Studies in Patients with Congenital GnRH Deficiency

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In this study we are performing phenotype/genotype studies in males and women with congenital deficiency in the secretion or responsiveness to gonadotropin releasing hormone (GnRH). Isolated GnRH deficiency is a rare disorder, with an estimated incidence of 1/50,000. Patients present with failure of normal pubertal development and hypogonadotropic hypogonadism (low LH, FSH and estradiol or testosterone), indicative of a hypothalamic or, less frequently, pituitary abnormality. The disorder is referred to as isolated hypogonadotropic hypogonadism (IHH). Approximately 50% of these patients lack a sense of smell (Kallmann Syndrome, KS) while the other half are normosmic (nIHH). Studies in KS/nIHH patients have been particularly informative in helping us understand the GnRH requirements for normal reproductive function and have led to development of a physiologic regimen of GnRH replacement in men and women. While pulsatile GnRH serves as treatment for patients interested in conceiving or in their potential to conceive, these patients have provided a clinical model that allows us to address key questions in reproductive physiology. Our currently active protocols focus on further understanding the genetic underpinnings of GnRH deficiency, understanding the full phenotype of the spectrum of patients who present with GnRH deficiency and understanding the genotype/phenotype correlations in this disorder. This study is being conducted in patients identified by the PI with the support of investigators at Massachusetts General Hospital and St Jude's Hospital as is part of the PIs long-term collaborative efforts.