Physiologic and genetic insights into the pathophysiology and management of hypogonadotropic hypogonadism.

Initiation and maintenance of reproductive capacity is contingent upon the pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus. While GnRH deficiency manifests itself clinically as hypogonadism, the time of onset of the defect in GnRH secretion (i.e. before or after the onset of puberty) determines the clinical presentation that is further modified by the severity of the defect. GnRH deficiency can be associated with structural lesions that interfere with the normal pattern of GnRH secretion through compression or destruction of critical areas of the median eminence of the hypothalamus. Idiopathic hypogonadotropic hypogonadism (IHH) has been described and is characterized by isolated GnRH deficiency in the absence of a hypothalamic or pituitary lesion. Typically, patients with hypogonadotropic hypogonadism and anosmia have been given the diagnosis of Kallmann's syndrome and those with normal olfaction, IHH. However, both entities can be present in the same family, demonstrating variability in phenotypic expression and raising questions about the usefulness of this distinction. GnRH deficiency may be inherited via autosomal dominant, autosomal recessive and X-linked modes of inheritance. Specific defects in a number of genes have now been found in association with GnRH deficiency in the human and including the KAL gene, the DAX gene and the GnRH receptor gene, but not the gene encoding GnRH itself. While these mutations account for only a small fraction of cases, genetic studies not only provide promise for future treatment, but also insights into the complexity of the GnRH neuronal system. The treatment of GnRH deficiency is highly successful whether designed for steroid hormone replacement or for fertility. The challenge in the treatment of these abnormalities is in the early and accurate diagnosis and the use of replacement therapies that are as close to physiologic as possible.