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Objective: Evaluate the efficacy and safety of elagolix, a GnRH antagonist, to treat polycystic ovarian syndrome (PCOS)., Design: A phase 2, multicenter, double-blind, randomized, placebo-controlled trial., Setting: Outpatient and academic medical centers., Patients: One hundred fourteen women with PCOS (aged 18-35 years, body mass index 18.5-38 kg/m 2 )., Interventions: Patients were randomized 2:2:2:2:2:3 to elagolix (25 mg twice daily, 50 mg once daily, 75 mg twice daily, 150 mg once daily, and 300 mg twice daily) or placebo., Main Outcome Measures: The primary endpoint was menstrual cycle normalization (defined as 2 menstrual cycles 21-35 days in length during the 4-month treatment period). The secondary endpoint was change from baseline to week 1 in the area under the luteinizing hormone (LH) serum concentration-time curve (AUC). Additional endpoints included change from baseline in serum hormone levels., Results: No significant improvement in restoring normal menstrual cycles was observed in treated subjects; 3 of 114 patients met the primary endpoint. Six patients experienced progesterone elevations indicative of ovulation. The LH levels decreased from baseline to week 16, and LH AUC was significantly reduced from baseline to week 1 in all elagolix treatment groups ( P <.1 vs placebo). Follicle-stimulating hormone (FSH) levels generally remained stable through week 16, with no significant differences in FSH AUCs. Serum estradiol and testosterone concentrations were consistently reduced from baseline in all elagolix dose groups compared with placebo. Adverse event rates were similar across treatment groups., Conclusions: Elagolix treatment did not normalize the ovulatory cycle in patients with PCOS., Clinical Trial Registration Number: NCT03951077., (© 2023 The Authors.)

Bone mineral density (BMD) changes during the life span, increasing rapidly during adolescence, plateauing in the third decade of life, and subsequently entering a phase of age-related decline. In women, menopause leads to accelerated bone loss and an increase in fracture risk. Between peak bone mass attainment and menopause, BMD is generally stable and the risk of fracture is typically low. This time period is marked by life events such as pregnancy and lactation, which transiently decrease BMD, yet their long-term effects on fracture risk are less certain. BMD may also be altered by exposure to medications that affect bone metabolism ( e.g. , contraceptives, glucocorticoids, antidiabetic medications, antiepileptic drugs). Although oral contraceptives are often believed to be neutral with regard to bone health, depot medroxyprogesterone acetate (DMPA) and gonadotropin-releasing hormone (GnRH) agonists have been associated with decreases in BMD. Development of newer medical therapies, principally GnRH antagonists ( e.g. , ASP1707, elagolix, linzagolix, relugolix), for treatment of endometriosis-associated pelvic pain and heavy menstrual bleeding due to uterine fibroids has renewed interest in the short- and long-term impacts of changes in BMD experienced by premenopausal women. It is important to understand how these drugs influence BMD and put the findings into context with regard to measurement variability and naturally occurring factors that influence bone health. This review summarizes what is known about the effects on bone health pregnancy, lactation, and use of DMPA, GnRH agonists, and GnRH antagonists in premenopausal women and potential consequences later in life. ClinicalTrials.gov identifier: NCT03213457.

Legal issues affect reproductive medical practice throughout the entire world. The breadth and depth of this interrelationship extend far beyond the scope of one series of articles in Views and Reviews. Given this limitation, we have chosen to present five topics, all different, but illustrative of key concepts that influence our practice of reproductive medicine. Our hope is that this "medical-legal sampler" will both inform and provoke thoughtful consideration of the ways we can best and most responsibly practice and serve our patients., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Uterine fibroids are one of the most common neoplasms found among women globally, with a prevalence of approximately 11 million women in the United States alone. The morbidity of this common disease is significant because it is the leading cause of hysterectomy and causes significant functional impairment for women of reproductive age. Factors including age, body mass index, race, ethnicity, menstrual blood loss, fibroid location, and uterine and fibroid volume influence the incidence of fibroids and severity of symptoms. Elagolix is an oral gonadotropin-releasing hormone receptor antagonist that competitively inhibits pituitary gonadotropin-releasing hormone receptor activity and suppresses the release of gonadotropins from the pituitary gland, resulting in dose-dependent suppression of ovarian sex hormones, follicular growth, and ovulation. In Elaris Uterine Fibroids 1 and Uterine Fibroids 2, 2 replicate multicenter, double-blind, randomized, placebo-controlled, phase 3 studies, treatment of premenopausal women with elagolix with hormonal add-back therapy demonstrated reduction in heavy menstrual bleeding associated with uterine fibroids., Objective: This analysis aimed to evaluate the safety and efficacy of elagolix (300 mg twice a day) with add-back therapy (1 mg estradiol/0.5 mg norethindrone acetate once a day) in reducing heavy menstrual bleeding associated with uterine fibroids in various subgroups of women over 6 months of treatment., Study Design: Data were pooled from Elaris Uterine Fibroid-1 and Uterine Fibroid-2 studies, which evaluated premenopausal women (18-51 years) with heavy menstrual bleeding (>80 mL menstrual blood loss per cycle, alkaline hematin methodology) and ultrasound-confirmed uterine fibroid diagnosis. Subgroups analyzed included age, body mass index, race, ethnicity, baseline menstrual blood loss, fibroid location, and uterine and primary fibroid volume (largest fibroid identified by ultrasound). The primary endpoint was the proportion of women with <80 mL menstrual blood loss during the final month and ≥50% menstrual blood loss reduction from baseline to final month. Secondary and other efficacy endpoints included mean change in menstrual blood loss from baseline to final month, amenorrhea, symptom severity, and health-related quality of life. Adverse events and other safety endpoints were monitored., Results: The overall pooled Elaris Uterine Fibroid-1 and Uterine Fibroid-2 population was typical of women with fibroids, with a mean age of 42.4 (standard deviation, 5.4) years and a mean body mass index of 33.6 (standard deviation, 7.3) kg/m 2 and 67.6% of participants being black or African American women. A wide range of baseline uterine and fibroid volumes and menstrual blood loss were also represented in the overall pooled study population. In all subgroups, the proportion of responders to the primary endpoint, mean change in menstrual blood loss, amenorrhea, reduction in symptom severity, and improvement in health-related quality of life were clinically meaningfully greater for women who received elagolix with add-back therapy than those who received placebo and consistent with the overall pooled study population for the primary endpoint (72.2% vs 9.3%), mean change in menstrual blood loss (-172.5 mL vs -0.8 mL), amenorrhea (50.4% vs 4.5%), symptom severity (-37.1 vs -9.2), and health-related quality of life score (39.9 vs 8.9). Adverse events by subgroup were consistent with the overall pooled study population., Conclusion: Elagolix with hormonal add-back therapy was effective in reducing heavy menstrual bleeding associated with uterine fibroids independent of age, body mass index, race, ethnicity, baseline menstrual blood loss, fibroid location, and uterine and primary fibroid volume., (Copyright © 2020 AbbVie Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the safety and efficacy of elagolix, an oral gonadotropin-releasing hormone antagonist, with hormonal add-back therapy for up to 12 months in women with heavy menstrual bleeding associated with uterine leiomyomas., Methods: Elaris UF-EXTEND was a phase 3 extension study that evaluated an additional 6 months (up to 12 months total) of elagolix 300 mg twice daily with hormonal add-back therapy (estradiol 1 mg and norethindrone acetate 0.5 mg once daily) in women who completed an initial 6 months of the same treatment in one of two preceding phase 3 studies. The primary endpoint was the percentage of women with both less than 80 mL menstrual blood loss during final month and a 50% or greater reduction in menstrual blood loss from baseline to final month. Safety evaluations included adverse events and bone mineral density changes. The planned sample size of UF-EXTEND was based on estimated rollover and discontinuation rates in the two preceding studies., Results: From September 2016 to March 2019, 433 women were enrolled in UF-EXTEND. Of these women, 218 received up to 12 months of elagolix with add-back therapy; the mean±SD age of this group was 42.4±5.4 years and 67.3% were black. The percentage of women who met the primary endpoint in this elagolix with add-back group was 87.9% (95% CI [83.4-92.3]). The most frequently reported adverse events with up to 12 months of elagolix plus add-back therapy were hot flush (6.9%), night sweats (3.2%), headache (5.5%), and nausea (4.1%). Mean percent decreases in bone mineral density from baseline to extension month 6 were significantly less with elagolix plus add-back therapy than with elagolix alone {between-group difference in lumbar spine: -3.3 (95% CI [-4.1 to -2.5])}., Conclusion: Up to 12 months of elagolix with add-back therapy provided sustained reduction in menstrual blood loss in women with uterine leiomyomas, with the addition of add-back therapy attenuating the hypoestrogenic effects of elagolix alone. No new or unexpected safety concerns were associated with an additional 6 months of elagolix with addback therapy., Clinical Trial Registration: ClinicalTrials.gov, NCT02925494., Funding Source: AbbVie Inc funded this study.

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., (Copyright © 2020. Published by Elsevier Inc.)

Background: Uterine fibroids are hormone-responsive neoplasms that are associated with heavy menstrual bleeding. Elagolix, an oral gonadotropin-releasing hormone antagonist resulting in rapid, reversible suppression of ovarian sex hormones, may reduce fibroid-associated bleeding., Methods: We conducted two identical, double-blind, randomized, placebo-controlled, 6-month phase 3 trials (Elaris Uterine Fibroids 1 and 2 [UF-1 and UF-2]) to evaluate the efficacy and safety of elagolix at a dose of 300 mg twice daily with hormonal "add-back" therapy (to replace reduced levels of endogenous hormones; in this case, estradiol, 1 mg, and norethindrone acetate, 0.5 mg, once daily) in women with fibroid-associated bleeding. An elagolix-alone group was included to assess the impact of add-back therapy on the hypoestrogenic effects of elagolix. The primary end point was menstrual blood loss of less than 80 ml during the final month of treatment and at least a 50% reduction in menstrual blood loss from baseline to the final month; missing data were imputed with the use of multiple imputation., Results: A total of 412 women in UF-1 and 378 women in UF-2 underwent randomization, received elagolix or placebo, and were included in the analyses. Criteria for the primary end point were met in 68.5% of 206 women in UF-1 and in 76.5% of 189 women in UF-2 who received elagolix plus add-back therapy, as compared with 8.7% of 102 women and 10% of 94 women, respectively, who received placebo (P<0.001 for both trials). Among the women who received elagolix alone, the primary end point was met in 84.1% of 104 women in UF-1 and in 77% of 95 women in UF-2. Hot flushes (in both trials) and metrorrhagia (in UF-1) occurred significantly more commonly with elagolix plus add-back therapy than with placebo. Hypoestrogenic effects of elagolix, especially decreases in bone mineral density, were attenuated with add-back therapy., Conclusions: Elagolix with add-back therapy was effective in reducing heavy menstrual bleeding in women with uterine fibroids. (Funded by AbbVie; Elaris UF-1 and Elaris UF-2 ClinicalTrials.gov numbers, NCT02654054 and NCT02691494.)., (Copyright © 2020 Massachusetts Medical Society.)

Osteoporosis continues to be a major public health challenge in both women and men. There are more than 2 million low-impact fractures in the United States every year, 39% of which occur in men. The mortality rate in the first year after hip fracture is estimated at 20% to 25% in women and is even higher in men. The goal of this Views and Reviews is to provide an update regarding bone metabolism and contemporary approaches to prevention and treatment of osteoporosis., (Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Context: Women with polycystic ovary syndrome (PCOS) have increased risk for pregnancy complications, possibly related to pre-existing obesity and excessive gestational weight gain (GWG)., Objectives: To assess the contributions of diagnosis and preconception weight on GWG and perinatal outcomes., Research Design and Methods: Prospective cohort study of singleton pregnancies in PCOS (n = 164) and ovulatory controls (n = 176) from infertility treatment., Main Outcome Measures: GWG, birthweight, pregnancy complications., Results: From preconception baseline, normal-weight women with PCOS gained 2.3 pounds more during the first trimester (95% CI, 0.3 to 4.3; P = 0.02), and by the end of the second trimester, 4.2 pounds more than controls (95% CI, 0.7 to 7.7; P = 0.02). Women who were overweight with PCOS gained significantly more weight than did controls by the end of the second trimester (5.2 pounds; 95% CI, 0.2 to 10.2; P = 0.04), whereas women with obesity and PCOS and control women had similar weight gain throughout pregnancy. Within normal-weight, overweight, and obese groups, prevalence of pre-eclampsia and gestational diabetes did not differ between the PCOS and control groups, nor was there a difference in birthweight. Preconception body mass index (BMI) was significantly associated with GWG; for every 1-kg/m2 increase in preconception BMI, GWG decreased by 0.62 pounds (95% CI, -0.85 to -0.40; P < 0.001)., Conclusions: Women with PCOS who are of normal weight or are overweight before conception experience more GWG than do ovulatory controls. Within normal-weight, overweight, and obese groups, rates of perinatal complications do not significantly differ between women with PCOS and controls. Preconception BMI is the strongest predictor of GWG.

This Views and Reviews explores existing data regarding the impact of nutrition, supplements, and lifestyle changes as they relate to weight on the fertility of both men and women. Challenges and shortcomings in developing and performing well-designed studies of nutrition and fertility are reviewed in these five papers, and the best evidence is presented. Recommendations are made based on the data, such as they are. It appears that folic acid supplementation above the level used by women to reduce the risk of neural tube defects may be of value in producing favorable pregnancy outcomes. Certain polyunsaturated fatty acids may have a beneficial effect on fertility, and a Mediterranean diet may prove advantageous in both men and women. Data do not consistently support a beneficial effect of vitamin D on reproduction, and caffeine use has not been shown to have a deleterious effect. Alcohol use may negatively impact reproductive success, and smoking appears to have a clearly negative impact in both men and women. Present data consistently show that obesity is associated with reduced reproductive efficiency in both women and men, but the data do not confirm that weight loss proximate to attempts at conception will reverse this effect. We would do well to appreciate that the ongoing state of being obese appears to be more relevant to reproduction than changing the obese state., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2017. Published by Elsevier Inc.)

The alarming trend in opiate misuse in developed countries is prompting an increasingly strident public call for action. Although many in our field have assumed that this building crisis does not really affect us or our patients, data show that the emerging demographic at highest risk for misusing opiates clearly includes patients who seek care in our practices. The goals of this Views and Reviews are to provide a clear understanding of emerging trends in opiate misuse, to review the impact of opiates on the reproductive axis, and to suggest practical recommendations aimed at both mitigating iatrogenic influences on promoting misuse and developing treatment frameworks when misuse is suspected or identified. Regrettably, there is little if any information on treatment of opiate misuse in the infertility population; we are perhaps best served by learning from successful approaches used in pregnant patients. It is hoped that this Views and Reviews will stimulate focused research and, ultimately, evidence-based guidelines and pathways that will address this widespread clinical problem., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Study Question: Does fertility-related quality of life (FertiQOL) differ by infertility diagnosis between women with polycystic ovary syndrome (PCOS) and their partners, compared with couples with unexplained infertility (UI)?, Summary Answer: Women with PCOS report lower QOL than those with UI, whereas males with UI report lower QOL than males with PCOS partners., What Is Known Already: The fertility-specific QOL survey, FertiQOL, has been used to examine fertility-related QOL in a number of worldwide cohorts. Few data have addressed fertility-related QOL as a function of infertility diagnosis. Overall, men report better QOL than women with infertility, and there is variation in FertiQOL scores across different samples from different countries., Study Design, Size, Duration: This was a prospective, cohort study derived from two concurrent, randomized clinical trials, and designed to examine QOL in infertile females with PCOS and UI at the time of enrollment compared with each other and their male partners; to compare concordance FertiQOL scores in this study across other worldwide cohorts; and to determine if baseline FertiQOL was associated with pregnancy outcome., Participants/materials, Setting, Methods: Women with PCOS and their partners (n = 733 and n = 641, respectively), and couples with UI (n = 865 women and 849 men) completed a validated fertility-specific QOL survey (FertiQOL) at the time of the study screening visit. PCOS women were randomized to either clomiphene citrate or letrozole treatment; couples with UI were randomized to clomiphene citrate, letrozole or gonadotrophin plus IUI. FertiQOL results were compiled by diagnosis (PCOS or UI) and compared by diagnosis and sex using Wilcoxon Rank-Sum testing. Relationships between baseline FertiQOL and pregnancy outcomes were examined using logistic regression. Multivariable models were performed to assess the association between FertiQOL scores and key participant characteristics., Main Results and the Role of Chance: Women with PCOS had lower total FertiQOL scores (72.3 ± 14.8) than those with UI (77.1 ± 12.8; P < 0.001); this was true for each domain (except Relational). These differences were largely explained by variation in BMI, hirsutism, household income and age. Women had lower overall FertiQOL scores than their male partners. Males with PCOS partners had higher scores than males with UI (84.9 ± 10.2 versus 83.3 ± 10.8; P = 0.003). Scores were not consistently associated with conception or pregnancy outcome., Limitations, Reasons for Caution: The use of multiple tests of association may have resulted in spurious statistically significant findings. Inherent sociodemographic differences between women with PCOS and those with UI largely account for the lower QOL in women with PCOS. Our study was unable to assess if changes in QOL affected pregnancy outcome as FertiQOL data were collected prior to treatment. Finally, the participants for both studies represent their local communities, but are not a population-based sample and thus firm conclusions about how representative these couples are to the general population must be made with caution., Wider Implications of the Findings: Women with PCOS with elevated BMI and hirsutism scores and with lower socioeconomic status may require more, targeted psychosocial support than those with other diagnoses. Possible attribution of infertility to the male partner appears to result in a lower QOL. There appears to be substantial national variation in FertiQOL scores, with US-based cohorts reporting overall higher QOL., Study Funding/competing Interests: This work was supported by National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Grants U10 HD39005 (to M.D.), U10 HD38992 (to R.S.L.), (to C.C.), U10 HD38998 (to R.A.), U10 HD055942 (to R.D.R.), HD055944 (to P.C.), U10 HD055936 (to G.C.), U10HD055925 (to H.Z.); and U10 U54-HD29834 (to the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core of the Specialized Cooperative Centers Program in Reproduction and Infertility Research). Most importantly, this research was made possible by the funding by American Recovery and Reinvestment Act. N.S., E.E., J.C.T., C.G., H.H., R.A., P.C., G.C., C.C., M.D., S.J., W.D.S. and H.Z. report no conflicts of interests/disclosures. L.B.C. reports research support from Ferring Pharmaceuticals and Roche Diagnostics; R.S.L. reports receipt of consulting fees from AstraZeneca, Euroscreen, Sprout Pharmaceuticals, Taken, Kindex, Clarus and Bayer, Inc., and research support from AstraZeneca and Ferring Pharmaceuticals. R.D.R. reports research support from AbbVie., Trial Registration Number: Pregnancy in Polycystic Ovary Syndrome II (PPCOS II), NCT00719186; Assessment of Multiple Intrauterine Gestations in Ovulation Stimulation (AMIGOS) NCT01044862, clinicaltrials.gov., Trial Registration Date: PPCOS II 17 July 2008; AMIGOS 7 January 2010., Date of First Patient's Enrolment: PPCOS II 19 February 2009; AMIGOS 2 August 2010., (Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Context: Anti-Müllerian hormone (AMH) reduces aromatase activity and sensitivity of follicles to FSH stimulation. Therefore, elevated serum AMH may indicate a higher threshold for response to ovulation induction in women with polycystic ovary syndrome (PCOS)., Objective: This study sought to determine the association between AMH levels and ovulatory response to treatment among the women enrolled into the Pregnancy in PCOS II (PPCOS II) trial., Design and Setting: This was a secondary analysis of data from a randomized clinical trial in academic health centers throughout the United States Participants: A total of 748 women age 18-40 years, with PCOS and measured AMH levels at baseline, were included in this study., Main Outcome Measures: Couples were followed for up to five treatment cycles to determine ovulation (midluteal serum progesterone > 5 ng/mL) and the dose required to achieve ovulation., Results: A lower mean AMH and AMH per follicle was observed among women who ovulated compared with women who never achieved ovulation during the study (geometric mean AMH, 5.54 vs 7.35 ng/mL; P = .0001; geometric mean AMH per follicle, 0.14 vs 0.18; P = .01) after adjustment for age, body mass index, T, and insulin level. As AMH levels increased, the dose of ovulation induction medication needed to achieve ovulation also increased. No associations were observed between antral follicle count and ovulation., Conclusions: These results suggest that high serum AMH is associated with a reduced response to ovulation induction among women with PCOS. Women with higher AMH levels may require higher doses of medication to achieve ovulation.

Context: Experimental evidence supports a relevance of vitamin D (VitD) for reproduction; however, data in humans are sparse and inconsistent., Objective: To assess the relationship of VitD status with ovulation induction (OI) outcomes in women with polycystic ovary syndrome (PCOS)., Design: A retrospective cohort., Setting: Secondary analysis of randomized controlled trial data., Participants: Participants in the Pregnancy in PCOS I (PPCOS I) randomized controlled trial (n = 540) met the National Institutes of Health diagnostic criteria for PCOS., Interventions: Serum 25OHD levels were measured in stored sera., Main Outcome Measures: Primary, live birth (LB); secondary, ovulation and pregnancy loss after OI., Results: Likelihood for LB was reduced by 44% for women if the 25OHD level was < 30 ng/mL (<75 nmol/L; odds ratio [OR], 0.58 [0.35-0.92]). Progressive improvement in the odds for LB was noted at thresholds of ≥38 ng/mL (≥95 nmol/L; OR, 1.42 [1.08-1.8]), ≥40 ng/mL (≥100 nmol/L; OR, 1.51 [1.05-2.17]), and ≥45 ng/mL (≥112.5 nmol/L; OR, 4.46 [1.27-15.72]). On adjusted analyses, VitD status was an independent predictor of LB and ovulation after OI., Conclusions: In women with PCOS, serum 25OHD was an independent predictor of measures of reproductive success after OI. Our data identify reproductive thresholds for serum 25OHD that are higher than recommended for the nonpregnant population.

Context: In overweight/obese women with polycystic ovary syndrome (PCOS), the relative benefit of delaying infertility treatment to lose weight vs seeking immediate treatment is unknown., Objective: We compared the results of two, multicenter, concurrent clinical trials treating infertility in women with PCOS., Design, Setting, and Participants: This was a secondary analysis of two randomized trials conducted at academic health centers studying women 18-40 years of age who were overweight/obese and infertile with PCOS., Intervention: We compared immediate treatment with clomiphene from the Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial (N = 187) to delayed treatment with clomiphene after preconception treatment with continuous oral contraceptives, lifestyle modification (Lifestyle: including caloric restriction, antiobesity medication, behavioral modification, and exercise) or the combination of both (combined) from the Treatment of Hyperandrogenism Versus Insulin Resistance in Infertile Polycystic Ovary Syndrome (OWL PCOS) trial (N = 142)., Main Outcome Measures: Live birth, pregnancy loss, and ovulation were measured., Results: In PPCOS II, after four cycles of clomiphene, the cumulative per-cycle ovulation rate was 44.7% (277/619) and the cumulative live birth rate was 10.2% (19/187), nearly identical to that after oral contraceptive pretreatment in the OWL PCOS trial (ovulation 45% [67/149] and live birth: 8.5% [4/47]). In comparison, deferred clomiphene treatment preceded by lifestyle and combined treatment in OWL PCOS offered a significantly better cumulative ovulation rate compared to immediate treatment with clomiphene. (Lifestyle: 62.0% [80/129]; risk ratio compared to PPCOS II = 1.4; 95% confidence interval [CI], 1.1-1.7; P = .003; combined: 64.3% [83/129]; risk ratio compared to PPCOS II = 1.4; 95% CI, 1.2-1.8; P < .001 and a significantly better live birth rate lifestyle: 25.0% [12/48]; risk ratio compared to PPCOS II = 2.5; 95% CI, 1.3-4.7; P = .01 and combined: 25.5% [12/47]; risk ratio compared to PPCOS II = 2.5; 95% CI, 1.3-4.8; P = .01)., Conclusions: These data show the benefit of improved ovulation and live birth with delayed infertility treatment with clomiphene citrate when preceded by lifestyle modification with weight loss compared with immediate treatment. Pretreatment with oral contraceptives likely has little effect on the ovulation and live birth rate compared with immediate treatment.

Objective: To determine if Chlamydia trachomatis (C. trachomatis) seropositivity, as detected by the C. trachomatis elementary body (EB)-based enzyme-linked immunosorbent assay [EB ELISA] predicts pregnancy and pregnancy outcome among infertile women with documented tubal patency., Design: Cohort study., Setting: Outpatient clinics., Patient(s): In all, 1,250 infertile women with documented tubal patency enrolled in 1 of 2 randomized controlled trials: Pregnancy in Polycystic Ovary Syndrome II; and the Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation., Intervention(s): Sera were analyzed for anti-C. trachomatis immunoglobulin G (IgG)1 and IgG3 antibodies, using a research C. trachomatis EB ELISA. The optical density (OD)405 readings of ≥ 0.35 and ≥ 0.1 were considered positive for IgG1 and IgG3, respectively., Main Outcome Measure(s): Primary outcomes included pregnancy, live birth, and ectopic pregnancy. Log-linear regression was used to determine the relative risk after adjusting for age, race, treatment medication, smoking status, and current alcohol use., Result(s): A total of 243 (19%) women were seropositive for anti-C. trachomatis IgG3. They tended to be nonwhite and smokers. Anti-C. trachomatis IgG3 seropositive women were significantly less likely to conceive (risk ratio [RR] 0.65, 95% confidence interval [CI] 0.52-0.83) or to have a live birth (RR 0.59, 95% CI 0.43-0.80); these associations were weakened after adjusting for number of hysterosalpingography-documented patent tubes (RR 0.73, 95% CI 0.56-0.97) and (RR 0.73, 95% CI 0.50-1.04), respectively. Anti-C. trachomatis IgG3 seropositive women who conceived had a ×2.7 risk (95% CI 1.40-5.34) of ectopic pregnancy., Conclusion(s): Even in the presence of tubal patency, anti-C. trachomatis IgG3 seropositivity is associated with a lower likelihood of pregnancy. Anti-C. trachomatis IgG3 seropositive women have as high as 3 times the risk of ectopic pregnancy., Clinical Trial Registration Number: PPCOSII: NCT00719186 and AMIGOS: NCT01044862., (Copyright © 2015 American Society for Reproductive Medicine. All rights reserved.)

Background: Recruitment of individuals into clinical trials is a critical step in completing studies. Reports examining the effectiveness of different recruitment strategies, and specifically in infertile couples, are limited., Methods: We investigated recruitment methods used in two NIH sponsored trials, Pregnancy in Polycystic Ovary Syndrome (PPCOS II) and Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS), and examined which strategies yielded the greatest number of participants completing the trials., Results: 3683 couples were eligible for screening. 1650 participants were randomized and 1339 completed the trials. 750 women were randomized in PPCOS II; 212 of the participants who completed the trial were referred by physicians. Participants recruited from radio ads (84/750) and the internet (81/750) resulted in similar rates of trial completion in PPCOS II. 900 participants were randomized in AMIGOS. 440 participants who completed the trial were referred to the study by physicians. The next most successful method in AMIGOS was the use of the internet, achieving 78 completed participants. Radio ads proved the most successful strategy in both trials for participants who earned <$50,000 annually. Radio ads were most successful in enrolling white patients in PPCOS II and black patients in AMIGOS. Seven ancillary Clinical Research Scientist Training (CREST) sites enrolled 324 of the participants who completed the trials., Conclusions: Physician referral was the most successful recruitment strategy. Radio ads and the internet were the next most successful strategies, particularly for women of limited income. Ancillary clinical sites were important for overall recruitment., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Mental health professionals serve an important role in guiding intended parents through a myriad of considerations from donor or surrogate selection to issues of disclosure with children. This role has evolved due to many considerations including evolving practice and ethics guidelines, as well as other factors such as access to the internet. This Views and Reviews will explore how team care, inclusive of the mental health professional, serves the interests of patients and provides a strong foundation for families created with the help of donors and/or surrogates., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The authors of this Views and Reviews describe the evolution of the role of mental health counseling in infertility care. As the use of assisted reproductive technologies and third-party reproduction has grown, so too has the interest and demand for mental health services. A historical perspective is presented that sets the stage for subsequent discussions of key areas where mental health practitioners are able to contribute to the utility and outcomes of infertile patients as well as those involved in their care. This series of articles stresses the value of more comprehensive integration of mental health support into infertility practice and highlights practical opportunities to do so., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Reproductive endocrinology and infertility (REI) is one of the original officially recognized subspecialties in obstetrics and gynecology and among the earlier subspecialties in medicine. Recognized by the American Board of Obstetrics and Gynecology in 1972, fellowship programs are now 3 years in length following an obstetrics and gynecology residency. Originally focused on endocrine problems related to reproductive function, the assisted reproductive technologies (ART) have recently become the larger part of training during REI fellowships. It is likely that the subspecialty of REI strengthens the specialty of obstetrics and gynecology and enhances the educational experience of residents in the field. The value of training and certification in REI is most evident in the remarkable and consistent improvement in the success of ART procedures, particularly in vitro fertilization. The requirement for documented research activity during REI fellowships is likely to stimulate a more rapid adoption (translation) of newer research findings into clinical care after training. Although mandatory reporting of outcomes has been proposed as a reason for this improvement the rapid translation of reproductive research into clinical practice is likely to be a major cause. Looking forward, REI training should emphasize and strengthen education and research into the endocrine, environmental, and genetic aspects of female and male reproduction to improve the reproductive health and fertility of all women., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Context: Obese men with normal semen parameters exhibit reduced fertility but few prospective data are available., Objective: This study aimed to determine the effect of male factors and body mass among the Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) participants., Methods: This is a secondary analysis of the PPCOS II trial. A total of 750 infertile women with polycystic ovary syndrome (PCOS) were randomly assigned to up to receive five cycles of letrozole or clomiphene citrate. Females were 18-39-years-old and had a male partner with sperm concentration of at least 14 million/mL who consented to regular intercourse. Analysis was limited to couples with complete male partner information (n = 710)., Results: Male body mass index (BMI) was higher in couples who failed to conceive (29.5 kg/m(2) vs 28.2 kg/m(2); P = .039) as well as those who did not achieve a live birth (29.5 kg/m(2) vs 28.1 kg/m(2); P = .047). At least one partner was obese in 548 couples (77.1%). A total of 261 couples were concordant for obesity (36.8%). After adjustment for female BMI, the association of male BMI with live birth was no longer significant (odds ratio [OR] = 0.85; 95 % confidence interval [CI], 0.68-1.05; P = .13). Couples in which both partners smoked had a lower chance of live birth vs nonsmokers (OR = 0.20; 95 % CI, 0.08-0.52; P = .02), whereas there was not a significant effect of female or male smoking alone. Live birth was more likely in couples with at least three sexual intercourse attempts over the previous 4 weeks (reported at baseline) as opposed to couples with lesser frequency (OR = 4.39; 95 % CI, 1.52-12. 4; P < .01)., Conclusions: In this large cohort of obese women with PCOS, effect of male obesity was explained by female BMI. Lower chance of success was seen among couples where both partners smoked. Obesity and smoking are common among women with PCOS and their partners and contribute to a decrease in fertility treatment success.

Study Question: Do women with polycystic ovary syndrome (PCOS) seeking fertility treatment report smoking accurately and does participation in infertility treatment alter smoking?, Summary Answer: Self-report of smoking in infertile women with PCOS is accurate (based on serum cotinine levels) and smoking is unlikely to change over time with infertility treatment., What Is Known Already: Women with PCOS have high rates of smoking and it is associated with worse insulin resistance and metabolic dysfunction., Study Design, Size, Duration: Secondary study of smoking history from a large randomized controlled trial of infertility treatments in women with PCOS (N = 626) including a nested case-control study (N = 148) of serum cotinine levels within this cohort to validate self-report of smoking., Participants/materials, Setting, Methods: Women with PCOS, age 18-40, seeking fertility who participated in a multi-center clinical trial testing first-line ovulation induction agents conducted at academic health centers in the USA., Main Results and the Role of Chance: Overall, self-report of smoking in the nested case-control study agreed well with smoking status as determined by measure of serum cotinine levels, at 90% or better for each of the groups at baseline (98% of never smokers had cotinine levels <15 ng/ml compared with 90% of past smokers and 6% of current smokers). There were minor changes in smoking status as determined by serum cotinine levels over time, with the greatest change found in the smoking groups (past or current smokers). In the larger cohort, hirsutism scores at baseline were lower in the never smokers compared with past smokers. Total testosterone levels at baseline were also lower in the never smokers compared with current smokers. At end of study follow-up insulin levels and homeostatic index of insulin resistance increased in the current smokers (P < 0.01 for both) compared with baseline and with non-smokers. The chance for ovulation was not associated with smoking status, but live birth rates were increased (non-significantly) in never or past smokers., Limitations, Reasons for Caution: The limitations include the selection bias involved in our nested case-control study, the possibility of misclassifying exposure to second hand smoke as smoking and our failure to capture self-reported changes in smoking status after enrollment in the trial., Wider Implications of the Findings: Because self-report of smoking is accurate, further testing of smoking status is not necessary in women with PCOS. Because smoking status is unlikely to change during infertility treatment, extra attention should be focused on smoking cessation in current or recent smokers who seek or who are receiving infertility treatment., Study Funding/competing Interests: Sponsored by the Eugene Kennedy Shriver National Institute of Child Health and Human Development of the U.S. National Institutes of Health., Clinical Trial Registration Numbers: ClinicalTrials.gov numbers, NCT00068861 and NCT00719186., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes., Methods: In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period., Results: Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P=0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P<0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups., Conclusions: As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00719186.).

Objective: To summarize baseline characteristics from a large multicenter infertility clinical trial., Design: Cross-sectional baseline data from a double-blind randomized trial of two treatment regimens (letrozole vs. clomiphene)., Setting: Academic Health Centers throughout the United States., Patient(s): Seven hundred fifty women with polycystic ovary syndrome (PCOS) and their male partners took part in the study., Intervention(s): None., Main Outcome Measure(s): Historic, biometric, biochemical, and questionnaire parameters., Result(s): Females averaged 30 years and were obese (body mass index [BMI] 35) with ∼20% from a racial/ethnic minority. Most (87%) were hirsute and nulligravid (63%). Most of the women had an elevated antral follicle count and enlarged ovarian volume on ultrasound. Women had elevated mean circulating androgens, LH-to-FSH ratio (∼2), and antimüllerian hormone levels (8.0 ng/mL). In addition, women had evidence for metabolic dysfunction with elevated mean fasting insulin and dyslipidemia. Increasing obesity was associated with decreased LH-to-FSH levels, antimüllerian hormone levels, and antral follicle counts but increasing cardiovascular risk factors, including prevalence of the metabolic syndrome. Men were obese (BMI 30) and had normal mean semen parameters., Conclusion(s): The treatment groups were well matched at baseline. Obesity exacerbates select female reproductive and most metabolic parameters. We have also established a database and sample repository that will eventually be accessible to investigators., Clinical Trial Registration Number: NCT00719186., (Copyright © 2014 American Society for Reproductive Medicine. All rights reserved.)

Objective: Many women with polycystic ovary syndrome (PCOS) experience infertility and hirsutism and often seek treatment for both concurrently. We investigated whether women who ovulate in response to treatment with clomiphene citrate, metformin, or both would have greater improvement in hirsutism compared with those who did not ovulate., Methods: This is a secondary analysis evaluating the change in Ferriman-Gallwey score for the hirsute women (n=505 [80.7%]) from the Pregnancy in Polycystic Ovary Syndrome I study. This was a prospective, randomized, doubled-blind trial of 626 women with PCOS and infertility recruited from 12 university sites. They were treated with clomiphene citrate, metformin, or both (combination) for up to six cycles, and hirsutism evaluators were blinded to group assignment., Results: There was a significant decrease in the Ferriman-Gallwey score between baseline and completion of the study in each of the three individual groups (clomiphene citrate, P=.024; metformin, P=.005; combination, P<.001). There was no significant difference in the degree to which the hirsutism score changed when comparing the three groups (P=.44). The change in hirsutism was not associated with the duration of treatment or with the presence or absence of ovulation., Conclusion: In infertile hirsute women with PCOS, treatment with clomiphene citrate, metformin, or both for up to six cycles does not alter hirsutism., Clinical Trial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00068861., Level of Evidence: II.