Regulation Of Testicular Function

Testicular function, as we have seen, depends on stimulation by two pituitary hormones, FSH and LH. Without them, the testes lose spermatogenic and steroi-dogenic capacities and either atrophy or fail to develop. Secretion of these hormones by the pituitary gland is driven by the central nervous system through its secretion of the gonadotropin-releasing hormone (GnRH), which reaches the pituitary by way of the hypophysial portal blood vessels (see Chapter 38). Separation of the pituitary gland from its vascular linkage to the hypothalamus results in total cessation of gonadotropin secretion and testicular atrophy. The central nervous system and the pituitary gland are kept apprised of testicular activity by signals related to each of the testicular functions: steroidogenesis and gametogenesis. Characteristic of a negative feedback, signals from the testis are inhibitory. Castration results in a prompt increase in secretion of both FSH and LH. The central nervous system also receives and integrates other information from the internal and external environments and modifies GnRH secretion accordingly.

Gonadotropin-Releasing Hormone and the Hypothalamic Pulse Generator

Gonadotropin-releasing hormone is a decapeptide produced by a diffuse network of about 2000 neurons whose perikarya are located primarily in the arcuate nuclei in the medial basal hypothalamus and whose axons terminate in the median eminence in the vicinity of the hypophysial portal capillaries. GnRH-secreting neurons also project to other parts of the brain and may mediate some aspects of sexual behavior. GnRH is released into the hypophysial portal circulation in discrete pulses at regular intervals ranging from about one every hour to one every 3 hours or longer. Each pulse lasts only a few minutes, and the secreted GnRH disappears rapidly with a half-life of about 4 minutes. GnRH secretion is difficult to monitor directly because hypophysial portal blood is inaccessible and because its concentration in peripheral blood is too low to measure even with the most sensitive assays. The pulsatile nature of GnRH secretion has been inferred from results of frequent measurements of LH concentrations in peripheral blood (Fig. 12). FSH concentrations tend to fluctuate much less, largely because FSH has a longer half-life than LH, 2 to 3 hours compared to 20 to 30 minutes.

Pulsatile secretion requires synchronous firing of many neurons, which therefore must be in communication with each other and with a common pulse generator. Because pulsatile secretion of GnRH continues even after

hours

FIGURE 12 Luteinizing hormone (LH) secretory pattern observed in a normal 36-year-old man; ?, statistically significant discrete pulse. (From Crowley WF, Jr, In: Krieger DT, Bardin CW, Eds., Current topics in endocrinology and metabolism, New York: Marcel Decker, 1985, p. 157. With permission.)

hours

FIGURE 12 Luteinizing hormone (LH) secretory pattern observed in a normal 36-year-old man; ?, statistically significant discrete pulse. (From Crowley WF, Jr, In: Krieger DT, Bardin CW, Eds., Current topics in endocrinology and metabolism, New York: Marcel Decker, 1985, p. 157. With permission.)

experimental disconnection of the medial basal hypothalamus from the rest of the central nervous system, the pulse generator must be located within this small portion of the hypothalamus. Pulsatile secretion of GnRH by neurons maintained in tissue culture indicate that episodic secretion is an intrinsic property of GnRH neurons. There is good correspondence between electrical activity in the arcuate nuclei and LH concentrations in blood, as determined in rhesus monkeys fitted with permanently implanted electrodes. The frequency and amplitude of secretory pulses and corresponding electrical activity can be modified experimentally (Fig. 13) and are regulated physiologically by gonadal steroids and probably by other information processed within the central nervous system.

The significance of the pulsatile nature of GnRH secretion became evident in studies of reproductive function in rhesus monkeys whose arcuate nuclei had been destroyed and whose secretion of LH and FSH therefore came to a halt. When GnRH was given as a constant infusion, gonadotropin secretion was restored only for a short while. FSH and LH secretion soon decreased and stopped even though the infusion of GnRH continued. Only when GnRH was administered intermittently for a few minutes of each hour was it possible to sustain normal gonadotropin secretion in these monkeys. Similar results have been obtained in human patients and applied therapeutically.

The cellular mechanisms that account for the complex effects of GnRH on gonadotropes are not fully understood. The GnRH receptor is a G-protein coupled hepti-helical receptor that activates phospholipase C through Gaq (Chapter 2). The resulting formation of inositol trisphosphate (IP3) and diacylglycerol (DAG) results in

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