Klinefelter syndrome (KS) is the most common chromosomal aberration in men. There are approximately 250,000 men with KS in the United States, and the prevalence of KS in male reproductive practices is 3 to 4%; however, most men are never diagnosed. KS has an effect on normal development, growth, social interactions, bone structure, and sexual and reproductive function, thus a multidisciplinary approach to men with KS is important in providing state of the art care to children and men with KS. Over the last 10 years, with advancements in artificial reproductive techniques and the successful delivery of healthy children from men with KS, the involvement of reproductive endocrinologists and urologists in the care of patients with KS is becoming commonplace. The new areas of intense research investigate optimal methods of hormonal manipulations, preservation of fertility in adolescents, and development of universal early screening programs for KS. This review provides the latest update in our understanding of the pathophysiology, natural history, and evolving paradigms of therapy in adolescents and men with KS.

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Growing interest in Klinefelter syndrome among translational scientists and clinicians will result in better understanding of the pathophysiology of testicular failure. In some states, screening programs for Klinefelter syndrome are already in place, which will increase the number of patients with Klinefelter syndrome seen by practicing urologists in the near future. Diagnosis and management of patients with Klinefelter syndrome is within the scope and training of urologists. Development of randomized clinical trials comparing different forms of interventions in men and children with Klinefelter syndrome will allow us to standardize the care of these patients.

PurposeEstradiol (E2) modulates testicular functions including steroidogenesis, but the mechanisms of E2 signaling in human testis are poorly understood. GPER-1 (GPR30), a G protein-coupled membrane receptor, mediates rapid genomic and non-genomic response to estrogens. The aim of this study was to evaluate GPER-1 expression in the testis, and its role in estradiol dependent regulation of steroidogenesis in isolated rat Leydig cells and human testis.Materials and MethodsIsolated Leydig cells (LC) from adult rats and human testicular tissue were used in this study. Expression and localization studies of GPER-1 were performed with qRT-PCR, immunofluorescence, immunohistochemistry and Western Blot. Luteinizing Hormone (LH) -stimulated, isolated LC were incubated with estradiol, G-1 (GPER-1-selective agonist), and estrogen receptor antagonist ICI 182,780. Testosterone production was measured with radioimmunoassay. LC viability after incubation with G-1 was measured using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay.ResultsGPER-1 mRNA is abundantly expressed in rat LC and human testis. Co-localization experiments showed high expression levels of GPER-1 protein in LC. E2-dependent activation of GPER-1 lowers testosterone production in isolated rats LCs and in human testis, with statistically and clinically significant drops in testosterone production by 20–30% as compared to estradiol-naïve LC. The exposure to G-1 does not affect viability of isolated LCs.ConclusionsOur results indicate that activation of GPER-1 lowers testosterone levels in the rat and human testis. The expression of GPER-1 in human testis, which lack ERα, makes it an exciting target for developing new agents affecting testosterone production in men.