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Objective: This study aimed to evaluate improvement of dyspareunia and associated vaginal dryness with a 17β-estradiol softgel vaginal insert (TX-004HR; TherapeuticsMD, Boca Raton, FL, USA) in women with postmenopausal vulvar and vaginal atrophy (VVA). Methods: Postmenopausal women with VVA and moderate to severe dyspareunia received TX-004HR (4, 10, or 25 μg) or placebo in the 12-week, randomized, double-blind, placebo-controlled, phase 3 REJOICE trial. Post hoc analyses examined improvement levels in dyspareunia and concurrent vaginal dryness with TX-004HR and assessed the effects of patient characteristics on vaginal dryness treatment. Results: Significantly more women treated with TX-004HR (all doses) than placebo had complete resolution or substantial improvement in dyspareunia or vaginal dryness (concurrent with dyspareunia) by 12 weeks, observed as early as week 2 with most doses. TX-004HR significantly improved both dyspareunia and vaginal dryness at least one level versus placebo by week 12 in women with both symptoms. Subgroup analyses showed TX-004HR improved vaginal dryness associated with dyspareunia regardless of age, body mass index, uterine status, prior pregnancy, and vaginal birth number. Conclusion: TX-004HR provided clinically meaningful improvements in dyspareunia and vaginal dryness associated with dyspareunia in postmenopausal women with VVA. Clinicians may be able to use this information when discussing patients' expectations regarding symptom improvement with the estradiol vaginal insert.

Prior to 1996, the use of postmenopausal estrogen was not believed to increase the risk of venous thrombosis. Subsequent studies, particularly the prospective, randomized, double-blind, clinical trial of the Women's Health Initiative, have clearly shown an increase in the incidence and risk of venous thrombosis in postmenopausal women using conjugated equine estrogens with or without medroxyprogesterone acetate. The risk of venous thrombosis in postmenopausal women is also increased by obesity and age. Oral hormone therapy has been used principally for management of menopausal symptoms. Transdermal estrogens have not been used as extensively in the United States but have a significant use in Europe. Recent observational studies have indicated no increased risk of venous thrombosis with use of transdermal estrogens. Norpregnane derivatives have been associated with an increased risk of venous thrombosis, suggesting that progestins may contribute to the increased risk in postmenopausal women using estrogen plus progestin therapy.

Objective: Because the secretion of dehydroepiandrosterone (DHEA), the exclusive source of sex steroids in postmenopausal women, is already decreased by 60% and continues to decline at the time of menopause, the objective of this study was to examine the effect of intravaginal DHEA on the symptoms and signs of vaginal atrophy., Methods: This prospective, randomized, double-blind and placebo-controlled phase III clinical trial studied the effect of Prasterone (DHEA) applied locally in the vagina on the signs and symptoms of vaginal atrophy in 216 postmenopausal women., Results: All three doses (0.25%, 0.5%, and 1.0%) of DHEA ovules applied daily intravaginally induced a highly significant beneficial change in the percentage of vaginal parabasal and superficial cells and pH as well as in the most bothersome symptom at 2 weeks. At the standard 12-week time interval, 0.5% DHEA caused a 45.9 +/- 5.31 (P < 0.0001 vs placebo) decrease in the percentage of parabasal cells, a 6.8 +/- 1.29% (P < 0.0001) increase in superficial cells, a 1.3 +/- 0.13 unit (P < 0.0001) decrease in vaginal pH, and a 1.5 +/- 0.14 score unit (P < 0.0001) decrease in the severity of the most bothersome symptom. Similar changes were seen on vaginal secretions, color, epithelial surface thickness, and epithelial integrity. Comparable effects were observed at the 0.25% and 1.0% DHEA doses., Conclusions: Local Prasterone, through local androgen and estrogen formation, causes a rapid and efficient reversal of all the symptoms and signs of vaginal atrophy with no or minimal changes in serum steroids, which remain well within the normal postmenopausal range. This approach avoids the fear of systemic effects common to all presently available estrogen formulations and adds a novel physiological androgenic component to therapy.

Objective: The objective of this study was to provide evidence that the transformation of DHEA into both androgens and/or estrogens locally in cells of the three layers of the vagina (epithelium, lamina propria, and muscularis) would have effects of greater impact, including effects on sexual function, than only effects on superficial epithelial cells as achieved with estrogens., Methods: This prospective, randomized, double-blind, and placebo-controlled phase III clinical trial has evaluated the effect of daily local intravaginal application of Prasterone (dehydroepiandrosterone; DHEA) for 12 weeks on the domains of sexual dysfunction, namely, desire/interest, arousal, orgasm, and pain at sexual activity, in 216 postmenopausal women with moderate to severe symptoms of vaginal atrophy., Results: A time- and dose-dependent improvement of the four domains of sexual function was observed. At the 12-week time interval, the 1.0% DHEA dose led, compared with placebo, to 49% (P = 0.0061) and 23% (P = 0.0257) improvements of the desire domains in the Menopause Specific Quality of Life and Abbreviated Sex Function questionnaires, respectively. Compared with placebo, the Abbreviated Sex Function arousal/sensation domain was improved by 68% (P = 0.006), the arousal/lubrication domain by 39% (P = 0.0014), orgasm by 75% (P = 0.047), and dryness during intercourse by 57% (P = 0.0001)., Conclusions: By a local action in the vagina, DHEA applied daily at doses at which serum steroids remain well within normal postmenopausal values exerts relatively potent beneficial effects on all four aspects of sexual dysfunction. Such data indicate that combined androgenic/estrogenic stimulation in the three layers of the vagina exerts important beneficial effects on sexual function in women without systemic action on the brain and other extravaginal tissues.

Objective: Because a previous 1-week study has shown no or minimal changes in the serum levels of dehydroepiandrosterone (DHEA) and its metabolites after up to daily 1.8% (23.4 mg) intravaginal DHEA, the objective of the present study was to investigate the serum steroid levels during a 12-week daily intravaginal administration of 0%, 0.25%, 0.5%, and 1.0% DHEA (Prasterone) 1.3 mL ovules., Methods: In a double-blind, placebo-controlled phase III study, 218 postmenopausal women (age range, 42-74 y) were randomized to receive daily one of four DHEA concentrations intravaginally. Serum steroids were measured by a Good Laboratory Practice-validated mass spectrometry technology in samples obtained at time of visit., Results: The serum levels of DHEA and 11 of its metabolites measured at screening, day 1, and weeks 2, 4, 8, and 12 in women showed no or minimal changes during the whole observation period, with all values remaining well within the limits of normal postmenopausal women. No accumulation of the steroid metabolites nor change in DHEA bioavailability was detected., Conclusions: The present data show that local daily intravaginal DHEA administration at DHEA doses of 3.25-13 mg was able to rapidly and efficiently achieve correction of all the signs and symptoms of vaginal atrophy and improve sexual function and caused no or minimal changes in serum sex steroid levels, which all remain within the normal postmenopausal range, thus avoiding the risks of all estrogen formulations.

Objective: To evaluate the effect of two ultra-low-dose hormone treatments containing estradiol (E2) 0.5 mg and norethisterone acetate (NETA) 0.1 or 0.25 mg on the endometrium and bleeding., Methods: A prospective, randomized, placebo-controlled trial of 6 months. Local Ethics Committee approval and informed consent were obtained prior to initiation and enrollment. Out of 577 postmenopausal women randomized, 575 took E2/NETA 0.1 (n = 194), or E2/NETA 0.25 (n = 181) or placebo (n = 200). Endometrial bleeding was monitored by daily diary cards and endometrial thickness by transvaginal ultrasound at baseline and on completion. An endometrial biopsy was obtained when indicated clinically., Results: In months 1-6, the amenorrhea rates with E2/NETA 0.1 were 89%, 89%, 86%, 85%, 89% and 89%, respectively and the no-bleeding rates were correspondingly high: 95%, 94%, 93%, 90%, 95% and 95%. The amenorrhea and spotting-only rates were similar with both ultra-low-dose combinations. The withdrawal rates due to bleeding were very low and the same in all three treatment arms (n = 1; 1%). There was a slight increase in the mean endometrial thickness in all three groups, which remained less than 5 mm., Conclusions: The ultra-low-dose combination of E2/NETA 0.1 or E2/NETA 0.25 resulted in a high incidence of amenorrhea and no bleeding in postmenopausal women, and a corresponding high level of compliance. Overall, there was no significant change in mean endometrial thickness during 6 months of active treatment or placebo.

The efficacy of estrogen with or without a progestogen as hormone replacement therapy (HRT) for menopausal symptoms is well-established. Recent large-scale randomized studies with combined estrogen/progestogen therapy (EPT) have raised a number of safety issues, specifically the potential risk for coronary heart disease. Subsequent analyses and other studies have indicated that HRT may be cardioprotective in younger postmenopausal women. A new continuous EPT combines natural 17beta-estradiol (E2) 1 mg with the novel progestin, drospirenone (DRSP) either 0.5 or 2 mg. DRSP has a physiological profile closer to that of natural progesterone than any other synthetic progestin. This paper reviews recent clinical trial data demonstrating the efficacy and safety of combined DRSP/E2 therapy as EPT in postmenopausal women. DRSP/E2 provides symptomatic relief of vasomotor symptoms and improvement in genitourinary atrophy. DRSP/E2 protects against endometrial hyperplasia and reduces the risk of osteoporosis. Combined DRSP/E2 therapy has a favorable impact on cholesterol and triglyceride levels, and decreases blood pressure in women with elevated blood pressure. The favorable efficacy and safety profile of DRSP/E2, and potential for long-term health benefits, represents a new option for the effective management of menopause and its clinical sequelae.

Objectives: To systematically review methods used to report data on bleeding patterns among postmenopausal women enrolled in clinical trials of continuous combined hormone replacement therapy (HRT); and to propose the use of standardized terms, definitions, and methods for collecting and reporting bleeding data in such trials., Methods: A MEDLINE search identified 18 published reports of bleeding patterns among postmenopausal women enrolled in prospective clinical trials that included a continuous combined HRT treatment arm. Only two of these trials were not randomized. Methods for collecting and analyzing bleeding pattern data were collated from these published reports and examined for consistency., Results: Comparisons across studies revealed little consistency in definitions and indices utilized to report bleeding patterns among postmenopausal women administered continuous combined HRT regimens in clinical trials. While a majority of the trials incorporated definitions established by the World Health Organization for the evaluation of bleeding with hormonal contraception, a number of the studies expanded on these definitions to reflect additional dimensions of bleeding such as volume. Indices calculated from daily bleeding data to describe bleeding patterns in treatment groups were highly variable among studies., Conclusion: Inconsistencies among clinical trials in bleeding pattern definitions and indices limit understanding and comparison of typical bleeding patterns with continuous combined HRT regimens. Standardized definitions, data collection procedures, and indices are proposed to enhance understanding of bleeding patterns with hormone therapy and enrich the quality of patient counselling on HRT.

Objective: Women who have ever used estrogen replacement therapy (ERT), even at a low dose, have an increased incidence of endometrial cancer. The addition of a progestin to ERT reduces the incidence of endometrial cancer. The duration of progestin administration is more important than the dose., Design: A MEDLINE review of the literature was performed using the search terms endometrial cancer, epidemiology, and hormone replacement therapy (HRT)., Results: Women who have ever used ERT have an increased incidence of endometrial cancer. The use of HRT for more than 5 years, with a progestin use of <10 days per cycle, has a relative risk = 1.8. Continuous combined HRT, or sequential or cyclic HRT with >10 days of progestin per cycle, appears to decrease the incidence of endometrial cancer to that found in nonusers of HRT., Conclusions: The use of HRT in postmenopausal women with a uterus reduces the incidence of endometrial cancer. The duration of progestin administration should be 14 days or more per cycle based on recent epidemiologic data.

Objective: Compare transvaginal uterine ultrasound and endometrial biopsy in evaluating the endometrium of postmenopausal women who are taking estrogen replacement therapy (ERT) or hormone replacement therapy (HRT; estrogen and progestin)., Design: Prospective multicenter study done in the United States with 148 healthy women with an intact uterus. A total of 121 women used hormonal preparations prescribed by personal physicians. Continuous combined HRT regimens, nonoral forms of ERT or HRT, and intrauterine devices were not allowed for 3 months before the study began. Endometrial biopsy samples were taken within 3 days of transvaginal ultrasound measurement. The uterus was scanned transversely and longitudinally. Endometrial thickness was measured at the thickest part of the longitudinal plane., Results: Endometrial thickness ranged from 1.0 to 25.0 mm. The range in 126 women with a normal endometrium (determined by diagnoses of endometrial biopsies) was 1.0-25.0 mm (median, 5.0 mm); in 15 women with an abnormal endometrium, the range was 2.8-23.0 mm (median, 6.2 mm). A significant difference (p = 0.006) in endometrial thickness was seen between the 38 subjects taking ERT and HRT (median, 6.1 mm) with unexpected bleeding or spotting and the 26 untreated women in the control group (median, 4.0 mm). Overall, results were clinically inconclusive., Conclusions: Results of ultrasound as a screening technique in postmenopausal women who were taking ERT or HRT did not correlate well with results of endometrial biopsy. Unscheduled bleeding in postmenopausal women should be investigated regardless of results of ultrasonographically determined endometrial thickness. Abnormalities may be found with an endometrial thickness of less than 4 mm with or without HRT and even with no bleeding.

Objective: To investigate the incidence of uterine bleeding during 12 months of treatment with 17beta-estradiol (E2) 1 mg, unopposed or in combination with three doses of norethindrone acetate., Methods: This study was a prospective, double-masked, randomized, multicenter trial. A total of 1176 healthy postmenopausal women age 45 years and older without evidence of endometrial abnormalities were randomly assigned to receive either unopposed E2 1 mg, or continuous-combined formulations of E2 1 mg and norethindrone acetate 0.1 mg, 0.25 mg, or 0.5 mg. Any spotting or bleeding episodes during the treatment period were recorded in a daily diary and reported by weekly telephone calls., Results: The incidence of bleeding was low in the combination groups, even during the initial 3 months of treatment (24-28%), after which it decreased with increasing doses of norethindrone acetate. Conversely, the incidence of bleeding increased over time with unopposed E2 1 mg. After the initial 3 months, the incidence of bleeding among the combination groups was lowest in the norethindrone acetate 0.5 mg group. Among women initiating therapy close to menopause, fewer reported bleeding with norethindrone acetate 0.5 mg than with the other combination groups. There was a significantly (P<.05) lower discontinuation rate due to bleeding in the norethindrone acetate 0.5 mg group compared with all other treatment groups., Conclusion: Continuous-combined formulations of E2 1 mg with norethindrone acetate 0.1, 0.25, or 0.5 mg are associated with a low incidence of uterine bleeding. After the initial 3 months of treatment, bleeding profiles improved with increasing doses of norethindrone acetate.

Intrauterine devices (IUD) provide effective contraception. The current study evaluates the concentration of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in the intrauterine fluid of postmenopausal women using an intrauterine delivery system releasing progesterone (IDS-P). Intrauterine fluid was obtained by lavage, and IL-6 and TNF-alpha were analyzed using an enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed with a one-way analysis of variance (ANOVA). Intrauterine fluid IL-6 levels were 33.6 vs 6.09 pg/sample IDS-P vs no IDS-P (p = 0.0301). Intrauterine TNF-alpha levels for women using the IDS-P were higher than in nonusers, but the differences did not reach statistical significance. IL-6 and TNF-alpha levels were increased in the intrauterine cavity of postmenopausal women with an IDS-P. These data suggest that secreted cytokines could be a potential mechanism of IUD contraceptive efficacy.

Objective: We evaluated bleeding as a predictor of endometrial hyperplasia in postmenopausal women receiving conjugated estrogens (Premarin) alone or with medroxyprogesterone acetate., Study Design: This study was a retrospective assessment of bleeding and endometrial histologic data gathered during the prospective Menopause Study Group trial., Results: Approximately 20% of women (n = 57) who received unopposed conjugated estrogens for 1 year had endometrial hyperplasia. These women (n = 56) had more bleeding days than did women who did not have hyperplasia (p < 0.001). For users of unopposed conjugated estrogens, the predictive value of amenorrhea to indicate a nonhyperplasia diagnosis was 95%. Irregular bleeding did not appear to be indicative of hyperplasia when continuous or cyclic medroxyprogesterone acetate was added to conjugated estrogens., Conclusion: Unanticipated prolonged bleeding in postmenopausal women receiving unopposed estrogen is suggestive of endometrial hyperplasia. Some irregular bleeding is anticipated in women who receive conjugated estrogens plus medroxyprogesterone acetate as they acclimate to therapy, and this was not associated with hyperplasia.

Objective: To compare the bleeding patterns obtained with two continuous combined and two sequential regimens of conjugated estrogens with medroxyprogesterone acetate (MPA) and conjugated estrogens alone., Methods: This was a 1-year double-blind, randomized study done with 1724 postmenopausal women at 99 sites in the United States and Europe. All five treatment groups received 0.625 mg/day of conjugated estrogens. Groups A and B also took continuous daily doses of 2.5 and 5.0 mg of MPA, respectively. Groups C and D took 5.0 and 10.0 mg of MPA, respectively, for the last 14 days of each 28-day cycle. Group E took continuous daily doses of placebo to match MPA., Results: The two continuous combined regimens (A and B) produced amenorrhea in 61.4 and 72.8%, respectively, of all evaluable cycles. Generally, the incidence of amenorrhea increased and irregular bleeding decreased with longer duration of treatment. In addition, amenorrhea occurred for at least the last seven consecutive cycles of the treatment year for about 40% of the patients taking the lower-dose continuous combined regimen (A), about 50% of the patients taking the higher-dose continuous combined regimen (B), and about 50% of the patients taking conjugated estrogens alone. About 5% of the patients who took either of the sequential regimens (C or D) had amenorrhea during that time. Most of the cycles (81.3 and 77.0% in groups C and D, respectively) for patients taking the sequential conjugated estrogens-MPA regimens had regular withdrawal bleeding or withdrawal spotting. There was no bleeding or spotting in 75.5% of the cycles for patients who took conjugated estrogens alone., Conclusions: Approximately half of the women who took the continuous combined conjugated estrogens-MPA regimens had amenorrhea, and the incidence tended to increase during the study. Women who took the sequential regimens had good cycle control with minimal irregular bleeding. More than half of those who took conjugated estrogens alone had amenorrhea.

Uterine bleeding is a common reason why women discontinue menopausal hormone therapy (HT). This systematic review compared bleeding profiles reported in studies for continuous-combined HT approved in North America and Europe for moderate to severe vasomotor symptoms in postmenopausal women with a uterus. Non-head-to-head studies showed that uterine bleeding varies by formulation and administration route, with oral having a better bleeding profile than transdermal formulations. Cumulative amenorrhea over a year ranged from 18 to 61% with oral HT and from 9 to 27% with transdermal HT, as reported for continuous-combined HT containing 17β-estradiol (E2)/progesterone (P4) (56%), E2/norethisterone acetate (NETA) (49%), E2/drospirenone (45%), conjugated equine estrogens/medroxyprogesterone acetate (18–54%), ethinyl estradiol/NETA (31–61%), E2/levonorgestrel patch (16%), and E2/NETA patch (9–27%). Amenorrhea rates and the mean number of bleeding/spotting days improved over time. The oral E2/P4 combination was amongst those with lower bleeding rates and may be an appropriate alternative for millions of women seeking bioidentical HT and/or those who have bleeding concerns with other HT. [ABSTRACT FROM AUTHOR]

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The US Preventive Services Task Force (USPSTF) Draft Recommendation statement on Menopausal Hormone Therapy: Primary Prevention for Chronic Diseases, released in May 2017, perpetuates a major disconnect between the primary population affected, women within roughly 10 years of menopause, and the data cited. Furthermore, major elements of the evidence relied upon have been misinterpreted or misstated, particularly in regard to coronary heart disease and breast cancer, for which there is no statistically significant evidence of harm. As currently drafted, the recommendations reiterate the USPSTF statements of 2012, 2005 and 2002, and will perpetuate egregious harm to the public health. In an attempt to avoid that outcome and to facilitate a return to rational discourse regarding menopausal hormone therapy, an ad hoc group of experts in menopausal health submitted this comprehensive response to the USPSTF. [ABSTRACT FROM AUTHOR]

The article focuses on the 2013 International Menopause Society (IMS) recommendations on menopausal hormone therapy (MHT) and the strategies to maintain the health of middle-age women. Topics discussed include the lifestyle recommendations for peri- and postmenopausal women, the importance of MHT, and the prevention of postmenopausal osteoporosis.

Prior to 1996, the use of postmenopausal estrogen was not believed to increase the risk of venous thrombosis. Subsequent studies, particularly the prospective, randomized, double-blind, clinical trial of the Women's Health Initiative, have clearly shown an increase in the incidence and risk of venous thrombosis in postmenopausal women using conjugated equine estrogens with or without medroxyprogesterone acetate. The risk of venous thrombosis in postmenopausal women is also increased by obesity and age. Oral hormone therapy has been used principally for management of menopausal symptoms. Transdermal estrogens have not been used as extensively in the United States but have a significant use in Europe. Recent observational studies have indicated no increased risk of venous thrombosis with use of transdermal estrogens. Norpregnane derivatives have been associated with an increased risk of venous thrombosis, suggesting that progestins may contribute to the increased risk in postmenopausal women using estrogen plus progestin therapy. [ABSTRACT FROM AUTHOR]

Bazedoxifene (Conbriza®, Viviant®) is the first third-generation selective estrogen receptor modulator (SERM) and it is approved for the treatment of postmenopausal osteoporosis in the EU and Japan. Bazedoxifene contains an indole-based core binding domain that binds with high affinity to estrogen receptors and exhibits favourable effects on bone and lipid profiles, with no clinically relevant endometrial or breast stimulation. Oral bazedoxifene once daily reduced the incidence of new vertebral fractures in patients with postmenopausal osteoporosis in a large, well designed trial of 3 years' duration; both bazedoxifene and raloxifene were significantly more effective than placebo. Neither bazedoxifene nor raloxifene reduced the incidence of nonvertebral fractures in the overall study population; however, bazedoxifene, but not raloxifene, reduced the rate of nonvertebral fractures in high- risk patients. Moreover, data from patients who continued to receive the drug during a 2-year extension phase of this trial indicate that bazedoxifene continues to provide protection against new vertebral fractures for up to 5 years. Bazedoxifene also increases bone mineral density and reduces the levels of bone turnover markers. Bazedoxifene was generally well tolerated and did not detrimentally affect the reproductive tract or breast tissue in clinical trials, thereby demonstrating a favourable risk-benefit profile. A pharmacoeconomic analysis conducted from an EU perspective predicted bazedoxifene to be cost effective in some EU countries. Therefore, bazedoxifene presents another useful option for the treatment of postmenopausal osteoporosis, especially in those at high risk for osteoporotic fracture. [ABSTRACT FROM AUTHOR]