Reversible hypogonadotrophic hypogonadism in sexually infantile male thalassaemic patients with transfusional iron overload

OBJECTIVE To determine the severity and reversibility of the lesion in the hypothalamic-pituitary (H-P) axis of male transfusion-dependant thalassaemic patients with failed puberty (FP). DESIGN AND SUBJECTS The hypothalamic-pituitary axes of 20 male thalassaemic patients (study group) were compared with two male subjects with idiopathic hypogonadotrophic hypogonadism (IHH) and five prepubertal healthy siblings (control group). GnRH-gonadotrophin insufficiency was characterized by nocturnal 12h ultradian gonadotrophin profiles followed by a 100 mu g GnRH bolus test (GBT) 4-6 times at 6 monthly intervals. Thalassaemic and IHH patients were then subjected to pulsatile subcutaneous GnRH infusions every 120 minutes for 3 months. Ultradian gonadotrophin profiles and GET were repeated after 6 weeks of GnRH infusion and again at 3 months following infusion. MEASUREMENTS FSH and LH were measured by radio-immunoassay, Ferritin was assayed by an immunoradiometric method. RESULTS Patients with IHH who were apulsatile prior to infusion, developed normal gonadotrophin pulses with marked increment in their gonadotrophin responses to the GET after 3 months of GnRH infusion, In contrast, the thalassaemic patients with apulsatile failed puberty (AFP) remained apulsatile (nonresponders) and had no increment in their gonadotrophin responses to the GET after GnRH infusion. All patients with pulsatile failed puberty (PFP) had abnormal gonadotrophin pulses prior to GnRH infusion. Their pulse defects were either totally or partially corrected (responders) following infusion, The serum ferritin levels (9500 +/- 500 mu g/l vs. 5966.67 +/- 1139 mu g/l; P<0.01) and percentage of organ dysfunction (87% vs, 17%; P<0.01) were higher in the nonresponders than the responders. CONCLUSIONS This study shows that thalassaemic patients with severe organ damage and iron overload are likely to be apulsatile with irreversible damage to their hypothalamo-pituitary axis, while those with less severe iron overload are likely to have potentially reversible hypogonadotrophic hypogonadism (HH). Our results also suggest that gonadotrophin pulse parameters, rather than the gonadotrophin response to a GnRH bolus following prolonged pulsatile GnRH infusion, may be more useful in discriminating reversible from irreversible hypogonadotrophic hypogonadism.