Neuroendocrine mechanisms that regulate testicular function are basically similar to those that regulate ovarian activity. The male hypothalamic-pituitary unit is responsible for the secretion of gonadotropins, which regulate the endocrine and spermatogenic activity of the testis, and this secretion of gonadotropin is subject to regulation with feedback.
The main difference between female and male reproductive endocrinology is that the production of gametes and steroid hormones in men is a continuous process after puberty, and not cyclical, as in women. This is reflected in the absence of a cyclical positive feedback control of gonadotropin release by testicular hormones. The hypothalamus integrates all of these signals and relays a response via the release of the peptide hormone GnRH. The hormone is released in pulses, with peaks every 90–120 minutes, and travels to the anterior pituitary gland, where it stimulates the synthesis and episodic release of gonadotropic hormones to regulate sperm production in the testes.
Interestingly and paradoxically, after the pituitary is initially stimulated to produce these gonadotropins, exposure to constant GnRH (or a GnRH agonist) occupies the receptors so that the signaling pathway is disrupted, and gonadotropin release is inhibited.
The process of spermatogenesis is a “two-cell” process, dependent on crosstalk between the Leydig (equivalent to ovarian theca) and Sertoli (equivalent to granulosa) cells via their respective gonadotropin receptors, LH and FSH. Sertoli cells respond to pituitary secretion and secrete androgen-binding proteins (ABPs). Pituitary LH stimulates the interstitial cells of Leydig to produce testosterone, which combines with ABP in the seminiferous tubules, and testosterone controls LH secretion by negative feedback to the hypothalamus, maintaining the high intratesticular testosterone that is appropriate for normal spermatogenesis. Sertoli cells also produce inhibin, which has a negative feedback effect on FSH secretion of the pituitary gland. It probably also has a minor controlling influence on the secretion of LH.
Although the role of inhibin in men is less clear than in women, molecules similar to inhibin have also been found in testicular extracts, which apparently also regulate the secretion of FSH. In humans, failure of spermatogenesis is correlated with elevated serum FSH levels, perhaps through reduced inhibin secretion by the testis. In the testis, LH acts on Leydig cells, and FSH on Sertoli cells; males are very sensitive to changes in activity of LH and are relatively resistant to changes in FSH activity.
Gonadotropins in the Male
Follicle-stimulating hormone (FSH): acts on the germinal epithelium to initiate spermatogenesis; receptors are found on Sertoli cells.
Sertoli cells secrete inhibin, which regulates FSH secretion.
Luteinizing hormone (LH): stimulates Leydig cells (interstitial) to produce testosterone.
Gonadotropic stimulation of the testes regulates the release of hormones (androgens) that are required for the development of puberty, and then to initiate and maintain male reproductive function and spermatogenesis. Testosterone is the main secretory product of the testes, responsible for male sexual characteristics such as facial hair growth, distribution of body fat/muscle and other “masculine” features.
Testosterone is metabolized in peripheral tissue to potent androgenic dihydrotestosterone or potent estrogen estradiol. These androgens and estrogens act independently, modulating LH secretion. In the testis, the androgen receptor is found on Sertoli cells, Leydig and peritubular myoid cells. Ablating the androgen receptor inhibits spermatogenesis.
Feedback mechanisms are an important part of the reproductive axis. Testosterone inhibits LH secretion, while the inhibin secreted by Sertoli cells in the testes regulates FSH secretion. If negative feedback is reduced, the pituitary responds by increasing its FSH secretion, similar to the situation in women reaching the menopause. Serum FSH levels in the male therefore act as an indicator of testicular germinal epithelial function—i.e., they are broadly correlated with spermatogenesis. Testosterone levels indicate Leydig cell function and reflect the presence of “masculine” characteristics:
Low in boys and castrates (<4 nm/L),
Varies throughout the day in adult males—highest in the morning,
levels decrease in older men.
Serum LH level is difficult to assess, because it is released in pulses. Prolactin also interacts with LH and FSH in a complex manner, via inhibition of GnRH release from the hypothalamus. In males with hyperprolactinemia, inhibition of GnRH decreases LH secretion and testosterone production; elevated prolactin levels may also have a direct effect on the CNS.