Differentiation of male hypogonadotropic hypogonadism and constitutional delay of puberty by pulsatile administration of gonadotropin-releasing hormone.

It is not possible to differentiate reliably between male idiopathic hypothalamic hypogonadism (HH) and severe constitutional delay of puberty (CD) on the basis of a standard GnRH bolus test (GBT) or other known endocrine or clinical parameters. Therefore, we studied the response of 17 hypogonadal men, 8 with a diagnosis of HH (age, 15.5-41; bone age, 12.5-19 yr; testes, 1-4 ml) and 9 with CD (age, 14.5-20; bone age, 11-15 yr, testes, 2-10 ml) to pulsatile GnRH stimulation. Basal and peak LH and FSH levels after a single dose of GnRH greatly overlapped between the two groups. In each patient, a spontaneous nocturnal plasma profile of LH and FSH, sampled every 20 min, was followed by a pulsatile GnRH stimulation (5 micrograms iv every 90 min) via a portable minipump for 36 h. Before and after this pulsatile GnRH stimulation, a GBT (60 micrograms/m2 iv) was performed and plasma LH, FSH, testosterone, androstenedione, and dehydroepiandrosterone sulfate were measured. Pulse analysis revealed 0-5 spontaneous nocturnal LH peaks in the CD patients but only one in all of the HH patients. During the 36 h of pulsatile GnRH, mean LH and FSH levels were significantly higher (P less than 0.0001) than during the spontaneous nocturnal profile in all patients (except 1 from each group for LH). The GBT after pulsatile stimulation caused significantly higher (P less than 0.001) LH increments in CD than in HH patients, with no overlap between the two groups (range, 4.1-15.6 in CD vs. 0.8-2.4 mIU/ml in HH). Plasma testosterone rose significantly (P less than 0.01) during pulsatile GnRH from 67 to 155 ng/dl (median) in the CD men, but did not change in the HH group (21 to 22.5 ng/dl). Plasma androstenedione and dehydroepiandrosterone sulfate did not rise in either group. We conclude that, in contrast to other parameters investigated so far, the LH increment in the second GBT after 36 h of pulsatile GnRH allows clear-cut differentiation between CD and HH. These results indicate significantly lower pituitary LH reserve in patients with permanent HH after short term priming of the pituitary by pulsatile GnRH administration.