Search

Objectives: To evaluate ovulation risk among women enrolling in an emergency contraception (EC) study by measuring contraceptive steroids and ovarian hormones., Study Design: We used standard chemiluminescent assays to evaluate endogenous hormones (estradiol, progesterone, follicle stimulating hormone, luteinizing hormone) and liquid chromatography-tandem triple quadrupole mass spectrometry to simultaneously analyze concentrations of ethinylestradiol, dienogest, norelgestromin (NGMN), norethindrone (NET), gestodene, levonorgestrel (LNG), etonogestrel (ENG), segesterone acetate, medroxyprogesterone acetate (MPA), and drospirenone in serum samples obtained at the time of enrollment in a recent study comparing oral ulipristal acetate and LNG EC in women with weight ≥80 kg reporting no recent use of hormonal contraception., Results: We enrolled 532 and obtained a valid baseline blood sample from 520 women. Of these, 117 (22.5%) had detectable concentrations of progestin (MPA [n = 58, 11.2%], LNG [50, 9.6%], ENG [11, 2.1%], NET [5, 0.96%], NGMN [3, 0.06%], or drospirenone [1, 0.02%]). LNG was co-detected in all three participants with samples containing NGMN. Multiple progestins were detected in eight other women: ENG/MPA (1), ENG/LNG (2), and MPA/LNG (5). Samples from 55 (10.6%) had concentrations of one or more progestin considered above the minimum level for contraceptive (MPA ≥ 0.1 ng/mL, n = 19; NGMN/LNG ≥ 0.2 ng/mL, n = 31; ENG ≥ 0.09 ng/mL, n = 8; NET ≥ 0.35 ng/mL, n = 4). We detected concentrations of serum progesterone ≥ 3 ng/mL, indicative of luteal phase (postovulation) status, in an additional 194 (37.3%) samples., Conclusions: More than one-third of enrolled in our clinical trial of oral EC had evidence of prior ovulation at the time of enrollment. Additionally, about 23% had evidence of recent use of hormonal contraception. These results would have decreased the expected risk of pregnancy in the study., Implications: Many participants in a recent clinical trial of oral emergency contraception did not appear to be at risk for pregnancy or would not have benefited from intervention due to cycle timing. Investigators should consider the effects of these findings on expected pregnancy rates when determining sample size in future EC clinical trials, particularly when using noninferiority designs or historical controls., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: To compare the efficacy of emergency contraception (EC) regimens used within 72 hours of unprotected intercourse in individuals weighing ≥80 kg., Study Design: We enrolled reproductive-aged healthy women in a multicenter, single-blind, randomized study of levonorgestrel 1.5 mg (LNG1X) and 3.0 mg (LNG2X) and ulipristal acetate 30 mg (UPA) (enrollment goal 1200). Key eligibility requirements included regular cycles, weight >/= 80kg, unprotected intercourse within 72 hours, no recent use of hormonal contraception, a negative urine pregnancy test (UPT), and willingness to abstain from intercourse until next menses. To assess our primary outcome of incidence of pregnancy, participants completed home UPTs; if no menses by 2-weeks post-treatment, or a positive UPT, they returned for an in-person visit with quantitative serum human chorionic gonadotropin and ultrasound., Results: We enrolled and randomized 532; 44 were not dosed or not evaluable for primary end point, leaving an analyzable sample of 488 (173 LNG1X, 158 LNG2X, 157 UPA) with similar demographics between groups (mean age 29.6 years [5.74], body mass index 37.09 kg/m 2 [6.95]). Five pregnancies occurred (LNG1X n = 1, LNG2X n = 1, UPA n = 3); none occurred during the highest at-risk window (day of ovulation and the 3 days prior). We closed the study before achieving our enrollment goal because the low pregnancy rate in all groups established futility based on an interim blinded analysis., Conclusions: Although slow enrollment limited our study power, we found no differences in pregnancy rates between EC regimens among women weighing 80 kg or more. Our results are not able to refute or support differences between the treatment arms., Clinical Trial Registration: ClinicalTrials.gov, www.clincialtrials.gov Clinical trials#: NCT03537768., Implications: Women weighing 80 kg or more experienced no differences in pregnancy rates between oral EC regimens but due to several significant study limitations including sample size and the lack of a study population at high risk of pregnancy, our results are not able to determine if differences in treatment effectiveness exist., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To study the role of PGE 2 in regulating plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) in human primary endometrial endothelial cells (HEECs) from women with normal menstrual bleeding (NMB) and heavy menstrual bleeding (HMB)., Design: In vitro study using endometrial endothelial cells., Setting: Research laboratory setting., Patients: Women with NMB and HMB provided endometrial biopsy samples., Interventions: Prostaglandin E 2 and PGE 2 receptor-selective agonists were administered to cultured HEECs., Main Outcome Measures: Levels of PAI-1 and tPA in NMB-HEECs and HMB-HEECs after treatment with PGE 2 and receptor-selective agonists., Results: Prostaglandin E 2 increased total PAI-1 levels in NMB-HEECs, but not in HMB-HEECs, which had higher baseline PAI-1 levels. PGE 2 receptors (PTGER)1 and PTGER2 agonists increased PAI-1 in NMB-HEECs, whereas PTGER3 and PTGER4 did not. Prostaglandin E 2 had no effect on tPA levels in either NMB-HEECs or HMB-HEECs., Conclusions: Prostaglandin E 2 , through PTGER1 and PTGER2, regulates the plasminogen activator system in NMB-HEECs, suggesting a role in reducing fibrinolytic activity during normal menstrual cycles. The lack of PGE 2 effect and elevated baseline PAI-1 in HMB-HEECs support using this in vitro model to further understand prostaglandin pathways in NMB and HMB., Competing Interests: Declaration of Interests S.S. and T.A.J. report funding from Jones Family Foundation, Eastern Virginia Medical School and Commonwealth Health Research Board for the submitted work. D.M.D. reports funding from Jones Family Foundation, Eastern Virginia Medical School and Commonwealth Health Research Board for the submitted work; funding from NIH, Organon & Co. (product donation – no direct financial support), Wisconsin National Primate Research Center, and American Heart Association; consulting fees from InnovaGyn Inc; InnovaGyn Inc, Chief Science Officer member of the Board of Directors; Society for the Study of Reproduction, Chair, Development Committee unpaid; Federation of American Societies for Experimental Biology (FASEB) Chair, Meetings Committee unpaid; and stock options from InnovaGyn Inc. outside the submitted work. D.F.A. reports funding from Jones Family Foundation, Eastern Virginia Medical School and Commonwealth Health Research Board for the submitted work; grant support for research from Jones Family Foundation at Eastern Virginia Medical School; and stock options as CEO of InnovaGyn, Inc outside the submitted work., (Copyright © 2024 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

With the aim to shorten the time for diagnosis and accelerate access to correct management, a non-invasive diagnostic test for endometriosis was developed and validated. The IVD test combines an ELISA test kit to quantify CA125 and BDNF concentrations in serum and a data treatment algorithm hosted in medical software processing results from the ELISA test and responses to six clinical variables. Serum samples and clinical variables extracted from psychometric questionnaires from 77 patients were collected from the Oxford Endometriosis CaRe Centre biobank (UK). Case/control classification was performed based on laparoscopy and histological verification of the excised lesions. Biomarkers serum concentrations and clinical variables were introduced to the software, which generates the qualitative diagnostic result ("positive" or "negative"). This test allowed the detection of 32% of cases with superficial endometriosis, which is an added value given the limited efficacy of existing imaging techniques. Even in the presence of various confounding medical conditions, the test maintained a specificity of 100%, supporting its suitability for use in patients with underlying medical conditions.

Objective: The aim of the study is to identify appropriate definitions and patient-reported outcome measures (PROMs) for each of the eight core outcomes previously selected for genitourinary symptoms associated with menopause: pain with sex, vulvovaginal dryness, vulvovaginal discomfort or irritation, discomfort or pain when urinating, change in most bothersome symptom, distress, bother or interference of genitourinary symptoms, satisfaction with treatment, and side effects., Methods: We conducted a systematic review to identify possible definitions and PROMs, including their measurement properties. Identified definitions and relevant PROMs with acceptable measurement properties were entered into an international consensus process involving 28 participants from 10 countries to achieve final recommendations for each core outcome., Results: A total of 87 publications reporting on 34 PROMs were identified from 21,207 publications screened. Of these 34 PROMs, 29 were not considered to sufficiently map onto the core outcomes, and 26 of these also had insufficient measurement properties. Therefore, only five PROMs corresponding to two core outcomes were considered for recommendation. We recommend the PROMIS Scale v2.0 - Sexual Function and Satisfaction: Vaginal Discomfort with Sexual Activity to measure the outcome of "pain with sexual activity" and the Day-to-Day Impact of Vaginal Aging (DIVA) Questionnaire to measure "distress, bother or interference" from genitourinary symptoms. Six definitions of "side effects" were identified and considered. We recommend that all trials report adverse events in study participants, which is a requirement of Good Clinical Practice., Conclusions: Suitable PROMs and definitions were identified to measure three of eight core outcomes. Because of the lack of existing measures, which align with the core outcomes and have evidence of high-quality measurement properties, future work will focus on developing or validating PROMs for the remaining five core outcomes., Competing Interests: Financial disclosure/conflicts of interest: M.G. received past funding from Effik SA. M.P. received institutional funding from University of Melbourne (Internal Grant Schemes), Royal Women's Hospital (Internal grant scheme), and Cancer Council NSW Project Grant RG 21-06, Centre for Research Excellence in Women's Health in Reproductive Life (CREWHiRL) Seed Funding and Project Support Grant, NHMRC (APP1163202), and Royal Children's Hospital Foundation. She received past funding from FertilityIQ webinar honorarium. She has received fee registration fees as an invited speaker by the Pacific Society of Reproductive Medicine 2023 Conference and had subsidized flights and accommodations as an invited speaker for the European Society of Human Reproduction and Embryology 2022 Conference. She was also given free registration as an invited speaker for the Annual Scientific Meeting of Breast Cancer Trials 2021. D.A. has consulted for Evestra, Exeltis, Lupin, Mithra, ObsEva, and TherapeuticsMD, received industry support for research from AbbVie, Mithra, Myovant, and ObsEva, and has stock holdings in Agile Therapeutics and InnovaGyn, Inc. R.B. was named CI on two grants to Monash University, one from the National Health and Medical Research Council of Australia and one from the Medical Research Future Fund for work not related to the current publication. M.C. has been paid for developing and delivering educational presentations for AllianceChicago, wrote a White Paper on GSM for Materna (no financial reimbursement), and is a member of The Menopause Society Board of Trustees, FDA BRUDAC Committee, and Grand Rounds Presenter University of Indians. S.R.D. reports honoraria from BesinsHealthcare, Mayne Pharma, Health Ed, BioSyent, Lawley Pharmaceuticals, Abbott Laboratories, and Que Oncology. She has served on advisory boards for Mayne Pharm, Astellas Pharmaceuticals, Theramex, Abbott Laboratories, and Gedeon Richterand and has been an institutional investigator for QueOncology and Ovoca Bio. L.K. has lectured and/or acted in an advisory capacity for Gedeon Richter, Dr. KADE Besins and Mithra. C.M.M. has served as a consultant for Scynexis and Ferring Pharmaceuticals, receives research funding from Scynexis, and receives Royalties from UpToDate. R.E.N. has ongoing relationships with Abbott, Astellas, Bayer HealthCare AG, Besins Healthcare, Exeltis, Fidia, Gedeon Richter, HRA Pharma, Merck Healthcare, Novo Nordisk, Shionogi Limited, Theramex, and Viatris. N.P. has lectured and/or acted in an advisory capacity for Abbott, Bayer, Besins, Gedeon Richter, Kora, Lawley, Mithra, Mylan, Novo Nordisk, Roche Diagnostics, SeCur, Shionogi, Theramex, and Viatris. S.R. has lectured and/or acted in an advisory capacity or conducted studies for Abbott, Bayer, Gedeon Richter, Mylan, Amgen, UCB, Theramex, and Viatris. J.S. receives grant/research support from AbbVie, Inc., Bayer Healthcare LLC., Dare´ Bioscience, Ipsen, Mylan/Viatris Inc., Myovant Sciences, and Sebela Pharmaceuticals Inc. He acts as a consultant is on advisory boards for Bayer HealthCare Pharmaceuticals Inc., Besins Healthcare, California Institute of Integral Studies (CIIS), Dare´ Bioscience, Femasys Inc., Khyria, Madorra Pty Ltd., Mayne Pharma, Inc., and Vella Bioscience Inc. He serves on speaker's bureaus for Astellas Pharma, Inc., Mayne Pharma, Inc., Myovant Sciences, Inc., Pfizer Inc., Pharmavite LLC., and Scynexis Inc. He is a stockholder (direct purchase) of Sermonix Pharmaceuticals. P.S. has received fees for giving educational presentations, and participating in advisory boards and conducting research by Besins Healthcare, Astellas, Mylan, Labatec, Exeltis, Effik, Theramex, and Gedeon-Richter. A.J.V. has received fees for presentations and participation in an advisory board from Besins and Theramex. W.W. has received institutional support with an unrestricted grant from Pfizer and sits on the advisory boards of Pfizer, Lupin, and Biosyent. She has received fees for educational presentations for Lupin, Astellas, Bayer and Pfizer, and Biosyent. She is currently president of the Canadian Menopause Society and a Board Member of the International Menopause Society. M.H. has received funding from Madorra for a study of a device to manage GU symptoms. All other authors report no conflicts of interest., (Copyright © 2024 by The Menopause Society.)

Objective: The aim of the study is to identify suitable definitions and patient-reported outcome measures (PROMs) to assess each of the six core outcomes previously identified through the COMMA (Core Outcomes in Menopause) global consensus process relating to vasomotor symptoms: frequency, severity, distress/bother/interference, impact on sleep, satisfaction with treatment, and side effects., Methods: A systematic review was conducted to identify relevant definitions for the outcome of side-effects and PROMs with acceptable measurement properties for the remaining five core outcomes. The consensus process, involving 36 participants from 16 countries, was conducted to review definitions and PROMs and make final recommendations for the measurement of each core outcome., Results: A total of 21,207 publications were screened from which 119 reporting on 40 PROMs were identified. Of these 40 PROMs, 36 either did not adequately map onto the core outcomes or lacked sufficient measurement properties. Therefore, only four PROMs corresponding to two of the six core outcomes were considered for recommendation. We recommend the Hot Flash Related Daily Interference Scale to measure the domain of distress, bother, or interference of vasomotor symptoms and to capture impact on sleep (one item in the Hot Flash Related Daily Interference Scale captures interference with sleep). Six definitions of "side effects" were identified and considered. We recommend that all trials report adverse events, which is a requirement of Good Clinical Practice., Conclusions: We identified suitable definitions and PROMs for only three of the six core outcomes. No suitable PROMs were found for the remaining three outcomes (frequency and severity of vasomotor symptoms and satisfaction with treatment). Future studies should develop and validate PROMs for these outcomes., Competing Interests: Financial disclosure/conflicts of interest: V.P. received past funding from Sigvaris AG. M.P. received institutional funding from University of Melbourne (Internal Grant Schemes), Royal Women's Hospital (Internal grant scheme), and Cancer Council NSW Project Grant RG 21-06, Centre for Research Excellence in Women's Health in Reproductive Life (CREWHiRL) Seed Funding and Project Support Grant, NHMRC (APP1163202), and Royal Children's Hospital Foundation. She received past funding from FertilityIQ webinar honorarium. She has received fee registration fees as an invited speaker by the Pacific Society of Reproductive Medicine 2023 Conference and had subsidized flights and accommodations as an invited speaker for the European Society of Human Reproduction and Embryology 2022 Conference. She was also given free registration as an invited speaker for the Annual Scientific Meeting of Breast Cancer Trials 2021. D.A. has consulted for Evestra, Exeltis, Lupin, Mithra, ObsEva, and TherapeuticsMD, received industry support for research from AbbVie, Mithra, Myovant, and ObsEva, and has stock holdings in Agile Therapeutics, InnovaGyn, Inc. N.A. receives ongoing institutional funding from the National Cancer Institute. J.C. is owner of JSCarpenter, LLC which received scale licensing fees from Mapi Research Trust (2022), consulting fees from the University of Wisconsin (spring 2022), and consulting fees from Simumetrix SMX Health (spring 2022). M.C. has been paid for developing and delivering educational presentations for Alliance Chicago, received fees for an educational video and speaking engagements with Fertility IQ, wrote a White Paper on GSM for Materna (no financial reimbursement), and is a member of The Menopause Society Board of Trustees. M.D. receives current institutional funding from National Institute of Health Research. She serves as a chief investigator on POISE study (research relevant to HRT) and a chief investigator for BLUSH study (research on treatment of menopause). She received past institutional funding from Best Practice & Research Clinical Obstetrics & Gynaecology as editor of volume on menopause management published 2022. She is an elected member of the Medical Advisory Council of the British Menopause Society, is a member of the ESHRE guideline update group on Premature Ovarian Insufficiency, is a member of the British Endocrine Society working group producing clinical guidelines on estrogen treatment, and is a member of the British Gynaecological Cancer Society working group producing clinical guidelines on HRT. T.H. received past funding from Besins and Astellas. M.H. receives ongoing funding from Rightsteps and current funding from Hello Therapeutics. L.K. has lectured and/or acted in an advisory capacity for Gedeon Richter, Dr. KADE Besins and Mithra. P.M. has received compensation as a member of the scientific advisory board of Astellas, Bayer, and Johnson & Johnson; compensation from AbbVie and Pfizer for consulting; and serves as a member of the scientific advisory board and has/had equity in Alloy, Estrigenix, and MidiHealth. She has received speaking fees and travel support from Mithra. R.E.N. has ongoing relationships with Abbott, Astellas, Bayer HealthCare AG, Besins Healthcare, Exeltis, Fidia, Gedeon Richter, HRA Pharma, Merck Healthcare, Novo Nordisk, Shionogi Limited, Theramex, and Viatris. N.P. has lectured and/or acted in an advisory capacity for Abbott, Lawley, Mithra, Novo, SeCur, and Viatris. S.R. has lectured and/or acted in an advisory capacity or conducted studies for Abbott, Bayer, Gedeon Richter, Mylan, Amgen, UCB, Theramex, and Viatris. J.S. receives grant/research support from AbbVie, Inc., Bayer Healthcare LLC., Dare´ Bioscience; Ipsen, Mylan/Viatris Inc., Myovant Sciences, Sebela Pharmaceuticals Inc. He acts as a consultant is on advisory boards for Bayer HealthCare Pharmaceuticals Inc., Besins Healthcare, California Institute of Integral Studies (CIIS), Dare´ Bioscience, Femasys Inc., Khyria, Madorra Pty Ltd., Mayne Pharma, Inc., and Vella Bioscience Inc. He serves on speaker's bureaus for Astellas Pharma, Inc., Mayne Pharma, Inc., Myovant Sciences, Inc., Pfizer Inc., Pharmavite LLC., Scynexis Inc. He is a stockholder (direct purchase) of Sermonix Pharmaceuticals. P.S. has received fees for giving educational presentations, participating in advisory boards and conducting research by Besins Healthcare, Astellas, Mylan, Labatec, Exeltis, Effik, Theramex, and Gedeon-Richter. A.J.V. has received fees for presentations and participation in an advisory board from Besins and Theramex. W.W. has received institutional support with an unrestricted grant from Pfizer and sits on the advisory boards of Pfizer, Lupin, and Biosyent. She has received fees for educational presentations for Lupin, Astellas, Bayer and Pfizer, and Biosyent. She is a board member of the International Menopause Society and the President of the Canadian Menopause Society. M.H. has received funding from Madorra for a study of a device to manage GU symptoms and is a clinical expert for the NICE Menopause Guidelines. J.T.G. is a speaker for NurtureMed Pharma, Bayer Phils, Corbridge Phils, and Zuellig Pharma. P.S. has a research consultancy relationship with Chugai Pharmaceuticals. H.J. receives grant funding from the National Institutes of Health, Merck, and Pfizer and is a consultant to Bayer, Merck, and Hello Therapeutics. She receives in kind support from Sage to her institution (drug provided to support NIH-funded trial), funds from Bayer support a pilot grant program she lead within an NIH-funded Center grant. Her spouse is employed by Arsenal Biosciences and receives equity from Merck Research Labs. N.J. is on the advisory board of Vira Health, UK. All other authors report no conflicts of interest., (Copyright © 2024 by The North American Menopause Society.)

Attempts have been made over the years to replace ethinyl estradiol (EE) in combined oral contraceptives (COCs) with the less potent natural estrogen estradiol (E 2 ), or its prodrug, E 2 valerate (E 2 V), to improve their safety and tolerability. Recently, a COC incorporating a novel weak natural estrogen, estetrol (E 4 ), combined with drospirenone, has become available. We present a comparative analysis of the three prevailing estrogens used in COCs, focusing on their structure-function relationships, receptor-binding affinity, potency, metabolism, pharmacokinetic parameters, and pharmacodynamics. The binding affinity of EE to estrogen receptor (ER)α is twice that of E 2 , whereas its affinity for ERβ is about one-half that of E 2 . E 4 has a lower binding affinity for the ERs than E 2 . The high potency of EE is notable in its dramatic increase in estrogen-sensitive hepatic globulins and coagulation factors. EE and E 2 undergo extensive and comparable metabolism, while E 4 produces only a very limited number of metabolites. E 4 has the highest bioavailability among the three estrogens, with E 2 having <5%. Studies demonstrate consistent ovulation inhibition, although a higher dose of E 4 (15 mg) in COCs is required to achieve follicular suppression compared to E 2 (1-3 mg) and EE (0.01-0.035 mg). E 2 and E 4 in COCs may be less stimulatory of coagulant proteins than EE. Studies with E 2 /dienogest suggest a comparable risk of venous thromboembolism to EE/levonorgestrel, while data assessing risk with an E 4 -based COC are insufficient. Nevertheless, the E 4 -based formulation shows promise as a potential alternative to EE and E 2 due to its lower potency and possibly fewer side effects., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: This study aimed to compare contraceptive efficacy and safety of drospirenone 4 mg in a 24/4-day regimen in nonobese and obese users and describe pharmacokinetics according to bodyweight., Study Design: We analyzed data from three drospirenone 4 mg trials (2 European and 1 United States) to report outcomes in nonobese (body mass index <30 kg/m 2 ) and obese (body mass index ≥30 kg/m 2 ) users. We used data from the US trial to calculate the Pearl Index (pregnancies per 100 woman-years) in nonbreastfeeding participants aged ≤35 years at enrollment for confirmed pregnancies. We assessed safety outcomes from all trials based on reported treatment-emergent adverse events. We evaluated pharmacokinetics by bodyweight in the US trial., Results: The three trials combined comprised 2152 nonobese and 425 obese participants, including 590 nonobese and 325 obese participants in the US trial. Eight nonobese and four obese participants had confirmed pregnancies in the US trial, resulting in Pearl Indices of 3.0 (95% CI: 1.3-5.8) and 2.9 (95% CI: 0.8-7.3), respectively. Two-hundred forty-four (11.3%) nonobese and 39 (9.2%) obese participants discontinued due to a treatment-emergent adverse event. The pharmacokinetic analysis included 814 participants with a median weight of 73 (interquartile range 61-89) kg and median plasma drospirenone exposure (AUC 0-24ss ) of 661.3 (interquartile range 522-828) ng∙h/mL. Changing bodyweight from the median to the fifth percentile (51 kg) or 95th percentile (118 kg) changed drospirenone exposure (AUC 0-24,ss ) by 22.2% and -23.6%, respectively., Conclusions: Drospirenone 4 mg demonstrated similar contraceptive efficacy for both nonobese and obese users despite a difference in exposure based on bodyweight., Implications: Our limited comparison between obese and nonobese users of drospirenone-only oral contraception demonstrated no evidence that efficacy or discontinuation for adverse events differs between groups. Serum drospirenone levels vary by bodyweight and may correlate with bleeding outcomes., (Copyright © 2023. Published by Elsevier Inc.)

Estetrol (E 4 ) has emerged as a novel and highly promising estrogen for therapeutic use. E 4 is a weak natural estrogen produced only in pregnancy. Because of its novelty, there is considerable interest by clinicians in how it is produced in pregnancy. Although the fetal liver plays a key role in its production, the placenta is also involved. A current view is that estradiol (E 2 ) formed in the placenta enters the fetal compartment and is then rapidly sulfated. E 2 sulfate then undergoes 15α-/16α-hydroxylation in the fetal liver thereby forming E 4 sulfate (phenolic pathway). However, another pathway involving 15α,16α-dihydroxy-DHEAS formed in the fetal liver and converted to E 4 in the placenta also plays a significant role (neutral pathway). It is not known which pathway predominates, but both pathways appear to be important in E 4 biosynthesis. In this commentary, we summarize the well-established pathways in the formation of estrogens in the nonpregnant and pregnant female. We then review what is known about the biosynthesis of E 4 and describe the 2 proposed pathways involving the fetus and placenta., Competing Interests: Declaration of Competing Interest FZS has previously received funding from Mithra Pharmaceuticals for manuscript writing, and is a consultant for Agile Therapeutics and owns stock in the company. DFA owns stock or options in Agile Therapeutics and Innova Gyn Inc., and is a consultant for AbbVie, Agile Therapeutics, Exeltis, Mayne Pharma, Mithra Pharmaceuticals, TherapeuticsMD. Eastern Virginia Medical School receives research funding from AbbVie, Bayer Healthcare, Estetra SRL (an affiliate company of Mithra Pharmaceuticals), Myovant Sciences, ObsEva, and TherapeuticsMD., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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.

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.)

Objective: This study employed population pharmacokinetic (popPK) models to predict levonorgestrel (LNG) and ethinyl estradiol (EE) exposure after dosing with the transdermal contraceptive TWIRLA® (LNG/EE TDS) as a 12-week extended regimen in a healthy female population., Methods: PopPK models were developed using data from a previously published phase 1, open-label, randomized clinical trial, ATI-CL14 (NCT01243580), in 36 healthy individuals. Models used cycle 2 data from 18 individuals who received the LNG/EE TDS, delivering LNG 120 μg/day and EE 30 μg/day, followed by a 1-week TDS-free period. Noncompartmental PK analyses were performed on simulated concentration-time profiles of 12 consecutive weeks of LNG/EE TDS use., Results: The simulated concentration-time profiles and PK parameters for the simulated extended regimen indicated that predicted LNG and EE exposures at week 12 were similar to week 3 (predicted geometric mean EE area under the concentration-time curve from time 0 to 168 h [AUC0-168] on week 3 was 0.2% lower than week 12 and LNG AUC0-168 on week 3 was 0.9% lower than week 12), suggesting both were at steady state by week 3. Therefore, no notable accumulation beyond that at week 3 is predicted for LNG and EE following a 12-week extended regimen. The results are supported by the accumulation ratios based on maximum concentration and the area under the curve being similar at weeks 3 and 12 for LNG and EE., Conclusion: These results indicate that a 12-week extended LNG/EE regimen would provide similar systemic hormonal exposure as that seen by week 3 in a standard 28-day regimen, without further hormonal accumulation. The data support the safe use of a non-daily, low-dose hormonal contraceptive in an extended regimen but should be confirmed in a clinical PK study., Competing Interests: Competing interests FZS: Consultant: Agile Therapeutics. DFA: Consultant: Agile Therapeutics, Bayer Healthcare, Exeltis, Mithra, Lupin, ObsEva; Grants: Bayer Healthcare, Dare Biosciences, Estetra, Myovant, ObsEva; Honoraria: Exeltis; Patent: pending; Member: DSMB; Board member: Diczfalusy foundation; Stock ownership: InnovaGyn Inc, Agile Therapeutics LRLL: Consultant: Agile Therapeutics. JP: Consultant: Agile Therapeutics. MP: Employee: Agile Therapeutics; Stock ownership: Agile Therapeutics. PK: Employee: Agile Therapeutics; Consultant: Voltron Therapeutics; Independent board director: Voltron Therapeutics; Support for business-related travel: Agile Therapeutics; Stipend: Laidlaw Venture Partners LLC Investment and Operations Committee; Stock ownership: Agile Therapeutics, Voltron Therapeutics., (Copyright: © 2022 Stanczyk et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: To evaluate tolerability and safety of estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg oral contraceptive using pooled data from two, multicenter, phase 3 trials., Study Design: The two trials enrolled participants aged 16-50 years with a body mass index ≤35.0 kg/m 2 to use E4/DRSP in a 24/4-day regimen for up to 13 cycles. We pooled data from participants who used at least one E4/DRSP dose and had a follow-up assessment to analyze adverse events (AEs), vital signs, and laboratory parameters, including serum lipids, glucose, glycated hemoglobin, and potassium. We consolidated similar Medical Dictionary for Regulatory Activities preferred terms into groupings., Results: Of 3725 participants enrolled, we included 3417 in the analyses of whom 1786 (52.3%) reported ≥1 AE. Most participants with reported AEs had AEs that investigators rated as mild or moderate (n = 1665, 93.2%); of participants reporting AEs, 1105 (61.9%) did so during cycles 1 to 3. In total, 981 (28.7%) participants experienced ≥1 treatment-related AE, most frequently related to bleeding complaints (n = 323, 9.5%), breast pain or tenderness (n = 136, 4.0%), acne (n = 113, 3.3%), and mood disturbance (n = 111, 3.2%). Discontinuation due to treatment-related AEs occurred in 272 participants (8.0%), with only bleeding complaints (n = 97, 2.8%) and mood disturbance (n = 38, 1.1%) at rates exceeding 1%. Three participants experienced serious AEs, which the site investigators considered treatment-related: one venous thromboembolism, one worsening of depression, and one ectopic pregnancy. We found no clinically relevant changes in weight, blood pressure, heart rate, or laboratory parameters during treatment., Conclusions: E4/DRSP is associated with a favorable tolerability and safety profile., Implications Statement: Pooling data allowed for a robust assessment of tolerability and safety, including relatively infrequent events. Other than bleeding complaints and mood disturbance, no adverse event resulted in E4/DRSP discontinuation at rates >1%. Post-marketing surveillance studies are needed to evaluate long-term safety of the E4/DRSP COC and population-based venous thromboembolism risks., (Copyright © 2022. Published by Elsevier Inc.)

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.

Bleeding irregularities are one of the major reasons for discontinuation of oral contraceptives (OCs), and therefore clinicians need to set expectations during consultations. In this review we provide an overview of bleeding data of recently marketed cyclic combined OCs (COCs) and one progestin-only pill (POP). We evaluated data from phase 3 trials (≥12 months) used to gain regulatory approval. Overall, each type of OC has its own specific bleeding pattern. These patterns however were assessed by using different bleeding definitions, which hampers comparisons between products. In COCs, the estrogen balances the effects of the progestin on the endometrium, resulting in a regular bleeding pattern. However, this balance seems lost if a too low dose of ethinylestradiol (EE) (e.g., 10 µg in EE/norethindrone acetate 1 mg) is used in an attempt to lower the risk of venous thromboembolism. Replacement of EE by 17β-estradiol (E2) or E2 valerate could lead to suboptimal bleeding profile due to destabilization of the endometrium. Replacement of EE with estetrol (E4) 15 mg in the combination with drospirenone (DRSP) 3 mg is associated with a predictable and regular scheduled bleeding profile, while the POP containing DRSP 4 mg in a 24/4 regimen is associated with a higher rate of unscheduled and absence of scheduled bleeding than combined products.

Objectives: To describe ovulation inhibition and safety of daily oral ulipristal acetate (UPA) over 84 days., Study Design: This multi-center phase 1 and/or 2 trial randomized participants to use oral ulipristal 10 mg or 5 mg daily or a 3 cycle regimen of 5 mg for 24 days followed by four placebo days. We stratified randomization by body mass index (BMI) <32 or 32-40 kg/m 2 . To estimate ovulation inhibition, the primary outcome, participants underwent transvaginal ultrasound and blood sampling twice weekly; we analyzed compliant participants who completed the 84 day study. Safety endpoints included 3 endometrial biopsies and liver chemistry tests., Results: We enrolled 180 participants and included 137 in the ovulation inhibition analyses. Progesterone values that remained below 3ng/mL throughout treatment suggested consistent ovulation inhibition in 52 of 137 (38%) participants; 25 of 47(53%), 20 of 44(45%), and 7 of 46(15%) among participants randomized to the 10 mg, 5 mg, and cyclic treatments, respectively (p < 0.01). Progesterone values consistently <3 ng/mL were more frequent in participants with a BMI > 32kg/m 2 (25/50(50%) vs 27/87(31%), p = 0.01). Average ulipristal concentrations were higher among participants with low progesterone concentrations (p < 0.01). Endometrial biopsies during treatment showed progesterone-receptor-modulator-associated endometrial changes in 52 of 164 participants (32%); 22 of 49(40%), 16 of 48(29%), and 14 of 51(26%) in women randomized to the 10 mg, 5 mg, and the cyclic treatments, respectively (p = 0.07, test-for-trend); these changes resolved after treatment cessation. Liver transaminase changes were rare., Conclusions: Oral ulipristal acetate over 12 weeks did not reliably suppress ovulation, particularly in the 5 mg cyclic-dose group. Ovulation inhibition and endometrial changes were dose dependent. Reversible endometrial changes occurred during treatment., Implications: Progesterone-receptor modulators have been suggested for daily oral contraception. Since progesterone concentrations suggest that ovulation occurred during treatment, further studies would be necessary to assess whether these were functional ovulations and to evaluate other possible mechanisms of contraception., (Copyright © 2022. Published by Elsevier Inc.)

Background: The most widely used copper intrauterine device (IUD) in the world (the TCu380A), and the only product available in many countries, causes side effects and early removals for many users. These problems are exacerbated in nulliparous women, who have smaller uterine cavities compared to parous women. We compared first-year continuation rates and reasons/probabilities for early removal of the TCu380A versus a smaller Belgian copper IUD among nulliparous users., Methods: This 12-month interim report is derived from a pre-planned interim analysis of a sub population and focused on key secondary comparative endpoints. In this participant-blinded trial at 16 centres in the USA, we randomised participants aged 17-40 in a 4:1 ratio to the NT380-Mini or the TCu380A. In the first year, participants had follow-up visits at 6-weeks and 3, 6, and 12-months, and a phone contact at 9 months; we documented continued use, expulsions, and reasons for removal. Among participants with successful IUD placement, we compared probabilities of IUD continuation and specific reasons for discontinuation using log-rank tests. This trial is registered with ClinicalTrials.gov number NCT03124160 and is closed to recruitment., Findings: Between June 1, 2017, and February 25, 2019, we assigned 927 nulliparous women to either the NT380-Mini ( n  = 744) or the TCu380A ( n  = 183); the analysis population was 732 (NT380-Mini) and 176 (TCu380A). Participants using the NT380-Mini, compared to the TCu380A, had higher 12-month continuation rates (78·7% [95% CI: 72·9-84·5%] vs. 70·2% [95% CI: 59·7-80·7], p  = 0·014), lower rates of removal for bleeding and/or pain (8·1% vs. 16·2%, p  = 0·003) and lower IUD expulsion rates (4·8% vs. 8·9%, p  = 0·023), respectively., Interpretation: The NT380-Mini offers important benefits for a nulliparous population compared to the TCu380A in the first twelve months, when pivotal experiences typically occur. Higher continuation rates with the NT380-Mini may avert disruptions in contraceptive use and help users avoid unintended pregnancy., Funding: Bill & Melinda Gates Foundation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and Mona Lisa, N.V. (Belgium)., Competing Interests: DH, PLC, and KN's institution (FHI 360) received funding from Bill & Melinda Gates Foundation and Mona Lisa, N.V. to conduct this study. The following investigators’ institutions received contract funding from FHI 360 (with funds originating from Bill & Melinda Gates Foundation) to help conduct this study: CAS, ID, BAC, ABG, CD, ALN. The following investigators’ institutions received contract funding from Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) to help conduct this study: DKT, JTJ, MDC, KOW, SBT, JLK, CD, MAT, DFA, PMC, AEB. These two employees of the NIH were supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) to help conduct this study: DLB and JEB. No author received personal financial payments for this work. No author has financial relationships with Mona Lisa, N.V. DH reports board membership on Society of Family Planning. CAS reports contracts or grants to institution from Bayer Pharma, Sebela Pharma, and Danco Pharma; royalties to self and institution from Atheneum Pharma; payment for expert testimony from Center for Reproductive Rights, Planned Parenthood Federation and ACLU; a U.S. Provisional Patent Application No. 62/777,369; honoraria from American Board of Obstetrics & Gynecology. DKT reports contracts or grants to institution from The Laura and John Arnold Foundation, Society of Family Planning Research Fund, the William and Flora Hewlett Foundation, the Willard L. Eccles Foundation, the Intermountain Community Care Foundation, Bayer Women's Health, Organon, Cooper Surgical, Medicines360, Sebela Pharmaceuticals and anonymous foundation. MCD reports contracts to institution from Chemo Research SL, Evofem, HRA Pharma, Medicines360, Merck, Sebela; consulting fees from Estetra SRL, FHI360, Libbs, Mayne, Medicines360; speaking honorarium from Gedeon Richter, Mayne; payment/reimbursement of expenses for travel to meetings to present research from Medicines360; payment/reimbursement of expenses for travel to meetings to present research or attend Advisory Board from Estetra SRL; payment/reimbursement of expenses for travel to attend Advisory Board from TherapeuticsMD; Advisory Board meetings with honorarium from Evofem, Fuji Pharma, Mayne, Merck, Searchlight and TherapeuticsMD; honorarium for duties as Deputy Editor of the journal Contraception. KOW reports grants or contracts to institution from Bayer Pharmaceuticals and honoraria for a remote consultancy from Bayer Pharmaceuticals. SBT reports contracts to institution from Sebela, Medicines 360, Bayer Healthcare, Chemo Research, S.L., Merck & Co.; DSMB for Merck & Co.; Advisory Board for Bayer Healthcare; Society of Family Planning board member; American Board of Obstetrics & Gynecology (Complex Family Planning Division Member). BAC reports contracts or grants to institution from Medicines360, Sebela, and Mylan; member of American College of Obstetrics and Gynecology working group. ABG reports grants or contracts to institution from Merck; royalties from Uptodate; consulting fees from Society of Family Planning; board member of Society of Family Planning. ALN reports contracts or grants to institution from Merck, Mylan, Myovant, Sagami Rubber Industries, Sebela; consulting fees from Agile Therapeutics, Bayer HealthCare, Mayne Pharma, Pfizer, TherapeuticsMD; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Agile Pharma, Bayer HealthCare, Myovant Sciences, Merck, TherapeuticsMD; support for attending meetings and/or travel from Agile Pharma, Bayer HealthCare, Myovant Sciences, Merck, Pfizer, TherapeuticsMD. MAT reports Board member of American Society for Reproductive Medicine. DFA reports grants or contracts to institution from Bayer Healthcare, Dare Biosciences, Estetra, Myovant, and ObsEva; consulting fees from Bayer Healthcare, Exeltis, Mithra, Lupin, ObsEva, Mithra; honoraria for lecture from Exeltis; DSMB member; Board of directors for Diczfalusy Foundation; stock ownership in InnovaGyn, Inc.; stock options with Agile Therapeutics. PMC reports consulting fees from Bayer to provide remote IUD consultative support to clinicians; payments to institution from Bayer for clinical research. AEB reports grants or contracts to institution from Merck & Co, Inc (USA) and Scope/Chemo (Spain); honorarium and travel to meetings from TherapeuticsMD; support for related work and travel as associate editor for ACOG Clinical Updates; support for travel/honorarium from American Board of Obstetrics & Gynecology. BK reports grants or contracts to institution from Contramed Pharmaceuticals (Sebela), Evofem Biosciences, Gynuity Health Projects; royalties from Uptodate; consulting fees from Merck. The remaining authors do not have any related relationships to disclose: JTJ, KN, ID, PLC, JLK, CD, JEB, DLB., (© 2022 The Author(s).)

Objective: To assess whether dose escalation (ie, doubling the dose) of emergency contraception that contains levonorgestrel (LNG) improves pharmacodynamic outcomes in individuals with obesity., Methods: We enrolled healthy, reproductive-age individuals with regular menstrual cycles, body mass index (BMI) higher than 30, and weight at least 176 lbs in a randomized pharmacodynamic study. After confirming ovulation (luteal progesterone level greater than 3 ng/mL), we monitored participants with transvaginal ultrasonography and blood sampling for progesterone, luteinizing hormone, and estradiol every other day until a dominant follicle measuring 15 mm or greater was visualized. At that point, participants received either oral emergency contraception with LNG 1.5 mg or 3 mg (double dose) and returned for daily monitoring for up to 7 days. Our primary outcome was the difference in the proportion of participants with no follicle rupture 5 days postdosing (yes or no) between groups. The study had 80% power to detect a 30% difference in the proportion of cycles with at least a 5-day delay in follicle rupture (50% decrease)., Results: A total of 70 enrolled and completed study procedures. The two groups had similar baseline demographics (mean age 28 years, BMI 38). We found no difference between groups in the proportion of participants without follicle rupture more than 5 days post-LNG dosing (LNG 1.5 mg: 18/35 [51.4%]; LNG 3.0 mg: 24/35 [68.6%], P=.14). Among participants with follicle rupture before 5 days, the time to rupture did not differ between groups (day at 75% probability of no rupture is day 2 for both groups)., Conclusion: Individuals with higher BMIs and weights experience a higher risk of failure of emergency contraception with LNG and exhibit an altered pharmacokinetic profile. However, the simple strategy of doubling the dose does not appear to be an effective intervention to improve outcomes., Clinical Trial Registration: ClinicalTrials.gov, 02859337., Competing Interests: Financial Disclosure Alison B. Edelman reports honoraria and travel reimbursement from ACOG, WHO, and Gynuity for committee activities and honoraria for peer review from the Karolinska Institute. She receives royalties from UpToDate, Inc. Oregon Health & Science University receives research funding from OHSU Foundation, Merck, HRA Pharma, and NIH, where she is the principal investigator. Jeffrey T. Jensen has received payments for consulting from AbbVie, Cooper Surgical, Bayer Health care, Merck, Sebela, and TherapeuticsMD. OHSU has received research support from AbbVie, Bayer Health care, Daré, Estetra SPRL, Medicines360, Merck, and Sebela. These companies and organizations may have a commercial or financial interest in the results of this research and technology. These potential conflicts of interest for Alison B. Edelman and Jeffrey T. Jensen have been reviewed and managed by OHSU. None of these have direct conflict with this manuscript. David F. Archer reports DFA grant support to Eastern Virginia Medical School from AbbVie, Bayer Healthcare, Dare, Mithra, Myovant Sciences, and ObsEva; consulting fees from Agile Therapeutics, Mithra, ObsEva and TherapeuticsMD; and stock options for Agile Therapeutics and InnovaGyn, Inc. Ganesh Cherala was involved in this study as a private consultant. He is employed by Gilead Sciences, which was not involved in this research. The other authors did not report any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To assess outcomes of women with uterine fibroids (UFs) and heavy menstrual bleeding (HMB) treated with 300 mg elagolix twice daily plus add-back therapy (E2 1 mg/NETA 0.5 mg once daily) or placebo who were not considered responders in pooled analysis of two phase 3, 6-month randomized clinical trials (Elaris UF-1 and UF-2). Methods: Responders were defined as women who met both primary end point bleeding criteria (<80 mL menstrual blood loss [MBL] during the final month and ≥50% reduction in MBL from baseline to the final month) and either completed the study or discontinued due to predefined reasons. Thus, women termed nonresponders who were analyzed in this study who met neither or one bleeding end point or met both criteria but prematurely discontinued treatment because of adverse events, perceived lack of efficacy, or required surgical or interventional treatment for UFs were analyzed in this study. This post hoc analysis assessed mean changes from baseline in MBL, as well as adverse events. Results: Among 367 women receiving elagolix with add-back with observed data, 89 (24%) were not considered responders. Within this subset, 17 (19%) women met both bleeding criteria but prematurely discontinued treatment for the reasons mentioned above, while 23 (26%) met one bleeding criterion and 49 (55%) met neither bleeding criteria, regardless of discontinuation status. Among all nonresponders, a numerical trend toward greater mean reductions in MBL was observed in those receiving elagolix with add-back, compared with placebo group nonresponders. No differences in adverse events were observed between responders and nonresponders. Conclusion: Forty of 89 (45%) women with HMB and UFs who were classified as nonresponders in the UF-1 or UF-2 trials may have had a clinically meaningful response to elagolix with add-back therapy because they met at least one of the objective bleeding criteria. Clinical Trial Registration: Clinicaltrials.gov, NCT02654054 and NCT02691494. (NEJM 2020; 382:328-340) DOI: 10.1056/NEJMoa1904351.

As a key mechanism in fibrinolysis and tissue remodeling, the plasminogen activator system has been suggested in the process of endometrial shedding and tissue remodeling. Previous studies have explored the role of estrogen, progesterone, and androgen receptors as well as elements of the renin-angiotensin-aldosterone system in shaping the morphology of the endometrium. This study investigates the distribution and concentrations of the mineralocorticoid receptor, glucocorticoid receptor, tissue plasminogen activator, urokinase plasminogen activator, and plasminogen activator inhibitor-1 within the endometrial stroma, glandular, and endothelial cells of the primate endometrium during artificial menstrual cycles. Our immunohistochemistry quantification shows mineralocorticoid and glucocorticoid receptors are ubiquitously distributed within the macaque endometrium with their patterns of expression following similar fluctuations to urokinase and tissue plasminogen activators particularly within the endometrial vasculature. These proteins are present in endometrial vasculature in high levels during the proliferative phase, decreasing levels during the secretory phase followed by rising levels in the menstrual phase. These similarities could suggest overlapping pathways and interactions between the plasminogen activator system and the steroid receptors within the endometrium. Given the anti-inflammatory properties of glucocorticoids and the role of plasminogen activators in endometrial breakdown, the glucocorticoid receptor may be contributing to stabilizing the endometrium by regulating plasminogen activators during the proliferative phase and menstruation. Furthermore, given the anti-mineralocorticoid properties of certain anti-androgenic progestins and their reduced unscheduled uterine bleeding patterns, the mineralocorticoid receptor may be involved in unscheduled endometrial bleeding., (© 2021. Society for Reproductive Investigation.)

Introduction: Estrogens used in women's healthcare have been associated with increased risks of venous thromboembolism (VTE) and breast cancer. Estetrol (E4), an estrogen produced by the human fetal liver, has recently been approved for the first time as a new estrogenic component of a novel combined oral contraceptive (E4/drospirenone [DRSP]) for over a decade. In phase 3 studies, E4/DRSP showed good contraceptive efficacy, a predictable bleeding pattern, and a favorable safety and tolerability profile., Areas Covered: This narrative review discusses E4's pharmacological characteristics, mode of action, and the results of preclinical and clinical studies for contraception, as well as for menopause and oncology., Expert Opinion: Extensive studies have elucidated the properties of E4 that underlie its favorable safety profile. While classical estrogens (such as estradiol) exert their actions via both activation of nuclear and membrane estrogen receptor α (ERα), E4 presents a specific profile of ERα activation: E4 binds and activates nuclear ERα but does not induce the activation of membrane ERα signaling pathways in specific tissues. E4 has a small effect on normal breast tissue proliferation and minimally affects hepatic parameters. This distinct profile of ERα activation, uncoupling nuclear and membrane activation, is unique.

Objective: To assess efficacy, cycle control, and safety of an oral contraceptive containing estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg., Study Design: Women aged 16 to 50 years with a body mass index ≤35 kg/m 2 enrolled in this multicenter, open-label, 13-cycle, phase 3 trial evaluating E4/DRSP in a 24-active/4-placebo regimen. Follow-up was scheduled at Cycles 2, 4, 7, and 10 and within 3 weeks of completing Cycle 13. Participants used daily diaries to record pill use and vaginal bleeding. We evaluated efficacy outcomes in women 16 to 35 years and bleeding patterns and safety (adverse events [AEs]) in all participants. We assessed overall and method-failure pregnancy rates using the Pearl index (PI) and life-table analysis. Scheduled bleeding included spotting or bleeding starting during the 4-day placebo period or first 3 days of the next cycle., Results: We enrolled 1864 women of whom 1674 were 16 to 35 years. Women 16 to 35 years had a PI of 2.65 (95% CI 1.73-3.88), method-failure PI of 1.43 (95% CI 0.7-2.39) and 13-cycle life-table pregnancy rate of 2.1%. Scheduled bleeding occurred in 82.9% to 87.0% of women per cycle; median duration was 4.5 days. Unscheduled bleeding decreased from 30.3% in Cycle 1 to 21.3% to 22.1% during Cycles 2 to 4 and remained stable (15.5% to 19.2%) thereafter. The most frequently reported AEs were headache (5.0%) and metrorrhagia (4.6%). One-hundred thirty-two (7.1%) women discontinued the study early for an AE, most commonly for metrorrhagia (0.9%) and menorrhagia (0.8%). No thromboembolic events occurred., Conclusion: E4/DRSP is an effective oral contraceptive with a predictable bleeding pattern for most women and low AE rates., Implications Statement: A new oral contraceptive with a novel estrogen, estetrol, combined with drospirenone has efficacy and safety within the range of other available oral contraceptives. Large phase 4 studies will be needed to confirm if this combination is associated with an improved adverse event profile or lower thrombosis risk., (Copyright © 2021. Published by Elsevier Inc.)

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.)

Drospirenone (DRSP) is a fourth-generation progestin that interacts with the progesterone receptor (PR) and androgen receptor (AR) in addition to uniquely interacting to the mineralocorticoid receptor (MR). The known effects of DRSP via the mineralocorticoid receptor (MR) are limited. This study seeks to determine if DRSP alters plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) in human immortalized endometrial endothelial cells (HEEC) and if such changes in the plasminogen activator system (PAS) are mediated through the MR or AR. The in vitro cell culture experiments utilizing an immortalized human endometrial endothelial cell line evaluated two concentrations of DRSP on PAI-1 and tPA levels in the culture media using specific enzyme-linked immunoassays (ELISA). Experiments adding DRSP with an androgen receptor blocker, flutamide, or a mineralocorticoid receptor agonist, aldosterone, were performed to elucidate which receptor(s) mediated the PAS effects. DRSP 10 μM significantly decreased both HEEC levels of PAI-1 and tPA to 0.75 ± 0.04 and 0.82 ± 0.05 of control, respectively. These direct effects were blunted by flutamide, an AR antagonist. PAI-1 and tPA were not changed by the MR agonist, aldosterone. DRSP significantly decreased both PAI-1 and tPA in the HEECs via the androgen receptor.

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 determine if coexisting adenomyosis limits the efficacy of elagolix, an oral gonadotropin-releasing hormone antagonist, with hormonal add-back therapy in reducing heavy menstrual bleeding in women with uterine fibroids., Design: Pooled analysis of two identical, double-blind, randomized, placebo-controlled, 6-month phase 3 trials (Elaris Uterine Fibroids [UF]-1 and UF-2)., Setting: A total of 153 gynecological clinical care settings in the United States and Canada., Patients: Premenopausal women (18-51 years) with >80 mL of menstrual blood loss (MBL)/cycle and uterine fibroids with and without coexisting adenomyosis diagnosed by ultrasound and/or magnetic resonance imaging at baseline., Interventions: Participants were randomized 1:1:2 to placebo, elagolix 300 mg twice daily alone, or elagolix 300 mg twice daily with estradiol 1 mg/norethindrone acetate 0.5 mg once daily., Main Outcome Measures: The primary endpoint was the proportion of women who had <80 mL of MBL during the final month and ≥50% reduction in MBL from baseline to the final month. Adverse events were monitored., Results: Of 786 women treated across the two trials, 16% (126 women) had coexisting adenomyosis. Among this subset, a significantly greater proportion of women who received elagolix with add-back therapy (77.1% [95% confidence interval, 66.2, 88.0]) met both primary endpoint criteria compared with women who received placebo (12.2% [95% confidence interval, 1.0, 23.4]). Adverse events most frequently reported in the elagolix with add-back adenomyosis subset were hot flushes (18.3%), nausea (11.7%), and night sweats (8.3%)., Conclusions: Elagolix with add-back therapy significantly reduced heavy menstrual bleeding in women with uterine fibroids and coexisting adenomyosis, suggesting that elagolix efficacy was not adversely affected by the presence of adenomyosis (Elaris UF-1 and UF-2 Clinical-Trials.gov numbers, NCT02654054 and NCT02691494)., (© 2021 The Author(s).)

Objective: In this post hoc analysis, we evaluated the impact of elagolix on dysmenorrhea and nonmenstrual pelvic pain across menstrual period (bleeding days) and nonmenstrual (nonbleeding) days., Methods: Data from two randomized, 6-month, placebo-controlled trials (Elaris Endometriosis (EM)-I and EM-II) of elagolix (150 mg once daily (QD) and 200 mg twice daily (BID)) in premenopausal women with moderate to severe endometriosis-associated pain (N = 1686) were pooled. Women recorded the presence of menstrual period and severity of dysmenorrhea or nonmenstrual pelvic pain in a daily electronic diary., Results: At baseline, women in the placebo group and both elagolix treatment groups reported moderate or severe dysmenorrhea, on average, 81% of their menstrual period days and moderate/severe nonmenstrual pelvic pain, on average, 56% of their nonmenstrual (nonbleeding) days. Compared with placebo at month 6, elagolix-treated women had a significantly lower mean (standard deviation (SD)) percentage of menstrual period days with moderate or severe dysmenorrhea (elagolix 150 mg QD = 52.4 (38.9), p = 0.002; elagolix 200 mg BID = 38.5 (43.6), p < 0.001, placebo = 61.3 (33.7)) and a significantly lower mean (SD) percentage of nonmenstrual (nonbleeding) days with moderate or severe nonmenstrual pelvic pain (elagolix 150 mg QD = 31.1 (35.8), p < 0.001; elagolix 200 mg BID = 19.7 (29.9), p < 0.001; placebo = 35.6 (33.9))., Conclusion: Following 6 months of elagolix treatment, women who still menstruated had a lower proportion of menstrual period days with moderate or severe dysmenorrhea compared with placebo, demonstrating pain reduction despite continued menses. Additionally, pain did not shift from dysmenorrhea to nonmenstrual pelvic pain, as the percentage of days with moderate or severe nonmenstrual pelvic pain was also reduced for elagolix-treated women compared with placebo., Trial Registration: The Elaris EM-I study is registered with the US National Library of Medicine, www.ClinicalTrials.gov, NCT01620528. The Elaris EM-II study is registered with the US National Library of Medicine, www.ClinicalTrials.gov, NCT01931670. Both studies are registered with the EU Clinical Trial Register, www.clinicaltrialsregister.ed, 2011-004295-11., Competing Interests: S.K.A. was a study investigator, has received research support from AbbVie and Sobi, and has served on the speakers’ bureau for AbbVie. S.K.A. reports personal fees from AbbVie and Myovant. S.S.S. was a study investigator in therapeutic trials for endometriosis and fibroids sponsored by Allergan, AbbVie, and Bayer, and served as a speaker and advisor for Allergan, AbbVie, Bayer, Hologic, Myovant, and Cooper Surgical. D.F.A. was a study investigator and has received grant support from Actavis and Glenmark; research support from Myovant, Mithra, and ObsEva; grant support, honoraria, and travel support from Bayer Healthcare, Endoceutics, Merck, Radius Health, Shionogi, and TherapeuticsMD; honoraria and travel support from Exeltis/CHEMO France, Pfizer, Sermonix Pharmaceuticals, and TEVA/HR Pharma; research support and consulting fees from AbbVie; and honoraria and travel support from Agile Therapeutics and Innovagyn. He also has an equity interest in Agile Therapeutics and an equity interest in Innovagyn. Y.M. and K.G. are AbbVie employees and have stock or stock/options. K.C. was an employee of AbbVie Inc. at the time the study was conducted and owns stock. K.C. also reports patent for “Methods of treating heavy menstrual bleeding” (PCT/US2018/043321). E.S. was a study investigator, has received research support from AbbVie, and has served on medical advisory boards and speakers’ bureaus for AbbVie, Ferring, and DOT Labs. The authors report no other conflicts of interest in this work., (© 2021 Agarwal et al.)

Background: Uterine fibroids are one of the most common neoplasms found among women globally, with a prevalence of approximately 11 million women in the United States alone. The morbidity of this common disease is significant because it is the leading cause of hysterectomy and causes significant functional impairment for women of reproductive age. Factors including age, body mass index, race, ethnicity, menstrual blood loss, fibroid location, and uterine and fibroid volume influence the incidence of fibroids and severity of symptoms. Elagolix is an oral gonadotropin-releasing hormone receptor antagonist that competitively inhibits pituitary gonadotropin-releasing hormone receptor activity and suppresses the release of gonadotropins from the pituitary gland, resulting in dose-dependent suppression of ovarian sex hormones, follicular growth, and ovulation. In Elaris Uterine Fibroids 1 and Uterine Fibroids 2, 2 replicate multicenter, double-blind, randomized, placebo-controlled, phase 3 studies, treatment of premenopausal women with elagolix with hormonal add-back therapy demonstrated reduction in heavy menstrual bleeding associated with uterine fibroids., Objective: This analysis aimed to evaluate the safety and efficacy of elagolix (300 mg twice a day) with add-back therapy (1 mg estradiol/0.5 mg norethindrone acetate once a day) in reducing heavy menstrual bleeding associated with uterine fibroids in various subgroups of women over 6 months of treatment., Study Design: Data were pooled from Elaris Uterine Fibroid-1 and Uterine Fibroid-2 studies, which evaluated premenopausal women (18-51 years) with heavy menstrual bleeding (>80 mL menstrual blood loss per cycle, alkaline hematin methodology) and ultrasound-confirmed uterine fibroid diagnosis. Subgroups analyzed included age, body mass index, race, ethnicity, baseline menstrual blood loss, fibroid location, and uterine and primary fibroid volume (largest fibroid identified by ultrasound). The primary endpoint was the proportion of women with <80 mL menstrual blood loss during the final month and ≥50% menstrual blood loss reduction from baseline to final month. Secondary and other efficacy endpoints included mean change in menstrual blood loss from baseline to final month, amenorrhea, symptom severity, and health-related quality of life. Adverse events and other safety endpoints were monitored., Results: The overall pooled Elaris Uterine Fibroid-1 and Uterine Fibroid-2 population was typical of women with fibroids, with a mean age of 42.4 (standard deviation, 5.4) years and a mean body mass index of 33.6 (standard deviation, 7.3) kg/m 2 and 67.6% of participants being black or African American women. A wide range of baseline uterine and fibroid volumes and menstrual blood loss were also represented in the overall pooled study population. In all subgroups, the proportion of responders to the primary endpoint, mean change in menstrual blood loss, amenorrhea, reduction in symptom severity, and improvement in health-related quality of life were clinically meaningfully greater for women who received elagolix with add-back therapy than those who received placebo and consistent with the overall pooled study population for the primary endpoint (72.2% vs 9.3%), mean change in menstrual blood loss (-172.5 mL vs -0.8 mL), amenorrhea (50.4% vs 4.5%), symptom severity (-37.1 vs -9.2), and health-related quality of life score (39.9 vs 8.9). Adverse events by subgroup were consistent with the overall pooled study population., Conclusion: Elagolix with hormonal add-back therapy was effective in reducing heavy menstrual bleeding associated with uterine fibroids independent of age, body mass index, race, ethnicity, baseline menstrual blood loss, fibroid location, and uterine and primary fibroid volume., (Copyright © 2020 AbbVie Inc. Published by Elsevier Inc. All rights reserved.)

While the most common symptom associated with endometriosis is pelvic pain, the systemic manifestations of the disease and the accompanying adverse psychological, emotional, social, familial, sexual, educational and workplace effects are increasingly recognized. Elagolix is an oral gonadotropin-releasing hormone receptor antagonist that is approved for the management of moderate to severe pain associated with endometriosis. However, the benefits of elagolix extend beyond reducing pain symptoms. This article reviews the non-pain systemic manifestations associated with endometriosis and summarizes the beneficial effects of elagolix on non-pain outcomes. This includes improvements in quality of life, reductions in fatigue and improvements in workplace and household productivity. These results indicate that elagolix provides non-pain benefits in women with endometriosis and improves outcomes that are clinically meaningful to patients., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: D.F.A. is a consultant to AbbVie, Agile Therapeutics, Exeltis, National Institute of Child Health and Human Development (NICHD), ObsEva and TherapeuticsMD, and receives grants/has contracts for clinical research from AbbVie, NICHD, Myovant, ObsEva and TherapeuticsMD. A.M.S. is an employee of AbbVie, Inc., and has stock/stock options. S.K.A. has served as a consultant for AbbVie and has received research support from AbbVie and DOBI. H.S.T. receives no personal funds from Pharma. Yale University received a grant to support his research from AbbVie., (© The Author(s), 2020.)

Uterine bleeding is a common reason why women discontinue menopausal hormone therapy (HT). This systematic review compared bleeding profiles reported in studies for continuous-combined HT approved in North America and Europe for moderate to severe vasomotor symptoms in postmenopausal women with a uterus. Non-head-to-head studies showed that uterine bleeding varies by formulation and administration route, with oral having a better bleeding profile than transdermal formulations. Cumulative amenorrhea over a year ranged from 18 to 61% with oral HT and from 9 to 27% with transdermal HT, as reported for continuous-combined HT containing 17β-estradiol (E2)/progesterone (P4) (56%), E2/norethisterone acetate (NETA) (49%), E2/drospirenone (45%), conjugated equine estrogens/medroxyprogesterone acetate (18-54%), ethinyl estradiol/NETA (31-61%), E2/levonorgestrel patch (16%), and E2/NETA patch (9-27%). Amenorrhea rates and the mean number of bleeding/spotting days improved over time. The oral E2/P4 combination was amongst those with lower bleeding rates and may be an appropriate alternative for millions of women seeking bioidentical HT and/or those who have bleeding concerns with other HT.

Objective: To evaluate serum estradiol (E2) concentrations during use of 90-day contraceptive vaginal rings releasing E2 75, 100, or 200 mcg/day and segesterone acetate (SA) 200 mcg/day to identify a dose that avoids hypoestrogenism., Study Design: We conducted a multicenter dose-finding study in healthy, reproductive-aged women with regular cycles with sequential enrollment to increasing E2 dose groups. We evaluated serum E2 concentrations twice weekly for the primary outcome of median E2 concentrations throughout initial 30-day use (target ≥40 pg/mL). In an optional 2-cycle extension substudy, we randomized participants to 2- or 4-day ring-free intervals per 30-day cycle to evaluate bleeding and spotting based on daily diary information., Results: Sixty-five participants enrolled in E2 75 (n = 22), 100 (n = 21), and 200 (n = 22) mcg/day groups; 35 participated in the substudy. Median serum E2 concentrations in 75 and 100 mcg/day groups were <40 pg/mL. In the 200 mcg/day group, median E2 concentrations peaked on days 4-5 of CVR use at 194 pg/mL (range 114-312 pg/mL) and remained >40 pg/mL throughout 30 days; E2 concentrations were 37 pg/mL (range 28-62 pg/mL) on days 88-90 (n = 11). Among the E2 200 mcg/day substudy participants, all had withdrawal bleeding following ring removal. The 2-day ring-free interval group reported zero median unscheduled bleeding and two (range 0-16) and three (range 0-19) unscheduled spotting days in extension cycles 1 and 2, respectively. The 4-day ring-free interval group reported zero median unscheduled bleeding or spotting days., Conclusions: Estradiol concentrations with rings releasing E2 200 mcg/day and SA 200 mcg/day avoid hypoestrogenism over 30-day use., Implications: A 90-day contraceptive vaginal ring releasing estradiol 200 mcg/day and segesterone acetate 200 mcg/day achieves estradiol concentrations that should avoid hypoestrogenism and effectively suppresses ovulation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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

Objective: We compared cervico-vaginal cytokines in hormone therapy (HT)-treated postmenopausal women with premenopausal women and explored the association of serum estradiol (E2) and progesterone (P4) with cervico-vaginal cytokines. Methods: Postmenopausal women were treated with oral E2 1 mg/day for 28 days, with oral P4 100 mg/day added for the last 14 days. Premenopausal women were evaluated over one menstrual cycle. Serum E2 and P4 levels and cervico-vaginal cytokines interleukin (IL)-8 and IL-1β were measured at baseline, 14 days, and 28 days and were estimated by specific enzyme-linked immunosorbent assays. Results: Among nine postmenopausal and seven premenopausal women, cervico-vaginal IL-8 levels were highest at baseline, decreased on day 14, and remained stable thereafter. Cervico-vaginal IL-1β levels were highest at baseline, decreased on day 14, and remained stable with HT in postmenopausal women while they increased in premenopausal women. Postmenopausal women treated with HT and premenopausal women had similar changes in IL-8 and IL-1β. Serum E2 levels negatively correlated with IL-8 and IL-1β levels. Increased serum E2 from HT was correlated with the decreased IL-8 level from baseline to day 14 ( p  = 0.03). Conclusion: Exogenous E2 and P4 decreased the cervico-vaginal IL-1β and IL-8 to those levels found in premenopausal women. These findings require confirmation in a larger prospective study.

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.

Context: Elagolix is an oral gonadotropin-releasing hormone (GnRH) antagonist recently approved for the treatment of endometriosis-associated pain and being developed for heavy menstrual bleeding associated with uterine fibroids., Objective: The objective was to evaluate the effects of elagolix on ovulation and ovarian sex hormones., Design and Setting: This was a randomized, open-label, multicenter study., Participants: Participants were healthy ovulatory women aged 18 to 40 years., Interventions: Elagolix was administered orally for 3 continuous 28-day dosing intervals at 100 to 200 mg once daily (QD), 100 to 300 mg twice daily (BID), and 300 mg BID plus estradiol/norethindrone acetate (E2/NETA) 1/0.5 mg QD., Main Outcome Measures: The main outcomes measures were ovulation rates measured by transvaginal ultrasound, progesterone concentrations, and hormone suppression., Results: Elagolix suppressed ovulation in a dose-dependent manner. The percentage of women who ovulated was highest at 100 mg QD (78%), intermediate at 150 and 200 mg QD and 100 mg BID (47%-57%), and lowest at 200 and 300 mg BID (32% and 27%, respectively). Addition of E2/NETA to elagolix 300 mg BID further suppressed the ovulation rate to 10%. Elagolix also suppressed luteinizing hormone and follicle stimulating hormone in a dose-dependent manner, leading to dose-dependent suppression of estradiol and progesterone. Elagolix had no effect on serum biomarker of ovarian reserve, and reduced endometrial thickness compared to the screening cycle., Conclusion: Women being treated with elagolix may ovulate and should use effective methods of contraception. The rate of ovulation was lowest with elagolix 300 mg BID plus E2/NETA 1/0.5 mg QD., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To evaluate contraceptive effectiveness and safety of oral drospirenone 4 mg 24/4-day regimen in the United States., Study Design: We performed a prospective, single-arm, multicenter phase 3 trial in sexually active women for up to thirteen 28-day treatment cycles. Primary outcome was the Pearl index, calculated using confirmed on-drug pregnancies and evaluable cycles in nonbreastfeeding women aged ≤ 35 years. We assessed adverse events (AEs), including hyperkalemia and venous thromboembolism., Results: Of 1006 women who received at least one dose of drospirenone, 352 women (35.0%) completed the trial and 654 (65.0%) women discontinued before trial end. Most participants (92.2%) were ≤ 35 years; one third had a body mass index (BMI) ≥ 30 kg/m 2 . Among nonbreastfeeding women aged ≤ 35 years, there were 17 pregnancies (Pearl index: 4.0; 95% confidence interval [CI], 2.3-6.4; n  = 953), of which three were unconfirmed and two were from sites excluded from the main analysis for major breaches of Food and Drug Administration regulations. The Pearl index was 2.9 (95% CI: 1.5-5.1) for confirmed pregnancies among 915 nonbreastfeeding women aged ≤ 35 years from sites with no protocol violations. Nearly all (95.4%) treatment-emergent AEs were mild or moderate in intensity. No cases of venous thromboembolism were reported. The frequency of hyperkalemia was 0.5%. Women with baseline systolic/diastolic blood pressure ≥ 130/85 mmHg had a mean reduction from baseline in blood pressure at exit visit (- 8.5/- 4.9 mmHg; n  = 119). No other clinically relevant changes were observed. Participant satisfaction was high., Conclusion: Drospirenone 4 mg 24/4 regimen provides effective contraception with a good safety/tolerability profile in a broad group of women, including overweight or obese women., Implications: This new progestin-only contraceptive, drospirenone 4 mg in a 24/4 regimen, provides a contraceptive option for the majority of women regardless of blood pressure or BMI., (© 2020 The Authors.)

Background: Uterine fibroids are hormone-responsive neoplasms that are associated with heavy menstrual bleeding. Elagolix, an oral gonadotropin-releasing hormone antagonist resulting in rapid, reversible suppression of ovarian sex hormones, may reduce fibroid-associated bleeding., Methods: We conducted two identical, double-blind, randomized, placebo-controlled, 6-month phase 3 trials (Elaris Uterine Fibroids 1 and 2 [UF-1 and UF-2]) to evaluate the efficacy and safety of elagolix at a dose of 300 mg twice daily with hormonal "add-back" therapy (to replace reduced levels of endogenous hormones; in this case, estradiol, 1 mg, and norethindrone acetate, 0.5 mg, once daily) in women with fibroid-associated bleeding. An elagolix-alone group was included to assess the impact of add-back therapy on the hypoestrogenic effects of elagolix. The primary end point was menstrual blood loss of less than 80 ml during the final month of treatment and at least a 50% reduction in menstrual blood loss from baseline to the final month; missing data were imputed with the use of multiple imputation., Results: A total of 412 women in UF-1 and 378 women in UF-2 underwent randomization, received elagolix or placebo, and were included in the analyses. Criteria for the primary end point were met in 68.5% of 206 women in UF-1 and in 76.5% of 189 women in UF-2 who received elagolix plus add-back therapy, as compared with 8.7% of 102 women and 10% of 94 women, respectively, who received placebo (P<0.001 for both trials). Among the women who received elagolix alone, the primary end point was met in 84.1% of 104 women in UF-1 and in 77% of 95 women in UF-2. Hot flushes (in both trials) and metrorrhagia (in UF-1) occurred significantly more commonly with elagolix plus add-back therapy than with placebo. Hypoestrogenic effects of elagolix, especially decreases in bone mineral density, were attenuated with add-back therapy., Conclusions: Elagolix with add-back therapy was effective in reducing heavy menstrual bleeding in women with uterine fibroids. (Funded by AbbVie; Elaris UF-1 and Elaris UF-2 ClinicalTrials.gov numbers, NCT02654054 and NCT02691494.)., (Copyright © 2020 Massachusetts Medical Society.)

Objective: To investigate whether rates of self-reported Woman's Condom (WC) clinical failure and semen exposure from a functionality study are comparable to results from a contraceptive efficacy substudy., Study Design: We structured our comparative analysis to assess whether functionality studies might credibly supplant contraceptive efficacy studies when evaluating new female condom products. Couples not at risk of pregnancy in the functionality (breakage/slippage/invagination/penile misdirection) study and women in the contraceptive efficacy study completed condom self-reports and collected precoital and postcoital vaginal samples for up to four uses of the WC. Both studies used nearly identical self-report questions and the same self-sampling procedures and laboratory for prostatic specific antigen (PSA), a well-studied semen biomarker. We compared condom failure and semen exposure proportions using generalized estimating equations methods accounting for within-couple correlation., Results: Ninety-five (95) efficacy substudy participants used 334 WC and 408 functionality participants used 1572 WC. Based on self-report, 19.2% WC (64 condoms) clinically failed in the efficacy substudy compared to 12.3% WC (194 condoms) in the functionality study (p=.03). Of the 207 WC efficacy uses with evaluable postcoital PSA levels, 14.5% (30 uses) resulted in semen exposure compared to 14.2% (184 uses) of the 1293 evaluable WC functionality study uses., Conclusions: When evaluating the ability of an experimental condom to prevent semen exposure, the rate of clinical condom failure reported by participants risking pregnancy in an efficacy substudy was significantly higher than the rate reported by participants not risking pregnancy in a functionality study. The rate of semen exposure, assessed by an objective biomarker was nearly identical for the two studies., Implications: Our results suggest that an objective marker of semen exposure in functionality studies could provide a reasonable alternative to contraceptive efficacy studies in evaluating risk of unintended pregnancy and inferring protection from sexually transmitted infection than condom failure rates based on self-report., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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

Introduction : Many women seek treatment to alleviate menopausal vasomotor symptoms (VMS). Numerous women use combination compounded hormone therapy (CHT) to achieve the benefits of estrogen/progesterone for endometrial protection. TX-001HR is a combination of bioidentical 17β-estradiol (E2) and progesterone (P4) in a single capsule designed for continuous daily use to treat moderate to severe VMS. Areas covered : This drug profile describes the efficacy and safety of 4 doses of this E2/P4 (mg/mg: 1/100, 0.5/100, 0.5/50, 0.25/50) for treating moderate to severe VMS in menopausal woman with a uterus. Expert opinion : In REPLENISH (NCT01942668), the two highest doses of TX-001HR significantly reduced VMS frequency and severity at 4 and 12 weeks versus placebo (co-primary endpoints); all doses met the primary endpoint of endometrial safety. Rates of amenorrhea were high and improved over time; the Menopause Quality of Life and Medical Outcomes Study-Sleep instruments improved with E2/P4. TX-001HR was well tolerated and had no clinically significant impact on vital signs, metabolic or coagulation parameters, or breast safety. The combination bioidentical E2/P4 capsule (1 mg/100 mg dose was FDA-approved as Bijuva in October 2018) may provide a safe, effective, rigorously studied alternative for women with a uterus who prefer CHT for relief of VMS.

Objective: This study aimed to evaluate improvement of dyspareunia and associated vaginal dryness with a 17β-estradiol softgel vaginal insert (TX-004HR; TherapeuticsMD, Boca Raton, FL, USA) in women with postmenopausal vulvar and vaginal atrophy (VVA). Methods: Postmenopausal women with VVA and moderate to severe dyspareunia received TX-004HR (4, 10, or 25 μg) or placebo in the 12-week, randomized, double-blind, placebo-controlled, phase 3 REJOICE trial. Post hoc analyses examined improvement levels in dyspareunia and concurrent vaginal dryness with TX-004HR and assessed the effects of patient characteristics on vaginal dryness treatment. Results: Significantly more women treated with TX-004HR (all doses) than placebo had complete resolution or substantial improvement in dyspareunia or vaginal dryness (concurrent with dyspareunia) by 12 weeks, observed as early as week 2 with most doses. TX-004HR significantly improved both dyspareunia and vaginal dryness at least one level versus placebo by week 12 in women with both symptoms. Subgroup analyses showed TX-004HR improved vaginal dryness associated with dyspareunia regardless of age, body mass index, uterine status, prior pregnancy, and vaginal birth number. Conclusion: TX-004HR provided clinically meaningful improvements in dyspareunia and vaginal dryness associated with dyspareunia in postmenopausal women with VVA. Clinicians may be able to use this information when discussing patients' expectations regarding symptom improvement with the estradiol vaginal insert.

Background: A ring-shaped, contraceptive vaginal system designed to last 1 year (13 cycles) delivers an average of 0·15 mg segesterone acetate and 0·013 mg ethinylestradiol per day. We evaluated the efficacy of this contraceptive vaginal system and return to menses or pregnancy after use., Methods: In two identically designed, multicentre, open-label, single-arm, phase 3 trials (one at 15 US academic and community sites and one at 12 US and international academic and community sites), participants followed a 21-days-in, 7-days-out segesterone acetate and ethinylestradiol contraceptive vaginal system schedule for up to 13 cycles. Participants were healthy, sexually active, non-pregnant, non-sterilised women aged 18-40 years. Women were cautioned that any removals during the 21 days of cyclic use should not exceed 2 h, and used daily paper diaries to record vaginal system use. Consistent with regulatory requirements for contraceptives, we calculated the Pearl Index for women aged 35 years and younger, excluding adjunctive contraception cycles, as the primary efficacy outcome measure. We also did intention-to-treat Kaplan-Meier life table analyses and followed up women who did not use hormonal contraceptives or desired pregnancy after study completion for 6 months for return to menses or pregnancy. The trials are registered with ClinicalTrials.gov, numbers NCT00455156 and NCT00263341., Findings: Between Dec 19, 2006, and Oct 9, 2009, at the 15 US sites, and between Nov 1, 2006, and July 2, 2009, at the 12 US and international sites we enrolled 2278 women. Our overall efficacy analysis included 2265 participants (1130 in the US study and 1135 in the international study) and 1303 (57·5%) participants completed up to 13 cycles. The Pearl Index for the primary efficacy group was 2·98 (95% CI 2·13-4·06) per 100 woman-years, and was well within the range indicative of efficacy for a contraceptive under a woman's control. The Kaplan-Meier analysis revealed the contraceptive vaginal system was 97·5% effective, which provided further evidence of efficacy. Pregnancy occurrence was similar across cycles. All 290 follow-up participants reported return to menses or became pregnant (24 [63%] of 38 women who desired pregnancy) within 6 months., Interpretation: The segesterone acetate and ethinylestradiol contraceptive vaginal system is an effective contraceptive for 13 consecutive cycles of use. This new product adds to the contraceptive method mix and the 1-year duration of use means that women do not need to return to the clinic or pharmacy for refills every few months., Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, the US Agency for International Development, and the WHO Reproductive Health Research Department., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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

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.

Objective: The aim of this study is to confirm the local beneficial effects of intravaginal dehydroepiandrosterone (DHEA, Prasterone) on moderate to severe dyspareunia or pain at sexual activity, the most frequent symptom of vulvovaginal atrophy due to menopause or genitourinary syndrome of menopause (GSM)., Methods: In a prospective, randomized, double-blind, and placebo-controlled phase III clinical trial, the effect of daily intravaginal 0.50% DHEA (6.5 mg) (Prasterone, EndoCeutics) was examined on four coprimary objectives, namely percentage of parabasal cells, percentage or superficial cells, vaginal pH, and moderate to severe pain at sexual activity (dyspareunia) identified by the women as their most bothersome vulvovaginal atrophy symptom. The intent-to-treat population included 157 and 325 women in the placebo and DHEA-treated groups, respectively., Results: After daily intravaginal administration of 0.50% DHEA for 12 weeks, when compared to baseline by the analysis of covariance test, the percentage of parabasal cells decreased by 27.7% over placebo (P < 0.0001), whereas the percentage of superficial cells increased by 8.44% over placebo (P < 0.0001), vaginal pH decreased by 0.66 pH unit over placebo (P < 0.0001), and pain at sexual activity decreased by 1.42 severity score unit from baseline or 0.36 unit over placebo (P = 0.0002). On the other hand, moderate to severe vaginal dryness present in 84.0% of women improved at 12 weeks by 1.44 severity score unit compared to baseline, or 0.27 unit over placebo (P = 0.004). At gynecological evaluation, vaginal secretions, epithelial integrity, epithelial surface thickness, and color all improved by 86% to 121% over the placebo effect (P < 0.0001 for all comparisons with placebo). Serum steroid levels remained well within the normal postmenopausal values according to the involved mechanisms of intracrinology. The only side effect reasonably related to treatment is vaginal discharge due to melting of the vehicle at body temperature and this was reported in about 6% of the participants., Conclusions: The daily intravaginal administration of 0.50% (6.5 mg) DHEA (Prasterone) has shown clinically and highly statistically significant effects on the four coprimary parameters suggested by the US Food and Drug Administration. The strictly local action of Prasterone is in line with the absence of significant drug-related adverse events, thus showing the high benefit-to-risk ratio of this treatment based upon the novel understanding of the physiology of sex steroids in women.

Objective: To evaluate elagolix, an oral gonadotropin-releasing hormone receptor antagonist, alone or with add-back therapy, in premenopausal women with heavy menstrual bleeding (greater than 80 mL per month) associated with uterine leiomyomas., Methods: This double-blind, randomized, placebo-controlled, parallel-group study evaluated efficacy and safety of elagolix in cohorts 1 (300 mg twice daily) and 2 (600 mg daily) with four arms per cohort: placebo, elagolix alone, elagolix with 0.5 mg estradiol/0.1 norethindrone acetate, and elagolix with 1.0 mg estradiol/0.5 mg norethindrone acetate. A sample size of 65 per group was planned to compare elagolix with add-back to placebo on the primary end point: the percentage of women who had less than 80 mL menstrual blood loss and 50% or greater reduction in menstrual blood loss from baseline to the last 28 days of treatment. Safety assessments included changes in bone mineral density., Results: From April 8, 2013, to December 8, 2015, 571 women were enrolled, 567 were randomized and treated (cohort 1=259; cohort 2=308), and 80% and 75% completed treatment, respectively. Participants had a mean±SD age of 43±5 years (cohort 2, 42±5 years), and 70% were black (cohort 2, 74%). Primary end point responder rates in cohort 1 (cohort 2) were 92% (90%) for elagolix alone, 85% (73%) for elagolix with 0.5 mg estradiol/0.1 mg norethindrone acetate, 79% (82%) for elagolix with 1.0 mg estradiol/0.5 mg norethindrone acetate, and 27% (32%) for placebo (all P<.001 vs placebo). Elagolix groups had significant decreases compared with placebo in lumbar spine bone mineral density, which was attenuated by adding 1.0 mg estradiol/0.5 mg norethindrone acetate., Conclusion: Elagolix with and without add-back significantly reduced menstrual blood loss in women with uterine leiomyomas. Add-back therapy reduced hypoestrogenic effects on bone mineral density., Clinical Trial Registration: ClinicalTrials.gov, NCT01817530; EU Clinical Trial Register, 2013-000082-37.

Objective: To evaluate the efficacy and safety of elagolix, an oral, nonpeptide gonadotropin-releasing hormone antagonist, over 12 months in women with endometriosis-associated pain., Methods: Elaris Endometriosis (EM)-III and -IV were extension studies that evaluated an additional 6 months of treatment after two 6-month, double-blind, placebo-controlled phase 3 trials (12 continuous treatment months) with two elagolix doses (150 mg once daily and 200 mg twice daily). Coprimary efficacy endpoints were the proportion of responders (clinically meaningful pain reduction and stable or decreased rescue analgesic use) based on average monthly dysmenorrhea and nonmenstrual pelvic pain scores. Safety assessments included adverse events, clinical laboratory tests, and endometrial and bone mineral density assessments. The power of Elaris EM-III and -IV was based on the comparison to placebo in Elaris EM-I and -II with an expected 25% dropout rate., Results: Between December 28, 2012, and October 31, 2014 (Elaris EM-III), and between May 27, 2014, and January 6, 2016 (Elaris EM-IV), 569 participants were enrolled. After 12 months of treatment, Elaris EM-III responder rates for dysmenorrhea were 52.1% at 150 mg once daily (Elaris EM-IV 550.8%) and 78.2% at 200 mg twice daily (Elaris EMIV 575.9%). Elaris EM-III nonmenstrual pelvic pain responder rates were 67.5% at 150 mg once daily (Elaris EM-IV 566.4%) and 69.1% at 200 mg twice daily (Elaris EM-IV 567.2%).”After 12 months of treatment, Elaris EM-III dyspareunia responder rates were 45.2% at 150 mg once daily (Elaris EM-IV=45.9%) and 60.0% at 200 mg twice daily (Elaris EM-IV=58.1%). Hot flush was the most common adverse event. Decreases from baseline in bone mineral density and increases from baseline in lipids were observed after 12 months of treatment. There were no adverse endometrial findings., Conclusion: Long-term elagolix treatment provided sustained reductions in dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia. The safety was consistent with reduced estrogen levels and no new safety concerns were associated with long-term elagolix use., Clinical Trial Registration: ClinicalTrials.gov, NCT01760954 and NCT02143713.