Hypogonadotropic Hypogonadism (HH) and Gonadotropin Therapy

Pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus is required for both the initiation and maintenance of the reproductive axis in the human. Pulsatile GnRH stimulates biosynthesis of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) that in turn initiate both intra-gonadal testosterone production and spermatogenesis as well as systemic testosterone secretion and virilization. Failure of this episodic GnRH secretion or action, or disruption of gonadotropin secretion, results in the clinical syndrome of hypogonadotropic hypogonadism (HH). Disorders causing HH are differentiated from primary testicular disease by the demonstration of low/normal gonadotropin levels in the setting of low testosterone concentrations and sperm counts (Fig. 1). Congenital abnormalities leading to HH are rare but well described and are usually the consequence of deficient GnRH secretion occurring either in isolation (normosmic congenital hypogonadotropic hypogonadism (nCHH)), or in association with anosmia (Kallmann syndrome (KS)). A growing number of loci have been associated with congenital GnRH deficiency and mutations in the GnRH receptor, as well as both LH-b and FSH-b subunits, have been reported. Acquired causes of HH are more common and can be due to any disorder that affects the hypothalamic-pituitary axis.