Human vaginal pH and microbiota: an update.

A woman's vaginal pH has many implications on her health and it can be a useful tool in disease diagnosis and prevention. For that reason, the further examination of the relationship between the human vaginal pH and microbiota is imperative. In the past several decades, much has been learned about the physiological mechanisms modulating the vaginal pH, and exogenous/genetic factors that may influence it. A unified, coherent understanding of these concepts is presented to comprehend their interrelationships and their cumulative effect on a woman's health. In this review, we explore research on vaginal pH and microbiota throughout a woman's life, vaginal intermediate cell anaerobic metabolism and net proton secretion by the vaginal epithelial, and the way these factors interact to acidify the vaginal pH. This review provides foundational information about what a microbiota is and its relationship with human physiology and vaginal pH. We then evaluate the influence of physiological mechanisms, demographic factors, and propose ideas for the mechanisms behind their action on the vaginal pH.

The Women's EMPOWER Survey: Identifying Women's Perceptions on Vulvar and Vaginal Atrophy and Its Treatment.

INTRODUCTION: Vulvar and vaginal atrophy (VVA) affects up to two thirds of postmenopausal women, but most symptomatic women do not receive prescription therapy. AIM: To evaluate postmenopausal women's perceptions of VVA and treatment options for symptoms in the Women's EMPOWER survey. METHODS: The Rose Research firm conducted an internet survey of female consumers provided by Lightspeed Global Market Insite. Women at least 45 years of age who reported symptoms of VVA and residing in the United States were recruited. MAIN OUTCOME MEASURES: Survey results were compiled and analyzed by all women and by treatment subgroups. RESULTS: Respondents (N = 1,858) had a median age of 58 years (range = 45-90). Only 7% currently used prescribed VVA therapies (local estrogen therapies or oral selective estrogen receptor modulators), whereas 18% were former users of prescribed VVA therapies, 25% used over-the-counter treatments, and 50% had never used any treatment. Many women (81%) were not aware of VVA or that it is a medical condition. Most never users (72%) had never discussed their symptoms with a health care professional (HCP). The main reason for women not to discuss their symptoms with an HCP was that they believed that VVA was just a natural part of aging and something to live with. When women spoke to an HCP about their symptoms, most (85%) initiated the discussion. Preferred sources of information were written material from the HCP's office (46%) or questionnaires to fill out before seeing the HCP (41%).The most negative attributes of hormonal products were perceived risk of systemic absorption, messiness of local creams, and the need to reuse an applicator. Overall, HCPs only recommended vaginal estrogen therapy to 23% and oral hormone therapies to 18% of women. When using vaginal estrogen therapy, less than half of women adhered to and complied with posology; only 33% to 51% of women were very to extremely satisfied with their efficacy. CONCLUSION: The Women's EMPOWER survey showed that VVA continues to be an under-recognized and under-treated condition, despite recent educational initiatives. A disconnect in education, communication, and information between HCPs and their menopausal patients remains prevalent. Kingsberg S, Krychman M, Graham S, et al. The Women's EMPOWER Survey: Identifying Women's Perceptions on Vulvar and Vaginal Atrophy and Its Treatment. J Sex Med 2017;14:413-424.

The Women's EMPOWER Survey: Women's Knowledge and Awareness of Treatment Options for Vulvar and Vaginal Atrophy Remains Inadequate.

INTRODUCTION: Postmenopausal women's knowledge about vulvar and vaginal atrophy (VVA) and available treatment options has historically been inadequate. Recent direct-to-consumer marketing and educational efforts would have been expected to increase awareness and treatment options. AIM: To compare results of the Women's EMPOWER survey with other available VVA surveys to assess progress in women's understanding and approaches to treatment of VVA. METHODS: The Women's EMPOWER survey, an internet-based survey of US women with VVA symptoms, assessed women's awareness of VVA and their behaviors and attitudes associated with symptom treatment. MAIN OUTCOME MEASURES: These survey results were compared with previously published results of the Revealing Vaginal Effects at Mid-Life (REVEAL), Women's Voices in Menopause (WVM), Vaginal Health: Insight, Views, & Attitudes (VIVA), Clarifying Vaginal Atrophy's Impact on Sex and Relationship (CLOSER), and Real Women's Views of Treatment Options for Menopausal Vaginal Changes (REVIVE) surveys. RESULTS: Results of the Women's EMPOWER survey were consistent with those of past VVA surveys and showed that postmenopausal women generally failed to recognize VVA and its chronic, progressive process and that they were reluctant to discuss vaginal or sexual symptoms with their health care professionals (HCPs). However, women indicated a strong desire for accurate medical information about VVA from their health care professionals and a willingness to learn if HCPs would initiate the conversation. Most women believed that vaginal symptoms are a normal part of aging and they just need to cope with the symptoms. In the United States, women were most concerned with safety-related issues, including increased risk of breast cancer, side effects, and systemic absorption. CONCLUSION: The Women's EMPOWER survey demonstrates and reinforces that even with multimedia marketing and educational strategies in the years after other major VVA surveys, minimal progress has been made toward increasing women's awareness of, knowledge about, or understanding of VVA. Based on these data, a focus on initiating discussions and education with postmenopausal women so that they better comprehend VVA as a chronic progressive medical condition (not just aging), the symptoms associated with VVA, and the benefit-risk profile regarding treatment options is warranted. Krychman M, Graham S, Bernick B, et al. The Women's EMPOWER Survey: Women's Knowledge and Awareness of Treatment Options for Vulvar and Vaginal Atrophy Remains Inadequate. J Sex Med 2017;14:425-433.

TX-004HR Improves Sexual Function as Measured by the Female Sexual Function Index in Postmenopausal Women With Vulvar and Vaginal Atrophy: The REJOICE Trial.

INTRODUCTION: TX-004HR is an investigational, applicator-free, vaginal soft gel capsule containing low-dose solubilized 17ß-estradiol. The phase 3, randomized, double-blinded, placebo-controlled, multicenter REJOICE trial has shown TX-004HR to be safe and effective for the treatment of moderate to severe dyspareunia in postmenopausal women with vulvar and vaginal atrophy (VVA). AIM: To evaluate the effect of TX-004HR on female sexual dysfunction in postmenopausal women with VVA. METHODS: The REJOICE study compared the effects of 12-week treatment with TX-004HR (4, 10, or 25 µg) with placebo in postmenopausal women (40-75 years old) with VVA and a most bothersome symptom of moderate to severe dyspareunia. Changes in the percentage of superficial and parabasal cells, vaginal pH, and dyspareunia were measured as co-primary end points. Female sexual dysfunction was evaluated as a secondary end point using the Female Sexual Function Index (FSFI) patient self-report inventory. MAIN OUTCOME MEASURES: Changes from baseline to week 12 in total and individual domain FSFI scores for each TX-004HR dose were compared with those for placebo. RESULTS: All three TX-004HR doses increased the baseline total FSFI score after 12 weeks, with 10 µg (P < .05) and 25 µg (P = .0019) having a significantly greater effect than placebo. A similar trend was observed for the individual FSFI domains, with 10 and 25 µg significantly improving baselines scores for pain and lubrication at 12 weeks (P ≤ .015 for all vs placebo). Changes from baseline to week 12 in arousal (P = .0085) and satisfaction (P = .0073) were significantly greater for TX-004HR 25 µg vs placebo. All three TX-004HR doses were comparable to placebo in their effect on desire and orgasm. CONCLUSION: TX-004HR improved FSFI scores in a dose-dependent manner. The observed improvements in sexual function suggest that TX-004HR is a promising treatment option for postmenopausal VVA with a potential added beneficial effect on female sexual dysfunction.

Prevalence of menopausal symptoms among mid-life women: findings from electronic medical records.

BACKGROUND: To assess the prevalence of menopausal symptoms among women prescribed hormone therapy (HT) using electronic medical record data from a regional healthcare organization. METHODS: Retrospective data from the Reliant Medical Group from 1/1/2006-12/31/2011 were assessed for 102 randomly-selected patients. Study eligibility criteria included: females aged 45 to 65; prescribed oral or transdermal HT; no history of breast cancer, venous thromboembolism, stroke, gynecological cancer, or hysterectomy; continuously enrolled in the health plan for 1 year before and after the first observed HT prescription. Prevalence of menopause-related symptoms was analyzed descriptively at both the patient and visit levels. RESULTS: Mean age of patients was 54 years. The most common menopausal symptoms were: hot flushes (40%), night sweats (17%), insomnia (16%), vaginal dryness (13%), mood disorders (12%), and weight gain (12%). Among the 102 patients, 163 individual visits listing menopausal symptoms were identified, of which hot flushes (71 visits) were the most common symptom identified. CONCLUSION: Our findings provide recent data on the types of menopausal symptoms experienced by mid-life women prescribed HT. Electronic medical records may be a rich source of data for future studies of menopausal symptoms in this population.

Breast-related effects of selective estrogen receptor modulators and tissue-selective estrogen complexes.

A number of available treatments provide relief of menopausal symptoms and prevention of postmenopausal osteoporosis. However, as breast safety is a major concern, new options are needed, particularly agents with an improved mammary safety profile. Results from several large randomized and observational studies have shown an association between hormone therapy, particularly combined estrogen-progestin therapy, and a small increased risk of breast cancer and breast pain or tenderness. In addition, progestin-containing hormone therapy has been shown to increase mammographic breast density, which is an important risk factor for breast cancer. Selective estrogen receptor modulators (SERMs) provide bone protection, are generally well tolerated, and have demonstrated reductions in breast cancer risk, but do not relieve menopausal symptoms (that is, vasomotor symptoms). Tissue-selective estrogen complexes (TSECs) pair a SERM with one or more estrogens and aim to blend the positive effects of the components to provide relief of menopausal symptoms and prevention of postmenopausal osteoporosis without stimulating the breast or endometrium. One TSEC combination pairing conjugated estrogens (CEs) with the SERM bazedoxifene (BZA) has completed clinical development and is now available as an alternative option for menopausal therapy. Preclinical evidence suggests that CE/BZA induces inhibitory effects on breast tissue, and phase 3 clinical studies suggest breast neutrality, with no increases seen in breast tenderness, breast density, or cancer. In non-hysterectomized postmenopausal women, CE/BZA was associated with increased bone mineral density and relief of menopausal symptoms, along with endometrial safety. Taken together, these results support the potential of CE/BZA for the relief of menopausal symptoms and prevention of postmenopausal osteoporosis combined with breast and endometrial safety.

Evolution of the tissue selective estrogen complex (TSEC).

Estrogens mediate gene transcription and signaling of numerous cellular processes in a variety of tissues, including the bone, breast, and endometrium, through binding and activation of estrogen receptors (ERs). Estrogen-mediated ER agonist activity has shown benefit in conditions related to estrogen deficiency in women; however, these effects have been associated with stimulation of breast and uterine tissues. Due to the complexity of ER signaling, selective estrogen receptor modulators (SERMs) can exhibit ER agonist or antagonist activity depending on the target tissue. A newer approach to menopausal therapy, the tissue selective estrogen complex (TSEC), pairs a SERM with one or more estrogens with the goal of maintaining the benefits of estrogens without the stimulatory effects on the breast and uterus. Preclinically, different TSECs have been associated with distinct gene expression profiles compared with each other and with their individual SERM/estrogen components. Studies in cultured breast cancer cells and animal models have demonstrated a lack of estrogen-induced stimulation with TSECs in the mammary gland and endometrium. In the breast, biochemical analyses indicate that degradation of the ER is an important mechanism by which TSECs exert their antagonistic effects. TSECs have also shown positive effects similar to estrogens in other tissue types, including bone and the central nervous system, although mechanisms underlying these activities are less clear. Overall, preclinical studies have shown that estrogens, SERMs, and TSECs each exert distinct and tissue specific molecular and pharmacologic effects.

Effects of E2/P4 oral capsules on bone turnover in women with vasomotor symptoms.

OBJECTIVE: To evaluate bone turnover markers (BTM) in the REPLENISH trial (NCT01942668). METHODS: REPLENISH evaluated oral estradiol/progesterone (E2/P4) for the treatment of moderate to severe vasomotor symptoms (VMS) in postmenopausal women with a uterus. Eligible women for this analysis had ≥50 moderate to severe VMS/wk, were <5 years since last menstrual period, and had BTM measurements at baseline, and months 6 and 12. Percent changes for three BTM (bone-specific alkaline phosphatase [BSAP], C-terminal telopeptide of type I collagen [CTX-1], and N-terminal propeptide of type I procollagen [P1NP]) assessed by immunoassay methods were evaluated from baseline to months 6 and 12 for the 1 mg E2/100 mg P4, 0.5 mg E2/100 mg P4, and placebo groups. RESULTS: A total of 157 women (40-61 y, 69% White) were analyzed. Mean baseline values ranged from 14.0 to 14.3 U/L for BSAP, 0.34 to 0.39 ng/mL for CTX-1, and 76.9 to 79.3 ng/mL for PINP. Mean differences in percent change from baseline for both E2/P4 doses versus placebo significantly decreased at months 6 and 12 and ranged from -8% to -16% for BSAP (all, P < 0.05), -30% to -41% for CTX-1 (all, P ≤ 0.001), and -14% to -29% for PINP (all, P < 0.01). CONCLUSIONS: REPLENISH data provide support for a potential skeletal benefit of E2/P4 when it is used for the treatment of moderate to severe VMS. Further studies are warranted.

Video Summary : http://links.lww.com/MENO/A894 .

Segesterone acetate serum levels with a regression model of continuous use of the segesterone acetate/ethinyl estradiol contraceptive vaginal system.

OBJECTIVE: To predict serum segesterone (SA) and ethinyl estradiol (EE) levels after 364 days of hypothetical continuous use (without removal) of a cyclic contraceptive vaginal system (CVS) containing 0.15 mg SA and 0.013 mg EE. STUDY DESIGN: We used pharmacokinetic (PK) data (n = 37) from a multicenter, open-label, nonrandomized study of healthy women (18-38 years) that used the CVS for 13 cycles in a 21 days-in/7 days-out regimen to develop a linear regression model to predict daily serum SA and EE levels for 364 days of continuous CVS use. We then determined residual SA/EE levels in vitro from 18 randomly chosen CVS used by women who completed 13 cycles. Serum SA and EE levels were also predicted for 364 days of continuous CVS use in another in vitro study. RESULTS: After a hypothetical 364 days of continuous CVS use, we predicted daily mean serum levels to be 184 pmol/L (95% confidence interval [CI], 102‒332 pmol/L) for SA and 43 pmol/L (95% CI, 19‒95 pmol/L) for EE. We did predict that serum EE levels would not accumulate over time. Residual SA and EE in the CVS were 60% and 80% of the original load after 13 cycles, respectively. CONCLUSION: The predicted serum SA level after 364 days of hypothetical continuous CVS use was comparable to reported levels at which no pregnancy occurred (>100 pmol/L), showing the potential of the CVS for one year of continuous use. Clinical trials on continuous CVS use are planned. IMPLICATIONS: Based on statistical modeling, the long-term, user-controlled contraceptive vaginal system containing segesterone acetate and ethinyl estradiol may have the potential to provide effective pregnancy prevention if used continuously (without removal) for one year. Further investigation is warranted.

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.

Estradiol softgel inserts for the treatment of VVA symptoms: an expert opinion.

INTRODUCTION: Vulvar and vaginal atrophy (VVA) affects up to two thirds of postmenopausal women, with symptoms of vaginal dryness, dyspareunia, and vulvar/vaginal irritation. Despite the availability of various treatments, women express dissatisfaction with their options. An estradiol (E2; 4-µg and 10-µg) softgel vaginal insert was approved by the Food and Drug Administration (FDA) to treat moderate to severe dyspareunia, a symptom of VVA, due to menopause. These inserts were designed to treat VVA effectively and safely while avoiding some of the drawbacks of other administration methods. AREAS COVERED: This article reviews the physical characteristics and pharmacokinetic data of the E2 softgel vaginal insert. Primary and secondary efficacy endpoints and safety data are reviewed from the pivotal REJOICE trial (NCT02253173), and substudies that explore response rates, changes in vaginal epithelium by visual assessment, efficacy in patient subgroups, effects on sexual function, and patient satisfaction compared with other treatments. EXPERT OPINION: The E2 insert shows that vaginal drug delivery is an optimal route of administration for locally treating VVA. This E2 softgel vaginal insert is a safe and effective treatment for symptoms of postmenopausal VVA. The E2 insert's pharmacokinetic characteristics are related to its unique formulation, rapid dissolution, and minimal systemic absorption. ABBREVIATIONS: AE: adverse event; AUC: area under the concentration-time curve; BMI: body mass index; Cavg: average concentration; CI: confidence interval; Cmax: maximum concentration; Cmin: minimum concentration; E2: estradiol; FDA: Food and Drug Administration; FSFI: Female Sexual Function Index; GSM: genitourinary symptoms of menopause: MBS: most bothersome symptom; NAMS: North American Menopause Society; OR: odds ratio; PI: pulsatility index; PK: pharmacokinetic; REVIVE: Real Women's Views of treatment options for menopausal Vaginal changEs; RI: resistance index; ROC: receiver operating characteristic; TEAE: treatment-emergent adverse event; tmax: time to maximum concentration; VVA: vulvar and vaginal atrophy.

Systemic estradiol levels with low-dose vaginal estrogens.

OBJECTIVES: To critically evaluate published systemic estradiol levels during use of low-dose vaginal estrogens considering detection method and estrogen dose; describe challenges with accurately measuring estradiol; and determine the normal estradiol level range in postmenopausal women. METHODS: PubMed was searched for studies reporting systemic estradiol levels with lower-dose vaginal estrogens (≤25 µg estradiol or 0.3 mg conjugated equine estrogens). Estradiol levels at baseline and during treatment, area under the curve, and maximum estradiol concentrations were summarized by dose within assay type. A proposed range of systemic estradiol in normal, untreated, postmenopausal women was estimated by conservatively pooling means and standard deviations from published studies. RESULTS: Mean basal estradiol levels were 3.1 to 4.9 pg/mL using liquid or gas chromatography/mass spectroscopy (LC or GC/MS/MS) with a range of undetectable to 10.5 pg/mL using radioimmunoassay. Systemic estradiol levels with vaginal estrogens reflected their doses as measured with LC or GC/MS/MS in different studies: 7.1 to 9.1 pg/mL and 16.7 to 22.7 pg/mL with a 25-µg softgel capsule insert and a tablet insert, respectively; 4.6 to 7.4 pg/mL and 6.6 to 14.8 pg/mL with a 10-µg softgel capsule and a tablet insert, respectively; and 3.6 to 3.9 pg/mL with a 4-µg softgel capsule insert. A mean systemic estradiol concentration ranging from undetectable to 10.7 pg/mL is proposed as an estimate for basal estradiol levels in normal, untreated, postmenopausal women. Systemic estradiol absorption may be influenced by the placement of estradiol higher (as with an applicator) versus lower (as without an applicator) in the vagina, as estradiol transport to the uterus would be more likely further away than closer to the introitus. CONCLUSION: Serum estradiol concentrations were generally lower when measured with more specific and sensitive assays. Estradiol absorption was dose-dependent, and may be influenced by dose, formulation, and positioning in the vagina. Very low systemic estradiol absorption with low/ultralow-dose vaginal estrogens may potentially decrease any adverse events that may be associated with higher doses of vaginal estrogens used for treating moderate to severe VVA due to less estradiol exposure.

Long-Lasting, Patient-Controlled, Procedure-Free Contraception: A Review of Annovera with a Pharmacist Perspective.

Annovera (segesterone acetate and ethinyl estradiol vaginal system) is a US Food and Drug Administration FDA-approved long-lasting, reversible contraceptive that is fully administered by the user and does not require a procedure for insertion or removal. The vaginal system is in the shape of a ring and contains low doses of a novel progestin, egesterone acetate, and ethinyl estradiol. It is made of silicone and is fully pliable and flexible. The vaginal system is reusable for 13 cycles, using a 21 days in/7 days out regimen, providing women with the ability to control their fertility. Particularly now during the COVID-19 pandemic when access to contraception has been further reduced, patients may benefit from a method that is both long-lasting and patient-controlled.

Breast effects of oral, combined 17ß-estradiol, and progesterone capsules in menopausal women: a randomized controlled trial.

OBJECTIVE: To evaluate the effect of a single-capsule, bioidentical 17ß-estradiol (E2) and progesterone (P4) hormone therapy on mammograms and breasts in postmenopausal women after 1 year of use. METHODS: In the 12-month, phase 3, randomized, double-blind, placebo-controlled, multicenter REPLENISH trial, postmenopausal women (40-65 y) with moderate to severe vasomotor symptoms and a uterus were randomized to four active daily dose groups of E2/P4 (TX-001HR) or a placebo group. Mammograms were performed and read locally at screening (or ≤6 months before first dose) and at study end using BI-RADS classification. Incidence of abnormal mammograms and breast adverse events was evaluated. RESULTS: All but 8 (0.4%) mammograms at screening were normal (BI-RADS 1 or 2). At 1 year, 39 (2.9%) of the 1,340 study-end mammograms were abnormal (BI-RADS 3 or 4); incidence was 1.7% to3.7% with active doses and 3.1% with placebo. Breast cancer incidence was 0.36% with active doses and 0% with placebo. Breast tenderness was reported at frequencies of 2.4% to 10.8% with active doses versus 0.7% with placebo, and led to eight study discontinuations (1.6% of discontinuations in active groups). CONCLUSIONS: In this phase 3 trial of a combined E2/P4, results of secondary outcomes suggest that E2/P4 may not be associated with increased risk of abnormal mammograms versus placebo, and the incidence of breast tenderness was low relative to most of the rates reported in other studies using hormone therapy.

Effects of combined 17ß-estradiol and progesterone on weight and blood pressure in postmenopausal women of the REPLENISH trial.

OBJECTIVE: To examine the impact of a single-capsule 17ß-estradiol (E2)/progesterone (P4) on weight and blood pressure (BP) when treating moderate to severe vasomotor symptoms in postmenopausal women with a uterus. METHODS: Healthy postmenopausal women with a uterus (aged 40-65, body mass index ≤34 kg/m2, BP ≤140/90 mm Hg) were randomized to daily E2/P4 (mg/mg; 1/100, 0.5/100, 0.5/50, 0.25/50) or placebo in the phase 3 REPLENISH trial (NCT01942668). Changes in weight and BP from baseline to month 12 were evaluated. Potentially clinically important changes were defined as increases or decreases from baseline in weight by ≥15% and ≥11.3 kg, systolic BP by ≥20 mm Hg (absolute value ≥160 or ≤90 mm Hg), and diastolic BP by ≥15 mm Hg (absolute value ≥90 or ≤60 mm Hg). RESULTS: Overall mean changes in weight and BP from baseline to month 12 with E2/P4 were modest and generally not statistically or clinically significant versus placebo. Incidence of potentially clinically important changes was low for weight (E2/P4 vs placebo: 1.1-2.6% vs 2.2%), systolic BP (0.3-1.1% vs 1.1%), and diastolic BP (1.4-4.2% vs 3.2%). A small number of women had treatment-related, treatment-emergent adverse events of weight gain (1.4-2.6% vs 1.3%) or hypertension (0.2-1.2% vs 0%). Few women who discontinued E2/P4 had weight gain (1.6%) or hypertension (0.6%) as a primary reason. Efficacy profile on VMS was consistent with previous findings and not modified by body mass index. CONCLUSIONS: Twelve-month use of E2/P4 had no clinically meaningful impact on weight or BP in postmenopausal women of the REPLENISH study.

Effects of Estradiol Dose and Serum Estradiol Levels on Metabolic Measures in Early and Late Postmenopausal Women in the REPLENISH Trial.

Background: To identify the association of estradiol (E2) dose and serum E2 levels with metabolic measures in early (<6 years) compared with late (≥10 years) postmenopausal women from the REPLENISH trial. Material and Methods: This is a post hoc analysis of a multicenter randomized clinical trial in the United States. Four doses of TX-001HR, an oral combination of E2 and progesterone (P4), and placebo were tested. This analysis included a total of 1,216 early and 297 late postmenopausal women. Linear mixed-effects models tested the association of E2 dose and serum E2 levels with changes in metabolic parameters; total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and glucose (GLUC) levels from six visits over 12 months, adjusted for the serum P4 level. Results: A higher E2 dose was significantly associated with lower TC (p = 0.02) and LDL-C (p = 0.002) and higher HDL-C (p = 0.04) levels in early, but not late, postmenopause. With longer time since menopause, the inverse association of E2 dose with TC and LDL-C and positive association with HDL-C were attenuated (interaction p < 0.05). Higher serum E2 levels were significantly associated with lower TC (p = 0.004), LDL-C (p = 0.0001), and fasting blood GLUC (p = 0.003) and higher TG (p = 0.002) levels in early postmenopause. Conclusion: E2 dose differentially affects metabolic measures among early compared with late postmenopausal women. No significant main effect of the serum P4 level was found. As the metabolic parameters studied are risk factors for cardiovascular events, these results support the timing hypothesis of E2 therapy and its cardiovascular benefits.

17ß-estradiol/progesterone in a single, oral, softgel capsule (TX-001HR) significantly increased the number of vasomotor symptom-free days in the REPLENISH trial.

OBJECTIVE: To examine responder rates and vasomotor symptom-free days with oral 17ß-estradiol/progesterone (E2/P4; TX-001HR) versus placebo in the REPLENISH trial. METHODS: REPLENISH (NCT01942668) was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial, evaluating single, oral, softgel E2/P4 capsules in postmenopausal women (40-65 y) with a uterus and vasomotor symptoms (VMS). Women with moderate to severe hot flushes (≥7/d or ≥50/wk) were randomized (VMS substudy) to daily E2/P4 (mg/mg) of 1/100, 0.5/100, 0.5/50, 0.25/50, or placebo. Proportions of women with ≥50% or ≥75% reductions in moderate to severe VMS (responders), and those with no severe VMS as well as the weekly number of days without moderate to severe VMS with TX-001HR versus placebo were determined. Mixed model repeated measures was used to analyze data and Fisher exact test was employed to compare E2/P4 versus placebo. RESULTS: Seven hundred twenty-six women were eligible for the VMS efficacy analysis (E2/P4 1/100 [n = 141], 0.5/100 [n = 149], 0.5/50 [n = 147], 0.25/50 [n = 154], or placebo [n = 135]). Significantly more women treated with all E2/P4 doses versus placebo were ≥50% responders and ≥75% responders at weeks 4 and 12 (P < 0.05) and also had significantly more days per week without moderate to severe VMS at week 12 (1.9-3.0 d for E2/P4 versus 1.3 d for placebo; P < 0.05). The proportion of women without severe hot flushes at week 12 was 43% to 56% for all E2/P4 doses versus 26% for placebo (P ≤ 0.01). CONCLUSIONS: Women treated with E2/P4 had a greater response to treatment with more VMS-free days than with placebo. The E2/P4 1/100 dose (Bijuva [E2 and P4] capsules) represents an oral treatment option for postmenopausal women with moderate to severe VMS and a uterus.

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.