Spontaneous and GnRH-provoked gonadotropin secretion and testosterone response to human chorionic gonadotropin in adolescent boys with thalassaemia major and delayed puberty

To elucidate whether the cause of sexual maturation arrest in thalassaemia is of gonadal or pituitary etiology, 10 males with thalassaemia and delayed puberty and 10 with constitutional delay of growth and pubertal maturation (CSS) were extensively studied. Their spontaneous nocturnal gonadotropin s ecretion and gonadotropin response to intravenous 100 mu g gonadotropin-rel easing hormone (GnRH) were evaluated, Circulating testosterone concentratio n and clinical response were evaluated after 3 days, 4 weeks and 6 months o f intramuscular administration of human chorionic gonadotropin (HCG) (2500 U/m(2)/dose). Thalassaemic boys had significantly lower circulating concent rations of testosterone compared to those with constitutional delay of grow th and sexual maturation (CSS) at the same pubertal stage. Short- and long- term testosterone response to administrations of HCG was markedly decreased in thalassaemic boys. After 6 months of HCG administration 50 per cent (5/ 10) of the boys did not show significant testicular enlargement or genital changes. Despite the low circulating concentrations of testosterone, none o f the patients had high basal or exaggerated gonadotropin response to gonad otropin releasing hormone (GnRH) stimulation. Luteinizing hormone (LH) peak responses to GnRH were significantly lower as compared to controls, Follic le-stimulating hormone (FSH) peak responses to GnRH did not differ among th e two study groups, The mean nocturnal LH and FSH secretion was significant ly decreased in all thalassaemic boys as compared to boys with CSS at the s ame pubertal stage (testicular volume). These data proved that hypogonadotr opic hypogonadism is the main cause of delayed/failed puberty in adolescent s with thalassaemia major. MRI studies revealed complete empty sella (n = 5 ), marked diminution of the pituitary size (n = 5), thinning of the pituita ry stalk (n = 3) with its posterior displacement (n = 2), and evidence of i ron deposition in the pituitary gland and midbrain (n = 8) in thalassaemic patients, denoting a high incidence of structural abnormalities (atrophy) o f the pituitary gland. Moreover, in many of the thalassaemic boys, the defe ctive testosterone response to long-term (6 months) HCG therapy denoted sig nificant testicular atrophy and/or failure secondary to siderosis, It appea rs that testosterone replacement might be superior to HCG therapy in these patients. This therapy should be introduced at the proper time in these hyp ogonadal patients to induce their sexual development and to support their l inear growth spurt and bone mineral accretion.