ABSTRACT
GnRH is produced and released from a group of loosely connected neurons located in the medial basal hypothalamus, primarily within the arcuate nucleus, and in the preoptic area of the ventral hypothalamus. It is synthesized in the cell body, transported along the axons to the synapse, and released in a pulsatile fashion into the complex capillary net of the portal system of the pituitary gland (4). GnRH binds selectively to highly specifi c receptors of the anterior pituitary gonadotropic cells and activates intracellular signaling pathways via the coupled G proteins (Gαs), leading to the generation of several second messengers, among which are diacylglycerol and inositol-4,5-triphosphate. The former leads to activation of protein kinase C and the latter to the production of cyclic AMP and release of calcium ions from intracellular pools (5-7). Both events result in secretion and synthesis of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). A pulsatile mode of GnRH release the hypothalamus to the pituitary is required to ensure gonadotropin secretion (8-10). In humans the pulsatile release frequencies range from the shortest interpulse frequency of about 71 minutes in the late follicular phase to an interval of 216 minutes in the late luteal phase (11-13). High frequent (>3 pulses/hour) and continuous exposure of the pituitary to GnRH failed to produce normal LH and FSH
release patterns (14-16) owing to pituitary desensitization. This mechanism is still not clear except that postreceptor signaling is involved, true receptor loss (downregulation) having only an initial role (17). The pulsatile release by the GnRH neurons is hypothesized to be based on an ultrashort loop feedback by GnRH itself; this autocrine process could serve as a timing mechanism to control the frequency of pulsatile neurosecretion. Several mechanisms, based on calcium and cyclic AMP signaling, have been proposed to account for the pulse secretion. Another role of intracellular signaling in pulsatile generation has been suggested by the marked inhibition of Gi protein activation by LH, human chorionic gonadotropin (hCG), muscarine, estradiol (E2), and GnRH levels (7,18,19).
