Search

Sanjay K Agarwal,1 Sukhbir S Singh,2 David F Archer,3 Yabing Mai,4 Kristof Chwalisz,5 Keith Gordon,6 Eric Surrey7 1Department of Obstetrics and Gynecology and Reproductive Sciences, Center for Endometriosis Research and Treatment, UC San Diego, La Jolla, CA, USA; 2Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; 3Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA, USA; 4 Statistics, AbbVie Inc, North Chicago, IL, USA; 5Clinical Development, AbbVie Inc, North Chicago, IL, USA; 6Medical Affairs, AbbVie Inc, North Chicago, IL, USA; 7Colorado Center for Reproductive Medicine, Lone Tree, CO, USACorrespondence: Sanjay K AgarwalDepartment of Obstetrics and Gynecology and Reproductive Sciences, Center for Endometriosis Research and Treatment, UC San Diego, 9500 Gilman Drive, #0633, La Jolla, CA, USATel +1 (858) 534-8930Email skagarwal@ucsd.eduObjective: 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.Keywords: bleeding, dysmenorrhea, elagolix, endometriosis, nonmenstrual pelvic pain

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: 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.)

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.

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 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).)

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.)

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: 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.)

Heavy menstrual bleeding (HMB) is a common gynecological problem that has a significant impact on a woman's quality of life and the activities of daily living. Due to the difficulty in accurately describing menstrual bleeding abnormalities using older terminology, the PALM-COEIN classification system of the Federation Internationale de Gynecologie et d'Obstetrique was proposed to describe and identify the etiology of abnormal endometrial bleeding. As there is no single pathway that is associated with HMB, there are several therapeutic interventions involving different molecular pathways to reduce HMB. This article will highlight the current evidence as it relates to the etiology of HMB as well as medical modalities of treatment.

Objective: To evaluate the safety and efficacy of elagolix vs. placebo and elagolix with low-dose E 2 /progestogen add-back therapy., Design: Proof-of-concept, dose-ranging, multiple-cohort study., Setting: Clinics., Patient(s): Premenopausal women with fibroids and heavy menstrual bleeding (menstrual blood loss [MBL] >80 mL per cycle)., Intervention(s): Three months' treatment with elagolix alone: 100 mg twice daily (BID), 200 mg BID, 300 mg BID, 400 mg once daily (QD), or 600 mg QD (all but the 600 mg QD arm were placebo controlled); or elagolix plus add-back therapy: 200 mg BID plus continuous low-dose E 2 0.5 mg/norethindrone acetate 0.1 mg or elagolix 300 mg BID plus E 2 1 mg continuously and cyclical P 200 mg., Main Outcome Measure(s): Least-squares mean percentage change in MBL; adverse events (AEs)., Result(s): Mean age was 41.8 years; 73.8% were black; mean baseline MBL was 267 mL. Of randomized women (elagolix alone, n = 160; placebo, n = 50; elagolix with add-back therapy, n = 61), 228 of 271 completed the 3-month treatment period. The MBL percentage change from baseline to last 28 days was significantly greater with elagolix alone (range, -72% to -98%; dose-dependent reduction was highest with 300 mg BID) vs. placebo (range, -8% to -41%); mean percentage changes with add-back regimens were -80% to -85%. Overall AEs were dose independent (elagolix alone, 70.0%-81.3%) but lower with placebo (56.0%) and add-back regimens (55.6%-70.6%). Hot flush was the most common AE (elagolix alone, 45.5%-62.5%; placebo, 12.0%; add-back regimens, 18.5%-26.5%)., Conclusion(s): Elagolix significantly reduced heavy menstrual bleeding in women with fibroids. Low-dose add-back regimens substantially reduced flushing., Clinical Trial Registration Number: NCT01441635., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To examine whether serum concentrations of C-reactive protein (CRP) and fibrinogen were associated with total score on a validated 12-item physical functioning scale and whether the magnitude and direction of these associations differed according to sex and physician-diagnosed arthritis. Method: Secondary analyses of cross-sectional data from the Third National Health and Nutrition Examination Survey were conducted using a representative sample of 4,606 older adults, 60 years and older. Results: Linear models suggested that overall physical functioning was strongly and independently associated with CRP (adjusted β = +.68, 95% confidence interval [CI] = [+0.42, +0.94]) and fibrinogen (adjusted β = +1.66, 95% CI = [+0.89, +2.42]); these associations were modified by physician-diagnosed arthritis status, with strongest associations observed among individuals diagnosed with rheumatoid arthritis or no arthritis and weakest association observed among those diagnosed with osteoarthritis. Conclusion: CRP and fibrinogen may be associated with poorer physical functioning in older adults, especially among those having rheumatoid arthritis or no arthritis., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Poor and inconsistent use of study products has hindered clinical HIV prevention studies. It is important to be able to monitor product adherence and protocol compliance in order to determine microbicide efficacy and safety more accurately. Current methods for monitoring adherence are subjective, non-specific, or invasive. Herein, we present a composite, objective measure of product adherence and protocol compliance to assess vaginal insertion, semen exposure and drug expulsion utilizing DNA, protein, and drug isolated directly from returned, vaginally used gel applicators., Methods: DNA, vaginal cells, and residual tenofovir were isolated from vaginally inserted applicators. Vaginal and semen biomarkers were amplified using a multiplex PCR to determine vaginal insertion. Vaginal cells were fixed followed by cytokeratin 4 immunocytochemistry to confirm DNA assessment of vaginal insertion. Tenofovir was extracted and quantitated through LC-MS/MS., Results: DNA isolated from vaginally inserted applicators were positive for vaginal bacteria DNA and the control eukaryotic gene, amelogenin, while manually handled, "sham", applicators were negative for both. Semen exposure was independently determined by simultaneous amplification of one or both Y-chromosomal genes, SRY and TSPY4. Vaginal insertion determination by DNA analysis was further confirmed by positive cytokeratin 4 (CK4) immunocytochemistry of vaginal cells remaining on the gel applicators. On the contrary, sham applicators provided very few cells when swabbed, and they were all negative for CK4. CK4 was not found in epidermal cells from the hand. Drug expulsion was detected through quantitation of residual gel present on the surface of returned applicators. Sham applicators had no detectable tenofovir., Conclusion: Utilizing a composite, triple marker based panel of DNA, protein, and drug present on the surface of returned vaginal gel applicators, it is possible to determine, objectively and non-invasively, product adherence, protocol compliance, and semen exposure in microbicide trials.

Objective: This phase 3 study evaluated the endometrial safety of bazedoxifene (BZA)/conjugated estrogens (CE) and bone mineral density (BMD) effects vs BZA alone, hormone therapy, and placebo (PBO)., Methods: The Selective estrogens, Menopause, And Response to Therapy (SMART)-5 trial was a multicenter, randomized, double-blind, PBO- and active-controlled study in postmenopausal women with an intact uterus (N = 1843; aged 40-65 years) seeking treatment for menopausal symptoms. Subjects received daily oral BZA 20 mg/CE 0.45 or 0.625 mg, BZA 20 mg, CE 0.45 mg/medroxyprogesterone acetate (MPA) 1.5 mg, or PBO. Primary endpoints were incidence of endometrial hyperplasia and percent change in lumbar spine BMD at 12 months. Secondary endpoints included additional osteoporosis parameters and assessments of tolerability and safety., Results: At 12 months, endometrial hyperplasia incidence was low (<1%) and similar among groups. The BZA/CE group showed significantly greater increases in lumbar spine and total hip BMD vs decreases with PBO (P < .001); the CE/MPA group had increased lumbar spine BMD compared with that in the BZA/CE group. The BZA 20 mg/CE 0.45 and 0.625 mg groups had cumulative amenorrhea rates similar to those with PBO and BZA and significantly higher than those with CE 0.45 mg/MPA 1.5 mg (P < .001). The incidence of breast tenderness with BZA/CE was similar to that with PBO and BZA and significantly lower than with that with CE/MPA (P < .01). Although adverse event (AE) rates were similar among the groups, the incidence of serious AEs overall and AE-related discontinuation rates were higher with CE/MPA than with BZA/CE, BZA, or PBO., Conclusions: BZA/CE showed low rates of endometrial hyperplasia and improved lumbar spine and total hip BMD and was generally safe and well tolerated.

Objective: Our objective was to provide a scholarly review of the published literature on menopausal hormonal therapy (MHT), make scientifically valid assessments of the available data, and grade the level of evidence available for each clinically important endpoint. PARTICIPANTS IN DEVELOPMENT OF SCIENTIFIC STATEMENT: The 12-member Scientific Statement Task Force of The Endocrine Society selected the leader of the statement development group (R.J.S.) and suggested experts with expertise in specific areas. In conjunction with the Task Force, lead authors (n = 25) and peer reviewers (n = 14) for each specific topic were selected. All discussions regarding content and grading of evidence occurred via teleconference or electronic and written correspondence. No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement., Evidence: Each expert conducted extensive literature searches of case control, cohort, and randomized controlled trials as well as meta-analyses, Cochrane reviews, and Position Statements from other professional societies in order to compile and evaluate available evidence. No unpublished data were used to draw conclusions from the evidence., Consensus Process: A consensus was reached after several iterations. Each topic was considered separately, and a consensus was achieved as to content to be included and conclusions reached between the primary author and the peer reviewer specific to that topic. In a separate iteration, the quality of evidence was judged using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system in common use by The Endocrine Society for preparing clinical guidelines. The final iteration involved responses to four levels of additional review: 1) general comments offered by each of the 25 authors; 2) comments of the individual Task Force members; 3) critiques by the reviewers of the Journal of Clinical Endocrinology & Metabolism; and 4) suggestions offered by the Council and members of The Endocrine Society. The lead author compiled each individual topic into a coherent document and finalized the content for the final Statement. The writing process was analogous to preparation of a multiauthored textbook with input from individual authors and the textbook editors., Conclusions: The major conclusions related to the overall benefits and risks of MHT expressed as the number of women per 1000 taking MHT for 5 yr who would experience benefit or harm. Primary areas of benefit included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes. Risks included venothrombotic episodes, stroke, and cholecystitis. In the subgroup of women starting MHT between ages 50 and 59 or less than 10 yr after onset of menopause, congruent trends suggested additional benefit including reduction of overall mortality and coronary artery disease. In this subgroup, estrogen plus some progestogens increased the risk of breast cancer, whereas estrogen alone did not. Beneficial effects on colorectal and endometrial cancer and harmful effects on ovarian cancer occurred but affected only a small number of women. Data from the various Women's Health Initiative studies, which involved women of average age 63, cannot be appropriately applied to calculate risks and benefits of MHT in women starting shortly after menopause. At the present time, assessments of benefit and risk in these younger women are based on lower levels of evidence.

Objective: To determine the effects of levonorgestrel (LNG) on serum androgens, sex hormone-binding globulin (SHBG), hair shaft diameter, and sexual function in women., Design: Substudy of a prospective randomized double-blind study in women using an LNG SC implant (LNG-SI), who were treated with doxycycline or placebo., Setting: Medical school department of obstetrics and gynecology., Patient(s): Forty women were enrolled; 36 completed the study., Intervention(s): Participants were randomized to doxycycline 20 mg or an identical placebo orally twice a day after LNG-SI insertion., Main Outcome Measure(s): Serum levels of total T (TT), free T (FT), androstenedione (A), dehydroepiandrosterone sulfate (DHEAS), dihydrotestosterone (DHT), androstanediol glucuronide (AG), SHBG, and LNG; hair shaft diameter; and sexual function using the Brief Index of Sexual Function for Women and the Arizona Sexual Experiences Scale were assessed., Result(s): Serum TT, A, DHT, DHEAS, and SHBG declined after LNG-SI insertion. No changes were found in FT, AG, hair shaft diameter, or sexual function. Serum LNG correlated with SHBG levels. There were no differences between the placebo and doxycycline groups., Conclusion(s): LNG reduced serum TT, A, DHT, DHEAS, and SHBG but had no effect on sexual function or markers of androgen bioactivity., (Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the effect of bazedoxifene/conjugated estrogens (BZA/CE), a tissue selective estrogen complex, on uterine bleeding in postmenopausal women., Design: International, multicenter, randomized, double-blind, placebo- and active-controlled, phase III study (Selective estrogen Menopause And Response to Therapy [SMART]-1)., Setting: Outpatient clinical., Patient(s): Healthy, postmenopausal women (N = 3,397) aged 40 to 75 years with an intact uterus., Intervention(s): Daily oral therapy with BZA 10, 20, or 40 mg, each with CE 0.625 or 0.45 mg, raloxifene 60 mg, or placebo., Main Outcome Measure(s): Cumulative amenorrhea profiles and the incidence of bleeding or spotting over 2 years., Result(s): Treatment with BZA 20 or 40 mg with CE 0.625 or 0.45 mg was associated with rates of cumulative amenorrhea (>83% during cycles 1-13 and >93% during cycles 10-13) and bleeding or spotting that were comparable to those with placebo. Subjects who received BZA 10 mg/CE 0.625 mg experienced slightly lower cumulative amenorrhea rates throughout the study compared with placebo-treated subjects., Conclusion(s): Postmenopausal women treated with BZA 20 or 40 mg with CE 0.625 or 0.45 mg had high rates of cumulative amenorrhea that were similar to those reported with placebo. This new menopausal therapy may offer a favorable bleeding and tolerability profile.

Objective: To address the endometrial safety of tibolone., Design: The Tibolone Histology of the Endometrium and Breast Endpoints Study (THEBES) is a randomized, double-blind, parallel-group trial of tibolone compared with continuous combined conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA)., Setting: Multi-country, multi-center ambulatory care setting., Patient(s): A total of 5,185 subjects were screened, and biopsies were obtained from 4,446 women., Intervention(s): Participants were randomized in a 1:1:2 ratio, to tibolone (1.25 or 2.5 mg/d) or CEE-MPA., Main Outcome Measure(s): The one-sided 95% confidence intervals for the incidence of hyperplasia or cancer were evaluated for tibolone compared with CEE-MPA., Result(s): Endometrial biopsy results at baseline: atrophic (87.29%), inactive (0.25%), proliferative (6.12%), secretory (2.86%), menstrual type (0.40%), and hyperplasia (0.18%). Only subjects with atrophic or inactive endometrium were eligible for this study, and 3% of the women at screening either had no tissue (0.18%) or had an amount of tissue that was insufficient for diagnosis (2.72%). Three thousand two hundred forty postmenopausal women with a mean (+/-SD) age of 54.4 +/- 4.4 years and a mean time since menopause of 4.5 +/- 3.6 years were randomized., Conclusion(s): The Tibolone Histology of the Endometrium and Breast Endpoints Study is a prospective, randomized clinical trial, designed to provide evidence of the endometrial safety of tibolone compared with estrogen and progestogen. Screening endometrial histology shows a low prevalence of endometrial hyperplasia (0.18%) and no carcinoma.

Background and Objectives: The Tibolone Histology of the Endometrium and Breast Endpoints Study is a multicenter, randomized, double-blind study designed to address the conflicting reports in the literature about the endometrial safety of tibolone (1.25 or 2.5 mg/d). Tibolone was compared with continuous combined conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) (0.625 + 2.5 mg/d)., Methods: Subjects were randomized in a 1:1:2 ratio to tibolone 1.25 mg/d, 2.5 mg/d, and CEE/MPA, respectively. The one-sided 95% confidence interval (CI) has been evaluated for the incidence of abnormal endometrial histology (hyperplasia or carcinoma) and hyperplasia and carcinoma separately for each of the two treatment groups and the treatment groups combined after 1 and 2 yr of treatment with tibolone, compared with CEE/MPA., Results: A total of 3240 women were randomized, with 3224 receiving at least one dose of study medication. The incidence and upper one-sided 95% CI for the incidence of abnormal endometrium (hyperplasia or carcinoma), and hyperplasia and carcinoma separately, were calculated at end point, yr 1, and yr 2. The incidence (upper one-sided 95% CI) of abnormal endometrium at end point was 0.0 (0.5), 0.0 (0.4), and 0.2 (0.5) in the tibolone 1.25 mg, 2.5 mg, and CEE/MPA groups, respectively. During the entire treatment period, amenorrhea was reported more frequently with tibolone 1.25 mg (78.7%) and 2.5 mg (71.4%) than CEE/MPA (44.9%)., Conclusion: The Tibolone Histology of the Endometrium and Breast Endpoints Study results confirm previous findings that tibolone does not induce endometrial hyperplasia or carcinoma in postmenopausal women, and it is associated with a better vaginal bleeding profile than CEE/MPA.

Background: Endometrial breakthrough bleeding is characterized by an inflammatory reaction and increased production of proinflammatory mediators, one of which may be epithelial neutrophil-activating peptide-78 (ENA-78), a chemokine with neutrophil-activating properties., Methods and Results: We therefore investigated the endometrial expression of ENA-78 in Norplant users as progestin-only contraceptive with various bleeding patterns (n=35) as compared with non-users with a normal menstrual cycle (n=55). The endometrial stromal cells (ESCs) were the major site of ENA-78 expression with the highest levels found during the secretory phase. The expression of ENA-78 was increased in Norplant users with irregular bleeding as compared with those with regular cycles and amenorrhoea. The levels of ENA-78 detected in uterine washes and sera after the use of Norplant for 3-6 months (n=25) increased compared with baseline (P < 0.05). These levels did not significantly change in Norplant users who received doxycycline (Dox) therapy (25 mg/twice daily for 6 months) when measured midway through or at the conclusion of study when compared with the baseline (n=25). Treatments with medroxyprogesterone acetate (MPA) and tumour necrosis factor-alpha (TNF-alpha) (25 ng/ml), but not 17beta-estradiol (E2) or E2 + MPA (10(-8) M), representing endometrium exposed to contraceptive and inflammatory conditions, respectively, increased the levels of ENA-78 production by ESCs, and this was reduced by co-treatments with Dox (25 microg/ml) (P < 0.05)., Conclusions: The endometrial production of ENA-78 is altered in progestin-only contraceptive users experiencing breakthrough bleeding and is regulated by MPA and TNF-alpha in ESCs. Although Dox therapy did not alter uterine ENA-78 secretion, its suppression in ESCs suggests that Dox, acting site-specifically and through an anti-inflammatory mechanism, may influence the outcome of breakthrough bleeding in contraceptive users.

Background: Increased production of pro-inflammatory mediators is considered central in the manifestation of events leading to irregular uterine bleeding in progestin-only contraceptive users. Evidence suggests that in addition to its antimicrobial property, doxycycline (Dox) acts as an anti-inflammatory agent mainly through the suppression of pro-inflammatory mediators., Methods: We tested this hypothesis in the endometrial environment using an in vitro model consisting of isolated human endometrial glandular epithelial and stromal cells and a human endometrial surface (HES) epithelial cell line cultured under defined conditions., Results: We found that Dox at doses ranging from 1 to 100 microg/ml had a limited growth-inhibitory effect on these cells, whereas Dox in a dose-dependent manner inhibited the production of tumour necrosis factor-alpha (TNF-alpha). Using multiplex cytokine/chemokine protein analysis to test a broader range of Dox activity, we found that Dox at 25 microg/ml either alone or in the presence of 17beta-estradiol (E2), medroxyprogesterone acetate (MPA) and E2+MPA (10(-8) M) as well as TNF-alpha (25 ng/ml), representing the endometrial environment exposed to contraceptives as well as inflammatory conditions, respectively, altered the production of multiple cytokines and chemokines as compared with untreated controls. These actions of Dox occurred in cell-, ovarian steroid- and cytokine/chemokine-dependent manners. Although Dox reduced the regulatory action of steroids on the production of these cytokines/chemokines, it was less effective on TNF-alpha-treated cells., Conclusions: The results support the hypothesis that Dox, by modulating the endometrial expression of multiple inflammatory-related cytokines/chemokines in a cell- and cytokine/chemokine-dependent manner, may have a therapeutic potential in patients experiencing irregular uterine bleeding, in particular in progestin-dominant contraceptive users.

Objective: To determine the effect of 17beta-estradiol, progesterone, medroxyprogesterone acetate, levonorgestrel, norethindrone, tibolone, and tibolone metabolites on vascular endothelial growth factor (VEGF) isoforms 121 and 165 mRNA in two breast cancer cell lines, MCF-7 (estrogen receptor rich) and T47-D (progesterone receptor rich), in vitro., Design: Prospective basic research study., Setting: Basic research laboratory., Patient(s): None., Intervention(s): MCF-7 and T47-D cells were cultured to 80% confluence in vitro. After 24 hours' incubation in serum-free media, 1.0, 0.1, and 0.01 microM of 17beta-estradiol, tibolone, 3alpha-hydroxytibolone and 3beta-hydroxytibolone were added to MCF-7 cells. Progesterone, medroxyprogesterone acetate, levonorgestrel, norethindrone, and Delta4 tibolone at 1.0, 0.1, and 0.01 microM were added to T47-D cells. The cells plus steroids were incubated for a further 24 hours., Main Outcome Measure(s): Isolation and identification of VEGF isoforms 121 and 165 using semiquantitative polymerase chain reaction, gel electrophoresis, with cyclophilin as an internal control., Result(s): 17beta-estradiol, tibolone, 3alpha-hydroxytibolone, and 3beta-hydroxytibolone had no effect on VEGF mRNA in MCF-7 cells. Progesterone, medroxyprogesterone acetate, levonorgestrel, and norethindrone increased VEGF mRNA in T47-D cells. Delta4-Tibolone also increased VEGF mRNA but to a lesser extent than the progestogens., Conclusion(s): 17beta-estradiol, tibolone, and tibolone hydroxy-metabolites had no effect on VEGF mRNA in MCF-7 cells. Progesterone and progestins increased VEGF mRNA in T47-D breast cancer cells, but Delta4-tibolone was less effective than progestogens on this angiogenic gene in the T-47 D cells. This differential effect may be related to breast cancer growth.

Objective: To determine the effect of 17beta-E(2), levonorgestrel, medroxyprogesterone acetate, and norethindrone on the expression of vascular endothelial growth factor (VEGF) isoforms 121 and 165 in Ishikawa cells in vitro., Design: Prospective basic research study., Setting: Basic research laboratory., Patient(s): None., Intervention(s): Ishikawa cells were cultured in vitro. After 24 hours' incubation in serum-free media, 1.0, 0.1, and 0.01 microM concentrations of E(2), levonorgestrel, medroxyprogesterone acetate, and norethindrone were added for a further 24 hours of incubation., Main Outcome Measure(s): Isolation and identification of VEGF isoforms 121 and 165 using semiquantitative polymerase chain reaction, gel electrophoresis, with beta-actin as an internal control., Result(s): Estradiol stimulated VEGF isoforms 121 and 165. The progestins studied increased mRNA for VEGF isoforms 121 and 165 at all doses. Medroxyprogesterone acetate resulted in the greatest increase in both VEGF 121 and 165 compared with norethindrone and levonorgestrel., Conclusion(s): Estradiol and progestins increased VEGF 121 and 165 isoform mRNA in Ishikawa cells in vitro. We hypothesize that differences in VEGF expression may be associated with the irregular bleeding during progestin use in clinical situations.

This overview of the current status of medical problems that affect women is related to current studies on pathophysiology and therapeutic interventions using nonhuman primates to demonstrate the utility of the primate model for the study of disease processes in women. The current medical literature on women's health is compared with the literature on nonhuman primate research. The findings reviewed in the articles of ILAR Journal Volume 45 Issue 2 of 2004 are evaluated in the context of the scope and problems associated with disease entities in women. Nonhuman primate research with known information regarding women's disease is discussed, and the utility of the animal model for the study of human disease is highlighted, based on its significant relevance due to similarities of nonhuman primate and human subjects' physiology, metabolism, and responses to therapeutic interventions. Additional advantages of the animal model include the ability to control the experimental environment and the capacity to perform chronic study procedures. These findings allow us to utilize the nonhuman primate as the most relevant model in the animal world for the study of human disease processes.

Objective: To compare the effects of the contraceptive patch to oral contraceptives (OCs) on follicular size and incidence of ovulation in normal cycles and after dosing errors., Design: Randomized, open-label., Setting: Twelve centers., Patient(s): One hundred twenty-four ovulatory women., Intervention(s): Subjects received either the patch (groups 1 and 2) or one of three OCs. Correct dosing occurred in cycles 1, 2, 3, and 5. The following dosing errors were planned during cycle 4, a shortened 10-day cycle: [1] patch group 1 subjects wore one patch for 10 consecutive days; [2] for patch group 2 and OC subjects, 7 dosing days were followed by 3 drug-free days., Main Outcome Measure(s): Follicular size, as determined at each cycle by the maximum mean follicular diameter., Result(s): After a 3-day dosing error, follicular size was significantly smaller in the patch group (mean, 7.0 mm) vs. each OC group (range of means, 11.8-17.1 mm). Similar results were seen after proper dosing. The incidence of ovulation was significantly lower for the patch users than for women using OCs., Conclusion(s): Follicular size and incidence of ovulation were significantly reduced among contraceptive patch users compared with women using OCs in normal cycles and after planned dosing errors.

Objective: To compare the mRNA expression of vascular endothelial growth factor (VEGF) 121 and 165 isoforms and thrombospondin-1 (TSP-1) after raloxifene, 17beta-E(2), and P administration in cultured Ishikawa cells., Design: Prospective basic research study., Setting: Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Norfolk, Virginia., Patient(s): None., Intervention(s): Ishikawa cells were cultured in vitro. Raloxifene, 17beta-E(2), and P at concentrations of 0.01, 0.1, and 1.0 microM were added to confluent cells., Main Outcome Measures: The VEGF 121 and 165 isoforms and TSP-1 mRNA expression from treated Ishikawa cells were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR)., Result(s): 17beta-Estradiol increased both VEGF 121 and 165 mRNA compared to control. Raloxifene did not increase either VEGF 121 or 165 mRNA above control values. Progesterone at all concentrations did not increase VEGF 121 isoform mRNA, whereas VEGF 165 isoform was minimally increased by P at the lowest concentration. Progesterone and raloxifene increased TSP-1 mRNA expression. 17beta-Estradiol did not stimulate TSP-1 mRNA expression at any concentration., Conclusion(s): Raloxifene did not stimulate VEGF 121 and 165, whereas it increased TSP-1 mRNA synthesis in Ishikawa cells. Our hypothesis is that raloxifene's lack of endometrial stimulation may be partly mediated by an antiangiogenic effect.

Objective: To determine compliance with the contraceptive patch (Ortho Evra/Evra) overall and by age among women in North America and to compare rates of perfect use with those of an established oral contraceptive., Design: Data were pooled for three contraceptive studies in which women participated for up to 13 cycles; the subset of centers in North America was used in this analysis., Setting: 76 North American centers., Patient(s): Healthy women 18-45 years of age., Intervention(s): In all studies, the patch regimen was three consecutive 7-day patches (21 days) followed by 1 patch-free week per cycle., Main Outcome Measure(s): Perfect use for the patch or oral contraceptive, defined as 21 consecutive days of drug-taking followed by a 7-day drug-free period; for contraceptive patch users, no patch could be worn for more than 7 days. Oral contraceptives were used according to package labeling., Results: For all contraceptive patch users in North America (n = 1,785), perfect use was consistent across age groups. The percentage of cycles with perfect use of the patch ranged within age groups from 88.1% to 91.0%. In the comparative study conducted only in North America, perfect use was also consistent across age groups for the patch (n = 812), but rates of perfect use for the oral contraceptive (n = 605) differed significantly by age., Conclusion(s): Age did not affect compliance with the patch among all North American women studied. In a comparative study of women at North American centers, compliance with the weekly contraceptive patch was significantly better than with an established oral contraceptive. The contraceptive patch is uniformly easy to use across all ages.

Objective: To evaluate the efficacy of a low-dose oral contraceptive (OC) containing 100 microg of levonorgestrel (LNG) and 20 microg of ethinyl estradiol (EE) compared with placebo for the treatment of moderate acne., Design: Multicenter, randomized, double-blind, placebo-controlled clinical trial., Setting: Outpatient dermatology clinics., Patient(s): Women (> or =14 years old; n = 350) with normal menstrual cycles and moderate acne were randomized to receive LNG/EE or placebo for six cycles., Intervention(s): Twenty microg of EE and 100 microg of LNG., Main Outcome Measure(s): Acne lesion counts and clinician global assessment were performed at baseline and at each cycle. Patient self-assessment was carried out at baseline and at cycles 4 and 6; blood pressure and weight were measured at baseline and at cycles 1, 3, and 6., Result(s): Inflammatory, noninflammatory, and total lesion counts at cycle 6 with LNG/EE were significantly lower compared to placebo. Patients in the LNG/EE group also had significantly better clinician global and patient self-assessment scores than those in the placebo group at cycle. Changes in weight from baseline were similar between patients in the LNG/EE and placebo groups at all measured time points., Conclusion(s): This double-blind, placebo-controlled study demonstrates that a low-dose OC containing 20 microg of EE and 100 microg of LNG is an effective and safe treatment for moderate acne.

Objective: To evaluate vaginal bleeding profiles with lower doses of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) as continuous combined therapy., Design: The Women's Health, Osteoporosis, Progestin, Estrogen (Women's HOPE) study, a randomized, double-blind, placebo-controlled trial., Setting: Study centers across the United States., Patient(s): Two thousand six hundred seventy-three healthy, postmenopausal women., Intervention(s): Women received CEE, 0.625 mg/d; CEE, 0.625 mg/d, plus MPA 2.5 mg/d; CEE, 0.45 mg/d; CEE, 0.45 mg/d, plus MPA, 2.5 mg/d; CEE 0.45 mg/d, plus MPA, 1.5 mg/d; CEE, 0.3 mg/d; CEE, 0.3 mg/d, plus MPA, 1.5 mg/d; or placebo for 1 year., Main Outcome Measure(s): Bleeding data were analyzed in efficacy-evaluable and intention-to-treat populations., Result(s): Cumulative amenorrhea and no bleeding rates were higher with lower doses of CEE/MPA than with CEE 0.625/MPA 2.5. A linear trend between time since menopause and cumulative amenorrhea was observed (P<.05) in all CEE/MPA groups except the CEE 0.45/MPA 1.5 group. The proportion of patients who experienced no bleeding in cycle 1 was 89%, 82%, and 80% in the CEE 0.3/MPA 1.5, CEE 0.45/MPA 1.5, and CEE 0.45/MPA 2.5 groups, respectively. These values were significantly greater than the incidence of no bleeding in the CEE 0.625/MPA 2.5 group (P<.05)., Conclusion(s): Lower-dose regimens of CEE and MPA produce higher rates of amenorrhea and no bleeding compared with CEE 0.625/MPA 2.5 and may be appropriate for newly menopausal patients.

One common side-effect of contraceptive use is that it often leads to disrupted endometrial bleeding patterns. This may be due to changes in endothelial density and vessel integrity. To investigate whether the level of endometrial immunoreactive vascular endothelial growth factor (VEGF), oestrogen receptor or progesterone receptor (PR) have any role in this, women were treated with either Mircette, a monophasic oral contraceptive, or Implanon, a long-acting gestagen, and immunohistochemistry performed. In addition a small number of endometria were studied from women treated with levonorgestrel released from an intrauterine coil. During the untreated normal cycle, there was a significant increase in glandular VEGF immunoreactivity and a significant decrease in PR immunoreactivity in the midand late secretory phases compared to the proliferative phase. There was a significant positive correlation between stromal VEGF immunoreactivity and endothelial cell density. This correlation was also apparent during treatment with Implanon, but not with Mircette. Disrupted bleeding patterns were associated with Implanon and to a lesser extent with Mircette. Both contraceptives significantly reduced glandular VEGF immunoreactivity but the intrauterine treatment with levonorgestrel resulted in strong glandular epithelial staining and intense staining of decidualized stromal cells. Implanon significantly increased glandular PR staining, but Mircette significantly reduced stromal PR staining when compared to secretory phase before-treatment biopsies. There were no changes in endothelial cell density or glandular or stromal ER during the normal cycle, or with use of either contraceptive. There was no association of the parameters measured with bleeding patterns or histological category.

Contraceptive use often leads to disrupted endometrial bleeding patterns in women. In this study, two different contraceptive regimes (Mircette, a monophasic oral contraceptive and Implanon, a long-acting gestagen) were used and their effects on the immunoreactivity of vascular endothelial growth factor (VEGF), oestrogen receptor (ER), progesterone receptor (PR) and endothelial cell number were determined. During the untreated normal cycle, there was a significant increase (P = 0.005) in glandular VEGF immunoreactivity and a significant decrease (P < 0.05) in PR immunoreactivity in the mid- and late secretory phases compared with the proliferative phase. There was a significant positive correlation (gamma = 0.38, P = 0.046) between stromal VEGF immunoreactivity and endothelial cell number. This correlation was also apparent during treatment with Implanon, but not with Mircette. Disrupted bleeding patterns were associated with Implanon and, to a lesser extent, with Mircette. Both contraceptives significantly reduced glandular VEGF immunoreactivity. Implanon significantly increased (P = 0.016) glandular PR staining, but Mircette significantly reduced (P = 0.027) stromal PR staining when compared with secretory before-treatment biopsies. There were no changes in endothelial cell number or glandular or stromal ER during the normal cycle, or with use of either contraceptive. There was no association between the parameters measured with bleeding patterns and histological category.

Objective: To investigate whether establishment and maintenance of chronic opioid blockade throughout the follicular phase of the menstrual cycle influences midcycle and luteal phase prolactin levels., Design: Randomized, double-blind, crossover study., Setting: Academic research environment., Patient(s): Volunteers, aged 21-35 years, with regular menstrual cycles., Intervention(s): Naltrexone (50 mg) or placebo were administered on cycle days 2-14. Blood samples were obtained in the early follicular phase and in the periovulatory and midluteal phases of the menstrual cycle., Main Outcome Measure(s): Serum prolactin levels., Result(s): In the early follicular phase, serum prolactin levels were equivalent in naltrexone (12.0 +/- 2.7 microgram/L; mean +/- SE) and placebo (12.1 +/- 2.9 micrograms/L) cycles. A statistically significant increase in serum prolactin was observed on the day of the LH surge (naltrexone: 22.6 +/- 3.7 micrograms/L; placebo: 21.7 +/- 2.7 micrograms/L; P < 0.05 versus early follicular phase), but no difference between treatments was observed. However, midluteal prolactin levels were statistically significantly lower in naltrexone cycles compared with placebo cycles (12.6 +/- 3.3 versus 15.4 +/- 3.0 micrograms/L; P < 0.05)., Conclusion(s): Chronic blockade of opioid activities during the follicular phase does not affect midcycle prolactin increments, but withdrawal of opioid blockade may enhance opioid effects on prolactin levels in the luteal phase.

Objective: To track the severity and location of pelvic pain associated with endometriosis throughout the reproductive-age years and to evaluate the association between these pain parameters and the stage of disease., Design: Historical prospective study., Setting: Tertiary care center., Patient(s): Forty-eight women with endoscopically staged endometriosis and chronic pelvic pain who had undergone medical and/or conservative surgical therapy., Intervention(s): Each participant was administered a questionnaire that included a determination of the severity and location of her pain., Main Outcome Measure(s): The stage of disease, the area of the pelvis that contained the bulk of disease, the severity of pain, and the location of the most severe pain were recorded., Result(s): The mean duration from the initial diagnosis until follow-up was 15.7 +/- 3.1 years, Twenty-one (43.8%) subjects denied any symptoms of pain on follow-up evaluation. Of the 27 patients with persistent pain, 21 (78%) identified the location of their most severe pain as being the same as at initial diagnosis. The stage of disease at initial diagnosis was significantly associated with a higher degree of pain at follow-up., Conclusion(s): These data suggest that endometriosis-associated chronic pelvic pain commonly persists throughout the reproductive years and that endometriosis stage is directly related to the persistence of pelvic pain.

Objective: To evaluate the contraceptive efficacy, pharmacokinetics, and safety of two formulations of Annuelle (Endocon, Inc., South Walpole, MA) biodegradable norethindrone (NET) SC pellet implants., Design: Prospective observational study., Setting: Two clinical sites in the United States., Patient(s): Thirty-nine healthy, fertile, sexually active women., Intervention(s): Nineteen women received a four-pellet system containing 174 mg NET; 20 women received a five-pellet system containing 266.5 mg NET., Main Outcome Measure(s): Contraceptive efficacy, median serum NET levels, adverse events., Result(s): No pregnancies were observed in 293 woman-months in the four-pellet group or in 375 woman-months in the five-pellet group. An initial burst in median serum NET levels occurred in the first 24 hours postinsertion followed by a steady decline over the next 3 years. Norethindrone levels varied considerably among women. The main side effect was bleeding abnormalities, which persisted in half the participants for up to 2 years. No serious adverse events were reported that were related to the pellets. Pellet insertion and removal generally were uncomplicated., Conclusion(s): Annuelle shows potential as an effective, safe contraceptive with distinct advantages over other long-acting agents, because it is biodegradable but can be removed if problems arise or if fertility is desired.

Norplant, a systemic contraceptive, has been used extensively throughout the world. A major problem for consumers utilizing Norplant has been irregular, unpredictable uterine bleeding or spotting. This study seeks to determine whether or not an appropriate treatment could be found that will reduce the incidence of spotting and bleeding. Both a pilot study and an interim report of a multi-center trial utilizing ethinyl estradiol 20 micrograms for 10 days, versus Ibuprofen 800 mg three times a day for 5 days, versus placebo is reported. Based on the interim analysis of the multi-center trial, there is a reduction in the mean number of spotting days with one of the three treatments compared to the other two treatments (p = 0.044). There was no difference in the number of bleeding days between treatment regimen. It appears from a review of the literature that both oestrogen, progesterone, and non-steriodal anti-inflammatory agents may reduce the number of bleeding days or inhibit acutely the bleeding in women utilizing Norplant. The completion of this randomized multi-center trial will hopefully give us further insight into an effective treatment for controlling the irregular bleeding and/or spotting that occurs in Norplant users.

Objective: To test the hypothesis that the inflammatory response stimulated by intrauterine devices (IUDs) plays a role in the antifertility action of IUDs. We treated rats with pentoxifylline (Trental; Hoechst-Roussel Pharmaceuticals, Inc., Somerville, NJ) and evaluated its effect on the anti-implantation action of IUDs. The number of embryos in treated compared with untreated rats was determined., Design: Breeder female Sprague-Dawley rats (Harlan Sprague Dawley, Indianapolis, IN) were randomized into one of five test groups (n = 20 per group). A monofilament nylon IUD was inserted transcervically into one horn of the bicornuate uterus in two groups. The IUD-bearing groups received either intraperitoneal (IP) injections of pentoxifylline (45 mg/kg per every 12 hours) or normal saline (NS). The two non-IUD-bearing groups received IP injections of pentoxifylline or NS. The non-IUD group was not injected. All injections were administered daily for 21 days and the animals then mated. Successful mating was determined by the presence of spermatozoa in vaginal washings. The injections of pentoxifylline or NS were continued until day 12 of pregnancy when the rats were killed. The total number of embryos in each uterine horn was determined., Setting: University research laboratory., Results: Embryo numbers (1.0 +/- 0.6 [mean +/- SEM]) were reduced in the IUD horn compared with the contralateral non-IUD horn (6.4 +/- 1.0) and with the uterine horns from each of the four other test groups. The number of embryos were increased in the IUD horn (3.5 +/- 0.9) of the pentoxifylline-treated rats., Conclusion: Pentoxifylline appeared to reduce the contraceptive effectiveness of the IUDs in this model.

Objective: To demonstrate that pharmacokinetic measurements were made at steady state. Subsequently, dose proportionality for desogestrel and ethinyl E2 kinetics were demonstrated., Design: Open-label, noncomparative study., Setting: Healthy volunteers in an academic research environment., Participants: Twenty white women who were 19 to 32 years old were solicited via an advertisement. Nineteen of the 20 women completed the study., Interventions: Study medication consisted of three cycles of a triphasic oral contraceptive containing desogestrel and ethinyl E2. Blood samples were taken at baseline and during cycle 3 between -48 and 24 hours on days 1, 7, 14, and 21, with additional sampling times on day 21 at 48, 60, and 72 hours., Main Outcome Measures: Serum concentrations of 3-keto-desogestrel and ethinyl E2., Results: Evaluation of the trough serum levels indicated that a steady state of 3-keto-desogestrel had been reached. Statistical analysis on the Cmax, area under the curve (AUC), and Css,min indicated dose proportionality for the administered desogestrel. Ethinyl E2 serum levels obtained at the same time points also reflected steady state levels and showed minimal variability. The statistical analysis on Cmax, AUC, Css,min, and Tmax indicated that the pharmacokinetics of ethinyl E2 on days 7, 14, and 21 were not statistically significantly different, indicating dose equivalency., Conclusions: Steady state of 3-keto-desogestrel is reached after each of the three phases and the pharmacokinetics are dose proportional. After reaching steady state, the pharmacokinetics of ethinyl E2 remain constant over time.

Objective: To review and evaluate published studies that have examined the role of peritoneal fluid (PF) in the development of endometriosis., Design: Important studies related to this topic have been identified through a computerized bibliographical search (MEDLINE), as well as by manually scanning the published literature of major reproductive journals over the last several years., Main Outcome Measures: Studies that examined the effect of PF or its components on the pathophysiology of endometriosis are discussed. These include reported effects on the histogenesis, maintenance and proliferation of endometriosis, as well as related actions on infertility., Results: The majority of investigations into the role PF plays in the pathogenesis of endometriosis have evaluated how it may adversely affect fertility. Suggestive but inconclusive data in the literature indicate that degenerating endometrial tissue may release a biochemical factor(s) into the peritoneal environment that is capable of inducing ectopic endometrium formation. Peritoneal fluid itself contains growth factor that may play a role in the implantation and maintenance of the ectopic endometrium., Conclusions: The PF of women with endometriosis has been shown to contain angiogenic as well as other growth factors. These compounds may contribute to the proliferation of the ectopic endometrium.

Two synthetic magainins A and G are shown to have spermicidal activity. Transmission electron microscopic micrographs show that both magainins alter the plasma membranes of sperm and that these actions are rapid. Further studies will better delineate the contraceptive potential of synthetic magainins.

Peristaltic movements of the endometrium were evaluated by serial transvaginal ultrasound throughout 21 spontaneous menstrual cycles, 15 oral contraceptives (OCs) cycles, and 18 in vitro fertilization (IVF) cycles. A score of 0, 1, or 2 was assigned for absent, mild, or strong movements. An average score of 1.5 was obtained at midcycle in spontaneously ovulating women, which was significantly different from early or late follicular (0.36 and 0.5) or luteal (0.4) phase scores. Significant differences were found among the three groups: IVF patients averaged more movements than natural cycle patients, who in turn had a higher incidence than patients taking OCs. Increased peristaltic endometrial movements appear to occur in women around midcycle, probably as an enhancing mechanism for sperm propulsion towards the tubal ostia.

The present study was designed to evaluate the effect of different serum concentrations of estradiol-17 beta (E2) on pituitary luteinizing hormone (LH) release in postmenopausal women. Serum E2 levels were evaluated in healthy postmenopausal women while they wore two, four, and six transdermal E2 delivery systems. The mean serum E2 levels at 48 hours after application of the devices were 185.5, 338.9, and 520.5 pg/mL, respectively, which were significantly different from each other. Serum E2 levels were stable throughout the first 48 hours of patch application but declined by a mean of 54% between 48 and 72 hours. Pituitary LH surges were induced with all three serum concentrations of E2 but were present more often with the higher serum values. There were no significant differences between the mean interval of device utilization and initiation, height, or duration of the induced pituitary LH surge at any of the three serum E2 concentrations studied.

Currently the physiology and pathophysiology of pituitary prolactin secretion are under intensive investigation. Development of sensitive, specific radioimmunoassays for hPRL and improved roentgenographic techniques have increased the diagnostic acumen for incipient pituitary microadenomas. Several modalities of treatment are available at the present time which can result in improvement in the clinical symptoms of the amenorrheagalactorrhea syndromes. Eponymic classification of amenorrhea-galactorrhea syndromes should be discarded and appropriate diagnostic studies initiated to determine the etiology of the inappropriate breast secretion and/or elevated serum hPRL level.

Infertile women with normal serum prolactin (PRL) levels have been known to establish a pregnancy after the use of bromocriptine, a dopamine agonist. These data imply that there may be a group of women with a slight but significant increase in PRL secretion that may have resulted in their infertility. This study evaluates the thyrotropin-releasing hormone (TRH)-induced PRL and thyroid-stimulating hormone (TSH) response in normal women (NL, n = 6), women with anovulation and/or inphase endometrial biopsies (AN/IN, n = 12), and women with histologic evidence of luteal phase deficiency (LPD, n = 12). Most of these women were found to have elevated serum PRL values on random testing. There was a statistically significant increase in PRL response at all time intervals after TRH between the NL and AN/IN groups compared with the group with LPD on the basis of repeated measures analysis (P = 0.0013). There was no statistical difference in the TSH response between these three groups. Although the PRL response was statistically different, individual PRL response patterns were not diagnostic. It appears from these data that there is an increased PRL secretion in infertile women who have histological evidence of a LPD.