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Objective: The aim of this study was to determine the success rate of cytogenetic analysis from specimens obtained at the time of second-trimester termination of pregnancy by dilation and evacuation.Study Design: All second-trimester dilation and evacuations performed by a single practitioner at a single institution from 1993 through 1995 were evaluated to pick out those patients in whom biopsy specimens were submitted for cytogenetic analysis. The main outcome studied was the ability to obtain karyotype results for these specimens.Results: Cytogenetic studies were performed on 258 dilation and evacuation specimens with a median gestational age of 18 weeks (range 13-25 weeks). The indications for termination were fetal aneuploidy (n = 88, 34%), sonographically diagnosed fetal malformations (n = 82, 32%), intrauterine fetal death (n = 67, 26%), oligohydramnios or premature rupture of membranes (n = 16, 6%), and others (hematologic and metabolic disorders, n = 5, 2%). Successful karyotyping was achieved for 99% of specimens obtained at second-trimester dilation and evacuation, with 3 failures of growth (1% failure rate). The failures included a 14-week molar pregnancy, an 18-week fetus with Dandy-Walker malformation, and a 19-week intrauterine fetal death. Of the samples obtained in cases of intrauterine fetal death, 99% (66/67) provided adequate cytogenetic information.Conclusions: Karyotyping for abnormal second-trimester pregnancies and intrauterine fetal deaths at the time of a dilation and evacuation procedure has a success rate nearing 100%. In contrast to previous reports, our data indicate that it is unnecessary to perform pretermination invasive karyotyping in patients with abnormal second-trimester pregnancies or intrauterine fetal death who elect to undergo dilation and evacuation. Chromosome analysis at the time of termination of pregnancy by dilation and evacuation reduces patient discomfort, risk of infection, and cost while still providing reliable and vital cytogenetic information for future genetic counseling. [ABSTRACT FROM AUTHOR]

Background: We evaluated satisfaction with use of a segesterone acetate and ethinyl estradiol (0.15/0.013 mg) contraceptive vaginal system (CVS) among women who had recently used a monthly contraceptive vaginal ring or contraceptive pills. The CVS is a ring-shaped device used in a 21-days-in/7-days-out regimen for 13 cycles. Materials and Methods: We analyzed post hoc satisfaction responses at cycle 3 and end of study (EOS) from a subset of participants with documented recent use of the monthly ring or daily pills before enrollment in a multinational, phase 3, 13-cycle trial evaluating the CVS. EOS included results from participants who had completed ≥10 cycles. Results were summarized descriptively. Results: We identified 128 recent ring and 219 recent pill users at cycle 3 (of 1033 survey participants), and 92 and 148, respectively, at EOS (of 622 survey participants); overall satisfaction with CVS use was high (≥90%). At EOS, most ring (89%) and pill (97%) users liked the CVS as much/better than any previous method. The two most-liked CVS features included ease of use and 1-year duration; the two most disliked features included ring insertion and feeling it coming out. At EOS, ≥88% of both groups reported no concern about using the same CVS for a year, and most (>80%) had recommended it to friends or family members. Conclusion: The CVS clinical trial participants who were recent ring/pill users reported high satisfaction and liked it as much/better than any previously used contraceptive; the CVS may be a good contraceptive option for switchers. Clinical trial registration NCT00263341.

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.

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., Competing Interests: Financial disclosures/conflicts of interest: M.R.M. consults for Amgen and Myovant; and has served on the speaker's bureau of Amgen. R.K. consults for Amgen, Astellas, and TherapeuticsMD; and has served on the speaker's bureau of TherapeuticsMD. S.G., B.B., and S.M. are employees of TherapeuticsMD with stock/stock options. G.C. consults to multiple pharmaceutical companies including but not limited to TherapeuticsMD and has stock options from TherapeuticsMD., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society.)

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., Competing Interests: Declaration of competing interest Dr. Liu consults for Allergan, AMAG, Bayer Healthcare, Daré, Ferring, Lupin, Mitsubishi-Tanabe, Sebela, and TherapeuticsMD and has received research support for clinical trials (paid to UH Cleveland Medical Center) from AbbVie, Allergan, Bayer Healthcare, Femasys, Ferring, and Palatin Technologies. Ms. Plagianos is an employee of Population Council. Dr. Archer has served as a consultant to AbbVie, Agile Therapeutics, Bayer Healthcare, Endoceutics, Evestra, Exeltis, InnovaGyn, Lupin, Mithra, OvsEva and TherapeuticsMD; and has received research support from Actavis, Bayer Healthcare, Endoceutics, Mithra, Myovant, ObsEva and TherapeuticsMD. He has stock in InnovaGyn and stock options from Agile Therapeutics. Dr. Simon (within the past year, or current) has grant/research support from: AbbVie, Inc., Bayer Healthcare LLC., Endoceutics, Inc., Ipsen, Myovant Sciences, ObsEva SA, TherapeuticsMD, Viveve Medical; has been a consultant/advisory boards of: Allergan, AbbVie, Inc., AMAG Pharmaceuticals, Inc., Bayer HealthCare Pharmaceuticals Inc., Camargo Pharmaceutical Services, LLC, CEEK Enterprises, LLC., Covance Inc., Dare´ Bioscience, Duchesnay USA, Hologic Inc., KaNDy/NeRRe Therapeutics Ltd., Madorra Pty Ltd., Mitsubishi Tanabe Pharma Development America, Inc., Sebela Pharmaceuticals Inc., Shionogi Inc., Sprout2 Inc., TherapeuticsMD; has served on the Speaker’s bureaus of: AMAG Pharmaceuticals, Inc., Duchesnay USA, TherapeuticsMD; and is a stockholder (direct purchase) in: Sermonix Pharmaceuticals. Dr. Kaunitz has served as a consultant to or on the advisory board of AMAG, Mithra and Pfizer; and has received research support (to University of FL) from Allergan, Bayer Healthcare, and TherapeuticsMD. Drs. Graham, Bernick, and Mirkin are employees of TherapeuticsMD with stock/stock options., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Financial disclosure/conflicts of interest: J.A.S. (within the past year, or current) has grant/research support from: AbbVie, Inc., Bayer Healthcare LLC., Endoceutics, Inc., Ipsen, Myovant Sciences, ObsEva SA, TherapeuticsMD, Viveve Medical; has been a consultant/advisory boards of: Allergan, AbbVie, Inc., AMAG Pharmaceuticals, Inc., Bayer HealthCare Pharmaceuticals Inc., Camargo Pharmaceutical Services, LLC, CEEK Enterprises, LLC., Covance Inc., Dare’ Bioscience, Duchesnay USA, Hologic Inc., KaNDy/NeRRe Therapeutics Ltd., Madorra Pty Ltd., Mitsubishi Tanabe Pharma Development America, Inc., Sebela Pharmaceuticals Inc., Shionogi Inc., Sprout2 Inc., TherapeuticsMD; has served on the Speaker's bureaus of: AMAG Pharmaceuticals, Inc., Duchesnay USA, TherapeuticsMD; and is a stockholder (direct purchase) in: Sermonix Pharmaceuticals. J.H.L. consults for Allergan, AMAG, Bayer Healthcare, Daré, Ferring, Lupin, Mitsubishi-Tanabe, Sebela, and TherapeuticsMD and has received research support for clinical trials (paid to UH Cleveland Medical Center) from AbbVie, Allergan, Bayer Healthcare, Femasys, Ferring, and Palatin Technologies. D.F.A. has served as a consultant to AbbVie, Agile Therapeutics, Bayer Healthcare, Endoceutics, Evestra, Exeltis, InnovaGyn, Lupin, Mithra, OvsEva and TherapeuticsMD; and has received research support from Actavis, Bayer Healthcare, Endoceutics, Mithra, Myovant, ObsEva and TherapeuticsMD. He has stock in InnovaGyn and stock options from Agile Therapeutics. B.K. has served as a consultant for TherapeuticsMD and Sermonix. B.B., S.G., and S.M. are employees of TherapeuticsMD with stock/stock options. P.D.C. has nothing to disclose., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society.)

Objective: To evaluate the effect of a single-capsule, bioidentical 17β-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.

Objective: To examine responder rates and vasomotor symptom-free days with oral 17β-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.

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; C avg : average concentration; CI: confidence interval; C max : maximum concentration; C min : 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; t max : time to maximum concentration; VVA: vulvar and vaginal atrophy.

Objective: The aim of the study was to evaluate the clinically meaningful effect of oral TX-001HR (17β-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.

Objective: To examine the impact of a single-capsule 17β-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., Competing Interests: Financial disclosure/conflicts of interest: Dr. Black consults for and/or is on the advisory board of BioSyent, Duchesnay, and Pfizer. Dr. Minkin consults for AMAG, Duchesnay, Pfizer, and TherapeuticsMD. Drs. Graham, Bernick and Mirkin are employees of TherapeuticsMD with stock/stock options., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society.)

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.

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.

Objective: The aim of the study was to evaluate the effect of a single-capsule 17β-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.

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.

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 · pg/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.

Objective: The softgel 17β-estradiol (E2) vaginal inserts (4 and 10 μg; Imvexxy; TherapeuticsMD, Boca Raton, FL) are FDA approved for treating moderate to severe dyspareunia associated with postmenopausal vulvar and vaginal atrophy (VVA). The objective here was to determine responder rates at week 2 and whether week-2 findings predicted week-12 responders in the REJOICE trial., Methods: Postmenopausal women received E2 vaginal inserts 4, 10, or 25 μg, or placebo for 12 weeks. Proportion of responders (having ≥2 of the following: vaginal superficial cells >5%, vaginal pH <5.0, or dyspareunia improvement of ≥1 category) were calculated. Odds ratios (ORs) for positive response at week 12 given a positive response at week 2 were determined in the efficacy evaluable (EE) population., Results: The responder rate (in EE population [n = 695]) was 74% to 82% with E2 inserts versus 24% with placebo at week 2, and 72% to 80% versus 33% at week 12. Positive treatment responses were 9- to 14-fold higher with vaginal E2 than with placebo at week 2, and 5- to 8-fold higher at week 12. Response at week 2 predicted response at week 12 in the total population (OR 13.1; 95% CI, 8.8-19.7) and with active treatment only (OR 7.9; 95% CI, 4.7-13.2)., Conclusions: A high percentage of postmenopausal women with moderate to severe dyspareunia responded with the E2 softgel vaginal insert at week 2, and a positive response at week 2 predicted a positive response at week 12.

Objective: The perceptions and attitudes of menopause shared by men are largely unknown. This analysis characterized men's awareness and their understanding of their partner's menopausal transition., Methods: A 35-question, online survey was used to assess men's perceptions and attitudes toward menopause. Men were recruited from an online research marketplace and were eligible to participate if their female partners (45-64 years old) experienced ≥1 of the following symptoms: hot flashes, night sweats, sleepless nights, difficulty sleeping, low libido, mood swings, pain during sex, or vaginal dryness. Couples either lived together full time, or, if living separately, resided together regularly two or more times a week., Results: Of the 1,356 surveys sent to eligible men, 450 (33%) were completed. Most men were between 50 and 69 years (80%), married and not separated (90%), and lived with their partner full time (97%). Men were aware of the symptoms regularly experienced by their partner, with difficulty sleeping (54%) and lack of energy (49%) being frequently identified; these symptoms were attributed to menopause (26%) and/or aging (22%). Of those who were affected by symptoms (63%), most men reported they negatively impacted them (77%), their partners (70%), and relationships (56%). Men engaged in discussions with their partners regarding menopausal symptoms (72%) and believed they were somewhat/very influential (75%) in their partner's decision to seek treatment or make lifestyle adjustments., Conclusions: Overall, men are aware of their partner's menopausal transition and may influence decisions relating to symptom management. Educational interventions would further benefit men's awareness of menopause and available treatment options.Video Summary:http://links.lww.com/MENO/A424.

Objective: In the REPLENISH trial, women receiving TX-001HR-an oral, softgel capsule, combining 17β-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.

Objective: The aim of the study was to systematically review studies that evaluated endometrial hyperplasia or cancer incidence with unopposed vaginal estrogens., Methods: PubMed and EMBASE were searched from inception to August 2017 for relevant articles and abstracts. Bibliographies of review articles and abstracts of major women's health medical meetings were examined. Eligible studies (independently reviewed by 4 authors) had to report menopausal vaginal estrogen use and endometrial histology, or incidence of endometrial hyperplasia or cancer., Results: Of 5,593 abstracts from the literature search and 47 articles from other sources, 36 articles and 2 abstracts were eligible, describing 20 randomized controlled studies, 8 interventional studies, and 10 observational studies. Collectively, the studies did not support an increased risk of endometrial hyperplasia or cancer with low-dose vaginal estrogens. Rates of endometrial cancer and hyperplasia were 0.03% and 0.4%, respectively, from 20 randomized controlled trials (2,983 women) of vaginal estrogens. Overall, reports of endometrial hyperplasia were observed with various doses and durations and appeared sporadic (except 1.25 mg conjugated equine estrogens), consistent with endometrial hyperplasia rates in the general population. A Denmark registry study was an exception and may be of limited applicability to the United States. The Women's Health Initiative Observational Study showed no association (1.3 cases/1,000 women-years with vaginal estrogens versus 1.0/1,000 women-years for nonuse)., Conclusion: This systematic review supports the use of low-dose vaginal estrogens for treating vulvar and vaginal atrophy in menopausal women without a concomitant progestogen. This review does not support increased endometrial hyperplasia or cancer risk with low-dose, unopposed vaginal estrogens; however, longer-term, real-world data are needed.

Objective: The aim of the study was to describe the effects of TX-001HR (17β-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.

Objective: The aim of this study was to determine the clinical meaningfulness of TX-001HR in reducing moderate to severe vasomotor symptoms (VMS) in menopausal women with a uterus., Methods: In the REPLENISH study (NCT01942668), women with moderate to severe hot flushes (≥7/d or ≥50/wk) were enrolled in a VMS substudy and randomized to four doses of daily TX-001HR (17β-estradiol/progesterone) or placebo. Participants assessed improvement of their VMS by the Clinical Global Impression and the Menopause-Specific Quality of Life (MENQOL) questionnaire, which were used to define clinical responders, clinically important differences (CIDs) or minimal CID (MCID) in VMS frequency. Response thresholds were determined by nonparametric discriminant analyses utilizing bootstrapping methods., Results: In the modified intent-to-treat VMS substudy population (n = 726), statistically significantly more Clinical Global Impression-based clinical responders were observed with TX-001HR than placebo for MCID (weekly reduction of ≥25 moderate to severe VMS: 82-88% vs 69%; all, P < 0.05) and CID (weekly reduction of ≥39 VMS: 68%-73% vs 52%; all, P < 0.05) at week 12. Week 4 results were similar. For Menopause Quality of Life-based analysis, significantly more clinical responders were observed with TX-001HR than placebo for MCID (weekly reduction of ≥34 VMS: 74%-81% vs 55%; all, P < 0.01) and CID (weekly reduction of ≥44 VMS: 61%-69% vs 42%; all, P < 0.01) at week 12., Conclusions: TX-001HR provided clinically meaningful improvements (as measured by 2 different methods), in addition to statistically significant reductions, in menopausal VMS frequency. TX-001HR may provide a new option, as a single oral capsule of estradiol and progesterone (identical to the hormones naturally occurring in women) for the treatment of moderate to severe VMS in menopausal women with a uterus.

Objective: To evaluate and compare physicians' behaviors and attitudes regarding vulvar and vaginal atrophy (VVA) treatment in menopausal women, including women with breast cancer, using an internet-based survey., Methods: The WISDOM survey queried obstetricians and gynecologists (OB/GYNs) and primary care physicians (PCPs) with 23 multipart questions assessing behaviors and attitudes towards VVA treatment., Results: Of 2,424 surveys sent, 945 (39%) responded and 644 (27%) were completed. Of the menopausal women seen by OB/GYNs and PCPs, 44% to 55% reported having VVA symptoms. Physicians prescribed VVA treatments primarily because of effectiveness. Only 34% of OB/GYNs and 17% of PCPs felt comfortable prescribing VVA therapies to women with a personal history of breast cancer. In general, the most common VVA treatment recommended by all was prescription therapy (49%; with or without other therapies) in the form of US Food and Drug Administration-approved vaginal estrogen creams. More OB/GYNs (72%) than PCPs (47%) disagreed that VVA was best treated with over the counter than prescription products. Out-of-pocket cost and fear of risks associated with estrogens were believed to be the main barriers for why women choose not to get treated and why they discontinue treatment., Conclusions: More OB/GYNs than PCPs prescribed VVA treatment, especially vaginal estrogens, for menopausal women, but both groups generally had similar attitudes and behaviors regarding VVA treatment. Physician comfort was low when prescribing to women with a history of breast cancer, despite women's health medical societies supporting vaginal estrogen use in women with a history of estrogen-dependent breast cancer who were unresponsive to nonhormonal therapies when offered in consultation with their oncologist.

Objective: To characterize the impact of TX-001HR on the relationship between vasomotor symptom (VMS) improvement and quality of life and sleep., Methods: REPLENISH (NCT01942668) was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial, which evaluated four daily doses of 17β-estradiol and progesterone (E2/P4) combined in a single, oral, softgel capsule in postmenopausal women (40-65 years) with a uterus and moderate to severe VMS (≥7/day or ≥50/week). In post hoc analyses, growth models were used to examine relationships between linear changes in VMS frequency and severity over 12 weeks and changes from baseline in the Menopause-Specific Quality of Life (MENQOL; total score and VMS domain) and the Medical Outcomes Study-Sleep (total score, sleep problems indices I and II) questionnaire outcomes at 12 weeks with treatment compared with placebo., Results: Outcomes with all four E2/P4 doses were combined (n = 591) and compared with placebo (n = 135). In all 5 growth models, the effects of TX-001HR on MENQOL total score and vasomotor domain were significantly associated with changes in VMS frequency and severity observed over 12 weeks (all, P < 0.001). Treatment-mediated effects on MENQOL via VMS frequency and severity models were significant. Similar results were found with Medical Outcomes Study-Sleep total score and sleep problems indices., Conclusions: TX-001HR improvements in quality of life and sleep outcomes are associated with and may be mediated through improvements in VMS frequency and severity.

Objective: The aim of the study was to evaluate the effects of TX-001HR, a single-capsule 17β-estradiol-progesterone on sleep parameters in postmenopausal women with vasomotor symptoms (VMS) using the Medical Outcomes Study (MOS)-Sleep scale questionnaire in the REPLENISH trial., Methods: In the REPLENISH trial (NCT01942668), women were randomized to one of four doses of TX-001HR or placebo, and the 12-item MOS-Sleep questionnaire (secondary endpoint) was self-administered at baseline, week 12, and months 6 and 12. Changes from baseline in the MOS-Sleep total score and 7 subscale scores were analyzed for treatment groups versus placebo at all time points. Somnolence was also collected as an adverse event., Results: Women (mean age 55 y) were randomized to TX-001HR (estradiol/ progesterone [E2/P4] [mg/mg]) doses: 1/100 (n = 415), 0.5/100 (n = 424), 0.5/50 (n = 421), 0.25/50 (n = 424), or placebo (n = 151). TX-001HR significantly improved MOS-Sleep total score, Sleep Problems Index II subscale, and sleep disturbance subscale versus placebo at all time points, except with 0.25 mg E2/50 mg P4 at week 12. Differences in LS mean changes between TX-001HR and placebo for MOS-Sleep total scores ranged from -6.5 to -7.6 at 12 months (all; P ≤ 0.001). All doses of TX-001HR significantly improved the Sleep Problems Index I subscale at all time points. The sleep somnolence subscale significantly improved from baseline with 0.5 mg E2/100 mg P4 and 0.5 mg E2/50 mg P4 at month 12. The incidence of somnolence as a treatment-emergent adverse event ranged from 0.2% to 1.2% versus 0% with placebo., Conclusion: TX-001HR significantly improved MOS-Sleep parameters from baseline to week 12, which was sustained for up to 12 months, and was associated with a very low incidence of somnolence.

Objective: To review safety, efficacy and pharmacokinetic (PK) data from the phase 3 REJOICE trial, which evaluated a 17β-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.