MATURATION OF THE REGULATION OF GROWTH-HORMONE SECRETION IN YOUNG MALES WITH HYPOGONADOTROPIC HYPOGONADISM PHARMACOLOGICALLY EXPOSED TO PROGRESSIVE INCREMENTS IN SERUM TESTOSTERONE

To study the onset of the action of gonadal sex steroids on the GH axi s in spontaneous puberty, which is prolonged and sparingly predictable , we present a clinical investigative paradigm in which six previously untreated boys with isolated hypogonadotropic hypogonadism were expos ed to progressively higher testosterone levels designed to mimic the a ndrogen environment recognized during the early stages of puberty. We administered three incremental doses of testosterone (25-, 50-, and 10 0-mg im injections), each over a period of 4 weeks. Studies of overnig ht pulsatile GH secretion and GH responses to GHRH alone or combined w ith L-arginine (a functional somatostatin antagonist) were performed b efore testosterone administration and after each dose of testosterone. Serum testosterone, but not estrogen, levels increased progressively in all subjects during therapy. Deconvolution analysis of GH release p rofiles disclosed that GH secretory burst mass was stimulated signific antly even by 25 mg testosterone. This parameter was not altered furth er by higher doses of testosterone. Spontaneous GH secretory burst num ber and amplitude increased significantly only after the 50- and 10O-m g testosterone treatments, after which the serum GH response to GHRH a nd arginine also rose significantly. In contrast, the GH response to G HRH alone was not significantly affected by any dose of testosterone. Serum testosterone levels correlated significantly with the primary pa rameters of nocturnal GH secretion. In summary, our experimental model suggests that in males even very small increases in circulating testo sterone occurring during the earliest stages of puberty are able to am plify pulsatile GH secretion. Our concomitant secretagogue data furthe r suggest that testosterone exerts its action at different sites in th e hypothalamo-somatotropic axis, i.e. directly at the pituitary level, and also at hypothalamic loci, possibly increasing both GHRH and soma tostatin release.