High estradiol levels in fresh embryo transfer cycles are not associated with detrimental impact on birth outcomes.

PURPOSE: There is an unclear relationship between estradiol levels and fresh embryo transfer (ET) outcomes. We determined the relationship between estradiol on the day of trigger, in fresh ET cycles without premature progesterone elevation, and good birth outcomes (GBO). METHODS: We identified autologous fresh ET cycles from 2015 to 2021 at multiple clinics in the USA. Patients with recurrent pregnancy loss, uterine factor, and elevated progesterone on the day of trigger (progesterone > 2 ng/mL or 3-day area under the curve > 4.5 ng/mL) were excluded. The primary outcome was GBO (singleton, term, live birth with appropriate weight). Log-binomial generalized estimating equations determined the likelihood of outcomes. RESULTS: Of 17,608 fresh ET cycles, 5025 (29%) yielded GBO. Cycles with estradiol ≥ 4000 pg/mL had a greater likelihood of GBO compared to cycles < 1000 pg/mL (aRR = 1.32, 95% CI 1.13-1.54). Pairwise comparisons of estradiol between < 1000 pg/mL versus 1000-1999 pg/mL and 1000-1999 pg/mL versus 2000-2999 pg/mL revealed a higher likelihood of GBO with higher estradiol (aRR 0.83, 95% CI 0.73-0.95; aRR 0.91, 95% CI 0.85-0.97, respectively). Comparisons amongst more elevated estradiol levels revealed that the likelihood of GBO remained similar between groups (2000-2999 pg/mL versus 3000-3999 pg/mL, aRR 1.04, 95% CI 0.97-1.11; 3000-3999 pg/mL versus ≥ 4000 pg/mL, aRR 0.96, 95% CI 0.9-1.04). CONCLUSION: In fresh ET cycles, higher estradiol levels were associated with an increased prevalence of GBO until estradiol 2000-2999 pg/mL, thereafter plateauing. In fresh ET candidates, elevated estradiol levels should not preclude eligibility though premature progesterone rise, and risk of ovarian hyperstimulation syndrome must still be considered.

Integrated stress response control of granulosa cell translation and proliferation during normal ovarian follicle development.

Mechanisms that directly control mammalian ovarian primordial follicle (PF) growth activation and the selection of individual follicles for survival are largely unknown. Follicle cells produce factors that can act as potent inducers of cellular stress during normal function. Consistent with this, we show here that normal, untreated ovarian cells, including pre-granulosa cells of dormant PFs, express phenotype and protein markers of the activated integrated stress response (ISR), including stress-specific protein translation (phospho-Serine 51 eukaryotic initiation factor 2α; P-EIF2α), active DNA damage checkpoints, and cell-cycle arrest. We further demonstrate that mRNAs upregulated in primary (growing) follicles versus arrested PFs mostly include stress-responsive upstream open reading frames (uORFs). Treatment of a granulosa cell (GC) line with the PF growth trigger tumor necrosis factor alpha results in the upregulation of a 'stress-dependent' translation profile. This includes further elevated P-eIF2α and a shift of uORF-containing mRNAs to polysomes. Because the active ISR corresponds to slow follicle growth and PF arrest, we propose that repair and abrogation of ISR checkpoints (e.g. checkpoint recovery) drives the GC cell cycle and PF growth activation (PFGA). If cellular stress is elevated beyond a threshold(s) or, if damage occurs that cannot be repaired, cell and follicle death ensue, consistent with physiological atresia. These data suggest an intrinsic quality control mechanism for immature and growing follicles, where PFGA and subsequent follicle growth and survival depend causally upon ISR resolution, including DNA repair and thus the proof of genomic integrity.

Ovarian stimulation for fertility preservation in an oncology patient with etonogestrel implant in place.

PURPOSE: To describe a case of a young woman who presented for fertility preservation and underwent ovarian stimulation with an etonogestrel implant in place. METHODS: A 24-year old, gravida 0, with an etonogestrel implant and newly diagnosed lower extremity sarcoma and DVT desiring oocyte cryopreservation prior to adjuvant chemotherapy and radiation. To avoid delay in her oncologic care and allow for continued use of contraception post-retrieval, the patient underwent controlled ovarian hyperstimulation (COH) without removal of the etonogestrel implant. RESULTS: Baseline labs included follicle-stimulating hormone 9 mIU/mL, luteinizing hormone 4.9 mIU/mL, estradiol 42 pg/mL, anti-Müllerian hormone 5.1 ng/mL, and antral follicle count greater than 40. The patient was placed on an antagonist protocol and stimulated with 125 IU Gonal-F and 75 IU Menopur. She received a total of 12 days of gonadotropin stimulation. On the day of trigger, her estradiol was 1472 pg/mL, lead follicle 21.5 mm with a total of 25 follicles measured > 12 mm. She was triggered with 5000 U hCG. She had a total of 23 oocytes retrieved, 17 of which were metaphase II and vitrified. CONCLUSIONS: COH and successful oocyte cryopreservation can be achieved in patients with an etonogestrel implant in situ without apparent detrimental effects to oocyte yield or maturity. Due to the etonogestrel implant's inhibitory effects on LH, it is recommended to use an hCG trigger for final oocyte maturation.

Birth outcomes are superior after transfer of fresh versus frozen embryos for donor oocyte recipients.

STUDY QUESTION: For donor oocyte recipients, are birth outcomes superior for fresh versus frozen embryos? SUMMARY ANSWER: Among fresh donor oocyte recipients, fresh embryos are associated with better birth outcomes when compared with frozen embryos. WHAT IS KNOWN ALREADY: Frozen embryo transfer (ET) with vitrification has been associated with improved pregnancy rates, but also increased rates of large for gestational age infants. Donor oocyte recipients represent an attractive biological model to attempt to isolate the impact of embryo cryopreservation on IVF outcomes, yet there is a paucity of studies in this population. STUDY DESIGN, SIZE, DURATION: A retrospective cohort of the US national registry, the Society for Assisted Reproductive Technology Clinic Outcome Reporting System, of IVF cycles of women using fresh donor oocytes resulting in ET between 2013 and 2015. Thawed oocytes were excluded. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Good obstetric outcome (GBO), defined as a singleton, term, live birth with appropriate for gestational age birth weight, was the primary outcome measure. Secondary outcomes included live birth, clinical pregnancy, spontaneous abortion, preterm birth, multiple births and gestational age-adjusted weight. Outcomes were modeled using the generalized estimating equation approach. MAIN RESULTS AND THE ROLE OF CHANCE: Data are from 25 387 donor oocyte cycles, in which 14 289 were fresh and 11 098 were frozen ETs. A GBO was 27% more likely in fresh ETs (26.3%) compared to frozen (20.9%) (adjusted risk ratio 1.27; 95% confidence interval (CI) 1.21-1.35; P < 0.001). Overall, fresh transfer was more likely to result in a live birth (55.7% versus 39.5%; adjusted risk ratio 1.21; 95% CI 1.18-1.26; P < 0.001). Among singleton births, there was no difference in gestational age-adjusted birth weight between groups. LIMITATION, REASONS FOR CAUTION: Our cohort findings contrast with data from autologous oocytes. Prospective studies with this population are warranted. WIDER IMPLICATIONS OF THE FINDINGS: Among donor oocyte recipients, fresh ETs may be associated with better birth outcomes. Reassuringly, given its prevalent use, modern embryo cryopreservation does not appear to result in phenotypically larger infants. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

Lower antimüllerian hormone is associated with lower oocyte yield but not live-birth rate among women with obesity.

BACKGROUND: Antimüllerian hormone is produced by small antral follicles and reflects ovarian reserve. Obesity is associated with lower serum antimüllerian hormone, but it is unclear whether lower levels of antimüllerian hormone in women with obesity reflect lower ovarian reserve. OBJECTIVE: To determine whether lower antimüllerian hormone in women with obesity undergoing in vitro fertilization is associated with oocyte yield and live-birth rate. MATERIALS AND METHODS: Retrospective cohort from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database of 13,316 women with obesity and 16,579 women with normal body mass index undergoing their first autologous in vitro fertilization with fresh transfers between 2012 and 2014. Normal body mass index was defined as body mass index 18.5-24.9 kg/m2, and obesity was defined as body mass index ≥30 kg/m2. Subjects with obesity were stratified as those with class 1 obesity (body mass index, 30.0-34.9 kg/m2), class 2 obesity (body mass index, 35.0-39.9 kg/m2), and class 3 obesity (body mass index, ≥40 kg/m2) based on the World Health Organization body mass index guidelines. Antimüllerian hormone levels were stratified as normal (>1.1 ng/mL), low (0.16-1-1 ng/mL), and undetectable (≤0.16 ng/mL). Multivariable modeling was used to assess oocyte yield using linear regression with a logarithmic transformation and odds of live birth using logistic regression. RESULTS: Women with obesity were older (36.0 ± 4.8 vs 35.5 ± 4.8, P < .001), had lower antimüllerian hormone (1.8 ± 2.0 ng/mL vs 2.1 ± 2.0 ng/mL, P < .001), and had fewer oocytes retrieved (11.9 ± 7.3 vs 12.8 ± 7.7, P < .001) than women with normal body mass index. Lower oocyte yield was observed among women with obesity and normal antimüllerian hormone levels compared to women with normal body mass index and normal antimüllerian hormone levels (13.6 ± 7.3 vs 15.8 ± 8.1, P < .001). No difference in oocyte yield was observed among women with obesity and low antimüllerian hormone levels (P = .58) and undetectabl antimüllerian hormone (P = .11) compared to women with normal BMI and similar antimüllerian hormone levels. Among women with a body mass index ≥30 kg/m2, antimüllerian hormone levels were associated with the number of oocytes retrieved (ß = 0.069; standard error, 0.005; P < .001) but not live-birth rate (odds ratio, 0.98; 95% confidence interval, 0.93-1.04, P = .57). CONCLUSION: Lower antimüllerian hormone in infertile women with obesity appears to reflect lower ovarian reserve, as antimüllerian hormone is associated with lower oocyte yield. Despite lower oocyte yield, lower antimüllerian hormone was not associated with lower live-birth rate among women with obesity.

Direct Methotrexate Injection into the Gestational Sac for Nontubal Ectopic Pregnancy: A Review of Efficacy and Outcomes from a Single Institution.

STUDY OBJECTIVE: To evaluate the efficacy of nontubal ectopic pregnancy (NTEP) management with direct methotrexate (MTX) injection into the gestational sac. DESIGN: A retrospective chart review. SETTING: A tertiary academic and teaching hospital. PATIENTS: All cases of confirmed NTEP were retrospectively identified from 2012 to 2017. INTERVENTIONS: Ultrasound-guided direct injection of MTX into the fetal pole and surrounding gestational sac and a single dose of systemic MTX with or without fetal intracardiac injection of potassium chloride. MEASUREMENTS AND MAIN RESULTS: Treatment failure, complications from treatment, operating time, and days to negative serum human chorionic gonadotropin (hCG) after treatment were measured. Fourteen women (age 34 ± 5.2 years) with NTEP underwent direct MTX injection (cesarean scar, n = 4; interstitial, n = 6; cervical, n = 4). The mean estimated gestational age was 49 ± 11, CI (43, 56 days). One patient required laparoscopic intervention with a failure rate of 1 of 14 (a double interstitial, heterotopic pregnancy). There were no other major complications. The time in the operating room was similar for all NTEP types. The average time to negative serum hCG was not different for cesarean scar (84.5 ± 36 days), cervical pregnancies (70.5 ± 19 days), or interstitial pregnancies (45.3 ± 38 days, p = .15). CONCLUSION: Direct MTX injection into the gestational sac for NTEP treatment is safe and effective. The failure rate of 7% is considerably lower than what was previously reported for a failure of systemic MTX in similar cases (25%). Resolution of serum hCG after treatment can be quite prolonged even in uncomplicated cases.

Preimplantation genetic testing and chances of a healthy live birth amongst recipients of fresh donor oocytes in the United States.

PURPOSE: To evaluate if preimplantation genetic testing (PGT) improves the odds of a healthy live birth amongst recipients of fresh donor oocytes. METHODS: We performed a retrospective cohort study including in vitro fertilization cycles of women using fresh donor oocytes reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System, between 2013 and 2015. Cycles were categorized based on PGT. Primary outcome measure was a good birth outcome (GBO), defined as a singleton, term, live birth with an average birthweight. Multivariable generalized estimating equation models were fit to analyze the effect of PGT. Interaction effect between cycle type (fresh vs frozen) and PGT was tested. RESULTS: Of 28,153 included cycles, 3708 had PGT while 24,445 did not. PGT cycles were less likely to result in an embryo transfer (ET) (64 vs 94%), but were associated with increased rates of frozen ET (70 vs 41%), single ET (67 vs 44%), and blastocyst ET (87 vs 65%). There was a significant interaction between PGT and cycle type. Cycles using PGT increased the probability of a GBO 12% in frozen cycles (RR 1.12; 95% CI 1.02, 1.22; p = 0.018), but PGT was detrimental to success in fresh cycles with a 53% reduced likelihood of GBO (RR 0.47; 9% CI 0.41, 0.54; p < 0.001). CONCLUSION: PGT, as practiced during the most recently available national data in women using fresh donor oocytes, was associated with increased probability of a healthy live birth amongst frozen cycles, but was not beneficial in fresh cycles.

The impact of infertility diagnosis on embryo-endometrial dialogue.

Initial stages of implantation involve bi-directional molecular crosstalk between the blastocyst and endometrium. This study investigated an association between infertility etiologies, specifically advanced maternal age (AMA) and endometriosis, on the embryo-endometrial molecular dialogue prior to implantation. Co-culture experiments were performed with endometrial epithelial cells (EEC) and cryopreserved day 5 blastocysts (n = 41 ≥ Grade 3BB) donated from patients presenting with AMA or endometriosis, compared to fertile donor oocyte controls. Extracellular vesicles isolated from co-culture supernatant were analyzed for miRNA expression and revealed significant alterations correlating to AMA or endometriosis. Specifically, AMA resulted in 16 miRNAs with increased expression (P ≤ 0.05) and strong evidence for negative regulation toward 206 target genes. VEGFA, a known activator of cell adhesion, displayed decreased expression (P ≤ 0.05), validating negative regulation by 4 of these increased miRNAs: miR-126; 150; 29a; 29b (P ≤ 0.05). In endometriosis patients, a total of 10 significantly altered miRNAs displayed increased expression compared to controls (miR-7b; 9; 24; 34b; 106a; 191; 200b; 200c; 342-3p; 484) (P ≤ 0.05), targeting 1014 strong evidence-based genes. Three target genes of miR-106a (CDKN1A, E2F1 and RUNX1) were independently validated. Functional annotation analysis of miRNA-target genes revealed enriched pathways for both infertility etiologies, including disrupted cell cycle regulation and proliferation (P ≤ 0.05). These extracellular vesicle-bound secreted miRNAs are key transcriptional regulators in embryo-endometrial dialogue and may be prospective biomarkers of implantation success. One of the limitations of this study is that it was a stimulated, in vitro model and therefore may not accurately reflect the in-vivo environment.

Modeling associations between latent event processes governing time series of pulsing hormones.

This work is motivated by a desire to quantify relationships between two time series of pulsing hormone concentrations. The locations of pulses are not directly observed and may be considered latent event processes. The latent event processes of pulsing hormones are often associated. It is this joint relationship we model. Current approaches to jointly modeling pulsing hormone data generally assume that a pulse in one hormone is coupled with a pulse in another hormone (one-to-one association). However, pulse coupling is often imperfect. Existing joint models are not flexible enough for imperfect systems. In this article, we develop a more flexible class of pulse association models that incorporate parameters quantifying imperfect pulse associations. We propose a novel use of the Cox process model as a model of how pulse events co-occur in time. We embed the Cox process model into a hormone concentration model. Hormone concentration is the observed data. Spatial birth and death Markov chain Monte Carlo is used for estimation. Simulations show the joint model works well for quantifying both perfect and imperfect associations and offers estimation improvements over single hormone analyses. We apply this model to luteinizing hormone (LH) and follicle stimulating hormone (FSH), two reproductive hormones. Use of our joint model results in an ability to investigate novel hypotheses regarding associations between LH and FSH secretion in obese and non-obese women.

Comparison of sonohysterography to hysterosalpingogram for tubal patency assessment in a multicenter fertility treatment trial among women with polycystic ovary syndrome.

PURPOSE: To compare saline infusion sonohysterography (SIS) versus hysterosalpingogram (HSG) for confirmation of tubal patency. METHODS: Secondary analysis of a randomized controlled trial, Pregnancy in Polycystic Ovary Syndrome II (PPCOS II). Seven hundred fifty infertile women (18-40 years old) with polycystic ovary syndrome (PCOS) were randomized to up to 5 cycles of letrozole or clomiphene citrate. Prior to enrollment, tubal patency was determined by HSG, the presence of free fluid in the pelvis on SIS, laparoscopy, or recent intrauterine pregnancy. Logistic regression was conducted in patients who ovulated with clinical pregnancy as the outcome and HSG or SIS as the key independent variable. RESULTS: Among women who ovulated, 414 (66.9%) had tubal patency confirmed by SIS and 187 (30.2%) had at least one tube patent on HSG. Multivariable analysis indicated that choice of HSG versus SIS did not have a significant relationship on likelihood of clinical pregnancy, after adjustment for treatment arm, BMI, duration of infertility, smoking, and education (OR 1.14, 95% CI 0.77, 1.67, P = 0.52). Ectopic pregnancy occurred more often in women who had tubal patency confirmed by HSG compared to SIS (2.8% versus 0.6%, P = 0.02). CONCLUSIONS: In this large cohort of women with PCOS, there was no significant difference in clinical pregnancy rate between women who had tubal patency confirmed by HSG versus SIS. SIS is an acceptable imaging modality for assessment of tubal patency in this population.

Racial and ethnic differences in the polycystic ovary syndrome metabolic phenotype.

BACKGROUND: Women with polycystic ovarian syndrome have a high prevalence of metabolic syndrome and type 2 diabetes mellitus. Blacks and Hispanics have a high morbidity and mortality due to cardiovascular disease and diabetes mellitus in the general population. Since metabolic syndrome is a risk factor for development of type 2 diabetes and cardiovascular disease, understanding any racial and ethnic differences in metabolic syndrome among women with polycystic ovarian syndrome is important for prevention strategies. However, data regarding racial/ethnic differences in metabolic phenotype among women with polycystic ovary syndrome are inconsistent. OBJECTIVE: We sought to determine if there are racial/ethnic differences in insulin resistance, metabolic syndrome, and hyperandrogenemia in women with polycystic ovarian syndrome. STUDY DESIGN: We conducted secondary data analysis of a prospective multicenter, double-blind controlled clinical trial, the Pregnancy in Polycystic Ovary Syndrome II study, conducted in 11 academic health centers. Data on 702 women with polycystic ovarian syndrome aged 18-40 years who met modified Rotterdam criteria for the syndrome and wished to conceive were included in the study. Women were grouped into racial/ethnic categories: non-Hispanic whites, non-Hispanic blacks, and Hispanic. The main outcomes were the prevalence of insulin resistance, metabolic syndrome, and hyperandrogenemia in the different racial/ethnic groups. RESULTS: Body mass index (35.1 ± 9.8 vs 35.7 ± 7.9 vs 36.4 ± 7.9 kg/m2) and waist circumference (106.5 ± 21.6 vs 104.9 ± 16.4 vs 108.7 ± 7.3 cm) did not differ significantly between non-Hispanic white, non-Hispanic black, and Hispanic women. Hispanic women with polycystic ovarian syndrome had a significantly higher prevalence of hirsutism (93.8% vs 86.8%), abnormal free androgen index (75.8% vs 56.5%), abnormal homeostasis model assessment (52.3% vs 38.4%), and hyperglycemia (14.8% vs 6.5%), as well as lower sex hormone binding globulin compared to non-Hispanic whites. Non-Hispanic black women had a significantly lower prevalence of metabolic syndrome (24.5% vs 42.2%) compared with Hispanic women, and lower serum triglyceride levels compared to both Hispanics and non-Hispanic whites (85.7 ± 37.3 vs 130.2 ± 57.0 vs 120.1 ± 60.5 mg/dL, P < .01), with a markedly lower prevalence of hypertriglyceridemia (5.1% vs 28.3% vs 30.5%, P < .01) compared to the other 2 groups. CONCLUSION: Hispanic women with polycystic ovarian syndrome have the most severe phenotype, both in terms of hyperandrogenism and metabolic criteria. Non-Hispanic black women have an overall milder polycystic ovarian syndrome phenotype than Hispanics and in some respects, than non-Hispanic white women.

High-Fat Diet Causes Subfertility and Compromised Ovarian Function Independent of Obesity in Mice.

Excess calorie consumption, particularly of a diet high in fat, is a risk factor for both obesity and reproductive disorders. Animal model studies indicate that elevated dietary fat can influence some reproductive functions independent of obesity. In the current study we sought to determine whether a high-fat diet (HFD) impacts ovarian function, long-term fertility, and local and systemic markers of inflammation independent of obesity. Five-week-old mice were fed either low-fat diet (control group-LF-Ln) or HFD for 10 wk and were divided based on body weight into high-fat obese (HF-Ob: >25 g) and high-fat lean (HF-Ln: <22 g). Ovaries were collected to assess ovarian follicles and to determine the degree of local inflammation. Serum proinflammatory cytokines were also measured. A group of animals was followed for breeding trials for 5 mo while being exposed to LFD or HFD. We found that both 10-wk and 32-wk exposure to HFD resulted in depleted primordial follicles regardless of obesity phenotype. Macrophage counts revealed increased tissue inflammation in the ovary independent of obesity. In addition, serum proinflammatory cytokines were increased in HF-Ln and HF-Ob in comparison to LF-Ln mice. Moreover, HFD had a sustained effect on litter production rate and number of pups per litter regardless of obese phenotype. This study describes for the first time that exposure to HFD causes significant reduction in primordial follicles, compromised fertility, produced higher proinflammatory cytokine levels, and increased ovarian macrophage infiltration, independent of obesity. The negative effects of HFD on primordial follicles may be mediated by increased tissue inflammation.

Luteal phase dynamics of follicle-stimulating and luteinizing hormones in obese and normal weight women.

OBJECTIVES: Female obesity is a state of relative hypogonadotrophic hypogonadism. The aim of this study is to examine gonadotrophin secretion and response to gonadotrophin-releasing hormone (GnRH) in the luteal phase of the menstrual cycle and to investigate the pharmacodynamics and pharmacokinetics of endogenous and exogenous luteinizing hormone (LH) in obese women. DESIGN: Participants underwent a luteal phase frequent blood sampling study. Endogenous LH pulsatility was observed, gonadotrophin-releasing hormone (GnRH) was given in two weight-based doses, and GnRH antagonist was administered followed by recombinant LH. PATIENTS: Regularly menstruating obese (n = 10) and normal weight (n = 10) women. MEASUREMENTS: Endogenous hypothalamic-pituitary function (as measured by LH pulsatility), pituitary sensitivity (GnRH-induced LH secretion), pharmacodynamics of endogenous LH and pharmacokinetics of exogenous LH were compared between the obese and normal weight groups. RESULTS: There were no statistically significant differences in endogenous LH pulsatility or pituitary responses to two weight-based doses of GnRH between the obese and normal weight women. There were no differences in the pharmacodynamics of endogenous LH or the pharmacokinetics of exogenous LH between the groups. FSH dynamics did not differ between the groups throughout the study. CONCLUSIONS: The relative hypogonadotrophic hypogonadism of obesity cannot be explained by differences in LH and FSH luteal phase dynamics or differences in endogenous LH pharmacodynamics or exogenous LH pharmacokinetics.

Prolonged gonadotropin stimulation for assisted reproductive technology cycles is associated with decreased pregnancy rates for all women except for women with polycystic ovary syndrome.

PURPOSE: To determine if etiology of infertility modifies the relationship between the duration of ovarian stimulation and success during assisted reproductive technology (ART) cycles. METHODS: A prospectively collected database was analyzed in an academic infertility practice. Eight hundred and twelve infertile women undergoing their initial fresh embryo, non-donor in vitro fertilization (IVF) or Intracytoplasmic Sperm Injection ICSI) cycle between January 1999 and December 2010 were evaluated. Clinical pregnancy was the main outcome measured. RESULTS: Out of 663 cycles resulting in oocyte retrieval, 299 produced a clinical pregnancy (45.1%). Women who achieved a clinical pregnancy had a significantly shorter stimulation length (11.9 vs. 12.1 days, p = 0.047). Polycystic ovary syndrome (PCOS) was the only etiology of infertility that was significantly associated with a higher chance for clinical pregnancy and was a significant confounder for the association of duration and success of treatment. Women with 13 days or longer of stimulation had a 34 % lower chance of clinical pregnancy as compared to those who had a shorter cycle (OR 0.66, 95% CI:0.46-0.95) after adjustment for age, ovarian reserve, number of oocytes retrieved, embryos transferred and PCOS diagnosis. CONCLUSION: Prolonged duration of stimulation is associated with decreased ART success for all couples, except for women with PCOS.

Adenomyosis within a uterine septum in a patient with secondary infertility.

BACKGROUND: Adenomyosis is a benign infiltration of endometrial stroma and glands into the myometrium. Until the advent and advancement of imaging techniques such as transvaginal ultrasound scan (TVUS) and magnetic resonance imaging (MRI), the diagnosis of adenomyosis could only be made with confidence using histology following hysterectomy. CASE: The patient is a 37-year-old woman, with a long history of secondary infertility. A hysterosalpingogram (HSG) and a pelvic MRI showed two separate uterine cavities. The patient underwent laparoscopy and hysteroscopy revealing a bicornuate appearance of the uterus and a uterine septum. Resection of the septum showed adenomyosis on histologic examination. COMMENT: Adenomyosis of uterine septum should be considered if MRI shows features of adenomyosis elsewhere in the uterus with thickened junctional zone. Further research is needed to investigate this association with the pathogenesis of adenomyosis.

Anti-Müllerian Hormone and Follicle-Stimulating Hormone Are Poor Independent Predictors of Live Birth After Assisted Reproductive Technology.

To query if anti-Müllerian hormone (AMH) and/or follicle-stimulating hormone (FSH) predict live birth at the University of Colorado Advanced Reproductive Medicine (CU ARM). This was a retrospective analysis using the Society for Assisted Reproductive Technology (SART) Clinic Outcome Reporting System database at CU ARM from 2017 to 2019 to identify the pregnancy outcomes of the initial fresh or frozen embryo transfer (FET) and their corresponding AMH and FSH. Fisher's exact tests were used to identify differences in pregnancy outcome by age group, and area under the receiver operator characteristic curves was used to quantify live birth prediction. A total of 1083 records from 557 patients were reviewed. After only including the first autologous transfer, 270 cycles were analyzed. Overall live birth (L/B) rate was 58.15% (157/270), which declined with increasing age group (p ≤ 0.01). Although AMH significantly decreased with increasing age (p < 0.001), it was not associated with pregnancy outcome (3.54 ng/mL vs. 3.41 ng/mL, p = 0.56); this relationship was unchanged after controlling for age in logistic regression models (p = 0.52). FSH was also not significantly related to pregnancy outcome (7.00 IU/L vs 6.00 IU/L, p = 0.15), and this relationship did not change after controlling for age (p = 0.61). Using AUC, the only variable predictive of live birth was age (p = 0.002). AMH and FSH are not associated with the probability of live birth. Only age was significantly associated with live birth in this series. AMH and FSH should therefore be used cautiously when counseling patients about ART outcomes.

Effects of pulsatile intravenous follicle-stimulating hormone treatment on ovarian function in women with obesity.

OBJECTIVE: To establish conditions for effective hypothalamic suppression in women with normal and high body mass index (BMI) and test the hypothesis that intravenous (IV) administration of pulsatile recombinant follicle-stimulating hormone (rFSH) can overcome the clinically evident dysfunctional pituitary-ovarian axis in women with obesity. DESIGN: Prospective interventional study. SETTING: Academic medical center. PATIENT(S): Twenty-seven normal-weight women and 27 women with obesity, who were eumenorrheic and aged 21-39 years. INTERVENTION(S): Two-day frequent blood sampling study, in early follicular phase, before and after cetrorelix suppression of gonadotropins and exogenous pulsatile IV rFSH administration. MAIN OUTCOME MEASURE(S): Serum inhibin B and estradiol (E2) levels (basal and rFSH stimulated). RESULT(S): A modified gonadotropin-releasing hormone antagonism protocol effectively suppressed production of endogenous gonadotropins in women with normal and high BMIs, providing a model to address the functional role of FSH in the hypothalamic-pituitary-ovarian axis. The IV rFSH treatment resulted in equivalent serum levels and pharmacodynamics in normal-weight women and those with obesity. However, women with obesity exhibited reduced basal levels of inhibin B and E2 and a significantly decreased response to FSH stimulation. The BMI was inversely correlated with serum inhibin B and E2. In spite of this observed deficit in ovarian function, pulsatile IV rFSH treatment in women with obesity resulted in E2 and inhibin B levels comparable with those in normal-weight women, in the absence of exogenous FSH stimulation. CONCLUSION(S): Despite normalization of FSH levels and pulsatility by exogenous IV administration, women with obesity demonstrate ovarian dysfunction with respect to E2 and inhibin B secretion. Pulsatile FSH can partially correct the relative hypogonadotropic hypogonadism of obesity, thereby providing a potential treatment strategy to mitigate some of the adverse effects of high BMI on fertility, assisted reproduction, and pregnancy outcomes. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov #NCT02478775.

Expression and T cell regulatory action of the PD-1 immune checkpoint in the ovary and fallopian tube.

PROBLEM: Immune cell trafficking and surveillance within the ovary and fallopian tube are thought to impact fertility and also tumorigenesis in those organs. However, little is known of how native cells of the ovary and fallopian tube interact with resident immune cells. Interaction of the Programmed Cell Death Protein-1 (PD-1/PDCD-1/CD279) checkpoint with PD-L1 is associated with downregulated immune response. We have begun to address the question of whether PD-1 ligand or its receptors (PD-L1/-L2) can regulate immune cell function in these tissues of the female reproductive tract. METHOD OF STUDY: PD-1 and ligand protein expression was evaluated in human ovary and fallopian tube specimens, the latter of which included stages of tubal cell transformation and early tumorigenesis. Ovarian expression analysis included the determination of the proteins in human follicular fluid (HFF) specimens collected during in vitro fertilization procedures. Finally, checkpoint bioactivity of HFF was determined by treatment of separately-isolated human T cells and the measurement of interferon gamma (IFNγ). RESULTS: We show that membrane bound and soluble variants of PD-1 and ligands are expressed by permanent constituent cell types of the human ovary and fallopian tube, including granulosa cells and oocytes. PD-1 and soluble ligands were present in HFF at bioactive levels that control T cell PD-1 activation and IFNγ production; full-length checkpoint proteins were found to be highly enriched in HFF exosome fractions. CONCLUSION: The detection of PD-1 checkpoint proteins in the human ovary and fallopian tube suggests that the pathway is involved in immunomodulation during folliculogenesis, the window of ovulation, and subsequent egg and embryo immune-privilege. Immunomodulatory action of receptor and ligands in HFF exosomes is suggestive of an acute checkpoint role during ovulation. This is the first study in the role of PD-1 checkpoint proteins in human tubo-ovarian specimens and the first examination of its potential regulatory action in the contexts of normal and assisted reproduction.

Iatrogenic hyperthyroidism does not promote weight loss or prevent ageing-related increases in body mass in thyroid cancer survivors.

CONTEXT: Thyroid cancer survivors represent a unique population in which the potential long-term effects of brief periods of intentional thyroid hormone withdrawal and/or prolonged periods of iatrogenic hyperthyroidism on body weight and body mass were evaluated. OBJECTIVES: The objectives of this study were to characterize body mass changes over several years in a cohort of thyroid cancer patients with iatrogenic hyperthyroidism and to compare these changes with the expected weight gain in age-matched healthy control populations. We also evaluated the possibility that the method of preparation [thyroid hormone withdrawal (THW) vs recombinant human TSH (rhTSH)] for radioactive iodine remnant ablation may be associated with differences in body mass at the time of the final follow-up. DESIGN/SETTING/PATIENTS/INTERVENTIONS: A retrospective review identified 153 patients with thyroid cancer who underwent total thyroidectomy at one major medical centre. Of the 153 patients, 143 also had radioactive iodine remnant ablation: 70 after THW and 73 after rhTSH. MAIN OUTCOME MEASURES: Change in weight and BMI at 1-2 and 3-5 years of follow-up points were examined. Annualized weight variation within the cohort was compared with age-matched population controls expressed in kilogram/year. RESULTS: Significant weight gain was noted for the full cohort after 3-5 years of follow-up as compared to baseline (76 ± 21 kg at baseline vs 79 ± 23 kg at 3-5 years of follow-up, P < 0·01), which represented a 3·2% increase. Female and male patients with thyroid cancer experienced 0·46 and 0·94 kg/year gain in weight, respectively, which is similar or somewhat higher than previously published age-matched population controls (ranging from 0·23 to 0·34 kg/year). When expressed as per cent change and comparing the final weight to the pre-operative baseline, the rhTSH group experienced approximately a 1·7% increase in weight compared with the 3·9% increase seen with THW patients (P = 0·02). When expressed as kg/year change, the rhTSH cohort had 0·34 kg/year change compared with the 0·64 kg/year change seen in the thyroid hormone withdrawal patients (P = 0·02). CONCLUSION: In otherwise, healthy patients with differentiated thyroid cancer, significant weight gain occurred during the 3-5 years of follow-up despite ongoing thyrotropin suppression. The data suggest that mild iatrogenic hyperthyroidism does not promote weight loss or prevent ageing-related weight gain. Greater weight gain was seen in patients prepared for radioactive remnant ablation with THW than with rhTSH.

Metabolic correlates of menopause: an update.

PURPOSE OF REVIEW: Metabolic syndrome (MetS) is a cluster of characteristics that increase the risk of cardiovascular disease and type 2 diabetes mellitus. We will review the most interesting and relevant studies on metabolic correlates of menopause published over the last year. RECENT FINDINGS: In the past year, studies have shifted focus from effects on cardiovascular disease and diabetes to effects of MetS on breast cancer as well as menopausal symptoms. Studies have found and further confirmed its negative effect on both breast cancer and menopausal symptoms. Focus has also been on treatment options including both lifestyle and pharmacologic. Recent studies also further investigate markers/predictors as well as genetic components influencing MetS development. SUMMARY: Over a quarter of the US population is affected by metabolic disease at midlife, and some studies have shown that the incidence of MetS increases with menopause. There are now more Americans who are age 65 and older than at any other time in US history. Thus, it is becoming ever more important to understand metabolic health, as well as the consequences of MetS.