The gene that encodes GnRH produces a 92 amino acid precursor protein, which contains the GnRH decapeptide and a 56 amino acid peptide known as GnRH-associated peptide (GAP). The GAP is a potent inhibitor of prolactin secretion and a stimulator of gonadotropin release.
GnRH is unique among releasing hormones in that it simultaneously regulates the secretion of two hormones—FSH and LH. It also is unique among the body’s hormones because it must be secreted in a pulsatile fashion to be effective, and the pulsatile release of GnRH inﬂuences the release of the two gonadotropins (11–13). Using animals that had undergone electrical destruction of the arcuate nucleus and had no detectable levels of gonadotropins, a series of experiments were performed with varying dosages and intervals of GnRH infusion (13,14). Continual infusions did not result in gonadotropin secretion, whereas a pulsatile pattern led to physiologic secretion patterns and follicular growth. Continual exposure of the pituitary gonadotroph to GnRH results in a phenomenon called down-regulation, through which the number of gonadotroph cell surface GnRH receptors is decreased (15). Similarly, intermittent exposure to GnRH will “up-regulate” or “autoprime” the gonadotroph to increase its number of GnRH receptors (16). This allows the cell to have a greater response to subsequent GnRH exposure. Similar to the intrinsic electrical pacemaker cells of the heart, this action most likely represents an intrinsic property of the GnRH-secreting neuron, although it is subject to modulation by various neuronal and hormonal inputs to the hypothalamus.
The continual pulsatile secretion of GnRH is necessary because GnRH has an extremely short half-life (only 2–4 minutes) as a result of rapid proteolytic cleavage. The pulsatile secretion of GnRH varies in both frequency and amplitude throughout the menstrual cycle and is tightly regulated (17,18) (Fig. 7.5). The follicular phase is characterized by frequent, small-amplitude pulses of GnRH secretion. In the late follicular phase, there is an increase in both frequency and amplitude of pulses. During the luteal phase, however, there is a progressive lengthening of the interval between pulses. The amplitude in the luteal phase is higher than that in the follicular phase, but it declines progressively over the 2 weeks. This variation in pulse frequency allows for variation in both LH and FSH throughout the menstrual cycle. For example, decreasing the pulse frequency of GnRH decreases LH secretion but increases FSH, an important aspect of enhancing FSH availability in the late luteal phase. The pulse frequency is not the sole determinant of pituitary response; additional hormonal inﬂuences, such as those exerted by ovarian peptides and sex steroids, can modulate the GnRH effect.
Although GnRH is primarily involved in endocrine regulation of gonadotropin secretion from the pituitary, it is apparent that this molecule has autocrine and paracrine functions throughout the body. The decapeptide is found in both neural and nonneural tissues; receptors are present in many extrapituitary structures, including the ovary and placenta. Data suggest that GnRH may be involved in regulating human chorionic gonadotropin (hCG) secretion and implantation, as well as in decreasing cell proliferation and mediating apoptosis in tumor cells (19). The role of GnRH in the extrapituitary sites remains to be fully elucidated.
Figure 7.4 Gonadotropin-releasing hormone is a decapeptide.
Figure 7.5 The pulsatile secretion of gonadotropin-releasing hormone in the follicular and luteal phases of the cycle.