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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.)

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: 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.)

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.).

Polycystic Ovary Syndrome (PCOS) is a common cause of female infertility and first line treatment is currently oral clomiphene citrate, a selective estrogen receptor modulator, which results in both a high nonresponse rate and multiple pregnancy rate. Aromatase inhibitors such as letrozole may have more favorable ovarian and endometrial effects. The goal of the Pregnancy in Polycystic Ovary Syndrome II (PPCOSII) study is to determine the safety and efficacy of clomiphene citrate (CC) compared to letrozole, in achieving live birth in infertile women with PCOS. The population will consist of 750 infertile women with PCOS. Additionally, the couple will have no other major infertility factor. This will be a multi-center, prospective, double-blind clinical trial of CC vs. letrozole for 5 treatment cycles (or approximately up to 25 weeks). The randomization scheme will be coordinated through the central data coordinating center (DCC) and the randomization is stratified by each participating site. After progestin withdrawal as needed, 750 women will be equally randomized to two different treatment arms: A) CC 50mg every day for 5 days (days 3-7 of cycle), or B) letrozole 2.5mg every day for 5 days (days 3-7 of cycle), for a total of 5 cycles or 25 weeks. The dose will be increased in subsequent cycles in both treatment groups for non-response or poor ovulatory response up to a maximum of 150 mg of CC a day (×5 days) or 7.5mg of letrozole a day (×5 days). The primary analysis will use an intent-to-treat approach to examine differences in the live birth rate in the two treatment arms., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Although histological dating of endometrial biopsies provides little help for prediction or diagnosis of infertility, analysis of individual endometrial proteins, proteomic profiling and transcriptome analysis have suggested several biomarkers with altered expression arising from intrinsic abnormalities, inadequate stimulation by or in response to gonadal steroids or altered function due to systemic disorders. The objective of this study was to delineate the developmental dynamics of potentially important proteins in the secretory phase of the menstrual cycle, utilizing a collection of endometrial biopsies from women of fertile (n = 89) and infertile (n = 89) couples., Methods and Results: Progesterone receptor-B (PGR-B), leukemia inhibitory factor, glycodelin/progestagen-associated endometrial protein (PAEP), homeobox A10, heparin-binding EGF-like growth factor, calcitonin and chemokine ligand 14 (CXCL14) were measured using a high-throughput, quantitative immunohistochemical method. Significant cyclic and tissue-specific regulation was documented for each protein, as well as their dysregulation in women of infertile couples. Infertile patients demonstrated a delay early in the secretory phase in the decline of PGR-B (P < 0.05) and premature mid-secretory increases in PAEP (P < 0.05) and CXCL14 (P < 0.05), suggesting that the implantation interval could be closing early. Correlation analysis identified potential interactions among certain proteins that were disrupted by infertility., Conclusions: This approach overcomes the limitations of a small sample number. Protein expression and localization provided important insights into the potential roles of these proteins in normal and pathological development of the endometrium that is not attainable from transcriptome analysis, establishing a basis for biomarker, diagnostic and targeted drug development for women with infertility.

To assess the practice patterns and personal beliefs of fertility physicians who care for obese patients seeking assisted reproduction, we conducted a national survey of fertility program directors from both private and academic practices and discovered that although few practices have firm guidelines regarding the management of obese patients, the overwhelming majority of providers believe that body mass index guidelines or cutoffs should exist., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Many clinical investigators think that the burden of Institutional Review Board (IRB) requirements has been consistently increasing over recent years, although there are few objective data describing these trends. Over a period of 7 years, the Reproductive Medicine Network observed a significant increase in the size and requirements of IRB submissions and significant variability of IRB performance in reviewing multicenter trials. These additional regulatory and administrative demands represent substantial burdens to researchers and to the IRBs themselves. It is timely to consider whether these changes better protect the interests and safety of human research participants., Clinical Trial Registration: ClinicalTrials.gov NCT00068861 and NCT00719186., (Copyright © 2011 American Society for Reproductive Medicine. All rights reserved.)

Background: Double-blind, randomized clinical trials are the preferred approach to demonstrating the effectiveness of one treatment against another. The comparison is, however, made on the average group effects. While patients and clinicians have always struggled to understand why patients respond differently to the same treatment, and while much hope has been held for the nascent field of predictive biomarkers (e.g. genetic markers), there is still much utility in exploring whether it is possible to estimate treatment efficacy based on demographic and baseline variables., Methods: The pregnancy in polycystic ovary syndrome (PPCOS) study was a prospective, multi-center, randomized clinical trial comparing three ovulation induction regimens: clomiphene citrate (CC), metformin and the combination of the two. There were 446 women who ovulated in response to the treatments among the entire 626 participants. In this report, we focus on the 418 women who received CC (alone or combined with metformin) to determine if readily available baseline physical characteristics and/or easily obtainable baseline measures could be used to distinguish treatment effectiveness in stimulating ovulation. We used a recursive partitioning technique and developed a node-splitting rule to build decision tree models that reflected within-node and within-treatment responses., Results: Overall, the combination of CC plus metformin resulted in an increased incidence of ovulation compared with CC alone. This is particularly so in women with relatively larger left ovarian volumes (≥ 19.5 cubic cm), and a left ovarian volume <19.5 cubic cm was related to treatment outcomes for all subsequent nodes. Women who were older, who had higher baseline insulin, higher waist-to-hip circumference ratio or higher sex hormone-binding globulin levels had better ovulatory rates with CC alone than with the combination of CC plus metformin., Conclusions: Polycystic ovary syndrome (PCOS) is a phenotypically diverse condition. Both baseline laboratory and clinical parameters can predict the ovulatory response in women with PCOS undergoing ovulation induction. Without a priori hypotheses with regard to any predictors, the observation regarding left ovary volume is novel and worthy of further investigation and validation.

Objective: To investigate the relationship among intercourse compliance, ovulation, and the occurrence of pregnancy in the Reproductive Medicine Network's Pregnancy in Polycystic Ovary Syndrome (RMNPPCOS) Trial., Design: Post hoc data analysis of subjects in the Reproductive Medicine Network PPCOS Trial., Setting: Academic medical centers., Intervention(s): None., Patient(s): Six hundred twenty-six infertile women with polycystic ovary syndrome with a mean age of 28.1+/-4 years and mean body mass index of 35.2+/-8.7 kg/m2., Main Outcome Measure(s): Intercourse compliance, ovulation, and pregnancy., Result(s): Data on 2925 cycles were included in the analysis, of which 1340 were ovulatory cycles and 1585 were nonovulatory cycles. The rates of intercourse compliance in the PPCOS trial were similar across all treatment groups at all cycles except cycle 4. Among cycles with known ovulation status, 81.2% of patients were compliant with intercourse instructions. Patients were more intercourse compliant in those cycles during which ovulation occurred (83.2% vs. 79.4%). With regard to ovulatory cycles, there was no difference in the occurrence of pregnancy when comparing intercourse compliant versus intercourse noncompliant cycles., Conclusion(s): Intercourse compliance was not associated with the occurrence of pregnancy in ovulatory cycles in the PPCOS Trial. The occurrence of ovulation still remains a critical predictor for the occurrence of pregnancy., (Copyright (c) 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

We investigated whether poor adherence with metformin tablets may have contributed to the poor success rates seen in the metformin-containing arms of the Pregnancy in Polycystic Ovary Syndrome (PPCOS) Trial. Median adherence for both metformin and clomiphene citrate tablets was within acceptable limits and unrelated to ovulation: thus, failure to comply with physician recommendations for metformin dosing was not the reason for low ovulation and pregnancy rates in the PPCOS Trial.

Background: The polycystic ovary syndrome is a common cause of infertility. Clomiphene and insulin sensitizers are used alone and in combination to induce ovulation, but it is unknown whether one approach is superior., Methods: We randomly assigned 626 infertile women with the polycystic ovary syndrome to receive clomiphene citrate plus placebo, extended-release metformin plus placebo, or a combination of metformin and clomiphene for up to 6 months. Medication was discontinued when pregnancy was confirmed, and subjects were followed until delivery., Results: The live-birth rate was 22.5% (47 of 209 subjects) in the clomiphene group, 7.2% (15 of 208) in the metformin group, and 26.8% (56 of 209) in the combination-therapy group (P<0.001 for metformin vs. both clomiphene and combination therapy; P=0.31 for clomiphene vs. combination therapy). Among pregnancies, the rate of multiple pregnancy was 6.0% in the clomiphene group, 0% in the metformin group, and 3.1% in the combination-therapy group. The rates of first-trimester pregnancy loss did not differ significantly among the groups. However, the conception rate among subjects who ovulated was significantly lower in the metformin group (21.7%) than in either the clomiphene group (39.5%, P=0.002) or the combination-therapy group (46.0%, P<0.001). With the exception of pregnancy complications, adverse-event rates were similar in all groups, though gastrointestinal side effects were more frequent, and vasomotor and ovulatory symptoms less frequent, in the metformin group than in the clomiphene group., Conclusions: Clomiphene is superior to metformin in achieving live birth in infertile women with the polycystic ovary syndrome, although multiple birth is a complication. (ClinicalTrials.gov number, NCT00068861 [ClinicalTrials.gov].)., (Copyright 2007 Massachusetts Medical Society.)

We investigated the prevalence of abnormal screening results (questionnaire and testing for other causes of oligo-ovulation, male or tubal factor infertility) in a group of 1,313 oligo-ovulatory women (included and excluded subjects) whose condition was screened for inclusion in the Pregnancy in Polycystic Ovary Syndrome trial, a multicenter clinical trial that was conducted at 13 sites in the United States. Other than failure to demonstrate laboratory evidence of hyperandrogenemia, the most common reasons for subject exclusion were persistent oligospermia and tubal factor infertility.

Objective: To report the baseline characteristics and racial differences in the polycystic ovary syndrome (PCOS) phenotype from a large multicenter clinical trial (PPCOS)., Design: Double-blind, randomized trial of three treatment regimens (with extended release metformin or clomiphene citrate)., Setting: Academic medical centers., Patient(s): Six hundred twenty-six infertile women with PCOS, aged 18-39 years, with elevated T levels and oligomenorrhea (exclusion of secondary causes), seeking pregnancy, with > or = 1 patent fallopian tube, normal uterine cavity, and a partner with sperm concentration > or = 20 x 10(6)/mL in > or = 1 ejaculate., Intervention(s): Baseline characterization., Main Outcome Measure(s): Historical, biometric, and biochemical measures of PCOS., Result(s): There were no significant differences in baseline variables between treatment groups. The overall mean (+/-SD) age of the subjects was 28.1 +/- 4.0 years, and the mean body mass index was 35.2 kg/m2 (+/-8.7). Polycystic ovaries (PCOs) were present in 90.3% of the subjects, and the mean volume of each ovary was 10 cm3 or more. Of the subjects, 7% had ovaries that were discordant for PCO morphology. At baseline, 18.3% of the subjects had an abnormal fasting glucose level (> 100 mg/dL). Asians tended to have a milder phenotype, and whites and African Americans were similar in these measures., Conclusion(s): The treatment groups were well matched for baseline parameters, and we have added further information to the PCOS phenotype.

Objective: To assess the ability of histological dating to discriminate between women of fertile and infertile couples. The utility of histological dating of endometrium in the evaluation of infertile couples is uncertain., Design: Prospective multicenter study, with subjects randomly assigned to biopsy timing. Criterion standard for infertility was 12 months of unprotected, regular intercourse without conception and for fertility at least one live birth within 2 years., Setting: University-based infertility practices., Patient(s): Volunteer subjects (847) recruited at 12 clinical sites participating in the National Institutes of Health-funded Reproductive Medicine Network. Inclusion criteria included ages 20-39 years, regular menstrual cycles, and no hormonal treatment or contraceptive use for 1 month before the study. Fertile controls were excluded if they had a history of infertility, recurrent pregnancy loss, or recent breastfeeding., Intervention(s): Subjects underwent daily urinary LH testing. After detection of the LH surge, subjects were randomized to biopsy in the mid (days 21-22) or the late (days 26-27) luteal phase. Pathologists at each site estimated the cycle day based on standard criteria. For the primary analysis, an out-of-phase biopsy was defined as a greater than 2-day delay in the histological maturation of the endometrium., Main Outcome Measure(s): The proportion of out-of-phase biopsies in fertile and infertile women was compared using logistic regression models with age at randomization as a covariate. Comparisons were also made between fertile vs. infertile at the midluteal or late luteal phase time points., Result(s): Biopsies were evaluated (301 mid and 318 late; N = 619). Out-of-phase biopsy results poorly discriminated between women from fertile and infertile couples in either the midluteal (fertile: 49.4%, infertile: 43.2%) or late luteal phase (fertile: 35.3%, infertile 23.0%). Results did not substantially differ using alternative definitions of "out-of-phase" or standardized cycle day., Conclusion(s): Histological dating of the endometrium does not discriminate between women of fertile and infertile couples and should not be used in the routine evaluation of infertility.

Objective: To examine the proportion of cases with proliferative endometrium on biopsies performed after positive home urine LH testing., Design: Multicenter clinical trial of the usefulness of endometrial biopsy in the evaluation of infertility, with women from fertile and infertile couples randomly assigned to midluteal vs. late luteal phase endometrial sampling., Setting: Twelve clinical sites of the National Institutes of Health/National Institute of Child Health and Human Development-sponsored Reproductive Medicine Network., Patient(s): All women in the study had regular menstrual cycles. Fertile volunteers who had delivered a live born infant within the past 2 years without medical intervention were recruited through advertisements at participating sites. Infertile women with regular cycles were recruited from the clinical practices of the sites' physicians., Intervention(s): Interview, informed consent, subject-interpreted home urine LH testing, and endometrial biopsy in either the midluteal or late luteal phase., Main Outcome Measure(s): Proportion of cases with proliferative endometrium on biopsy., Result(s): In both fertile and infertile women, more than 7% of endometrial biopsies performed 7-13 days after a positive home urine LH test revealed proliferative endometrium., Conclusion(s): Patient interpretation of home urine LH test kits not uncommonly results in false-positive tests. Women planning menstrual cycle testing or procedures related to ovulation may benefit from additional confirmatory testing.

Objective: Although laparoscopy is an important tool for evaluating pelvic pathology, visualization is limited to the surface of structures. A method of seeing below the surface during laparoscopy could be useful. We report on our early experience with new laparoscopic ultrasound., Study Design: Following diagnostic laparoscopy the pelvis is filled with fluid to obtain optimal imaging. A 10-mm ultrasound probe is introduced through the umbilical trocar and the uterus and adnexa examined., Results: High-resolution images can be obtained to delineate such abnormalities as suspected ovarian cysts and uterine myomata., Conclusion: Endoscopic ultrasound is a new instrument that allows the surgeon to evaluate and define pelvic pathology suspected at the time of laparoscopy. Endoscopic ultrasound may augment the diagnosis of subtle pathologic findings during laparoscopy.

Patients undergoing human menopausal gonadotropin (hMG) superovulation were reviewed retrospectively to determine whether fecundity was greater for intrauterine insemination (IUI) than timed intercourse. Forty patients with unexplained infertility, American Fertility Society I or II endometriosis, luteal phase defect and/or cervical factor were treated with hMG alone or hMG plus IUI. Twenty-eight underwent 52 cycles of hMG/IUI, and 19 underwent 31 cycles of hMG. The probability of pregnancy after four cycles was significantly better in the hMG/IUI group (.90) than the hMG group (.37, P = .049). There was a 54.5% multiple pregnancy rate, and one patient was admitted to the hospital for hyperstimulation. When traditional therapy fails, hMG/IUI significantly increases the pregnancy rates as compared to hMG with timed intercourse in a "good prognosis" group of patients.

Life table analysis and the two-parameter exponential method have been applied to pregnancy rates in 72 patients undergoing laparoscopic cautery exclusively. Patients with male factor infertility were excluded. Estimated cure rates for patients with stage I and II disease were 98.2% and 76.6%, respectively (not significantly different). No significant difference was seen when anovulation complicated the endometriosis (68.6%). When greater than one infertility factor was present, a significant difference was observed (50.6%). Patients with stage I disease had an average fecundity of 10.30% with decreasing values observed in stage II (7.59%), anovulation (6.67%), and more than one infertility factor (3.33%). We conclude that laparoscopic cauterization is an effective mode of therapy for the treatment of stage I and II endometriosis associated with infertility.