compared with placebo tablet and gel in diminishing the severity of vaginal symptoms.

Conclusions: The MsFLASH trials contributed substantially to our understanding of bothersome menopausal symptom treatment. It is important that clinicians counseling women about available treatment options consider all therapies-both nonhormonal and hormonal.
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http://dx.doi.org/10.1097/GME.0000000000001461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009305PMC
April 2020

Onset of the Menopause Transition: The Earliest Signs and Symptoms.

Obstet Gynecol Clin North Am 2018 Dec 25;45(4):585-597. Epub 2018 Oct 25.

Department of Obstetrics/Gynecology, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, USA; Department of Psychiatry, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, USA.

Although more than 80% of women experience some degree of psychological or physical symptoms around menopause, both women and clinicians have misconceptions about how hormonal changes relate to menopausal symptoms and psychological conditions. Recently, several large-scale, longitudinal studies have been conducted to better characterize symptoms and changes that occur around menopause. This article offers current evidence for symptoms that occur in the early menopause transition, including vasomotor symptoms, mood changes, sleep problems, and changes in sexual functioning.
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http://dx.doi.org/10.1016/j.ogc.2018.07.002DOI Listing
December 2018

Predictors of decreased libido in women during the late reproductive years.

Menopause 2018 11;25(11):1238-1243

Department of Biostatistics and Epidemiology and Center for Clinical Epidemiology.

Objective: To identify risk factors for decreased libido among women in the late reproductive years.

Design: Prospective cohort. Women aged 35 to 47 years identified through random digit dialing were prospectively followed for 4 years with serial hormone assays and standardized questionnaires. Mean hormone values, hormone trends over 4 years, and fluctuation in hormone levels were compared among women with and without a decrease in libido at the last assessment period. Total testosterone, dihydroepiandrosterone sulfate, estradiol, follicle-stimulating hormone, luteinizing hormone, body mass index, psychosocial, and socioeconomic variables were evaluated using multivariable logistic regression.

Results: Of 326 women, 87 (27%) reported a decreased libido, whereas 239 (73%) did not. Participant-specific means for all hormone levels over the study period were similar among both groups. However, total testosterone fluctuation over the study was significantly different between groups. Women whose testosterone levels fluctuated from 3.8 to 21.5 ng/dL around a mean value of 9 ng/dL were four times more likely to report decreased libido compared with women with little fluctuation in testosterone [odds ratio (OR) 4.0; 95% CI, 1.6-10.0]. Depression (OR 3.4; 95%CI, 1.9-6.1), vaginal dryness (OR 3.5; 95%CI, 1.8-6.6), and children living at home (OR 1.4; 95%CI, 1.1-1.7) were also independently associated with decreased libido.

Conclusions: Decreased libido in the late reproductive years is associated with a pronounced fluctuation in total testosterone over time. Other independent risk factors for decreased libido include vaginal dryness, depression, and living with children. Sexual dysfunction is a complex disorder, related to physiological and psychosocial factors, requiring further investigation.
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http://dx.doi.org/10.1097/GME.0000000000001225DOI Listing
November 2018

Guidelines for the Evaluation and Treatment of Perimenopausal Depression: Summary and Recommendations.

J Womens Health (Larchmt) 2019 02 5;28(2):117-134. Epub 2018 Sep 5.

11 Department of Psychiatry, Queen's University School of Medicine, Ontario Canada.

There is a new appreciation of the perimenopause-defined as the early and late menopause transition stages as well as the early postmenopause-as a window of vulnerability for the development of both depressive symptoms and major depressive episodes. However, clinical recommendations on how to identify, characterize and treat clinical depression are lacking. To address this gap, an expert panel was convened to systematically review the published literature and develop guidelines on the evaluation and management of perimenopausal depression. The areas addressed included: (1) epidemiology; (2) clinical presentation; (3) therapeutic effects of antidepressants; (4) effects of hormone therapy; and (5) efficacy of other therapies (e.g., psychotherapy, exercise, and natural health products). Overall, evidence generally suggests that most midlife women who experience a major depressive episode during the perimenopause have experienced a prior episode of depression. Midlife depression presents with classic depressive symptoms commonly in combination with menopause symptoms (i.e., vasomotor symptoms, sleep disturbance), and psychosocial challenges. Menopause symptoms complicate, co-occur, and overlap with the presentation of depression. Diagnosis involves identification of menopausal stage, assessment of co-occurring psychiatric and menopause symptoms, appreciation of the psychosocial factors common in midlife, differential diagnoses, and the use of validated screening instruments. Proven therapeutic options for depression (i.e., antidepressants, psychotherapy) are the front-line treatments for perimenopausal depression. Although estrogen therapy is not approved to treat perimenopausal depression, there is evidence that it has antidepressant effects in perimenopausal women, particularly those with concomitant vasomotor symptoms. Data on estrogen plus progestin are sparse and inconclusive.
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http://dx.doi.org/10.1089/jwh.2018.27099.mensocrecDOI Listing
February 2019

Guidelines for the evaluation and treatment of perimenopausal depression: summary and recommendations.

Menopause 2018 10;25(10):1069-1085

Department of Psychiatry, Queen's University School of Medicine, Ontario CA.

There is a new appreciation of the perimenopause - defined as the early and late menopause transition stages as well as the early postmenopause - as a window of vulnerability for the development of both depressive symptoms and major depressive episodes. However, clinical recommendations on how to identify, characterize and treat clinical depression are lacking. To address this gap, an expert panel was convened to systematically review the published literature and develop guidelines on the evaluation and management of perimenopausal depression. The areas addressed included: 1) epidemiology; 2) clinical presentation; 3) therapeutic effects of antidepressants; 4) effects of hormone therapy; and 5) efficacy of other therapies (eg, psychotherapy, exercise, and natural health products). Overall, evidence generally suggests that most midlife women who experience a major depressive episode during the perimenopause have experienced a prior episode of depression. Midlife depression presents with classic depressive symptoms commonly in combination with menopause symptoms (ie, vasomotor symptoms, sleep disturbance), and psychosocial challenges. Menopause symptoms complicate, co-occur, and overlap with the presentation of depression. Diagnosis involves identification of menopausal stage, assessment of co-occurring psychiatric and menopause symptoms, appreciation of the psychosocial factors common in midlife, differential diagnoses, and the use of validated screening instruments. Proven therapeutic options for depression (ie, antidepressants, psychotherapy) are the front-line treatments for perimenopausal depression. Although estrogen therapy is not approved to treat perimenopausal depression, there is evidence that it has antidepressant effects in perimenopausal women, particularly those with concomitant vasomotor symptoms. Data on estrogen plus progestin are sparse and inconclusive.
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http://dx.doi.org/10.1097/GME.0000000000001174DOI Listing
October 2018

Associations between improvement in genitourinary symptoms of menopause and changes in the vaginal ecosystem.

Menopause 2018 05;25(5):500-507

Fred Hutchinson Cancer Research Center, Seattle, WA.

Objective: The aim of the study was to identify associations between improvement in genitourinary symptoms of menopause (GSM) and vaginal microbiota, vaginal glycogen, and serum estrogen.

Methods: Thirty postmenopausal women enrolled in a hot flash treatment trial (oral estradiol vs venlafaxine vs placebo) who reported GSM and provided vaginal swabs at 0, 4, and 8 weeks were studied. Bacterial communities were characterized using deep sequencing targeting the 16S rRNA gene V3-V4 region. Participants selected a most bothersome genitourinary symptom (dryness, discharge, pain, itch/burn, or inability to have sex) and rated severity on a 10-point scale at baseline and 8 weeks. Vaginal glycogen and serum estradiol and estrone were measured at enrollment and 8 weeks. Comparisons according to improvement in most bothersome symptom (MBS) were made using χ, Wilcoxon signed-rank test, or Hotelling's t test.

Results: Of 30 participants, 21 (70%) had improvement in MBS over the 8-week study and 9 (30%) had no improvement or worsening of MBS. A higher proportion of women receiving estradiol or venlafaxine reported improvement in MBS (88%, 78%) compared with placebo (54%; P = 0.28). MBS improvement was associated with Lactobacillus-dominant vaginal microbiota at enrollment (57% vs 22%, P = 0.08). Vaginal glycogen, serum estradiol, and estrone significantly increased in women whose MBS improved.

Conclusions: A larger proportion of women whose MBS improved had a Lactobacillus dominant microbiota at enrollment than those who had no improvement during the trial, though this difference was not statistically significant. Larger trials are needed to determine whether vaginal microbiota modify or mediate treatment responses in women with GSM.
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http://dx.doi.org/10.1097/GME.0000000000001037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898977PMC
May 2018

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.

Sleep 2018 01;41(1)

Department of Psychosocial and Community Health, University of Washington, Seattle, WA.

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.
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http://dx.doi.org/10.1093/sleep/zsx190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380606PMC
January 2018

Vaginal microbiota and genitourinary menopausal symptoms: a cross-sectional analysis.

Menopause 2017 Oct;24(10):1160-1166

1Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, MA 2Fred Hutchinson Cancer Research Center, Seattle, WA 3Department of Obstetrics & Gynecology, University of Washington, Seattle, WA 4Department of Family Medicine and Public Health, University of California at San Diego, La Jolla, CA 5Department of Laboratory Medicine, University of Washington, Seattle, WA 6Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 7Group Health Research Institute, Seattle, WA 8Department of Obstetrics & Gynecology and Psychiatry, University of Pennsylvania, Philadelphia, PA 9Brigham and Women's Hospital and Dana Farber Cancer Center, Boston, MA 10Department of Psychiatry, Massachusetts General Hospital, Boston, MA.

Objective: To examine associations between the composition of the vaginal microbiota and genitourinary menopausal symptoms, serum estrogen, and vaginal glycogen.

Methods: For this cross-sectional study, 88 women aged 40 to 62 years, enrolled in a hot flash treatment trial, provided vaginal swabs and a blood sample at enrollment. Bacterial communities were characterized using 16S rRNA PCR and deep sequencing targeting the V3-V4 region. Quantities of Lactobacillus crispatus and Lactobacillus iners were measured using qPCR. Self-reported genitourinary symptoms included: presence and severity of individual symptoms and identification of most bothersome symptom. Glycogen was measured fluorometrically in swab eluate. Serum estradiol (E2) and estrone (E1) were measured by liquid chromatography/mass spectrometry. Associations between bacteria, symptoms, glycogen, and serum estrogens were tested by linear regression or Wilcoxon signed-rank test, adjusted for multiple comparisons. Comparisons between groups used Kruskall-Wallis or Fisher's exact test.

Results: Of the 88 women, 33 (38%) had a majority of Lactobacillus species, whereas 58 (66%) had any Lactobacillus detected. Over half (53%) reported at least one vulvovaginal symptom (most commonly dryness), but symptoms were not associated with the presence of Lactobacillus species. Women with Lactobacillus-dominant communities had higher unconjugated serum estrone, but no difference in vaginal glycogen levels, compared with those with non-Lactobacillus-dominant communities. Higher serum E2 and E1 were not associated with either higher vaginal glycogen or detection of individual genera.

Conclusions: Presence of Lactobacillus-dominant vaginal microbiota was not associated with fewer vulvovaginal symptoms. Serum estrone was higher in women with Lactobacillus dominance, but vaginal-free glycogen was not associated with composition of the vaginal microbiota.
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http://dx.doi.org/10.1097/GME.0000000000000904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607086PMC
October 2017

Validity, cut-points, and minimally important differences for two hot flash-related daily interference scales.

Menopause 2017 Aug;24(8):877-885

1School of Nursing, Indiana University, Indianapolis, IN 2Department of Biostatistics, Fairbanks School of Public Health, School of Medicine, Indiana University, Indianapolis, IN 3Department of Psychology, School of Science, Indiana University-Purdue University Indianapolis, IN 4University of Washington School of Nursing, Seattle, WA 5Group Health Research Institute, Seattle, WA 6Brigham and Women's Hospital, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 7Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, and Harvard School of Public Health, Boston, MA 8Departments of Obstetrics/Gynecology and Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 9MsFLASH Data Coordinating Center, Fred Hutchinson Cancer Research Center, Seattle, WA.

Objectives: To conduct psychometric analyses to condense the Hot Flash-Related Daily Interference Scale (HFRDIS) into a shorter form termed the Hot Flash Interference (HFI) scale; evaluate cut-points for both scales; and establish minimally important differences (MIDs) for both scales.

Methods: We analyzed baseline and postrandomization patient-reported data pooled across three randomized trials aimed at reducing vasomotor symptoms (VMS) in 899 midlife women. Trials were conducted across five MsFLASH clinical sites between July 2009 and October 2012. We eliminated HFRDIS items based on experts' content validity ratings and confirmatory factor analysis, and evaluated cut-points and established MIDs by mapping HFRDIS and HFI to other measures.

Results: The three-item HFI (interference with sleep, mood, and concentration) demonstrated strong internal consistency (alphas of 0.830 and 0.856), showed good fit to the unidimensional "hot flash interference factor," and strong convergent validity with HFRDIS scores, diary VMS, and menopausal quality of life. For both scales, cut-points of mild (0-3.9), moderate (4-6.9), and severe (7-10) interference were associated with increasing diary VMS ratings, sleep, and anxiety. The average MID was 1.66 for the HFRDIS and 2.34 for the HFI.

Conclusions: The HFI is a brief assessment of VMS interference and will be useful in busy clinics to standardize VMS assessment or in research studies where response burden may be an issue. The scale cut-points and MIDs should prove useful in targeting those most in need of treatment, monitoring treatment response, and interpreting existing and future research findings.
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http://dx.doi.org/10.1097/GME.0000000000000871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002749PMC
August 2017

Adverse Childhood Experiences and Risk for First-Episode Major Depression During the Menopause Transition.

J Clin Psychiatry 2017 Mar;78(3):e298-e307

Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Objective: Stress exposures may have a differential impact on risk and resilience for depression depending on their timing across development. We sought to determine whether adverse childhood experiences (ACEs) and their onset with respect to puberty contribute to the increased risk observed in first-episode major depressive disorder (MDD) during the menopause transition.

Methods: Participants were from the Penn Ovarian Aging Study cohort, which is composed of women from Philadelphia County, Pennsylvania, who underwent behavioral, cognitive, and endocrine evaluations approximately yearly from 1996 to 2012 and completed the Adverse Childhood Experiences Questionnaire at study end point (n = 243). ACEs that first occurred 2 or more years before menarche were considered prepubertal. Incident menopause MDD was defined as first observed onset of the disorder in the perimenopause to postmenopause transition using the Structured Clinical Interview for DSM-III-R and the Primary Care Evaluation of Mental Disorders.

Results: Incident menopause MDD occurred in 48% of the 100 women who reported lifetime MDD. Women reporting ≥ 2 total ACEs were at significantly greater risk for lifetime MDD (adjusted odds ratio [aOR] = 2.05, P = .034) and incident menopause MDD (aOR = 2.58, P = .03) compared to those reporting 0 ACEs; women with ≥ 2 postpubertal ACEs were 2.3 times more likely to experience incidence menopause MDD (P = .024) after controlling for race, smoking, body mass index, and employment. Experiencing only 1 ACE in the prepubertal window, regardless of additional ACEs in postpuberty, was associated with reduced risk for lifetime and incident menopause MDD.

Conclusions: Timing and number of adverse experiences with respect to puberty differentially impacted risk and resilience for MDD across the female life span and during the menopause transition in this community cohort.
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http://dx.doi.org/10.4088/JCP.16m10662DOI Listing
March 2017

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

J Clin Sleep Med 2017 01 15;13(1):11-18. Epub 2017 Jan 15.

Division of Epidemiology and Community Health, Department of Medicine, University of Minnesota, Minneapolis, MN.

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.
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http://dx.doi.org/10.5664/jcsm.6376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5181601PMC
January 2017

Pooled Analysis of the Effects of Conjugated Estrogens/Bazedoxifene on Vasomotor Symptoms in the Selective Estrogens, Menopause, and Response to Therapy Trials.

J Womens Health (Larchmt) 2016 11 27;25(11):1102-1111. Epub 2016 Sep 27.

5 Department of Obstetrics and Gynecology, University of Virginia Health System , Charlottesville, Virginia.

Objectives: Conjugated estrogens/bazedoxifene (CE/BZA) reduced menopause-related hot flashes (HFs) in the Selective estrogens, Menopause, And Response to Therapy (SMART) trials. This post hoc pooled analysis of SMART-1 and -2 further characterized effects of CE/BZA on HFs in the overall population and patient subgroups.

Methods: Data from two randomized, double-blind, placebo- and active-controlled, phase 3 studies were pooled for nonhysterectomized postmenopausal women with moderate/severe HFs given CE 0.45 mg/BZA 20 mg, CE 0.625 mg/BZA 20 mg, or placebo for 12 weeks. HF frequency and severity were assessed by daily diary.

Results: The pooled analysis included 403 participants. At 12 weeks, CE 0.45 mg/BZA 20 mg and CE 0.625 mg/BZA 20 mg significantly (all p < 0.001) decreased moderate/severe HF frequency versus placebo (-7.9, -8.2, -4.1), reduced adjusted average daily HF severity score versus placebo (-1.0, -1.3, -0.3), increased the percentage of women who had a ≥50% (81.2%,87.1%, 50.6%) and ≥75% (62.4%, 74.8%, 26.4%) reduction from baseline in daily frequency of moderate/severe HFs, increased the percentage with ≥50% (38.3%, 58.1%, 11.0%) and ≥75% (24.2%, 38.1%, 5.5%) reductions in average daily HF severity score, and improved MENQOL vasomotor function versus placebo (adjusted mean change-3.08, -3.69, -1.37). CE/BZA was significantly more effective than placebo irrespective of time since menopause, with some evidence of a lower placebo response in women in later menopause (>5 years) versus early menopause (≤5 years).

Conclusions: CE/BZA effectively reduces moderate/severe HFs in postmenopausal women. NCT#'s: NCT00675688; NCT00234819.
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http://dx.doi.org/10.1089/jwh.2015.5558DOI Listing
November 2016

Female Sexual Function Index Short Version: A MsFLASH Item Response Analysis.

Arch Sex Behav 2016 11 8;45(8):1897-1905. Epub 2016 Aug 8.

Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.

The Female Sexual Function Index (FSFI) is a psychometrically sound and popular 19-item self-report measure, but its length may preclude its use in studies with multiple outcome measures, especially when sexual function is not a primary endpoint. Only one attempt has been made to create a shorter scale, resulting in the Italian FSFI-6, later translated into Spanish and Korean without further psychometric analysis. Our study evaluated whether a subset of items on the 19-item English-language FSFI would perform as well as the full-length FSFI in peri- and postmenopausal women. We used baseline data from 898 peri- and postmenopausal women recruited from multiple communities, ages 42-62 years, and enrolled in randomized controlled trials for vasomotor symptom management. Goals were to (1) create a psychometrically sound, shorter version of the FSFI for use in peri- and postmenopausal women as a continuous measure and (2) compare it to the Italian FSFI-6. Results indicated that a 9-item scale provided more information than the FSFI-6 across a spectrum of sexual functioning, was able to capture sample variability, and showed sufficient range without floor or ceiling effects. All but one of the items from the Italian 6-item version were included in the 9-item version. Most omitted FSFI items focused on frequency of events or experiences. When assessment of sexual function is a secondary endpoint and subject burden related to questionnaire length is a priority, the 9-item FSFI may provide important information about sexual function in English-speaking peri- and postmenopausal women.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053877PMC
http://dx.doi.org/10.1007/s10508-016-0804-5DOI Listing
November 2016

Anxiety as a risk factor for menopausal hot flashes: evidence from the Penn Ovarian Aging cohort.

Menopause 2016 09;23(9):942-9

1Department of Obstetrics and Gynecology 2Department of Psychiatry 3Department of Biostatistics and Epidemiology and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Objective: The aim of this study was to identify temporal associations of anxiety dimensions with menopausal hot flashes in women progressing through the menopausal transition. We hypothesized that associations of both somatic and affective dimensions of anxiety with hot flashes increased in the menopausal transition, and that somatic anxiety was an independent risk factor for menopausal hot flashes.

Methods: Hot flashes, anxiety symptoms, hormone levels, and other psychosocial variables were assessed annually for 14 years of follow-up. The 233 women were premenopausal at baseline and continued through 1 year or more after the final menstrual period. Anxiety dimensions were assessed with the Zung Anxiety Scale, a validated measure of affective anxiety and somatic anxiety. Summed item scores were divided by the number of items rated, so that ranges of the two dimensions were comparable.

Results: Seventy-two percent of the sample reported moderate/severe hot flashes during the 14-year interval. There was no significant interaction between anxiety dimensions and menopausal stages. When adjusted for menopausal stage, the magnitude of association between somatic anxiety and hot flashes, however, dramatically increased (odds ratio [OR], 3.03; 95% CI, 2.12-4.32; P < 0.001), whereas the association between affective anxiety and hot flashes increased to a lesser extent (OR, 1.27; 95% CI, 1.03-1.57; P = 0.024). Women with high levels of somatic anxiety (top third of the sample) had the greatest risk of hot flashes (P < 0.001). When the anxiety dimensions were considered in combination, the additive effect of high affective anxiety symptoms was minimal, with no significant difference between the group with high affective/low somatic symptoms and the low symptom group in incident hot flashes at each menopausal stage (P = 0.54). In multivariable analysis, somatic anxiety increased the risk of hot flashes more than three times (OR, 3.13; 95% CI, 2.16-4.53; P < 0.001), but affective anxiety was not significantly associated with hot flashes after adjustment for other study variables (OR, 1.19; 95% CI, 0.96-1.48; P = 0.117). Time-lagged somatic anxiety scores significantly predicted hot flashes, with a 71% increase in risk (OR, 1.71; 95% CI, 1.21-2.41; P = 0.002). Time-lagged affective anxiety scores did not predict hot flashes (OR, 1.06; 95% CI, 0.87-1.31; P = 0.58).

Conclusions: This study showed a strong predictive association of somatic anxiety with the risk of menopausal hot flashes. The temporal associations suggest that somatic anxiety is not simply a redundant measure of hot flashes but predicts the risk of menopausal hot flashes and may be a potential target in clinical management of perimenopausal women.
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http://dx.doi.org/10.1097/GME.0000000000000662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993654PMC
September 2016

Fourth consensus of the International Society for Premenstrual Disorders (ISPMD): auditable standards for diagnosis and management of premenstrual disorder.

Arch Womens Ment Health 2016 12 5;19(6):953-958. Epub 2016 Jul 5.

Departments of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.

Whilst professional bodies such as the Royal College and the American College of Obstetricians and Gynecologists have well-established standards for audit of management for most gynaecology disorders, such standards for premenstrual disorders (PMDs) have yet to be developed. The International Society of Premenstrual Disorders (ISPMD) has already published three consensus papers on PMDs covering areas that include definition, classification/quantification, clinical trial design and management (American College Obstetricians and Gynecologists 2011; Brown et al. in Cochrane Database Syst Rev 2:CD001396, 2009; Dickerson et al. in Am Fam Physician 67(8):1743-1752, 2003). In this fourth consensus of ISPMD, we aim to create a set of auditable standards for the clinical management of PMDs. All members of the original ISPMD consensus group were invited to submit one or more auditable standards to be eligible in the inclusion of the consensus. Ninety-five percent of members (18/19) responded with at least one auditable standard. A total of 66 auditable standards were received, which were returned to all group members who then ranked the standards in order of priority, before the results were collated. Proposed standards related to the diagnosis of PMDs identified the importance of obtaining an accurate history, that a symptom diary should be kept for 2 months prior to diagnosis and that symptom reporting demonstrates symptoms in the premenstrual phase of the menstrual cycle and relieved by menstruation. Regarding treatment, the most important standards were the use of selective serotonin reuptake inhibitors (SSRIs) as a first line treatment, an evidence-based approach to treatment and that SSRI side effects are properly explained to patients. A set of comprehensive standards to be used in the diagnosis and treatment of PMD has been established, for which PMD management can be audited against for standardised and improved care.
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http://dx.doi.org/10.1007/s00737-016-0631-7DOI Listing
December 2016

Methods in a longitudinal cohort study of late reproductive age women: the Penn Ovarian Aging Study (POAS).

Womens Midlife Health 2016 27;2. Epub 2016 Jan 27.

2Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, U.S, Philadelphia, USA.

Background: This report describes the methods utilized in the Penn Ovarian Aging Study (POAS), which is a longitudinal cohort study of hormone dynamics and menopausal symptoms of women in the menopause transition.

Methods/design: The cohort is a community-based sample of generally healthy women enrolled in the late reproductive years. The study population is a stratified random sample of African-American and Caucasian women, identified by random digit dialing.Of the 1427 women who were identified as potentially eligible, 578 women were eligible after full screening; 75 % of the eligible women enrolled in the study (436/578). At Period 14 (14 years after study enrollment), 67 % remained active and were fully evaluated (293/436). Attrition was non-differential with respect to the sample characteristics.The aims of the project overall are to 1) identify within-woman trends of reproductive hormones (estradiol, follicle stimulating hormone, hormone, lutinizing hormone, inhibin B, dehydroepiandrosterone, testosterone, and anti-mullerian hormone), cofactors such as race, body mass index (BMI), age, physical and behavioral symptoms, and their predictions of menopausal symptoms, and patterns around the final menstrual period; 2) identify associations of hormone dynamics with physical and behavioral symptoms that occur with ovarian aging and identify racial differences in these factors; 3) identify associations of genetic polymorphisms with levels and longitudinal trends in menopausal symptoms. The cohort consists of 436 late reproductive-age women at enrollment, and now has 18 years of approximately annual follow-up assessments. Menopausal stage based on concurrent menstrual dates is identified at each follow-up period.

Discussion: Studies of the cohort have shown that hot flashes can occur well before menopause and extend 10 or more years beyond menopause for sizeable numbers of women; provide evidence for new-onset depressed mood in the menopause transition and show that the final menstrual period is pivotal in the increases in depressive symptoms prior to menopause and decreases postmenopausal; suggest that poor sleep is common in the late reproductive years but increases in relation to the final menstrual period in only a small proportion of women; and show effects of obesity on reproductive hormones in the menopause transition. To date, more than 50 studies of the cohort are published in medical journals, demonstrating the relevance of these data to the clinical care of mid-life women.
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http://dx.doi.org/10.1186/s40695-016-0014-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299955PMC
January 2016

Bayesian estimation of associations between identified longitudinal hormone subgroups and age at final menstrual period.

BMC Med Res Methodol 2015 Dec 18;15:106. Epub 2015 Dec 18.

Department of Statistics, University of Michigan, Ann Arbor, MI, USA.

Background: Although follicle stimulating hormone (FSH) is known to be predictive of age at final menstrual period (FMP), previous methods use FSH levels measured at time points that are defined relative to the age at FMP, and hence are not useful for prospective prediction purposes in clinical settings where age at FMP is an unknown outcome. This study is aimed at assessing whether FSH trajectory feature subgroups identified relative to chronological age can be used to improve the prediction of age at FMP.

Methods: We develop a Bayesian model to identify latent subgroups in longitudinal FSH trajectories, and study the relationship between subgroup membership and age at FMP. Data for our study is taken from the Penn Ovarian Aging study, 1996-2010. The proposed model utilizes mixture modeling and nonparametric smoothing methods to capture hypothesized latent subgroup features of the FSH longitudinal trajectory; and simultaneously studies the prognostic value of these latent subgroup features to predict age at FMP.

Results: The analysis identified two FSH trajectory subgroups that were significantly associated with FMP age: 1) early FSH class (15%), which displayed initial increases in FSH shortly after age 40; and 2) late FSH class (85%), which did not have a rise in FSH until after age 45. The use of FSH subgroup memberships, along with class-specific characteristics, i.e., level and rate of FSH change at class-specific pre-specified ages, improved prediction of FMP age by 20-22% in comparison to the prediction based on previously identified risk factors (BMI, smoking and pre-menopausal levels of anti-mullerian hormone (AMH)).

Conclusions: To the best of our knowledge, this work is the first in the area to demonstrate the existence of subgroups in FSH trajectory patterns relative to chronological age and the fact that such a subgroup membership possesses prediction power for age at FMP. Earlier ages at FMP were found in a subgroup of women with rise in FSH levels commencing shortly after age 40, in comparison to women who did not exhibit an increase in FSH until after 45 years of age. Periodic evaluations of FSH in these age ranges are potentially useful for predicting age at FMP.
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http://dx.doi.org/10.1186/s12874-015-0101-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683774PMC
December 2015

Symptom clusters among MsFLASH clinical trial participants.

Menopause 2016 Feb;23(2):158-65

1Biobehavioral Nursing, University of Washington 2Fred Hutchinson Cancer Research Center, Seattle, WA 3Science of Nursing Care, School of Nursing, Indiana University, Indianapolis, IN 4Center for Women's Mental Health; Perinatal and Reproductive Psychiatry Clinical Research Program, Massachusetts General Hospital, Boston, MA 5Department of Medicine and Division of Epidemiology and Community Health, University of Minnesota 6Center for Chronic Disease Outcomes Research, Minneapolis VA Health Care System, Minneapolis, MN 7Departments of Obstetrics/Gynecology and Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 8Harvard Medical School, Department of Psychiatry, Brigham and Women's Hospital and Dana Farber Cancer Institute, Boston, MA 9Department of Family Medicine and Public Health, University of California San Diego, San Diego, CA.

Objective: Our objective was to identify symptom clusters using standardized measures completed by participants in the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health clinical trial at baseline, including hot flash interference, and sleep, depressive, anxiety, and pain symptoms.

Methods: Data from all women randomized to interventions and controls from Menopausal Strategies: Finding Lasting Answers to Symptoms and Health studies 1, 2, and 3 (N = 899) were included; 797 with complete data were used in the analyses. Scores from standardized measures obtained at baseline included the following: Hot Flash-Related Daily Interference Scale, Insomnia Severity Index, Pittsburgh Sleep Quality Index, Patient Health Questionnaire-9 measure of depressed mood, Generalized Anxiety Disorder, and Brief Pain Inventory PEG scores (pain intensity [P], interference with enjoyment of life [E], and interference with daily activity [G]). Latent class analysis was used to identify symptom clusters using standardized scale scores and their established cut points.

Results: We identified five classes using the Bayesian Information Criterion and the Akaike Information Criterion. Women in classes 1 and 2 had high hot flash interference levels relative to the others, and class 1 (10.5% of total) included severe hot flash interference, severe sleep symptoms, and moderately severe pain symptoms (hot flash, sleep, pain). In class 2 (14.1%), severe hot flash interference was paired with the severe sleep symptoms, and moderate to severe depressed and anxious mood symptoms and pain (hot flash, sleep, mood, pain). In class 3 (39.6%), women reported moderately severe sleep symptoms with moderate hot flash interference, and low severity mood and pain symptoms (hot flash, sleep). Those in class 4 (7.0%) reported moderate hot flash interference with severe levels of anxiety and depressed mood symptoms, but low levels of other symptoms (hot flash, mood). Women in class 5 (28.7%) reported the lowest levels of all the five symptoms (low severity symptoms).

Conclusions: Women meeting hot flash frequency criteria for inclusion in clinical trials exhibited multiple co-occurring symptoms that clustered into identifiable groups according to symptom interference and severity. Variability of symptom profiles between the classes was evident, indicating that the classes were composed of differing symptom types and not simply differing severity levels. These symptom clusters may be useful phenotypes for differentiating treatment effects or evaluating associations with biomarkers or genes.
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http://dx.doi.org/10.1097/GME.0000000000000516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731298PMC
February 2016

Higher serum total testosterone levels correlate with increased risk of depressive symptoms in Caucasian women through the entire menopausal transition.

Psychoneuroendocrinology 2015 Dec 31;62:107-13. Epub 2015 Jul 31.

Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States. Electronic address:

Background: Despite the high prevalence of depressive symptoms in women, the precise role of sex hormones in mood changes during the menopausal transition is unclear. Previous studies have been inconsistent with regard to identifying the association of androgens, namely total testosterone, with depressive symptoms.

Objective: The objectives of this study were to evaluate changes in serum total testosterone levels and depressive symptoms during the entire menopausal transition, and examine the impact of covariates on the association between concurrent serum total testosterone levels and depressive symptoms during this time period.

Methods: A longitudinal cohort study (428 women at baseline with 3634 repeated measures) using data from the Penn Ovarian Aging Study, a population-based cohort of late reproductive-aged women, followed through the menopausal transition. Serum hormone parameters and depression scores using the Center for Epidemiological Studies of Depression scale (CES-D) were measured at each annual visit over a 14-year period. General linear (for testosterone) and a generalized negative-binomial model (for depressive symptoms) for repeated measures were used for analysis.

Results: Serum total testosterone levels increased progressively over the study period and were significantly associated with older age and with current smoking (p<0.001, respectively). In the post menopause total testosterone levels were significantly higher in African Americans compared to Caucasians (p=0.012). The proportion of women with CES-D ≥16 significantly decreased with increasing age and in the post-menopausal period, and were higher in women with a history of depression and hot flashes (p<0.001). The association between concurrent testosterone levels and high depressive symptoms (CES-D ≥16) differed by race (p=0.008). In Caucasians, but not African Americans, higher serum testosterone levels were associated with increased depressive symptoms after controlling for several variables including age, obesity status, hot flashes and menopausal status (RR 1.09, 95% CI 1.00-1.17, p=0.042).

Conclusion: In our cohort, testosterone levels were low but progressively increased from premenopause through post menopause. In addition to age and history of depression, we identified race to have a significant interaction between the association of testosterone levels and depressive symptoms. This study further supports the associations between sex hormones and increased risk of having depressive symptoms, although the precise underlying mechanisms for this association remain unclear.
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http://dx.doi.org/10.1016/j.psyneuen.2015.07.612DOI Listing
December 2015

Depression in the menopause transition: risks in the changing hormone milieu as observed in the general population.

Authors:
Ellen W Freeman

Womens Midlife Health 2015 11;1. Epub 2015 Aug 11.

Department of Obstetrics/Gynecology and Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, 3701 Market Street, Suite 820 (Mudd Suite), Philadelphia, PA 19104 USA.

There is accumulating evidence but no definitive answers about the incidence of depressed mood in the menopause transition and its association with the changing hormonal milieu. While a changing hormonal milieu is the natural condition for all women, only a minority of mid-life women experience debilitating depressive symptoms or clinical depression. This review focuses on associations between depressed mood and the menopause transition, primarily as identified in longitudinal, population-based studies in the past decade. Further aims were to present reported associations between depressed mood and reproductive hormones in the menopause transition as evaluated in the general population and associations of depressive symptoms or clinical depression with menopausal hot flashes or poor sleep in perimenopausal women. There is evidence to support the role of the changing endocrine milieu in the development of depressed mood in the menopause transition, but the contribution of hormones as measured is small. Disentangling the numerous factors that are associated with depression in midlife women is a major challenge for research and for clinical care, where treatments are needed to improve the most distressing menopausal symptoms.
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http://dx.doi.org/10.1186/s40695-015-0002-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214217PMC
August 2015

The menopause transition: interview with Ellen W Freeman.

Authors:
Ellen W Freeman

Womens Health (Lond) 2015 Jul 6;11(4):441-3. Epub 2015 Aug 6.

Department of Obstetrics & Gynecology, University of Pennsylvania School of Medicine, Mudd Professorship Suite, 3701 Market Street, 8th Floor, Philadelphia, PA 19104-5509, USA.

Ellen W Freeman is a Research Professor in the Department of Obstetrics/Gynecology and the Department of Psychiatry at the University of Pennsylvania School of Medicine in Philadelphia (PA, USA). She directs the PMS research program and is co-director of the Human Behavior and Reproduction unit in the Department of Obstetrics and Gynecology. She received her AB in history in Smith College in Northampton, Massachusetts and her MS and PhD in social research from Bryn Mawr College in Bryn Mawr, Pennsylvania. She has published more than 200 scientific articles, book chapters, reviews and abstracts on premenstrual syndromes, perimenopause, adolescent pregnancy, infertility and related topics as well as a book on teenage pregnancy. In addition, she has lectured extensively worldwide on mood disorders and menopause in women. She is also a member of the editorial boards of Medscape, Archives of Women's Mental Health and Mental Fitness: Psychiatry, OB/GYN, Primary Care and is a Fellow in the College of Physicians of Philadelphia.
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http://dx.doi.org/10.2217/whe.15.33DOI Listing
July 2015

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

Obstet Gynecol 2015 Aug;126(2):413-422

MsFLASH Data Coordinating Center, Fred Hutchinson Cancer Research Center, the Group Health Research Institute, and the University of Washington School of Medicine, Seattle, Washington; the Department of Family and Preventive Medicine, University of California, San Diego, San Diego, and the Division of Research, Kaiser Permanente, Oakland, California; the VA Medical Center/University of Minnesota, Minneapolis, Minnesota; Brigham and Women's Hospital, Dana Farber Cancer Institute, and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; the School of Nursing and the Department of Medicine, Division of Clinical Pharmacology, Indiana University, Indianapolis, Indiana; and the Departments of Obstetrics and Gynecology and Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.

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).
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http://dx.doi.org/10.1097/AOG.0000000000000927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526122PMC
August 2015

Placebo improvement in pharmacologic treatment of menopausal hot flashes: time course, duration, and predictors.

Psychosom Med 2015 Feb-Mar;77(2):167-75

From the Department of Obstetrics/Gynecology and Psychiatry (Freeman), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Division of Epidemiology and Community Health (Ensrud), Department of Medicine, Veterans Affairs Health System, Minneapolis, Minnesota; Department of Medicine (Ensrud), University of Minnesota, Minneapolis, Minnesota; MsFlash Data Coordinating Center (Larson, Guthrie), Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; School of Nursing (Carpenter), Indiana University, Indianapolis, Indiana; Department of Psychiatry (Joffe), Brigham and Women's Hospital and Massachusetts General Hospital, Boston, Massachusetts; Department of Psychosocial (Joffe) Dana Farber Institute, Harvard Medical School, Boston, Massachusetts; Group Health Research Institute (Newton), Seattle, Washington; Division of Research (Sternfeld), Kaiser Permanente of Northern California, Oakland, California; Women's Health Center, Family and Preventive Medicine (LaCroix), University of California San Diego, La Jolla, California.

Objectives: To characterize the time course, duration of improvement, and clinical predictors of placebo response in treatment of menopausal hot flashes.

Methods: Data were pooled from two trials conducted in the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health network, providing a combined placebo group (n = 247) and a combined active treatment group (n = 297). Participants recorded hot flash frequency in diaries twice daily during treatment (Weeks 0-8) and subsequent follow-up (Weeks 9-11). The primary outcome variable was clinically significant improvement, defined as a 50% or greater decrease in hot flash frequency from baseline and calculated for each week in the study. Subgroups were defined a priori using standard clinical definitions for significant improvement and partial improvement. Clinical and demographic characteristics of the participants were evaluated as predictors of improvement.

Results: Clinically significant improvement with placebo accrued each treatment week, with 33% significantly improved at Week 8. Of placebo responders who were improved at both Weeks 4 and 8, 77% remained clinically improved at Week 11 after treatment ended. Independent predictors of significant placebo improvement in the final multivariable model were African American race (odds ratio [OR] = 5.61, 95% confidence interval [CI] = 2.41-13.07, p < .001), current smokers (OR = 2.30, 95% CI = 1.05-5.06, p = .038), and hot flash severity in screening (OR = 1.45, 95% CI = 1.00-2.10, p = .047).

Conclusions: Clinically significant improvement with placebo accrued throughout treatment with a time course similar to improvement with active drug. A meaningful number of participants in the placebo group sustained a clinically significant response after stopping placebo pills. The results suggest that nonspecific effects are important components of treatment and warrant further studies to optimize their contributions in clinical care.
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http://dx.doi.org/10.1097/PSY.0000000000000143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333078PMC
November 2015

Poor sleep in relation to natural menopause: a population-based 14-year follow-up of midlife women.

Menopause 2015 Jul;22(7):719-26

From the 1Departments of Obstetrics/Gynecology and Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 2Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 3Center for Research in Reproduction and Women's Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; and 4Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD.

Objective: This study aims to estimate the prevalence and predictors of moderate/severe poor sleep in relation to the final menstrual period (FMP) in midlife women.

Methods: Annual assessments were conducted in a population-based cohort of 255 women. All were premenopausal at cohort enrollment and reached natural menopause during the 16-year follow-up. The outcome measure was severity of poor sleep, as reported by participants in annual interviews for 16 years and as evaluated in relation to the FMP.

Results: The annual prevalence of moderate/severe poor sleep largely ranged from about 28% to 35%, with no significant differences in any year relative to the FMP for the sample overall. When sleep status was stratified at premenopausal baseline, premenopausal sleep status strongly predicted poor sleep around the FMP. Women with moderate/severe poor sleep in premenopause were approximately 3.5 times more likely to have moderate/severe poor sleep around menopause than those with no poor sleep at baseline in adjusted analysis (odds ratio, 3.58; 95% CI, 2.50-5.11; P < 0.0001), whereas mild poor sleepers in premenopause were approximately 1.5 times more likely to have moderate/severe poor sleep around menopause (odds ratio, 1.57; 95% CI, 0.99-2.47; P = 0.053). There was no significant association between poor sleep and time relative to the FMP among women who had no poor sleep at premenopausal baseline. Hot flashes were significantly associated with poor sleep (odds ratio, 1.79; 95% CI, 1.44-2.21; P < 0.0001 in adjusted analysis) but had no interaction with baseline sleep severity (interaction P = 0.25), indicating that hot flashes contributed to poor sleep regardless of baseline sleep status.

Conclusions: Findings show a high prevalence of moderate/severe poor sleep in midlife women, with only a small "at-risk" subgroup having a significant increase in poor sleep in relation to the FMP. Sleep status at premenopausal baseline and concurrent hot flashes strongly and consistently predict poor sleep in the menopausal transition. Overall, poor sleep does not increase around the FMP and frequently occurs in the absence of hot flashes, indicating that sleep difficulties in the menopausal transition in generally healthy women are not simply associated with ovarian decline.
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http://dx.doi.org/10.1097/GME.0000000000000392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481144PMC
July 2015

Effects of estrogen and venlafaxine on menopause-related quality of life in healthy postmenopausal women with hot flashes: a placebo-controlled randomized trial.

Menopause 2015 Jun;22(6):607-15

From the 1Division of Research, Kaiser Permanente of Northern California, Oakland, CA; 2University of California, San Diego, CA; 3Brigham and Women's Hospital, Boston, MA; 4Dana Farber Cancer Institute, Boston, MA; 5MsFLASH Coordinating Center, Fred Hutchinson Cancer Research Center, Seattle, WA; 6School of Nursing, Indiana University, Indianapolis, IN; 7Massachusetts General Hospital, Boston, MA; 8Harvard Medical School, Boston, MA; 9Departments of Obstetrics/Gynecology and Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA; 10Group Health Research Institute, Seattle, WA; 11University of Washington School of Medicine, Seattle, WA; and 12VA Medical Center/University of Minnesota, Minneapolis, MN.

Objective: This study aims to evaluate the effects of low-dose estradiol (E2) or venlafaxine on menopause-related quality of life and associated symptoms in healthy perimenopausal and postmenopausal women with hot flashes.

Methods: A double-blind, placebo-controlled, randomized trial of low-dose oral 17β-E2 0.5 mg/day and venlafaxine XR 75 mg/day, versus identical placebo, was conducted among 339 women (aged 40-62 y) experiencing two or more vasomotor symptoms (VMS) per day (mean [SD], 8.07 [5.29]) who were recruited at three clinical sites from November 2011 to October 2012. The primary trial outcome, as reported previously, was frequency of VMS at 8 weeks. Here, we report on secondary endpoints of total and domain scores from the Menopause-Specific Quality of Life Questionnaire (MENQOL) and from measures of pain (Pain, Enjoyment in life, and General activity scale), depression (Patient Health Questionnaire-9), anxiety (Generalized Anxiety Disorder Questionnaire-7), and perceived stress (Perceived Stress Scale).

Results: Treatment with both E2 and venlafaxine resulted in significantly greater improvement in quality of life, as measured by total MENQOL scores, compared with placebo (E2: mean difference at 8 wk, -0.4; 95% CI, -0.7 to -0.2; P < 0.001; venlafaxine: mean difference at 8 wk, -0.2; 95% CI, -0.5 to 0.0; P = 0.04). Quality-of-life domain analyses revealed that E2 had beneficial treatment effects on all domains of the MENQOL except for the psychosocial domain, whereas venlafaxine benefits were observed only in the psychosocial domain. Neither E2 nor venlafaxine improved pain, anxiety, or depressive symptoms, although baseline symptom levels were low. Modest benefits were observed for perceived stress with venlafaxine.

Conclusions: Both low-dose E2 and venlafaxine are effective pharmacologic agents for improving menopause-related quality of life in healthy women with VMS.
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http://dx.doi.org/10.1097/GME.0000000000000364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610378PMC
June 2015

Effects of estradiol and venlafaxine on insomnia symptoms and sleep quality in women with hot flashes.

Sleep 2015 Jan 1;38(1):97-108. Epub 2015 Jan 1.

Department of Psychiatry, Brigham and Women's Hospital and Dana Farber Cancer Institute, Boston, MA.

Study Objectives: Determine effects of low-dose estradiol and low-dose venlafaxine on self-reported sleep measures in menopausal women with hot flashes.

Design: 3-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.

Setting: Academic research centers.

Participants: 339 community-dwelling perimenopausal and postmenopausal women with ≥2 bothersome hot flashes per day.

Measurements And Results: Insomnia 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).

Conclusions: Among 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 Registration: NCT01418209 at www.clinicaltrials.gov.
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http://dx.doi.org/10.5665/sleep.4332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262961PMC
January 2015

Effects of escitalopram on markers of bone turnover: a randomized clinical trial.

J Clin Endocrinol Metab 2014 Sep 11;99(9):E1732-7. Epub 2014 Jul 11.

University of Minnesota (S.J.D., K.E.E.), Minneapolis, Minnesota 55415; Brigham and Women's Hospital and Dana Farber Cancer Institute (H.J.), Boston, Massachusetts 02115; Fred Hutchinson Cancer Research Center (J.C.L., A.Z.L.), Seattle, Washington 98109; Massachusetts General Hospital (J.N.T., B.Z.L.), Boston, Massachusetts 02114; Minneapolis Veterans Affairs Health Care System (K.E.E.), Minneapolis, Minnesota 55417; and Perelman School of Medicine (E.W.F.), University of Pennsylvania, Philadelphia, Pennsylvania 19104.

Context: Recent observational studies have suggested that the use of selective serotonin reuptake inhibitors is associated with an increased fracture risk and an accelerated bone loss, although conflicting results have been reported. Furthermore, because many of these studies have been performed in depressed women, confounding by indication may influence these findings.

Objective: The objective of the study was to determine whether selective serotonin reuptake inhibitors affect bone metabolism Design: This was a randomized controlled trial.

Setting: The study was conducted in four US clinical sites.

Participants: Healthy peri- and postmenopausal women participated in the study.

Intervention: The intervention was escitalopram (10-20 mg/d) for the treatment of vasomotor symptoms.

Main Outcome Measures: Serum carboxyterminal collagen crosslinks (CTX) and serum amino-terminal propeptide of type I collagen (P1NP) were measured.

Results: One hundred forty-one peri- or postmenopausal nondepressed women (mean age 53.7 y, SD 4.1) had baseline and 8-week follow-up samples available for analysis and were included in the study (69 escitalopram, 72 placebo). The groups were balanced across a broad range of baseline characteristics, including age, race, body mass index, smoking status, and mood symptoms. The between-group differences in the change in CTX and P1NP from baseline to week 8 were compared by a repeated-measures linear regression model adjusted for race, clinical center, and baseline measurement. Treatment with escitalopram reduced serum P1NP by 1.02 ng/mL on average [95% confidence interval (CI) -5.17, 3.12] compared with a reduction of 1.88 ng/mL (95% CI -4.82, 1.06) in the placebo group (P = .65). Similarly, serum CTX decreased 0.02 ng/mL on average (95% CI -0.05, 0.01) in the escitalopram group compared with 0.00 ng/mL (95% CI -0.02, 0.02) in the placebo group (P = .24). The results were similar when the analysis was restricted to those women whose adherence to study medication was 70% or greater.

Conclusions: Although the study was limited to 8 weeks, these results suggest that escitalopram does not significantly alter bone metabolism in the short term.
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http://dx.doi.org/10.1210/jc.2014-2288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154080PMC
September 2014

Sexual function in women on estradiol or venlafaxine for hot flushes: a randomized controlled trial.

Obstet Gynecol 2014 Aug;124(2 Pt 1):233-241

Departments of Obstetrics and Gynecology and Epidemiology, University of Washington School of Medicine, the Group Health Research Institute, and the Data Coordinating Center, Fred Hutchinson Cancer Research Center, Seattle, Washington; the Departments of Psychiatry and Medicine, Brigham and Women's Hospital, the Departments of Psychiatry and Obstetrics and Gynecology, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts; and the Departments of Obstetrics and Gynecology and Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

Objective: To evaluate sexual function in midlife women taking low-dose oral estradiol or venlafaxine for hot flushes.

Methods: In an 8-week randomized controlled trial among women aged 40-62 years, sexual function was compared between 0.5 mg oral estradiol per day or 75 mg venlafaxine per day (both compared with a placebo). Measures included composite and six domain scores from the Female Sexual Function Index and sexually related personal distress.

Results: Participants were aged 54.6 years (standard deviation [SD] 3.8) years, 59% white, with 8.1 (SD 5.3) daily hot flushes. Median composite baseline Female Sexual Function Index score was 16.3 (SD 11.9, n=256) for all women and 21.7 (SD 9.3, n=198) among sexually active women. Composite mean Female Sexual Function Index change from baseline to week 8 was 1.4 (95% confidence interval [CI] -0.4 to 3.2) for estradiol, 1.1 (95% CI -0.5 to 2.7) for venlafaxine, and -0.3 (95% CI -1.6 to 1.0) for placebo. Composite Female Sexual Function Index and sexually related distress change from baseline did not differ between estradiol and placebo (P=.38, P=.30) or venlafaxine and placebo (P=.79, P=.48). Among sexually active women, Female Sexual Function Index domain score change from baseline differences (active compared with placebo) in desire was 0.3 (95% CI 0.0-0.6) for estradiol, -0.6 (95% CI -1.2 to 0.0) in orgasm for venlafaxine, and 0.9 (95% CI 0.2-1.6) in penetration pain for venlafaxine. No women reported adverse events related to sexual dysfunction.

Conclusion: Overall sexual function among nondepressed midlife women experiencing hot flushes did not change over 8 weeks with low-dose oral estradiol or venlafaxine (compared with placebo), although a subtle increase in desire (estradiol) and decreases in orgasm and pain (venlafaxine) may exist.

Clinical Trial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01418209.

Level Of Evidence: I.
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http://dx.doi.org/10.1097/AOG.0000000000000386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113909PMC
August 2014

Low-dose estradiol and the serotonin-norepinephrine reuptake inhibitor venlafaxine for vasomotor symptoms: a randomized clinical trial.

JAMA Intern Med 2014 Jul;174(7):1058-66

Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston.

Importance: Estrogen therapy is the gold standard treatment for hot flashes and night sweats, but some women are unable or unwilling to use it because of associated risks. The serotonin-norepinephrine reuptake inhibitor venlafaxine hydrochloride is used widely as a nonhormonal treatment. While the clinical impression is that serotonin-norepinephrine reuptake inhibitors are less effective than estrogen, these medications have not been simultaneously evaluated in one clinical trial to date.

Objective: To determine the efficacy and tolerability of low-dose oral 17β-estradiol and low-dose venlafaxine extended release in alleviating vasomotor symptoms (VMS).

Design, Setting, And Participants: In total, 339 perimenopausal and postmenopausal women with at least 2 bothersome VMS per day (mean, 8.1 per day) were recruited from the community to MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) clinical network sites between December 5, 2011, and October 15, 2012.

Interventions: Participants were randomized to double-blind treatment with low-dose oral 17β-estradiol (0.5 mg/d) (n = 97), low-dose venlafaxine hydrochloride extended release (75 mg/d) (n = 96), or placebo (n = 146) for 8 weeks.

Main Outcomes And Measures: The primary outcome was the mean daily frequency of VMS after 8 weeks of treatment. Secondary outcomes were VMS severity, bother, and interference with daily life. Intent-to-treat analyses compared the change in VMS frequency between each active intervention and placebo and between the 2 active treatments.

Results: Compared with baseline, the mean VMS frequency at week 8 decreased to 3.9 (95% CI, 2.9-4.9) VMS per day (52.9% reduction) in the estradiol group, to 4.4 (95% CI, 3.5-5.3) VMS per day (47.6% reduction) in the venlafaxine group, and to 5.5 (95% CI, 4.7-6.3) VMS per day (28.6% reduction) in the placebo group. Estradiol reduced the frequency of symptoms by 2.3 more per day than placebo (P < .001), and venlafaxine reduced the frequency of symptoms by 1.8 more per day than placebo (P = .005). The results were consistent for VMS severity, bother, and interference. Low-dose estradiol reduced the frequency of symptoms by 0.6 more per day than venlafaxine (P = .09). Treatment satisfaction was highest (70.3%) for estradiol (P < .001 vs placebo), lowest (38.4%) for placebo, and intermediate (51.1%) for venlafaxine (P = .06 vs placebo). Both interventions were well tolerated.

Conclusions And Relevance: Low-dose oral estradiol and venlafaxine are effective treatments for VMS in women during midlife. While the efficacy of low-dose estradiol may be slightly superior to that of venlafaxine, the difference is small and of uncertain clinical relevance.

Trial Registration: clinicaltrials.gov Identifier: NCT01418209.
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http://dx.doi.org/10.1001/jamainternmed.2014.1891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4179877PMC
July 2014

Hot flushes and the menopause: how long should they be expected to last?

Authors:
Ellen W Freeman

Maturitas 2014 Jul 20;78(3):153-4. Epub 2014 Apr 20.

Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States. Electronic address:

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http://dx.doi.org/10.1016/j.maturitas.2014.04.010DOI Listing
July 2014