The effects of compounded bioidentical transdermal hormone therapy on hemostatic, inflammatory, immune factors; cardiovascular biomarkers; quality-of-life measures; and health outcomes in perimenopausal and postmenopausal women. Sex Hormone Levels and Risk of Cardiovascular Events in Postmenopausal Women Relationship between serum levels of sex hormones and progression of subclinical atherosclerosis in postmenopausal women. Managing menopause. The endocrine transition around menopause ‐ a five years prospective study with profiles of gonadotropines, estrogens, androgens and SHBG among healthy women Testosterone addition to estrogen therapy – Effects on inflammatory markers for cardiovascular disease Reducing bioavailable sex hormones through a comprehensive change in diet: the diet and androgens (DIANA) randomized trial. Association of hyperandrogenemia and hyperestrogenemia with type 2 diabetes in Hispanic postmenopausal women. Effectiveness of a low dose testosterone undecanoate to improve sexual function in postmenopausal women Hormone replacement therapy use and menopausal symptoms among women participating in a behavioral lifestyle intervention. Relation of demographic factors, menstrual history, reproduction and medication use to sex hormone levels in postmenopausal women Age-specific reference ranges for serum testosterone and androstenedione concentrations in women measured by liquid chromatography-tandem mass spectrometry. Hormonal treatments of sexual unresponsiveness in postmenopausal women: a comparative study Sex hormone changes during weight loss and maintenance in overweight and obese postmenopausal African-American and non-African-American women Plasma sex steroid hormones and risk of developing type 2 diabetes in women: a prospective study Association of endogenous sex hormones and insulin resistance among postmenopausal women: results from the Postmenopausal Estrogen/Progestin Intervention Trial. Women’s Health Initiative clinical trials: interaction of calcium and vitamin D with hormone therapy Reduction in proliferation with six months of letrozole in women on hormone replacement therapy Testosterone inhibits estrogen/progestogen-induced breast cell proliferation in postmenopausal women SUBCUTANEOUS HORMONE IMPLANTS FOR THE CONTROL OF CLIMACTERIC SYMPTOMS: A Prospective Study The benefits of androgens combined with hormone replacement therapy regarding to patients with postmenopausal sexual symptoms. Reproductive hormone exposure timing and ischemic heart disease: Complicated answers to a simple question. Prospective Randomized Trial to Assess Effects of Continuing Hormone Therapy on Cerebral Function in Postmenopausal Women at Risk for Dementia
Menopause impacts 25 million women world wide each year , and the World Health Organization estimates 1.2 billion women will be postmenopausal by 2030 . Menopause has been associated with symptoms of hot flashes , night sweats , dysphoric mood , sleep disturbance , and conditions of cardiovascular disease , depression , osteoporosis , osteoarthritis , depression , dementia , and frailty . Conventional hormone replacement therapy results in increased thrombotic events , and an increased risk of breast cancer and dementia as evidence d in large prospect i ve clinical trials including Heart and Estrogen/Progestin Replacement Study I and the Women 's Health Initiative . A possible mechanism for these adverse events is the unfavorable net effects of conjugated equine estrogens and medroxyprogesterone acetate on the hemostatic balance and inflammatory and immune factors . Physiologic sex steroid therapy with transdermal delivery for peri/postmenopausal women may offer a different risk/benefit profile , yet long-term studies of this treatment model are lacking . The objective of this study was to examine the long-term effects of compounded bioidentical transdermal sex steroid therapy including estriol , estradiol , progesterone , DHEA , and testosterone on cardiovascular biomarkers , hemostatic , inflammatory , immune signaling factors ; quality -of-life measures ; and health outcomes in peri/postmenopausal women within the context of a hormone restoration model of care . A prospect i ve , cohort , closed-label study received approval from the Human Subjects Committee . Recruitment from outpatient clinics at an academic medical center and the community at large result ed in three hundred women giving signed consent . Seventy-five women who met strict inclusion /exclusion criteria were enrolled .  Baseline hormone evaluation was performed along with baseline experimental measures . Following this , women received compounded transdermal bioidentical hormone therapy of BiEst ( 80%Estriol/20%Estradiol ) , and /or Progesterone for eight weeks to meet established physiologic reference ranges for the luteal phase in premenopausal women . The luteal phase hormone ratios were selected based on animal and epidemiologic studies demonstrating favorable outcomes related to traumatic , ischemic , or neuronal injury . Follow-up testing was performed at eight weeks and adjustment to hormone regimens were made including addition of and rogens of DHEA and Testosterone if indicated . Experimental subjects were monitored for 36 months . Baseline , 2-month , and annual values were obtained for : blood pressure , body mass index , fasting glucose , Homeostasis Metabolic Assessment of Insulin Resistance ( HOMA-IR ) , fasting triglycerides , total Factor VII , Factor VIII , fibrinogen , Antithrombin III , Plasminogen Activator Inhibitor1(PAL-1 ) , C-reactive protein ( CRP ) , Interleukin-6 ( IL-6 ) , Matrix Metalloproteinase-9 ( MMP-9 ) , Tumor Necrosis Factor-alpha ( TNF ) , Insulin-like Growth Factor ( IGF-1 ) , and sex steroid levels . Psychosocial measures included : Greene Climacteric Scale , Visual Analog Pain Scale , Hamilton Anxiety Scale , Hamilton Depression Scale , Holmes Rahe Stress Scale , Job Strain , and Home Strain . Health outcome measures included the number of prescribed medications used , number of co-morbidities , and endometrial thickness in postmenopausal women with intact uteri . Subjects receiving  compounded transdermal bioidentical hormone therapy showed significant favorable changes in : Greene Climacteric Scale scores , Hamilton Anxiety Scale , Hamilton Depression Scale , Visual Analog Pain Scale , fasting glucose , fasting triglycerides , MMP-9 , C-reactive Protein , fibrinogen , Factor VII , Factor VIII , Insulin-Like Growth Factor 1 , and health outcomes of co-morbidities and a number of prescribed medications . Antithrombin III levels were significantly decreased at 36 months . All other measures did not exhibit significant effects . Administration of compounded transdermal bioidentical hormone therapy in doses targeted to physiologic reference ranges administered in a daily dose significantly relieved menopausal symptoms in peri/postmenopausal women . Cardiovascular biomarkers , inflammatory factors , immune signaling factors , and health outcomes were favorably impacted , despite very high life stress , and home and work strain in study subjects . The therapy did not adversely alter the net prothrombotic potential , and there were no associated adverse events . This model of care warrants consideration as an effective and safe clinical therapy for peri/postmenopausal women especially in population s with high perceived stress and a history of stressful life events prior to , or during the menopausal transition Background —Despite diffuse effects of sex hormones on the cardiovascular system , few prospect i ve studies have examined the relationship of plasma and rogens and estrogens with risk of cardiovascular disease ( CVD ) in postmenopausal women . Methods and Results —A nested case-control study was performed among women in the Women ’s Health Study . Two hundred women who developed CVD were matched 1:1 by age , smoking , and postmenopausal hormone therapy ( HT ) to controls who remained free of CVD . We measured testosterone , estradiol , and sex hormone binding globulin ( SHBG ) levels and calculated free and rogen index ( FAI ) , free estradiol index , and the FAI/free estradiol index ratio .  Results were stratified by HT use . Among HT nonusers , cases had significantly higher and rogen profiles ( higher median FAI and lower SHBG levels ) than controls . After adjustment for age , smoking , use of aspirin , vitamin E , and alcohol , family history of myocardial infa rct ion , and physical activity , nonusers in the lowest SHBG quartile had an OR of 2.25 ( 95 % CI , 1.03 to 4.91 ) for CVD , and there were significant trends across FAI quartiles ( P for trend=0.03 ) . Additional adjustment for body mass index , hypertension , diabetes , and elevated cholesterol eliminated associations with SHBG and FAI . Among women using HT , no significant differences in hormones or SHBG were observed among women who developed CVD and controls . Conclusions —Among HT nonusers , lower SHBG and higher FAI levels were noted among postmenopausal women who developed CVD events , but this was not independent of body mass index and other cardiovascular risk factors . Estradiol levels were not associated with risk of CVD in  HT  users or nonusers BACKGROUND Postmenopausal hormone therapy has been examined extensively in relation to cardiovascular disease . However , research relating serum levels of sex hormones to cardiovascular disease is sparse , and the results are inconclusive . METHODS We measured sex hormones in longitudinally collected sample s of 180 postmenopausal women , 91 r and omized to 17beta-estradiol and 89 to placebo , in the Estrogen in the Prevention of Atherosclerosis Trial . Repeated measures of sex hormone levels were tested for an association with carotid artery intima-media thickness ( CIMT ) , which was also assessed longitudinally over 2 yr . RESULTS In all women , changes in serum estrone ( P = 0.02 ) , total estradiol ( P = 0.01 ) , free estradiol ( P = 0.02 ) , and SHBG ( P = 0.005 ) were significantly inversely associated with CIMT progression , controlling for age and body mass index . All the estrogen compounds and SHBG were significantly inversely related with low-density lipoprotein cholesterol and positively associated with high-density lipoprotein cholesterol ( all P < 0.0001 ) , whereas free testosterone was positively related with low-density lipoprotein cholesterol and inversely associated with high-density lipoprotein cholesterol ( P < 0.003 ) . Despite an increase in serum-free estradiol with estradiol therapy , women with unchanged SHBG and free testosterone levels had an average ( se ) progression in CIMT of 8.53 ( 4.72 ) microm/yr , whereas women with increased free estradiol and SHBG and decreased free testosterone had the largest reduction in CIMT progression [ -5.45 ( 2.77 ) microm/yr ; trend P = 0.03 ] . CONCLUSION Estrogen and SHBG are associated with reduced sub clinical atherosclerosis progression in healthy postmenopausal women . These associations are partially mediated by their beneficial effects on lipids . Among women taking estradiol , the most beneficial hormone profile for CIMT progression was increased free estradiol and SHBG with concomitant decreased free testosterone OBJECTIVE To provide up date d guidelines for health care providers on the management of menopause in asymptomatic healthy women as well as in women presenting with vasomotor or urogenital symptoms and on considerations related to cardiovascular disease , breast cancer , urogynaecology , and sexuality . OUTCOMES Lifestyle interventions , prescription medications , and complementary and alternative therapies are presented according to their efficacy in the treatment of menopausal symptoms . Counselling and therapeutic strategies for sexuality concerns in the peri- and postmenopausal years are review ed . Approaches to the identification and evaluation of women at high risk of osteoporosis , along with options for prevention and treatment , are presented in the companion osteoporosis guideline . EVIDENCE Published literature was retrieved through search es of PubMed and The Cochrane Library in August and September 2012 with the use of appropriate controlled vocabulary ( e.g. , hormone therapy , menopause , cardiovascular diseases , and sexual function ) and key words ( e.g. , hormone therapy , perimenopause , heart disease , and sexuality ) . Results were restricted to clinical practice guidelines , systematic review s , r and omized control trials/controlled clinical trials , and observational studies . Results were limited to publication date s of 2009 onwards and to material in English or French . Search es were up date d on a regular basis and incorporated in the guideline until January 5 , 2013 . Grey ( unpublished ) literature was identified through search ing the websites of health technology assessment and health technology assessment -related agencies , national and international medical specialty societies , and clinical practice guideline collection OBJECTIVE The purpose of this study was to investigate the hormonal changes during the menopausal transition in a non- clinical population . METHODS Fifty-nine healthy Norwegian women participated in a five year prospect i ve longitudinal study during the transition from pre- to post-menopause , starting one to four years before menopause , and ending one to four years postmenopausal . None of these women were given hormone replacement therapy ( HRT ) . Blood sample s were collected every 12 months and luteinizing hormone ( LH ) , follicle stimulating hormone ( FSH ) , steroid hormone binding globuline ( SHBG ) , prolactin ( PRL ) , estradiol ( E2 ) , estrone ( E1 ) , testosterone , and rostendione , dehydroepi and rostendione-sulphate ( DHEA-S ) , and thyroid stimulating hormone ( TSH ) were analyzed . RESULTS The serum levels of FSH and LH , E2 and E1 profile essentially confirmed previous data obtained in cross-sectional studies . A continuous increase in serum FSH and LH and a concomitant fall in E2 and E1 were observed in all women before menopause and in the two postmenopausal years . Both and rostendione and testosterone showed a decline three years before menopause . After the menopause , however , there were fluctuations in the testosterone levels . And rostendione correlated positively with both E2 and E1 and testosterone postmenopausally . Body mass index ( BMI ) did correlate with testosterone , but not with and rostendione . BMI correlated negatively with SHBG . No correlation was found between BMI and E2 , E1 , FSH and LH . CONCLUSION This longitudinal prospect i ve study of hormonal changes during the transition from pre- to postmenopause indicates that not only estrogen hormonal changes , but and rogen hormonal changes as well , precedes the menopause by several years Objective . To analyze the effects of testosterone addition to estrogen therapy in comparison with estrogen alone on cardiovascular risk factors in postmenopausal women . Methods . Fifty surgically postmenopausal women were included in this double-blind , placebo-controlled and r and omized study to receive daily oral treatment with estradiol valerate 2 mg + placebo ( E/P ) or estradiol valerate 2 mg + testosterone undecanoate 40 mg ( E/T ) for 24 weeks and then switched to the other regimen for another 24 weeks . Sex hormones , High sensitivity CRP ( hsCRP ) , Interleukin-6 ( IL-6 ) , Tissue necrosis factor (TNF)-α , Insulin-like growth factor binding globulin ( IGFBP-1 ) , vascular cell adhesion molecule (VCAM)- 1 , and homocysteine were analyzed at baseline and after 6 and 12 months . Results . Estradiol and and rogens increased as expected during the treatments . After 6 months of E/P , increases of hsCRP and IGFBP-1 and a decline of VCAM were recorded , whereas IL-6 , TNF-α , and homocysteine were unchanged . When testosterone was added to estrogen , the increase of IGFBP-1 and decline in VCAM was similar as with estrogen treatment alone . However , testosterone addition counteracted the estrogen-induced rise in hsCRP but had no effects on IL-6 , TNF-α , and homocysteine . Conclusion . Data suggest that testosterone addition to estrogen treatment in postmenopausal women has a modest influence on inflammatory markers and there were no apparent adverse effects . On the contrary , the estrogen-induced increase in hsCRP was suppressed High serum levels of testosterone and estradiol , the bioavailability of which may be increased by Western dietary habits , seem to be important risk factors for postmenopausal breast cancer . We hypothesized that an ad libitum diet low in animal fat and refined carbohydrates and rich in low-glycemic-index foods , monounsaturated and n-3 polyunsaturated fatty acids , and phytoestrogens , might favorably modify the hormonal profile of postmenopausal women . One hundred and four postmenopausal women selected from 312 healthy volunteers on the basis of high serum testosterone levels were r and omized to dietary intervention or control .  The intervention included intensive dietary counseling and specially prepared group meals twice a week over 4.5 months . Changes in serum levels of testosterone , estradiol , and sex hormone-binding globulin were the main outcome measures . In the intervention group , sex hormone-binding globulin increased significantly ( from 36.0 to 45.1 nmol/liter ) compared with the control group ( 25 versus 4 % , ; P < 0.0001 ) and serum testosterone decreased ( from 0.41 to 0.33 ng/ml ; -20 versus -7 % in control group ; P = 0.0038 ) . Serum estradiol also decreased , but the change was not significant . The dietary intervention group also significantly decreased body weight ( 4.06 kg versus 0.54 kg in the control group ) , waist : hip ratio , total cholesterol , fasting glucose level , and area under insulin curve after oral glucose tolerance test . A radical modification in diet design ed to reduce insulin resistance and also involving increased phytoestrogen intake decreases the bioavailability of serum sex hormones in hyper and rogenic postmenopausal women . Additional studies are needed to determine whether such effects can reduce the risk of developing breast cancer OBJECTIVE Accumulating evidence suggests that hyper and rogenemia may be a risk factor for coronary heart disease ( CHD ) in women . The present study was carried out to test the hypothesis that hyper and rogenemia is associated with type 2 diabetes in women and thus may contribute to the increased risk of CHD in women with type 2 diabetes . RESEARCH DESIGN AND METHODS Sex hormones , sex hormone-binding globulin ( SHBG ) , and  risk factors for CHD were measured in 20 postmenopausal women with type 2 diabetes and in 29 control subjects . All of the diabetic and control subjects were Hispanic women aged > 55 years who were not taking hormone replacement therapy lipid-lowering drugs , or insulin and who were otherwise r and omly chosen from a cohort of stroke-free subjects from the Northern Manhattan Stroke Study RESULTS Mean age , BMI , total cholesterol , LDL cholesterol , HDL cholesterol , triglycerides , blood pressure , and smoking were not significantly different between cases and control subjects , but waist-to-hip ratio ( WHR ) was significantly higher in the diabetic subjects ( P = 0.01 ) . The mean levels of free testosterone ( FT ) ( P = 0.01 ) , dehydroepi and rosterone sulfate ( P<0.04 ) , and estradiol ( P = 0.01 ) ( controlled for WHR ) were significantly higher in the diabetic subjects ; with the statistical outliers removed , the testosterone ( P = 0.05 ) and and rostenedione ( P = 0.002 ) levels ( controlled for WHR ) were also significantly higher in the diabetic subjects . The mean levels of estrone , cortisol , and SHBG were not significantly different . The results were similar in the 10 diabetic subjects treated with diet only Significant positive correlations ( controlled for age and BMI ) were observed between FT or testosterone and cholesterol , LDL cholesterol , and blood pressure . CONCLUSIONS Postmenopausal Hispanic women with type 2 diabetes had both hyper and rogenemia and hyperestrogenemia , and testosterone or FT correlated positively with risk factors for CHD . Hyper and rogenemia may be a link between diabetes and CHD in women Background Adding testosterone to hormonal therapy could improve sexual function and general well-being among women during climacteric . We evaluated the effectiveness of testosterone undecanoate on sexual function in postmenopausal women utilizing the st and ardized question naire FSFI score . Methods Postmenopausal women with sexual complaints and Female Sexual Function Index ( FSFI ) ≤ 26.5 were enrolled in to this r and omized , double-blinded , placebo-controlled trial . Participants were r and omly assigned to 8-week treatment with either oral testosterone undecanoate 40 mg or placebo twice weekly with daily oral estrogen .  The FSFI scores before and after treatment were compared to assess any improvement of sexual function . Results Seventy women were recruited of which each group had 35 participants . The baseline characteristics and baseline FSFI scores were comparable between both groups . After 8 weeks of treatment , the FSFI scores significantly improved in both groups when compared to the baseline but the FSFI scores from the testosterone group were significantly higher than in the placebo group post-treatment ( 28.6 ± 3.6 , 25.3 ± 6.7 , respectively , p = 0.04 ) . There was no difference in adverse effect between the two groups Conclusions The twice weekly addition of testosterone undecanoate to daily oral estrogen was associated with a significant improvement in sexual function  among postmenopausal women than the use of the estrogen alone . Trial registration Clinical Trials.gov Identifier NCT01724658 ( February 17 , 2012 ) BACKGROUND The decision to take hormone replacement therapy ( HRT ) is a choice many women encounter when entering menopause . The purpose of this study was to examine the choice to take HRT while participating in a lifestyle intervention to reduce cardiovascular risk through the menopause . METHODS The Women 's Healthy Lifestyle Project is a r and omized clinical trial design ed to examine whether a behavioral lifestyle intervention can decrease the expected rise in cardiovascular risk through the menopause . Participants ( N = 535 ) completed question naires and were interviewed regarding menopausal symptoms , menopausal status , hot flashes , and  HRT  use at baseline and 54 months . RESULTS The intervention was successful in preventing risk elevation through the 54-month visit . At the final visit , there was no difference between the intervention and control groups in the percentage who had become postmenopausal ( 32.9 % vs 35.0 % , respectively ) , there was no difference between control and intervention with  HRT  use , with 31.2 % reporting use of HRT , and there was no difference between groups with menopausal symptoms . The women started HRT an average of 6 months after they missed a period . Baseline risk factors did not predict HRT use at the 54-month visit . CONCLUSIONS A sizable number of women reported HRT use . The decision to use HRT was not influenced by the lifestyle intervention or their baseline cardiovascular risk , and these women started HRT very early in the peri- to postmenopause . Further , weight loss in the perimenopause did not affect menopausal symptoms In postmenopausal women , levels of estrogens , and rogens , and perhaps prolactin have been related to risk of breast and other hormonal cancers in women . However , the determinants of these hormone concentrations have not been firmly established . Associations among various demographic , menstrual , and reproductive factors , medication use and endogenous sex hormone concentrations ( estradiol , free estradiol , estrone , estrone sulfate , testosterone , free testosterone , sex hormone binding globulin , and rostenedione , dehydroepi and rosterone ( DHEA ) , DHEA sulfate ( DHEAS ) , dihydrotestosterone , and prolactin )  were evaluated in a cross-sectional analysis from a simple r and om sample of 274 postmenopausal women selected from the Women ’s Health Initiative Dietary Modification Trial . In multiple regression analyses on log-transformed hormones , the concentrations of DHEA , and DHEAS were negatively and statistically significantly associated with age ( both β = −0.03 , P < 0.001 , respectively ) . Estradiol , estrone , DHEA , and free testosterone concentrations were higher in African-American than in non-Hispanic White women , but after multivariate adjustment the associations were statistically significant only for free testosterone ( β = 0.38 , P = 0.01 ) . Women who had a history of bilateral oophorectomy had a mean 35 % lower testosterone concentration compared with women with at least one ovary remaining ( β = −0.43 , P = 0.002 ) , and lower free testosterone ( β = −0.42 , P = 0.04 ) after multivariate adjustment . Women who reported regular use of NSAIDs had higher DHEA concentrations ( β = 0.20 , P = 0.04 ) and lower prolactin concentrations ( β = −0.18 , P = 0.02 ) compared with non-users . These results suggest that while age , oophorectomy status , and NSAID use may be associated with selected sex hormone concentrations , few menstrual or reproductive factors affect endogenous sex hormones in the postmenopausal period OBJECTIVE RIA-based sex hormone measurements offer only limited precision and specificity in the low concentration range of women . Therefore , we aim ed to establish age-specific reference ranges for serum sex hormone concentrations in women using mass spectrometry and quantile regression . METHODS AND RESULTS Data from 985 women aged 20 - 80 yr , recruited for the prospect i ve Study of Health in Pomerania , were included in the analyses . Quantile regressions models were performed to calculate the age-specific 2.5th and 97.5th percentiles for sex hormone concentrations in women . Serum total testosterone ( TT ) and and rostenedione ( AD ) concentrations were measured by liquid chromatography-t and em mass spectrometry . Measured concentrations of SHBG and TT were used to calculate free testosterone ( free T ) . TT , AD , and free T concentrations showed a distinct age-related decline across 10-yr age groups ( one way ANOVA P < 0.001 ) . Sex hormone reference ranges for TT , AD , and free T were determined across each single year of age and for 10-yr age groups . Reference ranges over the whole age range of 20 - 80 yr were 0.35 - 1.97 nmol/liter for TT , 0.89 - 4.56 nmol/liter for AD , and 0.0025 - 0.0253 nmol/liter for free T. Separate reference ranges were provided for pre- and postmenopausal women as well as after inclusion of women using oral contraceptives or hormone therapy ( n = 1357 ) . CONCLUSION This is the first study to establish age-specific reference ranges for liquid chromatography-t and em mass spectrometry-measured  TT and AD and calculated free T concentrations based on quantile regression analyses , accurately accounting for the observed low concentration range and the strong age dependency of these sex hormones in women Summary . Forty postmenopausal women , referred for hormone replacement therapy and all of whom reported a significant concern about a decline in their sexual interest , were r and omly allocated to one of two hormone implant  treatment groups : either oestradiol ( 50 mg ) alone , or oestradiol ( 50 mg ) and testosterone ( l00 mg ) . Comparison between the two groups as a whole revealed no significant differences on any measure , both treatments being associated with a significant reduction in the severity of psychological , somatic and vasomotor symptoms , and with a significant improvement in sexual interest and responsiveness . Similar effects were also observed in patients who denied , pretreatment , any concurrent dyspareunia .  Although it is not possible to identify the reasons for change , the results indicate no advantages of supplementary testosterone administration over oestradiol alone for sexually unresponsive postmenopausal women Introduction Changes in sex hormones with weight loss might have implication s for breast cancer prevention but have not been examined extensively , particularly in African-American ( AA ) women . Methods We conducted a prospect i ve study of 278 overweight/obese postmenopausal women ( 38 % AA ) not taking hormone therapy within the Weight Loss Maintenance Trial . All participants lost at least 4 kg after a 6-month weight-loss phase and attempted to maintain weight loss during the subsequent 12 months . We evaluated the percentage changes in estrone , estradiol , free estradiol , testosterone , free testosterone , and rostenedione , dehydroepi and rosterone sulfate and sex hormone-binding globulin ( SHBG ) using generalized estimating equations . Results In all study phases , AA women had higher levels of estrogen and testosterone concentrations , independent of adiposity . On average , participants lost 7.7 kg during the weight-loss phase , and concentrations of estrone ( -5.7 % , P = 0.006 ) , estradiol ( -9.9 % , P < 0.001 ) , free estradiol ( -13.4 % , P < 0.0001 ) , and free testosterone ( -9.9 % , P < 0.0001 ) decreased , while the SHBG concentration ( 16.2 % , P < 0.001 ) increased . Weight change did not significantly affect total testosterone or other and rogen concentrations . Compared with non-AA women , AA women experienced less change in estrogens per kilogram of weight change ( that is , per 1 kg weight loss : estrone , -0.6 % vs. -1.2 % , P-interaction = 0.10 ; estradiol , -1.1 % vs. -1.9 % , P-interaction = 0.04 ; SHBG , 0.9 % vs. 1.6 % , P-interaction = 0.006 ; free estradiol , -1.4 % vs. -2.1 % , P-interaction = 0.01 ) . Conclusion To the best of our knowledge this is the first study to examine and compare the effects of intentional weight loss and maintenance on a panel of sex hormones in AA women and non-AA women . Although speculative , these data suggest hormonal differences may contribute to different racial patterns of breast cancer incidence and mortality and encourage further investigations to underst and the long-term effects of weight loss on sex hormones in obese postmenopausal women . Trial Registration Clinical Trials.gov : Aims /hypothesis Prospect i ve data directly investigating the role of endogenous sex hormones in diabetes risk have been scant , particularly in women . We aim ed to examine comprehensively plasma sex hormones in connection with risk of developing type 2 diabetes  in postmenopausal women . Methods We conducted a prospect i ve , nested case – control study of  plasma oestradiol , testosterone and dehydroepi and rosterone sulfate  and risk of type 2 diabetes in a cohort of women health professionals with a mean age of 60.3 and 12.2 years since menopause . Among women not using hormone therapy and free of baseline cardiovascular disease , cancer and diabetes , 359 incident cases of type 2 diabetes were matched with 359 controls during an average follow-up of 10 years . Results Oestradiol and testosterone were each strongly and positively associated with risk of type 2 diabetes . After adjustment for BMI , family history , lifestyle and reproductive variables , the multivariable relative risks ( 95 % CI ) comparing the highest vs lowest quintile were 12.6 ( 2.83–56.3 ) for total oestradiol ( p = 0.002 for trend ) , 13.1 ( 4.18–40.8 ) for free oestradiol ( p < 0.001 for trend ) , 4.15 ( 1.21–14.2 ) for total testosterone ( p = 0.019 for trend ) and 14.8 ( 4.44–49.2 ) for free testosterone ( p < 0.001 for trend ) . These associations remained robust after adjusting and accounting for other metabolic syndrome components and baseline HbA1c levels . Conclusions /interpretationIn postmenopausal women , higher plasma levels of oestradiol and testosterone were strongly and prospect ively related to increased risk of developing type 2 diabetes . These prospect i ve data indicate that endogenous levels of sex hormones may play important roles in the pathogenesis of type 2 diabetes . Clinical Trials.gov ID no. : NCT00000479 Most studies of sex hormones and insulin resistance ( IR ) have focused on and rogens ; few have examined the association of endogenous estrogens and IR . We determined the cross-sectional association of endogenous levels of total and bioavailable testosterone and estradiol and SHBG with IR among 845 healthy , postmenopausal women aged 45 - 65 yr . Women were within 10 yr of menopause and not using hormone replacement therapy .  Total adiposity was estimated by body mass index , visceral adiposity by waist to hip ratio ( WHR ) , and IR by the homeostasis model assessment . We defined homeostasis model assessment -IR as the highest quartile ( cutpoint , 2.1 ) of the distribution in this cohort . In logistic regression analyses , the odds for IR were significant and increased in a dose-response fashion across each quartile of total estradiol , bioavailable estradiol , and bioavailable testosterone ( all P < 0.001 for linear trend ) . These associations remained significant after adjusting for WHR ; adjusted odds ratios were 4.0 , 6.1 , and 2.7 for total estradiol , bioavailable estradiol , and bioavailable testosterone , respectively , comparing the highest to the lowest quartile ( all P < 0.001 ) . Adjusting for body mass index and WHR together eliminated the linear association of IR with total estradiol and bioavailable testosterone , but the association with bioavailable estradiol remained ( adjusted odds ratio , 2.7 ; P < 0.001 , comparing the highest to the lowest quartile ) . IR was not associated with total testosterone before or after adjusting for adiposity . Lower SHBG levels were associated with higher odds of IR , independent of adiposity . These results suggest that estrogen may be equally or more important than testosterone in the pathway to IR in healthy , young postmenopausal women , with differences not entirely explained by body size Objective This study aims to test the added value of calcium and vitamin D ( CaD ) in fracture prevention among women taking postmenopausal hormone therapy ( HT ) . Methods This is a prospect i ve , partial-factorial , r and omized , controlled , double-blind trial among Women ’s Health Initiative postmenopausal participants aged 50 to 79 years at 40 centers in the United States with a mean follow-up of 7.2 years . A total of 27,347 women were r and omized to HT ( 0.625 mg of conjugated estrogens alone , or 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate daily ) , and 36,282 women were r and omized to 1,000 mg of elemental calcium ( carbonate ) plus 400 IU of vitamin D3 daily , each compared with placebo .  A total of 16,089 women participated in both arms . The predefined outcomes were adjudicated hip fractures and measured bone mineral density . Results Interaction between HT and CaD on hip fracture ( P interaction = 0.01 ) was shown . The effect of CaD  was stronger among women assigned to HT ( hazard ratio [ HR ] , 0.59 ; 95 % CI , 0.38 - 0.93 ) than among women assigned to placebo ( HR , 1.20 ; 95 % CI , 0.85 - 1.69 ) . The effect of HT on hip fracture was stronger among women assigned to active CaD ( HR , 0.43 ; 95 % CI , 0.28 - 0.66 ) than among women assigned to placebo ( HR , 0.87 ; 95 % CI , 0.60 - 1.26 ) . CaD supplementation enhanced the antifracture effect of HT at all levels of personal calcium intake . There was no interaction between HT and  CaD  on change in hip or spine bone mineral density .  Conclusions Postmenopausal women at normal risk for hip fracture who are on CaD supplementation  experience significantly reduced incident hip fractures beyond HT alone at all levels of personal baseline total calcium intake The objective of this study was to determine if 6 months of the aromatase inhibitor letrozole , administered to postmenopausal women taking a stable dose of hormone replacement remedy , would be safe and would modulate biomarkers of breast cancer risk . The intent was to reduce the proliferation marker Ki-67 while maintaining adequate systemic levels of estradiol so as to avoid perimenopausal symptoms . Postmenopausal women at high risk for development of breast cancer and taking a stable dose of estrogen or estrogen plus progestin were screened by r and om periareolar fine needle aspiration ( RPFNA ) . To be eligible , the acquired breast epithelial cells had to be characterized as cytologic atypia or borderline atypia with ≥1,000 epithelial cells on the cytomorphology slide ; plus ≥500 epithelial cells on a slide processed for Ki-67 immunocytochemistry . Forty-two women were enrolled in the one arm study and received 2.5 mg letrozole per day for 6 months , followed by repeat assessment of biomarkers . Ki-67 was reduced by a median relative value of 66 % . There was no significant change in breast cell cytomorphology ; ER weighted index score ; serum estradiol , testosterone , or IGF-1:IGFBP-3 ratio ; mammographic breast density , or frequency or severity of perimenopausal symptoms . Given the dramatic reduction in proliferation , the effect of letrozole on risk and response biomarkers should be explored further in a r and omized , placebo-controlled Phase IIB breast cancer chemoprevention trial Objective : During the past few years serious concern has been raised about the safety of combined estrogen/progestogen hormone therapy , in particular about its effects on the breast . Several observations suggest that and rogens may counteract the proliferative effects of estrogen and progestogen in the mammary gl and . Thus , we aim ed to study the effects of testosterone addition on breast cell proliferation during postmenopausal estrogen/progestogen therapy . Design : We conducted a 6-month prospect i ve , r and omized , double-blind , placebo-controlled study . A total of 99 postmenopausal women were given continuous combined estradiol 2 mg/norethisterone acetate 1 mg and were equally r and omly assigned to receive additional treatment with either a testosterone patch releasing 300 & mgr;g/24 hours or a placebo patch . Breast cells were collected by fine needle aspiration biopsy at baseline and after 6 months , and the main outcome measure was the percentage of proliferating breast cells positively stained by the Ki-67/MIB-1 antibody . Results : A total of 88 women , 47 receiving active treatment and 41 in the placebo group , completed the study . In the placebo group there was a more than fivefold increase ( P < 0.001 ) in total breast cell proliferation from baseline ( median 1.1 % ) to 6 months ( median 6.2 % ) . During testosterone addition , no significant increase was recorded ( 1.6 % vs 2.0 % ) . The different effects of the two treatments were apparent in both epithelial and stromal cells . Conclusions : Addition of testosterone may counteract breast cell proliferation as induced by estrogen/progestogen therapy in postmenopausal women 55 postmenopausal women on established hormone replacement therapy were treated with either oestradiol and testosterone implants or placebo at the time of return of climacteric symptoms . Their response to therapy was assessed prospect ively . The statistically highly significant levels of symptom relief that followed an oestradiol and testosterone implant were contrasted sharply with the lack of any significant relief with placebo . Despite the success of oestradiol and testosterone implants in relieving symptoms of the climacteric , symptoms returned once the treatment was stopped . Evidence is presented that it is the fall in hormone levels rather than the level itself that provokes the return of climacteric symptoms OBJECTIVE To evaluate the benefits and risks of hormone replacement therapy ( HRT ) combined with methyltestosterone ( MT ) in postmenopausal women with sexual dysfunction .  DESIGN This study was a r and omized , double-blind , placebo-controlled and crossover trial . Eighty-five women using HRT  were divided into four treatment groups : GI-HRT plus placebo for 4 months ; GII-HRT plus MT 2.5mg/day for 4 months ; GIII-HRT plus placebo for 2 months and then replaced with HRT plus MT 2.5mg/day for 2 months ; GIV-HRT plus MT 2.5mg/day and then replaced with HRT plus placebo for 2 months . Blood was collected at baseline , after 2 months ( T1 ) and 4 months ( T2 ) of treatment for hormone determinations of estradiol , FSH , total and free testosterone , GOT , GPT , glucose , total and fractions of cholesterol and triglycerides . All participants answered clinical questions and a vali date d question naire of modified McCoy 's sex scale . RESULTS The association of HRT with MT 2.5mg/day did not significantly change liver enzymes or increase cardiovascular risk factors . The patients of GII , GIIII and GIV when using MT presented amelioration of sex symptoms , mainly satisfaction and desire ( p<0.01 ) ; however , GIII at T1 ( 1.3+/-0.3 ) presented similar problem score results as compared to GIII at T2 ( 1.5+/-0.6 ) . CONCLUSION All data suggest that combined HRT- and rogen therapy may be beneficial for postmenopausal women receiving HRT who continue to complain of sexual difficulties or for postmenopausal women with sexual complaints who are not undergoing estrogen therapy Premenopausal women have a relatively lower risk of ischemic heart disease ( IHD )  compared to age matched men and this gender gap narrows after menopause . The observation that the onset of IHD occurs 10 years later in women than it does in men is said to suggest that endogenous reproductive hormones play a protective role . Indeed , animal models and human epidemiological studies suggest that oophorectomy is a risk factor for accelerated IHD . In animal models , hormone therapy ( HT ) has anti-atherosclerotic effects after oophorectomy , HT in the form of oral contraceptives ( OCs ) prevents atherosclerosis in anovulatory cycling women , and large numbers of premenopausal women taking OCs have relative safety from an IHD st and point ( 1 ) . Further , observational epidemiological studies in humans have consistently demonstrated protective effects for IHD among HT users . Such studies are typically performed on relatively younger women where  HT  is prescribed for  vasomotor symptoms during menopausal transition or shortly following menopause . In contrast , clinical trials in older , postmenopausal and often asymptomatic women have demonstrated no overall benefit and early adverse effects when r and omized to a variety of forms of HT ( 1 ) . These data discrepancies have called into question the validity of the reproductive hormone estrogen protection hypothesis , and raise the alternative possibility that  HT efficacy may differ according to the timing of exposure . Stated as a simple question , is the effect of HT on the risk of IHD in relatively young pre- or early menopausal women with vasomotor symptoms , different than it is in older , fully menopausal women ? Data from the Women ’s Ischemia Syndrome Evaluation ( WISE ) , a prospect i ve multi-center NHLBI-sponsored study design ed to explore female-specific pathophysiology in a large sample of women undergoing coronary angiography for suspected IHD ( 2 ) , may shed light on this controversy . These new data , prospect ively obtained using novel methods , including detailed reproductive health question naires , menopausal adjudication algorithms , and quantitative coronary angiography as a measure of atherosclerosis , allow a more precise inspection of this question . However , to answer this simple question we need to first answer others . Specifically , how can we integrate and underst and the findings from the available observational , animal and clinical trial data ? And to interpret these data other questions become relevant : 1 ) How accurately was menopause assessed in prior observational HT studies ? 2 ) Does HT in premenopausal women in the form of OC therapy confirm atherosclerosis benefit ? and 3 ) Does HT in early menopausal women confer reduced atherosclerosis and benefit on the risk of IHD The objective of this study was to examine the effects of estrogen-based hormone therapy ( HT ) on regional cerebral metabolism in postmenopausal women ( mean age = 58 , SD = 5 ) at risk for development of dementia . The prospect i ve clinical trial design included pre- and post-intervention neuroimaging of women r and omized to continue ( HT+ ) or discontinue ( HT− ) therapy following an average of 10 years of use . The primary outcome measure was change in brain metabolism during the subsequent two years , as assessed with  fluorodeoxyglucose-18 positron emission tomography ( FDG-PET ) . Longitudinal FDG-PET data were available for 45 study completers . Results showed that women r and omized to continue HT experienced relative preservation of frontal and parietal cortical metabolism , compared with women r and omized to discontinue HT . Women who discontinued 17-β estradiol (17βE)-based HT , as well as women who continued conjugated equine estrogen (CEE)-based HT , exhibited significant decline in metabolism of the precuneus/posterior cingulate cortical ( PCC ) area . Significant decline in PCC metabolism was additionally seen in women taking concurrent progestins ( with either 17βE or CEE ) . Together , these findings suggest that among postmenopausal subjects at risk for developing dementia , regional cerebral cortical metabolism is relatively preserved for at least two years in women r and omized to continue HT , compared with women r and omized to discontinue HT . In addition , continuing unopposed 17βE therapy is associated specifically with preservation of metabolism in PCC , known to undergo the most significant decline in the earliest stages of Alzheimer 's disease . Trial Registration Clinical Trials.gov
The pooled estimate from the studies suggested that the addition of testosterone to HT regimens improved sexual function scores for postmenopausal women .
A significant adverse effect was a decrease in high-density lipoprotein ( HDL ) cholesterol levels .
However , there is evidence that adding testosterone to HT has a beneficial effect on sexual function in postmenopausal women .
There was a reduction in HDL cholesterol associated with the addition of testosterone to the HT regimens .
It is , therefore , difficult to estimate the effect of testosterone on sexual function in association with any individual hormone treatment regimen
BACKGROUND : The value of adding testosterone to hormone therapy ( HT ) for the management of peri- and postmenopausal women is controversial and has not been systematic ally review ed .
OBJECTIVES : To determine the benefits and risks of testosterone therapy for peri- and postmenopausal women taking hormone therapy .