Genetics of hypogonadotropic hypogonadism

Male congenital hypogonadotropic hypogonadism (CHH) is a heterogenous group of genetic disorders that cause impairment in the production or action of gonadotropin releasing hormone (GnRH). These defects result in dysfunction of the hypothalamic-pituitary-gonadal hormone axis, leading to low testosterone levels and impaired fertility. Genetic testing techniques have expanded our knowledge of the underlying mechanisms contributing to CHH including over 30 genes to date implicated in the development of CHH. In some cases, non-reproductive signs or symptoms can give clues as to the putative genetic etiology, but many cases remain undiagnosed with less than 50% identified with a specific gene defect. This leads to many patients labelled as “idiopathic hypogonadotropic hypogonadism”. Medical and family history as well as physical exam and laboratory features can aid in the identification of hypogonadotropic hypogonadism (HH) that is associated with specific medical syndromes or associated with other pituitary hormonal deficiencies. Genetic testing strategies are moving away from the classic practice of testing for only a few of the most commonly affected genes and instead utilizing next generation sequencing techniques that allow testing of numerous potential gene targets simultaneously. Treatment of CHH is dependent on the individual’s desire to preserve fertility and commonly include human chorionic gonadotropin (hCG) and recombinant follicle stimulating hormone (rFSH) to stimulate testosterone production and spermatogenesis. In situations where fertility is not desired, testosterone replacement therapies are widely offered in order to maintain virilization and sexual function.