Emerging hormonal treatments for menopausal symptoms.

INTRODUCTION: The majority of women experience bothersome symptoms postmenopause (e.g., hot flushes, vaginal symptoms). Estrogen receptor agonists remain the most effective options for ameliorating menopausal symptoms. However, use of hormonal therapies has declined in the wake of issues raised by the Women's Health Initiative trials. As a result, there is a need for new safe and effective alternatives to estrogen-progestogen hormone therapy. AREAS COVERED: We review the efficacy and safety profile of hormonal menopausal therapies that are in Phase III clinical trials or recently approved. Investigational treatments discussed include two new vaginal estrogen products (TX-004HR, WC-3011); the first combination of estradiol and progesterone, and a novel combination of dehydroepiandrosterone and acolbifene. We also review a new selective estrogen receptor modulator (SERM), ospemifene, recently approved for treatment of dyspareunia related to menopause, and conjugated estrogens plus bazedoxifene, an estrogens/SERM combination, recently approved for moderate-to-severe vasomotor symptoms and prevention of osteoporosis. EXPERT OPINION: New and emerging hormonal treatments for managing menopausal symptoms may have improved safety and efficacy profiles compared with traditional estrogen-progestogen therapy; however, long-term safety data will be needed.

TX-001HR is associated with a clinically meaningful effect on severity of moderate to severe vasomotor symptoms in the REPLENISH trial.

OBJECTIVE: The aim of the study was to evaluate the clinically meaningful effect of oral TX-001HR (17ß-estradiol [E2]/progesterone [P4]) capsules on hot flushes severity (vasomotor symptoms [VMS] severity scale) using the patient-reported Clinical Global Impression (CGI). METHODS: REPLENISH (NCT01942668) was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial that evaluated TX-001HR in postmenopausal women (40-65 y) with a uterus. Those with frequent moderate to severe hot flushes (≥7/d or ≥50/wk) were randomized in a VMS substudy to daily E2/P4 (1/100, 0.5/100, 0.5/50, or 0.25/50 mg/mg), or placebo. Patients rated VMS severity from 1 (mild) to 3 (severe) and symptom improvements with the CGI. CGI results were an anchor in a nonparametric discriminant analysis to define clinically important differences (CIDs) and minimal CID in VMS severity at weeks 4 and 12. RESULTS: In the VMS substudy (n = 726), determined CID and minimal CID severity thresholds were reductions of 0.525 and 0.350 points at week 4, respectively, and 0.775 and 0.225 points at week 12. Significantly more women taking the two highest E2/P4 doses (1/100 and 0.5/100) versus placebo met CID severity thresholds at weeks 4 (40% and 44% vs 17%; P < 0.05) and 12 (56% and 48% vs 29%; P < 0.05). CONCLUSION: REPLENISH trial data demonstrated that E2/P4 1/100 and 0.5/100 provided clinically meaningful improvements in hot flushes severity in postmenopausal women. In conjunction with previously demonstrated clinically meaningful VMS frequency improvements, these data support oral E2/P4 1/100 and 0.5/100 for postmenopausal women with a uterus seeking treatment for moderate to severe VMS.

Endometrial safety and bleeding profile of a 17ß-estradiol/progesterone oral softgel capsule (TX-001HR).

OBJECTIVE: The aim of the study was to evaluate the effect of a single-capsule 17ß-estradiol/progesterone (E2/P4), TX-001HR, on endometrial safety, to report on amenorrhea and bleeding patterns of users, and to identify predictors of amenorrhea. METHODS: The REPLENISH trial (NCT01942668) evaluated use of TX-001HR in menopausal women (40-65 y) with vasomotor symptoms (VMS) and a uterus. Women were randomized to daily E2/P4 (mg/mg: 1/100, 0.5/100, 0.5/50, or 0.25/50), or placebo for 12 months. Incidence rate of endometrial hyperplasia was calculated from endometrial biopsies conducted at screening and study completion. Women reported bleeding and spotting in daily diaries. The number of bleeding and/or spotting days and the proportion of women with no bleeding or amenorrhea were compared between treatment and placebo using the Fisher exact test. Predictors of cumulative amenorrhea were assessed by univariate analyses. RESULTS: Women (n = 1,835) who took at least one study dose comprised the safety population; 1,255 had baseline and 12-month biopsies and comprised the endometrial safety population. Incidence of endometrial hyperplasia was ≤0.36% with any dose of TX-001HR after 1 year of use (one-sided upper 95% confidence interval ≤4%). Cumulative amenorrhea (no bleeding/spotting) rates increased over time and were relatively high from cycle 1 to 13 with TX-001HR (56%-73%; placebo 79%; P < 0.05 except with 0.25/50 dose). Few vaginal bleeding adverse events (1.0%-4.6% TX-001HR vs 0.7% placebo) were reported and discontinuations due to bleeding were low (0.4%-1.4% vs 0%). Cumulative amenorrhea was significantly more frequent in older women, those further from their last menstrual period, and those with lower baseline E2 concentrations (all; P < 0.01). CONCLUSIONS: All doses of TX-001HR provided endometrial protection and were associated with an improved bleeding profile over time; older age, further last menstrual period, or lower baseline E2 may predict amenorrhea with TX-001HR.

Physical characteristics and properties of estradiol softgel vaginal inserts.

OBJECTIVE: TX-004HR is a low-dose estradiol (E2) softgel vaginal insert designed to be rapidly dissolving and mucoadhesive. This report describes the physical attributes and pharmacokinetic parameters of the softgel vaginal insert evaluated for the treatment of moderate to severe dyspareunia due to menopausal vulvar and vaginal atrophy. METHODS: In vitro dissolution studies with 25-µg E2 inserts were performed and media samples were analyzed for E2 by high-performance liquid chromatography. Effects of body position on E2 bioavailability were assessed in a phase 1, randomized trial of the 25-µg softgel capsule versus a reference product in which women remained supine after dosing (n = 16), and in a substudy (n = 16) in which women were ambulatory or seated after dosing. Estradiol C max, AUC0-24, and t max were measured by high-performance liquid chromatography-tandem mass spectroscopy. A phase 2, randomized study (n = 50) of 10-µg E2 versus placebo inserts assessed timing of capsule disintegration at days 1 and 15. RESULTS: In vitro testing detected more than 80% of E2 in the dissolution medium by 15 minutes (first time point measured). In the phase 1 studies, baseline-corrected E2 plasma levels were not significantly different regardless of supine versus ambulatory/seated position after dosing: C max, 24.1 versus 34.3 pg/mL; AUC0-24, 77.6 versus 93.7 h ·â€Špg/mL; and t max, 2.1 versus 1.9 hours, respectively. In the phase 2 study, no remnants of the softgel capsule were found at day 1 (6 hours) after dosing and day 15. Vaginal discharge was minimal (1/48 women; 2.1%). CONCLUSIONS: The presented data support rapid dissolution of the softgel capsule and similar E2 pharmacokinetic parameters regardless of body position after dosing.

A double-blind, randomly assigned, placebo-controlled study of desvenlafaxine efficacy and safety for the treatment of vasomotor symptoms associated with menopause.

OBJECTIVE: The objective of the study was to assess the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) for menopausal vasomotor symptoms. STUDY DESIGN: Postmenopausal women (n = 458) experiencing 50 or more moderate to severe hot flushes per week received desvenlafaxine 100 or 150 mg/d, with titration at therapy initiation, or placebo. Hot flush number and severity were assessed at weeks 4 and 12. Safety data were collected throughout the trial. RESULTS: Desvenlafaxine 100 and 150 mg/d significantly reduced the number of hot flushes compared with placebo at weeks 4 and 12 (all P < or = .012), achieving 65.4% and 66.6% reductions from baseline at week 12, respectively (placebo, 50.8%). Hot flush severity and number of nighttime awakenings were significantly reduced at both time points (all P < or = .048). Desvenlafaxine groups reported significantly more adverse events compared with placebo during week 1 only. No difference in discontinuations because of adverse events was observed. CONCLUSION: Desvenlafaxine is an effective nonhormonal treatment for menopausal hot flushes. Dose titration improves initial tolerability.

Desvenlafaxine for the treatment of vasomotor symptoms associated with menopause: a double-blind, randomized, placebo-controlled trial of efficacy and safety.

OBJECTIVE: The objective of the study was to assess the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) for the treatment of vasomotor symptoms. STUDY DESIGN: This was a 26 week, double-blind, placebo-controlled trial of 567 postmenopausal women (mean age, 53.7 years; time since natural menopause, 4.8 years) experiencing 50 or more hot flushes (HFs) per week, randomly assigned to desvenlafaxine (100 or 150 mg) or placebo. Change from baseline in average daily number of moderate to severe HFs and average daily HF severity were compared with placebo at weeks 4, 12, and 26. RESULTS: A significantly greater decrease from baseline in number of HFs occurred at weeks 4 and 12 with 100 and 150 mg desvenlafaxine compared with placebo (week 12 reductions: 60%, 66%, and 47%, respectively; all P < or = .002). Only the 150 mg dose showed significant improvement from baseline at 26 weeks compared with placebo (week 26 reductions: 61%, 69%, and 51%, respectively), although the study was not powered to demonstrate efficacy beyond the initial 12 weeks of therapy. The average daily severity decreased significantly more at weeks 4 and 12 with desvenlafaxine compared with placebo (all P < or = .002). Significantly more desvenlafaxine-treated subjects than placebo-treated subjects discontinued because of adverse events during week 1 only. CONCLUSION: Desvenlafaxine is an effective treatment for menopausal HFs.

Estradiol and progesterone bioavailability for moderate to severe vasomotor symptom treatment and endometrial protection with the continuous-combined regimen of TX-001HR (oral estradiol and progesterone capsules).

OBJECTIVE: In the REPLENISH trial, women receiving TX-001HR-an oral, softgel capsule, combining 17ß-estradiol (E2) and progesterone (E2 mg/P4 mg 1/100, 0.5/100), had significantly improved vasomotor symptoms, while having their endometrium protected from hyperplasia. The objective here was to describe P4 levels sufficient to counteract the potential endometrial effects of 1 or 0.5 mg oral E2 with TX-001HR. METHODS: In REPLENISH (phase 3; NCT01942668), serum P4, E2, and estrone (E1) levels were characterized in postmenopausal women treated with TX-001HR (E2 mg/P4 mg: 1/100, 0.5/100, [0.5/50, 0.25/50 and placebo not reported here]) at baseline, week 12, and month 12 for P4, and at baseline, weeks 4 and 12, and months 6, 9, and 12 for E2 and E1. In a phase 1 study, pharmacokinetic parameters were assessed after 7 daily doses of oral E2 mg/P4 mg (1/100 and 0.5/100). RESULTS: In REPLENISH (n = 1,835), mean P4 levels were 0.39 to 0.55 ng/mL with 100-mg P4 doses; E2 levels were 42.3 to 45.6 pg/mL and 23.0 to 27.4 pg/mL for the 1-mg and 0.5-mg E2 doses, respectively; E1 levels were 214 to 242 pg/mL and 114 to 129 pg/mL for the 1-mg and 0.5-mg E2 doses. In the phase 1 study (n = 40; day 7), mean Cavg for P4 was 0.66 ng/mL with 100-mg P4 doses; E2 was 38.1 pg/mL and 29.2 pg/mL for 1 mg and 0.5 mg E2, respectively; and E1 was 211 and 106 pg/mL for 1 mg and 0.5 mg E2. All three analytes reached steady state within 7 days; accumulation ratios were 1.36 to 1.94. CONCLUSIONS: P4 levels observed with TX-001HR were similar in the phase 1 and 3 studies, and were associated with no endometrial hyperplasia with either E2 daily dose over 1 year in the REPLENISH phase 3 study, which showed significant improvements in menopausal vasomotor symptoms.

Tissue selective estrogen complex (TSEC): a review.

OBJECTIVE: This review describes historical development of selective estrogen receptor modulators (SERMs) and their combination with estrogens, termed a tissue selective estrogen complex (TSEC), and considers the potential for future TSEC development. METHODS: This narrative review is based on literature identified on PubMed and the TSEC research and development experience of the authors. RESULTS: SERMs have estrogenic and antiestrogenic effects in various tissues; however, no single agent has achieved an optimal balance of agonist and antagonist effects for the treatment of menopausal symptoms. Clinically, a number of SERMs protect against osteoporosis and breast cancer but can exacerbate vasomotor symptoms. Estrogens alleviate menopausal hot flushes and genitourinary symptoms as well as reduce bone loss, but the addition of a progestogen to menopausal hormone therapy to protect against endometrial cancer increases vaginal bleeding risk, breast tenderness, and potentially breast cancer. The search for an effective menopausal therapy with better tolerability led to the investigation of TSECs. Clinical development of a TSEC consisting of conjugated estrogens/bazedoxifene increased understanding of the importance of a careful consideration of the combination's components and their respective doses to balance safety and efficacy. Bazedoxifene is an estrogen receptor agonist in bone but an antagonist/degrader in the endometrium, which has contributed to its success as a TSEC component. Other oral TSEC combinations studied thus far have not demonstrated similar endometrial safety. CONCLUSIONS: Choice of SERM, selection of doses, and clinical trial data evaluating safety and efficacy are key to ensuring safety and adequate therapeutic effect of TSECs for addressing menopausal symptoms.

Initial investigation into the optimal dose ratio of conjugated estrogens and bazedoxifene: a double-blind, randomized, placebo-controlled phase 2 dose-finding study.

OBJECTIVE: The aim of the study was to explore dose-related endometrial effects of conjugated estrogens/bazedoxifene (CE/BZA). METHODS: In this randomized, double-blind, phase 2 study, 408 nonhysterectomized, symptomatic (with hot flushes [HFs]) postmenopausal women received ≥1 dose of CE 0.3 or 0.625 mg alone or with BZA 5, 10, or 20 mg/d; placebo; BZA 5 mg/d alone; or CE 0.625 mg with medroxyprogesterone acetate 2.5 mg/d for 84 days. The primary outcome was endometrial thickness on transvaginal ultrasound. HF frequency and severity based on diaries were key secondary outcomes. RESULTS: CE 0.625 mg alone increased endometrial thickness compared with placebo (mean 5.5 vs 2.95 mm, P < 0.001); BZA countered this in a dose-related manner such that average thickness with the addition of BZA 5, 10, and 20 mg was 5.99, 4.33, and 3.54 mm, respectively. On average, endometrium was significantly less thick with CE 0.625 mg/BZA 20 mg than CE 0.625 mg (P < 0.001) and CE 0.3 mg/BZA 20 mg versus CE 0.3 mg (2.94 vs 3.92 mm, P < 0.05); endometrial thickness was similar to placebo with CE 0.625 mg/BZA 20 mg. Lower BZA doses failed to reduce endometrial thickness relative to the same dose of CE alone. Regimens containing CE 0.625 mg reduced HF frequency and severity versus placebo; CE 0.3 mg with BZA 10 or 20 mg was ineffective. CONCLUSIONS: BZA ≥20 mg is needed to counter endometrial growth resulting from treatment with CE 0.3 or 0.625 mg. CE 0.3 mg inadequately controls HFs if given with BZA 20 mg.

Estradiol vaginal inserts (4 µg and 10 µg) for treating moderate to severe vulvar and vaginal atrophy: a review of phase 3 safety, efficacy and pharmacokinetic data.

OBJECTIVE: To review safety, efficacy and pharmacokinetic (PK) data from the phase 3 REJOICE trial, which evaluated a 17ß-estradiol (E2) softgel vaginal insert approved in 2018 for moderate to severe dyspareunia associated with menopausal vulvar and vaginal atrophy (VVA). METHODS: REJOICE (Clinicaltrials.gov: NCT02253173) was a randomized, double-blind, placebo-controlled trial in which women with moderate to severe dyspareunia due to menopausal VVA received 4 µg, 10 µg or 25 µg of an E2 vaginal insert or placebo for 12 weeks. The published data for the recently approved 4 µg and 10 µg doses of the E2 vaginal insert, including four co-primary efficacy endpoints (change from baseline to week 12 in percentages of superficial and parabasal cells, vaginal pH and severity of dyspareunia), safety and PK (which included serum E2 levels measured by gas chromatography and tandem mass spectrometry), are summarized here. RESULTS: Women were randomized to receive the E2 vaginal insert (4 µg [n = 186] or 10 µg [n = 188]; Imvexxy a ) or placebo (n = 187) in the modified intention-to-treat population. The E2 vaginal insert (4 µg and 10 µg) significantly improved the percentages of superficial and parabasal cells (p < .0001), vaginal pH (p < .0001), and the severity score for dyspareunia (p < .05) from baseline to week 12 compared with placebo. The recently approved E2 vaginal insert was well tolerated, with no clinically significant differences in treatment-emergent or serious adverse events versus placebo. Systemic absorption of E2 with both doses was minimal. CONCLUSIONS: The recently FDA-approved E2 softgel vaginal insert (4 µg and 10 µg) was safe and effective over 12 weeks for treating moderate to severe dyspareunia due to menopausal VVA with minimal systemic E2 levels.

A 17ß-Estradiol-Progesterone Oral Capsule for Vasomotor Symptoms in Postmenopausal Women: A Randomized Controlled Trial.

OBJECTIVE: To evaluate efficacy, endometrial safety, and overall safety of a single-capsule 17ß-estradiol-progesterone (TX-001HR) for treating menopausal moderate-to-severe vasomotor symptoms. METHODS: REPLENISH was a phase 3, 12-month, randomized, double-blind, placebo-controlled, multicenter trial. Women (aged 40-65 years) with vasomotor symptoms and a uterus were randomized to daily estradiol (mg)-progesterone (mg) (1/100, 0.5/100, 0.5/50, or 0.25/50), and women in the vasomotor symptoms substudy (women with moderate-to-severe hot flushes [seven or greater per day or 50 or greater per week]) to those estradiol-progesterone doses or placebo. The primary safety endpoint was endometrial hyperplasia incidence at 12 months in all women (the total population), and the primary efficacy endpoints were frequency and severity changes (from daily diaries) in moderate-to-severe vasomotor symptoms with estradiol-progesterone compared with placebo at weeks 4 and 12 in the vasomotor symptoms substudy. A sample size of 250 women in each active treatment arm with two or less endometrial hyperplasia cases would result in 1% or less annual incidence (upper bound 2.5% or less, one-sided 95% CI). RESULTS: One thousand eight hundred forty-five women were enrolled and randomized from August 2013 to October 2015; 1,835 received medication (safety population); 1,255 were eligible for the endometrial safety population; 726 comprised the vasomotor symptoms substudy; their mean age and body mass index were 55 years and 27, respectively; one third were African American. No endometrial hyperplasia was found. Frequency and severity of vasomotor symptoms significantly decreased from baseline with 1 mg estradiol and 100 mg progesterone and 0.5 mg estradiol and 100 mg progesterone compared with placebo at week 4 (frequency: by 40.6 and 35.1 points [1 mg and 100 mg and 0.5 mg and 100 mg, respectively] vs 26.4 points [placebo]; severity: by 0.48 and 0.51 vs 0.34 points) and week 12 (by 55.1 and 53.7 vs 40.2; severity: by 1.12 and 0.90 vs 0.56); 0.5 mg estradiol and 50 mg progesterone improved (P<.05) frequency and severity at week 12, and 0.25 mg estradiol and 50 mg progesterone frequency but not severity at weeks 4 and 12. CONCLUSION: No endometrial hyperplasia was observed while single-capsule estradiol-progesterone provided clinically meaningfully improvements in moderate-to-severe vasomotor symptoms. This estradiol-progesterone formulation may represent a new option, using naturally occurring hormones, for the estimated millions of women using nonregulatory-approved, compounded hormone therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01942668.

Body composition during treatment with conjugated estrogens with and without medroxyprogesterone acetate: analysis of the women's Health, Osteoporosis, Progestin, Estrogen (HOPE) trial.

OBJECTIVE: The objective of the study was to determine the effects of several doses of conjugated estrogens (CE) and CE plus medroxyprogesterone acetate (MPA) on body composition (BC). STUDY DESIGN: This was a randomized, double-blind, placebo-controlled substudy of the Women's Health, Osteoporosis, Progestin, Estrogen (HOPE) trial. Healthy women (n = 822, 1-4 years after menopause) were randomly assigned to receive the following treatments daily for 2 years: CE, 0.625 mg; CE, 0.625 mg, and MPA, 2.5 mg; CE, 0.45 mg; CE, 0.45 mg, and MPA, 2.5 mg; CE, 0.45 mg, and MPA, 1.5 mg; CE, 0.3 mg; CE, 0.3 mg, and MPA, 1.5 mg; or placebo. Body weight (BW) was assessed every 3-4 cycles and fat body mass (FBM), lean body mass (LBM), and percent body fat (PBF) at cycles 6, 13, 19, and 26. RESULTS: In the placebo group, BW, FBM, and PBF increased at each visit during the study. Changes in these parameters were smaller in the active groups. These effects were independent of CE dose and the presence of MPA. Changes in LBM were small and comparable across groups. CONCLUSION: Treatment with CE or CE and MPA for up to 2 years does not affect BC.

Do journals have a publication bias?

The timely publication of accurate and unbiased results of research is necessary to ensure that the knowledge gained is effectively shared with both the scientific community and the public. The ability to publish will be dependent not only on the significance of the findings, but also on the editorial staff of the journal and the peer review process. The manner in which the peer review process can be influenced by a journal's staff, as well as by the potential bias of reviewers, needs appreciation. Additionally, the routine practice of a journal providing copies of articles and press releases related to those articles in advance of the journal's publication and general availability requires evaluation.

Safety and benefit considerations for menopausal hormone therapy.

INTRODUCTION: While benefits and risks of hormone therapy (HT) have been shown in rigorous randomized, controlled trials, clinical use and further study have discovered effects of age, time of HT initiation, and differential effects of various regimens and administration routes on its safety profile. Areas covered: The safety of HT with regard to cardiovascular disease, thrombosis, the endometrium, the breast, and cognition was reviewed. Differential safety effects of estradiol versus conjugated equine estrogens, and progesterone versus synthetic progestins are reported. Expert opinion: Perceived safety of HT has evolved based on data from observational studies, the Women's Health Initiative and its subsequent analyses, more recent randomized, controlled trials, and studies examining the differences between different estrogens and between different progestogens. Unexpected safety concerns with HT became apparent with release of the first results from WHI. Differences between estrogen-alone versus estrogen-progestogen therapies, estradiol versus conjugated equine estrogens, and progesterone versus progestins were found in subsequent WHI analyses and studies examining components of various regimens. The decision to use HT depends on balancing risks and benefits for each individual and determining the most appropriate choice of therapy, dosing, and route of administration, while also considering the safety evidence of different estrogens and progestogens.