CONTOUR OF THE GNRH PULSE INDEPENDENTLY MODULATES GONADOTROPIN-SECRETION IN THE HUMAN MALE

GnRH pulse frequency, amplitude, and interpulse interval have all been demonstrated to regulate gonadotropin secretion individually. We test ed the hypothesis that the contour of the GnRH pulse also modulates go nadotropin output in 10 men with isolated GnRH deficiency in whom a fi xed GnRH dose was administered at a constant physiologic frequency by either instantaneous bolus or by 1-, 5-, or 30-min infusions. LH, FSH and free alpha subunit (FAS) responses were also compared to spontaneo us gonadotropin secretion in normal adult men. While the LH and FAS pu lses following the instantaneous bolus and 1-min infusion of GnRH were indistinguishable, further increases in the duration of gonadotrope s timulation by GnRH were associated with progressive decreases in all p arameters of gonadotropin secretion (mean levels, amplitude, peak leve ls, AUG). FSH secretion was also decreased following variations in the contour of the GnRH pulse, although overall changes were less dramati c than for LH and FAS. The LH pulses following the bolus GnRH stimulat ion were indistinguishable from spontaneous LH pulses occurring in nor mal men whereas those stimulated by the 1-, 5-, and 30-min infusions o f GnRH became progressively blunted with the lowest levels of secretio n occurring after the longest infusion. In sharp contrast, FAS pulse p arameters in the GnRH-deficient subjects greatly exceeded those of nor mal men regardless of the contour of the GnRH stimulus, whereas mean F SH levels were all modestly (although significantly) higher than those of normal adult men. These results demonstrate that the pituitary is sensitive to subtle changes in the contour of the GnRH stimulus, with a more prolonged duration of GnRH stimulation resulting in a diminishe d pituitary response. Alterations of the contour of endogenous GnRH se cretion may represent an additional mechanism for altering gonadotrope function and provide additional evidence for the differential regulat ion of LH, FAS, and FSH by GnRH. However, the previously reported elev ated levels of FAS secretion in GnRH-deficient men undergoing long-ter m GnRH replacement are not explained by abnormalities of GnRH contour.