Levonorgestrel 52-mg Intrauterine Device Efficacy and Safety After More Than 8 Years of Use.

FUNDING SOURCE: Medicines360. The Sponsor, Medicines360, designed the study and oversaw its conduct, including funding the trial and providing all study product free of charge to participants. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00995150.

A 1-year prospective, open-label, single-arm, multicenter, phase 3 trial of the contraceptive efficacy and safety of the oral progestin-only pill drospirenone 4 mg using a 24/4-day regimen.

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/m2. 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.

Acceptability of the Woman's Condom in a phase III multicenter open-label study.

OBJECTIVE: This study aimed to evaluate the acceptability of the Woman's Condom (WC) over 6 months (183 days) and ≥6 menstrual cycles in a US-based multicenter open-label phase III contraceptive efficacy trial. STUDY DESIGN: We assessed acceptability via written questionnaire at visit 2 (after the third cycle) and visit 3 (after the sixth cycle or >183 days, or upon early discontinuation). Key domains included ease of use, comfort/lubrication, sexual satisfaction, male partner satisfaction and confidence in pregnancy and sexually transmitted infection (STI) prevention. We analyzed quantitative data using descriptive statistics. We conducted a content analysis to identify major themes from four open-ended questions. RESULTS: Most women [327/405 (81%)] had limited or no previous experience with female (internal) condoms. Of 405 evaluable women, 346 women completed questionnaires at visit 2 and 303 women at visit 3; 282 women attended both visits. Of women attending both visits, 165/282 (59%) reported at visit 2 that WC insertion was easy/very easy; this increased to 195/282 (69%) at visit 3 (p=.03). Many women [166/281 (59%)] preferred the WC [105/281 (37%)] or were neutral [61/281 (22%)], while 115/281 (41%) preferred male condoms. Women attending visit 3 felt confident that the WC could prevent pregnancy [246/303 (81%)] and STIs [217/303 (72%)]. Many women expressed empowerment with having control over their contraception; some disliked the design, esthetics and insertion process. Most women (254/299 (85%)] would recommend the WC to a friend. CONCLUSION: The WC's acceptability and ease of use is promising for wider dissemination as a female-controlled method that can protect against both pregnancy and STIs. IMPLICATIONS: The WC's overall acceptability and ease of use is promising for a new female-controlled barrier contraceptive option that can protect against both pregnancy and sexually transmitted infections.

Five-Year Contraceptive Efficacy and Safety of a Levonorgestrel 52-mg Intrauterine System.

OBJECTIVE: To assess the 5-year contraceptive efficacy and safety of a levonorgestrel (LNG) 52-mg intrauterine system (IUS) from an ongoing 10-year phase 3 contraceptive trial. METHODS: Study investigators enrolled 1,751 nulliparous and parous females aged 16-45 years and desiring contraception to receive a novel LNG 52-mg IUS at 29 centers in the United States, including reproductive health clinics, private offices, and university centers. Participants had scheduled follow-up visits four times during the first year. After year 1, study visits occurred every 6 months, with phone contact at the 3-month point between visits. We assessed the primary outcome of pregnancy rate (Pearl Index) in females aged 16-35 years at enrollment through 60 months. The safety evaluation included all females for their entire duration of participation. RESULTS: The 1,751 enrollees included 1,600 females aged 16-35 years and 151 aged 36-45 years. Successful IUS placement occurred in 1,714 (97.9%) participants. At the time of the data evaluation, 495 participants finished 5 years and 176 had entered the seventh year of IUS use. Nine pregnancies occurred, six of which were ectopic. The Pearl Indices for years 1 and 5 were 0.15 (95% CI 0.02-0.55) and 0.20 (95% CI 0.01-1.13) pregnancies per 100 women-years, respectively. The cumulative life-table pregnancy rate was 0.92% (0.46-1.82%) through 5 years. Participants aged 16-35 years at enrollment were significantly more likely to report new or worsening acne, dyspareunia, pelvic pain, and dysmenorrhea; participants aged 36-45 years at enrollment were more likely to report new or worsening weight increase. Discontinuation for adverse events occurred in 322 (18.8%) participants, most commonly related to expulsion (n=65 [3.8%]). Only 39 (2.2%) IUS users discontinued as a result of bleeding symptoms. Pelvic infection was diagnosed in 14 (0.8%) participants. CONCLUSION: This LNG 52-mg IUS is highly effective and safe over 5 years of use in U.S. females. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT00995150. FUNDING SOURCE: Medicines360.

Ulipristal Acetate for Treatment of Uterine Leiomyomas: A Randomized Controlled Trial.

OBJECTIVE: To assess the efficacy and tolerability of ulipristal acetate, a selective progesterone receptor modulator, for treatment of symptomatic uterine leiomyomas. METHODS: This phase 3, double-blind, double-dummy, placebo-controlled trial randomized premenopausal women (18-50 years) with uterine leiomyomas and abnormal uterine bleeding to once-daily 5 mg ulipristal, 10 mg ulipristal, or placebo in two 12-week treatment courses separated by a drug-free interval of two menses. Coprimary end points were rates of and time to amenorrhea during course 1. Change from baseline to end of course 1 in the Revised Activities subscale of the Uterine Fibroid Symptom and Health-Related Quality of Life questionnaire was a secondary end point. A sample size of 400 was planned to compare separately each ulipristal dose with placebo. RESULTS: From January 2014 through November 2016, 432 women were randomized. Demographic characteristics were similar across treatment groups. In course 1, 68 of 162 (42.0% [97.5% CI 33.3-51.1]) and 86 of 157 (54.8% [97.5% CI 45.5-63.8]) patients treated with 5 mg and 10 mg ulipristal, respectively, compared with 0 of 113 (0.0% [97.5% CI 0.0-3.8]) patients treated with placebo achieved amenorrhea (P<.001 for each dose); most women who achieved amenorrhea did so within 10 days (time to amenorrhea, P<.001 for each dose). Significantly greater improvements in Uterine Fibroid Symptom and Health-Related Quality of Life Revised Activities subscale scores were reported with 5 mg and 10 mg ulipristal compared with placebo (least squares mean change from baseline: 48.3, 56.7, and 13.0, respectively; P<.001 for each dose). Both ulipristal doses were well tolerated; in course 1, hot flush occurred in 7.5%, 11.6%, and 1.7% of patients treated with 5 mg ulipristal, 10 mg ulipristal, and placebo, respectively. CONCLUSION: Treatment with 5 mg or 10 mg ulipristal was superior to placebo in achieving amenorrhea and generally well tolerated for the medical management of symptomatic uterine leiomyomas. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02147158.

Differences in Local and Systemic TFV PK Among Premenopausal Versus Postmenopausal Women Exposed to TFV 1% Vaginal Gel.

OBJECTIVE: We describe and compare the local and systemic pharmacokinetics (PK) of tenofovir (TFV) and TFV-diphosphate (TFV-DP) in healthy premenopausal (PRE) and postmenopausal (POST) women using TFV 1% gel and correlate local PK with other mucosal end points. METHODS: PRE (n = 20) and POST (n = 17) women used 2 doses of TFV 1% vaginal gel, separated by 2 hours. Blood and cervicovaginal samples were obtained 3 and 23 hours after the second dose. PRE women used gel in the follicular and luteal phases of the menstrual cycle. POST women used gel at baseline and again after approximately 2 months of treatment with 0.01% vaginal estradiol (E2) cream. RESULTS: Median TFV concentrations in cervicovaginal aspirate (ng/mL) and vaginal tissue (ng/mg) were significantly higher in PRE (4.3E10, 49.8) versus POST women (2.6E10, 2.2). POST women had significantly higher median molecular ratios of TFV-DP to TFV (3.7%) compared with PRE (0.19%). After vaginal E2 treatment, the local and systemic PK end points in POST women were generally similar to PRE women (all P values > 0.05). Importantly, median vaginal tissue TFV-DP concentrations (fmol/mg) among PRE, POST, and POST women after E2 therapy were similar (292.5, 463.3, and 184.6, respectively). Vaginal tissue TFV concentrations were significantly positively correlated with vaginal epithelial thickness, whereas vaginal tissue TFV-DP concentrations were positively correlated with density of vaginal CD4 and CD8 immune cells. CONCLUSIONS: The state of the cervicovaginal mucosa has a significant impact on local and systemic PK of a topically applied microbicide.

A Randomized, Multicenter, Double-Blind, Study to Evaluate the Safety and Efficacy of Estradiol Vaginal Cream 0.003% in Postmenopausal Women with Vaginal Dryness as the Most Bothersome Symptom.

BACKGROUND: Vulvovaginal atrophy (VVA) is characterized by vaginal/vulvar dryness, irritation, dyspareunia, or dysuria. The objective of this study was to examine the efficacy and safety of a very low-dose estradiol vaginal cream (0.003%) applied twice per week in postmenopausal women with VVA-related vaginal dryness. MATERIALS AND METHODS: In this phase 3, randomized, double-blind, placebo-controlled, multicenter study, postmenopausal women with moderate-severe vaginal dryness as the most bothersome VVA symptom were randomized (1:1) to estradiol cream 0.003% (15 µg estradiol; 0.5 g cream) or placebo (0.5 g cream). Treatments were applied vaginally once daily for 2 weeks followed by two applications/week for 10 weeks. Coprimary outcomes were changes in severity of vaginal dryness, percentage of vaginal superficial and parabasal cells, and vaginal pH at final assessment. Additional outcomes comprised changes in severity of other VVA signs and symptoms. Adverse events (AEs) were assessed. RESULTS: Of the 576 randomized participants, most were white and had an average age of 59 years. At final assessment, estradiol reduced vaginal dryness severity, decreased vaginal pH, increased superficial cell percentage, and decreased parabasal cell percentage versus placebo (p ≤ 0.05, all). Estradiol also reduced vaginal dryness severity at Weeks 4-12 and dyspareunia at Week 8 versus placebo (p ≤ 0.05, all). Improvements in vaginal/vulvar irritation/itching severity and dysuria were similar between estradiol and placebo. Estradiol had comparable rates of treatment-emergent AEs to placebo. No deaths occurred. CONCLUSIONS: Very low-dose estradiol vaginal cream (0.003%) dosed twice weekly is an effective and well-tolerated treatment for VVA symptoms and dryness associated with menopause.

Heavy menstrual bleeding diagnosis and medical management.

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.

A phase I randomized postcoital testing and safety study of the Caya diaphragm used with 3% Nonoxynol-9 gel, ContraGel or no gel.

OBJECTIVES: The Caya® Diaphragm is a newly approved single-size, nonlatex diaphragm. Contragel® is a personal lubricant containing lactic acid approved in Europe and other countries for use with vaginal barrier devices. This study assessed the effectiveness in preventing sperm from penetrating midcycle cervical mucus of Caya with Contragel, Caya with 3% nonoxynol-9 (N-9) and Caya alone. STUDY DESIGN: Phase I multicenter, single-blind, randomized, crossover, nonsignificant risk study at two sites: Eastern Virginia Medical School, Norfolk, VA, USA, and Profamilia, Santo Domingo, Dominican Republic. Healthy, sexually active women 18-45years old, not at risk for pregnancy due to tubal occlusion, were eligible. Each participant was seen in nine visits, completing a baseline cycle (without product use) followed by three test cycles (sequence determined by randomization), each consisting of a cervical mucus check visit and a postcoital test visit. To proceed to test cycles, the baseline postcoital test had to show adequate cervical mucus and >5 progressively motile sperm per high power field (PMS/HPF). RESULTS: All women had an average of <5 PMS/HPF during the test cycle of each study arm, the primary endpoint. Caya with ContraGel and Caya with N-9 reduced the average number of PMS/HPF from 22.5 to 0. Caya alone reduced the average number of PMS/HPF from 22.5 to 0.4. There were two possibly product-related mild adverse events. CONCLUSION: This study supports that Caya with ContraGel is safe and functions as well as Caya with N-9 in preventing PMS from reaching midcycle cervical mucus. IMPLICATIONS: A single-size diaphragm used with a personal lubricant gel containing lactic acid appears to be safe and to function as well as the same diaphragm used with N-9 in preventing PMS from reaching midcycle cervical mucus.

Comparison of Mucosal Markers of Human Immunodeficiency Virus Susceptibility in Healthy Premenopausal Versus Postmenopausal Women.

The objective of this study was to characterize cervicovaginal (CV) mucosal factors modulating susceptibility to human immunodeficiency virus (HIV) acquisition in healthy premenopausal (PRE) and postmenopausal (POST) women before and after treatment with estradiol (E2). We compared CV mucosal epithelial histology and immune cells, vaginal microbiota, antimicrobial activity of and soluble mucosal protein concentrations in the CV fluid lavage (CVL), and p24 antigen production after ex vivo infection of ectocervical tissues with HIV-1BaL among PRE women (n = 20) in the follicular and luteal phases of the menstrual cycle and POST women (n = 17) at baseline and after ∼1 month of treatment with 0.01% vaginal E2 cream. Compared to PRE women, we measured higher levels of p24 antigen after ex vivo infection in tissues from POST women. POST women had a significantly thinner vaginal epithelium with decreased tight junction proteins and a higher density of mucosal immune T cells and lower levels of CD1a antigen-presenting cells, antimicrobial peptides, and inflammatory cytokines in the CVL (p values <.05). POST women had higher vaginal pH and lower vaginal Lactobacilli (p values <.05) than PRE women. After vaginal E2 therapy, CV endpoints and ex vivo HIV replication in POST tissues were similar to those observed in PRE tissues. The CV mucosa in POST women is thinned and compromised, with increased HIV-target immune cells and decreased antimicrobial factors, being more susceptible to HIV infection. After POST women receive topical E2 treatment, mucosal endpoints are similar to PRE levels.

Assessment of the vaginal residence time of biomarkers of semen exposure.

OBJECTIVE: The primary objective of this pilot study is to determine and compare the residence time in the vagina of biomarkers of semen exposure for up to 15 days post exposure. The biomarkers are prostate-specific antigen (PSA), Y chromosome DNA, the sex determining region of the Y chromosome (SRY) and testis-specific protein Y-encoded 4 (TSPY4). The secondary objectives are to determine if biomarker concentrations differed between intercourse and inoculation groups, to establish whether the sampling frequency post exposure affected biomarker concentrations and decay profile and to determine if biomarker concentrations in vaginal swabs obtained by the participant at home were similar to swabs obtained by the nurse in the clinic. STUDY DESIGN: We randomized healthy women to unprotected intercourse (n=17) versus vaginal inoculation with the male partner's semen in the clinic (n=16). Women were then further randomized to have vaginal swabs obtained at either 7 or 4 time points after semen exposure, up to 15 days post exposure, either obtained at home by the participant or in the clinic by the research nurse. RESULTS: PSA and SRY were markers of recent semen exposure. TSPY4 was detectable in approximately 50% of participants at 15 days post exposure. Unprotected intercourse resulted in significantly higher concentrations of select biomarkers. Sampling frequency and home versus clinic sampling had no significant effect on biomarker concentrations. CONCLUSIONS: Objective biomarkers of recent or distant semen exposure may have great utility for verifying protocol compliance in a variety of clinical trials.

Comparison of Follicular and Luteal Phase Mucosal Markers of HIV Susceptibility in Healthy Women.

The purpose of this study was to evaluate differences in vaginal immune cell populations, vaginal tissue gene expression, antimicrobial activity of the cervicovaginal (CV) lavage (CVL), vaginal flora, and p24 antigen production from CV tissues after ex vivo human immunodeficiency virus (HIV) infection between follicular (FOL) and luteal (LUT) phases of the menstrual cycle. CV tissue biopsies, CV secretions, and blood samples were obtained as part of two longitudinal clinical trials of healthy women (CONRAD D11-119 and A12-124 studies). Participants (n = 39) were HIV-seronegative women not using exogenous hormone supplementation, with normal menstrual cycles, who were screened to exclude sexually transmitted and reproductive tract infections. Serum levels of estradiol and progesterone were significantly higher in the LUT versus the FOL phase of the menstrual cycle. Controlling for race, reported contraceptive use/sexual practices, and clinical trial, we found no differences in vaginal tissue immune cell populations and activation status, transcriptomes, inhibition of HIV, herpes simplex virus type 2 and Escherichia coli by the CVL, vaginal pH or Nugent score, or production of p24 antigen after ex vivo infection by HIV-1BaL between CV samples obtained in the FOL phase versus the LUT phase of the menstrual cycle. There were no significant correlations between serum estradiol and progesterone levels and CV endpoints. The hypothesis that the LUT phase of the menstrual cycle represents a more vulnerable stage for mucosal infection with HIV was not supported by data from samples obtained from the lower genital tract (ectocervix and vagina) from these two clinical trials.

Bacterial Vaginosis and Subclinical Markers of Genital Tract Inflammation and Mucosal Immunity.

Bacterial vaginosis (BV) has been linked to an increased risk of human immunodeficiency virus (HIV) acquisition and transmission in observational studies, but the underlying biological mechanisms are unknown. We measured biomarkers of subclinical vaginal inflammation, endogenous antimicrobial activity, and vaginal flora in women with BV and repeated sampling 1 week and 1 month after completion of metronidazole therapy. We also compared this cohort of women with BV to a healthy control cohort without BV. A longitudinal, open label study of 33 women with a Nugent score of 4 or higher was conducted. All women had genital swabs, cervicovaginal lavage (CVL) fluid, and cervicovaginal biopsies obtained at enrollment and received 7 days of metronidazole treatment. Repeat sampling was performed approximately 1 week and 1 month after completion of therapy. Participant's baseline samples were compared to a healthy, racially matched control group (n=13) without BV. The CVL from women with resolved BV (Nugent 0-3) had significantly higher anti-HIV activity, secretory leukocyte protease inhibitor (SLPI), and growth-related oncogene alpha (GRO-α) levels and their ectocervical tissues had significantly more CD8 cells in the epithelium. Women with persistent BV after treatment had significantly higher levels of interleukin-1ß, tumor necrosis factor alpha (TNF-α), and intercellular adhesion molecule 1 (ICAM-1) in the CVL. At study entry, participants had significantly greater numbers of CCR5(+) immune cells and a higher CD4/CD8 ratio in ectocervical tissues prior to metronidazole treatment, compared to a racially matched cohort of women with a Nugent score of 0-3. These data indicate that BV is associated with changes in select soluble immune mediators, an increase in HIV target cells, and a reduction in endogenous antimicrobial activity, which may contribute to the increased risk of HIV acquisition.

Comparison of visual and ultraviolet light inspection versus DNA/protein biomarkers to assess product adherence with vaginal microbicide applicators.

BACKGROUND: Objective biomarkers of product use and protocol compliance are urgently needed. We compared the sensitivity and specificity of DNA and protein-based biomarkers, obtained from used vaginal gel applicators, to visual inspection of those applicators under ambient light (visual inspection of returned applicator [VIRA]) and ultraviolet light (UVL). METHODS: Forty women inserted hydroxyethylcellulose placebo gel vaginal applicators under direct observation. Applicators were evaluated by VIRA, UVL, and DNA/protein-based methods at 2 time points: within 7 days of the visit and after storing applicators for approximately 30 days. Semen biomarkers were assayed from vaginal swabs and returned applicators. RESULTS: The overall sensitivity and specificity of DNA and protein-based biomarkers in determining vaginal insertion versus sham handling of returned applicators were 98.3% and 100%, respectively, at both 7- and 30-day evaluations. The overall sensitivity and specificity of VIRA at 7 and 30 days after collection were significantly lower than those of DNA and protein-based biomarkers. Ultraviolet light inspection also had significantly lower overall sensitivity and overall specificity compared with DNA and protein biomarkers. The sensitivity of DNA and protein-based biomarkers for detecting insertion of wiped applicators was 95%, whereas the sensitivity of VIRA (range of 24%-28%) and UVL inspection (range, 38%-84%) was low for this subset. It was feasible to obtain semen biomarkers from vaginal swabs and returned used applicators. CONCLUSIONS: DNA and protein-based biomarkers offer significantly higher sensitivity and specificity compared with VIRA and UVL assessment. The accuracy of these objective biomarkers is maintained despite storage of returned products for approximately 30 days and under conditions potentially modeling field use.

Medroxyprogesterone acetate and estradiol cypionate injectable suspension (Cyclofem) monthly contraceptive injection: steady-state pharmacokinetics.

BACKGROUND: Cyclofem is a combined injectable contraceptive, containing medroxyprogesterone acetate (MPA) and estradiol cypionate. The objective was to characterize the steady-state pharmacokinetics (PK) using tandem liquid chromatography/mass spectrometry and compare these data to a previous PK study of this formulation in US women. STUDY DESIGN: Fifteen ovulatory, surgically sterile women received three Cyclofem injections, once every 28 days, with serum PK measurements on 23 separate days. Trough levels of estradiol and MPA were obtained on Days 1, 29 and 57, prior to each of the three injections. Steady-state concentrations of MPA and estradiol were assessed during the third treatment month on Days 58, 60, 62, 64, 67, 69, 71, 75, 78 and 85. MPA and serum progesterone levels were measured during the follow-up phase to assess MPA clearance (Days 92, 99, 106, 113, 120, 127, 134 and 141) and return of ovulation (Days 103, 106, 131 and 134). RESULTS: In the steady state, mean serum MPA concentrations peaked at 1.31 ng/mL at 4.1 days. Mean estradiol levels peaked at 254 pg/mL by 3.3 days. Ovulation was suppressed for at least 77 days post third injection in all but one woman. CONCLUSIONS: Once monthly injections of Cyclofem resulted in contraceptive levels of MPA without accumulation of hormones, consistent with a previous US study.

Anti-Müllerian hormone serum levels predict response to controlled ovarian hyperstimulation but not embryo quality or pregnancy outcome in oocyte donation.

The objective of this retrospective cross-sectional study was to evaluate the value of basal serum anti-Müllerian hormone (AMH) levels as a predictor of ovarian response and pregnancy outcome in a donor egg program. The study showed that AMH was superior to other biomarkers of ovarian reserve in predicting low and high response in young women selected as oocyte donors, but that it was not predictive of embryo morphology or pregnancy outcome in the recipient population.

Effects of progesterone, levonorgestrel and medroxyprogesterone acetate on apoptosis in human endometrial endothelial cells.

BACKGROUND: We evaluated apoptosis in human endometrial endothelial cells (HEECs) incubated with progesterone, levonorgestrel (LNG) and medroxyprogesterone acetate (MPA). STUDY DESIGN: HEECs were cultured to near confluence, and the progestogens were added. SETTING: Academic Department of Obstetrics and Gynecology. PATIENTS: No patients were involved. INTERVENTIONS: Progestogens at 5-, 250- and 500-ng/mL concentrations were added to incubations of HEECs for 12, 24 and 48 h. MAIN OUTCOME MEASURE: Apoptosis based on terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick-end labeling (TUNEL), and semiquantification of Bax and Bcl-2. RESULTS: No apoptosis was found by TUNEL, Bax and Bcl-2 after 12 h incubation with any progestogen. TUNEL increased after incubation for 24 and 48 h with progesterone 500 ng/mL; LNG 250, 500 ng/mL and all concentrations of MPA (p<.001), Bax increased and Bcl-2 decreased at all concentrations of MPA and the two highest concentrations of LNG at 48 h (p<.05). CONCLUSION: MPA results in apoptosis of HEECs.

Assessment of ovarian reserve with anti-Müllerian hormone: a comparison of the predictive value of anti-Müllerian hormone, follicle-stimulating hormone, inhibin B, and age.

OBJECTIVE: The objective of this study was to evaluate basal anti-Müllerian hormone as a marker for ovarian responsiveness to fertility treatment. STUDY DESIGN: Frozen basal menstrual cycle day 3 serum samples were evaluated retrospectively for anti-Müllerian hormone, inhibin B, and follicle-stimulating hormone levels in 123 in vitro fertilization cycles (93 patients) and compared with in vitro fertilization records. RESULTS: Anti-Müllerian hormone values correlated the best with the number of retrieved oocytes (r = 0.539; P < .001) relative to age (r = -0.323; P < .01), follicle-stimulating hormone (r = -0.317; P < .01), inhibin B (P > .05), luteinizing hormone (P > .05), and estradiol (r = -0.190; P < .05). Receiver operating characteristic curve analysis demonstrated that, for the prediction of <4 oocytes retrieved, anti-Müllerian hormone had the largest area under the curve (AUC = 0.81; P = .0001) relative to age (r = 0.74; P = .005), follicle-stimulating hormone (0.71; P = .02), inhibin B (0.66; P = .03), and estradiol (0.54; P > .05). Similarly, for the prediction of >or=15 retrieved oocytes, anti-Müllerian hormone had the largest area under the curve (0.80; P = .0001) relative to age (0.63; P = .02), follicle-stimulating hormone (0.64; P = .005), inhibin B (r = 0.57; P > .05), and estradiol (0.58; P > .05). CONCLUSION: Anti-Müllerian hormone correlates better than age, follicle-stimulating hormone, luteinizing hormone, inhibin B, and estradiol with the number of retrieved oocytes. Receiver operating characteristic curves estimated that anti-Müllerian hormone accurately predicts ovarian responsiveness to controlled ovarian stimulation with high sensitivity and specificity.