Ellen W Freeman, Mary D Sammel, Hui Lin, Deborah B Nelson
Associations of hormones and menopausal status with depressed mood in women with no history of depression.
Arch Gen Psychiatry. 2006 Apr;63(4):375-82. doi: 10.1001/archpsyc.63.4.375.
Abstract/Text
CONTEXT: Whether depressed mood reported in the transition to menopause by women with no history of depression is associated with menopausal status and changes in reproductive hormones is controversial and lacks scientific information.
OBJECTIVES: To identify new onset of depressive symptoms and diagnosed depressive disorders in the menopausal transition and to determine the associations of menopausal status, reproductive hormones, and other risk factors with these cases.
DESIGN: A within-woman, longitudinal (8-year) study to identify risk factors of depressed mood.
SETTING: A subset of a randomly identified, population-based cohort.
PARTICIPANTS: Premenopausal women with no history of depression at cohort enrollment.
MAIN OUTCOME MEASURES: The Center for Epidemiological Studies of Depression scale (CES-D) was used to assess depressive symptoms, and the Primary Care Evaluation of Mental Disorders (PRIME-MD) was used to identify clinical diagnoses of depressive disorders.
RESULTS: High CES-D scores (> or=16) were more than 4 times more likely to occur during a woman's menopausal transition compared with when she was premenopausal (odds ratio, 4.29; 95% confidence interval, 2.39-7.72; P<.001). Within-woman change in menopausal status, increased levels of follicle-stimulating hormone and luteinizing hormone, and increased variability of estradiol, follicle-stimulating hormone, and luteinizing hormone around the woman's own mean levels were each significantly associated with high CES-D scores after adjusting for smoking, body mass index, premenstrual syndrome, hot flashes, poor sleep, health status, employment, and marital status. A diagnosis of depressive disorder was 2(1/2) times more likely to occur in the menopausal transition compared with when the woman was premenopausal (odds ratio, 2.50; 95% confidence interval, 1.25-5.02; P=.01); the hormone measures were also significantly associated with this outcome.
CONCLUSION: Transition to menopause and its changing hormonal milieu are strongly associated with new onset of depressed mood among women with no history of depression.
Masakazu Terauchi, Shiro Hiramitsu, Mihoko Akiyoshi, Yoko Owa, Kiyoko Kato, Satoshi Obayashi, Eisuke Matsushima, Toshiro Kubota
Associations between anxiety, depression and insomnia in peri- and post-menopausal women.
Maturitas. 2012 May;72(1):61-5. doi: 10.1016/j.maturitas.2012.01.014. Epub 2012 Feb 11.
Abstract/Text
OBJECTIVES: To determine the correlation between somatic and psychological symptoms and insomnia and the contribution of depression and anxiety to insomnia in a sample of peri- and post-menopausal women in a clinical setting.
STUDY DESIGN: The responses of 237 peri- and post-menopausal women enrolled in the Systematic Health and Nutrition Education Program (SHNEP) at the Menopause Clinic of the Tokyo Medical and Dental University Hospital between November 2007 and December 2010 to the Menopausal Health-Related Quality of Life (MHR-QOL) and Hospital Anxiety and Depression Scale (HADS) questionnaires were subjected to Spearman's rank correlation and logistic regression analyses.
RESULTS: The analysis revealed that (1) insomnia is highly prevalent, (2) the symptoms of difficulty in initiating sleep (DIS) and experiencing non-restorative sleep (NRS) are more strongly correlated with psychological than somatic symptoms, and (3) DIS is strongly associated with anxiety while NRS is strongly associated with depression in the population studied.
CONCLUSIONS: Insomnia is highly prevalent among peri- and post-menopausal female patients in a clinical setting and more closely associated with psychological than somatic symptoms. DIS is strongly correlated with anxiety while NRS is strongly correlated with depression.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
日本産科婦人科学会雑誌、53(5):883-888, 2001.
M Terauchi, S Obayashi, M Akiyoshi, K Kato, E Matsushima, T Kubota
Insomnia in Japanese peri- and postmenopausal women.
Climacteric. 2010 Oct;13(5):479-86. doi: 10.3109/13697130903353478.
Abstract/Text
OBJECTIVE: To determine the prevalence and to identify the correlates of insomnia in Japanese peri- and postmenopausal women.
METHOD: We retrospectively analyzed the records of 1451 peri- and postmenopausal women enrolled in the Systematic Health and Nutrition Education Program, conducted at the Menopause Clinic of the Tokyo Medical and Dental University Hospital, between 1995 and 2009.
RESULTS: The prevalence of insomnia was 50.8%. The severity of insomnia correlated negatively with health-related quality of life (HR-QOL) scores on all the four domains assessed: physical health, mental health, life satisfaction and social involvement. With regard to other menopausal symptoms, insomnia correlated more strongly with depressed mood than with vasomotor symptoms, and one-third of insomniac women were seriously depressed. On categorizing the participants into four groups--not insomniac or depressed, N; insomniac but not depressed, I; not insomniac but depressed, D; insomniac and depressed, ID--the HR-QOL scores were observed to worsen in order N > I > D > ID. No significant difference was detected between groups I and ID with regard to their sleep quality measures. The number of heavy smokers was high in groups I and ID. With regard to the effect of the combination of medication and health/nutrition education, hormone therapy and nightly hypnotics significantly improved the insomnia symptoms, but hypnotics administered 'as needed' did not.
CONCLUSIONS: Insomnia in Japanese peri- and postmenopausal women correlates more strongly with depressed mood than with vasomotor symptoms. Cessation of smoking may improve the women's sleep quality, and hormone therapy and nightly hypnotics are both effective treatments.
Masakazu Terauchi, Shiro Hiramitsu, Mihoko Akiyoshi, Yoko Owa, Kiyoko Kato, Satoshi Obayashi, Eisuke Matsushima, Toshiro Kubota
Associations among depression, anxiety and somatic symptoms in peri- and postmenopausal women.
J Obstet Gynaecol Res. 2013 May;39(5):1007-13. doi: 10.1111/j.1447-0756.2012.02064.x. Epub 2013 Feb 4.
Abstract/Text
AIM: The aim of this study was to investigate the associations among depression, anxiety and physical symptoms in peri- and postmenopausal women in a clinical setting.
MATERIAL AND METHODS: Two hundred and thirty-seven peri- and postmenopausal women enrolled in the Systematic Health and Nutrition Education Program at the Menopause Clinic of the Tokyo Medical and Dental University Hospital. Their responses to the Menopausal Health-Related Quality of Life (MHR-QOL) and Hospital Anxiety and Depression Scale (HADS) questionnaires were subjected to a cross-sectional analysis. The study focused on the relationship between the scores for HADS depression (HADS-D) and anxiety (HADS-A) subscales and those for somatic (nausea, dizziness, numbness, muscle and joint pains, tiredness, headaches), urinary (frequent urination), and vasomotor symptoms (hot flashes, night sweats) in the MHR-QOL questionnaire.
RESULTS: The correlations among the scores for the six somatic symptoms and HADS-D and HADS-A were stronger than those for urinary or vasomotor symptoms. Multiple logistic regression analysis revealed that the score for headaches and that for HADS-A were significantly associated with severe depression after adjustment (odds ratio (OR) [95% confidence interval (CI)]: 1.49 [1.06-2.10] and 1.58 [1.37-1.83], respectively), whereas the scores for nausea and numbness, as well as HADS-D, were significantly associated with severe anxiety (OR [95% CI]: 1.65 [1.15-2.39], 1.39 [1.05-1.84], and 1.36 [1.23-1.50], respectively).
CONCLUSION: Headaches were associated with depression, whereas nausea and numbness were associated with anxiety in peri- and postmenopausal women. The assessment of underlying mood disorders is required for the management of middle-aged women presenting with these somatic symptoms.
© 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.
Masakazu Terauchi, Asuka Hirose, Mihoko Akiyoshi, Yoko Owa, Kiyoko Kato, Toshiro Kubota
Subgrouping of Japanese middle-aged women attending a menopause clinic using physical and psychological symptom profiles: a cross-sectional study.
BMC Womens Health. 2014 Nov 25;14:148. doi: 10.1186/s12905-014-0148-z. Epub 2014 Nov 25.
Abstract/Text
BACKGROUND: Women in the menopausal transition and the postmenopausal period are affected with vasomotor symptoms, urogenital atrophy, sexual dysfunction, somatic symptoms, cognitive difficulty, sleep disturbance, and psychological problems. It is important to gain a better understanding of the complexity and diversity of climacteric disturbance in order to optimize treatments for individual patients. The aim of this study was to identify subgroups of Japanese perimenopausal and postmenopausal women attending a menopause clinic based on their physical and psychological symptom profiles.
METHODS: We administered the Menopausal Health-Related Quality of Life questionnaire to 491 Japanese women aged 40-64 years who had enrolled in the Systematic Health and Nutrition Education Program at the Menopause Clinic of the Tokyo Medical and Dental University Hospital between 2005 and 2012. We performed a principal component analysis followed by a hierarchical cluster analysis of the responses to 9 physical and 12 psychological items on the questionnaire.
RESULTS: The first analysis extracted 3 principal components that defined the variance of physical and psychological symptom profiles: depression, somatic, and vasomotor/sleep. A subsequent cluster analysis was performed based on the 3 principal components to generate 4 clusters, CL8 (N = 162; 33.0%), CL6 (N = 111; 22.6%), CL5 (N = 102; 20.8%), and CL4 (N = 116; 23.6%). CL8 included women who only had mild-to-moderate musculoskeletal pains and tiredness. All women in CL6, CL5, and CL4 described their musculoskeletal pains and tiredness as moderate to severe. The women in CL5 also had moderate-to-severe vasomotor symptoms, while the women in CL4 also suffered from moderate-to-severe psychological symptoms, such as depression, anxiety, and insomnia.
CONCLUSIONS: Distinct subgroups of Japanese perimenopausal and postmenopausal women were identified based on their symptom profiles. Menopausal symptoms were shown to accumulate in this population in the order of musculoskeletal pains and tiredness, vasomotor symptoms, and psychological symptoms.
M Terauchi, A Hirose, M Akiyoshi, K Kato, N Miyasaka
Feelings of unattractiveness in peri- and postmenopausal women are associated with depressed mood, poor memory and unsatisfactory sexual relationships.
Climacteric. 2017 Jun;20(3):228-232. doi: 10.1080/13697137.2017.1293647. Epub 2017 Mar 11.
Abstract/Text
OBJECTIVES: This study aimed to investigate the prevalence of, and risk factors associated with, the feeling of unattractiveness in peri- and postmenopausal women.
METHODS: The records of 351 women aged 40-76 who enrolled in a health and nutrition education program at a menopause clinic were analyzed in a cross-sectional manner. Perceptions of unattractiveness were estimated according to responses for the item 'feeling less attractive than before' on the Menopausal Health-Related Quality of Life Questionnaire. Age, menopausal status, body composition, cardiovascular parameters, physical fitness, and genitourinary, physical, and psychological symptoms of menopause were assessed for associations with feeling unattractive.
RESULTS: The percentage of women who felt they were less attractive than before for more than half of the previous week was 33.6%. Multivariate logistic regression analysis revealed that independent risk factors for feeling unattractive included depression (adjusted odds ratio (OR) 1.35; 95% confidence interval (CI) 1.24-1.47), dissatisfaction with sexual relationship (adjusted OR 1.74; 95% CI 1.21-2.57), and poor memory (adjusted OR 1.89; 95% CI 1.46-2.49).
CONCLUSIONS: Feelings of unattractiveness are highly prevalent in peri- and postmenopausal women. Such feelings are associated with depressed moods, poor memory, and unsatisfactory sexual relationships, rather than with age or body composition.
Masakazu Terauchi, Satoshi Obayashi, Mihoko Akiyoshi, Kiyoko Kato, Eisuke Matsushima, Toshiro Kubota
Effects of oral estrogen and hypnotics on Japanese peri- and postmenopausal women with sleep disturbance.
J Obstet Gynaecol Res. 2011 Jul;37(7):741-9. doi: 10.1111/j.1447-0756.2010.01424.x. Epub 2011 Mar 13.
Abstract/Text
AIM: To assess the effects of estrogen and hypnotics on Japanese peri- and postmenopausal women with sleep disturbance.
METHODS: Among the records of 1451 participants enrolled in the Systematic Health and Nutrition Education Program conducted at the Menopause Clinic of the Tokyo Medical and Dental University Hospital between 1995 and 2009, those of 202 peri- and postmenopausal women were retrospectively analyzed. These women, who had moderate to severe sleep disturbances, had either received only health and nutrition education (control; n = 119), or had received education with either conjugated estrogen (estrogen [0.625 mg/day]; n = 55) or nightly hypnotics (hypnotics; n = 28), and were followed up for a median interval of six months.
RESULTS: Both oral estrogen and hypnotics improved the subjective sleep disturbance scores, while administration of hypnotics decreased the percentage of women reporting difficulty in initiating sleep or non-restorative sleep. Oral estrogen was also effective in alleviating various menopausal symptoms, while hypnotics were not. The health-related quality of life of these patients was significantly promoted by health and nutrition education alone, and neither estrogen nor hypnotics had an additive effect on it. Administration of hypnotics substantially lowered the blood pressure of the subjects (systolic pressure, -10.2%; diastolic pressure, -8.3%) and significantly reduced body weight (-2.1%), body mass index (-2.2%) and body fat (-7.8%), without affecting lean body mass.
CONCLUSIONS: Oral estrogen and hypnotics are effective for sleep disturbance in Japanese peri- and postmenopausal women. They can be admininstered either singly or in combination, according to the patient's characteristics.
© 2011 The Authors. Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology.
Masakazu Terauchi, Shiro Hiramitsu, Mihoko Akiyoshi, Yoko Owa, Kiyoko Kato, Satoshi Obayashi, Eisuke Matsushima, Toshiro Kubota
Effects of the kampo formula tokishakuyakusan on headaches and concomitant depression in middle-aged women.
Evid Based Complement Alternat Med. 2014;2014:593560. doi: 10.1155/2014/593560. Epub 2014 Feb 4.
Abstract/Text
Objectives. To identify the correlates of headaches in middle-aged women and investigate the effects of Tokishakuyakusan (TJ-23), a formula of traditional Japanese herbal therapy Kampo, on headache and concomitant depression. Methods. We examined cross-sectionally the baseline records of 345 women aged 40-59 years who visited our menopause clinic. Among them, 37 women with headaches were treated with either hormone therapy (HT) or TJ-23; the data of these women were retrospectively analyzed to compare the effects of the treatment. Results. The women were classified into 4 groups on the basis of their headache frequency, and no significant intergroup differences were noted in the physical or lifestyle factors, except age. Multiple logistic regression analysis revealed that the significant contributors to the women's headaches were their age (adjusted OR 0.92 (95% CI 0.88-0.97)) and their depressive symptoms (adjusted OR 1.73 (95% CI 1.39-2.16)). Compared to women treated with HT, women treated with TJ-23 reported relief from headaches (65% versus 29%) and concomitant depression (60% versus 24%) more frequently. Improvement in the scores of headaches and depression correlated significantly with TJ-23 treatment. Conclusions. Headache in middle-aged women is significantly associated with depression; TJ-23 could be effective for treating both of these symptoms.
Masakazu Terauchi, Shiro Hiramitsu, Mihoko Akiyoshi, Yoko Owa, Kiyoko Kato, Satoshi Obayashi, Eisuke Matsushima, Toshiro Kubota
Effects of three Kampo formulae: Tokishakuyakusan (TJ-23), Kamishoyosan (TJ-24), and Keishibukuryogan (TJ-25) on Japanese peri- and postmenopausal women with sleep disturbances.
Arch Gynecol Obstet. 2011 Oct;284(4):913-21. doi: 10.1007/s00404-010-1779-4. Epub 2010 Dec 1.
Abstract/Text
PURPOSE: To assess the effects of Kampo, a traditional Japanese adaptation of Chinese herbal medicine, on peri- and postmenopausal women with sleep disturbances.
METHODS: Among the records of 1,523 peri- and postmenopausal women who are enrolled in the Health and Nutrition Education Program at the Tokyo Medical and Dental University, Menopause Clinic, during 1995-2009, about 151 women suffering from moderate to severe sleep disturbances were retrospectively analyzed. These women had received only health/nutrition education (control; n = 77) or received treatment with one of the three major Kampo formulae: Tokishakuyakusan (TJ-23; n = 42), Kamishoyosan (TJ-24; n = 16), or Keishibukuryogan (TJ-25; n = 16) according to their "Sho" or symptom patterns. Subjective sleep parameters, menopausal symptoms, health-related quality of life, body composition, blood pressure, and pulse rate were compared before and after the intervention.
RESULTS: The TJ-25 group had significantly higher body weight, body mass index, body fat, lean body mass, resting energy expenditure, and relatively high blood pressure and heart rate at baseline than the other groups. After ~5-month follow up, TJ-23 reduced the sleep disruption frequency, increased lean body mass, and decreased diastolic pressure. TJ-24 alleviated subjective sleep disturbances; improved difficulties in initiating sleep, disrupted sleep, and non-restorative sleep; and relieved headache/dizziness. TJ-25 improved subjective sleep disturbances, alleviated perspiration, and reduced systolic/diastolic pressure and heart rate.
CONCLUSIONS: Each of the Kampo formulae effectively alleviated sleep disturbances in Japanese peri- and postmenopausal women. Middle-aged female patients having sleeping disorder could successfully be treated using Kampo medicines.
Masakazu Terauchi, Mihoko Akiyoshi, Yoko Owa, Kiyoko Kato, Satoshi Obayashi, Toshiro Kubota
Effects of the Kampo medication keishibukuryogan on blood pressure in perimenopausal and postmenopausal women.
Int J Gynaecol Obstet. 2011 Aug;114(2):149-52. doi: 10.1016/j.ijgo.2011.03.006. Epub 2011 Jun 12.
Abstract/Text
OBJECTIVE: To examine the effects of keishibukuryogan (TJ-25)-a medicine of the Kampo tradition (the Japanese adaptation of Chinese herbal medicine)-on middle-aged women with high blood pressure.
METHODS: The records of 77 peri- and postmenopausal women with high-normal blood pressure or hypertension were analyzed retrospectively. The women had participated in the Systematic Health and Nutrition Education Program at the Tokyo Medical and Dental University in Tokyo, Japan, and had received education only (controls; n = 47) or education and treatment with TJ-25 (n = 30).
RESULTS: The baseline characteristics of the 2 groups were comparable. After approximately 6 months, women in the TJ-25 group showed significant reductions in their systolic blood pressure (from 148.4mm Hg to 134.8mm Hg), diastolic blood pressure (from 89.7 mm Hg to 83.7 mm Hg), pulse rate (from 79.5 beats/min to 73.5 beats/min), and resting energy expenditure (from 1552 kcal/day to 1373 kcal/day). Several menopausal symptoms including perspiration, difficulty in initiating sleep, nonrestorative sleep, and headaches/dizziness were also improved. In addition, women in the TJ-25 group had increased health-related quality of life scores in the domains of physical health and life satisfaction.
CONCLUSION: TJ-25 alleviates menopausal symptoms and concurrently lowers the blood pressure of middle-aged women with high blood pressure.
Copyright © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
Claudio N Soares, Helga Arsenio, Hadine Joffe, Bettina Bankier, Paolo Cassano, Laura F Petrillo, Lee S Cohen
Escitalopram versus ethinyl estradiol and norethindrone acetate for symptomatic peri- and postmenopausal women: impact on depression, vasomotor symptoms, sleep, and quality of life.
Menopause. 2006 Sep-Oct;13(5):780-6. doi: 10.1097/01.gme.0000240633.46300.fa.
Abstract/Text
OBJECTIVE: To examine the efficacy and tolerability of escitalopram (ESCIT) compared to estrogen and progestogen therapy (EPT) for the treatment of symptomatic peri- and postmenopausal women.
DESIGN: Forty women (aged 40-60 years) with depressive disorders and menopause-related symptoms were randomly assigned to an 8-week open trial with ESCIT (flexible dose, 10-20 mg/day; fixed dose, 10 mg/day for the first 4 weeks) or estrogen plus progestogen therapy (ethinyl estradiol 5 microg/day plus norethindrone acetate 1 mg/day). Primary outcome measures included Montgomery-Asberg Depression Rating Scale and the Greene Climacteric Scale at week 8. Secondary outcome measures included the Clinical Global Impressions as well as sleep and quality of life assessments.
RESULTS: Thirty-two women (16 on EPT, 16 on ESCIT) were included in the analyses. Full remission of depression (score of <10 on the Montgomery-Asberg Depression Rating Scale) was observed in 75% (12/16) of subjects treated with ESCIT, compared to 25% (4/16) treated with EPT (P = 0.01, Fisher's exact tests). Remission of menopause-related symptoms (>50% decrease in Greene Climacteric Scale scores) was noted in 56% (9/16) of women treated with ESCIT compared to 31.2% (5/16) on EPT (P = 0.03, Pearson's chi2 tests). Improvement in sleep, hot flashes, and quality of life was observed with both treatments.
CONCLUSIONS: ESCIT is more efficacious than EPT for the treatment of depression and has a positive impact on other menopause-related symptoms. ESCIT may constitute a treatment option for symptomatic menopausal women who are unable or unwilling to use hormone therapy.
Ellen W Freeman, Katherine A Guthrie, Bette Caan, Barbara Sternfeld, Lee S Cohen, Hadine Joffe, Janet S Carpenter, Garnet L Anderson, Joseph C Larson, Kristine E Ensrud, Susan D Reed, Katherine M Newton, Sheryl Sherman, Mary D Sammel, Andrea Z LaCroix
Efficacy of escitalopram for hot flashes in healthy menopausal women: a randomized controlled trial.
JAMA. 2011 Jan 19;305(3):267-74. doi: 10.1001/jama.2010.2016.
Abstract/Text
CONTEXT: Concerns regarding the risks associated with estrogen and progesterone to manage menopausal symptoms have resulted in its declining use and increased interest in nonhormonal treatments with demonstrated efficacy for hot flashes.
OBJECTIVE: To determine the efficacy and tolerability of 10 to 20 mg/d escitalopram, a selective serotonin reuptake inhibitor, in alleviating the frequency, severity, and bother of menopausal hot flashes.
DESIGN, SETTING, AND PATIENTS: A multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel group trial that enrolled 205 women (95 African American; 102 white; 8 other) between July 2009 and June 2010.
INTERVENTION: Women received 10 to 20 mg/d of escitalopram or a matching placebo for 8 weeks.
MAIN OUTCOME MEASURES: Primary outcomes were the frequency and severity of hot flashes assessed by prospective daily diaries at weeks 4 and 8. Secondary outcomes were hot flash bother, recorded on daily diaries, and clinical improvement (defined as hot flash frequency ≥50% decrease from baseline).
RESULTS: Mean (SD) daily hot flash frequency was 9.78 (5.60) at baseline. In a modified intent-to-treat analysis that included all randomized participants who provided hot flash diary data, the mean difference in hot flash frequency reduction was 1.41 (95% CI, 0.13-2.69) fewer hot flashes per day at week 8 among women taking escitalopram (P < .001), with mean reductions of 4.60 (95% CI, 3.74-5.47) and 3.20 (95% CI, 2.24-4.15) hot flashes per day in the escitalopram and placebo groups, respectively. Fifty-five percent of women in the escitalopram group vs 36% in the placebo group reported a decrease of at least 50% in hot flash frequency (P = .009) at the 8-week follow-up. Reductions in hot flash severity scores were significantly greater in the escitalopram group (-0.52; 95% CI, -0.64 to -0.40 vs -0.30; 95% CI, -0.42 to -0.17 for placebo; P < .001). Race did not significantly modify the treatment effect (P = .62). Overall discontinuation due to adverse events was 4% (7 in the active group, 2 in the placebo group). Three weeks after treatment ended, women in the escitalopram group reported a mean 1.59 (95% CI, 0.55-2.63; P = .02) more hot flashes per day than women in the placebo group.
CONCLUSION: Among healthy women, the use of escitalopram (10-20 mg/d) compared with placebo resulted in fewer and less severe menopausal hot flashes at 8 weeks of follow-up.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00894543.
Hadine Joffe, Laura Fagioli Petrillo, Alexia Koukopoulos, Adele C Viguera, April Hirschberg, Ruta Nonacs, Brittny Somley, Erica Pasciullo, David P White, Janet E Hall, Lee S Cohen
Increased estradiol and improved sleep, but not hot flashes, predict enhanced mood during the menopausal transition.
J Clin Endocrinol Metab. 2011 Jul;96(7):E1044-54. doi: 10.1210/jc.2010-2503. Epub 2011 Apr 27.
Abstract/Text
BACKGROUND: The antidepressant effect of estrogen in women undergoing the menopause transition is hypothesized to be mediated by central nervous system effects of increasing estradiol on mood or through a pathway involving suppression of hot flashes and associated sleep disturbance. Estrogen therapy (ET) and the hypnotic agent zolpidem were selected as interventions in a three-arm, double-blind, placebo-controlled trial to distinguish the effects of estradiol, sleep, and hot flashes on depression.
METHODS: Women with depressive disorders, hot flashes, and sleep disturbance were randomly assigned to transdermal 17β-estradiol 0.05 mg/d, zolpidem 10 mg/d, or placebo for 8 wk. Changes in serum estradiol, perceived sleep quality, objectively measured sleep, and hot flashes were examined as predictors of depression improvement [Montgomery-Åsberg Depression Rating Scale (MADRS)] using multivariate linear regression.
RESULTS: Seventy-two peri/postmenopausal women with depression disorders were randomized to 17β-estradiol (n = 27), zolpidem (n = 31), or placebo (n = 14). There was no significant difference between groups in depression improvement (overall MADRS decrease 11.8 ± 8.6). Increasing estradiol (P = 0.009) and improved sleep quality (P < 0.001) predicted improved mood in adjusted models but reduced hot flashes (P = 0.99) did not. Post hoc subgroup analyses revealed that the therapeutic effect of increasing estradiol levels on mood was seen in perimenopausal (P = 0.009), but not postmenopausal, women.
CONCLUSIONS: For women with menopause-associated depression, improvement in depression is predicted by improved sleep, and among perimenopausal women, by increasing estradiol levels. These results suggest that changes in estradiol and sleep quality, rather than hot flashes, mediate depression during the menopause transition. Therapies targeting insomnia may be valuable in treating menopause-associated depression.
Hadine Joffe, Laura Petrillo, Adele Viguera, Alexia Koukopoulos, Kate Silver-Heilman, Adriann Farrell, Gary Yu, Michael Silver, Lee S Cohen
Eszopiclone improves insomnia and depressive and anxious symptoms in perimenopausal and postmenopausal women with hot flashes: a randomized, double-blinded, placebo-controlled crossover trial.
Am J Obstet Gynecol. 2010 Feb;202(2):171.e1-171.e11. doi: 10.1016/j.ajog.2009.10.868. Epub 2009 Dec 24.
Abstract/Text
OBJECTIVE: Menopause-associated insomnia is commonly associated with other symptoms (hot flashes, depression, anxiety). Given frequent symptom cooccurrence, therapies targeting sleep may provide an important approach to treatment during midlife.
STUDY DESIGN: Peri/postmenopausal women (40-65 years old) with sleep-onset and/or sleep-maintenance insomnia cooccurring with hot flashes and depressive and/or anxiety symptoms were randomized to eszopiclone 3 mg orally or placebo in a double-blinded, crossover 11 week trial. Changes in the Insomnia Severity Index (ISI) scale and secondary outcomes (diary-based sleep parameters, depression/anxiety, hot flashes, quality of life) were analyzed using repeated-measure linear models.
RESULTS: Of 59 women, 46 (78%) completed the study. Eszopiclone reduced ISI scores by 8.7 + or - 1.4 more points than placebo (P < .0001). Eszopiclone improved (P < .05) all sleep parameters, depressive symptoms, anxiety symptoms, quality of life, and nighttime but not daytime hot flashes.
CONCLUSION: Eszopiclone treats insomnia and cooccurring menopause-related symptoms. Our results provide evidence that hypnotic therapies may improve multiple domains of well-being during midlife.
Copyright 2010 Mosby, Inc. All rights reserved.
Wendy J Brown, Jessica H Ford, Nicola W Burton, Alison L Marshall, Annette J Dobson
Prospective study of physical activity and depressive symptoms in middle-aged women.
Am J Prev Med. 2005 Nov;29(4):265-72. doi: 10.1016/j.amepre.2005.06.009.
Abstract/Text
BACKGROUND: Although many studies support an inverse association between physical activity (PA) and depressive symptoms, prospective relationships between these variables have been confounded by pre-existing psychological and physical health problems.
METHODS: This study examined the dose-response relationships between self-reported PA and depressive symptoms, using cross-sectional and prospective data from a population-based cohort of middle-aged women who participated in the Australian Longitudinal Study on Women's Health (ALSWH) between 1996 and 2001. Participants completed three mailed surveys (S1, 1996; S2, 1998; S3, 2001), which included questions about time spent in walking, moderate- and vigorous-intensity PA, and measures of psychological health (Center for Epidemiologic Studies Depression scale [CESD-10], and Mental health [MH] subscale of the Short Form 36 survey). Relationships between previous (S1, S2), current (S3), and habitual (S1, S2, S3) PA and "depressive symptoms" were examined, adjusting for sociodemographic and health-related variables (n=9207).
RESULTS: Mean CESD-10 scores decreased, and MH scores increased with increasing levels of previous, current, and habitual activity. Odds ratios for CESD-10 scores > or =10 or MH scores < or =52 at S3 were 30% to 40% lower among women who reported the equivalent of > or =60 minutes of moderate-intensity PA per week, compared with those who reported less PA than this. Women who were in the lowest PA category at S1, but who subsequently reported > or =240 metabolic equivalent minutes (MET.mins) per week had lower odds of CESD-10 scores of > or =10 or MH scores < or =52 at S3 than those who remained in the very low PA category.
CONCLUSIONS: These data suggest that there is a clear relationship between increasing PA and decreasing depressive symptoms in middle-aged women, independent of pre-existing physical and psychological health.
Beverley Ayers, Melanie Smith, Jennifer Hellier, Eleanor Mann, Myra S Hunter
Effectiveness of group and self-help cognitive behavior therapy in reducing problematic menopausal hot flushes and night sweats (MENOS 2): a randomized controlled trial.
Menopause. 2012 Jul;19(7):749-59. doi: 10.1097/gme.0b013e31823fe835.
Abstract/Text
OBJECTIVE: The aim of this study was to examine the effectiveness of group cognitive behavioral therapy (CBT) and guided self-help CBT in reducing hot flush and night sweat (HF/NS) problem rating at 6 and 26 weeks after randomization.
METHODS: This was a randomized control trial of 140 women having 10 or more problematic HF/NS a week for at least a month. The primary outcome was HF/NS problem rating (1-10) at 6 weeks after randomization. Secondary outcomes were physiologically measured HF/NS at 6 weeks; HF/NS problem rating at 6 weeks; and frequency, mood (Women's Health Questionnaire), and health-related quality of life (General Health Survey Short Form-36) at 6 and 26 weeks. Intention-to-treat analysis was used, and between-group differences were estimated using linear mixed models.
RESULTS: Baseline mean (SD) HF/NS weekly frequency was 63.15 (49.24), and problem rating was 5.87 (2.28). Group and self-help CBT both significantly reduced HF/NS problem rating at 6 weeks-group CBT versus no treatment control (NTC; adjusted mean difference, 2.12; 95% CI, 1.36-2.88; P < 0.001) and self-help CBT versus NTC (adjusted mean difference, 2.08; 95% CI, 1.29-2.86; P < 0.001)-and at 26 weeks-group CBT versus NTC (adjusted mean difference, 1.33; 95% CI, 0.54-2.13; P = 0.001) and self-help CBT versus NTC (adjusted mean difference, 1.19; 95% CI, 0.36-2.02; P = 0.005). Group and self-help CBT significantly reduced night sweat frequency at 6 and 26 weeks. There were improvements in mood and quality of life at 6 weeks and improved emotional and physical functioning for group CBT at 26 weeks.
CONCLUSIONS: These results suggest that CBT delivered in group or self-help format is an effective treatment option for women during the menopause transition and postmenopause with problematic HF/NS.
Susan M McCurry, Katherine A Guthrie, Charles M Morin, Nancy F Woods, Carol A Landis, Kristine E Ensrud, Joseph C Larson, Hadine Joffe, Lee S Cohen, Julie R Hunt, Katherine M Newton, Julie L Otte, Susan D Reed, Barbara Sternfeld, Lesley F Tinker, Andrea Z LaCroix
Telephone-Based Cognitive Behavioral Therapy for Insomnia in Perimenopausal and Postmenopausal Women With Vasomotor Symptoms: A MsFLASH Randomized Clinical Trial.
JAMA Intern Med. 2016 Jul 1;176(7):913-20. doi: 10.1001/jamainternmed.2016.1795.
Abstract/Text
IMPORTANCE: Effective, practical, nonpharmacologic therapies are needed to treat menopause-related insomnia symptoms in primary and women's specialty care settings.
OBJECTIVE: To evaluate the efficacy of telephone-based cognitive behavioral therapy for insomnia (CBT-I) vs menopause education control (MEC).
DESIGN, SETTING, AND PARTICIPANTS: A single-site, randomized clinical trial was conducted from September 1, 2013, to August 31, 2015, in western Washington State among 106 perimenopausal or postmenopausal women aged 40 to 65 years with moderate insomnia symptoms (Insomnia Severity Index [ISI] score, ≥12) and 2 or more daily hot flashes. Blinded assessments were conducted at baseline, 8, and 24 weeks postrandomization. An intent-to-treat analysis was conducted.
INTERVENTIONS: Six CBT-I or MEC telephone sessions in 8 weeks. Participants submitted weekly electronic sleep diaries and received group-specific written educational materials. The CBT-I sessions included sleep restriction, stimulus control, sleep hygiene education, cognitive restructuring, and behavioral homework; MEC sessions provided information about menopause and women's health.
MAIN OUTCOMES AND MEASURES: Primary outcome was scores on the ISI (score range, 0-28; scores ≥15 indicate moderate to severe insomnia). Secondary outcome was scores on the Pittsburgh Sleep Quality Index (score range, 0-21; higher scores indicate worse sleep quality). Additional outcomes included sleep and hot flash diary variables and hot flash interference.
RESULTS: At 8 weeks, ISI scores had decreased 9.9 points among 53 women receiving CBT-I (mean [SD] age, 55.0 [3.5] years) and 4.7 points among 53 women receiving MEC (age, 54.7 [4.7] years), a mean between-group difference of 5.2 points (95% CI, -6.1 to -3.3; P < .001). Pittsburgh Sleep Quality Index scores decreased 4.0 points in women receiving CBT-I and 1.4 points in women receiving MEC, a mean between-group difference of 2.7 points (95% CI, -3.9 to -1.5; P < .001). Significant group differences were sustained at 24 weeks. At 8 and 24 weeks, 33 of 47 women (70%) and 37 of 44 (84%) in the CBT-I group, respectively, had ISI scores in the no-insomnia range compared with 10 of 41 (24%) and 16 of 37 (43%) in the MEC group, respectively. The CBT-I group also had greater improvements in diary-reported sleep latency, wake time, and sleep efficiency. There were no between-group differences in frequency of daily hot flashes, but hot flash interference was significantly decreased at 8 weeks for the CBT-I group (-15.7; 95% CI, -20.4 to -11.0) compared with the MEC group (-7.1; 95% CI, -14.6 to 0.4) (P = .03), differences that were maintained at 24 weeks for the CBT-I group (-22.8; 95% CI, -28.6 to -16.9) and MEC group (-11.6; 95% CI, -19.4 to -3.8) (P = .003).
CONCLUSIONS AND RELEVANCE: Telephone-based CBT-I improved sleep in perimenopausal and postmenopausal women with insomnia and hot flashes. Results support further development and testing of centralized CBT-I programs for treating menopausal insomnia.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01936441.
Jacques E Rossouw, Garnet L Anderson, Ross L Prentice, Andrea Z LaCroix, Charles Kooperberg, Marcia L Stefanick, Rebecca D Jackson, Shirley A A Beresford, Barbara V Howard, Karen C Johnson, Jane Morley Kotchen, Judith Ockene, Writing Group for the Women's Health Initiative Investigators
Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.
JAMA. 2002 Jul 17;288(3):321-33.
Abstract/Text
CONTEXT: Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain.
OBJECTIVE: To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States.
DESIGN: Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998.
INTERVENTIONS: Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102).
MAIN OUTCOMES MEASURES: The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.
RESULTS: On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years.
CONCLUSIONS: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.
JoAnn E Manson, Aaron K Aragaki, Jacques E Rossouw, Garnet L Anderson, Ross L Prentice, Andrea Z LaCroix, Rowan T Chlebowski, Barbara V Howard, Cynthia A Thomson, Karen L Margolis, Cora E Lewis, Marcia L Stefanick, Rebecca D Jackson, Karen C Johnson, Lisa W Martin, Sally A Shumaker, Mark A Espeland, Jean Wactawski-Wende, WHI Investigators
Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials.
JAMA. 2017 Sep 12;318(10):927-938. doi: 10.1001/jama.2017.11217.
Abstract/Text
Importance: Health outcomes from the Women's Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality.
Objective: To examine total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the 2 Women's Health Initiative hormone therapy trials.
Design, Setting, and Participants: Observational follow-up of US multiethnic postmenopausal women aged 50 to 79 years enrolled in 2 randomized clinical trials between 1993 and 1998 and followed up through December 31, 2014.
Interventions: Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8506) vs placebo (n = 8102) for 5.6 years (median) or CEE alone (n = 5310) vs placebo (n = 5429) for 7.2 years (median).
Main Outcomes and Measures: All-cause mortality (primary outcome) and cause-specific mortality (cardiovascular disease mortality, cancer mortality, and other major causes of mortality) in the 2 trials pooled and in each trial individually, with prespecified analyses by 10-year age group based on age at time of randomization.
Results: Among 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6% white), mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7489 deaths occurred (1088 deaths during the intervention phase and 6401 deaths during postintervention follow-up). All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95% CI, 0.96-1.08); and with CEE alone, the HR was 0.94 (95% CI, 0.88-1.01). In the pooled cohort for cardiovascular mortality, the HR was 1.00 (95% CI, 0.92-1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality, the HR was 1.03 (95% CI, 0.95-1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes, the HR was 0.95 (95% CI, 0.88-1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76-1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials.
Conclusions and Relevance: Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years.
Trial Registration: clinicaltrials.gov Identifier: NCT00000611.
Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial.
JAMA. 1996 Feb 7;275(5):370-5.
Abstract/Text
OBJECTIVE: To report the histological findings of the endometrium of postmenopausal women who were randomized to receive placebo, estrogen only, or one of three estrogen plus progestin (E+P) regimens in the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.
DESIGN: A 3-year multicenter, randomized, double-masked, placebo-controlled trial.
PARTICIPANTS: A total of 596 postmenopausal women aged 45 through 64 years without contraindication to hormone therapy.
INTERVENTION: Participants were randomized and stratified in equal numbers to one of the following treatments in 28-day cycles: placebo, 0.625 mg/d of conjugated equine estrogens (CEE), 0.625 mg/d of CEE plus 10 mg/d of medroxyprogesterone acetate (MPA) for the first 12 days, 0.625 mg/d of CEE plus 2.5 mg/d of MPA, or 0.625 mg/d of CEE plus 200 mg/d of micronized progesterone (MP) for the first 12 days.
OUTCOME MEASURE: Histology of endometrium collected at baseline, annual, or unscheduled visits by biopsy, curettage, or hysterectomy.
ANALYSIS: Intention to treat.
RESULTS: During follow-up women assigned to estrogen alone were more likely to develop simple (cystic), complex (adenomatous), or atypical hyperplasia than those given placebo (27.7% vs 0.8%, 22.7% vs 0.8%, and 11.8% vs 0%, respectively) for the same types of hyperplasia (P < .001). Participants administered one of the three E+P regimens had similar rates of hyperplasia as those given placebo (P = .16). The occurrence of hyperplasia was distributed evenly across the 3 years of the trial. Women taking estrogens alone also had more unscheduled biopsies (66.4% vs 8.4%; P < .001) and curettages (17.6% vs 0.8%; P < .001) than women receiving placebo. The number of surgical procedures was similar for women receiving placebo and women receiving the E+P regimens (P = .38). Of the 45 women with complex (adenomatous) or atypical hyperplasia, study medications were discontinued in all, and the biopsy results of 34 (94%) of 36 women with hyperplasia reverted to normal with progestin therapy. The remainder had dilatation and curettage (n = 2) or hysterectomy with (n = 2) or without (n = 6) prior medical therapy, or refused further biopsies (n = 1). One woman developed adenocarcinoma of the endometrium while receiving placebo.
CONCLUSIONS: At a dosage of 0.625 mg, the daily administration of CEE enhanced the development of endometrial hyperplasia. Combining CEE with cyclic or continuous MPA or cyclic MP protected the endometrium from hyperplastic changes associated with estrogen-only therapy.
Garnet L Anderson, Rowan T Chlebowski, Aaron K Aragaki, Lewis H Kuller, JoAnn E Manson, Margery Gass, Elizabeth Bluhm, Stephanie Connelly, F Allan Hubbell, Dorothy Lane, Lisa Martin, Judith Ockene, Thomas Rohan, Robert Schenken, Jean Wactawski-Wende
Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomised placebo-controlled trial.
Lancet Oncol. 2012 May;13(5):476-86. doi: 10.1016/S1470-2045(12)70075-X. Epub 2012 Mar 7.
Abstract/Text
BACKGROUND: By contrast with many observational studies, women in the Women's Health Initiative (WHI) trial who were randomly allocated to receive oestrogen alone had a lower incidence of invasive breast cancer than did those who received placebo. We aimed to assess the influence of oestrogen use on longer term breast cancer incidence and mortality in extended follow-up of this cohort.
METHODS: Between 1993 and 1998, the WHI enrolled 10,739 postmenopausal women from 40 US clinical centres into a randomised, double-masked, placebo-controlled trial. Women aged 50-79 years who had undergone hysterectomy and had expected 3-year survival and mammography clearance were randomly allocated by a computerised, permuted block algorithm, stratified by age group and centre, to receive oral conjugated equine oestrogen (0·625 mg per day; n=5310) or matched placebo (n=5429). The trial intervention was terminated early on Feb 29, 2004, because of an adverse effect on stroke. Follow-up continued until planned termination (March 31, 2005). Consent was sought for extended surveillance from the 9786 living participants in active follow-up, of whom 7645 agreed. Using data from this extended follow-up (to Aug 14, 2009), we assessed long-term effects of oestrogen use on invasive breast cancer incidence, tumour characteristics, and mortality. We used Cox regression models to estimate hazard ratios (HRs) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00000611.
FINDINGS: After a median follow-up of 11·8 years (IQR 9·1-12·9), the use of oestrogen for a median of 5·9 years (2·5-7·3) was associated with lower incidence of invasive breast cancer (151 cases, 0·27% per year) compared with placebo (199 cases, 0·35% per year; HR 0·77, 95% CI 0·62-0·95; p=0·02) with no difference (p=0·76) between intervention phase (0·79, 0·61-1·02) and post-intervention phase effects (0·75, 0·51-1·09). In subgroup analyses, we noted breast cancer risk reduction with oestrogen use was concentrated in women without benign breast disease (p=0·01) or a family history of breast cancer (p=0·02). In the oestrogen group, fewer women died from breast cancer (six deaths, 0·009% per year) compared with controls (16 deaths, 0·024% per year; HR 0·37, 95% CI 0·13-0·91; p=0·03). Fewer women in the oestrogen group died from any cause after a breast cancer diagnosis (30 deaths, 0·046% per year) than did controls (50 deaths, 0·076%; HR 0·62, 95% CI 0·39-0·97; p=0·04).
INTERPRETATION: Our findings provide reassurance for women with hysterectomy seeking relief of climacteric symptoms in terms of the effects of oestrogen use for about 5 years on breast cancer incidence and mortality. However, our data do not support use of oestrogen for breast cancer risk reduction because any noted benefit probably does not apply to populations at increased risk of such cancer.
FUNDING: US National Heart, Lung, and Blood Institute; Wyeth.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Pierre-Yves Scarabin, Emmanuel Oger, Geneviève Plu-Bureau, EStrogen and THromboEmbolism Risk Study Group
Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk.
Lancet. 2003 Aug 9;362(9382):428-32. doi: 10.1016/S0140-6736(03)14066-4.
Abstract/Text
BACKGROUND: Oral oestrogen-replacement therapy (ERT) activates blood coagulation and increases the risk of venous thromboembolism (VTE) in postmenopausal women. Transdermal ERT has little effect on haemostasis, but data assessing its effect on thrombotic process are scarce. We aimed to examine the effect of the route of oestrogen administration on VTE risk.
METHODS: We did a multicentre hospital-based case-control study of postmenopausal women in France. During 1999-2002, we recruited 155 consecutive cases with a first documented episode of idiopathic VTE (92 with pulmonary embolisms and 63 with deep venous thrombosis), and 381 controls matched for centre, age, and time of recruitment.
FINDINGS: Overall, 32 (21%) cases and 27 (7%) controls were current users of oral ERT, whereas 30 (19%) cases and 93 (24%) controls were current users of transdermal ERT. After adjustment for potential confounding variables, the odds ratio for VTE in current users of oral and transdermal ERT compared with non-users was 3.5 (95% CI 1.8-6.8) and 0.9 (0.5-1.6), respectively. Estimated risk for VTE in current users of oral ERT compared with transdermal ERT users was 4.0 (1.9-8.3).
INTERPRETATION: Oral but not transdermal ERT is associated with risk of VTE in postmenopausal women. These data suggest that transdermal ERT might be safer than oral ERT with respect to thrombotic risk.
Marianne Canonico, Emmanuel Oger, Geneviève Plu-Bureau, Jacqueline Conard, Guy Meyer, Hervé Lévesque, Nathalie Trillot, Marie-Thérèse Barrellier, Denis Wahl, Joseph Emmerich, Pierre-Yves Scarabin, Estrogen and Thromboembolism Risk (ESTHER) Study Group
Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study.
Circulation. 2007 Feb 20;115(7):840-5. doi: 10.1161/CIRCULATIONAHA.106.642280.
Abstract/Text
BACKGROUND: Oral estrogen therapy increases the risk of venous thromboembolism (VTE) in postmenopausal women. Transdermal estrogen may be safer. However, currently available data have limited the ability to investigate the wide variety of types of progestogen.
METHODS AND RESULTS: We performed a multicenter case-control study of VTE among postmenopausal women 45 to 70 years of age between 1999 and 2005 in France. We recruited 271 consecutive cases with a first documented episode of idiopathic VTE (208 hospital cases, 63 outpatient cases) and 610 controls (426 hospital controls, 184 community controls) matched for center, age, and admission date. After adjustment for potential confounding factors, odds ratios (ORs) for VTE in current users of oral and transdermal estrogen compared with nonusers were 4.2 (95% CI, 1.5 to 11.6) and 0.9 (95% CI, 0.4 to 2.1), respectively. There was no significant association of VTE with micronized progesterone and pregnane derivatives (OR, 0.7; 95% CI, 0.3 to 1.9 and OR, 0.9; 95% CI, 0.4 to 2.3, respectively). In contrast, norpregnane derivatives were associated with a 4-fold-increased VTE risk (OR, 3.9; 95% CI, 1.5 to 10.0).
CONCLUSIONS: Oral but not transdermal estrogen is associated with an increased VTE risk. In addition, our data suggest that norpregnane derivatives may be thrombogenic, whereas micronized progesterone and pregnane derivatives appear safe with respect to thrombotic risk. If confirmed, these findings could benefit women in the management of their menopausal symptoms with respect to the VTE risk associated with oral estrogen and use of progestogens.
Marianne Canonico, Geneviève Plu-Bureau, Gordon D O Lowe, Pierre-Yves Scarabin
Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis.
BMJ. 2008 May 31;336(7655):1227-31. doi: 10.1136/bmj.39555.441944.BE. Epub 2008 May 20.
Abstract/Text
OBJECTIVE: To assess the risk of venous thromboembolism in women using hormone replacement therapy by study design, characteristics of the therapy and venous thromboembolism, and clinical background.
DESIGN: Systematic review and meta-analysis.
DATA SOURCES: Medline.
STUDIES REVIEWED: Eight observational studies and nine randomised controlled trials.
INCLUSION CRITERIA: Studies on hormone replacement therapy that reported venous thromboembolism. REVIEW MEASURES: Homogeneity between studies was analysed using chi(2) and I(2) statistics. Overall risk of venous thromboembolism was assessed from a fixed effects or random effects model.
RESULTS: Meta-analysis of observational studies showed that oral oestrogen but not transdermal oestrogen increased the risk of venous thromboembolism. Compared with non-users of oestrogen, the odds ratio of first time venous thromboembolism in current users of oral oestrogen was 2.5 (95% confidence interval 1.9 to 3.4) and in current users of transdermal oestrogen was 1.2 (0.9 to 1.7). Past users of oral oestrogen had a similar risk of venous thromboembolism to never users. The risk of venous thromboembolism in women using oral oestrogen was higher in the first year of treatment (4.0, 2.9 to 5.7) compared with treatment for more than one year (2.1, 1.3 to 3.8; P<0.05). No noticeable difference in the risk of venous thromboembolism was observed between unopposed oral oestrogen (2.2, 1.6 to 3.0) and opposed oral oestrogen (2.6, 2.0 to 3.2). Results from nine randomised controlled trials confirmed the increased risk of venous thromboembolism among women using oral oestrogen (2.1, 1.4 to 3.1). The combination of oral oestrogen and thrombogenic mutations or obesity further enhanced the risk of venous thromboembolism, whereas transdermal oestrogen did not seem to confer additional risk in women at high risk of venous thromboembolism.
CONCLUSION: Oral oestrogen increases the risk of venous thromboembolism, especially during the first year of treatment. Transdermal oestrogen may be safer with respect to thrombotic risk. More data are required to investigate differences in risk across the wide variety of hormone regimens, especially the different types of progestogens.
Marianne Canonico, Agnès Fournier, Laure Carcaillon, Valérie Olié, Geneviève Plu-Bureau, Emmanuel Oger, Sylvie Mesrine, Marie-Christine Boutron-Ruault, Françoise Clavel-Chapelon, Pierre-Yves Scarabin
Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study.
Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):340-5. doi: 10.1161/ATVBAHA.109.196022. Epub 2009 Oct 15.
Abstract/Text
OBJECTIVE: Oral estrogen therapy increases venous thromboembolism risk among postmenopausal women. Although recent data showed transdermal estrogens may be safe with respect to thrombotic risk, the impact of the route of estrogen administration and concomitant progestogens is not fully established.
METHODS AND RESULTS: We used data from the E3N French prospective cohort of women born between 1925 and 1950 and biennially followed by questionnaires from 1990. Study population consisted of 80 308 postmenopausal women (average follow-up: 10.1 years) including 549 documented idiopathic first venous thromboembolism. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional models. Compared to never-users, past-users of hormone therapy had no increased thrombotic risk (HR=1.1; 95% CI: 0.8 to 1.5). Oral not transdermal estrogens were associated with increased thrombotic risk (HR=1.7; 95% CI: 1.1 to 2.8 and HR=1.1; 95% CI: 0.8 to 1.8; homogeneity: P=0.01). The thrombotic risk significantly differed by concomitant progestogens type (homogeneity: P<0.01): there was no significant association with progesterone, pregnanes, and nortestosterones (HR=0.9; 95% CI: 0.6 to 1.5, HR=1.3; 95% CI: 0.9 to 2.0 and HR=1.4; 95% CI: 0.7 to 2.4). However, norpregnanes were associated with increased thrombotic risk (HR=1.8; 95% CI: 1.2 to 2.7).
CONCLUSIONS: In this large study, we found that route of estrogen administration and concomitant progestogens type are 2 important determinants of thrombotic risk among postmenopausal women using hormone therapy. Transdermal estrogens alone or combined with progesterone might be safe with respect to thrombotic risk.
C Renoux, S Dell'Aniello, S Suissa
Hormone replacement therapy and the risk of venous thromboembolism: a population-based study.
J Thromb Haemost. 2010 May;8(5):979-86. doi: 10.1111/j.1538-7836.2010.03839.x. Epub 2010 Mar 4.
Abstract/Text
SUMMARY BACKGROUND: Hormone replacement therapy (HRT) using oral estrogen alone or combined with a progestogen is associated with an increased risk of venous thromboembolism (VTE) in postmenopausal women. This risk may differ for tibolone and transdermal HRT.
METHODS: Among the United Kingdom's General Practice Research Database, we identified the cohort of all women aged 50-79 between 1 January 1987 and 1 March 2008. Using a nested case-control approach, all incident cases of VTE occurring during the study period were identified and matched with up to 10 controls selected from the cohort members. Rate ratios (RR) of VTE with current use of tibolone, transdermal and oral HRT were estimated using conditional logistic regression.
RESULTS: The cohort of 955 582 postmenopausal women included 23 505 cases of VTE matched with 231 562 controls. The risk of VTE was not increased with current use of transdermal estrogen alone (RR 1.01; 95% CI, 0.89-1.16) or combined with a progestogen (RR 0.96; 95% CI, 0.77-1.20), or with current use of tibolone (RR 0.92; 95% CI: 0.77-1.10), relative to non-use. On the other hand, the risk was increased with current use of oral estrogen (RR 1.49; 95% CI, 1.37-1.63) and oral estrogen-progestogen (RR 1.54; 95% CI, 1.44-1.65), and increased with estrogen dosage. The risks with oral formulations were particularly elevated during the first year of use but disappeared 4 months after discontinuation.
CONCLUSION: Transdermal HRT and tibolone were not associated with an increased risk of VTE in postmenopausal women.
François Laliberté, Katherine Dea, Mei Sheng Duh, Kristijan H Kahler, Melanie Rolli, Patrick Lefebvre
Does the route of administration for estrogen hormone therapy impact the risk of venous thromboembolism? Estradiol transdermal system versus oral estrogen-only hormone therapy.
Menopause. 2011 Oct;18(10):1052-9. doi: 10.1097/gme.0b013e3182175e5c.
Abstract/Text
OBJECTIVE: The aim of this study was to quantify the magnitude of risk reduction for venous thromboembolism events associated with an estradiol transdermal system relative to oral estrogen-only hormone therapy agents.
METHODS: A claims analysis was conducted using the Thomson Reuters MarketScan database from January 2002 to October 2009. Participants 35 years or older who were newly using an estradiol transdermal system or an oral estrogen-only hormone therapy with two or more dispensings were analyzed. Venous thromboembolism was defined as one or more diagnosis codes for deep vein thrombosis or pulmonary embolism. Cohorts of estradiol transdermal system and oral estrogen-only hormone therapy were matched 1:1 based on both exact factor and propensity score matching, and an incidence rate ratio was used to compare the rates of venous thromboembolism between the matched cohorts. Remaining baseline imbalances from matching were included as covariates in multivariate adjustments.
RESULTS: Among the matched estradiol transdermal system and oral estrogen-only hormone therapy users (27,018 women in each group), the mean age of the cohorts was 48.9 years; in each cohort, 6,044 (22.4%) and 1,788 (6.6%) participants had a hysterectomy and an oophorectomy at baseline, respectively. A total of 115 estradiol transdermal system users developed venous thromboembolism, compared with 164 women in the estrogen-only hormone therapy cohort (unadjusted incidence rate ratio, 0.72; 95% CI, 0.57-0.91; P = 0.006). After adjustment for confounding factors, the incidence of venous thromboembolism remained significantly lower for estradiol transdermal system users than for estrogen-only hormone therapy users.
CONCLUSIONS: This large population-based study suggests that participants receiving an estradiol transdermal system have a significantly lower incidence of venous thromboembolism than do participants receiving oral estrogen-only hormone therapy.
P J Schmidt, L Nieman, M A Danaceau, M B Tobin, C A Roca, J H Murphy, D R Rubinow
Estrogen replacement in perimenopause-related depression: a preliminary report.
Am J Obstet Gynecol. 2000 Aug;183(2):414-20. doi: 10.1067/mob.2000.106004.
Abstract/Text
OBJECTIVES: We examined the efficacy of estrogen in the treatment of depression in perimenopausal women with and without hot flushes.
STUDY DESIGN: Women with perimenopause-related depression were randomized in a double-blind parallel design to receive either 17beta-estradiol or placebo for 3 weeks. Subsequently, women receiving estradiol during the first 3 weeks continued receiving estradiol for an additional 3 weeks, whereas women who had received placebo crossed over to estradiol for 3 weeks. Outcome measures included standardized mood rating scales and a visual analog scale self-report instrument.
RESULTS: Of 34 female subjects, 16 received estradiol first and 18 received placebo first. After 3 weeks of estradiol, standardized mood rating scale scores and visual analog scale symptom scores (eg, sadness, anhedonia, and social isolation) were significantly decreased compared with baseline scores (P <.01) and were significantly lower than scores in women receiving placebo (P <.01), who showed no significant improvement. Neither the presence of hot flushes nor the duration of treatment (3 weeks vs 6 weeks) influenced outcome. A full or partial therapeutic response was seen in 80% of subjects receiving estradiol and 22% of those receiving placebo.
CONCLUSION: In this preliminary study estradiol replacement effectively treats perimenopausal depression independent of its salutary effects on vasomotor symptoms.
C N Soares, O P Almeida, H Joffe, L S Cohen
Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial.
Arch Gen Psychiatry. 2001 Jun;58(6):529-34.
Abstract/Text
BACKGROUND: Results of previous studies suggest that estrogen improves somatic and mild depressive symptoms experienced by perimenopausal women. This study investigated the efficacy of 17beta-estradiol for the treatment of clinically significant depressive disorders in endocrinologically confirmed perimenopausal women.
METHODS: Perimenopausal women (aged 40-55 years, with irregular menstrual periods and serum concentrations of follicle-stimulating hormone >25 IU/L), meeting criteria for major depressive disorder, dysthymic disorder, or minor depressive disorder, according to DSM-IV, were randomized to receive transdermal patches of 17beta-estradiol (100 microgram) or placebo in a 12-week, double-blind, placebo-controlled study. A 4-week washout period followed the 12-week treatment phase. Outcome measures were the Montgomery-Asberg Depression Rating Scale and Blatt-Kupperman Menopausal Index scores.
RESULTS: Fifty women were enrolled in the study; 26 met DSM-IV criteria for major depressive disorder, 11 for dysthymic disorder, and 13 for minor depressive disorder. Remission of depression was observed in 17 (68%) women treated with 17beta-estradiol compared with 5 (20%) in the placebo group (P =.001). Subjects responded similarly to estradiol treatment, regardless of DSM-IV diagnosis. Patients treated with estradiol sustained antidepressant benefit of treatment after the 4-week washout period, although somatic complaints increased in frequency and intensity. Treatment was well tolerated and adverse events were rare in both groups.
CONCLUSION: Transdermal estradiol replacement is an effective treatment of depression for perimenopausal women.
James A Simon, David J Portman, Andrew M Kaunitz, Hana Mekonnen, Kazem Kazempour, Sailaja Bhaskar, Joel Lippman
Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled trials.
Menopause. 2013 Oct;20(10):1027-35. doi: 10.1097/GME.0b013e3182a66aa7.
Abstract/Text
OBJECTIVE: The efficacy and safety of low-dose paroxetine 7.5 mg for the treatment of menopausal vasomotor symptoms were evaluated in two multicenter, double-blind, placebo-controlled, phase 3 studies of 12 and 24 weeks' duration.
METHODS: Postmenopausal women were randomly assigned 1:1 to receive paroxetine 7.5 mg or placebo once daily. The four primary efficacy endpoints included mean changes in the frequency and severity of moderate to severe vasomotor symptoms on weeks 4 and 12; an additional endpoint was persistence of treatment benefit on week 24.
RESULTS: Five hundred ninety-one participants were randomly assigned to treatment with paroxetine 7.5 mg, and 593 participants were randomly assigned to treatment with placebo. All primary endpoints were met in the 24-week study; three of four primary endpoints were met in the 12-week study. In both studies, paroxetine 7.5 mg significantly reduced the mean weekly vasomotor symptom frequency compared with placebo on week 4 (P < 0.0001 for both studies) and week 12 (P = 0.0090, 12-wk study; P = 0.0001, 24-wk study). Mean weekly reduction in vasomotor symptom severity was significantly greater for paroxetine 7.5 mg than for placebo on week 4 (P = 0.0048) in the 12-week study and on week 4 (P = 0.0452) and week 12 (P = 0.0114) in the 24-week study. Persistence of treatment benefit was demonstrated in the 24-week study. Most treatment-emergent adverse events were mild or moderate in severity. No clinically significant changes in laboratory values or vital signs were noted, and no short-term discontinuation of symptoms followed treatment cessation.
CONCLUSIONS: Paroxetine 7.5 mg is well-tolerated, is effective in reducing the frequency and severity of menopausal vasomotor symptoms, and demonstrates persistence of treatment benefit through 24 weeks of treatment.
