Oral lasofoxifene's effects on moderate to severe vaginal atrophy in postmenopausal women: two phase 3, randomized, controlled trials.

OBJECTIVE: The aim of this study was to demonstrate whether lasofoxifene improves vaginal signs/symptoms of genitourinary syndrome of menopause. METHODS: Two identical, phase 3 trials randomized postmenopausal women with moderate to severe vaginal symptoms to oral lasofoxifene 0.25 or 0.5 mg/d, or placebo, for 12 week. Changes from baseline to week 12 in most bothersome symptom, vaginal pH, and percentages of vaginal parabasal and superficial cells were evaluated. These coprimary endpoints were analyzed using analysis of covariance, except superficial cells, which were analyzed by the nonparametric, rank-based Kruskal-Wallis test. RESULTS: The two studies enrolled 444 and 445 women (mean age, ~60 y), respectively. Coprimary endpoints at week 12 improved with lasofoxifene 0.25 and 0.5 mg/d greater than with placebo ( P < 0.0125 for all). Study 1: most bothersome symptom (least square mean difference from placebo: -0.4 and -0.5 for 0.25 and 0.5 mg/d, respectively), vaginal pH (-0.65, -0.58), and vaginal superficial (5.2%, 5.4%), and parabasal (-39.9%, -34.9%) cells; study 2: most bothersome symptom (-0.4, -0.5), vaginal pH (-0.57, -0.67), and vaginal superficial (3.5%, 2.2%) and parabasal (-34.1%, -33.5%) cells. Some improvements occurred as early as week 2. Most treatment-emergent adverse events were mild or moderate and hot flushes were most frequently reported (lasofoxifene vs placebo: 13%-23% vs 9%-11%). Serious adverse events were infrequent and no deaths occurred. CONCLUSIONS: In two phase 3 trials, oral lasofoxifene 0.25 and 0.5 mg/d provided significant and clinically meaningful improvements in vaginal signs/symptoms with a favorable safety profile, suggesting beneficial effects of lasofoxifene on genitourinary syndrome of menopause.

A Contemporary View of Menopausal Hormone Therapy.

Enthusiasm for the use of hormones to ameliorate symptoms of perimenopause and menopause has waxed and waned over the years. Both treatment for symptoms and training of women's health care practitioners in the management of menopause have sharply declined since publication of the Women's Health Initiative initial results in 2002. Findings from that trial, which treated a population of older, asymptomatic patients, have been extrapolated over the past 21 years to all estrogen products, all menopausal women, and all delivery mechanisms. Our patients deserve a more nuanced, individualized approach. Conjugated equine estrogens and medroxyprogesterone acetate are no longer the predominant medications or medications of choice available for management of menopausal symptoms. All hormones are not equivalent any more than all antiseizure medications or all antihypertensives are equivalent; they have different pharmacodynamics, duration of action, and affinity for receptors, among other things, all of which translate to different risks and benefits. Consideration of treatment with the right formulation, at the right dose and time, and for the right patient will allow us to recommend safe, effective, and appropriate treatment for people with menopausal symptoms.

Efficacy, tolerability, and endometrial safety of ospemifene compared with current therapies for the treatment of vulvovaginal atrophy: a systematic literature review and network meta-analysis.

IMPORTANCE: Ospemifene is a novel selective estrogen receptor modulator developed for the treatment of moderate to severe postmenopausal vulvovaginal atrophy (VVA). OBJECTIVE: The aim of the study is to perform a systematic literature review (SLR) and network meta-analysis (NMA) to assess the efficacy and safety of ospemifene compared with other therapies used in the treatment of VVA in North America and Europe. EVIDENCE REVIEW: Electronic database searches were conducted in November 2021 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomized or nonrandomized controlled trials targeting postmenopausal women with moderate to severe dyspareunia and/or vaginal dryness and involving ospemifene or at least one VVA local treatment were considered. Efficacy data included changes from baseline in superficial and parabasal cells, vaginal pH, and the most bothersome symptom of vaginal dryness or dyspareunia, as required for regulatory approval. Endometrial outcomes were endometrial thickness and histologic classifications, including endometrial polyp, hyperplasia, and cancer. For efficacy and safety outcomes, a Bayesian NMA was performed. Endometrial outcomes were compared in descriptive analyses. FINDINGS: A total of 44 controlled trials met the eligibility criteria ( N = 12,637 participants). Network meta-analysis results showed that ospemifene was not statistically different from other active therapies in most efficacy and safety results. For all treatments, including ospemifene, the posttreatment endometrial thickness values (up to 52 wk of treatment) were under the recognized clinical threshold value of 4 mm for significant risk of endometrial pathology. Specifically, for women treated with ospemifene, endometrial thickness ranged between 2.1 and 2.3 mm at baseline and 2.5 and 3.2 mm after treatment. No cases of endometrial carcinoma or hyperplasia were observed in ospemifene trials, nor polyps with atypical hyperplasia or cancer after up to 52 weeks of treatment. CONCLUSIONS AND RELEVANCE: Ospemifene is an efficacious, well-tolerated, and safe therapeutic option for postmenopausal women with moderate to severe symptoms of VVA. Efficacy and safety outcomes with ospemifene are similar to other VVA therapies in North America and Europe.

Review of menopausal hormone therapy with estradiol and progesterone versus other estrogens and progestins.

Objective: The objective of the present document was to review/summarize reported outcomes compared between menopausal hormone therapy (MHT) containing estradiol (E2) versus other estrogens and MHT with progesterone (P4) versus progestins (defined as synthetic progestogens).Methods: PubMed and EMBASE were systematically searched through February 2021 for studies comparing oral E2 versus oral conjugated equine estrogens (CEE) or P4 versus progestins for endometrial outcomes, venous thromboembolism (VTE), cardiovascular outcomes, breast outcomes, cognition, and bone outcomes in postmenopausal women.Results: A total of 74 comparative publications were identified/summarized. Randomized studies suggested that P4 and progestins are likely equally effective in preventing endometrial hyperplasia/cancer when used at adequate doses. E2- versus CEE-based MHT had a similar or possibly better risk profile for VTE and cardiovascular outcomes, and P4- versus progestin-based MHT had a similar or possibly better profile for breast cancer and cardiovascular outcomes. E2 may potentially protect better against age-related cognitive decline and bone fractures versus CEE; P4 was similar or possibly better versus progestins for these outcomes. Limitations are that many studies were observational and some were not adequately powered for the reported outcomes.Conclusions: Evidence suggests a differential effect of MHT containing E2 or P4 and those containing CEE or progestins, with some evidence trending to a potentially better safety profile with E2 and/or P4.

Individual Benefits and Risks of Intravaginal Estrogen and Systemic Testosterone in the Management of Women in the Menopause, With a Discussion of Any Associated Risks for Cancer Development.

ABSTRACT: Several formulations of intravaginal oestrogen are available for the treatment of genitourinary syndrome of menopause (GSM). These are safe and effective treatments for the symptoms of GSM. Licensed doses of intravaginal oestrogen do not elevate systemic estradiol levels above the normal postmenopausal range with long term use and there is no evidence of an increased risk of coronary heart disease, stroke, thromboembolism, colorectal cancer, endometrial cancer, breast cancer or breast cancer recurrence with their use. This should reassure both women and their healthcare professionals and should lead to more women receiving these localised, vaginally administered hormonal treatments. Available evidence also suggests a positive safety profile for transdermal testosterone treatment when delivered at physiological concentrations.

Bone Mineral Density Changes Associated With Pregnancy, Lactation, and Medical Treatments in Premenopausal Women and Effects Later in Life.

Bone mineral density (BMD) changes during the life span, increasing rapidly during adolescence, plateauing in the third decade of life, and subsequently entering a phase of age-related decline. In women, menopause leads to accelerated bone loss and an increase in fracture risk. Between peak bone mass attainment and menopause, BMD is generally stable and the risk of fracture is typically low. This time period is marked by life events such as pregnancy and lactation, which transiently decrease BMD, yet their long-term effects on fracture risk are less certain. BMD may also be altered by exposure to medications that affect bone metabolism (e.g., contraceptives, glucocorticoids, antidiabetic medications, antiepileptic drugs). Although oral contraceptives are often believed to be neutral with regard to bone health, depot medroxyprogesterone acetate (DMPA) and gonadotropin-releasing hormone (GnRH) agonists have been associated with decreases in BMD. Development of newer medical therapies, principally GnRH antagonists (e.g., ASP1707, elagolix, linzagolix, relugolix), for treatment of endometriosis-associated pelvic pain and heavy menstrual bleeding due to uterine fibroids has renewed interest in the short- and long-term impacts of changes in BMD experienced by premenopausal women. It is important to understand how these drugs influence BMD and put the findings into context with regard to measurement variability and naturally occurring factors that influence bone health. This review summarizes what is known about the effects on bone health pregnancy, lactation, and use of DMPA, GnRH agonists, and GnRH antagonists in premenopausal women and potential consequences later in life. ClinicalTrials.gov identifier: NCT03213457.

Evaluation of endometrial progesterone receptor expression after 12 weeks of exposure to a low-dose vaginal estradiol insert.

OBJECTIVE: To evaluate endometrial progesterone receptor (PGR) expression in menopausal women who used vaginal 4-µg and 10-µg estradiol (E2) inserts or placebo. METHODS: REJOICE was a randomized, placebo-controlled trial investigating vaginal E2 inserts in women with moderate to severe dyspareunia due to menopause. In this post hoc analysis, 25 eligible women with endometrial biopsies were randomly selected from each treatment group (4-µg and 10-µg E2 vaginal inserts and placebo). Endometrial biopsy sections were immunostained using an anti-PR (A and B) monoclonal antibody. Cell staining was quantified using an artificial intelligence feature-recognition algorithm. Mean PGR expression levels were analyzed between baseline and week 12. RESULTS: PGR expression results were available for 22 women in the 4-µg E2 group, and 25 women each for the 10-µg E2 and placebo groups. Similar PGR expression levels were observed at baseline (0.301-0.470 pmol/mg) and after 12 weeks of treatment (0.312-0.432 pmol/mg) for all treatment groups, with no significant differences between baseline and week 12. CONCLUSIONS: No meaningful differences in endometrial PGR expression were observed with the vaginal E2 (4- and 10-µg) inserts at week 12 from baseline, supporting the hypothesis that local exposure to E2 from a low-dose, vaginal insert placed near the vaginal introitus will not be sufficient to upregulate endometrial PGR expression. Coupled with the lack of histologic changes and systemic absorption, our data suggest that these softgel vaginal E2 inserts would not be expected to stimulate endometrial hyperplasia leading to a potential endometrial safety issue in postmenopausal women with moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy. Further study on the endometrial safety of softgel vaginal E2 inserts is under way.

Efficacy, safety, and tolerability of a levonorgestrel/ethinyl estradiol transdermal delivery system: Phase 3 clinical trial results.

OBJECTIVE: To assess the contraceptive efficacy, safety, and tolerability of a contraceptive transdermal delivery system, (TDS; TWIRLAⓇ) containing levonorgestrel (LNG) and ethinyl estradiol (EE). STUDY DESIGN: This single-arm, open-label, multicenter, 1-year (13 cycle), phase 3 study enrolled sexually active women ≥18 years old at risk for pregnancy irrespective of body mass index (BMI). Women used patches in 28-day cycles (3 consecutive administrations of 7-day patches followed by 7 days off-treatment/patch-free week). We assessed contraceptive efficacy by the Pearl Index (PI) in women 18 to 35 years, excluding cycles without intercourse or when other contraceptive methods were used. RESULTS: The study enrolled 2032 demographically diverse women in the US, of which 35.3% had a BMI ≥30 kg/m2. In the primary efficacy analysis, the PI (95% confidence interval) was 5.8 (4.5-7.2) pregnancies per 100 woman-years. PIs trended higher as BMI increased; the PI was 4.3 (2.9-5.8) in women with BMI <30 kg/m2 and 8.6 (5.8-11.5) in women with BMI ≥30 kg/m2. Hormone-related treatment-emergent adverse events included nausea (4.1%) and headache (3.6%); 11% of women discontinued due to adverse events. Four women (all with BMIs ≥30 kg/m2) reported thromboembolic events considered related to treatment. CONCLUSIONS: The low-dose LNG/EE TDS was effective in preventing pregnancy in a population of women representative of US demographics. Efficacy was reduced in women with BMI ≥30 kg/m2. The TDS safety and tolerability profile was consistent with other similar dose combined hormonal contraceptives. Results of this phase 3 study supported the US Food and Drug Administration approval of TWIRLAⓇ for prevention of pregnancy in women with BMI <30 kg/m2. IMPLICATIONS: TDS (120 µg/day levonorgestrel and 30 µg/day ethinyl estradiol) is an effective, low-dose transdermal contraceptive patch with favorable tolerability profile approved for prevention of pregnancy in women with BMI <30 kg/m2. TDS has reduced effectiveness in women with BMI ≥30 kg/m2.

Predictors of response for elagolix with add-back therapy in women with heavy menstrual bleeding associated with uterine fibroids.

BACKGROUND: Uterine fibroids are one of the most common neoplasms found among women globally, with a prevalence of approximately 11 million women in the United States alone. The morbidity of this common disease is significant because it is the leading cause of hysterectomy and causes significant functional impairment for women of reproductive age. Factors including age, body mass index, race, ethnicity, menstrual blood loss, fibroid location, and uterine and fibroid volume influence the incidence of fibroids and severity of symptoms. Elagolix is an oral gonadotropin-releasing hormone receptor antagonist that competitively inhibits pituitary gonadotropin-releasing hormone receptor activity and suppresses the release of gonadotropins from the pituitary gland, resulting in dose-dependent suppression of ovarian sex hormones, follicular growth, and ovulation. In Elaris Uterine Fibroids 1 and Uterine Fibroids 2, 2 replicate multicenter, double-blind, randomized, placebo-controlled, phase 3 studies, treatment of premenopausal women with elagolix with hormonal add-back therapy demonstrated reduction in heavy menstrual bleeding associated with uterine fibroids. OBJECTIVE: This analysis aimed to evaluate the safety and efficacy of elagolix (300 mg twice a day) with add-back therapy (1 mg estradiol/0.5 mg norethindrone acetate once a day) in reducing heavy menstrual bleeding associated with uterine fibroids in various subgroups of women over 6 months of treatment. STUDY DESIGN: Data were pooled from Elaris Uterine Fibroid-1 and Uterine Fibroid-2 studies, which evaluated premenopausal women (18-51 years) with heavy menstrual bleeding (>80 mL menstrual blood loss per cycle, alkaline hematin methodology) and ultrasound-confirmed uterine fibroid diagnosis. Subgroups analyzed included age, body mass index, race, ethnicity, baseline menstrual blood loss, fibroid location, and uterine and primary fibroid volume (largest fibroid identified by ultrasound). The primary endpoint was the proportion of women with <80 mL menstrual blood loss during the final month and ≥50% menstrual blood loss reduction from baseline to final month. Secondary and other efficacy endpoints included mean change in menstrual blood loss from baseline to final month, amenorrhea, symptom severity, and health-related quality of life. Adverse events and other safety endpoints were monitored. RESULTS: The overall pooled Elaris Uterine Fibroid-1 and Uterine Fibroid-2 population was typical of women with fibroids, with a mean age of 42.4 (standard deviation, 5.4) years and a mean body mass index of 33.6 (standard deviation, 7.3) kg/m2 and 67.6% of participants being black or African American women. A wide range of baseline uterine and fibroid volumes and menstrual blood loss were also represented in the overall pooled study population. In all subgroups, the proportion of responders to the primary endpoint, mean change in menstrual blood loss, amenorrhea, reduction in symptom severity, and improvement in health-related quality of life were clinically meaningfully greater for women who received elagolix with add-back therapy than those who received placebo and consistent with the overall pooled study population for the primary endpoint (72.2% vs 9.3%), mean change in menstrual blood loss (-172.5 mL vs -0.8 mL), amenorrhea (50.4% vs 4.5%), symptom severity (-37.1 vs -9.2), and health-related quality of life score (39.9 vs 8.9). Adverse events by subgroup were consistent with the overall pooled study population. CONCLUSION: Elagolix with hormonal add-back therapy was effective in reducing heavy menstrual bleeding associated with uterine fibroids independent of age, body mass index, race, ethnicity, baseline menstrual blood loss, fibroid location, and uterine and primary fibroid volume.

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.

Workshop on normal reference ranges for estradiol in postmenopausal women, September 2019, Chicago, Illinois.

The North American Menopause Society (NAMS) organized the Workshop on Normal Ranges for Estradiol in Postmenopausal Women from September 23 to 24, 2019, in Chicago, Illinois. The aim of the workshop was to review existing analytical methodologies for measuring estradiol in postmenopausal women and to assess existing data and study cohorts of postmenopausal women for their suitability to establish normal postmenopausal ranges. The anticipated outcome of the workshop was to develop recommendations for establishing normal ranges generated with a standardized and certified assay that could be adopted by clinical and research communities. The attendees determined that the term reference range was a better descriptor than normal range for estradiol measurements in postmenopausal women. Twenty-eight speakers presented during the workshop.

Elagolix Treatment for Up to 12 Months in Women With Heavy Menstrual Bleeding and Uterine Leiomyomas.

OBJECTIVE: To investigate the safety and efficacy of elagolix, an oral gonadotropin-releasing hormone antagonist, with hormonal add-back therapy for up to 12 months in women with heavy menstrual bleeding associated with uterine leiomyomas. METHODS: Elaris UF-EXTEND was a phase 3 extension study that evaluated an additional 6 months (up to 12 months total) of elagolix 300 mg twice daily with hormonal add-back therapy (estradiol 1 mg and norethindrone acetate 0.5 mg once daily) in women who completed an initial 6 months of the same treatment in one of two preceding phase 3 studies. The primary endpoint was the percentage of women with both less than 80 mL menstrual blood loss during final month and a 50% or greater reduction in menstrual blood loss from baseline to final month. Safety evaluations included adverse events and bone mineral density changes. The planned sample size of UF-EXTEND was based on estimated rollover and discontinuation rates in the two preceding studies. RESULTS: From September 2016 to March 2019, 433 women were enrolled in UF-EXTEND. Of these women, 218 received up to 12 months of elagolix with add-back therapy; the mean±SD age of this group was 42.4±5.4 years and 67.3% were black. The percentage of women who met the primary endpoint in this elagolix with add-back group was 87.9% (95% CI [83.4-92.3]). The most frequently reported adverse events with up to 12 months of elagolix plus add-back therapy were hot flush (6.9%), night sweats (3.2%), headache (5.5%), and nausea (4.1%). Mean percent decreases in bone mineral density from baseline to extension month 6 were significantly less with elagolix plus add-back therapy than with elagolix alone {between-group difference in lumbar spine: -3.3 (95% CI [-4.1 to -2.5])}. CONCLUSION: Up to 12 months of elagolix with add-back therapy provided sustained reduction in menstrual blood loss in women with uterine leiomyomas, with the addition of add-back therapy attenuating the hypoestrogenic effects of elagolix alone. No new or unexpected safety concerns were associated with an additional 6 months of elagolix with addback therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02925494. FUNDING SOURCE: AbbVie Inc funded this study.

Elagolix for Heavy Menstrual Bleeding in Women with Uterine Fibroids.

BACKGROUND: Uterine fibroids are hormone-responsive neoplasms that are associated with heavy menstrual bleeding. Elagolix, an oral gonadotropin-releasing hormone antagonist resulting in rapid, reversible suppression of ovarian sex hormones, may reduce fibroid-associated bleeding. METHODS: We conducted two identical, double-blind, randomized, placebo-controlled, 6-month phase 3 trials (Elaris Uterine Fibroids 1 and 2 [UF-1 and UF-2]) to evaluate the efficacy and safety of elagolix at a dose of 300 mg twice daily with hormonal "add-back" therapy (to replace reduced levels of endogenous hormones; in this case, estradiol, 1 mg, and norethindrone acetate, 0.5 mg, once daily) in women with fibroid-associated bleeding. An elagolix-alone group was included to assess the impact of add-back therapy on the hypoestrogenic effects of elagolix. The primary end point was menstrual blood loss of less than 80 ml during the final month of treatment and at least a 50% reduction in menstrual blood loss from baseline to the final month; missing data were imputed with the use of multiple imputation. RESULTS: A total of 412 women in UF-1 and 378 women in UF-2 underwent randomization, received elagolix or placebo, and were included in the analyses. Criteria for the primary end point were met in 68.5% of 206 women in UF-1 and in 76.5% of 189 women in UF-2 who received elagolix plus add-back therapy, as compared with 8.7% of 102 women and 10% of 94 women, respectively, who received placebo (P<0.001 for both trials). Among the women who received elagolix alone, the primary end point was met in 84.1% of 104 women in UF-1 and in 77% of 95 women in UF-2. Hot flushes (in both trials) and metrorrhagia (in UF-1) occurred significantly more commonly with elagolix plus add-back therapy than with placebo. Hypoestrogenic effects of elagolix, especially decreases in bone mineral density, were attenuated with add-back therapy. CONCLUSIONS: Elagolix with add-back therapy was effective in reducing heavy menstrual bleeding in women with uterine fibroids. (Funded by AbbVie; Elaris UF-1 and Elaris UF-2 ClinicalTrials.gov numbers, NCT02654054 and NCT02691494.).

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.

Ospemifene for the treatment of menopausal vaginal dryness, a symptom of the genitourinary syndrome of menopause.

Introduction: Vulvovaginal atrophy (VVA), a component of the genitourinary syndrome of menopause, is a progressive condition due to decline in estrogen leading to vaginal and vulvar epithelial changes. Accompanying symptoms of dryness, irritation, burning, dysuria, and/or dyspareunia have a negative impact on quality of life. Ospemifene is a selective estrogen receptor modulator (SERM) approved by the FDA for moderate to severe dyspareunia and vaginal dryness due to postmenopausal VVA. Areas covered: PubMed was searched from inception to March 2019 with keywords ospemifene and vulvar vaginal atrophy to review preclinical and clinical data describing the safety and efficacy of ospemifene for vaginal dryness and dyspareunia due to VVA. Covered topics include efficacy of ospemifene on vaginal cell populations, vaginal pH, and most bothersome VVA symptoms; imaging studies of vulvar and vaginal tissues; effects on sexual function; and safety of ospemifene on endometrium, cardiovascular system, and breast. Expert opinion: Ospemifene is significantly more effective than placebo in all efficacy analyses studied, working through estrogen receptors and possibly androgen receptors. Safety as assessed by adverse events was generally comparable to that with placebo and to other SERMs, and/or adverse events were not clinically meaningful. No cases of endometrial or breast cancer were reported.

Effects of ospemifene on genitourinary health assessed by prospective vulvar-vestibular photography and vaginal/vulvar health indices.

OBJECTIVE: To prospectively evaluate the effects of ospemifene on the vulva and vagina in postmenopausal women using vulvar-vestibular photography and direct visual assessments. METHODS: Postmenopausal women (aged 40-80 years) with moderate to severe vaginal dryness as their most bothersome symptom (MBS) were randomized to daily ospemifene 60 mg or placebo in this 12-week, multicenter, double-blind, phase 3 study. Vulvar-vestibular photographic images were captured at baseline and week 12 and were independently assessed with the Vulvar Imaging Assessment Scale (VIAS). Changes from baseline in Vaginal and Vulvar Health Indices (VHI and VuHI) with ospemifene versus placebo were analyzed at weeks 4, 8, and 12. Correlations between VIAS, VHI, and VuHI, with vaginal dryness severity and the Female Sexual Function Index (FSFI) scores were also assessed. RESULTS: In all, 631 eligible participants were randomized (ospemifene 316, placebo 315) and included in the intention-to-treat population. Compared with placebo, ospemifene significantly improved total scores for VIAS (P = 0.0154), VHI (P < 0.0001), and VuHI (P < 0.0001) from baseline to week 12; significant VHI (P < 0.0001) and VuHI (P = 0.002) improvements were observed at week 4. Most VHI and VuHI individual items were significantly better with ospemifene versus placebo at week 12 (P < 0.05). Most correlations between the vulvovaginal assessment total scores versus vaginal dryness severity and FSFI scores were significant (P < 0.05). CONCLUSION: Improvements observed in vulvovaginal health with ospemifene assessed by prospective vulvar-vestibular photography and other direct visual assessments support its efficacy in addition to the treatment of moderate to severe vaginal dryness due to menopause and the use of photographic and direct visual evaluations in future clinical trials. VIDEO SUMMARY: Supplemental Digital Content 1, http://links.lww.com/MENO/A415.

Efficacy and safety of ospemifene in postmenopausal women with moderate-to-severe vaginal dryness: a phase 3, randomized, double-blind, placebo-controlled, multicenter trial.

OBJECTIVE: To evaluate the safety and efficacy of ospemifene for the treatment of moderate to severe vaginal dryness in postmenopausal women with vulvovaginal atrophy (VVA). METHODS: This 12-week, multicenter, double-blind phase 3 study randomized postmenopausal women (aged 40-80 years) with VVA and moderate to severe vaginal dryness as their most bothersome symptom to daily oral ospemifene 60 mg or placebo. Coprimary efficacy endpoints included changes from baseline to week 12 in percentages of vaginal parabasal and superficial cells, vaginal pH, and vaginal dryness severity with ospemifene versus placebo; other secondary endpoints were evaluated (weeks 4, 8, and 12). Safety was assessed by treatment-emergent adverse events (TEAEs) and endometrial biopsies. RESULTS: Women (n = 631; ospemifene [n = 316], placebo [n = 315]) had a mean age of 59.8 years, a mean body mass index of 27.2 kg/m, and most were white. Ospemifene significantly improved (P < 0.0001) the percentages of parabasal and superficial cells, vaginal pH, and severity of vaginal dryness severity compared with placebo at week 12; significant between-group differences were noted by week 4. Secondary endpoints of dyspareunia (P < 0.001), maturation value (P < 0.0001), and the Female Sexual Function Index (P < 0.05) also significantly improved with ospemifene versus placebo at week 12. Significantly more women responded (31.5% vs 6.0%; P < 0.0001) or were satisfied (49.2% vs 33.8%; P = 0.0007) with ospemifene versus placebo at week 12. No unexpected TEAEs, treatment-related serious TEAEs, thrombotic events, or endometrial hyperplasia or carcinoma were observed. CONCLUSIONS: Ospemifene was effective and well tolerated for the treatment of moderate-to-severe vaginal dryness in postmenopausal women with VVA.

Oral 17ß-estradiol/progesterone (TX-001HR) and quality of life in postmenopausal women with vasomotor symptoms.

OBJECTIVE: The aim of the study was to describe the effects of TX-001HR (17ß-estradiol [E2] and natural progesterone [P4] in a single oral capsule) on menopause-specific quality of life in women with moderate to severe vasomotor symptoms (VMS). METHODS: The REPLENISH study (NCT01942668) was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial which evaluated four E2/P4 doses in postmenopausal women with VMS and a uterus. Women with moderate to severe hot flushes (≥7/d or ≥50/wk) were included in a VMS substudy. Participants self-administered the Menopause-Specific Quality of Life (MENQOL) questionnaire. Baseline changes in MENQOL overall and domains were determined as well as correlations between changes in MENQOL scores and VMS frequency or severity. RESULTS: In the VMS substudy, women treated with E2/P4 had significantly greater improvements from baseline in their MENQOL overall score at week 12, and months 6 and 12, compared with placebo (all, P < 0.05, except the lowest E2/P4 dose at months 6 and 12). Improvements from baseline for the MENQOL vasomotor domain score were significantly greater with TX-001HR doses versus placebo at all time points (all, P < 0.01). Changes in MENQOL vasomotor scores moderately correlated with changes in VMS frequency (r = 0.56, P < 0.0001) and severity (r = 0.55, P < 0.0001). CONCLUSION: In the REPLENISH trial, women with moderate to severe VMS treated with most E2/P4 doses reported significant improvements in quality of life from baseline to 12 weeks compared with placebo, which were maintained up to 12 months. TX-001HR, if approved, may provide the first oral hormone therapy formulation in a single capsule containing E2 and P4 for the treatment of VMS in postmenopausal women with a uterus.