Normal development of the genitourinary (GU) tract is a complex process that frequently goes awry. In male children the most frequent congenital GU anomalies are cryptorchidism (1–4%), hypospadias (1%) and micropenis (0.35%). Bladder exstrophy and epispadias complex (BEEC) (1∶47000) occurs less frequently but significantly impacts patients' lives. Array comparative genomic hybridization (aCGH) identified seven individuals with overlapping deletions in the 2p15 region (66.0 kb-5.6 Mb). Six of these patients have GU defects, while the remaining patient has no GU defect. These deletions encompass the transcription factor OTX1. Subjects 2–7 had large de novo CNVs (2.39–6.31 Mb) and exhibited features similar to those associated with the 2p15p16.1 and 2p15p14 microdeletion syndromes, including developmental delay, short stature, and variable GU defects. Subject-1 with BEEC had the smallest deletion (66 kb), which deleted only one copy of OTX1. Otx1-null mice have seizures, prepubescent transient growth retardation and gonadal defects. Two subjects have short stature, two have seizures, and six have GU defects, mainly affecting the external genitalia. The presence of GU defects in six patients in our cohort and eight of thirteen patients reported with deletions within 2p14p16.1 (two with deletion of OTX1) suggest that genes in 2p15 are important for GU development. Genitalia defects in these patients could result from the effect of OTX1 on pituitary hormone secretion or on the regulation of SHH signaling, which is crucial for development of the bladder and genitalia.

Objective To identify gene dosage changes associated with non-obstructive azoospermia (NOA) using array comparative genomic hybridization (aCGH). Design Prospective study. Patients 110 men with NOA and 78 fertile controls. Settings Medical School Interventions None Main Outcome Measure The study has four distinct analytic components: aCGH, a molecular karyotype that detects copy-number-variations (CNV), Taqman-CNV assays to validate CNVs, mutation identification by Sanger sequencing and histologic analyses of testicular tissues. Results A microduplication at 20q11.22 encompassing E2F1 was identified in one of eight men with NOA analyzed using aCGH. CNVs were confirmed and an additional 102 men with NOA screened using Taqman CNV assays for a total of 110 NOA men analyzed for CNVs in E2F1. Eight of 110 (7.3%) NOA men had microduplications or microdeletions of E2F1 that were absent in fertile controls. Conclusions E2F1 microduplications or microdeletions are present in NOA men (7.3%). Duplications or deletions of E2F1 occur very rarely in the general population (0.011%), but E2F1 gene dosage changes, previously reported only in cancers, are present in a subset of NOA men. These results recapitulate the infertility phenotype seen in mice lacking or over-expressing E2f1.

Introduction:Both clomiphene citrate (CC) and testosterone supplementation therapy (TST) are effective treatments for men with hypogonadism. We sought to compare changes in symptoms and treatment efficacy in hypogonadal men before and after receiving CC and TST.Patients and Methods:52 men who received TST and 23 men who received CC for symptomatic hypogonadism were prospectively followed for change in hormone levels and symptoms after treatment. These men were also compared to eugonadal men who were not on CC or TST during the same period. Comparisons were made between baseline and posttreatment hormone levels and symptoms. Symptoms were evaluated using the androgen deficiency in aging male (ADAM) and quantitative ADAM (qADAM) questionnaires.Results:Serum total testosterone increased from pretreatment levels in all men (P < 0.05), regardless of therapy type (TST: 281–541 ng/dL, CC: 235.5–438 ng/dL). Men taking TST reported fewer ADAM symptoms after treatment (5–2, P < 0.05). Similarly, men taking CC reported fewer ADAM symptoms after treatment (3.5–1.5, P < 0.05). Conversely, eugonadal men had similar T levels (352 vs. 364 ng/dL) and hypogonadal symptoms (1.5 vs. 1.4) before and after follow-up. When we evaluated individual symptoms, men treated with TST showed significant increases in qADAM scores in libido, erectile function, and sports performance. However, among the men who received CC, qADAM subscore for libido was lower following treatment (3.75–3.2, P = 0.04), indicating that CC could have an adverse effect on libido in hypogonadal men.Conclusions:Both TST and CC are effective medications in treating hypogonadism; however, our study indicates that TST is more effective in raising serum testosterone levels and improving hypogonadal symptoms. CC remains a viable treatment modality for hypogonadal men but its adverse effect on libido warrant further study.

ObjectiveTo investigate the association between hypogonadal symptoms and serum total testosterone (TT) levels in young men (aged <40 years), in an attempt to determine whether there exists a clear-cut discriminatory threshold of TT below which hypogonadal symptoms become more prevalent. Patients and methodsWe retrospectively reviewed the charts of 352 men who presented to an outpatient Men's Health Clinic with chief complaint of 'low testosterone'. Sexual, psychological and physical symptoms were evaluated using the Androgen deficiency in Aging Male (ADAM) questionnaire. Serum levels of TT were collected on the same day that men completed their ADAM questionnaires. We subsequently performed univariate (t-test, chi-square) and multivariate analyses (ordinal logistic regression) to evaluate factors that predicted a low TT level. ResultsThe probability of hypogonadal symptoms increased at a serum TT level of 400 ng/dL. A cluster of symptoms: two psychological ('decreased energy', 'sadness'), and three physical ('decreased strength and endurance', 'decreased ability to play sports', and 'deterioration in work performance') were most strongly associated with serum TT levels of <400 ng/dL. On multivariable analysis, only 'lack of energy' predicted a TT level of <400 ng/dL. ConclusionsHypogonadal symptoms in men aged <40 years can be associated with a TT level of <400 ng/dL. Of the hypogonadal symptoms evaluated with the ADAM questionnaire, 'lack of energy' appears to be the most important symptom that predicts a TT level of <400 ng/dL.

Cryptorchidism is the most common urologic birth defect in men and is a predisposing factor of male infertility and testicular cancer, yet the etiology remains largely unknown. E2F1 microdeletions and microduplications contribute to cryptorchidism, infertility and testicular tumors. Although E2f1 deletion or overexpression in mice causes spermatogenic failure, the mechanism by which E2f1 influences testicular function is unknown. This investigation revealed that E2f1-null mice develop cryptorchidism with severe gubernacular defects and progressive loss of germ cells resulting in infertility and, in rare cases, testicular tumors. It was hypothesized that germ cell depletion resulted from an increase in WNT4 levels. To test this hypothesis, the phenotype of a double-null mouse model lacking both Wnt4 and E2f1 in germ cells was analyzed. Double-null mice are fertile. This finding indicates that germ cell maintenance is dependent on E2f1 repression of Wnt4, supporting a role for Wnt4 in germ cell survival. In the future, modulation of WNT4 expression in men with cryptorchidism and spermatogenic failure due to E2F1 copy number variations may provide a novel approach to improve their spermatogenesis and perhaps their fertility potential after orchidopexy.