Randall W. Whitcomb

Neuroendocrine control of human reproduction in the male

The traditional difficulty in studying the neuroendocrine control of reproduction in the human male has been the inability to tease out the hypothalamic from the pituitary component of this neuroendocrine system. The use of multiple models, each with its own strength and weakness, represents an overlapping approach that has permitted further insights to be gained into the hypothalamic control of the neuroendocrine regulation of gonadotropin secretion in the human. Such an insight is an important prerequisite to the understanding of the pathophysiology of various disease states, the unraveling of a control of FSH secretion by GnRH vs other modulators, and the subsequent design of rational therapies for male reproductive disorders.

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 tested the hypothesis that the contour of the GnRH pulse also modulates gonadotropin output in 10 men with isolated GnRH deficiency in whom a fixed 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 spontaneous gonadotropin secretion in normal adult men. While the LH and FAS pulses following the instantaneous bolus and 1-min infusion of GnRH were indistinguishable, further increases in the duration of gonadotrope stimulation by GnRH were associated with progressive decreases in all parameters of gonadotropin secretion (mean levels, amplitude, peak levels, AUC). FSH secretion was also decreased following variations in the contour of the GnRH pulse, although overall changes were less dramatic than for LH and FAS. The LH pulses following the bolus GnRH stimulation were indistinguishable from spontaneous LH pulses occurring in normal men whereas those stimulated by the 1-, 5-, and 30-min infusions of GnRH became progressively blunted with the lowest levels of secretion occurring after the longest infusion. In sharp contrast, FAS pulse parameters in the GnRH-deficient subjects greatly exceeded those of normal men regardless of the contour of the GnRH stimulus, whereas mean FSH 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 diminished pituitary response. Alterations of the contour of endogenous GnRH secretion may represent an additional mechanism for altering gonadotrope function and provide additional evidence for the differential regulation of LH, FAS, and FSH by GnRH. However, the previously reported elevated levels of FAS secretion in GnRH-deficient men undergoing long-term GnRH replacement are not explained by abnormalities of GnRH contour.

Gonadotropin-releasing hormone deficiency in men: Diagnosis and treatment with exogenous gonadotropin-releasing hormone

Idiopathic hypogonadotropic hypogonadism in men is the result of absent or abnormal secretion of gonadotropin-releasing hormone, which prevents pubertal development. Isolated gonadotropin-releasing hormone deficiency is clinically and neuroendocrinologically heterogeneous, largely because of variation in the degree of gonadotropin-releasing hormone deficiency. Treatment with pulsatile gonadotropin-releasing hormone results in normal pubertal changes and virilization. Such treatment has been uniformly successful in normalizing release of gonadotropins and secretion of testosterone. Improvement in secondary sex characteristics and induction of spermatogenesis have been achieved in most patients. Eight of nine patients desiring induction of fertility were able to father a child. Use of pulsatile gonadotropin-releasing hormone presents a powerful model in which to examine regulation of gonadotropin secretion and the role of hypothalamic gonadotropin-releasing hormone in control of the male reproductive axis.

Priapism in Hypogonadal Men Receiving Gonadotropin Releasing Hormone

To our knowledge we report the first 2 cases of priapism occurring in hypogonadal men receiving gonadotropin releasing hormone therapy. Hypogonadal patients receiving hormonal therapy should be informed about the possibility of priapism and the importance of early urological consultation.

Critical Determinants of GnRH-Gonadotrope Interactions in the Human

The study of GnRH physiology in the human has proven to be complex, with both technical and practical obstacles. Specifically, the rapid metabolism of GnRH continues to make its direct measurement in the peripheral circulation limited in utility in defining the neuroendocrine control of reproduction in the human (1, 2). The inaccessibility of the hypophyseal-portal blood supply to direct sampling also means that a series of indirect approaches must be undertaken, using several strategies to piece together a complete story of the hypothalamic control of gonadotropin function. Thus, we have chosen to use complementary approaches involving the tandem study of GnRH-deficient men as well as of normal men with intact hypothalamic pituitary axes (3).