Benefit of Delayed Fertility Therapy With Preconception Weight Loss Over Immediate Therapy in Obese Women With PCOS.

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.

Recruitment strategies in two reproductive medicine network infertility trials.

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.

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.

Letrozole versus clomiphene for infertility in the polycystic ovary syndrome.

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.).

Reduction in hematocrit level after pioglitazone treatment is correlated with decreased plasma free testosterone level, not hemodilution, in women with polycystic ovary syndrome.

Thiazolidinediones have gained widespread use for the treatment of type 2 diabetes mellitus and other insulin resistance states, including polycystic ovary syndrome (PCOS). In thiazolidinedione-treated patients a small reduction in hemoglobin and hematocrit levels often is observed, and this generally has been attributed to fluid retention. Because testosterone is a hematopoietic hormone, we investigated whether a reduction in plasma free testosterone concentration was associated with the decrease in hemoglobin and hematocrit levels in 22 nondiabetic women (9 with normal glucose tolerance and 13 with impaired glucose tolerance; mean age, 29 +/- 5 years; mean body mass index, 35.6 +/- 5.8 kg/m2) with PCOS who were treated with pioglitazone, 45 mg/d. Before treatment and after 4 months, subjects underwent an oral glucose tolerance test and measurement of total body water content with bioimpedance. Plasma testosterone, androstenedione, dehydroepiandrosterone sulfate, hemoglobin, and hematocrit levels were evaluated at baseline and every month for 4 months. The fasting plasma glucose concentration (98 +/- 9 mg/dL) was unchanged after pioglitazone treatment, whereas the 2-hour plasma glucose concentration declined from 146 +/- 41 to 119 +/- 20 mg/dL (P = .002). Both the free androgen index and the free testosterone levels calculated according to Vermeulen et al decreased significantly (from 14.4 +/- 7.1 to 10.6 +/- 7.8 [P = .02] and from 59.4 +/- 23.4 to 46.6 +/- 23.3 [P = .03], respectively). The plasma androstenedione level declined from 259 +/- 134 to 190 +/- 109 ng/dL (P = .01), whereas the dehydroepiandrosterone sulfate level did not change significantly (from 139 +/- 90 to 127 +/- 84 mug/dL, P = .2 [not significant]). The levels of both hemoglobin (from 13.6 +/- 1.0 to 12.8 +/- 1.1 g/dL, P = .0002) and hematocrit (from 39.7% +/- 2.2% to 37.9% +/- 2.7%, P = .002) fell slightly after 4 months of pioglitazone administration. Collectively, before and after pioglitazone administration, the plasma free testosterone level according to Vermeulen et al correlated positively with the levels of hemoglobin (r = 0.49, P < .0001) and hematocrit (r = 0.40, P < .0001), as well as the free androgen index (r = 0.38 [P < .0003] with hemoglobin and r = 0.29 [P < .006] with hematocrit); the decrement in plasma free testosterone level and free androgen index also correlated with the decrements in the levels of both hemoglobin (r = 0.51 [P = .01] and r = 0.54 [P = .01], respectively) and hematocrit (r = 0.42 [P = .05] and r = 0.50 [P = .02], respectively). Body weight increased from 90.5 +/- 17.3 to 92.4 +/- 18.8 kg after pioglitazone administration (P = .05), as did body fat content (from 42.7 +/- 15.3 to 44.8 +/- 17.1 kg, P = .03), which could explain the increase in weight, because edema did not develop in any of the subjects. Total body water content did not change significantly after pioglitazone administration (from 37.7 +/- 5.0 to 37.8 +/- 4.9 L, P = .68 [not significant]). In summary, pioglitazone treatment is associated with a mild decline in hematocrit or hemoglobin level, which is correlated with the reduction in plasma testosterone level. These results suggest that increased body water content cannot explain the reduction in hematocrit or hemoglobin level in women with PCOS. Further studies are necessary to evaluate whether the same scenario is applicable to normoandrogenic women and individuals with type 2 diabetes mellitus.