Gonadotropin-releasing hormone deficiency: Differential diagnosis and treatment

A normal frequency and amplitude of gonadotropin-releasing hormone (GnRH) s ecretion from the hypothalamus is critical for both the initiation and main tenance of reproductive function in the human. Hypogonadotropic hypogonadis m (HH) is the clinical syndrome that results from absence, decreased freque ncy or decreased amplitude of pulsatile GnRH release. Typically, the diagno sis of GnRN deficiency is made in adolescence when secondary sexual charact eristics fail to develop. In a subset of patients, HH may present postpuber tally with decreased libido, impotence, and oligo- or azoospermia in men an d secondary amenorrhea and infertility in women. HH can be congenital or ca n arise from a variety of structural or functional lesions of the hypothala mic-pituitary axis. Congenital GnRH deficiency can be an isolated finding, as in idiopathic hypogonadotropic hypogonadism, or it may occur in associat ion with anosmia +/- a variety of midline defects, in which case the term K allmann's syndrome is applied. One-third of cases of congenital HH are fami lial. Autosomal inheritance is the commonest mode of inheritance, although X-linked transmission due to a mutation in the KAL gene is the best generic ally characterized form of GnRH deficiency. In prepubertal patients, sex steroid replacement is necessary to allow norm al development of secondary sexual characteristics. In adult women, estroge n replacement with an oral contraceptive or with conjugated estrogens and a progestogen is important to protect bone mass. Androgen replacement in adu lt men with HH may take the farm. of either an intramuscular or transdermal preparation. The fertility potential of patients with HH is generally exce llent. Ovulation may be induced in more than 90% of HH women with either go nadotropin therapy or with intravenous pulsatile GnRH. GnRH therapy has the advantage of not causing higher order multiple births. In GnRH-deficient m en, spermatogenesis can be stimulated using the combination of hCG and FSH or with pulsatile subcutaneous GnRH therapy. Although both are very effecti ve therapeutic modalities, testicular growth is greater and the time taken to achieve spermatogenesis is shorter in patients treated with GnRH.