title: Early effects of continuous low-dosage all-norgestrel administered alone or with estrogen. Dose-response efficacy of a new estradiol transdermal matrix patch for 7-day application: a randomized, double-blind, placebo-controlled study The effect of hormone therapy on women's quality of life in the first year of the Estonian Postmenopausal Hormone Therapy trial Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. Estradiol and the addition of progesterone increase the sensitivity to a neurosteroid in postmenopausal women Ultra-low-dose estradiol and norethisterone acetate: effective menopausal symptom relief Low-dose estradiol for climacteric symptoms in Japanese women: a randomized, controlled trial Treatment of menopausal symptoms with three low-dose continuous sequential 17β-estradiol/progesterone parenteral monthly formulations using novel non-polymeric microsphere technology Efficacy on climacteric symptoms and safety of low dose estradiol transdermal matrix patches. A randomized, double-blind placebo-controlled study. A randomized, double-blind, placebo-controlled, crossover study on the effect of oral oestradiol on acute menopausal symptoms. Low and ultra low-dose estrogen therapy for climacteric symptom control--preliminary report. Micro-dose transdermal estradiol for relief of hot flushes in postmenopausal Asian women: a randomized controlled trial Vasomotor symptoms and quality of life in previously sedentary postmenopausal women randomised to physical activity or estrogen therapy. Suppression of vasomotor and vulvovaginal symptoms with continuous oral 17&bgr;‐estradiol Low-Dose Estradiol Spray to Treat Vasomotor Symptoms: A Randomized Controlled Trial Percutaneous 17&bgr;-estradiol gel for the treatment of vasomotor symptoms in postmenopausal women Efficacy of biorhythmic transdermal combined hormone treatment in relieving climacteric symptoms: a pilot study Clinical and endometrial effects of oestradiol and progesterone in post-menopausal women. Efficacy of pulsed estrogen therapy in relatively younger patients with surgically induced menopause. Bleeding pattern and climacteric symptoms during different sequential combined HRT regimens in current use. National use of postmenopausal hormone therapy: annual trends and response to recent evidence Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial Efficacy and tolerability of a new 7-day transdermal estradiol patch versus placebo in hysterectomized women with postmenopausal complaints. Efficacy and tolerability of a new estradiol delivering matrix patch (Estraderm MX) in postmenopausal women. Quality of life of postmenopausal women on a regimen of transdermal estradiol therapy: a double-blind placebo-controlled study. A short study in the treatment of hot flashes with buccal administration of 17-beta estradiol. Pulsed estrogen therapy improves postmenopausal quality of life: a 2-year placebo-controlled study. A prospective randomized comparative study of the effects of intranasal and transdermal 17 beta-estradiol on postmenopausal symptoms and vaginal cytology. Progestogens: therapeutic and adverse effects in early post-menopausal women. Comparison of transdermal to oral estradiol administration on hormonal and hepatic parameters in women with premature ovarian failure. A menopause-specific quality of life questionnaire: development and psychometric properties. Pulsed estrogen therapy in prevention of postmenopausal osteoporosis. A 2-year randomized, double blind, placebo-controlled study Low Dose of Transdermal Estradiol Gel for Treatment of Symptomatic Postmenopausal Women: A Randomized Controlled Trial Transdermal estradiol gel for the treatment of symptomatic postmenopausal women Clinical usefulness of a low-dose maintenance therapy with transdermal estradiol gel in Japanese women with estrogen deficiency symptoms Chlormadinone acetate versus micronized progesterone in the sequential combined hormone replacement therapy of the menopause. The effect of tibolone versus 17beta-estradiol on climacteric symptoms in women with surgical menopause: a randomized, cross-over study. Comparison of Alora estradiol matrix transdermal delivery system with oral conjugated equine estrogen therapy in relieving menopausal symptoms. Alora Study Group. Efficacy and safety of a seven-day, transdermal estradiol drug-delivery system: comparison with conjugated estrogens and placebo. The Transdermal Estradiol Patch Study Group. Clinical hypnosis in the treatment of postmenopausal hot flashes: a randomized controlled trial Effects of ultralow-dose transdermal estradiol on postmenopausal symptoms in women aged 60 to 80 years 17β-Estradiol and natural progesterone for menopausal hormone therapy: REPLENISH phase 3 study design of a combination capsule and evidence review. Randomized Comparison of Intranasal and Transdermal Estradiol A randomized, open-label, crossover study comparing the effects of oral versus transdermal estrogen therapy on serum androgens, thyroid hormones, and adrenal hormones in naturally menopausal women Effects and acceptability of a new 17 beta-oestradiol-releasing vaginal ring in the treatment of postmenopausal complaints. Efficacy and Local Tolerance of a Low‐Dose, 7‐Day Matrix Estradiol Transdermal System in the Treatment of Menopausal Vasomotor Symptoms Evidence-based review of therapies at the menopause. Preserved forearm endothelial responses with acute exposure to progesterone: A randomized cross-over trial of 17-beta estradiol, progesterone, and 17-beta estradiol with progesterone in healthy menopausal women. Estradiol in micellar nanoparticles: the efficacy and safety of a novel transdermal drug-delivery technology in the management of moderate to severe vasomotor symptoms Bioidentical compounded hormones: a pharmacokinetic evaluation in a randomized clinical trial. Vaginal ring delivering estradiol and progesterone: a possible alternative to relieve climacteric symptoms. Women and Menopause: Beliefs, Attitudes, and Behaviors. The North American Menopause Society 1997 Menopause Survey Quality of life and costs associated with micronized progesterone and medroxyprogesterone acetate in hormone replacement therapy for nonhysterectomized, postmenopausal women. Continuous versus cyclical transdermal estrogen replacement therapy in postmenopausal women: influence on climacteric symptoms, body weight and bleeding pattern. Climacteric symptoms after oral and percutaneous hormone replacement therapy. Percutaneous estradiol gel with an intrauterine levonorgestrel releasing device or natural progesterone in hormone replacement therapy. Effects of estrogen therapy on well-being in postmenopausal women without vasomotor complaints. Lowest Effective Transdermal 17β-Estradiol Dose for Relief of Hot Flushes in Postmenopausal Women: A Randomized Controlled Trial Efficacy and tolerability of Estraderm MX, a new estradiol matrix patch. Transdermal estradiol gel 0.1% for the treatment of vasomotor symptoms in postmenopausal women Beliefs about bioidentical hormone therapy: a cross-sectional survey of pharmacists.
abstract: Twenty-six postmenopausal women participated in a double-blind trial involving treatment according to a Latin square design with either ( i ) dl-norgestrel alone ( 0.075 mg/day ) continuously for two cycles , ( ii ) estradiol-17 beta alone ( 1 mg on 25 of 28 days ) for two cycles , or ( iii ) the combined hormones for six cycles . A placebo control cycle followed each hormonal treatment . Plasma triglycerides decreased by an average 22 % during treatment with either dl-norgestrel alone ( 123 + /- 11 vs. 160 + /- 10 mg/dl , n = 25 , P < 0.005 ) or combination therapy ( 126 + /- 11 vs. 162 + /- 11 , n = 25 , P < 0.005 ) as compared with control . Plasma total cholesterol fell by 5 % during two cycles of treatment with either dl-norgestrel alone ( 229 + /- 11 vs. 242 + /- 10 mg/dl , n = 25 , P < 0.02 ) or combination therapy ( 233 + /- 11 vs. 246 + /- 10 , n = 25 , P < 0.05 ) versus placebo . During the fifth and sixth cycles of combination therapy 94 % of cycles were free of flushing ( vs. 31 % for control , P < 0.01 ) , 64 % of cycles were free of spotting not requiring protection ( control 75 % ) , 96 % of cycles were free of vaginal bleeding ( control 100 % ) , endometrial biopsy showed inactive endometrium in nine of the 10 subjects re-biopsied , fasting blood pyruvate decreased by 20 % ( P < 0.05 ) and diastolic blood pressure fell by 4 % compared with control ( P < 0.05 ) , whereas glucose tolerance was unchanged . There was a significant reduction in vasomotor flushing beginning with the third to fourth cycles of combination therapy New estradiol ( E2 ) transdermal matrix patches developed for once-a-week application , releasing 25 μg E2 ( 7D-25 ) or 50 μg E2 ( 7D-50 ) daily , were investigated in comparison with a placebo patch and the twice-weekly parent patch releasing 50 μg E2 ( Derm-50 ) daily . Three hundred and eleven postmenopausal patients suffering at least seven hot flushes daily were r and omly assigned to the four parallel groups and treated continuously for 12 weeks without progestin opposition . The daily number of hot flushes significantly decreased in all groups . At the 12th week the decrease from a baseline average of eight to nine episodes per day was 78 % with 7D-25 , 93 % and 97 % respectively with 7D-50 and Derm-50 , and significantly ( p < 0.001 ) lower with placebo ( 59 % ) . Comparable efficacy was observed in terms of severity of hot flushes , Kupperman Index and patient self-rated overall efficacy . Minor systemic adverse events occurred in 10.0 % , 8.8 % , 16.9 % ) and 13.5 % patients in the placebo , 7D-25 , 7D-50 and Derm-50 groups respectively . Occasional mild and transient itching and /or erythema at the site of application was reported by a few patients , with no difference between groups or between once-weekly or twice-weekly application . In conclusion all E2 patches were significantly more effective than placebo in relieving climacteric symptoms in a dose-dependent fashion and all were well tolerated Background For postmenopausal women , the main reason to start hormone therapy ( HT ) is to reduce menopausal symptoms and to improve quality of life ( QOL ) . The aim of this study was to analyse the impact of HT on different aspects of symptom experience and QOL during a r and omised trial . A total of 1823 postmenopausal women were recruited into the Estonian Postmenopausal Hormone Therapy ( EPHT ) trial in 1999–2001 . Women were r and omised to blind HT , open-label HT , placebo or non-treatment arm . After one year in the trial , a question naire was mailed and 1359 women ( 75 % ) responded , 686 in the HT arms and 673 in the non-HT arms . Mean age at filling in the question naire was 59.8years . The question naire included Women 's Health Question naire ( WHQ ) to assess menopause specific QOL of middle-aged women together with a 17-item question naire on symptoms related to menopause , a question about painful intercourse , and a question about women 's self-rated health . Results After one year in the trial , fewer women in the HT arms reported hot flashes , trouble sleeping , and sweating on the symptom question naire . According to WHQ , women in the HT arms had fewer vasomotor symptoms , sleep problems , and problems with sexual behaviour , but more menstrual symptoms ;  HT had no effect on depression , somatic symptoms , memory , attractiveness , or anxiety . A smaller proportion of women reported painful intercourse in the HT arms . There were no significant differences between the trial arms in women ’s self-rated subjective health . Conclusions The results from the EPHT trial confirm that HT is not justified for treating symptoms , other than vasomotor symptoms , among postmenopausal women . WHQ proved to be a useful and sensitive tool to assess QOL in this age group of women OBJECTIVES We sought to compare the effects of estrogen/transvaginal progesterone gel with estrogen/medroxyprogesterone acetate ( MPA ) on exercise-induced myocardial ischemia in postmenopausal women with coronary artery disease or previous myocardial infa rct ion , or both . BACKGROUND Estrogen therapy beneficially affects exercise-induced myocardial ischemia in postmenopausal women ; however , women with an intact uterus also take progestin to protect against uterine malignancies . The effects of combination estrogen/progestin therapy on myocardial ischemia are unknown . METHODS Eighteen postmenopausal women ( mean + /- SD age 59+/-7 years ) were given 17-beta-estradiol in single-blinded manner for four weeks ( 1 mg/day for three weeks then 2 mg/day for one week ) . Estradiol ( 2 mg/day ) was then continued , and the patients were r and omized ( double-blind ) for 12 days to either transvaginal progesterone gel ( 90 mg on alternate days ) and oral MPA placebo ( 10 mg/day ) , or vice versa . After another two weeks on estradiol alone , the patients crossed over to progestin treatment and repeated the protocol on the opposite treatment . Patients underwent treadmill exercise testing after each estradiol phase and at day 10 of each progestin phase . RESULTS Exercise time to myocardial ischemia increased after the first estrogen phase as compared with baseline ( mean difference with 95 % confidence interval [ CI ] : 72 s [ 34 to 110 ] , p = 0.001 ) , and was increased by combination estradiol/progesterone therapy as compared with estradiol/MPA therapy ( 92 s [ 35 to 149 ] , p = 0.001 ) ) . Two patients ( 11 % ) were withdrawn while taking estradiol/MPA owing to unstable angina . CONCLUSIONS Combination estrogen/transvaginal progesterone gel increases exercise time to myocardial ischemia , as compared with estrogen/MPA . These results imply that the choice of progestin in women at higher cardiovascular risk requires careful consideration The aim of this study was to compare the pharmacodynamic response to a neuroactive steroid , pregnanolone , before and during different hormonal setting s of postmenopausal hormone replacement therapy ( HRT ) , using natural progesterone . A second aim was to investigate whether the response to pregnanolone was associated with cyclicity in negative mood symptoms during treatment . Twenty six postmenopausal women with climacteric symptoms were administered HRT in a r and omized , double blinded , placebo-controlled , crossover study . The women received 2 mg oral estradiol ( E(2 ) ) continuously during two 28-day cycles and 800 mg of vaginal progesterone or placebo sequentially for the last 14 days of each treatment cycle . Pharmacodynamic response to pregnanolone was assessed before treatment , and during the last week of each treatment cycle , by comparing the effects of intravenous pregnanolone ( 3alpha-hydroxy-5beta-pregnan-20-one ) on saccadic eye velocity ( SEV ) , saccade acceleration , saccade latency and self-rated sedation . Throughout the study daily symptom rating scales were kept . According to the daily symptom rating scales , patients were divided into two groups ; one group who displayed a significant variance in negative mood symptoms during HRT ( cyclicity ) and one group with no cyclical changes in negative mood symptoms during treatment . During treatment with either E(2 ) alone or E(2)+progesterone the response in saccadic eye movement parameters and in self-rated sedation to pregnanolone was enhanced compared to pretreatment values . The SEV , saccade acceleration and sedation responses to pregnanolone was also increased in women expressing cyclicity in negative mood symptoms compared to women with no cyclical changes in negative mood during HRT . In conclusion , during treatment with either E(2 ) alone , or E(2)+progesterone , pregnanolone  sensitivity was increased . Women expressing cyclicity in negative mood symptoms were more sensitive to pregnanolone than women without symptom cyclicity during HRT Objective To evaluate the efficacy of two ultra-low-dose 17β-estradiol plus norethisterone acetate ( NETA ) treatment regimens for relieving  menopausal symptoms . Design A total of 577 postmenopausal women were enrolled , in three treatment groups in a double-blind , r and omized , placebo-controlled study of 0.5 mg 17β-estradiol + 0.1 mg NETA or 0.5 mg 17β-estradiol + 0.25 mg NETA or placebo . Participants returned at weeks 4 , 8 , 12 and 24 for climacteric complaint evaluation based on a daily diary vasomotor symptom record . Patients were assessed by the Greene Climacteric Scale and urogenital symptoms were also evaluated . Results Treatment with ultra-low-dose 0.5 mg 17β-estradiol + 0.1 mg NETA ( 0.1 Group ) or 0.5 mg 17β-estradiol + 0.25 mg NETA ( 0.25 Group ) effectively reduced the severity and number of hot flushes within the initial weeks of therapy . Compared to placebo , a rapid , statistically significant decrease in the frequency and severity of hot flushes was achieved by week 3 , followed by further improvement which continued throughout the study . There were no statistically significant differences between the active treatment arms . Conclusions The data show that both ultra-low-dose regimens are effective in reducing the severity and number of hot flushes compared to placebo , with good safety profiles Objectives To investigate two different doses of oral estradiol to reduce the number of hot flushes in Japanese women with climacteric symptoms . Methods Women ( n = 211 ) aged 40–64 years who had experienced natural menopause or bilateral oophorectomy , with ≥ three moderate/severe hot flushes per day in the week before study , were r and omized to receive micronized estradiol ( E2 ) 0.5 or 1.0 mg or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change in mean daily number of hot flushes over 7 days from baseline to final examination . Results Percentage change in mean daily number of hot flushes at final examination was similar for E2 0.5 mg and E2 1.0 mg ( −79.58 ± 28.29 % vs. −82.49 ± 25.31 % , p = 0.555 ) but was significantly lower with placebo ( −57.89 ± 34.15 % , p < 0.001 vs. E2 , both doses ) . There was no significant difference in number of treatment-related adverse events occurring in the E2 0.5 and 1.0 mg groups ( 25 % and 36.6 % , respectively ) . The higher E2 dose showed more pronounced effects on symptom severity . Conclusions The dose of 0.5 mg/day was effective as the oral E2 starting dose for treatment of hot flushes in Japanese women Abstract Objective : To analyze the short-term efficacy and safety over menopausal symptoms of three low-dose continuous sequential 17β-estradiol (E)/progesterone ( P ) parental monthly formulations using novel non-polymeric microspheres . Methods : This was a multicenter , r and omized , single blinded study in which peri- and postmenopausal women were assigned to receive a monthly intramuscular injection of 0.5 mg E + 15 mg P ( Group A , n = 34 ) , 1 mg E + 20 mg P ( Group B , n = 24 ) or 1 mg E + 30 mg P ( Group C , n = 26 ) for 6 months . Primary efficacy endpoints included mean change in the frequency and severity of hot flushes and the effect over urogenital atrophy symptoms at 3 and 6 months . Safety variables included changes in the rate of amenorrhea , endometrial thickness and histopathology , and local and systemic adverse events . Results : Compared to baseline at month 6 , the three treatment schemes significantly decreased the rate of urogenital atrophy symptoms and the frequency ( mean number per day ) and severity ( mean number grade d as moderate and severe per month ) of hot flushes . No differences in studied efficacy parameters were observed between studied groups at baseline or at the end of the study . For all groups the most frequent adverse event was pain at the injection site ; however they were all rated as mild . At the end of the study peri- and postmenopausal women displayed no significant changes in endometrial thickness or histopathology in all treated groups . The rate of amenorrhea at the end of the study decreased for all studied groups yet was less evident among postmenopausal women as compared to perimenopausal ones . Conclusions : The three low-dose continuous sequential intramuscular monthly treatments of E/P using novel microsphere technology were effective at reducing menopausal symptoms at short-term with a low rate of adverse events . More long-term and comparative research is warranted to support our positive findings Two estradiol ( E2 ) transdermal patches releasing 25 micrograms/day E2 ( D-25 ) or 37.5 micrograms/day E2 ( D-37.5 ) were compared to a placebo patch on 156 patients in natural or surgical menopause suffering from at least 5 hot flushes per day , r and omly and blindly assigned to three parallel groups of 52 patients each , to be treated continuously for 12 weeks , without progestin opposition . " Responders " ( patients with less than 3 hot flushes per day at the end of treatment ) , were 82 % and 90 % under D-25 or D-37.5 , respectively , both significantly ( p < 0.001 ) more than under placebo ( 44 % ) . Comparable efficacy was observed on severity of hot flushes , Kupperman Index and on the self-rated efficacy . Systemic adverse events occurred in 10 % , 10 % and 8 % of patients , respectively , under D-25 , D-37.5 or placebo . Occasional mild and transient itching and /or erythema on the site of application was reported by few patients and did never require discontinuation of application . In conclusion D-25 and D-37.5 were significantly more effective than placebo in relieving climacteric symptoms and were systemically and locally as well tolerated as placebo . D-25 ( Demestril 25 ) releasing 25 micrograms/day E2 can therefore be recommended for low-dosed estrogen replacement therapy Acute menopausal symptoms occur less frequently in Asian than in Caucasian women .  Oestrogen replacement therapy has been shown to be effective in controlling acute symptoms in Caucasians , but the effect of oestrogens is not well documented in Asian women . A r and omized , double-blind , placebo-controlled , crossover study of the effect of oral oestradiol on the incidence of acute menopausal symptoms was conducted in 83 Hong Kong Chinese women who had experienced a surgical menopause . Although there was a significant increase in the oestradiol concentration with treatment compared with placebo ( P < 0.001 ) , there were no significant differences in the reporting of symptoms between the treatment and placebo groups . There is no obvious explanation for this apparent lack of effect of oestrogen on acute menopausal symptoms in Chinese women . Whilst it may be related to the generally low incidence of symptoms or to a higher dietary intake of phytoestrogens in Chinese women , further studies are necessary to explain these findings INTRODUCTION Recent clinical trials have caused physicians to reconsider the use of hormone therapy ( HT ) . Low-dose therapy has been proposed for those patients who tolerate st and ard doses poorly . OBJECTIVE to evaluate low-dose and ultra low-dose estrogen therapy ( ET ) for vasomotor symptom control . MATERIAL S AND METHOD Thirty five healthy postmenopausal women with moderate to severe climacteric symptoms were recruited . Symptoms were evaluated at baseline and three months after the beginning of treatment by a modified Kupperman 's index ( KI ) . Endometrial thickness was assessed with pelvic ultrasonography . Patients were r and omly assigned to one of these therapies : I ) Esterified conjugated estrogens ( ECE ) 0.156 mg/day ( ultra low-dose ) ( n = 18 ) or II ) ECE 0.312 mg/day ( low-dose ) ( n = 17 ) for 12 weeks . Statistical analysis was done with student 's t test for independent and paired sample s. RESULTS In groups I and II , the ab and on rate was 33.3 % and 47.0 % , respectively . No differences were found among the groups in general data nor in KI . The KI at the end of the study was 47.8+/-37.9 and 48.9+/-33.2 for group I and group II , respectively , for a mean decrease of 32.1 % and 37 % without differences between the groups . When comparing each group separately , KI decreased in group 1 , but without statistical significance . In group II there was significant decrease in KI . Endometrial thickness increased from 2.5+/-1.0 to 4.2+/-1.7 mm in group I , and from 3.5+/-1.3 to 6.0 + /-1.4 mm in group II . CONCLUSION low dose and ultra-low dose ET were useful in decreasing climacteric symptoms Objectives To compare the effect of micro-dose transdermal estradiol and placebo on the incidence and severity of menopausal symptoms and well-being in postmenopausal Asian women with vasomotor symptoms . Design Multicenter , double-blind , r and omized , placebo-controlled study . Results Of 165 subjects r and omized to estradiol 0.014 mg/day or placebo for 12 weeks , 80 per group were included in the analysis . Groups were comparable at baseline , although time since menopause was slightly shorter in the estradiol group . There was a greater reduction in mean weekly hot flushes at week 12 in the estradiol group ( 55 % ) than the placebo group ( 40 % ; p < 0.01 ) , which was evident by week 4 . A similar pattern was seen for moderate and severe hot flushes ( −58 % vs. −39 % , respectively ) . Reductions were statistically significant at weeks 4 , 8 , and 12 . Vaginal pH fell significantly in the estradiol group by week 4 and then remained stable throughout the treatment period , but there were no significant changes in the placebo group . Vaginal maturation value increased more in the estradiol than the placebo group ( p < 0.001 ) . Few subjects had vaginal bleeding or spotting . Quality of life improved similarly in both groups . Urogenital symptoms improved considerably from baseline in both treatment groups , with no significant differences . Eight subjects experienced treatment-related adverse events ( seven in the estradiol group ) . Conclusions In Asian women , micro-dose estradiol was significantly superior to placebo in improving vasomotor symptoms . The bleeding profile was comparable with that of placebo . Micro-dose estradiol was safe and well tolerated in Asian women OBJECTIVE To assess if regular physical exercise or oral oestradiol therapy decreased vasomotor symptoms and increased quality of life in previously sedentary postmenopausal women . SETTING A prospect i ve , r and omised trial at a University Hospital . METHODS 75 postmenopausal , sedentary women with vasomotor symptoms were r and omised to : exercise three-times weekly over 12 weeks ( 15 women ) , oral oestradiol therapy for 12 weeks ( 15 women ) and 45 women to three other treatment arms . Results from the exercise and oestradiol groups are presented here . The effects on vasomotor symptoms and wellbeing were assessed with logbooks and vali date d question naires . RESULTS Ten women fulfilled 12 weeks of exercise . The number of flushes was rather unchanged in five women and decreased to 28 % ( range 18 - 42 % ) of baseline in the other five women . Five of the ten women continued to exercise another 24 weeks , thus in all 36 weeks . The mean number of flushes decreased by about 50 % in these five women ( from 6.2/24 to 3.2 flushes/24 h at 36 weeks ) . In the same group a score made as the product of reduction in number and severity of flushes decreased by 92 % at 12 weeks , 75 % at 24 weeks and 72 % at 36 weeks compared with baseline . In the estrogen group flushes decreased from 8.4 to 0.8 ( P<0.001 ) after 12 weeks of therapy and remained at this level after 36 weeks . Well-being according to different measurements improved significantly in both groups , albeit more markedly in the estrogen group . CONCLUSIONS Apart from many other health benefits regular physical exercise may decrease vasomotor symptoms and increase quality of life in postmenopausal women , but this has to be further evaluated scientifically . Exercise should be introduced gradually to ensure compliance Objectives : To evaluate the efficacy and safety of different doses of 17&bgr;‐estradiol for the treatment of vasomotor and vulvovaginal symptoms . Design : This was a r and omized , double‐blind , multicenter , parallel‐group study . One hundred forty‐five subjects , including naturally postmenopausal women aged 40‐60 ( who had not experienced menses for at least 12 months ) , women who had undergone hysterectomy , and women aged 25‐60 who had undergone bilateral oophorectomy with or without hysterectomy were studied . Either placebo or 17&bgr;‐estradiol ( 1 mg or 0.5 mg ) was given orally every day for 12 weeks , and vasomotor symptoms and vaginal epithelial cytology were evaluated . Results : There were significant differences between placebo and the active treatments in the percentage change from baseline in the number of hot flushes ( all hot flushes , 1 mg vs. placebo , p < 0.001 ; 0.5 mg vs. placebo , p = 0.007 ) , with a more substantial proportion of subjects responding in the 1‐mg group ( mean change in mean number of hot flushes of 83.2 % ) . Both doses were also more effective than placebo in increasing the proportion of mature vaginal cells ( end‐of‐treatment mean values of 0 % , 78.5 % , and 21.5 % for parabasal , intermediate , and superficial cells , respectively , in the 1‐mg group ; mean values of 0.3 % , 80.8 % , and 18.9 % in the 0.5‐mg group ; and mean values of 15.2 % , 74.7 % , and 10.2 % in the placebo group ) . The proportion of subjects reporting no vaginal dryness was greatest in the 1‐mg group ( mean percentage of days without dryness of 86.1 % at weeks 9‐12 ) . Conclusions : For the relief of vasomotor and vulvovaginal symptoms , 17&bgr;‐estradiol 1 mg is effective and has an excellent safety profile . ( Menopause 2000;7:310‐317 . © 2000 , The North American Menopause Society . OBJECTIVE : To investigate the safety and efficacy of a transdermal estradiol ( E2 ) spray in women with postmenopausal vasomotor symptoms . METHOD : A r and omized , double-blind , placebo-controlled , multicenter , parallel-group clinical trial was conducted . Postmenopausal women ( N=454 ) with at least eight moderate-to-severe hot flushes per day applied daily , one , two , or three E2 ( 90 microliter spray contains 1.53 mg E2 ) or matching placebo sprays .  The primary efficacy endpoints were mean change from baseline in frequency and severity of moderate-to-severe hot flushes at weeks 4 and 12 . RESULTS : All three E2 groups showed a significant decrease in hot flushes at weeks 4 and 12 compared with their placebo groups ( P<.010 ) . The mean change in frequency at week 12 was eight fewer flushes per day for women in the E2 groups and between four and six fewer flushes for women in the placebo groups . Women in the three- and two-E2 spray groups demonstrated significant ( P<.050 ) reductions in severity score at weeks 4 and 12 ; women in the one-spray group showed significant reductions at week 5 . At week 12 , the majority ( 74–85 % ) of women on E2 showed at least a 50 % hot flush frequency reduction as compared with 46 % in the placebo group . The systemic E2 delivery rates at week 12 were approximately 0.021 mg/d , 0.029 mg/d , and 0.040 mg/d for the one- , two- , and three-spray doses , respectively . Common adverse events were similar to those previously reported with other transdermal products . Treatment-related application site reaction rate was similar to placebo ( 1.3 % compared with 1.8 % ) . CONCLUSION : The three dose levels of E2 spray achieved efficacy at 0.021–0.040 mg/d delivery rates . The spray is a well-tolerated , new , convenient method of delivering low-dose E2 transdermally . Clinical Trial Registration : Clinical Trials.gov , www . clinical trials.gov , NCT00122200 LEVEL OF EVIDENCE : Objective To determine the efficacy and tolerability of two strengths of percutaneous 17&bgr;-estradiol in a hydroalcoholic gel and placebo in controlling vasomotor symptoms of menopause . Design A total of 221 postmenopausal women were assigned r and omly to treatment with percutaneous 17&bgr;-estradiol gel 1.25 g ( containing 0.75 mg of estradiol ) or 2.5 g ( containing 1.5 mg of estradiol ) or placebo gel applied once daily for 12 weeks . The primary efficacy variable was the mean change from baseline in the frequency of moderate/severe hot flushes . In addition , the mean changes from baseline in the frequency and severity of all hot flushes were assessed . Safety and tolerability were evaluated from endometrial biopsy , adverse events , and laboratory tests . Results A significant reduction ( P < 0.05 ) in the mean frequency of moderate-to-severe hot flushes and mean frequency and severity of all hot flushes was observed with both 17&bgr;-estradiol gel groups compared with placebo . The mean number of moderate-to-severe hot flushes at the end of the study with 17&bgr;-estradiol gel 2.5 g , 17&bgr;-estradiol gel 1.25 g , and placebo gel was 2.0 , 2.8 and 5.2 , respectively . The overall incidence of adverse events was not significantly different among groups , though a higher incidence of estrogen-related adverse events was reported with the 17&bgr;-estradiol gel 2.5-g dose . Conclusions 17&bgr;-estradiol gel was effective and well tolerated for alleviating moderate-to-severe hot flushes in postmenopausal women . Therapy may be initiated with the 1.25-g dose with an increase to the 2.5-g dose if needed Objective : To evaluate the efficacy of a combination of bioidentical combined 17β-estradiol and progesterone transdermal delivery system ( lipophilic emulsion-type base ) to relieve  climacteric symptoms . The hormonal replacement was given during a period of 6 months at four different cyclic doses to mimic the normal ovary secretory pattern . Design : An open , r and omized , comparative , between-patient trial conducted over 6 months in 29 menopausal women with climacteric symptoms assessed with the Kupperman index at baseline and during treatments . Saliva and serum values of 17β-estradiol and progesterone were quantitated before treatment and after 3 and 6 months . Pharmacokinetic data following transdermal administration of 17β-estradiol ( 0.3 mg , daily ) and progesterone ( 100 mg , daily ) were calculated from saliva levels using high-performance liquid chromatography analysis . Results : Improvement in climacteric symptoms was reported in 93 % of women evaluated before and after 3 and 6 months of treatment . Values of saliva 17β-estradiol increased after 6 months from 0.6 ± 0.3 pg/mL to 14.1 ± 3.3 pg/mL , and the values of serum 17β-estradiol increased from 3.3 ± 2.8 pg/mL to 80.6 ± 21.9 pg/mL. Of responders , 88 % characterized symptom relief as complete . No adverse health-related events were attributed to the bioidentical hormone therapy . Time to maximum saliva concentrations ( Tmax ) , in all experimental cases , was observed after 6 hours . Baseline values were reached within 24 hours , indicating a diurnal rhythm of 17β-estradiol seen in normally cyclic women over the 24-hour period , ie , its daily biological rhythm . Conclusion : Percutaneous absorption of 17β-estradiol , as well as the absorption of progesterone , was associated with relief of climacteric symptoms . The cyclical transdermal delivery of combined bioidentical hormones may be advantageous because it mimics the secretory profiles of 17β-estradiol and progesterone in normally cyclic women over a 28-day period . Larger studies are needed to determine the long-term effects of our therapy This study reports the clinical effects in a group of post-menopausal women after 4 months of treatment with 2 mg micronized 17 beta-oestradiol ( E2 ) in combination with different doses of micronized progesterone ( 50 , 100 or 200 mg ) for 25 days each month . The 30 participants were divided into three groups . All of the subjects tolerated the preparation well and obtained relief from their climacteric complaints . None dropped out because of side effects and no changes were observed in blood pressure , weight or Papanicolaou cytology . Breakthrough bleeding was noted in the first cycle , mainly in the group receiving the lowest dose of progesterone . Endometrial biopsies performed before and after 4 months of treatment showed an atrophic endometrium in most of the women who received 100 mg progesterone and in all of the women on 200 mg progesterone . The results showed that this new combination of 2 mg E2 and micronized progesterone in different doses was both effective and well accepted BACKGROUND Pulsed estrogen therapy is a new approach in estrogen replacement therapy . We carried out a prospect i ve study to evaluate the efficacy of pulsed estrogen therapy in relatively younger patients with surgically induced menopause . METHODS Patients ( n=138 ) < 45 years old and suffering from severe vasomotor symptoms secondary to surgically induced menopause were included in the study . After the initiation of pulsed estrogen therapy ( 300 microg/day ) , the patients were re-evaluated every 4 weeks . The dose was increased at each follow-up , if necessary ( to a maximum of 600 microg/day ) . The patients who preferred another method after the first 12 weeks were prescribed oral conjugated estrogen ( 0.625 mg/day ) and at the end of the second 12 weeks their satisfaction levels were assessed . RESULTS At the end of the first 12 weeks , 26 patients were completely satisfied ( 18.8 % ) and 47 were moderately satisfied ( 34.1 % ) , whereas 65 concluded that the pulsed estrogen therapy they received was ineffective ( 47.1 % ) . At the end of the second 12 weeks , all the patients were completely satisfied . CONCLUSION Pulsed estrogen therapy for 12 weeks reduced the frequency of hot flushes in relatively younger patients with surgically induced menopause ; however , 81.2 % of patients were not completely satisfied at the end of this period Four sequential combined oestrogen and progestogen regimens were compared in terms of bleeding pattern and relief of climacteric symptoms . Treatment was with either 2 mg 17 beta-oestradiol with 1 mg norethisterone acetate [ E2 + NETA ] ; 2 mg oestradiol valerate with 75 micrograms levonorgestrel [ E2V + LNG ] ; 2 mg oestradiol valerate with 10 mg medroxyprogesterone acetate [ E2V + MPA ] ; or 1.5 mg 17 beta-oestradiol with 150 micrograms desogestrel [ E2 + DG ] . A placebo-controlled study lasting 12 - 24 months was completed by 143 healthy early postmenopausal women .  Bleeding lengths were not substantially different ; in all regimens the majority of women were bleeding for 3 - 6 days . Bleeding onset showed differences when related to the 11th day of progestogen addition ; in the regimen with E2V + LNG , 21 % of the women women were bleeding before the 11th day of progestogen addition 26 % on , and 53 % after that day . In the regimen with E2V + MPA , 56 % of the women were bleeding before the 11th day , 28 % on , and 17 % after that day , whereas in the regimen with E2 + DG , 15 % of the women were bleeding before the 11th day , 5 % on , and 80 % after that day . All regimens reduced climacteric symptoms to the same extent . Breast tenderness occurred in all the regimens , except in the E2 + DG . Conclusively , the differences between the responses to treatment were not conspicuous . However , our data indicate that one regimen ( E2 + DG ) result ed in optimal bleeding control , optimal effect on climacteric symptoms , and no production of breast tenderness CONTEXT  Postmenopausal hormone therapy use increased dramatically during the past 2 decades because of a prevailing belief in its health benefits . Recent evidence from r and omized trials published in July 2002 demonstrated adverse cardiovascular disease events and other risks with hormone therapy in the form of oral estrogen combined with progestin . OBJECTIVE To describe patterns of hormone therapy use from 1995 until July 2003 , including the impact of recent evidence . DESIGN , SETTING , AND POPULATION Two data bases were used to describe national trends in  hormone therapy use from January 1995 to July 2003 . The National Prescription Audit data base provided data on the number of hormone therapy prescriptions filled by retail pharmacies and the National Disease and Therapeutic Index data base provided data on patient visits to office-based physicians during which hormone therapy was prescribed . MAIN OUTCOME MEASURES Annual number of hormone therapy prescriptions and characteristics of visits to physicians during which hormone therapy was prescribed . RESULTS Annual hormone therapy prescriptions increased from 58 million in 1995 to 90 million in 1999 , representing approximately 15 million women per year , then remained stable through June 2002 . Adoption of new oral estrogen/progestin combinations , primarily Prempro , accounted for most of this growth . Obstetrician/gynecologists provided more than 70 % of hormone therapy prescriptions , and more than one third of patients were older than 60 years . Following the publication of trial results in July 2002 ,  hormone therapy prescriptions declined in successive months . Relative to January-June 2002 , prescriptions from January-June 2003 declined by 66 % for Prempro and 33 % for Premarin . Small increases were observed in vaginal formulations and in new prescriptions for low-dose Premarin . If prescription rates observed through July 2003 remain stable , a decline to 57 million prescriptions for 2003 , similar to the rate in 1995 , is projected . CONCLUSIONS Clinical practice responded rapidly to recent evidence of harms associated with hormone therapy . Since July 2002 , many patients have discontinued hormone therapy or are tapering to lower doses 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 OBJECTIVES To investigate the efficacy and tolerability of a continuously applied 7-day-Estradiol patch ( Fem7 , Merck KGaA , Germany ) delivering 50 microg estradiol per day in the treatment of hysterectomized women with postmenopausal complaints compared with placebo . DESIGN A multicentre , r and omized , double-blind study with an initial screening phase ( phase I ) , a 3-month double-blind placebo-controlled phase ( phase II ) and a 3-month open follow-up phase ( phase III ) . METHODS 186 patients were r and omized for a 3-cycle  placebo-controlled  study followed by a 3-cycle open follow-up ( total duration ; 6 months ) . The changes in Kupperman Index ( primary efficacy variable ) , hot flushes and urogenital symptom score were studied from baseline to the end of the study . In addition , skin tolerability was assessed and patients were also asked to grade the subjective acceptance of therapy . RESULTS A reduction in Kupperman Index was observed in both groups , and at each cycle of the placebo-controlled treatment phase the 7-day-Estradiol patch was superior compared with placebo ( last value vs. baseline P = 0.0006 ) . From the second treatment week onwards a distinct difference was noted in the reduction of hot flushes from baseline between the 7-day-Estradiol patch group and the placebo group . The difference between the groups was statistically significant for each cycle and at the end of the controlled treatment phase ( mean weekly hot flush reduction at the end of the placebo-controlled treatment phase : -32.5 for the 7-day-Estradiol patch vs. -22.0 for placebo , P = 0.0025 ) . The efficacy of the 7-day-Estradiol patch within the application period did not show any difference between days 1 - 3 and 4 - 7 . Subjective acceptance of the 7-day-Estradiol patch was good and 72.4 % of patients who took active medication throughout the study were willing to consider continuing its use . CONCLUSIONS The 7-day-Estradiol patch is well tolerated and provides effective relief of moderate to severe vasomotor symptoms in hysterectomized women , with a rapid onset of action and 7-day duration of therapeutic effect . Although a placebo effect was observed , the 7-day-Estradiol patch significantly reduced hot flushes and other menopausal symptoms throughout the application period OBJECTIVE To examine the efficacy and tolerability of a new matrix patch delivering estradiol ( E2 Matrix ) at doses of 0.05 and 0.10 mg per day ( Estraderm MX 50 , 100 ) in the treatment of moderate to severe postmenopausal symptoms . METHODS A total of 254 postmenopausal women were r and omized to receive treatment with E2 Matrix 0.10 mg ( N = 86 ) , E2 Matrix 0.05 mg ( N = 82 ) , or placebo ( N = 86 ) in a double-blind , double-dummy fashion for a period of 12 weeks continuously . Patches were applied twice weekly to the buttocks with each patient wearing two patches at all times . The primary efficacy criterion was the difference from baseline of the mean number of moderate to severe hot flushes per 24 h during the last 2 weeks of treatment . Other efficacy variables included reduction in hot flushes at 4 and 8 weeks , reduction in daytime flushing and night sweats , and Kupperman Index at 4 , 8 , and 12 weeks . RESULTS E2 Matrix 0.10 and 0.05 mg were both significantly superior to placebo in reducing hot flushes per 24 h after 4 , 8 , and 12 weeks of treatment ( P < 0.001 ) . Also , for all other efficacy parameters studied , both dosage strengths of E2 Matrix were statistically significantly superior to placebo at all time points ( P < 0.001 ) . Local tolerability was good in both groups . A slight increase in estrogen related adverse effects ( breast tenderness , leukorrhoea ) was seen with the 0.10 mg patch . Adhesion of patches and compliance were good . Overall systemic tolerability was good in both treated groups . However , a 4.8 % overall incidence of endometrial hyperplasia was observed in patients with an intact uterus . CONCLUSIONS This new matrix patch offers an effective and well tolerated dosage form for delivery of 0.05 and 0.1 mg estradiol per day . It may be particularly suitable for those women who experience local sensitivity to alcohol-containing systems . In light of the observed hyperplasia after treatment in five patients , estrogen therapy should as yet be supplemented monthly with a progestogen in women with an intact uterus OBJECTIVE The effect of transdermal estradiol and placebo therapy on the quality of life of postmenopausal women was compared in a r and omized trial over 12 weeks . STUDY DESIGN Two hundred forty-two women were r and omized , and 223 were analyzed for efficacy ( n = 112 for estradiol and n = 111 for placebo ) . The quality of life was assessed by means of a battery of st and ard question naires . RESULTS Quality of life improved after both therapies , but health-related quality of life ( p = 0.0003 ) and well being ( p = 0.003 ) improved more after transdermal estradiol therapy than after placebo . This was also the case for all specific climacteric aspects , including sexual problems ( p < 0.0001 ) and dysfunction ( p = 0.01 ) , at comparison with placebo .  Self-rated symptom relief was more pronounced with estrogen therapy than with placebo ( p < 0.0001 ) . CONCLUSION It was concluded that estradiol therapy was superior to placebo in relieving symptoms and improving quality of life OBJECTIVE To assess the efficacy and safety of 17-beta estradiol buccal tablets in reducing hot flush frequency ( HFF ) in postmenopausal women . METHODS Estradiol buccal tablets containing 0.05 , 0.1 , 0.2 , or 0.4 mg or placebo were administered for 28 days to 99 postmenopausal women in a r and omized , double-blind study ; 19 premenopausal women were studied concurrently for comparison of laboratory data . Objective and subjective assessment s of HFF were obtained along with measures of  estradiol , estrone , follicle-stimulating hormone ( FSH ) , and luteinizing hormone ( LH ) . RESULTS Measurements of HFF revealed significant decreases from baseline in all estradiol groups ( P < 0.01 ) . In the 0.4 mg group , HFF decreased significantly compared to placebo ( P < 0.01 ) . All estradiol doses produced similar improvement in the vaginal maturation index . Mean serum estradiol levels increased as doses increased but were lower than in the premenopausal subjects . Mean serum FSH and LH levels decreased in all estradiol groups but not to the levels of the premenopausal subjects ; the greatest decrease occurred at the two highest estradiol doses . CONCLUSION A numerical dose-response relationship with hot flushes was seen in this pilot study comparing 0.05 , 0.1 , 0.2 , and 0.4 mg buccal estradiol . Only 0.4 mg 17-beta estradiol significantly reduced the occurrence of hot flushes compared to placebo 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 CONTEXT Investigating the adverse effects of oral hormone replacement therapy ( HRT ) , the clinical effectiveness of alternative combinations and route of administrations . AIM To compare the effects of intranasal and transdermal 17 beta-estradiol combined with vaginal progesterone on vasomotor symptoms and vaginal cytology . SETTING S AND DESIGN A 12-week , prospect i ve , r and omized comparative study was conducted between July 2005 and September 2006 . MATERIAL S AND METHODS Eighty postmenopausal women aged between 42 - 57 years , who had scores of > or = 1.7 on the menopause rating scale-I ( MRS-I ) items " 1 - 6 " , were r and omly assigned to receive intranasal ( 300 microg/day , n = 40 ) or transdermal ( 50 microg/day , n = 40 ) 17 beta-estradiol continuously . All patients also received a vaginal progesterone gel twice weekly . Vasomotor symptoms were evaluated at weeks 0 , 4 , 8 and 12 . Vaginal maturation index ( VMI ) was evaluated at weeks 0 and 12 of the study . STATISTICAL ANALYSES The Mann-Whitney U and the Wilcoxon tests were used . P < 0.05 was regarded as significant . RESULTS Thirty-two women in the intranasal and 29 women in the transdermal group completed the study . The total score of the MRS , the sum-scores of Factor 1 " HOT FLUSHES " and Factor 2 " PSYCHE " significantly decreased in both groups at week 4 . Factor 3 " ATROPHY " scores significantly decreased only in the transdermal group at week 12 . The VMI showed no changes within and between the two groups at the end of the study . CONCLUSION Intranasal and transdermal 17beta-estradiol combined with vaginal progesterone gel as a continuous HRT caused a similar decrease in vasomotor symptoms but did not have any significant effect on VMI after 12 weeks of treatment in this study population Progestogen treatment is associated with a number of subjective symptoms . In the present study , 148 healthy post-menopausal women suffering from mild climacteric symptoms were r and omly allocated to 12 weeks of treatment with ( a ) 2 mg oestradiol valerate combined with cyproterone acetate , medroxyprogesterone acetate or levonorgestrel ; ( b ) 1.5 mg 17 beta-oestradiol combined with desogestrel ; or ( c ) placebo .  Climacteric symptoms , Kupperman index scores and potential adverse progestogen effects were recorded before treatment and three times per month during therapy . All the hormone regimens had a rapid effect , reducing the severity of climacteric symptoms to about 30 % of the baseline values ( P less than 0.001 ) within one month . Hot flushes were reduced in severity and /or frequency by 76 100 % within 3 months ( P less than 0.001 ) . The regimens which included hydroxyprogesterone derivatives produced a transient increase in breast tenderness . Other recorded potential adverse progestogen effects showed no significant changes during the study . We concluded that the addition of progestogens ( whether 19-nortestosterone or hydroxyprogesterone derivatives ) does not produce significant side effects during combined hormone replacement therapy Five women with premature ovarian failure were studied in a r and omized cross-over design to compare the biochemical effects of transdermal to oral estradiol administration when used in doses appropriate for endometrial preparation in a donor oocyte program . Patients r and omly received increasing dosages of oral micronized or transdermal estradiol for 4 week , with progesterone added in the last 2 weeks , to mimic a normal hormonal cycle . Serum sample s were assayed throughout treatment and compared to those from normally cycling premenopausal controls . In general , serum estradiol remained within the normal range in both treatment groups , whereas peak serum estrone levels were 10-fold higher in the orally treated group than those in the transdermally treated group . Serum levels of sex hormone-binding globulin , thyroid binding globulin , and renin substrate were all significantly elevated by day 14 in the orally treated patients and unchanged in the transdermal subjects . While plasminogen was unaltered by either route of administration , antithrombin-III levels fell with both treatments . Changes in gonadotropin levels were similar in both groups , with suppression of FSH by the end of the simulated cycles , but not into the normal premenopausal range . In conclusion , both estrogen replacement regimens provided near-normal serum estradiol profiles . However , despite the relatively high doses necessary to mimic a hormonally normal cycle , the transdermal route did not significantly alter the hepatic parameters studied , suggesting that this route of administration may have less adverse hepatic effects OBJECTIVE To develop a condition-specific quality of life question naire for the menopause with documented psychometric properties , based on women 's experience . METHODS SUBJECTS Women 2 - 7 years post-menopause with a uterus and not currently on hormone replacement therapy . Question naire development : A list of 106 menopause symptoms was reduced using the importance score method . Replies to the item-reduction question naire from 88 women result ed in a 30-item question naire with four domains , vasomotor , physical , psychosocial and sexual , and a global quality of life question . Psychometric properties : A separate sample of 20 women was used to determine face validity , and a panel of experts was used to confirm content validity . Reliability , responsiveness and construct validity were determined within the context of a r and omized controlled trial . Construct validation involved comparison with the Neugarten and Kraines'Somatic , Psychosomatic and Psychologic subscales , the reported intensity of hot flushes , the General Well-Being Schedule , Channon and Ballinger 's Vaginal Symptoms Score and Libido Index , and the Life Satisfaction Index . RESULTS The face validity score was 4.7 out of a possible 5 . Content validity was confirmed . Test-retest reliability measures , using intraclass correlation coefficients were 0.81 , 0.79 , 0.70 and 0.55 for the physical , psychosocial , sexual domains and the quality of life question . The intraclass correlation coefficient for the vasomotor domain was 0.37 but there is evidence of systematic change . Discriminative construct validity showed correlation coefficients of 0.69 for the physical domain , 0.66 and 0.40 for the vasomotor domain , 0.65 and -0.71 for the psychosocial domain , 0.48 and 0.38 for the sexual domain , and 0.57 for the quality of life question . Evaluative construct validity showed correlation coefficients of 0.60 for the physical domain , 0.28 for the vasomotor domain , 0.55 and -0.54 for the psychosocial domain , 0.54 and 0.32 for the sexual domain , and 0.12 for the quality of life question . Responsiveness scores ranged from 0.78 to 1.34 . CONCLUSIONS The MENQOL ( Menopause-Specific Quality of Life ) question naire is a self-administered instrument which functions well in differentiating between women according to their quality of life and in measuring changes in their quality of life The aim of this study was to evaluate the efficacy of pulsed estrogen therapy ( intranasal 17β-estradiol ) in the prevention of  postmenopausal bone loss . A total of 386 women ( 40–65 years old ) , less than 5 years past menopause , were r and omized to intranasal placebo , 17β-estradiol 150 µg , or 300 µg daily for 2 years . Women with an intact uterus received micronised progesterone 200 mg per day , 14 days of each 28-day cycle . Women r and omised to placebo-treatment received placebo progesterone . The primary endpoints were changes in BMD at the spine ( L2–L4 ) and femoral neck . Secondary endpoints were changes in bone turnover markers : serum osteocalcin ( sOC ) as a marker of bone formation and urinary C-terminal telopeptides ( uCTX ) as a marker of bone resorption . BMD increased at all measured sites in women receiving active treatment in a dose-related manner , the difference compared to placebo being 5.2 % and 6.7 % at the spine , and 3.2 % and 4.7 % at the hip , respectively , with 150 μg and 300 μg ( P<0.001 ) . On the other h and , a decrease versus baseline of −3.2 % and −3.3 % at the spine and hip , respectively , was observed in women receiving placebo ( P<0.001 ) . In the patients with at least one risk factor for osteoporotic fracture , the difference between placebo and 150 μg or 300 µg was even higher at the spine ( 5.4 % and 7.4 % , respectively ) , and at the femoral neck ( 4.0 % and 5.2 % , respectively ) . Correspondingly , uCTX decreased from baseline by 39 % and 46 % , and sOC by 22 % and 27 % , in the 150 µg group and 300 µg group ( all P<0.001 versus placebo ) . A strong correlation was found between variations of bone turnover markers after 1 year and BMD after 2 years , emphasizing that bone markers can predict BMD response during hormonal treatment . Acceptability and general tolerance were good . This study demonstrates that pulsed estrogen therapy at the dose of 150 μg and 300-μg per day prevents bone loss in a dose-dependant manner at each site studied , and normalizes bone turnover markers to premenopausal levels OBJECTIVE : To investigate safety and efficacy and identify the lowest effective dose of a new transdermal estradiol ( E2 ) gel for relief of menopausal symptoms in a population of postmenopausal women . METHODS : This study was a r and omized , double-blind , placebo-controlled , multicenter , parallel-group study . Postmenopausal women with at least 60 hot flushes per week applied 0.87 g/d ( n=136 ) , 1.7 g/d ( n=142 ) , or 2.6 g/d ( n=69 ) E2 gel or placebo gel ( n=137 ) topically for 12 weeks . The changes from baseline in hot flush frequency and severity at 4 and 12 weeks and changes from baseline in vaginal atrophy symptoms at 12 weeks were examined . RESULTS : With increasing E2 doses , mean trough serum E2 increased from 17 to 29 pg/mL. By weeks 3–5 , E2 gel reduced moderate-to-severe hot flush rate by at least seven hot flushes per day ( P<.001 ) and reduced the severity score ( P<.01 ) . The numbers needed to treat for benefit for an 80 % and 100 % decrease in hot flush number were 3.2 and 6.3 for the 0.87-g/d group and 1.3 and 2.3 for the 2.6-g/d group . At week 12 , vaginal pH was more acidic and vaginal maturation index more mature compared with placebo ( P<.001 ) . The lowest dose improved most bothersome vulvovaginal atrophy symptoms ( P<.05 ) . Estradiol gel was well tolerated at the site of application and produced no unexpected adverse effects . The 0.87 g/d dose produced fewest adverse events . CONCLUSION : The 0.87 g/d dose of this new transdermal E2 gel , which delivers an estimated 0.0125 mg E2 daily , delivered the lowest effective dose for treatment of vasomotor symptoms and vulvovaginal atrophy in a population of postmenopausal women . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00391417 LEVEL OF EVIDENCE : Objective The aim of this study was to determine the efficacy , safety , and lowest practical dose of a transdermal estradiol gel in the treatment of symptomatic postmenopausal women . Methods Healthy postmenopausal women with seven or more moderate to severe hot flushes per day or 50 to 60 or more per week were r and omized to transdermal gel containing 1.5 mg ( n = 73 ) or 0.75 mg ( n = 75 ) estradiol ( EstroGel 0.06 % ) or placebo ( n = 73 ) in a phase 3 study , or to 0.375 mg ( n = 119 ) or 0.27 mg ( n = 118 ) estradiol ( 0.03 % gel ) or placebo ( n = 114 ) in a phase 4 study . Results The frequency of moderate to severe hot flushes and severity of all hot flushes significantly decreased versus placebo at weeks 4 and 12 with 1.5 , 0.75 , and 0.375 mg estradiol . Overall participant responder rates were generally lower in the phase 4 study than those in the phase 3 study with the approved 0.75-mg estradiol dose . Vaginal maturation index ( VMI ) shifts from baseline to week 12 were significant ( P < 0.001 ) with 0.75 and 1.5 mg estradiol versus placebo ;  VMI improved ( P < 0.001 ) , superficial cells increased ( P = 0.005 ) , and parabasal cells decreased ( P = 0.002 ) with 0.375 mg estradiol vs placebo but not with 0.27 mg estradiol . The most frequently reported treatment-emergent adverse events , although not necessarily treatment related , were headache , infection , breast pain , and nausea ( phase 3 study ) and insomnia and headache ( phase 4 study ) . No serious adverse events were related to treatment ; no deaths occurred . Conclusion A transdermal gel with 0.75 mg estradiol was the lowest practical dose that effectively reduced the frequency and severity of moderate to severe hot flushes , improved VMI , and was well tolerated ABSTRACT Objectives To determine the efficacy and safety of low-dose maintenance therapy with transdermal estradiol ( E2 ) gel in Japanese women with climacteric disorder and estrogen deficiency symptoms . Methods Women ( n = 209 ) aged 37–59 years who had climacteric disorder or estrogen deficiency symptoms received a st and ard dose of transdermal E2 gel ( 1.8 g/day , containing E2 1.08 mg/day ) for 8 weeks as induction treatment . A total of 177 women in whom the number of daily hot flushes had decreased to less than one-third of the baseline value ( marked improvement ) at week 8 were double-blindly r and omized to receive low-dose E2 ( n = 88 , 0.9 g/day , containing E2 0.54 mg/day ) or E2-free placebo ( n = 89 ) for 16 weeks . Results Improvement rates in the number of daily hot flushes at the final evaluation ( primary endpoint ) in the low-dose E2 group ( marked 90.8 % , moderate 6.9 % , mild 1.1 % , no change 1.1 % , worsening 0 % ) were significantly greater than in the placebo group ( marked 77.0 % , moderate 10.3 % , mild 4.6 % , no change 2.3 % , worsening 5.7 % ) ( p = 0.0097 ) , showing an inhibitive effect on the flare-up of climacteric symptoms . The incidence of treatment-related adverse events in the low-dose group ( 21.6 % ) was similar to that in the placebo ( 22.5 % ) but was lower than that in the st and ard-dose treatment ( 32.5 % ) . Conclusions Low-dose maintenance therapy that was half the st and ard dose of transdermal E2 gel ( 0.9 g/day ) applied to women who had achieved marked improvement in the number of hot flushes at the st and ard dose ( 1.8 g/day ) was demonstrated to be effective ( inhibition of recurrence ) and safe for the treatment of climacteric disorder and estrogen deficiency symptoms OBJECTIVE The efficacy and safety of chlormadinone acetate ( CA ) versus micronized progesterone ( P ) were assessed in non-hysterectomized postmenopausal women . MATERIAL S AND METHODS This was a multicenter , r and omized , parallel group study with a 6-month double-blind period followed by a 12-month open period . Patients were r and omized to receive every month during 18 months percutaneous 17 beta-estradiol ( E(2 ) ) 1.5 mg/day from Day 1 to 24 of treatment cycle , combined from Day 11 to 24 to either CA 10 mg/day ( n=167 ) or P 200 mg/day ( n=169 ) .  Endometrial biopsy ( EB , main analysis criterion ) was performed at baseline , and at Day 18 - 24 of the 6th and 18th cycles . RESULTS At Month 6 , EB did not evidence any hyperplasia . EB were inadequate for assessment in 24.5 % and 47.5 % of patients in the CA and MP groups , respectively . CA was found to be as protective as P ( 96.3 % and 92.0 % of success ) . However , the hormonal status of the endometrium differed ( P<0.001 ) : a secretory endometrium was found in 81.5 % of the CA patients , compared to 50.7 % in the P group . These transformations result ed in predictable , cyclic bleeding in 94.5 % of the CA patients , compared to only 62.3 % of the P patients ( P=0.0001 ) . Unscheduled bleeding , spotting and /or metrorrhagia , were more frequent under P than under CA ( 17.9 % and 13.7 % , respectively ) . The beneficial effects on hot flushes were more important in the CA group than in the P ( P<0.001 ) . At Month 18 , the biopsy and clinical results were similar to those obtained at Month 6 . The safety profile , particularly the lipid one , was similar in both groups , except for drowsiness and dizziness , which were significantly more frequent under P than under CA . CONCLUSION The progestative effects of CA on the endometrium and on menopause-related symptoms were at least as good as those of P. Moreover , CA result ed more often than P in secretory effects , and in satisfying bleeding patterns OBJECTIVE To compare the effectiveness of tibolone and 17beta-estradiol on climacteric symptoms , in a r and omized , single-blind , cross-over study in surgically menopausal women . MATERIAL AND METHODS Forty surgically menopausal women were divided r and omly into two groups . Group A received treatment with tibolone for 6 months , while group B received 17beta-estradiol . After 3 weeks washout period , treatment protocol s were exchanged for another 6 months . The climacteric symptoms were assessed with Greene Climacteric Scale at baseline , during washout and after the treatments . Statistical analysis was done with the Wilcoxon 's Sign Rank test . RESULTS Both treatments significantly improved the scores of all subscales with respect to baseline . However , the improvement in psychological , somatic and sexual subscales were significantly superior in the tibolone group compared with 17beta-estradiol group . Both treatments showed comparable improvements in the relief of vasomotor symptoms . CONCLUSION Our findings suggest that tibolone may improve mood , libido and somatic symptoms in surgically menopausal women to a greater extent than estrogen therapy alone OBJECTIVE To compare the efficacy of two strengths of an estradiol matrix transdermal delivery system with daily oral doses of conjugated equine estrogens in reducing the frequency of moderate-to-severe hot flushes in postmenopausal women . DESIGN The design of the study provided for the following treatment regimens : an estradiol transdermal delivery system ( Alora 0.05 or 0.1 mg/day ) administered twice weekly or oral doses of conjugated equine estrogens ( CEE 0.625 or 1.25 mg ) administered daily were given to 321 highly symptomatic postmenopausal women for 12 weeks following a r and omized , parallel-group , double-blind , double-dummy design . RESULTS Results indicate no statistically significant differences at any time point in mean frequency or mean percentage reduction in frequency of moderate-to-severe hot flushes between patients given Alora 0.1 mg/day and those receiving CEE 1.25 mg/day . Similarly , no significant differences were observed at any time in mean frequency of moderate-to-severe hot flushes between the Alora 0.05 mg/day and CEE 0.625 mg/day groups , although the group receiving CEE 0.625 mg/day exhibited a statistically greater percentage reduction than the Alora 0.05 mg/day group at weeks 3 , 4 and 8 . By week 12 , these two treatments were statistically indistinguishable . There were no serious or unexpected adverse events with the two transdermal systems and local skin tolerability was excellent . Other estrogenic effects such as restoration of vaginal cytology , breast tenderness and unexpected vaginal bleeding were comparable between transdermal and oral administration groups except for a lower incidence of bleeding in those women receiving the lower dose transdermal regimen OBJECTIVE To evaluate the efficacy and safety of a new , seven-day , transdermal estradiol system in healthy postmenopausal women with hot flushes . METHODS Two studies are described . In the first study , subjects were r and omized to treatment with a 0.05 mg/day estradiol patch , a 0.1 mg/day estradiol patch , or a placebo patch ; and in the second study , to treatment with either of the two estradiol patches or oral conjugated estrogens ( as Premarin ) 0.625 mg/day .  Efficacy was evaluated on the basis of diary entries recording hot-flush frequency and severity . Subjects ' and investigators ' global assessment s of treatment efficacy were recorded at follow-up visits . RESULTS In Study 1 , both the 0.05-mg and 0.1-mg estradiol patches were significantly more effective than placebo in reducing hot flushes and were associated with higher global assessment s. In Study 2 , all three active treatments produced a significant reduction in the number of hot flushes compared with base-line . There were no statistically significant between-group differences , although the response to the 0.1-mg estradiol patch was greater , and to the 0.05-mg estradiol patch less , than the response to conjugated estrogens . The patches were generally well tolerated . Skin irritation from the patch was the most common adverse experience in both studies . CONCLUSIONS The new , seven-day , transdermal system effectively and safely treats post-menopausal vasomotor symptoms Objective The use of estrogen and progesterone to manage vasomotor symptoms ( ie , hot flashes and night sweats ) has declined because of concerns about their risks , and there is an increased interest in alternate , effective , and low-risk treatments . This study reports the results of a r and omized controlled trial of clinical hypnosis for treating vasomotor symptoms among postmenopausal women . Methods This is a r and omized , single-blind , controlled , clinical trial involving 187 postmenopausal women reporting a minimum of seven hot flashes per day ( or at least 50 hot flashes a week ) at baseline between December 2008 and April 2012 . Eligible participants received five weekly sessions of either clinical hypnosis or structured-attention control . Primary outcomes were hot flash frequency ( subjectively and physiologically recorded ) and hot flash score assessed by daily diaries on weeks 2 to 6 and week 12 . Secondary outcomes included measures of hot flash – related daily interference , sleep quality , and treatment satisfaction . Results In a modified intent-to-treat analysis that included all r and omized participants who provided data , reported subjective hot flash frequency from baseline to week 12 showed a mean reduction of 55.82 ( 74.16 % ) hot flashes for the clinical hypnosis intervention versus a mean reduction of 12.89 ( 17.13 % ) hot flashes for controls ( P < 0.001 ; 95 % CI , 36.15 - 49.67 ) . The mean reduction in hot flash score was 18.83 ( 80.32 % ) for the clinical hypnosis intervention as compared with 3.53 ( 15.38 % ) for controls ( P < 0.001 ; 95 % CI , 12.60 - 17.54 ) . At 12-week follow-up , the mean reduction in physiologically monitored hot flashes was 5.92 ( 56.86 % ) for clinical hypnosis and 0.88 ( 9.94 % ) for controls ( P < 0.001 ; 95 % CI , 2.00 - 5.46 ) . Secondary outcomes were significantly improved compared with controls at 12-week follow-up : hot flash – related interference ( P < 0.001 ; 95 % CI , 2.74 - 4.02 ) , sleep quality ( P < 0.001 ; 95 % CI , 3.65 - 5.84 ) , and treatment satisfaction ( P < 0.001 ; 95 % CI , 7.79 - 8.59 ) . Conclusions Compared with structured-attention control , clinical hypnosis results in significant reductions in self-reported and physiologically measured hot flashes and hot flash scores in postmenopausal women Objective : To investigate the effect of ultralow-dose transdermal estradiol on postmenopausal symptoms and side effects in a cohort of largely asymptomatic postmenopausal women aged 60 to 80 years . Design : This secondary analysis used data from the UltraLow-dose Transdermal estRogen Assessment trial , a r and omized , placebo-controlled , double-blind trial in postmenopausal women to determine the skeletal effects and safety of ultralow-dose transdermal estradiol .  Four hundred seventeen postmenopausal women , aged 60 to 80 years , were r and omly assigned to receive either unopposed transdermal estradiol at 0.014 mg/d ( n = 208 ) or placebo ( n = 209 ) . Participants were queried at each clinic visit about postmenopausal symptoms and side effects purported to be associated with estrogen therapy using a st and ardized question naire . Results : At baseline , 16 % of women reported hot flashes , 32 % reported vaginal dryness , and 35 % reported trouble sleeping . Women who received ultralow-dose estradiol were no more likely to report improvement of hot flashes , vaginal dryness , or sleep difficulties than those who received placebo . Treatment with ultralow-dose estradiol did not cause breast tenderness , uterine bleeding , or other symptoms often attributed to estrogen , but vaginal discharge was more common in women who received estradiol compared with those who received placebo . Conclusion : In this population of older , largely asymptomatic women , ultralow-dose transdermal estradiol did not improve postmenopausal symptoms and did not cause side effects other than vaginal discharge . Further study is needed to determine whether this dose of transdermal estradiol is effective in treating symptoms of postmenopause in younger , more symptomatic women Several formulations combining estrogens and progestins for hormone therapy ( HT ) have been approved worldwide for the treatment of menopausal symptoms , yet recent data indicate a decline in their use and an increase in compounded bioidentical HT . Up to now , no single product combining natural 17β-estradiol and progesterone has been approved by the US Food and Drug Administration ( FDA ) or the European Medicines Agency ( EMA ) . A phase 3 trial ( REPLENISH ) is underway to study a novel oral formulation of solubilized 17β-estradiol and natural progesterone combined in a single gelatin capsule ( TX-001HR ; TherapeuticsMD , Inc , Boca Raton , FL ) for treating vasomotor symptoms ( VMS ) in postmenopausal women . The REPLENISH trial evaluates the efficacy and safety of TX-001HR ( 4 doses ) versus placebo for the reduction of moderate to severe VMS frequency and severity at 4 and 12 weeks and evaluates the endometrial safety of the combinations at 1 year . TX-001HR contains hormones that are molecularly identical to endogenous estradiol and progesterone and is intended as an option for women who prefer bioidentical hormones ; further , it does not contain peanut oil , a common allergen . The constituents of TX-001HR , in a pharmacokinetic report , showed similar bioavailability and safety compared with reference estradiol tablets and micronized progesterone capsules administered together . Published data suggest a safer profile of estradiol and natural progesterone compared with HT containing conjugated equine estrogens and progestins . This report summarizes the methodology of the REPLENISH trial and review s the evidence suggesting clinical differences between HT containing progesterone or progestins , and estradiol or conjugated equine estrogens Objective To compare the efficacy and patient acceptability of intranasal versus transdermal 17β-estradiol ( E2 ) delivery systems for postmenopausal symptoms . Methods Postmenopausal women were r and omly assigned to intranasal 17β-E2  , 300 μg daily ( n = 176 )  or transdermal 17β-E2 ( delivering 50 μg/day ) , two patches per week ( n = 185 ) for 12 weeks , followed by a 4-week period with the alternate treatment . Efficacy was compared between groups using the Kupperman Index and vasomotor symptoms at week 12 . Patient acceptability was compared by patient choice of administration route and by question naire at week 16 . Results Intranasal and transdermal therapy produced significant reductions in the Kupperman Index and in the occurrence of hot flushes and night sweats at week 12 . Alleviation of climacteric symptoms was statistically equivalent in the two treatment groups ( P < .001 ) . The difference between groups in the Kupperman Index score of −0.5 ± 0.9 ( 95 % confidence interval −2.3 , 1.3 ) was within the predetermined interval of equivalence . Both therapies were well tolerated with similar adverse event rates , except for moderate and severe mastalgia which was significantly less frequent with intranasal E2 ( 7.2 % ) than with the patch ( 15.5 % , P = .02 ) . Sixty-six percent of patients chose to continue the intranasal therapy and 34 % the transdermal therapy ( P < .001 ) . Satisfaction was greater with intranasal therapy at week 16 ( P < .001 ) . Conclusion Intranasal and transdermal estrogen delivery systems had equivalent efficacy and similar safety profiles . Intranasal therapy was the patients ' choice for long-term treatment Objective : To compare the changes induced by oral versus transdermal estrogen therapy on the total and free serum concentrations of testosterone ( T ) , thyroxine ( T4 ) , and cortisol ( C ) and the concentrations of their serum binding globulins sex hormone-binding globulin , thyroxine-binding globulin , and cortisol-binding globulin in naturally menopausal women . Design : R and omized , open-label , crossover . Interventions included a 6-week withdrawal from previous hormone therapy ( baseline ) , followed in r and omized order by 12 weeks of oral conjugated equine estrogens ( CEE ) ( 0.625 mg/d ) and 12 weeks of transdermal estradiol ( TD E2 ) ( 0.05 mg/d ) , with oral micronized progesterone ( 100 mg/d ) given continuously during both transdermal estrogen therapy regimens . Results : Twenty-seven women were enrolled in the study , and 25 completed both treatment periods . The mean(SD ) percentage changes from baseline of sex hormone-binding globulin , total T , and free T with oral CEE were + 132.1 % ( 74.5 % ) , + 16.4 % ( 43.8 % ) , and −32.7 % ( 25.9 % ) , respectively , versus + 12.0 % ( 25.1 % ) , + 1.2 % ( 43.7 % ) , and + 1.0 % ( 45.0 % ) with TD E2 . The mean ( SD ) percentage changes of thyroxine-binding globulin , total T4 , and free T4 with oral CEE were + 39.9 % ( 20.1 % ) , + 28.4 % ( 29.2 % ) , and −10.4 % ( 22.3 % ) , respectively , versus + 0.4 % ( 11.1 % ) , −0.7 % ( 16.5 % ) , and + 0.2 % ( 26.6 % ) with TD E2 . The mean ( SD ) percentage changes of cortisol-binding globulin , total C , and free C with oral CEE were + 18.0 % ( 19.5 % ) , + 29.2 % ( 46.3 % ) , and + 50.4 % ( 126.5 % ) , respectively , versus −2.2 % ( 11.3 % ) , −6.7 % ( 30.8 % ) , and + 1.8 % ( 77.1 % ) with TD E2 . Concentrations of all hormones and binding globulins were significantly different ( P ≤ 0.003 ) during administration of oral versus transdermal estrogen therapy , except for free T4 and free C. Conclusions : Compared with oral CEE , TD E2 exerts minimal effects on the total and free concentrations of T , T4 , and C and their binding proteins The treatment of postmenopausal symptoms was studied in 26 healthy women using a new synthetic rubber ( Kraton D 2109 ) vaginal ring containing 53 mg of 17 beta-oestradiol . All women were postmenopausal , at least 6 months after the last vaginal bleeding and suffering from daily hot flushes . The study was conducted in a double-blind placebo-controlled intrapatient cross-over fashion , and the study period was 6 months . The rings used give an initial in vitro release rate of 0.4 mg/E2 per day . The in vitro release rate decreases to about 0.2 mg/day after 20 days and levels off asymptotically to about 0.1 mg/day after 50 days . Serum E2 levels equivalent to the follicular phase of the normal menstrual cycle were measured after 1 month 's use , and serum E2 level stayed above postmenopausal levels throughout the study period . FSH was suppressed during use of the E2-releasing vaginal ring , while LH showed no statistically significant suppression in continued use . Postmenopausal complaints were recorded by Visual Analogue Scales ( VAS ) as judged by both the patient and the examining doctor ; all complaints had favourable outcomes during use of the E2-releasing vaginal ring without deterioration of symptoms during use of the placebo ring . No serious side-effects were encountered , and the possibility of managing all postmenopausal complaints with intravaginal oestrogen treatment is discussed Objective To determine the efficacy and local tolerance of a new matrix transdermal drug-delivery system that delivers 0.02 mg of 17β-estradiol ( E2 ) daily for 7 days for the relief of vasomotor symptoms . Methods A total of 324 surgically or naturally menopausal women , all with prior hysterectomy and moderate to severe vasomotor symptoms ( 56 - 140 hot flushes per week , with episodes of sweating , during a baseline observation period ) , participated in two independent , 12-week , r and omized , double-blind , placebo-controlled studies . After a 4-week , treatment-free period , each woman received a continuous regimen of either one E2 transdermal system , two E2 transdermal systems , or placebo transdermal system(s ) applied every week for 12 weeks . Efficacy was measured as reduction in hot flush frequency , determined from subject diaries . To measure local tolerance , skin irritation ( erythema and edema ) was objective ly and systematic ally evaluated under blue light after removal of the transdermal system(s ) . Serum E2 and estrone concentrations were determined in one of the studies during baseline and on days 1 , 9 , 30 , 58 , 79 , and 84 . Results Mean hot flush frequency decreased from 80 hot flushes per week at baseline to approximately 13 hot flushes per week ( 84 % decrease ) after 12 weeks of transdermal E2 treatment . Compared with placebo , the decrease in hot flush frequency was significant as early as weeks 2 and 3 , and was maintained through the end of the study . Few clinical ly significant skin reactions occurred , and only nine ( 3 % ) of the subjects withdrew because of a skin effect . After initial increase , serum E2 concentrations remained stable throughout the study , achieving values of approximately 20 and 40 pg/mL above baseline for one and two E2 transdermal systems , respectively . Conclusion The E2 transdermal system effectively reduced the frequency of moderate to severe vasomotor symptoms as early as the second week of therpy and was very well tolerated . The decrease in hot flush frequency was similar to that reported for oral and other transdermal estrogens , but at lower serum E2 concentrations . This result may be due to the stable E2 blood level achieved with this transdermal system Background and Objective The highest level of scientific evidence available for each therapy for menopausal symptoms was sought , for example , systematic review s of r and omised controlled trials ( RCTs ) . Results There is reasonable evidence that some symptoms are modified by lifestyle , for example , cessation of smoking , exercise , reduction of alcohol , diet and alleviation of psychosocial stress . No complementary medicine , for example , phytoestrogens , black cohosh , herbal or homeopathic medicines or complementary therapies , for example , acupuncture , yoga , chiropractic manipulation , reflexology or magnetic devices have a greater effect than the usual placebo effect seen in quality blinded RCTs . Some have potential side-effects . So-called ' bioidentical hormones ' have no evidence -base and potential for harm . None of the above therapies have evidence of efficacy and long-term safety . Selective serotonin and noradrenaline re-uptake inhibitors ameliorate vasomotor symptoms and sometimes menopausal depression better than placebo . The most effective therapy for menopausal ( oestrogen ) deficiency symptoms is oestrogen which is the main component of hormone replacement therapies ( HRT ) . Compared with placebo HRT is highly effective in relieving hot flushes , night sweats , dry vagina and dyspareunia . It also improved joint pains , sexuality and sleeplessness and reduced subsequent fractures in RCTs . The increased risk of oral HRT for thromboembolism is small around menopause , for those without thrombotic risk factors , and is not elevated with non-oral routes . Cardiovascular disease may be reduced when HRT is initiated near menopause . Breast cancer risk increases after several years with the use of oral HRT containing progestogens at an annual rate of 8/10 000 ( < 0.1 % ) . No increase in breast cancer risk was seen with oestrogen-only HRT Regularly menstruating women are relatively protected from cardiovascular disease . Epidemiological and endothelial function studies attribute this protection to estradiol ( E(2 ) ) , but both progesterone ( P ) and E(2 ) are normally present . A range of vascular effects of added progestins have been described , from neutral to detrimental , but the effects of P per se on endothelial function in humans have not been reported . We therefore investigated the acute effects of E(2 ) , P , and E(2 ) combined with P , on endothelium-dependent and -independent forearm blood flow responses . Using venous occlusion plethysmography , forearm blood flow ( FBF ) was measured during acute brachial artery infusions , achieving physiologic levels of 17-beta-E(2 ) , P , and 17-beta-E(2 ) with P in healthy menopausal women with no cardiovascular disease risk factors . Vehicle or hormones were infused , in r and om order , on 4 days , 1 week apart . Flow responses were measured during coinfusions of hormone with the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator sodium nitroprusside . Twenty-seven healthy menopausal women were studied , and all had normal baseline endothelial responses . Small ( approximately 15 % ) , statistically nonsignificant increases in endothelium-dependent flow responses were seen after all acute hormone treatments . No impairment in response was seen with P alone or in combination with 17-beta-E(2 ) . In healthy menopausal women without cardiovascular disease risk factors and without baseline defects in endothelial function , acute exposure to physiologic levels of 17-beta-E(2 ) , P , and 17-beta-E(2 ) with P produced equivalent endothelium-dependent responses . These data suggest that P does not have detrimental vascular effects in humans Objective : To assess the efficacy and safety of topical micellar nanoparticle estradiol emulsion ( MNPEE ; Estrasorb ; Novavax , Inc. , Malvern , PA ) in postmenopausal women with moderate to severe vasomotor symptoms . Design : A multicenter , r and omized , double-blind , placebo-controlled study was conducted in 200 postmenopausal women with seven or more moderate to severe hot flushes per day . The study consisted of a 3-week screening period followed by a 1-week placebo emulsion run-in period and a 12-week active or placebo treatment period . Women were r and omized ( 1:1 ) to receive MNPEE ( 3.45 g daily dose of emulsion containing 8.6 mg estradiol ) or matching placebo emulsion . The primary efficacy variable was the change from baseline in the frequency of moderate and severe hot flushes at weeks 4 and 12 . Adverse events were monitored throughout the trial . Results : Topical micellar nanoparticle estradiol emulsion was statistically significantly superior to placebo emulsion in reducing the mean frequency of moderate to severe vasomotor symptoms by week 3 ( P = 0.003 ) , with superiority to placebo maintained from weeks 4 to 12 ( P < 0.001 ) . At week 12 ( peak benefit ) , MNPEE reduced mean daily frequency of hot flush count by 11.1 ( P < 0.001 vs placebo ) . MNPEE significantly reduced mean symptom severity from weeks 4 to 12 ( P < 0.001 ) compared with placebo . At endpoint , mean serum concentrations of estradiol and estrone were 63 and 89 pg/mL , respectively , in the MNPEE group . The mean endpoint ratio of estradiol to estrone in these patients was 0.774 . MNPEE was safe and well tolerated . Conclusion : Once-daily application of 3.45 g of micellar nanoparticle estradiol emulsion containing 8.6 mg of estradiol was safe and effective in providing significant relief of vasomotor symptom frequency and severity in postmenopausal women OBJECTIVE Bioidentical compounded hormone therapy is popular among patients , but providers do not have pharmacokinetic information or dosing guidelines for these preparations . Our objective was to compare the pharmacokinetics of the commonly used compounded preparations with conventional hormonal preparations that are considered bioequivalent in practice . METHODS We conducted a r and omized , blinded , four-arm 16-day clinical trial of forty postmenopausal women assigned to one of three doses of a compounded estrogen cream ( Bi-est ( 80:20 ) ; 2.0 , 2.5 , or 3.0 mg)+compounded oral progesterone 100 mg , or to a conventional estradiol patch ( Vivelle-Dot ™ 0.05 mg)+Prometrium ™ 100 mg . Serum levels of estrone , estradiol , estriol , and progesterone were obtained at multiple time intervals during the first 24-h , and at steady-state . RESULTS Results were analyzable for 37/40 women .  Study medications were well tolerated . The AUC at 24h and at steady-state for estrogens remained consistently lower for all doses of Bi-est tested relative to the patch . The difference was statistically significant for Bi-est 2.0 mg ( AUC-estradiol=181 vs. 956 ; p<0.001 ) and 2.5 mg ( AUC-estradiol=286 vs. 917 ; p<0.001 ) . Estriol levels remained low in all study arms . Serum progesterone levels were comparable in conventional vs. compounded groups . CONCLUSIONS This pharmacokinetic trial showed that the currently used doses of compounded hormones yield lower levels of estrogen compared to the st and ard-dose estradiol patch . To find comparable doses , further studies are needed . This successfully conducted r and omized controlled study attests to the feasibility of using a similar design in the setting of a larger clinical trial BACKGROUND Relief of climacteric symptoms is currently the main role of hormone therapy . However , vaginal bleeding complicating this therapy is among the leading causes for its early discontinuation . OBJECTIVES To assess the effect of a vaginal ring delivering estradiol and progesterone in postmenopausal women and to determine whether continuous administration can relieve climacteric symptoms , produce an acceptable pattern of vaginal bleeding and control endometrial proliferation . METHODS Twenty-nine postmenopausal women with an intact uterus were studied . All had climacteric symptoms . The vaginal rings contained 0.36 g estradiol and either 3.6 g progesterone ( high dose progesterone ) or 1.8 g ( low dose progesterone ) , and were kept in place for 4 - 6 months . Serum progesterone , estradiol and estrone were measured and endometrial thickness determined . All women kept a daily diary of bleeding/spotting and completed a question naire on climacteric symptoms at monthly intervals . The low dose progesterone group comprised 14 women and the high dose progesterone group 15 women . RESULTS A total of 18 patients ( 9 in each group ) completed the study .  Mean levels of estradiol , estrone and progesterone were at their peak after 2 to 4 weeks . All rings were effective in alleviating vasomotor symptoms , although there was evidence of " escape from effect " in month 6 . Endometrial thickness increased in 6 of the 29 women but biopsy in each case showed no evidence of hyperplasia . Of the 18 women who completed the study , 5 had amenorrhea throughout , 7 had amenorrhea after 3 months , and the remainder had one or two bleeding episodes after 3 months . Therapy was discontinued in 11 women . CONCLUSIONS A vaginal ring delivering estradiol and progesterone controlled climacteric symptoms , prevented endometrial proliferation , and provided an acceptable bleeding pattern . It should be viewed as a possible alternative for short-term estrogen-progesterone therapy OBJECTIVE The main purpose in organizing this survey was to collect information relevant to The North American Menopause Society 's ( NAMS ) educational mission and to document women 's knowledge of , and attitudes toward , menopause . DESIGN During June-July 1997 , The Gallup Organization conducted 750 telephone interviews with a r and omly selected sample of women 45 - 60 years of age from across the United States . Women were asked about their sources of information on menopause , what changes in health they anticipated as a result of menopause , why they used hormone therapy , and their attitudes toward menopause as a natural or a medical event . RESULTS Women are more likely to believe that depression and irritability are associated with menopause than heart disease , but only a few associate menopause with an increasing vulnerability to either memory loss or Alzheimer 's disease . Relief of physical symptoms of menopause was mentioned as the reason for starting hormone therapy more often than to protect against osteoporosis ( 25 % relative to 15 % ) , or to prevent stroke or a heart attack ( 10 % ) , or to reduce the risk of developing Alzheimer 's disease ( 2 % ) . The single main source of women 's information on menopause was a health professional ( 49 % ) . The majority of women who were already menopausal or experiencing menstrual changes expressed an attitude toward menopause that was either neutral ( 42 % ) or positive ( 36 % ) . CONCLUSIONS Women are divided in their views of menopause , some seeing it as a medical condition requiring medical treatment , whereas others see it as a natural transition to be managed by " natural " means . Providing women with accurate , up-to- date information and enhancing communication between healthcare providers and menopausal women remain the challenges for NAMS BACKGROUND Because natural progesterone is poorly absorbed and rapidly metabolized , synthetic derivatives of progesterone , such as medroxyprogesterone acetate ( MPA ) , are used in combination with estrogen in hormone replacement therapy . A micronized form of natural progesterone is available that is readily absorbed and reaches peak serum concentrations from 1 to 4 hours after administration . OBJECTIVE The purpose of this study was to compare the quality of life ( QOL ) , menopausal symptoms , and costs associated with a natural micronized progesterone ( MP ) formulation versus MPA as add-on therapy to estrogen in hormone replacement for post-menopausal women . METHODS This prospect i ve , multicenter , r and omized , fixed-dose , open-label , parallel-group study enrolled postmenopausal , otherwise healthy , nonhysterectomized women 45 to 65 years of age who had been amenorrheic for > or = 6 months and exhibited symptoms of estrogen deficiency . All women received 0.625 mg conjugated equine estrogens on days 1 to 25 of a 30-day cycle ; on days 12 to 25 , women were r and omized to receive either MP 200 mg or MPA 5 mg ; patients were followed for 9 months . QOL , the primary end point , was measured at baseline and months 3 , 6 , and 9 using the 36-Item Short-Form Health Survey ( SF-36 ) , the Nottingham Health Profile ( NHP ) , and the condition-specific Women 's Health Question naire ( WHQ ) . Bleeding pattern , compliance , menopausal symptoms , and cost were evaluated as secondary end points . Costs ( in 1997 Canadian dollars ) were assessed from the societal perspective and included costs of study medication , hormone therapy monitoring , concomitant medication , outpatient re sources , out-of-pocket expenses , and patient and caregiver time loss . RESULTS A total of 182 women were enrolled ; 89 received MP and 93 received MPA . Improvements in climacteric symptoms were observed from baseline to month 9 for both treatments . Mean scores on all domains of the SF-36 at month 9 were greater than scores at baseline in both treatment groups but the increases were not statistically significant . All domains within the NHP and WHQ improved significantly over this period for both groups ( P < or = 0.008 ) . Only patients receiving MP showed specific improvements in the menstrual problems and cognitive domains of the WHQ . The difference in average 9-month cost per patient was not statistically significant , at Can 367 dollars + /- 120 dollars and Can 360 dollars + /- 369 dollars for patients receiving MP and MPA , respectively . CONCLUSIONS MP is a clinical ly effective , well-tolerated , and cost-comparable alternative to MPA OBJECTIVES To compare continuous and cyclical transdermal estrogen replacement therapy ( ERT ) with or without an oral progestogen regarding climacteric symptoms , body weight and bleeding pattern . METHODS A total of 2459 postmenopausal women were treated for three cycles of 28 days in an open , r and omized , parallel group multicenter study . Patients received an estrogen matrix patch ( 50 micrograms 17/beta-estradiol/day ) twice weekly , either continuously ( eight patches/cycle ) or cyclically ( six patches/cycle , i.e. 3 weeks on , 1 week off ) . A total of 1232 patients were treated continuously and 1227 cyclically . In the study group 1150 patients had an intact uterus ( 543 in the continuous and 607 in the cyclical treatment arm ) and received , in addition to the estrogen patch , an oral progestogen in a transformation dose for 12 days of each cycle . Hysterectomized patients totaling 1309 ( 689 in the continuous versus 620 in the cyclical group ) did not receive progestogen . Of the 2459 patients , 771 ( 31.4 % ) participated in a follow-up study with two further treatment cycles , which was offered to the patients at the end of the main study . The main outcome measures were climacteric symptoms , measured at the end of cycles 1 - 3 by a Visual Analogue Scale at baseline , and body weight measured at baseline at the end of cycles 3 and 5 . In addition , the bleeding time per cycle ( days ) was evaluated in all patients with an intact uterus . RESULTS Continuous and cyclical transdermal ERT reduced , over three treatment cycles , the average climacteric symptom score by 1.77 and 1.70 , respectively . The percentage remission and improvement rates for the ten climacteric symptoms ranged between 69.3 and 88.0 % and did not differ between the two groups . In patients with a higher symptom score at baseline , the continuous treatment was slightly more effective . However , this effect was statistically not significant . After three treatment cycles body weight increased in both treatment groups by between 500 and 700 g. Further treatment during the follow-up study induced an additional average weight gain of 200 - 400 g. These results were not influenced by the addition of an oral progestogen . In patients with an intact uterus , the average bleeding time at the end of the first cycle ( 5.4 days in the continuous versus 5.3 days in the cyclical group ) increased slightly during cycle 2 and returned to baseline values at the end of cycle 3 . CONCLUSIONS Continuous and cyclical transdermal ERT were equally effective in reducing climacteric symptoms . The short term use of five cycles transdermal ERT induced a slight increase in body weight which was independent of the treatment regimen . These results were not influenced by the type and mode of administration of a progestogen . Both ERT regimens were very well tolerated and are suitable alternatives for estrogen replacement therapy of postmenopausal women One hundred and ten ( 110 ) healthy early post-menopausal women with mild subjective vasomotor symptoms ( mean Kupperman index score 11 ) participated in a long-term , double-blind , placebo-controlled therapeutic trial . The effects of 2 hormone regimens were evaluated . Group I received percutaneous oestrogen therapy for 2 yr , opposed by oral micronized progesterone ( 200 mg ) during the second year , while Group II received oral 17 beta-oestradiol valerate together with cyproterone acetate ( CPA ) . The serum oestrogen concentrations differed markedly in the 2 treatment groups . In Group I the serum/oestrone/oestradiol ratio was 1 ( comparable to the pre-menopausal value ) , but in group II the ratio was greater than 5 . Despite the difference in the serum oestradiol and oestrone concentrations , the mean symptom scores were rapidly and similarly reduced in both treatment groups ( P less than 0.001 ) . They remained low throughout the study and were not significantly different from pre-menopausal values OBJECTIVE To evaluate the bleeding patterns and clinical compliance associated with postmenopausal amenorrhea-inducing forms of hormone replacement therapy using either percutaneous estradiol-gel and a levonorgestrel-releasing intrauterine device or an oral/vaginal natural progesterone . METHODS Sixty postmenopausal women with an intact uterus were followed over 12 months in this open , non-r and omised , parallel group study . All patients continuously received a gel containing 1.5 mg of estradiol daily . The women were divided into three groups on the basis of progestin administration . Twenty women ( group I ) had a levonorgestrel-releasing device ( LNG-IUD ) inserted at the beginning of the study . Twenty-one women ( group II ) received oral natural micronised progesterone ( oral P ) 100 mg daily during 25 calendar days each month , and 19 women ( group III ) used vaginal natural micronised progesterone ( vaginal P ) 100 - 200 mg daily during 25 calendar days each month ( higher dose if spotting occurred ) . Clinic visits were at 0 , 3 , 6 and 12 months . Bleeding patterns were recorded by the patient in a diary and clinical compliance was evaluated at control visits during the treatment . Symptoms were recorded using a modified Kuppermann index . The serum estradiol concentration was determined at the 0 , 6 and 12 month control visits . RESULTS 80 % ( n = 16 ) of the patients in the LNG-IUD group , 67 % ( n = 14 ) in the oral P group II and 53 % ( n = 10 ) in the vaginal P group were without bleeding at 12 months . Spotting was common during the first 3 months . Symptom relief was good in each group . The LNG-IUD did not cause any serious side-effects . Compliance was good for LNG-IUD and oral progesterone but not for vaginal progesterone . CONCLUSIONS Percutaneous estradiol-gel associated with LNG-IUD is an appropriate method of hormone replacement therapy . The combination of oral natural progesterone with estradiol-gel is also useful , although bleeding episodes complicated the treatment in one third of the patients . The vaginal administration of natural progesterone was impractical due to bleeding disorders OBJECTIVE To establish whether estrogen treatment affects well-being in postmenopausal women without current or previous vasomotor symptoms . DESIGN Forty postmenopausal women , aged 45 - 59 years , without current or previous vasomotor complaints , were included . They were r and omized to masked treatment with either transdermal 17beta-estradiol 50 microg/24 h or to placebo . At baseline and after 12 and 14 weeks of treatment , the women completed a question naire which reflects well-being , the Psychological General Well-Being ( PGWB ) Index . RESULTS The women scored high on the PGWB Index , both at baseline and after 12 and 14 weeks of treatment . There was no significant difference in well-being according to PGWB Index between the groups treated with estrogen and placebo , neither at baseline , nor after therapy . Furthermore , there was no difference in change during therapy between the treatment groups . CONCLUSION There is a gradual decline in estrogen during the climacteric , and it is controversial to which extent this affects women 's mental health . The PGWB scores in this study were high before therapy , reflecting that these women without previous or current vasomotor complaints represented a selected sample . Neither short-term estrogen treatment over 12 weeks nor addition with medroxyprogesterone acetate during 2 weeks improved well-being in postmenopausal women without vasomotor symptoms who had high well-being at baseline OBJECTIVE : To investigate the efficacy of micro-dose transdermal estrogen in relieving  menopausal vasomotor symptoms . METHODS : A r and omized , double-blind , placebo-controlled , multi-center trial . Healthy postmenopausal women with at least seven moderate or severe hot flushes per day for at least 1 week , or at least 50 per week , applied transdermal patches with a nominal delivery of 0.023 mg/d 17β-estradiol and 0.0075 mg/d levonorgestrel ( low-dose E2/levonorgestrel ; n=145 ) , 0.014 mg/d E2 ( micro-dose ; n=147 ) , or placebo ( n=133 ) for 12 weeks . The co primary efficacy variables were the mean changes from baseline in frequency and severity of moderate and severe hot flushes at the week 4 and 12 endpoints . RESULTS : At the week 12 endpoint , mean weekly frequencies of moderate and severe hot flushes were significantly reduced compared with placebo with low-dose E2/levonorgestrel ( −51.80 ; P<.001 ) and micro-dose E2 ( −38.46 ; P<.001 ) . Severity scores were also significantly reduced with both treatments compared with placebo . At week 12 endpoint , 41.3 % of women receiving micro-dose E2 were treatment responders ( 75 % or more reduction from baseline in hot flush frequency ; P=.003 compared with 24.2 % placebo ) . In this group , the mean reduction in moderate and severe hot flushes from baseline was approximately 50 % after 2 , 70 % after 4 , 90 % after 8 , and 95 % after 12 weeks . There were no differences between active treatments and placebo regarding adverse events . CONCLUSION : Micro-dose E2 ( 0.014 mg/d ) was clinical ly and statistically significantly more effective than placebo in reducing the number of moderate and severe hot flushes , with a 41 % responder rate , supporting the concept of the lowest effective dose . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00206622 LEVEL OF EVIDENCE : OBJECTIVES To assess the efficacy and tolerability of a new matrix patch delivering 0.05 mg estradiol per day ( Estraderm MX 50 ) in postmenopausal women with moderate to severe postmenopausal symptoms . METHODS A multicenter , double-blind , r and omized , between-patient , placebo controlled trial in 109 postmenopausal women was carried out . Patches were applied twice weekly for 12 weeks . Patients were assessed at 4 , 8 and 12 weeks of treatment . The primary efficacy variable was change from baseline in mean number of moderate to severe hot flushes ( including night sweats ) per 24 h during the last 2 weeks of treatment . Other variables included Kupperman Index , local and systemic tolerability . Plasma concentrations of estradiol ( E2 ) , estrone ( E1 ) and estrone sulfate ( E1S ) were determined before and after treatment . RESULTS Estraderm MX was significantly superior to placebo ( P < 0.001 ) in reducing mean number of moderate to severe hot flushes ( including night sweats ) per 24 h after 4 , 8 and 12 weeks of treatment . The estimate of treatment group differences after 12 weeks was 4.2 hot flushes ( 95 % confidence interval : 2.6 - 5.8 ) . Estraderm MX also significantly reduced Kupperman Index at all time points compared to placebo ( P < 0.001 ) . Estraderm MX induced increases in mean E2 , E1 and E1S plasma levels as expected ( E2 : baseline 2.7 pg/ml , 12 weeks 38.9 pg/ml ; E1 : baseline 18.8 pg/ml , 12 weeks 41.6 pg/ml ; E1S : baseline 235.6 pg/ml , 12 weeks 765.1 pg/ml ) . Overall rates of adverse experiences were similar for Estraderm MX and placebo . The number of patients reporting skin irritation was low and similar in both groups . CONCLUSIONS Estraderm MX 50 , a new matrix patch , offers an effective and well tolerated dosage form for transdermal delivery of 0.05 mg E2 per day Objective : The objective of this study was to evaluate the efficacy and safety of three doses of estradiol gel 0.1 % ( Divigel , a novel formulation consisting of 1 mg estradiol per 1 g transdermal gel ) to reduce the frequency and severity of vasomotor symptoms and signs of vulvar and vaginal atrophy associated with menopause . Design : A total of 488 postmenopausal women were evaluated in a 12-week study comparing placebo with estradiol gel 0.1 % at doses of 1.0 , 0.5 , and 0.25 mg/day , with estimated daily deliveries of 0.027 , 0.009 , and 0.003 mg of estradiol , respectively . Primary endpoints were the change from baseline in daily frequency and severity of moderate to severe vasomotor symptoms . Change from baseline in the signs of vulvar and vaginal atrophy ( vaginal pH and percentage of superficial cells ) was also assessed . Results : Treatment with estradiol gel 0.1 % showed statistically significant reductions in frequency and severity of vasomotor symptoms from baseline compared with placebo as early as Week 2 that were maintained throughout treatment . Signs of vulvar and vaginal atrophy were also significantly improved from baseline with all three doses of estradiol gel 0.1 % compared with placebo . Conclusions : Low-dose transdermal estradiol gel 0.1 % is an effective treatment for relief of vasomotor symptoms , as well as signs of vulvar and vaginal atrophy , associated with menopause . Estradiol gel 0.1 % offers multiple dosing options to individualize patient therapy , including the lowest available effective dose ( 0.25 mg estradiol , delivering 0.003 mg/d estradiol ) to treat the vasomotor symptoms of menopause OBJECTIVE The aim of this study was to assess pharmacists ' beliefs about bioidentical hormone therapy ( BHT ) and to identify factors influencing these beliefs . STUDY DESIGN This was a cross-sectional survey of pharmacists . An email invitation to participate in the online survey  was sent to a r and om sample of 2000 pharmacists in Alberta . The survey was accessible for a six-week period from May to July , 2011 . A 54-item question naire was used to capture knowledge and beliefs about , and confidence in BHT . Summary statistics and multivariate regression were used for analyses . RESULTS Overall , 401 pharmacists completed the survey ( response rate 20 % ) . Respondents were mainly female ( 64 % ) , above 30 years of age ( 81 % ) and in practice for more than 10 years ( 63 % ) . Only 35 % of respondents correctly classified BHT as including both compounding and commercial products . In regards to beliefs , 68 % of respondents agreed that BHT is as effective as non-bioidentical hormones for vasomotor symptoms , while 60 % agreed BHT had equal risk . Beliefs on estriol , progesterone , and saliva testing however , were more diverse with many " do not know " responses ( 40 % ) . In multivariate analysis , pharmacists who worked in pharmacies that compounded BHT were more likely to believe in BHT safety ( p<0.001 ) , and have greater confidence with BHT ( p<0.001 ) . CONCLUSIONS Results from this survey indicated that pharmacists had varying beliefs on BHT . In addition , beliefs on the safety of BHT were associated with pharmacists ' practice , specifically working in a pharmacy that compounds BHT . This study helps identify areas for targeted education
target: Subgroup analysesSubgroup analyses by dose of BHT suggested that higher doses of BHT may be associated with more effectiveness but also higher risk of adverse effects .
  There was low to moderate quality evidence that BHT in various forms and doses is more effective than placebo for treating moderate to severe menopausal hot flushes .
  There was some evidence to suggest that higher doses of BHT are associated with greater effectiveness but also with higher risk of adverse effects .
  No data are yet available about the safety of BHT with regard to long-term outcomes such as heart attack , stroke and breast cancer .
background: BACKGROUND Various hormone therapies ( HT ) are available to treat  menopausal vasomotor symptoms .
  Bioidentical hormones are chemically identical to those produced by the human body , and several types are well-tested and available on prescription .
  Many women have opted for bioidentical hormone therapy ( BHT ) on the assumption that it is safer than other forms of HT .
  We evaluated the evidence .
  OBJECTIVES To determine the effectiveness and safety of bioidentical hormones compared to placebo or non-bioidentical hormones for the relief of vasomotor symptoms .