Thomas Kimble

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.

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.

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. Participants 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-1β, 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.

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.

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.

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 partners 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 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.

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 HIV 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.