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PURPOSE: Successful identification of transcriptomic biomarkers within human IVF embryos may enhance implantation prediction and provide insights not available through conventional embryo biopsy genomic analysis. We demonstrate proof-of-concept for a methodology to assess overall embryo gene expression using qPCR with blastocoel fluid-conditioned media by examining the comparative presence of apoptotic genes. METHODS: Blastocoel fluid-conditioned media were collected from 19 embryos (11 euploid) following trophectoderm biopsy of day-5 ICSI-IVF blastocysts. Media were assessed for apoptotic gene expression via qPCR. Statistical analysis of gene expression was conducted via Wilcoxon Signed-Ranks test (overall expression), multivariate ANOVA (functional gene groups), and chi-square test of independence (gene level). RESULTS: A significantly higher overall apoptotic gene expression within euploid versus aneuploid embryos (p = 0.001) was observed. There was significantly (p = 0.045) higher expression of pro-apoptotic genes between implanted and not implanted embryos. Pro- vs. anti-apoptotic gene expression from all euploid embryos approached significance (p = 0.053). The ploidy status-based claim is further substantiated at the gene level with significantly higher expression of BBC3 (p = 0.012) and BCL2L13 (p = 0.003) in euploid embryos compared to aneuploid embryos. CONCLUSIONS: In this preliminary study, we demonstrate that (1) qualitative analysis of blastocoel fluid-conditioned media gene expression is possible, (2) global trends of expression are potentially related to clinical outcomes, and (3) gene-level expression trends exist and may be another viable metric for comparative expression between samples. The presence of statistical significance within analyses conducted with this sample size warrants a larger investigation of blastocoel fluid-conditioned media as an additional beneficial predictive tool for future IVF cases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-022-02510-3.

STUDY QUESTIONAre intrauterine insemination (IUI) performance characteristics and post-processing total motile sperm count (TMC) related to live birth rate in couples with unexplained infertility?SUMMARY ANSWERPatient discomfort with IUI and lower inseminate TMC were associated with a reduced live birth rate, while time from hCG injection to IUI, sperm preparation method and ultrasound guidance for IUI were not associated with live birth success.WHAT IS ALREADY KNOWNWe previously determined that some baseline characteristics of couples with unexplained infertility, including female age, duration of infertility, history of prior loss and income, were related to live birth rate across a course of ovarian stimulation and IUI treatment. However, the relationship between treatment outcomes and per-cycle characteristics, including ultrasound guidance for IUI, timing of IUI relative to hCG injection, difficult or painful IUI and inseminate TMC, are controversial, and most prior investigations have not evaluated live birth outcome.STUDY DESIGN, SIZE, DURATIONThis was a secondary analyses of 2462 cycles from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial. This prospective, randomised, multicentre clinical trial determined live birth rates following IUI after ovarian stimulation with clomiphene citrate, letrozole or gonadotropins in 854 couples with unexplained infertility. It was conducted between 2011 and 2014, and couples could undergo up to four consecutive treatment cycles.PARTICIPANTS/MATERIALS, SETTING, METHODSAMIGOS was an NIH-sponsored Reproductive Medicine Network trial conducted at 12 clinical sites. Participants were women with unexplained infertility who were between 18 and 40 years of age. Cluster-weighted generalised estimating equations (GEE), which account for informative clustering of multiple IUI treatment cycles within the same patient, were used to determine associations between IUI performance characteristics, including inseminate TMC, and live birth rate. Efficiency curves were also generated to examine the relationship between inseminate TMC and live birth rate.MAIN RESULTS AND THE ROLE OF CHANCEAfter adjustment for treatment group and baseline factors previously associated with live birth across a course of OS-IUI treatment, patient discomfort during the IUI procedure was associated with a reduction in live birth rate (aRR 0.40 (0.16–0.96)). Time from hCG trigger injection to IUI was not significantly associated with outcome. Higher TMC was associated with greater live birth rate (TMC 15.1–20.0 million (14.8%) compared to ≤5 million (5.5%)) (aRR 2.09 (1.31–3.33)). However, live births did occur with TMC ≤ 1 million (5.1%).LIMITATIONS, REASONS FOR CAUTIONThis investigation is a secondary analysis, and AMIGOS was not designed to address the present question. Since timed intercourse was allowed as part of the AMIGOS trial, we cannot rule out the possibility that any given pregnancy resulted from intercourse rather than IUI.WIDER IMPLICATIONS OF THE FINDINGSMost factors associated with the performance of IUI were not significantly related to obtaining live birth. Our findings suggest that higher TMC inseminated leads to an increase in live birth rate up to TMC ~20 million. However, there may be no reasonable threshold below which live birth is not possible with IUI.STUDY FUNDING/COMPETING INTEREST(S)Funding was received through grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): U10 HD077680, U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936 and U10 HD055925. This research was made possible by funding by the American Recovery and Reinvestment Act. Dr Hansen reports grants from NIH/NICHD and Yale University during the conduct of the study, grants from Roche Diagnostics and grants from Ferring International Pharmascience Center US outside the submitted work. Dr Peck reports support from Ferring Pharmaceuticals outside the submitted work. Dr Coward has nothing to disclose. Dr Wild reports grants from NICHD during the conduct of the study. Dr Trussell has nothing to disclose. Dr Krawetz reports grants from NICHD during the conduct of the study, grants from Merck and support from Taylor and Frances and from Springer, outside the submitted work. Dr Diamond reports grants from NIH/NICHD, Yale University, during the conduct of the study and support from Advanced Reproductive Care AbbVie, Bayer and ObsEva, outside the submitted work. Dr Legro reports support from Bayer, Kindex, Odega, Millendo and AbbVie and grants and support from Ferring, outside the submitted work. Dr Coutifaris reports grants from NICHD/NIH and personal fees from American Society for Reproductive Medicine, outside the submitted work. Dr Alvero has nothing to disclose. Dr Robinson reports grants from NIH during the conduct of the study. Dr Casson has nothing to disclose. Dr Christman reports grants from NICHD during the conduct of the study. Dr Santoro reports grants from NIH during the conduct of the study. Dr Zhang reports grants from NIH during the conduct of the study and support from Shangdong University outside the submitted work.TRIAL REGISTRATION NUMBERn/a

Objective To determine whether biochemical or clinical markers of androgenic activity predict live birth rate with ovarian stimulation in the unexplained infertility population. Design Secondary analysis of the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial. Setting Multicenter university-based clinical practices. Patient(s) Nine hundred couples with unexplained infertility were included. Women were 18–40 years old with regular menses, a normal uterine cavity, at least one patent fallopian tube, and a male partner with ≥5 million motile sperm. Women were randomized to receive gonadotropin, clomiphene, or letrozole with IUI for four or fewer four treatment cycles. Women were evaluated for biochemical (total testosterone, DHEAS, and free androgen index) and clinical markers of androgenic activity (sebum, acne, and hirsutism). Multivariable logistic regression models adjusting for treatment group, maternal age, and body mass index were performed. Intervention(s) None. Main Outcome Measure(s) The primary outcome was live birth. Secondary outcomes included conception, clinical pregnancy, and pregnancy loss. Result(s) When comparing 900 women in the AMIGOS trial based on quartiles of serum TT, women were of younger age, higher body mass index, and higher waist circumference with increasing TT. Increasing quartiles of TT also showed increasing DHEAS and free androgen index values. Serum androgens were not associated with outcomes of live birth, conception, clinical pregnancy, or pregnancy loss. Clinical androgen markers were not associated with pregnancy outcomes. Conclusion(s) In a randomized cohort of women with unexplained infertility, biochemical and clinical measures of androgens did not predict live birth rate after ovarian stimulation treatment. Clinical Trial Registration Number NCT 01044862.

Objective To evaluate similarities and differences in clinical and laboratory practices among high-performing fertility clinics. Design Cross-sectional questionnaire study of selected programs. Setting Academic and private fertility practices performing in vitro fertilization (IVF). Patient(s) Not applicable. Intervention(s) A comprehensive survey was conducted of 13 IVF programs performing at least 100 cycles a year and having high cumulative singleton delivery rates for 2 years. Main Outcome Measure(s) Clinical and laboratory IVF practices. Result(s) Although many areas of clinical practice varied among top programs, some commonalities were observed. All programs used a combination of follicle-stimulating hormone and luteinizing hormone for IVF stimulation, intramuscular progesterone in frozen embryo transfer cycles, ultrasound-guided embryo transfers, and a required semen analysis before starting the IVF cycle. Common laboratory practices included vitrification of embryos at the blastocyst stage, air quality control with positive air pressure and high-efficiency particulate air filtration, use of incubator gas filters, working on heated microscope stages, and incubating embryos in a low-oxygen environment, most often in benchtop incubators. Conclusion(s) Some areas of consistency in clinical and laboratory practices were noted among high-performing IVF programs that are likely contributing to their success. High-performing programs focused on singleton deliveries. As the field of IVF is rapidly evolving, it is imperative that we share best practices in an effort to improve outcomes from all clinics for the good of our patients.

PURPOSE: To assess the effect of assisted hatching (AH) on live birth rate (LBR) in first cycle, fresh in vitro fertilization (IVF) in good and poor prognosis patients. METHODS: Retrospective cohort using cycles reported to the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System. Live birth rate was compared in women who underwent first cycle, autologous, fresh IVF cycles with (n = 48,858) and without (n = 103,413) AH from 2007 to 2015. RESULTS: The propensity-weighted LBR was 39.2% with AH versus 43.9% without AH in all patients. The rate difference (RD) with AH was − 4.7% ([CI − 0.053, − 0.040], P < 0.001) with the calculated number needed to harm being 22. AH affected live birth in both good prognosis and poor prognosis patients. The propensity-weighted monozygotic twinning (MZT) rate was 2.3% in patients treated with AH as compared to 1.2% patients that did not receive AH. The RD with AH on MZT in fresh, first IVF cycles was 1.1% ([0.008, 0.014], P < 0.001). CONCLUSION: AH may affect LBR across all patients and in poor prognosis patients in fresh IVF cycles. Caution should be exercised when applying this technology. More prospective research is needed. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10815-019-01619-2) contains supplementary material, which is available to authorized users.

Context The relationship between reproductive and cardiometabolic aging is unclear. It is unknown if the relationship differs across different clinical populations. Objective To determine whether markers of ovarian reserve are associated with cardiometabolic risk in reproductive aged women with unexplained infertility (UI), polycystic ovary syndrome (PCOS), and regularly cycling women (OVA). Design and setting Cross-sectional data from 8 US-based academic centers. Participants Women aged 25–40 from 3 clinical populations: 870 with UI, 640 with PCOS, and 921 community-based OVA. Main Outcome Measures Multivariable linear regression models were used to relate anti-mullerian hormone (AMH) and antral follicle count with cardiometabolic parameters including body mass index (BMI), waist circumference (WC), fasting glucose and insulin, homeostasis model assessment-insulin resistance (HOMA-IR), lipids, and C-reactive protein. Results In age and study site-adjusted models, AMH inversely related to BMI in the UI and OVA groups (P = 0.02 and P < 0.001). Among women with PCOS, AMH inversely related to BMI (P < 0.001), and also to WC (P < 0.001), fasting insulin (P < 0.01), HOMA-IR (P < 0.01), triglycerides (P = 0.04), and C-reactive protein (P < 0.001) and directly related to higher total (P = 0.02), low-density lipoprotein (P < 0.01), and high-density lipoprotein cholesterol (P < 0.01). In OVA, AMH also varied inversely with WC (P < 0.001), fasting insulin (P = 0.02), and HOMA-IR (P = 0.02). Adjustment for BMI eliminated associations in the OVA group but in PCOS, the relationship of AMH to total (P = 0.03) and low-density lipoprotein cholesterol (P = 0.003) remained. Conclusion Associations observed between AMH and cardiometabolic indices are largely explained by BMI in women with and without PCOS. (J Clin Endocrinol Metab XX: 0-0, 2019)

Background Endometriosis impacts 6–10% of all reproductive- age women. Studies have shown the more effectively endometriosis is removed, the better the patient outcomes for pain reduction and fertility (2, 3). Hemosiderin, glands, and stroma are the histologic markers of endometriosis; optical coherence tomography (OCT) can identify glands and hemosiderin has a known endogenous fluorescence than can be detected by two-photon microscopy (TPM). The hypothesis was that the identification of optical properties of endometriosis using OCT and TPM combined would improve a surgeon’s ability to diagnose and treat by improving endometriosis detection compared to current standards of visual diagnosis. Methods Forty-one women with clinically suspected endometriosis undergoing laparoscopy were consented. Women were enrolled at two clinical sites: University of Texas Health Science Center, San Antonio and Methodist Healthcare System, San Antonio. The surgeon made a clinical diagnosis of suspected endometriosis as 1) yes present 2) maybe present, and 3) not present (controls) from the peritoneum without suspected disease. One-hundred-twenty biopsies were collected from 27 women with visually suspected endometriosis. All three patient biopsy classes were excised and underwent histologic examination as the gold-standard diagnosis for endometriosis. The samples were imaged ex-vivo for optical markers of endometriosis; OCT for endometrial glands and TPM for hemosiderin. Histologic markers were co-registered with optical properties. Biopsies were embedded in agar to maintain orientation during imaging and histological processing. TPM used the endogenous fluorescence of hemosiderin as a marker. OCT used glands as a marker. Sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) were calculated. Results The main-outcome-measure was the statistical comparison of clinical impression, imaging results, and histologic truth. Glands, stroma and hemosiderin were present in 49, 72 and 86% of endometriosis samples confirmed by histology. Clinical suspicion of endometriosis had 98% sensitivity, 53% specificity, 68% PPV, and 96% NPV. In 31 samples of endometriosis maybe being present, 39% were histologically confirmed. Eighty-eight samples were analyzed using OCT-TPM. OCT-TPM had 93% sensitivity, 100% specificity, 100% PPV, and 93% NPV. Conclusions OCT-TPM is useful in identifying endometriosis’ presence or absence. Evaluation of suspected endometriosis by OCT-TPM improves surgeons’ abilities to diagnose and treat endometriosis.

Endometriosis is an invasive disease, and a leading cause of pain, infertility and disability among women, with an incidence 10 fold that of cancer. A more complete understanding of disease pathogenesis is essential for the development of non-surgical diagnostic assays and non-hormonal therapeutics. Avoidance of immune clearance and implantation of endometrial tissue on peritoneal surfaces are features of endometriosis lesion formation that overlap with cancer metastasis. Connexins, and the gap junctions they form, have been implicated in cancer progression, and may be associated endometriosis pathophysiology. Single cell transcriptomic profiling of endometrial epithelial and stromal cells from women with endometriosis reveals a striking and progressive shift in expression of connexins and related regulatory and junctional genes. We demonstrate that gap junction coupling between endometrial cells and the peritoneal mesothelium is dramatically induced, specifically in endometriosis patients, and is required for invasion by inducing breakdown of the mesothelial barrier function.

OBJECTIVE: To study the association of endometrial thickness (EMT) with live birth rates (LBR) in ovarian stimulation with intrauterine insemination (OS-IUI) treatments for unexplained infertility DESIGN: Prospective cohort analysis of the Reproductive Medicine Network’s Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) randomized controlled trial SETTING: multicenter randomized controlled trial PATIENTS: 868 couples with unexplained infertility (n=2459 cycles) INTERVENTIONS: OS-IUI treatment cycles (n = 2,459) as part of the AMIGOS clinical trial MAIN OUTCOME MEASURES: Live birth rates (LBR); unadjusted and adjusted risk ratios (RR) for live birth by EMT category calculated using generalized estimating equations. RESULTS: The overall mean EMT on day of hCG administration in cycles with a live birth (9.5 mm, 95% CI 9.1–9.8) was significantly greater than in those without (8.9, 8.8–9.1; p=0.004). Compared to the referent EMT group of 9–12 mm, the unadjusted RR for live birth for the EMT groups of ≤5 and 6–8 were 0.48 (95% CI 0.22–1.03) and 0.92 (0.69–1.23), respectively. The test for trend indicated evidence of decreasing LBR with decreasing EMT (p=0.03). After adjustment for ovarian stimulation medication, a linear trend was no longer supported (p=0.41). Stratified analyses revealed no differences in associations by treatment group. CONCLUSIONS: In OS-IUI for unexplained infertility, higher LBR are observed with increasing EMT; however, EMT is not significantly associated with LBR when adjusted for OS treatment type. Appreciable LBR are seen at all EMTs, even those of ≤5 mm, suggesting that OS-IUI cycles should not be canceled for thin endometrium. TRIAL REGISTRATION: clinicaltrials.gov NCT01044862

Chlamydia trachomatis (C. trachomatis) is a major pathogen implicated in the formation of hydrosalpinx in the female reproductive tract. In mice, a related strain of Chlamydia, Chlamydia trachomatis (C. trachomatis) can induce almost 100% bilateral hydrosalpinx. This model was used as a hydrosalpinx induction model to test whether oviduct delivery of platelet-rich plasma (PRP) can attenuate chlamydia induction of hydrosalpinx in a mouse model. Mice were infected intravaginally with Chlamydia muridarum organisms, and 21 days after the infection, PRP was instilled into the lumen of one oviduct, and a sham instillation with phosphate buffer solution was performed on the contralateral oviduct. Mice were then sacrificed at designated time points after infection for oviduct pathologic evaluation including incidence, severity, and histopathologic grade of chronic inflammation. Oviduct instillation of PRP was associated with a 36% reduction in the incidence of hydrosalpinx and a 33% reduction in severity compared with sham. The median grade of chronic inflammation on histopathology was significantly lower with PRP instillation compared with sham and control. No differences were observed in vaginal or rectal shedding of C. muridarum between the test group and the control group. In short, the results suggest that oviduct instillation of PRP can significantly reduce the incidence and severity of C. muridarum-induced hydrosalpinx without affecting chlamydial infection courses in CBA/J mice.

Study question Among infertile women undergoing ovarian stimulation, is allostatic load (AL), a measure of chronic physiological stress, associated with subsequent fertility and pregnancy outcomes? Summary answer AL at baseline was not associated with conception, spontaneous abortion or live birth, however, it was significantly associated with increased odds of pre-eclampsia and preterm birth among women who had a live birth in the study. What is known already Several studies have linked AL during pregnancy to adverse outcomes including preterm birth and pre-eclampsia, hypothesizing that it may contribute to well-documented disparities in pregnancy and birth outcomes. However, AL biomarkers change over the course of pregnancy, raising questions as to whether gestational AL assessment is a valid measure of cumulative physiologic stress starting long before pregnancy. To better understand how AL may impact reproductive outcomes, AL measurement in the non-pregnant state (i.e. prior to conception) is needed. Study design, size, duration A secondary data analysis based on data from 836 women who participated in Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS), a multi-center, randomized clinical trial of ovarian stimulation conducted from 2011 to 2014. Participants/materials, setting, methods Ovulatory women with unexplained infertility (ages 18-40) were enrolled and at baseline, biological and anthropometric measures were collected. AL scores were calculated as a composite of the following baseline variables determined a priori: BMI, waist-to-hip ratio, systolic blood pressure, diastolic blood pressure, dehydroepiandrosterone sulfate, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, C-reactive protein and HOMA score. Participants received ovarian stimulation for up to four cycles and if they conceived, were followed throughout pregnancy. We fit multi-variable logistic regression models examining AL (one-tailed and two-tailed) in relation to the following reproductive outcomes: conception, spontaneous abortion, live birth, pre-eclampsia, preterm birth and low birthweight. Main results and the role of chance Adjusting for covariates, a unit increase in two-tailed AL score was associated with 62% increased odds of pre-eclampsia (OR: 1.62, 95% CI: 1.14, 2.38) 44% increased odds of preterm birth (OR: 1.44, 95% CI: 1.02, 2.08), and 39% increased odds of low birthweight (OR: 1.39, 95% CI: 0.99, 1.97). The relationship between AL and preterm birth was mediated by pre-eclampsia (P = 0.0003). In one-tailed AL analyses, associations were similar, but slightly attenuated. AL was not associated with fertility outcomes (conception, spontaneous abortion, live birth). Limitations, reasons for caution Results may not be generalizable to fertile women who conceive naturally or women with other types of infertility. Comparisons to previous, related work are difficult because variables included in AL composite measures vary across studies. AL may be indicative of overall poor health, rather than being specific to chronic physiological stress. Wider implications of the findings Our results suggest that chronic physiological stress may not impact success of ovarian stimulation, however, they confirm and extend previous work suggesting that AL is associated with adverse pregnancy outcomes. Physiological dysregulation due to chronic stress has been proposed as a possible mechanism underlying disparities in birth outcomes, which are currently poorly understood. Assessing biomarkers of physiological dysregulation pre-conception or in early pregnancy, may help to identify women at risk of adverse pregnancy outcomes, particularly pre-eclampsia. Study funding/competing interest(s) Support for AMIGOS was provided by: U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936 and U10HD055925. Support for the current analysis was provided by T32ES007271, R25HD075737, P30ES001247 and P30ES005022. This research was made possible by funding by American Recovery and Reinvestment Act. The content is solely the responsibility of the authors and does not necessarily represent the official views of NICHD, NIEHS or NIH. E.B., W.V., O.M., R.A., M.R., V.B., G.W.B., C.C., E.E., S.K., R.U., P.C, H.Z., N.S. and S.T. have nothing to disclose. R.L. reported serving as a consultant to Abbvie, Bayer, Kindex, Odega, Millendo and Fractyl and serving as a site investigator and receiving grants from Ferring. K.H. reported receiving grants from Roche Diagnostics and Ferring. R.R. reported a grant from AbbVie. M.D. reported being on the Board of Directors of and a stockholder in Advanced Reproductive Care. Trial registration number Clinical Trials.gov number: NCT01044862.

Context Adequate luteal phase progesterone exposure is necessary to induce endometrial changes required for a successful pregnancy outcome. The relationship between low midluteal progesterone concentration and the outcome of live birth in ovarian stimulation with intrauterine insemination (OS-IUI) treatments is not defined. Objective To determine the level of midluteal progesterone portending a low chance of live birth after OS-IUI in couples with unexplained infertility. Design and setting Secondary analyses of data from a prospective, randomized, multicenter clinical trial that determined pregnancy outcomes following OS-IUI with clomiphene citrate, letrozole, or gonadotropins for couples with unexplained infertility. Participants Couples (n = 900) underwent 2376 OS-IUI cycles during the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation clinical trial. Main outcome measures Live birth as it relates to midluteal progesterone level and thresholds below which no live births occur by treatment group. Results Thresholds for non-live birth cycles were similar for clomiphene (14.4 ng/mL) and letrozole (13.1 ng/mL) yet were lower for gonadotropin (4.3 ng/mL) treatments. A midluteal progesterone level >10th percentile specific for each treatment group independently was associated with greater odds for a live birth in all OS-IUI cycles (adjusted OR: 2.17; 95% CI: 1.05, 4.48). Conclusions During OS-IUI, a low midluteal progesterone level was associated with a low probability of live birth. Thresholds differed by medication, with the lowest threshold for gonadotropin. Several pathophysiologic mechanisms may account for low progesterone levels. Refinement of the predictive range associated with particular ovarian stimulation medications during treatment of unexplained infertility may improve accuracy.

OBJECTIVE: To study whether preconceptual thyroid-stimulating hormone (TSH) and antithyroid peroxidase (TPO) antibodies are associated with poor reproductive outcomes in infertile women. DESIGN: Secondary analysis of data from two multicenter, randomized, controlled trials conducted by the Reproductive Medicine Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Multivariable logistic regression analyses were performed to assess the association between preconceptual TSH levels and anti-TPO antibodies. SETTING: Not applicable. PATIENT(S): Serum samples from 1,468 infertile women were utilized. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Cumulative conception, clinical pregnancy, miscarriage, and live birth rates were calculated. RESULT(S): Conception, clinical pregnancy, miscarriage, and live birth rates did not differ between patients with TSH ≥2.5 mIU/L vs. TSH < 2.5 mIU/L. Women with anti-TPO antibodies had similar conception rates (33.3% vs. 36.3%) but higher miscarriage rates (43.9% vs. 25.3%) and lower live birth rates (17.1% vs. 25.4%) than those without anti-TPO antibodies. Adjusted, multivariable logistic regression models confirmed elevated odds of miscarriage (odds ratio 2.17, 95% confidence interval 1.12-4.22) and lower odds of live birth (oddr ratio 0.58, 95% confidence interval 0.35-0.96) in patients with anti-TPO antibodies. CONCLUSION(S): In infertile women, preconceptional TSH ≥2.5 mIU/L is not associated with adverse reproductive outcomes; however, anti-TPO antibodies are associated with increased risk of miscarriage and decreased probability of live birth. CLINICAL TRIAL REGISTRATION NUMBER: PPCOS II NCT00719186; AMIGOS NCT01044862.

Recent studies have suggested that GnRH agonists (GnRHags) protect ovarian function following chemotherapy. Here, we study the effect of a combination of GnRH antagonist (GnRHan) and GnRHag for gonadal protection from gonadotoxic chemotherapy in adolescent female rats. Cycling Sprague Dawley rats were treated at adolescent age. Thirty female rats were randomized to 5 treatment groups (n = 6/group): (1) placebo, (2) cyclophosphamide (CPA) alone, (3) GnRHan followed by GnRHag with placebo, (4) GnRHan followed by GnRHag with CPA, and (5) GnRHag with CPA. The main outcome measure was live birth rate (LBR), and secondary measures included rat weight, ovarian volume, and follicles. Group 2 had decreased LBR compared to all other groups. Group 4 and 5 had LBR similar to placebo. There was no difference in the ovarian volume. The CPA-alone group had decreased number of antral follicles compared to control. These studies demonstrate that the combination of GnRHan and GnRHag and GnRHag alone preserved fertility in female adolescent rats following gonadotoxic chemotherapy treatment. The addition of a GnRHan to a GnRHag does not confer a greater protective effect.

Objective To determine if short-term weight change among women with unexplained infertility (UI) and polycystic ovary syndrome (PCOS) undergoing ovulation induction is associated with live birth. Design Secondary analysis of randomized trials. Setting Multicenter fertility trial sites. Patient(s) A total of 900 women with UI and 750 women with PCOS. Main Outcome Measure(s) Live birth. Intervention(s) Weight assessment at enrollment and start of up to 4–5 cycles of clomiphene, letrozole, or gonadotropins and intrauterine insemination for women with UI and clomiphene or letrozole with regular intercourse for women with PCOS. Result(s) Weight data were available for 856 women with UI and 697 women with PCOS. Mean weight change was −0.2 ± 0.3 kg among women with UI and +2.2 ± 0.2 kg among women with PCOS and did not differ based on treatment allocation. There were 115 women with PCOS (16.4%) who gained ≥3 kg. Increased body mass index and three or more cycles were associated with weight gain in women with PCOS. There was no difference in live birth rate among women with PCOS and ≥3 kg weight gain and women with PCOS who did not gain weight. Conclusion(s) Women with PCOS gained an average of 2.2 kg regardless of the medication received, whereas women with UI experienced no short-term weight change during ovulation induction. Weight gain in women with PCOS was not associated with live birth rate.

We sought to determine whether lower fertility related quality of life or depression in men of couples with unexplained infertility is associated with low total testosterone levels, abnormal semen quality or erectile dysfunction.This study is a secondary analysis of a large, multicenter, randomized controlled trial in couples with unexplained infertility. Male partners underwent baseline semen analysis with measurement of fasting total testosterone and gonadotropin. They also completed surveys, including the FertiQOL (Fertility Quality of Life), the PHQ-9 (Patient Health Questionnaire-9) and the IIEF (International Index of Erectile Function). The primary study outcomes were total testosterone with low total testosterone defined as less than 264 ng/dl, semen parameters and the IIEF score. We performed multivariable logistic regression analyses adjusted for patient age, race, body mass index, education, smoking, alcohol use, infertility duration and comorbidity.A total of 708 men with a mean ± SD age of 34.2 ± 5.6 were included in study. Of the men 59 (8.3%) had a PHQ-9 score of 5 or greater, which was consistent with depression, 99 (14.0%) had low total testosterone and 63 (9.0%) had mild or worse erectile dysfunction. Neither the FertiQOL score nor depression was associated with total testosterone or any semen parameter. The FertiQOL score was inversely associated with erectile dysfunction (for every 5-point score decline AOR 1.30, 95% CI 1.16-1.46). Depressed men were significantly more likely to have erectile dysfunction than nondepressed men (AOR 6.31, 95% CI 3.12-12.77).In men in couples with unexplained infertility lower fertility related quality of life and depression are strongly associated with erectile dysfunction. However, neither is associated with spermatogenesis or testosterone levels. Erectile dysfunction in infertile men merits longitudinal investigation in future studies.

Objective To study the development of children conceived from non-IVF infertility treatments consisting of gonadotropins, clomiphene, or letrozole. Design Prospective cohort study. Setting U.S. academic health centers. Patient(s) Children of women with polycystic ovary syndrome who conceived with letrozole (LTZ) or clomiphene (CC) in the PPCOS II study or women with unexplained infertility (AMIGOS study) who conceived with LTZ, CC, or gonadotropin (GN). Intervention(s) Longitudinal annual follow-up from birth to age 3. Main Outcome Measure(s) Scores from Ages and Stages Developmental Questionnaire (ASQ), MacArthur-Bates Communicative Development Inventory (MCDI), and annual growth. Result(s) One hundred eighty-five children from 160 families participated in at least one follow-up evaluation from the two infertility trials. Most multiple gestations in the follow-up study resulted from GN treatment (n = 14) followed by CC (n = 6) and LTZ (n = 3). There were no significant differences among the three groups at any time point with respect to abnormal scores on the ASQ. On the MCDI Words and Gestures, the LTZ group scored significantly higher than the GN group for most items (phrases, early gestures, later gestures, and total gestures). Children in the CC group scored significantly higher than the GN group for the later gestures and total gestures items. Conclusion(s) Differences in growth and cognitive developmental rates among children conceived with first-line infertility therapies, including LTZ, are relatively minor and likely due to differences in multiple pregnancy rates.

Fertility preservation for children and young adults with cancer is an important part of comprehensive patient care. In 2013, the American Society of Clinical Oncology (ASCO) released updated clinical practice guidelines addressing fertility preservation. This study aimed to evaluate if pediatric oncologists were performing fertility preservation counseling, if the new guidelines were being adopted, and how reproductive endocrinologists can educate this patient population and their providers.A cross-sectional study was performed from May 26, 2014, to August 26, 2014. An online survey addressing fertility preservation practice patterns was created and provided to the members of the Children's Oncology Group (COG).Thirty-five percent of the 234 respondents reported reading the new 2013 ASCO guidelines. Ninety-five percent of providers reported mentioning fertility preservation options prior to treatment, most commonly including referral to a reproductive endocrinologist (28%), and sperm banking (57%). The most commonly reported barrier to fertility preservation counseling was the cost of treatment.Fertility preservation counseling is being performed by pediatric oncology providers. Familiarity of the ASCO guidelines is limited, revealing that the established methods for fertility preservation in women--embryo and oocyte cryopreservation--may be offered less than experimental methods in this younger patient population. Such differences in apparent practice patterns highlight the need for more education for providers.

Objective Bilateral tubal ligation (BTL) is a common form of birth control in the United States. There are limited, contradictory data examining BTL and the risk of endometrial cancer and none examining type I and type II cancers separately. We investigated the association between BTL and endometrial cancer risk using the Women’s Health Initiative (WHI) Observational and Dietary Modification Studies. Methods Demographic information and history of BTL were obtained from the baseline questionnaires from 76,483 WHI participants in the Observational and Dietary Modification Studies. Univariable and multivariable models were used to examine the association of BTL with type I and type II endometrial cancers. Results A total of 1137 women were diagnosed with incident endometrial cancer (972 type I and 128 type II) during a mean follow-up of 11.3 years. Overall, 14,499 (19%) women had undergone BTL. There were no statistically significant associations noted between BTL and age at BTL for type I or type II cancers. Conclusions We examined the largest patient cohort to date in an effort to determine the impact of BTL on endometrial cancer risk. In the WHI trial, we observed no overall effect of BTL on the risk of type I or type II endometrial cancer, suggesting that patients undergoing this popular birth control method likely do not have an associated change in their baseline risk for endometrial cancer.

PURPOSE: The number of in vitro fertilization (IVF) cycles is increasing and the majority of patients undergoing IVF pay out of pocket. Reproductive endocrinology and infertility practitioners employ different business models to help create financial pathways for patients needing IVF but details regarding the different types of business models being used and physician satisfaction with those models have not been described previously. METHODS: A cross-sectional survey was sent to members of the Society of Reproductive Endocrinology and Infertility. The survey included 30 questions designed to assess demographics, practice patterns, and business models utilized. RESULTS: A total of 222/736 (30%) physicians responded to the survey. The majority of physicians offer a-la-carte (67%), bundled services (69%), grants (57%), and cost/risk-sharing (50%). The majority answered that the single ideal business model is bundled services (53%). There was no significant association between financial package offered and region of practice or state-mandated insurance. The largest barrier to care reported was cost with or without state-mandated coverage (94% and 99%, respectively). The majority of practices are satisfied with their business model (75%). Higher physician satisfaction was associated with private practice [69% vs 27%; OR (95%CI) = 3.8 (1.7, 8.6)], male gender [59% vs 30%; OR = 2.4 (1.1, 5.4)], and offering bundled services [83% vs 59%; OR = 2.8 (1.2, 6.7)]. CONCLUSIONS: Physicians utilize a variety of business models and most are satisfied with their current model. Cost is the major barrier to care in states with and without mandated coverage.

Of graduating obstetrics and gynecology residents, 40% apply for fellowship training and this percentage is likely to increase. The fellowship interview process creates a substantial financial burden on candidates as well as significant challenges in scheduling the multiple interviews for residents, residency programs, and fellowship programs. Coverage with relatively short lead time is needed for some resident rotations, multiple residents may request time off during overlapping time periods, and applicants may not be able to interview based on conflicting interview dates or the inability to find coverage from other residents for their clinical responsibilities. To address these issues, we propose that each subspecialty fellowship within obstetrics and gynecology be allocated a specified and limited time period to schedule their interviews with minimal overlap between subspecialties. Furthermore, programs in close geographic areas should attempt to coordinate their interview dates. This will allow residents to plan their residency rotation schedules far in advance to minimize the impact on rotations that are less amenable to time away from their associated clinical duties, and decrease the numbers of residents needing time off for interviews during any one time period. In addition, a series of formal discussions should take place between subspecialties related to these issues as well as within subspecialties to facilitate coordination.

Synopsis: Adolescent and pre-menarchal patients with symptomatic unilateral labial hypertrophy should be counselled extensively prior to surgical management regarding risks of recurrence or contralateral occurrence. Purpose: Present the management of two unique cases of adolescent girls with unilateral labial hypertrophy. Case 1: 9 year-old pre-menarchal patient with a five-month history of unilateral labial hypertrophy causing discomfort that limited daily activities. External pelvic examination revealed grossly asymmetric labia minora. The left labia minora measured 5 cm in length. After counseling, the patient underwent unilateral labioplasty with resolution of symptoms. Patient returned after two years complaining of contralateral labial hypertrophy.The patient again underwent surgical management due to discomfort and interference with normal daily activities. Case 2: 12 year-old post-menarchal patient with a history of unilateral labial hypertrophy causing irritation and discomfort starting prior to menarche. External pelvic exam revealed grossly asymmetric labia minora. The right labia minora measured 4.5cm in length. The patient underwent unilateral labioplasty with resolution of her symptoms. After 2 years of follow up, patient remained asymptomatic. Conclusion: Adolescence unilateral labial hypertrophy may represent a normal variant and surgery should be delayed until achieving full puberty. However, when it causes significant discomfort or interferes with normal daily activities, surgical management should be considered after counseling regarding recurrence or contralateral occurrence

Objective To determine if maternal major depression (MD), antidepressant use, or paternal MD are associated with pregnancy outcomes after non-IVF fertility treatments. Design Cohort study. Setting Clinics. Patient(s) Participants in two randomized trials: PPCOS II (clomiphene citrate versus letrozole for polycystic ovary syndrome), and AMIGOS (gonadotropins versus clomiphene citrate versus letrozole for unexplained infertility). Intervention(s) Female and male partners completed the Patient Health Questionnaire (PHQ-9). Female medication use was collected. PHQ-9 score ≥10 was used to define currently active MD. Main Outcome Measure(s) Primary outcome: live birth. Secondary outcomes: pregnancy, first-trimester miscarriage. Poisson regression models were used to determine relative risks after adjusting for age, race, income, months trying to conceive, smoking, and study (PPCOS II versus AMIGOS). Result(s) Data for 1,650 women and 1,608 men were included. Among women not using an antidepressant, the presence of currently active MD was not associated with poorer fertility outcomes (live birth, miscarriage), but rather was associated with a slightly increased likelihood of pregnancy. Maternal antidepressant use (n = 90) was associated with increased risk of miscarriage, and male partners with currently active MD were less likely to achieve conception. Conclusion(s) Currently active MD in the female partner does not negatively affect non-IVF treatment outcomes; however, currently active MD in the male partner may lower the likelihood of pregnancy. Maternal antidepressant use is associated with first-trimester pregnancy loss, which may depend upon the type of antidepressant. Clinical Trial Registration Numbers NCT00719186 and NCT01044862.

OBJECTIVE: To study whether there is a difference in the prevalence of non-cavity-distorting uterine fibroids between infertile patients with polycystic ovary syndrome (PCOS) and those with unexplained infertility (UI). DESIGN: A secondary analysis of data from three randomized clinical trials. SETTING: Academic health centers. PATIENTS: A total of 2249 patients with a normal uterine cavity. INTERVENTIONS(S): None MAIN OUTCOME MEASURE(S): The presence or absence of non-cavity-distorting fibroids. RESULTS: Compared to women with UI, those with PCOS were younger, had a higher body mass index, were more likely to be Hispanic and African American, with a lower percentage of prior conception and live birth, a higher percentage of current smokers and lower percentage of current alcohol users, had a higher total testosterone, fasting insulin, and homeostatic model assessment-insulin resistance. The prevalence of women with non-cavity-distorting uterine fibroids was lower in women with PCOS than those with UI (6.7% vs 12.4%, p=4 cm nor the volume of the largest fibroid was found between the two groups. CONCLUSION(S): A lower prevalence of non-cavity-distorting uterine fibroids was found in infertile women with PCOS than those with UI.

Highlights • STUMPs are rare smooth muscle tumors with an overall favorable prognosis. • Pregnancy is possible after diagnosis of STUMP treated with myomectomy • Management of patients desiring fertility with STUMPs requires a multidisciplinary approach.

Background: 4% icodextrin is a fluid that can be instilled laparoscopically to prevent adhesion formation. There are few complications reported in the literature associated with its use. Case: A 38-year-old woman, gravida 2, para 0, abortus 2 underwent laparoscopic salpingectomy. 4% icodextrin was instilled in an effort to prevent adhesion formation. Postoperatively, the patient experienced urinary retention and gross vulvar edema that required foley catheter use until the 4% icodextrin solution had absorbed. Conclusion: Postoperative complications that may be associated with the use of 4% icodextrin include urinary retention and vulvar edema.

Objective To assess the effect of assisted hatching (AH) on live-birth rates in a retrospective cohort of patients undergoing first-cycle, autologous frozen embryo transfer (FET). Design Longitudinal cohort using cycles reported to the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System between 2004 and 2013. Setting Not applicable. Patient(s) Women who underwent first-cycle, autologous FET with (n = 70,738) and without (n = 80,795) AH reported from 2004 to 2013. Intervention(s) None. Main Outcome Measure(s) Live births. Result(s) Propensity matching was used to account for confounding covariates, and a logistic regression model was constructed to identify the predictors of live-birth rates in relationship to AH. In all first-cycle FETs, there was a slight but statistically significant decrease in the live-birth rate with AH compared with no AH (34.2% vs. 35.4%). In older patients and in the years 2012–2013 AH was associated with decreased live births. Live-birth rates and the number of AH cycles performed before FET vary by the geographic location of clinics. Conclusion(s) Assisted hatching slightly decreases the live-birth rate in first-cycle, autologous FET. Its use should be carefully considered, especially in patients 38 years old and older. Prospective, clinical studies are needed to improve our knowledge of the impact of AH.

Objective To identify baseline characteristics of couples that are likely to predict conception, clinical pregnancy, and live birth after up to four cycles of ovarian stimulation with IUI in couples with unexplained infertility. Design Secondary analyses of data from a prospective, randomized, multicenter clinical trial investigating pregnancy, live birth, and multiple pregnancy rates after ovarian stimulation-IUI with clomiphene citrate, letrozole, or gonadotropins. Setting Outpatient clinical units. Patient(s) Nine-hundred couples with unexplained infertility who participated in the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation clinical trial. Intervention(s) As part of the clinical trial, treatment was randomized equally to one of three arms and continued for up to four cycles or until pregnancy was achieved. Main Outcome Measure(s) Conception, clinical pregnancy, and live-birth rates. Result(s) In a multivariable logistic regression analysis, after adjustment for other covariates, age, waist circumference, income level, duration of infertility, and a history of prior pregnancy loss were significantly associated with at least one pregnancy outcome. Other baseline demographic and lifestyle characteristics including smoking, alcohol use, and serum levels of antimullerian hormone were not significantly associated with pregnancy outcomes. Conclusion(s) While age and duration of infertility were significant predictors of all pregnancy outcomes, many other baseline characteristics were not. The identification of level of income as a significant predictor of outcomes independent of race and education may reflect differences in the underlying etiologies of unexplained infertility or could reveal disparities in access to fertility and/or obstetrical care. Clinical Trial Registration NCT01044862.

To test the hypothesis that day 5 ET (D5ET) is superior to day 3 ET (D3ET) in pregnancy outcome and that it also reduces multiple gestations.Retrospective cohort study.Assisted reproductive technologies program at Wilford Hall Medical Center.Patients electing for either D3ET or D5ET.Participants meeting inclusion criteria for D5ET elected either D3ET or D5ET.Cycles were compared by day of transfer and further stratified by patient age (35 years and 35-40 years). The number of oocytes retrieved, embryos on day 3, embryos transferred, pregnancy rate, implantation rate, and twin and high order multiples (or=triplets) rates were compared.Of the 274 patients who met our inclusion criteria, 153 underwent a D3ET and 121 underwent a D5ET. The D5ET group had a significantly lower mean age and number of embryos transferred and a higher implantation rate (56% vs. 42%) than the D3ET group. Patients who were 35-40 years old had a significantly higher live-birth rate (68% vs. 40%). Although not statistically significant, the D5ET groups had higher clinical pregnancy (73% vs. 65%) and twin pregnancy (33% vs. 25%) rates.Blastocyst transfer resulted in fewer embryos transferred, with a trend toward improved clinical pregnancy and higher twin pregnancy rates. Live-birth rates were improved in patients 35-40 years of age. Younger patients opting for D5ET should do so with a commitment toward single ET.

The purpose of this study was to assess the possible association between scores of200 on U.S. Medical Licensure Examination (USMLE) step 1 and the Council on Resident Education in Obstetrics and Gynecology (CREOG) in-training examinations and the pass rate on the American Board of Obstetrics and Gynecology (ABOG) written examination.The USMLE step 1 and postgraduate year 1 to 4 CREOG in-training examination scores for the graduating chief residents in eight accredited obstetrics and gynecology residency programs were obtained. Performance on USMLE step 1 was correlated with ABOG examination performance and CREOG in-training examination scores. The correlations between USMLE step 1 and CREOG in-training examination scores and ABOG examination performance were analyzed by using the Spearman correlation coefficient.USMLE step 1 scores were significantly correlated with CREOG in-training examination scores (p0.000). None of the residents who scored200 on USMLE step 1 and a mean of200 on the CREOG in-training examinations failed the ABOG written examination.Program directors have used USMLE step 1 to identify trainees who are likely to perform well on the CREOG in-training examination. The CREOG in-training examination has been used to identify residents who are likely to pass the ABOG written examination. The results of this study document the strength of these associations.