title: Health related quality of life after combined hormone replacement therapy: randomised controlled trial Percutaneous estradiol/oral micronized progesterone has less-adverse effects and different gene regulations than oral conjugated equine estrogens/medroxyprogesterone acetate in the breasts of healthy women in vivo Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Effect of estrogen replacement therapy on symptoms of depression and anxiety in non-depressive menopausal women Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. A longitudinal analysis of the association between menopause and depression. Results from the Massachusetts Women's Health Study. Short-term transdermal estradiol therapy, cognition and depressive symptoms in healthy older women. A randomised placebo controlled pilot cross-over study Effects of combination estrogen plus progestin hormone treatment on cognition and affect. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. A 20-week randomized controlled trial of estradiol replacement therapy for women aged 70 years and older: Effect on mood, cognition and quality of life Pulsed estrogen therapy improves postmenopausal quality of life: a 2-year placebo-controlled study. Modulation of cognition-specific cortical activity by gonadal steroids: a positron-emission tomography study in women. Raloxifene and Estrogen Effects on Quality of Life in Healthy Postmenopausal Women: A Placebo‐Controlled Randomized Trial Influence of a continuous combined HRT (2 mg estradiol valerate and 2 mg dienogest) on postmenopausal depression Increase of estrogen dose deteriorates mood during progestin phase in sequential hormonal therapy. Increased estradiol and improved sleep, but not hot flashes, predict enhanced mood during the menopausal transition. Effects of low-dose, continuous combined estradiol and noretisterone acetate on menopausal quality of life in early postmenopausal women. A comparison of the effect of estrogen with or without progesterone on mood and physical symptoms in postmenopausal women. A prospective, randomized, placebo-controlled study of the dose effect of oral oestradiol on menopausal symptoms, psychological well being, and quality of life in postmenopausal Chinese women. Hormonal treatment and psychological function during the menopausal transition: an evaluation of the effects of conjugated estrogens/cyclic medroxyprogesterone acetate. The effect of 3-year treatment with 0.25 mg/day of micronized 17beta-estradiol on cognitive function in older postmenopausal women. Estrogen replacement in perimenopause-related depression: a preliminary report. Lack of efficacy of estradiol for depression in postmenopausal women: a randomized, controlled trial Quality-of-life and depressive symptoms in postmenopausal women after receiving hormone therapy: results from the Heart and Estrogen/Progestin Replacement Study (HERS) trial. Menopause and the risk of coronary heart disease in women. Combined versus Sequential Hormonal Replacement Therapy: A Double-Blind, Placebo-Controlled Study on Quality of Life-Related Outcome Measures Treatment with hormone therapy and calcitriol did not affect depression in older postmenopausal women: no interaction with estrogen and vitamin D receptor genotype polymorphisms
abstract: Objective To assess the effect of  combined hormone replacement therapy ( HRT )  on health related quality of life . Design R and omised placebo controlled double blind trial . Setting General practice s in United Kingdom ( 384 ) , Australia ( 94 ) , and New Zeal and ( 24 ) . Participants Postmenopausal women aged 50 - 69 at r and omisation ; 3721 women with a uterus were r and omised to combined oestrogen and progestogen  ( n=1862 ) or placebo  ( n=1859 ) . Data on health related quality of life at one year were available from 1043 and 1087 women , respectively . Interventions Conjugated equine oestrogen 0.625 mg plus medroxyprogesterone acetate 2.5/5.0 mg or matched placebo orally daily for one year . Main outcome measures Health related quality of life and psychological wellbeing as measured by the women ’s health question naire . Changes in emotional and physical menopausal symptoms as measured by a symptoms question naire and depression by the Centre for Epidemiological Studies depression scale ( CES-D ) . Overall health related quality of life and overall quality of life as measured by the European quality of life instrument ( EuroQol ) and visual analogue scale , respectively . Results After one year small but significant improvements were observed in three of nine components of the women ’s health question naire for those taking combined HRT compared with those taking placebo :  vasomotor symptoms ( P<0.001 ) , sexual functioning ( P<0.001 ) , and sleep problems ( P<0.001 ) . Significantly fewer women in the combined HRT group reported hot flushes ( P<0.001 ) , night sweats ( P<0.001 ) , aching joints and muscles ( P=0.001 ) , insomnia ( P<0.001 ) , and vaginal dryness ( P<0.001 ) than in the placebo group , but greater proportions reported breast tenderness ( P<0.001 ) or vaginal discharge ( P<0.001 ) . Hot flushes were experienced in the combined HRT and placebo groups by 30 % and 29 % at trial entry and 9 % and 25 % at one year , respectively . No significant differences in other menopausal symptoms , depression , or overall quality of life were observed at one year . Conclusions Combined HRT started many years after the menopause can improve health related quality of life . Trial registration IS RCT N 63718836 Gene expression analysis of healthy postmenopausal women in a prospect i ve clinical study indicated that genes encoding for epithelial proliferation markers Ki-67 and progesterone receptor B mRNA are differentially expressed in women using hormone therapy ( HT ) with natural versus synthetic estrogens .  Two 28-day cycles of daily estradiol ( E2 ) gel 1.5 mg and oral micronized progesterone ( P ) 200 mg/day for the last 14 days of each cycle did not significantly increase breast epithelial proliferation ( Ki-67 MIB-1 positive cells ) at the cell level nor at the mRNA level ( MKI-67 gene ) . A borderline significant beneficial reduction in anti-apoptotic protein bcl-2 , favouring apoptosis , was also seen followed by a slight numeric decrease of its mRNA . By contrast , two 28-day cycles of daily oral conjugated equine estrogens ( CEE ) 0.625 mg and oral medroxyprogesterone acetate ( MPA ) 5 mg for the last 14 days of each cycle significantly increased proliferation at both the cell level and at the mRNA level , and significantly enhanced mammographic breast density , an important risk factor for breast cancer . In addition , CEE/MPA affected around 2,500 genes compared with just 600 affected by E2/P. These results suggest that HT with natural estrogens affects a much smaller number of genes and has less-adverse effects on the normal breast in vivo than conventional , synthetic therapy The authors further analyzed results from the Women 's Health Initiative r and omized trials ( 1993 - 2004 ) of conjugated equine estrogens , with or without medroxyprogesterone acetate , focusing on health benefits versus risks among women who initiated hormone therapy soon after menopause . Data from the Women 's Health Initiative observational study ( 1993 - 2004 ) were included in some analyses for additional precision . Results are presented here for incident coronary heart disease , stroke , venous thromboembolism , breast cancer , colorectal cancer , endometrial cancer , or hip fracture ; death from other causes ; a summary global index ; total cancer ; and total mortality . Hazard ratios for breast cancer and total cancer were comparatively higher ( P < 0.05 ) among women who initiated hormone therapy soon after menopause , for both regimens . Among these women , use of conjugated equine estrogens appeared to produce elevations in venous thromboembolism and stroke and a reduction in hip fracture .  Estrogen plus progestin results among women who initiated use soon after menopause were similar for venous thromboembolism , stroke , and hip fracture but also included evidence of longer-term elevations in breast cancer , total cancer , and the global index . These analyses provide little support for the hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause , either for coronary heart disease or for health benefits versus risk indices considered The efficacy of estrogen replacement therapy ( ERT ) for mood disturbances associated with menopause has yet to be firmly established . The objective of this study was to investigate the efficacy of ERT for improving mood and anxiety of non-depressive postmenopausal women . This double-blind , r and omized , placebo-controlled study involved two treatment groups : one receiving conjugated equine estrogens ( CEEs ; 0.625 mg/day ) and the other placebo , for six cycles of 28 days each . Subjects were hysterectomized , healthy , non-depressive ( according to Schedule for Affective Disorders and Schizophrenia , Life Time Version [ SADS-L ] ) women .  Depressive and anxiety symptoms were assessed with the Beck Depression Inventory ( BDI ) , and the Hamilton Anxiety Scale ( HAMA ) , respectively . The Profile of Mood States ( POMS ) and other scales were used to characterize symptoms . In both groups , BDI scores were significantly lower at cycles 1 , 2 , 3 , and 6 , compared with baseline assessment s ( p < 0.01 ) . Anxiety scores for both groups significantly improved from cycle 3 to study endpoint . The only significant difference favoring the active group occurred at cycle 1 . POMS scores were significantly improved at the end of cycles 1 , 2 , 3 and 6 among treated subjects and at the end of cycles 2 , 3 , and 6 among placebo subjects . ERT is not associated with improvements in mood or anxiety symptoms in non-depressive , hysterectomized , postmenopausal women Postmenopausal hormone replacement therapy is associated with a reduction in the incidence of coronary heart disease . However , inconclusive results have been reported with respect to the risk of stroke , and recent studies consistently showed an increased risk of venous thromboembolism in postmenopausal women using oral estrogen .  There are surprisingly few interventional studies to assess the true effects of estrogen-progestin regimens on blood coagulation and fibrinolysis , and the impact of the route of estrogen administration on hemostasis has not been well documented . Therefore , we investigated the effects of oral and transdermal estradiol/progesterone replacement therapy on hemostatic variables . Forty-five healthy postmenopausal women , aged 45 to 64 years , were assigned r and omly to one of the three following groups : cyclic oral or transdermal estradiol , both combined with progesterone , or no hormonal treatment .  Hemostatic variables were assayed at baseline and after a 6-month period . Pairwise differences in the mean change between the three groups were compared using nonparametric tests . Oral but not transdermal estradiol regimen significantly increased the mean value of prothrombin activation peptide ( F1 + 2 ) and decreased mean antithrombin activity compared with no treatment . Differences in fragment F1 + 2 levels between active treatments were significant . The oral estrogen group was associated with a significant decrease in both mean tissue-type plasminogen ( t-PA ) concentration and plasminogen activator inhibitor ( PAI-1 ) activity and a significant rise in global fibrinolytic capacity ( GFC ) compared with the two other groups . A transdermal estrogen regimen had no significant effect on PAI-1 , t-PA , and GFC levels . There were no significant changes in mean values of fibrinogen , factor VII , von Willebr and factor , protein C , fibrin D-dimer , and plasminogen between and within the three groups . We conclude that oral estrogen/progesterone replacement therapy may result in coagulation activation and increased fibrinolytic potential , whereas opposed transdermal estrogen appears without any substantial effects on hemostasis . Whereas these results may account for an increased risk of venous thromboembolism in users of oral postmenopausal estrogen  , they emphasize the potential importance of the route of estrogen administration in prescribing hormone replacement therapy to postmenopausal women , especially to those at high risk of thrombotic disease The present article prospect ively examines the effect of change in menopause status on depression , while controlling for prior depression . This is a longitudinal follow-up of previous cross-sectional analyses reported by McKinlay , McKinlay , and Brambilla who examined the relative contribution of menopause to depression . The data derive from the Massachusetts Women 's Health Study , a 5-year longitudinal study of a cohort of 2565 women aged 45 to 55 years at baseline ( 1981 to 1982 ) . Results show that prior depression is the variable most predictive of subsequent depression , as measured by the Center for Epidemiologic Studies -Depression ( CES-D ) scale . Onset of natural menopause was not associated with increased risk of depression . Experiencing a long perimenopausal period ( at least 27 months ) , however , was associated with increased risk of depression . The association between a long perimenopause and depression appeared to be explained by increased menopausal symptoms rather than by the menopause status itself . The observed increase in depression during a lengthy perimenopause appears to be transitory The potential role of estrogen in protecting women from cognitive decline and reducing depressive symptoms is of great therapeutic interest . In a pilot r and omised placebo controlled cross-over study , we aim ed to determine the short-term effects of transdermal estradiol therapy on cognition and depressive symptoms in healthy cognitively normal post-menopausal women over 60 years of age . Nineteen cognitively normal women , without clinical depression whom had undergone a hysterectomy in the past were recruited . Women were r and omised to receive either transdermal estradiol 50 microg/24 h ( Femseven ) or transdermal placebo for 12 weeks before crossing over to the other medication for a further 12 weeks . Cognition was assessed every 6 weeks by the cognitive drug research ( CDR ) computerised assessment which recorded both accuracy and speed in the following cognitive tests ; simple reaction time , choice reaction time , digit vigilance , visual tracking , spatial working memory , immediate and delayed word recall and delayed face and picture recall . Depressive symptoms were measured using the brief assessment scale depression card ( BASDEC ) depression rating scale at baseline , 12 and 24 weeks . Participants had a mean age of 71 , IQ of 115 and MMSE of 29 .  Simple reaction time and the BASDEC depression rating scale improved after 12 weeks of estradiol use . All other tests were unaltered by estradiol . Twelve weeks of transdermal estradiol therapy did not consistently improve the speed or accuracy of older women in various cognitive tests . However , the results do support the concept that depressive symptoms may be reduced by estradiol , and not simply due to the relief of climacteric symptoms CONTEXT Some studies of hormone treatment in postmenopausal women suggest benefits on specific cognitive functions , particularly memory . OBJECTIVE The objective of this study was to determine whether hormone therapy influences changes in specific cognitive functions and affect in older women . DESIGN This study was a r and omized , double-blind , placebo-controlled clinical trial . SETTING Participants were women from 14 of 40 clinical centers of the Women 's Health Initiative ( WHI ) . PARTICIPANTS Postmenopausal women ( 1416 ) aged 65 yr and older , free of probable dementia , and enrolled in WHI and the WHI Memory Study ( WHIMS ) trial of combination estrogen and progestin for a mean of 3 yr and followed for a mean of 1.35 yr , were studied . INTERVENTION Intervention was conjugated equine estrogen ( CEE ; 0.625 mg ) with 2.5 mg medroxyprogesterone acetate ( MPA ) in one daily tablet ( CEE + MPA ) or placebo . MAIN OUTCOME MEASURES Annual rates of change in specific cognitive functions and affect , adjusted for time since r and omization , were measured . RESULTS CEE + MPA had a negative impact on verbal memory ( P < or= 0.01 ) and a trend to a positive impact on figural memory ( P = 0.012 ) over time compared with placebo , but other cognitive domains were not affected . Both effects on memory were evident only after long-term therapy . CEE + MPA did not significantly influence positive affect , negative affect , or depressive symptoms . CONCLUSIONS The effect of CEE + MPA on cognitive function varies across cognitive domains in older women , reflecting both possible beneficial and detrimental actions of ovarian steroids on the aging brain . Our results extend prior findings about dementia and global cognitive function to age-related changes in specific cognitive functions and suggest directions for future research 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 r and omized 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 infa rct ion 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 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 clinical ly 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 r and omized 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 The results of several observational studies suggest that the use of estrogen replacement is associated with better mood , cognitive function and quality of life . Such findings are consistent with those of laboratory-based research showing that estrogen promotes neuronal sprouting , enhances cholinergic activity in the brain , decreases brain and plasma levels of beta-amyloid , increases serotonin postsynaptic responsivity and the turnover of noradrenaline , and inhibits monoamine oxidase activity . However , the findings from the Women 's Health Initiative controlled trial showed that hormone replacement ( estrogen plus progestin ) not only failed to improve mood , cognition and quality of life but also increased the risk of dementia . At present , there is limited information about the effect of unopposed estradiol replacement therapy ( ERT ) on the mental health outcomes of women at increased risk of cognitive decline ( aged 70 years and over ) . We design ed the present r and omized , double-blind , placebo-controlled trial to clarify this issue . One hundred and fifteen women were r and omized to treatment with estradiol ( n=58 ; 2 mg per day ) or placebo for a total period of 20 weeks . The outcomes of interest in this study included changes in the Beck Depression Inventory ( BDI ) scores between baseline and week 20 , as well as changes in quality of life scores ( as measured by the SF-36 ) and cognitive function ( CAMCOG , Block Design , Memory for Faces , California Verbal Learning Test ( CVLT ) and verbal fluency ( VF ) ) .  Nineteen women treated with estradiol  and 10 of those treated with  placebo discontinued the use of the medication during trial , most frequently due to adverse reactions ( OR=4.11 , 95 % CI=1.29 - 15.37 ) . Intention-to-treat analysis showed that the active and placebo groups did not differ in their response to treatment in any of the outcome measures ( p>0.05 ) . A separate analysis restricted to women who completed the 20-week-trial produced similar negative results . The results of this trial indicate that the use of a relatively high dosage of unopposed estrogen replacement for 20 weeks is not associated with significant changes in cognitive function , mood and quality of life . Other more efficacious and safer interventions need to be devised with the aim of improving the mental state and quality of life of older women OBJECTIVE To investigate the effect of pulsed estrogen therapy S21400 ( intranasal 17 beta-estradiol ) on different quality of life ( QoL ) dimensions in early postmenopausal women treated with S21400 150 microg per day , S21400 300 microg per day , or placebo in a double blind , r and omized , controlled 2-year study . STUDY DESIGN QoL was assessed based on the vali date d Women 's Health Question naire design ed for peri- and post-menopausal women . Three hundred and thirty-five healthy , early postmenopausal Danish women , 53 years of age in average , who completed one question naire at baseline and one under study treatment were included in the analysis set . All analyses were performed on an intention-to-treat basis . RESULTS QoL improved significantly in both S21400 groups compared to placebo in the dimensions ' memory/concentration ' , ' vasomotor symptoms ' , ' sleep problems ' and ' sexual behavior ' ( difference in mean change scores being respectively + 7.9 , + 28.3 , + 9.9 and + 10.8 % , p < 0.001 , between the S21400 300 microg and placebo group ) . There were no significant differences between actively treated groups and placebo in the dimensions ' anxiety/depressed mood ' and ' well-being ' . CONCLUSION Pulsed estradiol therapy had a pronounced effect not only on vasomotor symptoms but also a significant and clinical ly relevant improvement in several other QoL dimensions There is considerable evidence from animal studies that gonadal steroid hormones modulate neuronal activity and affect behavior . To study this in humans directly , we used H215O positron-emission tomography to measure regional cerebral blood flow ( rCBF ) in young women during three pharmacologically controlled hormonal conditions spanning 4 - 5 months : ovarian suppression induced by the gonadotropin-releasing hormone agonist leuprolide acetate ( Lupron ) , Lupron plus estradiol replacement , and Lupron plus progesterone replacement . Estradiol and progesterone were administered in a double-blind cross-over design . On each occasion positron-emission tomography scans were performed during ( i ) the Wisconsin Card Sorting Test , a neuropsychological test that physiologically activates prefrontal cortex ( PFC ) and an associated cortical network including inferior parietal lobule and posterior inferolateral temporal gyrus , and ( ii ) a no-delay matching-to- sample sensorimotor control task . During treatment with Lupron alone ( i.e. , with virtual absence of gonadal steroid hormones ) , there was marked attenuation of the typical Wisconsin Card Sorting Test activation pattern even though task performance did not change . Most strikingly , there was no rCBF increase in PFC . When either progesterone or estrogen was added to the Lupron regimen , there was normalization of the rCBF activation pattern with augmentation of the parietal and temporal foci and return of the dorsolateral PFC activation . These data directly demonstrate that the hormonal milieu modulates cognition-related neural activity in humans Objective To assess the effects of raloxifene , estrogen , and placebo on quality of life in healthy , asymptomatic , postmenopausal women . Methods In a multicenter , double-blind , 12-month study , 398 women were assigned r and omly to one of four groups : raloxifene HCl , 60 ( n = 97 ) or 150 mg/day ( n = 100 ) ; conjugated equine estrogens , 0.625 mg/day ( n = 96 ) ; or placebo ( n = 105 ) . The Women 's Health Question naire , a vali date d quality -of-life instrument for perimenopausal and postmenopausal women , was administered at baseline and 3-month intervals . Results Overall , quality of life from baseline to end point was preserved equally in all treatment groups . Six domains ( depressed mood , somatic symptoms , memory/ concentration , sexual behavior , sleep problems , and perceived attractiveness ) were unchanged in all groups . Three domains ( menstrual symptoms , vasomotor symptoms , and anxiety/fears ) were statistically significantly different among groups . Mean scores for menstrual symptoms significantly worsened and vasomotor symptoms significantly improved from baseline to end point in the estrogen group . Mean scores for vasomotor symptoms did not worsen at any point in the raloxifene 60 mg/day group . Mean anxiety/fears scores improved significantly during raloxifene 60 mg/day administration throughout treatment ( P < .05 ) , irrespective of previous hormone replacement therapy , baseline estradiol ( E2 ) levels , or years postmenopause . Conclusion Most quality -of-life domains were not affected by treatment with estrogen or raloxifene . Estrogen provided relief from vasomotor symptoms but caused menstrual symptoms . Raloxifene 60 mg/day improved anxiety levels in postmenopausal women Objective This r and omized , double-blind , placebo-controlled study was planned to investigate the effects of continuous combined hormone replacement therapy ( HRT ) with 2 mg estradiol valerate and 2 mg dienogest ( Climodien ® /Lafamme ® ) over 24 weeks on postmenopausal depression . Method A total of 129 patients with a mild to moderate depressive episode according to ICD-10 : F32.0 , F32.1 in the context of a postmenopausal syndrome ( ICD-10 : N95.1 ) and a baseline score in the Hamilton depression scale ( HAMD ) ⩾ 16 were included in the study . The primary target variable was depression severity as measured by the HAMD after 24 weeks of treatment . A four-point difference between HRT and placebo at the end of the study and , in addition , a final score ⩽ 8 ( corresponding to an improvement of ⩾ 50 % as compared to baseline ) for the individual patient ( responders analysis ) were considered clinical ly relevant . Clinical global impression ( CGI ) of investigators ( therapeutic and side-effects ) at the end of the study was investigated . Secondary effects of HRT  on depression severity caused by its effect on vasomotor symptoms or sleep disturbances ( domino hypothesis ) were taken into consideration . Also , the study addressed the question of whether the effect of HRT on depression severity depends on a history of premenstrual syndrome ( PMS ) or postnatal depression ( PND ) . Results The results showed a clear and clinical ly relevant reduction of depression severity  under HRT after 24 weeks of treatment and superiority over placebo ( p < 0.0005 ) in spite of a strong placebo effect . The effects of the estrogen – progestin combination thereby seemed only partially to be dependent on the improvement of vasomotor symptoms and sleep disturbances . Also , the effects of HRT could not be shown to be dependent on a history of PMS and /or PND , even though women with and without this history clearly differed in baseline depression scores ( p < 0.0001 ) . The assessment of CGI was positive : whereas HRT was clearly superior to placebo with regard to therapeutic effects ( p = 0.0014 ) , there were no differences with regard to side-effects ( p = 0.35 ) . Conclusion The combination of 2 mg estradiol valerate and 2 mg dienogest can be regarded as an effective and safe treatment option for women with mild to moderate depression in the context of postmenopausal syndrome Previous studies have indicated that the addition of progestins during sequential  hormonal replacement therapy ( HRT ) causes negative mood and physical symptoms . History of premenstrual syndrome , type of progestin , and dose of progestin have thus far been shown to influence the progestin-induced adverse mood symptoms during HRT . The aim of this study was to compare adverse mood effects of two different doses of estradiol , in combination with a progestin , during postmenopausal HRT . Twenty-eight perimenopausal women were included in this r and omized , double-blind , crossover study comparing 2- or 3-mg continuous estradiol , with an addition of 10 mg medroxyprogesterone acetate on d 17 - 28 during each treatment cycle . The main outcome measures were mood and physical symptoms kept on a daily rating scale . Together with the progestin , the higher dose of estrogen caused significantly more negative mood symptoms than the lower dose . Tension , irritability , and depressed mood were all significantly augmented during the progestin phase of cycles with 3 mg estradiol ( P < 0.001 ) . Physical symptoms also increased during the progestin phase of 3-mg estradiol cycles ( P < 0.001 ) , whereas positive mood symptoms were less affected . The only positive mood that changed with estrogen dose was friendliness , which decreased during the progestin phase of high estradiol cycles compared with cycles with lower estradiol ( P < 0.05 ) . Our conclusion is that an increase of the estrogen dose accentuates negative mood and physical symptoms during the progestin phase of sequential hormonal therapy 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 r and omly 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 , objective ly 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 r and omized 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 OBJECTIVES To describe the effects of low dose hormonal replacement therapy ( LD-HRT ) on quality of life in early postmenopausal women , since the postmenopausal estrogen deprivation in mid age women often brings along a series of changes and symptoms , which may greatly affect quality of life . METHODS Fifty normal postmenopausal women were recruited and r and omly treated with LD-HRT , 17beta-estradiol ( 1 mg/day ) and norethisterone acetate ( 0.5 mg/day ) ( LD-HRT ) or calcium supplement ( controls ) . No significant differences in age , age at menopause , the presence of chronic diseases and socio-economic status were present in the two groups . The Women 's Health Question naire ( WHQ ) , a vali date d quality -of-life instrument for perimenopausal and postmenopausal women , was administered at baseline and after 6 and 12 weeks of treatment in both groups . RESULTS At baseline no significant differences in WHQ scores were present in the two groups . In the control group the scores in all different areas showed no significant modification either after 6 and 12 weeks of observation . Conversely , the LD-HRT group showed a significant decrease in the scores of vasomotor symptoms , somatic symptoms , anxiety/fear , depressed mood and sleep problem items . No effects on memory/concentration and menstrual symptoms areas were evident . CONCLUSION Although quality of life is also and may be mainly influenced by socio-economic and cultural factors , LD-HRT definitively can improve not only vasomotor symptoms , but also more general aspects of physical and psychological well-being of symptomatic postmenopausal women Using a r and omized , placebo-controlled design , this study assessed the effects of estrogen alone ( ES ) or in combination with cyclic progesterone ( EP ) on daily ratings of mood and physical symptoms before and after 6 months of daily hormone treatment . Fifty-four postmenopausal women were recruited from the community at large and specifically selected as being asymptomatic at the time of enrollment and without significant psychiatric history . Ratings were obtained every day for 30 days prior to treatment and again every day during the last 30 days of treatment . Results revealed that when compared with pretreatment levels , women r and omized to EP ( n = 16 ) exhibited statistically significant increases in daily depression , cramping , and breast tenderness and a marginally significant increase in daily anxiety . However , these increases were mild , not clinical ly significant , and did not interfere with normal functioning . Women r and omized to ES ( n = 20 ) showed no significant change in daily mood measures , although they did experience an increase in breast tenderness with estrogen . A significant placebo ( n = 18 ) effect was observed , as there was a reliable reduction in daily irritability ratings ( p < 0.05 ) with placebo . These findings suggest that for most postmenopausal women , the use of hormones will not be associated with clinical ly significant changes in mood or physical symptoms , which weighs favorably into the cost-benefit ratio for women considering hormone replacement therapy OBJECTIVES Hypoestrogenism occurring in association with the menopause may result in the development of vasomotor symptoms and it may also have a detrimental effect on psychological well being and quality of life ( QOL ) . The aims of this study were to measure menopausal symptoms , mood and QOL in postmenopausal Chinese women and to assess the effect of different doses of oestrogen on these outcome indicators . METHODS A prospect i ve , r and omized , placebo-controlled study of the effect of 1 and 2 mg oestradiol on menopausal symptoms , anxiety and depressive symptoms , and QOL in 152 postmenopausal women over a 12 month study period .  Menopausal symptoms were measured using a modified Kupperman 's scale . Anxiety and depressive symptoms and QOL were measured using the Hospital Anxiety and Depression Scales and a modification of the World Health Organization Quality of Life question naire , respectively . RESULTS Baseline scoring of vasomotor symptoms in our population was low whilst QOL scoring was relatively high . Over 12 months , after adjustment for differences in baseline scoring , there was a significant reduction in menopausal symptom scores in the 2 mg oestradiol group compared with placebo but not in the 1 mg group . There were no statistically significant changes in levels of anxiety and depression or QOL in either the 1 or the 2 mg group compared with placebo . CONCLUSIONS These results suggest that relatively few Chinese women will be expected to benefit from hormone replacement in terms of either QOL or mood . In addition , the overall benefit of treatment for vasomotor symptoms will be less for a given number of Chinese women than for Caucasians . Therefore , when considering the reasons for prescribing hormone replacement therapy in this population , protection against osteoporosis will for most women be the prime consideration OBJECTIVE To investigate the effect of hormone treatment on  psychosocial distress of women during the menopausal transition ( aged 40 - 52 years , still menstruating and with minor symptoms ) , in a study carefully design ed to reduce bias and placebo effect . METHODS The study was r and omized , controlled by placebo , blinded to the subject , investigators and biostatistician , crossed-over after 6 months , and evaluated by a 77-item question naire every month for 12 months . The medication tested was continuous conjugated estrogens ( Premarin ) and cyclic medroxyprogesterone acetate ( Provera ) . RESULTS Of an eligible 105 apparently healthy women , recruited by advertisement , 83 completed the question naires for the study . R and omization was successful . While there was a substantial variation over time in the change of scores for all the psychosocial outcomes , there was no significant difference between active and placebo treatment when order of treatment allocation was ignored . However , a strong and consistent effect of the order of treatment allocation for many of the scores was found ; in particular , the effect of active treatment was substantially stronger when it was administered second . Positive effects of active treatment were found for the score for the overall symptom rating test ( p < 0.009 ) and its components of depression and feeling of inadequacy ( p = 0.011 ; p = 0.001 , respectively ) . CONCLUSIONS The use of hormones , given as a continuous estrogen and cyclic progestogen formulation after a formal calibration/run-in period , may have a beneficial effect on psychosocial distress experienced by women towards the end of their reproductive function OBJECTIVES To evaluate the effect of ultra-low-dose ( 0.25 mg/d ) micronized 17beta-estradiol on cognitive function in older postmenopausal women . DESIGN R and omized , placebo-controlled trial conducted for 3 years . SETTING Academic health center in greater Hartford , Connecticut . PARTICIPANTS Fifty-seven healthy , community-dwelling , older postmenopausal women . INTERVENTION Women received 0.25 mg/d of micronized 17beta-estradiol ( estrogen therapy ( ET ) , n=32 ) or placebo ( n=25 ) ; all women who had not had a hysterectomy received 100 mg/d of oral micronized progesterone for 2-week periods every 6 months . MEASUREMENTS Neuropsychological measures of memory , language , mood , and executive function were collected at baseline , 3 months , and 36 months . Measures of executive function included the Controlled Oral Word Association Test , the Trail Making Test , and the Wisconsin Card Sorting Test . The Boston Naming Test was used to measure language skills . The Symbol Digit Modalities Test was used as a measure of sustained attention . Measures of memory included the Complex Figure Test , Fuld Object Memory Test , and a selected subtest from the Wechsler Memory Scale . Scores from the Geriatric Depression Scale and the Beck Anxiety Inventory were used to assess symptoms of depression . RESULTS No differences were found between ET and placebo on any of the neurocognitive measures or depression instruments , nor were there any differences when the groups were stratified according to age . CONCLUSION This small study , which had adequate power to detect change in some but not all domains of cognition tested , revealed that low-dose estrogen neither benefits nor harms cognitive function in older women after 3 years of treatment , but confirmation is needed from larger trials 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 r and omized 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 st and ardized 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 , st and ardized 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 BACKGROUND Estrogen has been considered as a potential antidepressant in postmenopausal women . Our goal was to study whether estrogen therapy is effective in treating depressive disorders in older postmenopausal women and to determine whether progestins are associated with a deterioration of mood . METHODS After 2 weeks of single-blind placebo treatment in 87 patients , 57 were r and omly assigned to receive 8 weeks of treatment with estradiol ( .1 mg/day ; n = 31 ) or placebo ( n = 26 ) . All patients were then treated with medroxyprogesterone 10 mg/day for 2 weeks combined with the study patch .  Depressive symptoms were rated with the 21-item Hamilton Depression and Center for Epidemiologic Studies Depression scales . RESULTS A clinical ly significant antidepressant effect of estradiol was excluded after 8 weeks of estradiol treatment . The estradiol group and placebo group improved in depressive symptoms at a similar rate based on the Hamilton Depression Scale ( 40 % decreases in depression for estradiol vs. 44 % for placebo ) . No significant increase in depressive symptoms was demonstrated with the use of progestins ; however , positive affect decreased slightly with the use of combined estradiol-medroxyprogesterone compared with medroxyprogesterone alone ( 5.8 % , p = .027 ) . CONCLUSIONS Estradiol can not be considered as an effective treatment in postmenopausal women with mild to moderate depression CONTEXT Postmenopausal hormone therapy is commonly used by women for disease prevention , but its effects on quality of life have not been well documented . OBJECTIVE To determine the effect on quality of life of estrogen plus progestin therapy used as secondary prevention in women with coronary artery disease . DESIGN , SETTING , AND PARTICIPANTS A total of 2763 postmenopausal women with documented coronary artery disease ( mean age , 67 years ) in the Heart and Estrogen/Progestin Replacement Study , a r and omized , placebo-controlled , double-blind trial conducted from January 1993 to July 1998 at outpatient and community setting s at 20 US clinical centers . INTERVENTION Participants were r and omly assigned to receive either 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate ( n = 1380 ) or placebo ( n = 1383 ) for 36 months . MAIN OUTCOME MEASURES Physical activity , measured by the Duke Activity Status Index ; energy/fatigue and mental health , measured by R AND scales ; and depressive symptoms , measured on the Burnam screening scale , at 3 years of follow-up . RESULTS In all patients , scores declined significantly over 3 years for physical function ( -3.8 ; P<.001 ) , mental health ( -0.6 ; P = .05 ) , and energy/fatigue ( -3.8 ; P<.001 ) , but depressive symptoms were not significantly changed ( P = .20 ) . The effect of hormone therapy on these measures depended on the presence ( n = 434 ) or absence ( n = 2325 ) of flushing at study entry . Women with flushing who were assigned to hormone therapy had improved mental health ( + 2.6 vs - 0.5 ; P = .04 ) and fewer depressive symptoms ( -0.5 vs + 0.007 ; P = .01 ) over follow-up compared with those assigned to placebo . Women without flushing who were assigned to hormone therapy had greater declines in physical function ( -4.2 vs -3.3 ; P = .04 ) and energy/fatigue ( -4.6 vs -3.1 ; P = .03 ) over follow-up . Quality -of-life scores were significantly lower among patients with older age , diabetes , hypertension , chest pain , or heart failure . These differences in quality of life among women classified by clinical characteristics were much greater than the effects of hormone therapy . CONCLUSION Hormone therapy has mixed effects on quality of life among older women . The effects of hormone therapy depend on the presence of menopausal symptoms ; women without flushing had greater declines in physical measures , while women with flushing had improvements in emotional measures of quality of life To determine the relation of menopause to the risk of coronary heart disease , we analyzed data on a prospect i ve cohort of 121,700 U.S. women 30 to 55 years old who were followed from 1976 to 1982 . Information on menopausal status , the type of menopause , and other risk factors was obtained in 1976 and up date d every two years by mailing question naires . Through 1982 , the follow-up rate was 98.3 percent for mortality and 95.4 percent for nonfatal events . After we controlled for age and cigarette smoking , women who had had a natural menopause and who had never taken replacement estrogen had no appreciable increase in the risk of coronary heart disease , as compared with premenopausal women ( adjusted rate ratio , 1.2 ; 95 percent confidence limits , 0.8 and 1.8 ) . Again compared with premenopausal women , the occurrence of a natural menopause together with the use of estrogens did not affect the risk ( rate ratio , 0.8 , 95 percent confidence limits , 0.4 and 1.3 ) . Women who had undergone bilateral oophorectomy and who had never taken estrogens after menopause had an increased risk ( rate ratio , 2.2 ; 95 percent confidence limits , 1.2 and 4.2 ) . However , the use of estrogens in the postmenopausal period appeared to eliminate this increased risk among these women as compared with premenopausal women ( rate ratio , 0.9 ; 95 percent confidence limits , 0.6 and 1.6 ) . These data suggest that , in contrast to a natural menopause , bilateral oophorectomy increases the risk of coronary heart disease . This increase appears to be prevented by estrogen-replacement therapy Background : To compare combined and sequential hormonal replacement therapies to each other as well as placebo in patients suffering from the postmenopausal syndrome . Clinical outcomes were measured concerning both the specific postmenopausal symptoms ( using the Kupperman scale ) and health or well-being dimensions ( using subscales of the General Health Question naire and specific depression and anxiety scales ) . Methods : A prospect i ve r and omized double-blind study over 12 months of 105 normal early postmenopausal women in the setting of a general hospital . Results : Both hormone replacement therapies were superior to placebo on the Kupperman scale ( sweating , hot flushing , myalgia and vertigo ) . The psychic symptoms on the Kupperman scale were psychometrically invalid . However , psychic symptoms as measured by the Beck Depression Inventory and the General Health Question naire were significantly improved by the hormonal replacement therapies . No differences were observed when combined therapy was compared to sequential therapy . Conclusion : One-year treatment with hormonal replacement therapy is superior to placebo in measuring the somatic and psychic symptoms of the menopausal syndrome . No differences were found in this respect between combined and sequential replacement therapy Objective The aim of this study was to examine the effect of hormone therapy and calcitriol on  depression in older postmenopausal women and to determine whether the response was associated with polymorphisms of estrogen receptor & agr ; and vitamin D receptor . Methods In a double-blind placebo-controlled prospect i ve trial involving 489 postmenopausal older women , a secondary analysis of depression was done . The Geriatric Depression Scale was used to screen for depression . We used binary logistic regression to examine the effect of treatment on depression and one-way analysis of variance to find a relationship between gene polymorphisms and depression . Results There was no effect of hormone therapy ( odds ratio [ OR ] , 1.65 ; 95 % CI , 0.66 - 4.12 ; P = 0.277 ) , calcitriol ( OR , 1.15 ; 95 % CI , 0.43 - 3.11 ; P = 0.772 ) , or hormone therapy with calcitriol ( OR , 1.01 ; 95 % CI , 0.36 - 2.80 ; P = 0.979 ) on depression . Neither the polymorphisms of estrogen receptor & agr ; ( XbaI-&bgr ; = 0.093 ; CI , −0.337 to 1.350 ; P = 0.239 and PvuII-&bgr ; = −0.064 ; CI , −1.171 to 0.491 , P = 0.421 ) nor those of vitamin D receptor ( BsmI-&bgr ; = 0.044 , CI −2.546 to 3.030 , P = 0.865 and TaqI-&bgr ; = −0.015 , CI −2.900 to 2.738 , P = 0.955 ) were associated with depression . Conclusion In older postmenopausal women , there was no effect of hormone therapy and calcitriol either individually or in combination with depression . Estrogen receptor & agr ; and vitamin D receptor polymorphisms are not associated with depression or the response to intervention in older postmenopausal women . Additional trials are required to confirm these findings
target: This moderate to large effect size , showing lower ratings of depressed mood in treated patients compared with controls , implicated HRT as a potential treatment of or prophylactic for depression in menopausal women .
  One can generalize from the studies review ed here only with great caution , but there is little evidence to support the use of estradiol to improve mood in nondepressed patients ( not surprisingly ) and some evidence to support the antidepressant efficacy of estradiol in perimenopausal but not postmenopausal women
background: BACKGROUND Controversy regarding the antidepressant efficacy of hormone replacement therapy ( HRT ) stems almost from its inception and reflects the same method ological inconsistencies that have compromised efforts to determine whether the perimenopause is accompanied by an increase in mood symptoms or depression .
  Since this publication , multiple studies have aim ed to discern the relationship between HRT and menopausal mood .
  METHODS The purpose of this systematic review is to examine the findings and quality of the evidence amassed since Zweifel and O'Brien 's meta- analysis .