Validation of an ICD-10 case-finding algorithm for endometrial cancer in US insurance claims.

PURPOSE: To evaluate the positive predictive value (PPV) of an endometrial cancer case finding algorithm using International Classification of Disease 10th revision Clinical Modification (ICD-10-CM) diagnosis codes from US insurance claims for implementation in a planned post-marketing safety study. Two algorithm variants were evaluated. METHODS: Provisional incident endometrial cancer cases were identified from 2016 through 2020 among women aged ≥50 years. One algorithm variant used diagnosis codes for malignant neoplasms of uterine sites (C54.x), excluding C54.2 (malignant neoplasm of myometrium); the other used only C54.1 (malignant neoplasm of endometrium). A random sample of medical records of recent incident provisional cases (2018-2020) was requested for adjudication. Confirmed cases showed biopsy evidence of endometrial cancer, documentation of cancer staging, or hysterectomy following diagnosis. We estimated the PPV of the variants with 95% confidence intervals (CI) excluding cases that had insufficient information. RESULTS: Of 294 provisional cases adjudicated, 85% were from outpatient settings (n = 249). Mean age at diagnosis was 69.3 years. Among the 294 adjudicated cases (identified with the broader algorithm variant), the same 223 were confirmed endometrial cancer cases by both algorithm variants. The PPV (95% CI) for the broader algorithm variant was 84.2% (79.2% and 88.3%), and for the variant using only C54.1 was 85.8% (80.9% and 89.8%). CONCLUSION: We developed and validated an algorithm using ICD-10-CM diagnosis codes to identify endometrial cancer cases in health insurance claims with a sufficiently high PPV to use in a planned post-marketing safety study.

Satisfaction with a Segesterone Acetate and Ethinyl Estradiol Contraceptive Vaginal System Among Recent Oral Contraceptive or Hormonal Contraceptive Vaginal Ring Users.

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.

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.

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 .

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.

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.

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.

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.

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.

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.

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

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

Physical characteristics and properties of estradiol softgel vaginal inserts.

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

Early onset of action with a 17ß-estradiol, softgel, vaginal insert for treating vulvar and vaginal atrophy and moderate to severe dyspareunia.

OBJECTIVE: The softgel 17ß-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.

Endometrial safety of low-dose vaginal estrogens in menopausal women: a systematic evidence review.

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.

Relationship between vasomotor symptom improvements and quality of life and sleep outcomes in menopausal women treated with oral, combined 17ß-estradiol/progesterone.

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 17ß-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.

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.

Increased Incidence of Endometrial Cancer Following the Women's Health Initiative: An Assessment of Risk Factors.

BACKGROUND: The Surveillance, Epidemiology, and End Result (SEER) database shows a variable increase in endometrial cancer incidence over time. The objective of this review was to examine published endometrial cancer rates and potential etiologies. METHODS: Endometrial cancer incidence was obtained from the SEER Program database from 1975 through 2014, and a test for trend in incidence was calculated. Changes in risk factors thought to be associated with endometrial cancer, including age, obesity, diabetes, diet and exercise, reproductive factors, and medications (hormone therapy [HT] including Food and Drug Administration [FDA]-approved and non-FDA-approved [compounded] estrogens and progestogens, tamoxifen, and hormonal contraceptives) were found through PubMed searches. Temporal trends of risk factors were compared with endometrial cancer trends from SEER. RESULTS: Although endometrial cancer rates were constant from 1992 to 2002 (women 50-74 years of age), they increased 2.5% annually with a 10% increase from 2006 to 2012 (trend test 0.82). Use of approved prescription estrogen-progestogen combination products decreased after the publication of the Women's Health Initiative (WHI) data, whereas other risk factors either remained constant or decreased during the same time; however, compounded bioidentical HT (CBHT) use increased coincident with the endometrial cancer increase. CONCLUSION: Endometrial cancer rate increases after the first publication of WHI data in 2002 may be associated with the decreased use of approved estrogen-progestogen therapy, the increase in CBHT use, and the prevalence of obesity and diabetes; potential relationships require further evaluation.

Evaluation of clinical meaningfulness of estrogen plus progesterone oral capsule (TX-001HR) on moderate to severe vasomotor symptoms.

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 (17ß-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.

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

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

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

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