Effects of preconception lifestyle intervention in infertile women with obesity: The FIT-PLESE randomized controlled trial.

BACKGROUND: Women with obesity and infertility are counseled to lose weight prior to conception and infertility treatment to improve pregnancy rates and birth outcomes, although confirmatory evidence from randomized trials is lacking. We assessed whether a preconception intensive lifestyle intervention with acute weight loss is superior to a weight neutral intervention at achieving a healthy live birth. METHODS AND FINDINGS: In this open-label, randomized controlled study (FIT-PLESE), 379 women with obesity (BMI ≥ 30 kg/m2) and unexplained infertility were randomly assigned in a 1:1 ratio to 2 preconception lifestyle modification groups lasting 16 weeks, between July 2015 and July 2018 (final follow-up September 2019) followed by infertility therapy. The primary outcome was the healthy live birth (term infant of normal weight without major anomalies) incidence. This was conducted at 9 academic health centers across the United States. The intensive group underwent increased physical activity and weight loss (target 7%) through meal replacements and medication (Orlistat) compared to a standard group with increased physical activity alone without weight loss. This was followed by standardized empiric infertility treatment consisting of 3 cycles of ovarian stimulation/intrauterine insemination. Outcomes of any resulting pregnancy were tracked. Among 191 women randomized to standard lifestyle group, 40 dropped out of the study before conception; among 188 women randomized to intensive lifestyle group, 31 dropped out of the study before conception. All the randomized women were included in the intent-to-treat analysis for primary outcome of a healthy live birth. There were no significant differences in the incidence of healthy live births [standard 29/191(15.2%), intensive 23/188(12.2%), rate ratio 0.81 (0.48 to 1.34), P = 0.40]. Intensive had significant weight loss compared to standard (-6.6 ± 5.4% versus -0.3 ± 3.2%, P < 0.001). There were improvements in metabolic health, including a marked decrease in incidence of the metabolic syndrome (baseline to 16 weeks: standard: 53.6% to 49.4%, intensive 52.8% to 32.2%, P = 0.003). Gastrointestinal side effects were significantly more common in intensive. There was a higher, but nonsignificant, first trimester pregnancy loss in the intensive group (33.3% versus 23.7% in standard, 95% rate ratio 1.40, 95% confidence interval [CI]: 0.79 to 2.50). The main limitations of the study are the limited power of the study to detect rare complications and the design difficulty in finding an adequate time matched control intervention, as the standard exercise intervention may have potentially been helpful or harmful. CONCLUSIONS: A preconception intensive lifestyle intervention for weight loss did not improve fertility or birth outcomes compared to an exercise intervention without targeted weight loss. Improvement in metabolic health may not translate into improved female fecundity. TRIAL REGISTRATION: ClinicalTrials.gov NCT02432209.

Metabolic syndrome in obesity: treatment success and adverse pregnancy outcomes with ovulation induction in polycystic ovary syndrome.

BACKGROUND: Obesity is common in women with polycystic ovary syndrome. polycystic ovary syndrome and obesity are associated with reduced fertility. The effect of metabolic syndrome on the success of infertility treatment and pregnancy outcomes in women with polycystic ovary syndrome undergoing ovulation induction has not been investigated. OBJECTIVE: The objectives of this study were to determine the associations of metabolic syndrome on the rate of live birth after ovulation induction and pregnancy complications in obese women with polycystic ovary syndrome and determine whether there is a difference in outcomes concerning specific medications used for ovulation induction. STUDY DESIGN: This prospective cohort analysis used data collected from participants in the Pregnancy in Polycystic Ovary Syndrome II clinical trial conducted by the Reproductive Medicine Network. In the Pregnancy in Polycystic Ovary Syndrome II trial, 750 women with polycystic ovary syndrome and infertility were randomized to either clomiphene citrate or letrozole for ovulation induction for 1 to 5 cycles or until pregnancy occurred. Cox regression and modified Poisson regression, chi-square test, and Student t test or Wilcoxon test were used in this study. Outcomes of interest were rates of live birth and clinical pregnancy and pregnancy complications. Having metabolic syndrome was defined by the presence of at least 3 of 5 cardiometabolic risk factors (waist circumference of >88 cm, low high-density lipoprotein cholesterol of <50 mg/dL, triglycerides of ≥150 mg/dL, systolic blood pressure of ≥130 or diastolic blood pressure of ≥85 mm Hg, and fasting glucose of >100 mg/dL). In addition, we used a continuous metabolic syndrome z score. Body mass index categories were defined as normal (body mass index of <25 kg/m2), high (25 to 35 kg/m2), and very high (>35 kg/m2). RESULTS: As illustrated in the Table, early pregnancy losses showed no difference by metabolic syndrome. Fewer women achieved a clinical pregnancy (20.5% vs 29.7%; P=.007) or had a live birth (16.5% vs 27%; P=.001) in the presence of metabolic syndrome. Early pregnancy losses showed no difference by metabolic syndrome status. However, at least 1 pregnancy complication occurred more often with metabolic syndrome: 61.9% (26 of 42 cases) with metabolic syndrome vs 44.4% (59 of 133 cases) (P=.05) without metabolic syndrome. Gestational diabetes mellitus (35.7% vs 18.2%; P=.02) and macrosomia (21.4% vs 8.3%; P=.02) were more common in the presence of metabolic syndrome. After adjustment for other potential confounders, the rate ratio for live births for a 1-unit change in the metabolic syndrome z score was 0.89 (95% confidence interval, 0.79-1.00; P=.04) for those whose body mass index was 25 to 35 kg/m2. For the very high body mass index subgroup (>35 kg/m2), the independent effects of metabolic syndrome from obesity were harder to discern. The rate of live birth was higher with the use of letrozole, although metabolic syndrome had a different detrimental effect concerning the medication given. The overall incidence of pregnancy complications was high (approximately 49%) in the Pregnancy in Polycystic Ovary Syndrome II trial and the 2 medications. Letrozole was associated with more obstetrical complications in the presence of metabolic syndrome, and clomiphene was associated with a lower rate of live birth rate when metabolic syndrome was present. CONCLUSION: Metabolic syndrome is a risk factor that lowers the rate of live birth after ovulation for women with polycystic ovary syndrome, independent of obesity, and it is particularly associated with a lower rate of live birth for women using clomiphene compared with women using letrozole. In addition, metabolic syndrome is a risk factor for pregnancy complications for women with obesity using letrozole. Furthermore, having metabolic syndrome is a risk factor for gestational diabetes mellitus and macrosomia.

The relationship of plasma antioxidant levels to semen parameters: the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial.

PURPOSE: The understanding of the role of plasma antioxidant levels in male fertility in the USA is limited. In a secondary analysis of the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial, we sought to determine whether serum levels of vitamin E (α-tocopherol), zinc, and selenium were correlated with semen parameters and couple fertility outcomes. METHODS: This study is a secondary analysis of the MOXI clinical trial. The primary endpoints in this secondary analysis include semen parameters, and DNA fragmentation and clinical outcomes including pregnancy and live birth. Analyses were completed using Wilcoxon's rank-sum test and linear regression models. RESULTS: At baseline, the analysis included plasma labs for vitamin E (n = 131), selenium (n = 124), and zinc (n = 128). All baseline plasma values were in the normal ranges. There was no association between selenium, zinc, or vitamin E levels and semen parameters or DNA fragmentation. Baseline antioxidant levels in the male partners did not predict pregnancy or live birth among all couples. Among those randomized to placebo, baseline male antioxidant levels did not differ between those couples with live birth and those that did not conceive or have a live birth. CONCLUSIONS: Among men attending fertility centers in the USA, who have sufficient plasma antioxidant levels of zinc, selenium, or vitamin E, no association was observed between vitamins and semen parameters or clinical outcomes in couples with male infertility. Higher levels of antioxidants among men with circulating antioxidants in the normal range do not appear to confer benefit on semen parameters or male fertility.

Effect of an Active vs Expectant Management Strategy on Successful Resolution of Pregnancy Among Patients With a Persisting Pregnancy of Unknown Location: The ACT or NOT Randomized Clinical Trial.

Importance: Women with an early nonviable pregnancy of unknown location are at high risk of ectopic pregnancy and its inherent morbidity and mortality. Successful and timely resolution of the gestation, while minimizing unscheduled interventions, are important priorities. Objective: To determine if active management is more effective in achieving pregnancy resolution than expectant management and whether the use of empirical methotrexate is noninferior to uterine evacuation followed by methotrexate if needed. Design, Setting, and Participants: This multicenter randomized clinical trial recruited 255 hemodynamically stable women with a diagnosed persisting pregnancy of unknown location between July 25, 2014, and June 4, 2019, in 12 medical centers in the United States (final follow up, August 19, 2019). Interventions: Eligible patients were randomized in a 1:1:1 ratio to expectant management (n = 86), active management with uterine evacuation followed by methotrexate if needed (n = 87), or active management with empirical methotrexate using a 2-dose protocol (n = 82). Main Outcomes and Measures: The primary outcome was successful resolution of the pregnancy without change from initial strategy. The primary hypothesis tested for superiority of the active groups combined vs expectant management, and a secondary hypothesis tested for noninferiority of empirical methotrexate compared with uterine evacuation with methotrexate as needed using a noninferiority margin of -12%. Results: Among 255 patients who were randomized (median age, 31 years; interquartile range, 27-36 years), 253 (99.2%) completed the trial. Ninety-nine patients (39%) declined their randomized allocation (26.7% declined expectant management, 48.3% declined uterine evacuation, and 41.5% declined empirical methotrexate) and crossed over to a different group. Compared with patients randomized to receive expectant management (n = 86), women randomized to receive active management (n = 169) were significantly more likely to experience successful pregnancy resolution without change in their initial management strategy (51.5% vs 36.0%; difference, 15.4% [95% CI, 2.8% to 28.1%]; rate ratio, 1.43 [95% CI, 1.04 to 1.96]). Among active management strategies, empirical methotrexate was noninferior to uterine evacuation followed by methotrexate if needed with regard to successful pregnancy resolution without change in management strategy (54.9% vs 48.3%; difference, 6.6% [1-sided 97.5% CI, -8.4% to ∞]). The most common adverse event was vaginal bleeding for all of the 3 management groups (44.2%-52.9%). Conclusions and Relevance: Among patients with a persisting pregnancy of unknown location, patients randomized to receive active management, compared with those randomized to receive expectant management, more frequently achieved successful pregnancy resolution without change from the initial management strategy. The substantial crossover between groups should be considered when interpreting the results. Trial Registration: ClinicalTrials.gov Identifier: NCT02152696.

Intrauterine insemination performance characteristics and post-processing total motile sperm count in relation to live birth for couples with unexplained infertility in a randomised, multicentre clinical trial.

STUDY QUESTION: Are intrauterine insemination (IUI) performance characteristics and post-processing total motile sperm count (TMC) related to live birth rate in couples with unexplained infertility? SUMMARY ANSWER: Patient 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 KNOWN: We 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, DURATION: This 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, METHODS: AMIGOS 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 CHANCE: After 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 CAUTION: This 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 FINDINGS: Most 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 NUMBER: n/a.

Fertility Related Quality of Life, Gonadal Function and Erectile Dysfunction in Male Partners of Couples with Unexplained Infertility.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

The efficiency of single institutional review board review in National Institute of Child Health and Human Development Cooperative Reproductive Medicine Network-initiated clinical trials.

BACKGROUND/AIMS: Timely review of research protocols by institutional review boards leads to more rapid initiation of clinical trials, which is critical to expeditious translation from bench to bedside. This observational study examined the impact of a single institutional review board on time and efforts required to initiate clinical trials by the National Institute of Child Health and Human Development Cooperative Reproductive Medicine Network. METHODS: Collection of data from the same six main clinical sites for three current clinical trials and two past clinical trials, including time from institutional review board submission to approval, pages submitted, consent form length, number of required attachments, other regulatory requirements, order of review at central or local sites, and language in documents at individual participating sites. Results from two past clinical trials were also included. RESULTS: While time required for actual institutional review board submission's review and initial approval was reduced with use of a single institutional review board for multicenter trials (from a mean of 66.7-24.0 days), total time was increased (to a mean of 111.2 or 123.3 days). In addition to single institutional review board approval, all institutions required local approval of some components (commonly consent language and use of local language), which varied considerably. The single institutional review board relied on local institutions for adding or removing personnel, conflict of interest review, and auditing of activities. CONCLUSION: A single institutional review board reduced time for initial review and approval of protocols and informed consents, although time for the entire process was increased, as individual institutions retained oversight of components of required regulatory review. In order to best achieve the National Institute of Health's goals for improved efficiency in initiation and conduct of multisite clinical research, greater coordination with local institutional review boards is key to streamlining and accelerating initiation of multisite clinical research.

Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility.

BACKGROUND: The standard therapy for women with unexplained infertility is gonadotropin or clomiphene citrate. Ovarian stimulation with letrozole has been proposed to reduce multiple gestations while maintaining live birth rates. METHODS: We enrolled couples with unexplained infertility in a multicenter, randomized trial. Ovulatory women 18 to 40 years of age with at least one patent fallopian tube were randomly assigned to ovarian stimulation (up to four cycles) with gonadotropin (301 women), clomiphene (300), or letrozole (299). The primary outcome was the rate of multiple gestations among women with clinical pregnancies. RESULTS: After treatment with gonadotropin, clomiphene, or letrozole, clinical pregnancies occurred in 35.5%, 28.3%, and 22.4% of cycles, and live birth in 32.2%, 23.3%, and 18.7%, respectively; pregnancy rates with letrozole were significantly lower than the rates with standard therapy (gonadotropin or clomiphene) (P=0.003) or gonadotropin alone (P<0.001) but not with clomiphene alone (P=0.10). Among ongoing pregnancies with fetal heart activity, the multiple gestation rate with letrozole (9 of 67 pregnancies, 13%) did not differ significantly from the rate with gonadotropin or clomiphene (42 of 192, 22%; P=0.15) or clomiphene alone (8 of 85, 9%; P=0.44) but was lower than the rate with gonadotropin alone (34 of 107, 32%; P=0.006). All multiple gestations in the clomiphene and letrozole groups were twins, whereas gonadotropin treatment resulted in 24 twin and 10 triplet gestations. There were no significant differences among groups in the frequencies of congenital anomalies or major fetal and neonatal complications. CONCLUSIONS: In women with unexplained infertility, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomiphene. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01044862.).

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.

Sexual function in infertile women with polycystic ovary syndrome and unexplained infertility.

BACKGROUND: While female sexual dysfunction is a frequent occurrence, characteristics in infertile women are not well delineated. Furthermore, the impact of infertility etiology on the characteristics in women with differing androgen levels observed in women with polycystic ovary syndrome and unexplained infertility has not been assessed. OBJECTIVE: The objective of the study was to determine the characteristics of sexual dysfunction in women with polycystic ovary syndrome and unexplained infertility. STUDY DESIGN: A secondary data analysis was performed on 2 of Eunice Kennedy Shriver National Institute of Child Health and Human Development Cooperative Reproductive Medicine Networks clinical trials: Pregnancy in Polycystic Ovary Syndrome Study II and Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation. Both protocols assessed female sexual function using the Female Sexual Function Inventory and the Female Sexual Distress Scale. RESULTS: Women with polycystic ovary syndrome had higher weight and body mass index than women with unexplained infertility (each P < .001), greater phenotypic (Ferriman-Gallwey hirsutism score, sebum score, and acne score; each P < .001), and hormonal (testosterone, free testosterone, and dehydroepiandrosterone; each P < .001) evidence of androgen excess. Sexual function scores, as assessed by the Female Sexual Function Inventory, were nearly identical. The Female Sexual Distress Scale total score was higher in women with polycystic ovary syndrome. The mean Female Sexual Function Inventory total score increased slightly as the free androgen index increased, mainly as a result of the desire subscore. This association was more pronounced in the women with unexplained infertility. CONCLUSION: Reproductive-age women with infertility associated with polycystic ovary syndrome and unexplained infertility, despite phenotypic and biochemical differences in androgenic manifestations, do not manifest clinically significant differences in sexual function.

Lifestyle factors associated with histologically derived human ovarian non-growing follicle count in reproductive age women.

STUDY QUESTION: Are lifestyle factors (smoking, BMI, alcohol use and oral contraceptive pill use) associated with the human ovarian reserve as determined by the total ovarian non-growing follicle number? SUMMARY ANSWER: Light to moderate alcohol use was significantly associated with greater ovarian non-growing follicle (NGF) count, whereas other lifestyle factors were not significantly related. WHAT IS KNOWN ALREADY: A single previous investigation has suggested that smoking and alcohol use are associated with lower ovarian follicle density. However, this investigation utilized follicle density as the outcome of interest rather than the estimated total ovarian NGF count. STUDY DESIGN, SIZE, DURATION: This cross-sectional investigation included a convenience sample of premenopausal women from two different academic sites, the University of Washington (n = 37, from 1999-2004) and the University of Oklahoma (n = 73, from 2004-2013), undergoing incidental oophorectomy at the time of hysterectomy (total n = 110, age range 21-52 years). PARTICIPANTS/MATERIALS, SETTING, METHODS: Prior to undergoing oophorectomy, participants completed detailed questionnaires regarding lifestyle exposures. Following surgery, total ovarian NGF counts were determined with systematic random sampling rules and a validated fractionator/optical dissector technique. Associations between lifestyle factors and log-transformed ovarian follicle counts were determined using multivariable linear regression. MAIN RESULTS AND THE ROLE OF CHANCE: After controlling for age, BMI, oral contraceptive pill (OCP) use, tobacco use and site of collection, cumulative alcohol use (measured in alcoholic drinks per day multiplied by years of drinking) was associated with ovarian NGF count. Women reporting light (>0 to <1 drink-years) and moderate (1-3 drink-years) alcohol use had greater NGF counts (ß = 0.75, P = 0.04, and ß = 1.00, P = 0.03; light and moderate use, respectively) as compared with non-users. Neither heavier alcohol use (>3 drink-years), BMI, OCP use, nor tobacco use were significantly associated with the ovarian NGF count. Similar patterns of association with moderate cumulative alcohol use were observed when evaluating associations with pre-antral follicles and total follicle counts. LIMITATIONS, REASONS FOR CAUTION: All participants in this convenience sample had a benign indication for hysterectomy, and therefore may not be broadly representative of the population without such an indication. Additionally, lifestyle factors were self-reported, and the sample size of the present investigation limits our ability to detect associations of smaller magnitude. WIDER IMPLICATIONS OF THE FINDINGS: While our findings are in disagreement with a single investigation that utilized human follicle density as the outcome of interest, they are consistent with many studies investigating the relationship between lifestyle factors and the age of spontaneous menopause. Furthermore, they suggest a mechanism that does not involve accelerated follicular atresia to explain the association between smoking and an earlier age of menopause. STUDY FUNDING/COMPETING INTERESTS: This investigation was funded by NIA R29-HD37360-04 (N.A.K.) and OCAST HR04-115 (K.R.H.) and by the National Institute of General Medical Sciences, Grant 1 U54GM104938 (J.D.P.). There is no conflict of interest.

Identification and replication of prediction models for ovulation, pregnancy and live birth in infertile women with polycystic ovary syndrome.

STUDY QUESTION: Can we build and validate predictive models for ovulation and pregnancy outcomes in infertile women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: We were able to develop and validate a predictive model for pregnancy outcomes in women with PCOS using simple clinical and biochemical criteria particularly duration of attempting conception, which was the most consistent predictor among all considered factors for pregnancy outcomes. WHAT IS KNOWN ALREADY: Predictive models for ovulation and pregnancy outcomes in infertile women with polycystic ovary syndrome have been reported, but such models require validation. STUDY DESIGN, SIZE, AND DURATION: This is a secondary analysis of the data from the Pregnancy in Polycystic Ovary Syndrome I and II (PPCOS-I and -II) trials. Both trials were double-blind, randomized clinical trials that included 626 and 750 infertile women with PCOS, respectively. PPCOS-I participants were randomized to either clomiphene citrate (CC), metformin, or their combination, and PPCOS-II participants to either letrozole or CC for up to five treatment cycles. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: Linear logistic regression models were fitted using treatment, BMI, and other published variables as predictors of ovulation, conception, clinical pregnancy, and live birth as the outcome one at a time. We first evaluated previously reported significant predictors, and then constructed new prediction models. Receiver operating characteristic (ROC) curves were constructed and the area under the curves (AUCs) was calculated to compare performance using different models and data. Chi-square tests were used to examine the goodness-of-fit and prediction power of logistic regression model. MAIN RESULTS AND THE ROLE OF CHANCE: Predictive factors were similar between PPCOS-I and II, but the two participant samples differed statistically significantly but the differences were clinically minor on key baseline characteristics and hormone levels. Women in PPCOS-II had an overall more severe PCOS phenotype than women in PPCOS-I. The clinically minor but statistically significant differences may be due to the large sample sizes. Younger age, lower baseline free androgen index and insulin, shorter duration of attempting conception, and higher baseline sex hormone-binding globulin significantly predicted at least one pregnancy outcome. The ROC curves (with AUCs of 0.66-0.76) and calibration plots and chi-square tests indicated stable predictive power of the identified variables (P-values ≥0.07 for all goodness-of-fit and validation tests). LIMITATIONS, REASONS FOR CAUTION: This is a secondary analysis. Although our primary objective was to confirm previously reported results and identify new predictors of ovulation and pregnancy outcomes among PPCOS-II participants, our approach is exploratory and warrants further replication. WIDER IMPLICATIONS OF THE FINDINGS: We have largely confirmed the predictors that were identified in the PPCOS-I trial. However, we have also revealed new predictors, particularly the role of smoking. While a history of ever smoking was not a significant predictor for live birth, a closer look at current, quit, and never smoking revealed that current smoking was a significant risk factor. STUDY FUNDING/COMPETING INTERESTS: The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Grants U10 HD27049, U10 HD38992, U10HD055925, U10 HD39005, U10 HD33172, U10 HD38998, U10 HD055936, U10 HD055942, and U10 HD055944; and U54-HD29834. Heilongjiang University of Chinese Medicine Grants 051277 and B201005. R.S.L. reports receiving consulting fees from Euroscreen, AstraZeneca, Clarus Therapeutics, and Takeda, and grant support from Ferring, Astra Zeneca, and Toba. K.R.H. reports receiving grant support from Roche Diagnostics and Ferring Pharmascience. G.C. reports receiving Honorarium and grant support from Abbvie Pharmaceuticals and Bayer Pharmaceuticals. M.P.D. holds equity from Advanced Reproductive Care Inc. and DS Biotech, receives fees from Advanced Reproductive Care Inc., Actamax, Auxogyn, ZSX Medical, Halt Medical, and Neomed, and receives grant support from Boehringer-Ingelheim, Abbott, and BioSante, Ferring Pharmaceuticals, and EMD Serono. H.Z. receives research support from the Chinese 1000-scholar plan. Others report no disclosures other than NIH grant support. TRIAL REGISTRATION NUMBER: PPCOS-I and -II were respectively registered at Clinicaltrials.gov: NCT00719186 and NCT00719186.

In high responding patients undergoing an initial IVF cycle, elevated estradiol on the day of hCG has no effect on live birth rate.

BACKGROUND: The impact of elevated estradiol on the day of human chorionic gonadotropin (hCG) administration on in vitro fertilization (IVF) outcomes has been debated for over 25 years. Some investigators have shown a positive effect, others a negative effect; while most have shown no effect. Few studies have expressed their findings based on live birth. This study examined the relationship between estradiol level and other IVF cycle response parameters in relation to pregnancy, with a focus on live births after controlling for embryo quality. METHODS: We performed a retrospective cohort study on 489 patients <40 years old that underwent an initial IVF cycle. Estradiol concentration on the day of hCG was categorized as; low <2000 pg/ml), mid (2001-4000 pg/ml) and high (>4000 pg/ml) to determine how estradiol level on the day of hCG affected response variables during the IVF cycle. We performed a subgroup analysis restricted to patients with good/fair quality embryos transferred (n=428), to control for embryo quality and assessed pregnancy outcome. The association between estradiol and live birth (LB) was then evaluated after identifying and controlling for confounding factors. Multivariate analysis was used to identify significant main effects and interactions in the model. Estradiol levels were also compared in patients having a LB or not (NLB) in both populations. RESULTS: We found that estradiol was significantly related to + hCG, clinical pregnancy rate, age, and most other IVF cycle response variables. After performing the subgroup analysis controlling for embryo quality, we found that LB rates were not different. Only the main effects of average embryo quality at transfer (AEQS), age and transferring two embryos influenced LB. Estradiol levels were also compared in patients having a LB or NLB in both populations and was found to be higher/not different in LB patients. LB rates and AEQS were also not different in a subgroup of patients having an elevated level of estradiol (>4200 pg/ml) on the day of hCG in patients having embryo transfer on day 3 or day 5. CONCLUSIONS: After controlling for embryo quality, elevated estradiol on the day of hCG had no effect on LB.

Assessment of clinical pregnancies in up to eight ovarian stimulation with intrauterine insemination treatment cycles in those unable to proceed with in vitro fertilization.

OBJECTIVE: To study the primary objective of clinical pregnancy (CP) rate per ovarian stimulation with intrauterine insemination (OS-IUI) treatment cycle in patients with repetitive cycles up to a maximum of 8 cycles. DESIGN: Retrospective cohort. SETTING: Large fertility clinic. PATIENTS: A total of 37,565 consecutive OS-IUI cycles from 18,509 patients were included in this study. INTERVENTIONS: Those with anovulatory diagnoses, tubal factor infertility, male factor infertility, using donor sperm, canceled cycles, and those with missing data for either baseline characteristics or outcome were excluded. The CP rate was analyzed using generalized estimating equations and controlled for age, stimulation protocol, and body mass index. MAIN OUTCOMES MEASURES: Clinical pregnancy was defined as intrauterine gestation with fetal heartbeat visible on ultrasound. RESULTS: A total of 37,565 consecutive OS-IUI cycles from 2002 through 2019 at a private practice facility were evaluated. All cycles met inclusion criteria and were used in generalized estimating equation modeling. Patients aged <35 years comprised 47.6% of the cohort. After adjustment for confounders, the mean predicted probability of CP for cycles one to 8 was 15.7% per cycle. The mean predicted probability of CP in aggregated data from cycles 2 to 4 was only 1.7% lower compared with cycle 1 as the referent (16.7% vs. 15.0%, 95% confidence interval [CI] 2nd: 0.88 {0.82, 0.95}, 3rd: 0.86 {0.79, 0.93}, 4th: 0.88 {0.79, 0.98}). However, the 15.0% mean predicted probability of CP for the second through the fourth cycle was concordant with the mean for all included cycles (15.7%). The mean predicted probability of CP of cycles 5 to 8 was not significantly different compared with the referent (16.7% vs. 16.1%, 95% CI 5th: 0.97 [0.85, 1.11], 6th: 0.93 [0.79, 1.10], 7th: 1.01 [0.81, 1.26], 8th: 1.01 [0.76, 1.34]). The modeling of consecutive cycles suggested that the adjusted cumulative predicted probability of CP from OS-IUI continues to increase with each of the 8 successive cycles. CONCLUSION: Clinical pregnancy rates are satisfactory in up to 8 consecutive OS-IUI treatment cycles. These data are useful for counseling, especially in those patients for whom in vitro fertilization is not financially or ethically feasible.

Association between obesity and fecundity in patients undergoing intrauterine insemination.

Objective: To determine if an association exists between body mass index (BMI) and fecundity after intrauterine insemination (IUI). Design: Retrospective cohort study. Setting: Academic-based fertility clinic. Patients: Patients undergoing IUI July 2007 to May 2012. Interventions: None. Main Outcome Measures: Primary outcome: live-birth rate (LBR) per IUI cycle; secondary outcomes: positive pregnancy test and clinical pregnancy rates (CPRs). Results: A total of 1959 cycles were performed on 661 women (mean age, 31.9 ± 4.9 years). When examined by obesity class, LBR and CPR were similar for women with class I, II, and III obesity when compared with women with normal BMI. However, class III obese women (adjusted risk ratio [aRR], 1.70; 95% confidence interval [CI], 1.12-2.59) had increased pregnancy rates compared with normal BMI, but no differences in pregnancy rates were observed for women with class I or II obesity. In addition, pregnancy rates (aRR, 1.50; 95% CI, 1.12-2.02) and CPR (aRR, 1.51; 95% CI, 1.07-2.14) were higher in overweight women relative to normal BMI. Notably, among patients with ovulatory dysfunction, CPRs after IUI were reduced by 43% in obese women (aRR, 0.57; 95% CI, 0.37-1.07), whereas women without ovulatory dysfunction were twice as likely to achieve a clinical pregnancy when they were obese (aRR, 1.96; 95% CI, 1.19-3.24). The CIs for the obesity risk ratios in each stratum of ovulatory function exhibited no overlap, suggesting evidence of potential effect modification by ovulatory function. Conclusions: LBRs after IUI were similar across BMI subgroups. This is in contrast to research of in vitro fertilization treatments showing lower LBR with increasing BMI. However, obesity may adversely affect IUI CPR in those with ovulatory dysfunction in particular. The reason for this discrepancy is unclear and warrants further study.

Moderate and increased physical activity is not detrimental to live birth rates among women with unexplained infertility and obesity.

Objective: To determine if moderate physical activity is associated with live birth rates in women with unexplained infertility and obesity. Design: Secondary analysis of the Improving Reproductive Fitness through Pretreatment with Lifestyle Modification in Obese Women with Unexplained Infertility trial. Setting: US fertility centers, 2015-2019. Patients: A total of 379 women participated in Improving Reproductive Fitness through Pretreatment with Lifestyle Modification in Obese Women with Unexplained Infertility trial, a lifestyle modification program with increased physical activity (phase I, 16 weeks) and up to three cycles of clomiphene citrate treatment and intrauterine insemination (phase II). Interventions: Participants were instructed to add 500 steps/day weekly until a maximum of 10,000 steps/day was reached and maintained. Participants were stratified as active (top third, N = 125) and less active (lower third, N = 125) on the basis of the average number of steps per day recorded using a FitBit activity tracker. Main Outcome Measures: Live birth rate. Results: Active participants were more physically active at the time of enrollment than less active participants (average baseline steps per day, 8,708 [7,079-10,000] vs. 4,695 [3,844-5,811]; P ≤ 0.001) and were more likely to reach 10,000 steps/day than less active participants (average steps per day, 10,526 [9,481-11,810] vs. 6,442 [4,644-7,747]; P ≤ 0.001), although both groups increased their average steps per day by a similar amount (1,818 vs.1,747; P = 0.57). There was no difference in live birth rates (24/125 [19.2%] vs. 25/125 [20%]; P = 0.87) between active and less active participants nor were there differences in clinical pregnancy rates (P = 0.45) or miscarriage rates (P = 0.49) between the two groups. Conclusions: Active participants were more likely to achieve the physical activity goal, although this was not associated with benefit or harm with respect to live birth. Clinical Trial Registration Number: ClinicalTrials.gov (NCT02432209), first posted: May 4, 2015.

Follicular phase length is not related to live birth outcome in women with unexplained infertility undergoing ovarian stimulation with intrauterine insemination cycles in a multicenter trial.

Objective: To evaluate the effect of follicular phase length (FPL) on pregnancy outcomes and endometrial thickness (ET) among women with unexplained infertility undergoing ovarian stimulation with intrauterine insemination (OS-IUI) with clomiphene citrate, letrozole, or gonadotropins. Design: Cohort analysis of the Reproductive Medicine Network's Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation randomized controlled trial. Setting: Multicenter randomized controlled trial. Patients: A total of 869 couples with unexplained infertility who underwent OS-IUI treatment cycles as part of the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation study. Interventions: FPL was evaluated as a categorical variable defined by quintiles (q1: ≤11 days, q2: 12 days, q3: 13 days, q4: 14-15 days, and q5: ≥16 days). Main outcome measures: Clinical pregnancy, live birth rates, and ET. Results: Decreasing FPL quintiles did not reduce clinical pregnancy or live birth rates in unadjusted or adjusted models with all treatment groups combined or when stratified by the ovarian stimulation medication. All FPL categories had significantly thinner ET compared with the 5th quintile (≥16 days) among women treated with clomiphene citrate or letrozole. Similar but diminished associations were observed among women who underwent ovarian stimulation with gonadotropins, but the observed differences were limited to those with FPL of 12 days or shorter when compared with FPL ≥16 days. Conclusions: Although shorter FPL was associated with reduced ET, it was not associated with the outcomes of clinical pregnancy or live birth in women with unexplained infertility undergoing OS-IUI in all treatment groups combined. Similar patterns existed when analyses of clinical pregnancy and live birth rates were stratified by treatment. Clinical trial registration: NCT01044862.

Sperm very long-chain polyunsaturated fatty acids: relation to semen parameters and live birth outcome in a multicenter trial.

OBJECTIVE: To determine whether the levels of sperm very long-chain polyunsaturated fatty acids (VLC-PUFAs) are correlated with sperm parameters and the outcome of live birth after conventional therapy for unexplained infertility. DESIGN: Cohort analysis of the Reproductive Medicine Network's Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation randomized controlled trial. SETTING: Multicenter randomized controlled trial. PATIENTS: Male partners from 185 couples with unexplained infertility who provided baseline semen samples for analysis. INTERVENTION: We determined the levels of VLC-PUFAs in total lipid isolated from sperm membranes using liquid chromatography-mass spectrometry/mass spectrometry analyses. MAIN OUTCOME MEASURES: Sperm concentration, motility, morphology, total motile count (TMC), and live birth after standard treatment for unexplained infertility. RESULTS: Total VLC-PUFA percentage was positively correlated with sperm concentration (Spearman's rank correlation (rs) 0.56, P<.0001), TMC (rs = 0.40, P<.0001), and morphology (rs = 0.26, P=.0005). After adjustment for male body mass index, age, and race, a one-standard-deviation increase in the percentage of total VLC-PUFA was associated with a 62% increase in the geometric mean (GM) of sperm concentration (GM Ratio: 1.62 [95% confidence intervals {CI}: 1.45, 1.82]) and a 43% increase in the geometric mean of TMC (GM Ratio: 1.43 [95% CI; 1.24, 1.63]). Although no evidence of association was observed for sperm motility, a positive relationship was also observed between the percentage of total VLC-PUFA and sperm morphology [adjusted incidence rate ratio (IRR) for one-standard-deviation increase in total VLC-PUFA: 1.18 (95% CI; 1.02, 1.36)]. After adjustment for female age and treatment group, the probability of a live birth outcome was 72% more likely among those in the third tertile of hydroxylated VLC-PUFA percentage than in the first tertile (RR 1.72 [95% CI; 1.01, 2.94]). CONCLUSIONS: The positive correlation between sperm VLC-PUFAs percentage and sperm parameters, as well as the significant association between hydroxylated VLC-PUFA percentage and the outcome of live birth, strongly suggest that this class of fatty liquid chromatography-mass spectrometry/mass spectrometry acids is essential for normal sperm structure and function.