Prader Willi Syndrome

Prader-Willi syndrome is a genetic disorder characterized by short stature, low lean body mass, hypotonia, mental retardation, behavioral abnormalities, dysmorphic features, excessive appetite, and progressive obesity. Most patients also present with reduced GH secretion and hypogonadism. The principal genetic mutation identified is a deletion of the paternally derived segment of chromosome 15 (15q11-15q13). Several other genetic abnormalities have been linked to the syndrome (114,115). The majority of individuals with Prader-Willi syndrome present with delayed or partial pubertal development. There are no detailed studies of the neonatal or childhood period in children with Prader-Willi syndrome. Decreased gonadotropin levels, consistent with hypogonadotropic hypogonadism, have been found in some patients, whereas others have hypergonadotropic hypogonadism secondary to cryptorchidism (116). In those with hypogonadotropic hypogonadism, the localization of the defect is unclear, because some affected individuals respond poorly to GnRH, whereas some individuals have a normal gonadotropin response to GnRH (116-118). Finally, the contribution of morbid obesity to the changes in the hypothalamic-pituitary-gonadal axis has not yet been clarified in patients with Prader-Willi syndrome.

Other Causes of Hypogonadotropic Hypogonadism Structural Defect of the Hypothalamic-Pituitary Area

Structural lesions of the hypothalamus and pituitary can lead to an abnormal pattern of GnRH and/or gonadotropin secretion (see Chapter 8). Most patients with such tumors have multiple pituitary hormone deficiencies, whereas isolated hypogo-nadotropism is rare (119,120). However, patients with mass lesions can present with hypogonadotropic hypogonadism without adrenal or thyroid hormone deficiency, but GH deficiency with or without hyperprolactimemia is almost always present. Indeed, a mass in the pituitary or hypothalamus is more likely to decrease the secretion of gonadotropins than that of adrenocorticotropic hormone (ACTH) or TSH. Cranio-pharyngioma is the most common tumor resulting in hypogonadotropic hypogo-nadism in childhood. It is often associated with growth retardation, diabetes insipidus, and visual field defects. Prolactinoma is the most frequent tumor causing hypogonadotropic hypogonadism in adult men (121,122). Although rare, infiltrative hypothalamus or pituitary disorders, such as hemochromatosis (123), sarcoidosis, lymphocytic hypophysitis (124), and histiocytosis may also lead to hypogonadotropic hypogonadism. Irradiation therapy for CNS tumors or leukemia may lead to a progressive onset of hypothalamic-pituitary failure (125-127). The degree of impairment depends on both the dose and the type of radiation and typically is the consequence of hypothalamic dysfunction, because the hypothalamus is significantly more radiosensi tive than the pituitary gland. Sudden and severe hemorrhage into the pituitary can also result in permanent impairment of pituitary function, including hypogonadism (128).

Functional Hypogonadotropic Hypogonadism

Functional forms of hypogonadotropic hypogonadism are characterized by a transient defect in GnRH secretion. This clinical presentation is well described in female hypogonadotropic subjects with hypothalamic amenorrhea (HA) but has received little study in men. In susceptible individuals, factors such as significant weight loss, exercise, or stress may precipitate HA (129-131). However, in contrast to congenital hypogonadotropic hypogonadism, GnRH secretion in these subjects will resume after correcting the precipitating factor and menstruation will recur. In healthy men, moderate to severe dietary restriction is associated with mild decreased T levels, because GnRH secretion is impaired (132,133). In addition, some (134,135), but not all (136,137), studies have shown that strenuous physical exercise may cause a transient decrease in T levels (see Chapter 16). However, to date, a clinical syndrome of functional GnRH deficiency in men, that is analogous to HA, has not been well characterized.

Drug-Induced GnRH Deficiency

The use of anabolic steroids may result in reversible hypogonadotropic hypogonadism (see Chapter 16) and is manifested by a decrease in T and dihydrotestosterone concentrations and suppressed spermatogenesis (138,139). Suppression of the hypothalamic-pitu-itary-gonadal axis after androgen therapy may last more than 16 wk after discontinuation of the drug (138). Chronic treatment with pharmacologic doses of glucocorticoids may also cause hypogonadism (140). Chronic use of narcotic analgesics may also suppress LH secretion and result in reversible hypogonadotropic hypogonadism (141).

Critical Illness

Any severe chronic (142) or acute illness, such as surgery (143), myocardial infarction (144), or burn injury (145) may result in decreased T levels (146). Acute injury causes an immediate suppression of Leydig cell function (147). Prolonged severe stress may inhibit pulsatile LH secretion, resulting in hypogonadotropic hypogonadism (147) (see Chapter 11).

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