The concept of a neuronal signal generator in the central nervous system that causes the rhythmic release of GnRH into the pituitary portal circulation and the consequent pulsatile secretion of the pituitary gonadotropic hormones was first proposed nearly three decades ago. Since then, this notion has been verified experimentally by the measurement of GnRH pulses coincident with LH pulses in several species. In all mammals studied to date, this "GnRH pulse generator" has been localized to the arcuate region of the mediobasal hypothalamus. It is an intrinsic property of this structure capable of functioning without extrahypothalamic neural or humoral inputs. More recently, its electrophysiological components have also been described. These are rhythmic increases in multiunit electrical activity (MUA "volleys") that are invariably synchronous with the initiation of LH pulses. Analysis of single-unit components of the multiunit signal has revealed that the MUA volleys represent the increase in firing rate of individual units and not the activation of previously quiescent cells.
The physiological significance of pulsatile GnRH secretion was first demonstrated in female rhesus monkeys bearing bilateral lesions in the mediobasal hypothalamus that abolished endogenous GnRH production. In these animals, continuous GnRH infusion failed to sustain gonadotropin secretion. Pulsatile administration of GnRH at the physiological frequency of one pulse/in, however, reestablished the pre-lesion levels of LH and FSH. These findings have all been repeated in several other species including man and have led to the development of various therapeutic applications. More importantly, the pulsatile administration of GnRH at an unvarying frequency of one pulse/in to such lesioned monkeys with intact ovaries sustained entirely normal, 28-day ovulatory menstrual cycles. Similar findings have been reported in women deprived of endogenous GnRH secretion undergoing replacement therapy with exogenous GnRH. These results also indicate that the GnRH pulse generator plays but a permissive role in the regulation of the female reproductive cycle, with peripheral factors (notably the ovaries) being responsible for the timing of the phases of the menstrual cycle ("pelvic clock"). Despite this, pulse generator frequency undergoes dramatic variations throughout the menstrual cycle, mostly under the inhibitory influence of gonadal steroids. In addition, a number of neurotransmitters and neuropeptides modulate pulse generator activity. Some of them mediate the actions of steroid hormones while others mediate the inhibitory effects of environmental factors (e.g. "stress," severe excercise, caloric deprivation). GnRH pulse generator activity is also arrested during pregnancy and lactation.
Intermittency of gonadotropin secretion is well conserved, having been described in most vertebrates. Although recent in vitro evidence suggests that the rhythmic signals may originate from the GnRH cells themselves, the actual hypothalamic Zeitgeber remains to be identified. This and the elucidation of the mechanisms for pacemaking and integration of the component cells represent the greatest challenges for the future.
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