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, highly heritable complex disorder of unknown aetiology characterized by hyperandrogenism, chronic anovulation and defects in glucose homeostasis. Increased luteinizing hormone relative to follicle-stimulating hormone secretion, insulin resistance and developmental exposure to androgens are hypothesized to play a causal role in PCOS. Here we map common genetic susceptibility loci in European ancestry women for the National Institutes of Health PCOS phenotype, which confers the highest risk for metabolic morbidities, as well as reproductive hormone levels. Three loci reach genome-wide significance in the case–control meta-analysis, two novel loci mapping to chr 8p32.1 and chr 11p14.1, and a chr 9q22.32 locus previously found in Chinese PCOS. The same chr 11p14.1 SNP, rs11031006, in the region of the follicle-stimulating hormone B polypeptide (FSHB) gene strongly associates with PCOS diagnosis and luteinizing hormone levels. These findings implicate neuroendocrine changes in disease pathogenesis.

Objective. Cyclophosphamide (CYC) therapy for systemic lupus erythematosus (SLE), a disease predominantly affecting women of childbearing age, causes an unacceptably high incidence of irreversible premature ovarian failure (POF). This study was performed to evaluate the effectiveness of depot leuprolide acetate, a synthetic gonadotropin-releasing hormone analog (GnRH-a), for protection against POF during CYC therapy.Methods. Young women with severe SLE treated in a standardized protocol of monthly intravenous bolus CYC were offered treatment with GnRH-a (depot leuprolide acetate; a 3.75-mg monthly injection during the standard CYC regimen). Patients treated with GnRH-a were compared with controls individually matched by age (؎5 years) and by cumulative CYC dose (؎5 gm). Reproductive status was determined after a minimum followup of 3 years after CYC therapy. The primary outcome was time to POF. Paired summary statistical analyses, Kaplan-Meier survival estimates, and Cox regression analyses were performed to assess differences in outcome between groups.Results. POF developed in 1 of 20 women treated with GnRH-a (5%) compared with 6 of 20 controls (30%) matched by age and cumulative CYC dose (matched odds ratio 0.09, P < 0.05). Kaplan-Meier estimates demonstrated improved cumulative ovarian protection over time in the GnRH-a-treated group (P ‫؍‬ 0.04).Conclusion. Treatment with GnRH-a during CYC therapy was associated with a significant reduction of POF in young women with severe SLE.Cyclophosphamide (CYC) administration prolongs survival and reduces end-organ damage in patients with severe rheumatic diseases such as systemic lupus erythematosus (SLE), Wegener's granulomatosis, and polyarteritis nodosa. However, treatment with CYC and other alkylating agents such as chlorambucil is associated with an unacceptably high incidence of significant toxicities, including premature ovarian failure (POF; hypergonadotropic hypogonadism), with consequent irreversible amenorrhea and infertility (1-3). This has particular significance in the SLE population, since lupus disproportionately affects women of reproductive age. In experimental animals, CYC exposure results in DNA crosslinking in granulosa cells, reduced numbers of granulosa cells, decreased circulating levels of progesterone and estrogen, and ovarian fibrosis (4,5). In humans, CYC-induced damage to the ovary is generally regarded as cumulative and irreversible, due in part to progressive reduction of a limited number of cells (2).The incidence of POF in both the rheumatic disease and cancer populations treated with CYC ranges from 12% to 83% depending on variables such as patient characteristics and mode of administration. Both age at initiation of therapy and the cumulative CYC dose are strong predictors of POF (1-3,6-9). A study of breast cancer patients showed that the cumulative CYC doses associated with a 50% incidence of ovarian failure were 20.4 gm, 9.3 gm, and 5.2 gm among women in their 20s, 30s, and 40s, respectively (10).

A testosterone RIA is comparable to LC/MS assays. There is significant variability between LC/MS assays and poor precision with all assays at low testosterone levels.

Objective-Uterine leiomyoma produce an extracellular matrix (ECM) that is abnormal in its volume, content, and structure. Alterations in ECM can modify mechanical stress on cells, leading to activation of Rho-dependent signaling. Here we sought to determine whether the altered ECM produced by leiomyoma was accompanied by an altered state of mechanical homeostasis.Study Design-Measurement of the mechanical response in paired leiomyoma and myometrium, immunogold, confocal microscopy, and immunohistochemical analyses.Results-Leiomyoma were significantly stiffer than matched myometrium. The increased stiffness was associated with a moderate increase in total sulfated glycosaminoglycan content and a slight increase in hydroxyproline. Levels of the Rho-GEF, AKAP13, were increased and subcellular localization was altered in leiomyoma. Phosphorylation of p38MAPK was greater in leiomyoma extracts. Conclusions-Leiomyoma

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

Objective-To evaluate the current literature on the impact and potential mechanisms of varicocele repair on male fertility.Design-Pertinent articles were identified through computer PubMed search on varicocele repair and male infertility. References of selected articles were hand searched for additional citations.Conclusions-Varicocele repair has been shown to reverse a spectrum of effects contributing to men with impaired fertility. Clinical studies on the intervention have illustrated variable effects on postoperative sperm parameters and pregnancy rates. Studies with conflicting results suffer from a significant number of confounding variables, such variable repair technique or lack of controls. Further studies are warranted on the role of modern microsurgical varicocelectomy given the improvements in assisted reproductive technologies.

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