The timely secretion of gonadal sex steroids is essential for the initiation of puberty, the postpubertal maintenance of secondary sexual characteristics and the normal perinatal development of male external genitalia. Normal gonadal steroid production requires the actions of the pituitary-derived gonadotropins, luteinizing hormone and follicle-stimulating hormone. We report four human pedigrees with severe congenital gonadotropin deficiency and pubertal failure in which all affected individuals are homozygous for loss-of-function mutations in TAC3 (encoding Neurokinin B) or its receptor TACR3 (encoding NK3R). Neurokinin B, a member of the substance P-related tachykinin family, is known to be highly expressed in hypothalamic neurons that also express kisspeptin, a recently identified regulator of gonadotropin-releasing hormone secretion. These findings implicate Neurokinin B as a critical central regulator of human gonadal function and suggest new approaches to the pharmacological control of human reproduction and sex hormone-related diseases.

Insulin resistance (IR) is one of the common features of the polycystic ovary syndrome (PCOS), and recent studies indicate the possible role of vitamin D in the pathogenesis of IR and glucose metabolism. Aim of this study was aimed to determine the effect of vitamin D replacement therapy on glucose metabolism, insulin, and androgen levels in obese, insulin-resistant women with PCOS. Eleven women with PCOS were included in the study. Mean age of the patients was 23.6+/-5.7 yr, body mass index 33.9+/-5.1 kg/m(2). Six patients (54.5%) had acantosis nigricans and 10 (90.9%) oligoamenorrhea. The mean Ferriman Gallwey score was 14.1+/-4.6. Only 2 women were within the normal limits of vitamin D levels as >20 ng/ml. Three weeks after the administration of the single dose of 300,000 units of vitamin D3 orally, 25-hydroxyvitamin D3 significantly increased from 16.9+/-16 ng/ml to 37.1+/-14.6 ng/ml (p: 0.027) and only 2 women were detected to have vitamin D3 levels <20 ng/ml. Although glucose and insulin levels were decreased non-significantly, homeostasis model assessment (HOMA)-IR significantly decreased from 4.41+/-1.38 to 3.67+/-1.48 (p: 0.043). No significant alterations were witnessed at the levels of DHEAS, total and free testosterone, androstenedione. No correlation was found between vitamin D with HOMA and other hormonal parameters. In conclusion, women with PCOS have mostly insufficient vitamin D levels, and vitamin D replacement therapy may have a beneficial effect on IR in obese women with PCOS.

These results suggest that NTE-dependent alteration of phospholipid homeostasis in GHS causes both neurodegeneration and impaired LH release from pituitary gonadotropes, leading to nHH.

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