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Objectives: The Women's Health Initiative study reported an increased risk of venous thromboembolism among menopausal women treated with conjugated equine estrogens/medroxyprogesterone acetate (CEE/MPA) versus placebo. Newer hormone therapies may have a lower venous thromboembolism risk. The study compared the risk of venous thromboembolism between women treated with the combined oral product 17β-estradiol/micronized progesterone (E2/P4) and those treated with oral CEE/MPA regimens., Study Design: In a retrospective longitudinal study using real-world claims data from April 2019 to June 2021, women aged 40 years or more treated with oral E2/P4 or oral CEE/MPA who did not have a venous thromboembolism diagnosis before first dispensing claim of CEE/MPA or E2/P4 identified on or after May 1st 2019 (index date) were observed for 6 months or more after the index date. Oral E2/P4 and oral CEE/MPA had been prescribed by the treating physician in real-world practice and were observed through pharmacy dispensing records., Main Outcome Measures: Venous thromboembolism risk was compared between women receiving oral E2/P4 versus oral CEE/MPA., Results: The study included 36,061 women treated with oral E2/P4 or oral CEE/MPA. In the analyses weighted by the inverse probability of treatment for control of potential confounding factors, the incidence of venous thromboembolism was significantly lower for oral E2/P4 compared with oral CEE/MPA (37/10,000 women-years for oral E2/P4 vs 53/10,000 women-years for oral CEE/MPA; incidence rate ratio 0.70, 95 % confidence interval: 0.53-0.92)., Conclusions: Real-world evidence suggests that the risk of venous thromboembolism is significantly lower among women treated with oral E2/P4 compared with oral CEE/MPA., Competing Interests: Declaration of competing interest N. Panay has lectured and acted in an advisory capacity for a number of pharma companies, including Theramex. R.E. Nappi has lectured and acted in an advisory/consultant capacity for a number of pharma companies, including Theramex. P. Stute has been a consultant with honorarium for Theramex. S. Palacios has been a consultant with honorarium for Theramex and has lectured and acted in and advisory/consultant capacity for other pharma companies. T. Paszkowski has been a consultant with honorarium for Theramex and received honoraria as consultant/member of advisory boards/lecturer from a number of pharma companies, including Theramex. R. Kagan has been an Advisor/Consultant with honorarium and has lectured for a number of pharma companies, including TherapeuticsMD. D. F. Archer has been a consultant with honorarium for a number of pharma companies, including TherapeuticsMD. J. Heroux is an employee and the owner of Heroux Consulting, which received research funding for the conduct of the current study. M. Boolell is an employee of and stockholder in Theramex., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

This paper reviews the efficacy, safety, and systemic absorption of estradiol with TX-004HR, an investigational, low-dose 17β-estradiol vaginal softgel capsule, designed to treat vulvar and vaginal atrophy (VVA) in postmenopausal women, with an improved user experience. In phase 2 (NCT02449902) and phase 3 REJOICE (NCT02253173) studies, TX-004HR significantly improved the proportions of vaginal superficial and parabasal cells and vaginal pH, and in the phase 3 study decreased the severity of dyspareunia, vaginal dryness, and vulvar and/or vaginal itching or irritation. In two randomized, phase 1 trials, estradiol C max and AUC 0-24 were significantly lower with 10μg and 25μg TX-004HR than with the same doses of an approved vaginal estradiol tablet. A substudy (n=72) of the REJOICE trial showed that estradiol C avg and AUC 0-24 with 4μg and 10μg TX-004HR were not different from placebo on days 1 and 14. While TX-004HR 25μg was associated with higher C avg and AUC 0-24 versus placebo on days 1 and 14, these levels remained within the postmenopausal range. Estradiol day-84 values for all three doses were not different from placebo, demonstrating no estradiol accumulation. All TX-004HR doses were well tolerated and had an acceptable safety profile in all reviewed studies. The local vaginal efficacy of TX-004HR was significantly better than that of placebo, while the overall safety profile was similar to that of placebo. Negligible to very low systemic estradiol absorption was observed whether given at 4, 10, or 25μg. If approved, TX-004HR may be an alternative option for women with symptomatic VVA without increasing mean systemic estradiol absorption above postmenopausal levels., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Several formulations combining estrogens and progestins for hormone therapy (HT) have been approved worldwide for the treatment of menopausal symptoms, yet recent data indicate a decline in their use and an increase in compounded bioidentical HT. Up to now, no single product combining natural 17β-estradiol and progesterone has been approved by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA). A phase 3 trial (REPLENISH) is underway to study a novel oral formulation of solubilized 17β-estradiol and natural progesterone combined in a single gelatin capsule (TX-001HR; TherapeuticsMD, Inc, Boca Raton, FL) for treating vasomotor symptoms (VMS) in postmenopausal women. The REPLENISH trial evaluates the efficacy and safety of TX-001HR (4 doses) versus placebo for the reduction of moderate to severe VMS frequency and severity at 4 and 12 weeks and evaluates the endometrial safety of the combinations at 1 year. TX-001HR contains hormones that are molecularly identical to endogenous estradiol and progesterone and is intended as an option for women who prefer bioidentical hormones; further, it does not contain peanut oil, a common allergen. The constituents of TX-001HR, in a pharmacokinetic report, showed similar bioavailability and safety compared with reference estradiol tablets and micronized progesterone capsules administered together. Published data suggest a safer profile of estradiol and natural progesterone compared with HT containing conjugated equine estrogens and progestins. This report summarizes the methodology of the REPLENISH trial and reviews the evidence suggesting clinical differences between HT containing progesterone or progestins, and estradiol or conjugated equine estrogens., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Objective: An objective was to analyze the time course of efficacy of daily intravaginal administration of 0.5% (6.5mg) DHEA (prasterone) for 52 weeks on the moderate to severe (MS) symptoms and signs of vulvovaginal atrophy (VVA)., Method: Five hundred twenty-one postmenopausal women were enrolled and received daily intravaginal administration of 0.5% DHEA in an open-label phase III study. The severity of the VVA symptoms examined in detail in the different groups., Results: A parallel improvement of pain at sexual activity was observed in women who had moderate to severe (MS) dyspareunia as their most bothersome symptom (MBS) (n=183) or not MBS (n=240) and MS without being MBS (n=57) with a 1.70 severity unit change in the MBS group for a decrease of 66.1% from baseline (p<0.0001 versus baseline) over 52 weeks. A further improvement of dyspareunia, namely 0.33 severity unit (19.4%), was observed with continuing treatment from 12 weeks to 52 weeks. Similar results were observed on vaginal dryness and irritation/itching. Highly significant beneficial effects (p<0.0001 versus baseline for all) were observed at gynecological examination on vaginal secretions, color, epithelial integrity and epithelial surface thickness., Conclusion: The present study shows, in addition to the parallel benefits on the three symptoms of VVA, that the choice of any of the MS symptoms as being or not being MBS by women has no influence on the observed therapeutic effect (NCT01256671)., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To determine the effect of 17beta-estradiol, medroxyprogesterone acetate, tibolone and tibolone metabolites on Angiopoietin-1, Tie-2, and tumor necrosis factor-alpha in Ishikawa cells, in vitro. We hypothesized that differential effects on angiogenic factors or inflammatory cytokines by individual hormones may be related to the endometrial bleeding in postmenopausal women using hormone therapy., Design: Ishikawa cells were cultured to 80% confluence, in vitro. After 24h incubation in serum-free media, 1.0, 0.1 and 0.01 microM of 17beta-estradiol, medroxyprogesterone acetate, tibolone, 3alpha-hydroxytibolone, 3beta-hydroxytibolone, and Delta4-tibolone were added to the Ishikawa cells. The cells plus steroids were then incubated for a further 24h. Total RNA was extracted from control and treated Ishikawa cells. After reverse transcription, Angiopoietin-1, Tie-2, tumor necrosis factor-alpha, and beta-actin cDNAs were amplified in a polymerase chain reaction spiked with 33p-dCTP. Relative abundance of Angiopoietin-1, Tie-2, and tumor necrosis factor-alpha mRNA was measured by scintillation spectroscopy., Results: 17Beta-estradiol and medroxyprogesterone acetate increased Angiopoietin-1 mRNA significantly higher than control, tibolone and tibolone hydroxy metabolites. Delta4-Tibolone at all concentrations tested did not increase Angiopoietin-1. None of the steroids tested at any concentration altered Tie-2 mRNA expression compared to control. 17Beta-Estradiol at 1.0 and 0.1 microM increased tumor necrosis factor-alpha mRNA significantly higher than control. Medroxyprogesterone acetate only at 1.0 microM increased tumor necrosis factor-alpha mRNA above control levels. Tibolone, 3alpha-hydroxytibolone, 3beta-hydroxytibolone, and Delta4-tibolone at every concentration had no effect on tumor necrosis factor-alpha mRNA abundance., Conclusions: Delta4-Tibolone did not stimulate Angiopoietin-1, while the other steroids had differential effects greater than control. None of the steroids changed the expression of Tie-2 mRNA. Tumor necrosis factor-alpha was increased by 17beta-estradiol and by the highest concentration of medroxyprogesterone acetate. We interpret these results as supportive of our hypothesis that differential effects on angiogenic factors or inflammatory cytokines by individual steroids may be related to the clinical occurrence of endometrial bleeding in postmenopausal women using hormone therapy.

Postmenopausal women using continuous combined estrogen/progestin therapy (ccEPT) are likely to have irregular bleeding or spotting. The use of estrogen with 12-14 days of a progestin is called cyclic (scEPT). This method results in regular endometrial bleeding at a scheduled time. The mechanism(s) involved in this regimen that result in bleeding could be similar to a spontaneous menstrual bleeding episode in a menachal woman, but there are no data in this regard. This aspect of regular scheduled bleeding in postmenopausal women will not be addressed in this article due to the paucity of information. The effect of cyclic progestogen with continuous estrogen on the endometrium could result in similar local mechanisms for endometrial bleeding as seen wth ccEPT. The mechanism(s) involved in endometrial bleeding is unknown. Several reports have highlighted a number of potential pathophysiologic mechanisms. Most of the investigation into the mechanisms involved in endometrial bleeding has been in women using progestin only contraceptive methods not ccEPT. The use of ccEPT could be construed as similar but not identical to that of a continuous progestin only contraceptive since the progestin in ccEPT is delivered daily. The potential mechanism(s) involved in endometrial bleeding includes the following: changes in the ratio of vascular endothelial growth factor to Thrombospondin-1 (pro- versus anti-angiogenic factors); alterations in metalloproteinases and tissue inhibitor of metalloproteinases (TIMP); changes in tissue factor a known haemostasis mediator in the endometrium; and increased endometrial leukocytes with a particular emphasis on uterine natural killer (uNK) cells. Each of these potential causes has been the subject of both in vivo and in vitro investigations. There is no clear linkage between any of these hypotheses and the onset or cessation of uterine bleeding in ccEPT users. No good therapeutic option to control the bleeding or spotting exists at this time. Evaluation and monitoring of the patient regarding endometrial safety is of paramount importance.