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Objective To evaluate the relationship between semen regurgitation and intrauterine insemination (IUI) outcomes. We hypothesized that clinical pregnancy rates and live birth rates would be reduced when regurgitation occurred. Design Retrospective cohort study. Setting A university-based reproductive endocrinology and infertility clinic. Patient(s) Retrospective review of 1,957 IUI cycles performed on 660 patients between July 2007 and May 2012. Intervention(s) None. Main Outcome Measure(s) The primary outcome was live birth. Secondary outcomes were positive serum pregnancy result and clinical pregnancy. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using a cluster-weighted generalized estimating equations method to estimate modified Poisson regression models with robust standard errors to account for multiple IUI cycles in the same patient. Result(s) Live birth rates were similar in IUI cycles with and without regurgitation (6.3% vs. 6.8%, respectively, RR = 0.82, 95% CI [0.53–1.26]). Clinical pregnancy rates in the presence or absence of regurgitation were 10.5% vs. 10.0% (RR = 0.99, 95% CI [0.73–1.35]). Positive serum pregnancy tests after IUI did not differ by regurgitation status (15.0% vs. 15.4%, RR = 0.97, 95% CI [0.75–1.24]). Results were unchanged when adjusted for covariates (age, race and ethnicity, body mass index, duration of infertility, medication, infertility diagnosis, total motile count, and method of sperm preparation). Conclusion(s) The presence of regurgitation during the IUI procedure is not related to pregnancy outcome.

PURPOSE: The recently identified agonistic autoantibodies (AAb) to the gonadotropin-releasing hormone receptor (GnRHR) are a novel investigative and therapeutic target for polycystic ovary syndrome (PCOS). In this study, we used a new cell-based fluorescence resonance energy transfer (FRET) bioassay to analyze serum GnRHR-AAb activity and examine its relationship with testosterone and proinflammatory cytokines in patients with PCOS. METHODS: Serum samples from 33 PCOS patients, 39 non-PCOS ovulatory infertile controls and 30 normal controls were tested for GnRHR-AAb activity and proinflammatory cytokines in a FRET-based bioassay and multiplex bead-based immunoassay, respectively. Correlation was analyzed using the Spearman’s correlation test. RESULTS: Serum GnRHR-AAb activity was significantly higher in the PCOS patients than for the ovulatory infertile (p < 0.05) and normal (p < 0.01) controls. GnRHR-AAb were positive in 39% of PCOS patients, 10% of ovulatory infertile controls, and 0% of normal controls. PCOS IgG-induced GnRHR activation was specifically blocked by the GnRHR antagonist cetrorelix. Serum levels of proinflammatory cytokines interleukin-2, interleukin-6, interferon-γ and tumor necrosis factor-α were significantly increased in PCOS patients compared with ovulatory infertile and normal controls (p < 0.01). Correlation analysis demonstrated positive correlations of GnRHR-AAb activity with testosterone and proinflammatory cytokine levels in the PCOS group. CONCLUSION: Elevated GnRHR-AAb activity, as assessed by a new FRET assay, is associated with increased testosterone and proinflammatory cytokines in PCOS, suggesting autoimmune activation of GnRHR may contribute to the pathogenesis of this common disorder.

Objectives 1) To confirm the correlation of GnRH receptor (GnRHR) activating autoantibody (AAb) activity with polycystic ovary syndrome (PCOS) diagnosis in large well defined cohorts; and 2) to evaluate suppression of AAb activity with GnRH antagonist medication in transfected GnRHR cells exposed to serum of PCOS patients. Design Cross-sectional matched case-control study. Setting University-based research facility. Patient(s) Sera from 200 patients with PCOS from the Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial and from 200 race, parity-, age-, and body mass index (BMI)–matched ovulatory unexplained infertile control patients from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) trial were obtained and used for this study. Intervention(s) GnRHR AAb activity was determined with the use of the GeneBlazer cell-based fluorescence resonance energy transfer assay with and without cetrorelix, a GnRH antagonist. Main Outcome Measure(s) 1) GnRHR AAb activity in PCOS patients compared with control subjects; and 2) effectiveness of GnRH antagonist in suppressing GnRHR AAb activity. Result(s) GnRHR AAb activity levels in the PCOS group were significantly higher than in the control group. With cetrorelix, GnRHR AAb activity was largely suppressed in the PCOS group but not in the control group. These differences remained significant after adjusting for within-pair differences in age, BMI, and antimullerian hormone (AMH) levels. Conclusion(s) We confirmed higher GnRHR AAb activity levels in the sera of a large cohort of PCOS patients compared with unexplained infertile control subjects. Addition of cetrorelix resulted in significant suppression of AAb activity levels in PCOS patients as a group whereas control subjects were unaffected. GnRHR AAb, along with patient age and AMH level, may provide a promising future diagnostic test for PCOS.

Purpose We have recently demonstrated that gonadotrophin-releasing hormone receptor-activating autoantibodies (GnRHR-AAb) are associated with polycystic ovary syndrome (PCOS). The aim of this study was to map the antigenic epitopes of GnRHR-AAb from PCOS patients, and develop retro-inverso peptide inhibitors that specifically target GnRHR-AAb. Methods Serum samples from ten GnRHR-AAb-positive PCOS patients and ten GnRHR-AAb-negative healthy controls were tested. Epitope mapping for GnRHR-AAb was performed using a set of 11 overlapping octapeptides spanning the second extracellular loop of GnRHR. Antibody-blocking effect of the designed retro-inverso peptide inhibitors was evaluated in a cell-based bioassay. Results Two peptide sequences, FSQCVTHC and HCSFSQWW, were found to react with all PCOS sera, but not with control sera. Two retro-inverso peptides that mimic the identified epitopes, d-CHTVCQSF and d-WWQSFSCH, significantly inhibited PCOS serum IgG-induced GnRHR activation. One of these two peptide inhibitors, d-CHTVCQSF, largely suppressed autoantibody-induced GnRHR activation, suggesting that the epitope sequence FSQCVTHC may be a major functional target of GnRHR-AAb. Conclusion We have identified a dominant functional epitope for GnRHR-AAb associated with PCOS, and demonstrated effective blocking of GnRHR-AAb activity with epitope-mimicking retro-inverso peptide inhibitors. These proteolytically stable decoy peptides may have important therapeutic implications in subjects who harbor these autoantibodies.

The obstetrician/gynecologist frequently serves as the primary care physician for women. Specialty-specific guidelines vary in screening recommendations for lipid disorders; women's health practitioners often follow recommendations to screen at age 45 in the absence of other risk factors. However, 2013 American College of Cardiology/American Heart Association cholesterol guidelines recommend screening at age 21 to capture those at risk of cardiovascular disease and allow for early intervention with lifestyle and, in the most severe cases, evidence-based statins. We discuss the care of women who primarily benefit from screening: those with familial hypercholesterolemia (FH), those with the metabolic syndrome (MetS) or polycystic ovary syndrome, and those with hypertriglyceridemia. Those with FH have elevated low-density lipoprotein cholesterol from birth and a propensity for premature coronary heart disease. Early recognition of FH can allow risk-reducing interventions, as well as identification of additional affected relatives. Early detection of metabolic variables, such as in the MetS and hypertriglyceridemia, can lead to an enhanced focus on physical activity and heart-healthy diet. Finally, we discuss a practical approach to lipid management and review concerns regarding drug safety. Our objective is to provide a current overview of cardiovascular risk factor optimization that women's health practitioners can use in identifying and/or treating patients at risk for cardiovascular disease and diabetes.

Objective Is polycystic ovary syndrome (PCOS) associated with activating autoantibodies (AAb) to the second extracellular loop (ECL2) of gonadotropin-releasing hormone receptor (GnRHR)? Design and Methods We retrospectively screened sera from 40 patients with PCOS and 14 normal controls (NCs) with regular menses using enzyme-linked immunosorbent assay (ELISA) for the presence of GnRHR-ECL2-AAb. We obtained similar data from 40 non-PCOS ovulatory but infertile patients as a control group (OIC) of interest. We analyzed GnRHR-ECL2-AAb activity in purified immunoglobulin (Ig)G using a cell-based GnRHR bioassay. Results The mean ELISA value in the PCOS group was markedly higher than the NC (P = .000036) and the OIC (P = .0028) groups. IgG from a sample of 5 PCOS subjects, in contrast to a sample of 5 OIC subjects, demonstrated a dose-dependent increase in GnRHR-stimulating activity qualitatively similar to the acute action of the natural ligand GnRH and the synthetic agonist leuprolide. The GnRHR antagonist cetrorelix significantly suppressed (P Conclusions GnRHR-ECL2-AAb are significantly elevated in patients with PCOS compared with NCs. Their presence raises important etiological, diagnostic, and therapeutic implications.

Objective To determine whether there is an increased risk of ovarian cancer in women undergoing radical cystectomy (RC) for bladder cancer using a large population-based data source. Current American Urologic Association guidelines suggest removal of ovaries during RC in women with bladder cancer, presumably to mitigate the risk ovarian cancer. However, recent data have demonstrated an increased risk of all-cause mortality, cardiovascular disease, osteoporosis, cognitive impairment, and diminished sexual function in some populations of women after oophorectomy. Methods We queried the surveillance, epidemiology and end results (SEER) database for all women with a diagnosis of primary bladder cancer who underwent RC between 1998 and 2010. Patients with concurrent or subsequent primary ovarian cancer were then identified using the SEER multiple primaries dataset. Multiple primary standardized incidence ratio was calculated as an estimate of the relative risk of a concurrent or subsequent ovarian malignancy using SEER*Stat software. Results A total of 1851 women met inclusion criteria for analysis. Of this population, 221 (11.9%) women developed a subsequent nonbladder malignancy, of which 2 (0.11%) women developed subsequent ovarian cancer during the observation period. Multiple primary standardized incidence ratio for development of an ovarian malignancy was 2/4 (0.50). Conclusion The risk of concurrent or subsequent ovarian malignancy in women undergoing RC for bladder cancer is very low. Therefore, oophorectomy at the time of RC may be obviated in order to mitigate the undue risk of cardiovascular disease, osteoporosis, cognitive impairment, and diminished sexual function.

We evaluated endometrial pattern (defined as the relative echogenicity of the endometrium on a longitudinal uterine ultrasonic section) as a surrogate for endometrial receptivity in an attempt to evaluate the association between endometrial pattern and pregnancy outcome in women who underwent ART treatment. The primary outcome was live birth and secondary outcomes were clinical intrauterine pregnancy and miscarriage. Potential associations were evaluated using cluster-weighted generalized estimating equations to account for within-couple correlation among repeated ART cycles while adjusting for potentially confounding variables. There were 1034 ART cycles with embryo transfer (778 fresh, 256 frozen) among 695 women (median age: 31.0 (6.0) years). The average number of embryos transferred per cycle was 2.1 embryos. The clinical intrauterine pregnancy rate per transfer was 56.0% for fresh and 54.3% for frozen cycles. The overall live birth rate per embryo transfer was 48.4%. Live birth rates were unchanged when the endometrium was semi-trilinear (RR:0.91 CI:0.74,1.12) or unilinear (RR:1.15 CI:0.89,1.49) in comparison to trilinear endometrium after controlling for potentially confounding variables. Results were similar when analysed separately for fresh and frozen cycles and when evaluating associations with clinical intrauterine pregnancy and miscarriage rates. It appears that endometrial pattern does not significantly affect live birth in ART and our data do not support cancelling an ART cycle if the endometrium is less than trilinear.

Background: Activating autoantibodies (AAb) are directed to the gonadotropin releasing hormone receptor second extracellular loop (GnRHR-ECL2) and are pathogenic when induced in rats. We previously reported GnRHR-ECL2-AAb were elevated in sera from patients with PCOS (Rotterdam criteria) compared to ovulatory infertile controls (OIC). Methods:Human studies: ELISA detection of GnRHR Abs used a synthetic h-GnRHR-ECL2 28 mer peptide (LifeTein) as the target antigen. We assayed AAb activity in GnRHR transfected cells using a GeneBLAzer FRET assay (Invitrogen). ELISA AAb epitope locations on the ECL2 were identified on a minipin plate (pins 1-11 containing sequential 2 aa offsetting octapeptides, Mimotope, Inc) using sera from 30 PCOS subjects, 33 OIC and 18 normal controls (NC). Results:Human sera: An ELISA assay for GnRHR-ECL2-AAbs in the PCOS group was markedly higher than the NC group (P 0.2). There was no significant change in activity in the OIC subjects by the addition of peaks 5 + 8 RID peptides. Conclusion: These PCOS GnRHR-AAb data confirm the presence of significant activation of the GnRHR by AAb targeted to specific epitope(s) proximate to the disulfide GnRHR-ECL2 linkage to the nearby ECL1. These data are compatible with a pathophysiological role for GnRHR-AAb in PCOS and may provide both diagnostic and therapeutic opportunities.

Providing reasonable expectations to patients with diminished ovarian reserve prior to attempting pregnancy through in vitro fertilization (IVF) is one of the most challenging aspects of fertility care. In some instances, advice from the clinician to pursue more effective treatment, such as donor oocytes, may not be acceptable to the patient. In this case report, a patient is presented who represents a poor prognosis candidate for IVF treatment. She was 43 years old with six prior failed IVF cycles and repetitive basal FSH values above 30 mIU/mL. Presented are the challenges in patient counseling and decision making. In her seventh IVF cycle, which she was strongly counseled against pursuing, the patient experienced the desired outcome of live birth. Increasing reports are emerging of live birth using autologous oocytes among women of advanced reproductive age. These instances, as well as the case of our patient, raise issues commonly encountered in patient counseling in poor prognosis patients. This discussion should include an emphasis on patient goals as well as an acknowledgement that no test for ovarian reserve has a 100% positive predictive value.

The objective of this article was to review and synthesize information from the scientific literature pertaining to the preparation of endometrium for cryopreserved embryo transfer. This article is a critical review of selected scientific literature, synthesis, and formulation of opinion. Estrogen and progesterone are necessary and sufficient to induce endometrial receptivity in cryopreserved embryo transfer cycles. A variety of regimens have been described including natural cycles using endogenous ovarian hormones and artificial or programmed cycles with exogenously administered steroid hormones. To achieve optimal synchrony between embryo and endometrium, the timing of progesterone administration needs to be adjusted to the developmental stage of the thawed embryos. There is currently no evidence that any single regimen or adjuvant substance results in superior outcomes in cryopreserved embryo transfer cycles, although timing of progesterone administration does matter. Although no single regimen of endometrial preparation for cryopreserved embryo transfer has been proven superior to the others, the relative convenience and ease of use do vary, depending on the route of administration chosen and any adjuvant added to the cycle.

Background Age-adjusted rates of obesity are reported to be 35.8 % among US adult women and 49 % in some race/ethnicity, underserved populations. (1). Underserved populations often have less access to weight-loss intervention options and are at high risk for obesity related problems including anovulation, infertility, pregnancy-related complications and adverse long-term health outcomes. (2). The purpose of this study was to evaluate a home exercise plan using a pedometer on weight loss, ovulation induction and pregnancy rates in our overweight and obese underserved clinic population. Methods Twenty one overweight (BMI ≥ 25–29.9) and obese I-II (BMI ≥ 30–39.9) 18–42 years old were recruited. Participants received an exercise/nutrition questionnaire at the initiation and completion and called weekly for 4 weeks. Ten participants were randomly assigned to the home exercise program (PedGp). PedGp received a pedometer, daily step-count goal, and were called to increase goal by 50 % weekly. All participants then underwent clomiphene stair-step ovulation induction. All study participants were referred to the University Wellness Clinic for diet and exercise counseling. Results There were high percentages of women with co-morbidities in both groups including fatty liver, low vitamin D, hyperlipidemia, hypothyroidism, prediabetes and diabetes. 1. Those completing the 4-week home program increased baseline steps by 21.2 % weekly. Only 3/10 women reached at least one weekly goal of 50 % increase. Although the goal was rarely met, participants who completed study had increased number of daily steps. 2. Greater number in PedGp lost weight or stayed the same (5/10 vs. 2/11). 3. Greater number in PedGp spontaneously ovulated (4/10 vs. 1/11) or became pregnant (4/10 vs. 3/11). (not statistically significant due to small sample size). Conclusion There are high percentages of comorbidities in this population. Although the goal was rarely met, participants who completed study had increased number of daily steps. A greater number in PedGp lost weight or stayed the same. A greater number in PedGp spontaneously ovulated or became pregnant (not statistically significant due to small sample size). Importantly, 40 % of women who lost weight became pregnant. This is highly encouraging and suggests that the development of pedometer interventions may prove a cost effective option. Weight loss programs for this population hold promise and efficient hospital or community-based programs may prove beneficial.

OBJECTIVE The objective of the current study was to describe outcomes among women with low-grade abnormalities on cervical cytology screening in the setting of previous excisional or ablative treatment for cervical intraepithelial neoplasia (CIN). METHODS Study participants were recruited into the Study to Understand Cervical Cancer Early Endpoints and Determinants. At enrollment, the patient's previous cytology results, previous colposcopic biopsy results, and previous cervical procedures were recorded. Study procedures included collection of biospecimens followed by colposcopy and biopsy. From clinical records, additional information regarding previous treatment for CIN was collected. RESULTS Two hundred seventy-four women had an atypical squamous cells of uncertain significance (ASCUS) referral Pap and 532 women had a low-grade squamous intraepithelial lesion (LSIL) referral Pap. For patients with an ASCUS referral Pap, previous treatment was associated with an odds ratio for CIN 2+ (45.0% vs 28.2% of untreated patients) of 2.08 (95% confidence interval = 1.05-4.13, p = .04). For patients with an LSIL referral Pap, 33.3% of those women with previous treatment had CIN 2+ compared with 16.7% of those patients enrolled with no previous treatment (odds ratio = 2.49, 95% confidence interval = 1.12-5.51, p = .03). CONCLUSIONS Patients with a history of previous treatment for CIN have a 2-fold risk of CIN 2+ at the time of colposcopy referral for ASCUS or LSIL cervical cytology.

In fresh IVF cycles, embryos reaching the eight-cell stage on day 3 of development are thought to have a higher chance of implantation than those reaching this stage on day 4. To determine whether this difference persists after cryopreservation, we compared pregnancy and implantation rates between frozen embryo transfer (FET) cycles using delayed cleavage-stage embryos (cryopreserved day 4) and normal cleavage-stage embryos (cryopreserved day 3).Participants underwent FET between 2008 and 2012 using embryos cryopreserved on either day 3 (n = 76) or day 4 (n = 48), depending on the length of time needed to achieve the eight-cell stage. All embryos, regardless of day of cryopreservation, were thawed and transferred on the 4th day of vaginal progesterone following endometrial preparation with oral estradiol. Chi-square and Mann-Whitney U tests were used to compare patient demographics and cycle outcomes.More women in the day 4 group had diminished ovarian reserve (44 vs 16 %, p = 0.003). Pregnancy outcomes in preceding fresh cycles were not different between the two groups. Pregnancy, implantation, and live birth rates following FET did not differ between the day 3 and day 4 groups.This is the first study to address outcomes using day 3 versus day 4 cryopreserved embryos. Despite a higher prevalence of diminished ovarian reserve (DOR) in the day 4 group, delayed cleavage-stage embryos utilized in FET cycles performed as well as embryos growing at the normal rate, suggesting delayed embryo development does not affect embryo implantation as long as endometrial synchrony is maintained.

To determine whether a newer commercially available antimüllerian hormone (AMH) enzyme-linked immunosorbent assay (picoAMH ELISA, AnshLabs) with a lower threshold of detection is predictive of successful ovarian stimulation in a population of women with diminished ovarian reserve (DOR).Retrospective case-control study.University-based IVF program.Cases were patients whose first IVF cycle was cancelled for lack of ovarian response (3 follicles; n = 24). Controls were patients with DOR (early follicular FSH of ≥10 IU/L), whose first cycle resulted in aspiration of at least 3 oocytes (n = 24).Frozen serum samples collected during routine clinical care between 2008 and 2012 before starting IVF were analyzed for AMH using the picoAMH ELISA.Serum AMH levels in patients who successfully reached oocyte retrieval compared with patients with a failed controlled ovarian hyperstimulation (COH) cycle. Receiver operator curve analysis was used to identify a predictive threshold AMH value.No demographic differences were found between groups. The successful group had a higher antral follicle count (8.5 vs. 6) and higher AMH levels (847 vs. 406 pg/mL). The AMH level correlated with the antral follicle count (R = 0.61). The AMH level of500 pg/mL had 83.3% sensitivity and 70.8% specificity to detect patients who proceeded to successful oocyte retrieval. Below AMH levels of 100 pg/mL, no patients achieved oocyte retrieval.Due to a lower threshold of detection, picoAMH may be able to predict successful ovarian stimulation among women with DOR using a threshold of 500 pg/mL, with good sensitivity and specificity.

Polycystic ovary syndrome (PCOS) is considered as the most common endocrine disorder amongst reproductive-age women. While characterized by a chronic course, and features that suggest varying combinations of reproductive functional deficits (such as ovulatory dysfunction or polycystic ovarian morphology) and androgen excess (such as acne, and hirsutism), the diagnosis of PCOS is based on well-defined criteria. Ethnicity, lifestyle, and certain underlying secondary disorders can impact on diagnostic accuracy of the disorder. There are currently three major sets of diagnostic criteria for the polycystic ovary syndrome (PCOS), with slight variations between them. The prevalence of PCOS varies depending on the diagnostic criteria utilized as well as the region and ethnicity studied. The prevalence of PCOS is high among women with resistant acne and hirsutism, so patients presenting with these findings should be screened for menstrual irregularities. A timely diagnosis of this chronic disorder allows an opportunity for early detection of a spectrum of morbidities that are commonly encountered in women with PCOS (such as metabolic syndrome, impaired glucose tolerance, type 2 diabetes mellitus, dyslipidemia and depression), and will allow for timely institution of preventive strategies aimed at minimizing the overall health risk in this population.