The male reproductive system regulates sex differentiation, virilization, and the hormonal changes that accompany puberty, ultimately leading to spermatogenesis and fertility. Under the control of the pituitary hormones—luteinizing hormone (LH) and follicle-stimulating hormone (FSH)—the Leydig cells of the testes produce testosterone and germ cells are nurtured by Sertoli cells to divide, differentiate, and mature into sperm. During embryonic development, testosterone and dihydrotestosterone (DHT) induce the wolffian duct and virilization of the external genitalia. During puberty, testosterone promotes somatic growth and the development of secondary sex characteristics. In adults, testosterone is necessary for spermatogenesis, stimulation of libido, normal sexual function, and maintenance of muscle and bone mass. This chapter focuses on the physiology of the testes and disorders associated with decreased androgen production, which may be caused by gonadotropin deficiency or primary testis dysfunction. A variety of testosterone formulations now allow more physiologic androgen replacement. Infertility occurs in ∼5% of men and is increasingly amenable to treatment by hormone replacement or by using sperm transfer techniques. For further discussion of sexual dysfunction, disorders of the prostate, and testicular cancer, see Chaps. 48, 95, and 96, respectively.
The fetal testis develops from the undifferentiated gonad after expression of a genetic cascade that is initiated by the SRY (sex-related gene on the Y chromosome) (Chap. 349). SRY induces differentiation of Sertoli cells, which surround germ cells and, together with peritubular myoid cells, form testis cords that later develop into seminiferous tubules. Fetal Leydig cells and endothelial cells migrate into the gonad from the adjacent mesonephros but also may arise from interstitial cells that reside between testis cords. Leydig cells produce testosterone, which supports the growth and differentiation of wolffian duct structures that develop into the epididymis, vas deferens, and seminal vesicles. Testosterone is also converted to DHT (see below), which induces formation of the prostate and the external male genitalia, including the penis, urethra, and scrotum. Testicular descent through the inguinal canal is controlled in part by Leydig cell production of insulin-like factor 3 (INSL3), which acts via a receptor termed LGR8 (leucine-rich repeat-containing G protein–coupled receptor 8, also known as GREAT: G protein–coupled receptor affecting testis descent). Sertoli cells produce müllerian inhibiting substance (MIS), which causes regression of the müllerian structures, including the fallopian tube, uterus, and upper segment of the vagina.
Although puberty commonly refers to the maturation of the reproductive axis and the development of secondary sex characteristics, it involves a coordinated response of multiple hormonal systems that include the adrenal gland and the growth hormone (GH) axis (Fig. 346-1). The development of secondary sex characteristics is initiated by adrenarche, which usually occurs between 6 and 8 years of age when the adrenal gland begins to produce greater amounts of androgens from the zona reticularis, the principal site of dehydroepiandrosterone (DHEA) production. The sex maturation process is greatly accelerated by the activation of the hypothalamic-pituitary axis and the production of gonadotropin-releasing hormone (GnRH). The GnRH pulse generator in the hypothalamus is active during fetal life and early infancy but is restrained until the early stages of puberty by a neuroendocrine brake imposed by the inhibitory actions of glutamate, γ-amino butyric acid (GABA), and neuropeptide Y. Although the pathways that initiate reactivation of the GnRH pulse generator at the onset of puberty have been elusive, mounting evidence supports involvement of GPR54, a G protein–coupled receptor that binds an endogenous ligand, kisspeptin. Individuals with mutations of GPR54 fail to enter puberty, and experiments in primates demonstrate that infusion of kisspeptin is sufficient to induce premature puberty. Kisspeptin signaling plays an important role in mediating the feedback action of sex steroids on gonadotropin secretion and in regulating the tempo of sexual maturation at puberty. Leptin, a hormone produced by adipose cells, plays a permissive role in the resurgence of GnRH secretion at the onset of puberty, as leptin-deficient individuals also fail to enter puberty (Chap. 77).
Pubertal events in males. Sexual maturity ratings for genitalia and pubic hair and divided into five stages. (From WA Marshall, JM Tanner: Arch Dis Child 45:13, 1970.)
The early stages of puberty are characterized by nocturnal surges of LH and FSH. Growth of the testes is usually the first sign of puberty, reflecting an increase in seminiferous tubule volume. Increasing levels of testosterone deepen the voice and increase muscle growth. Conversion of testosterone to DHT leads to growth of the external genitalia and pubic hair. DHT also stimulates prostate and facial hair growth and initiates recession of the temporal hairline. The growth spurt occurs at a testicular volume of about 10–12 mL. GH increases early in puberty and is stimulated in part by the rise in gonadal steroids. GH increases the level of insulin-like growth factor I (IGF-I), which enhances linear bone growth. The prolonged pubertal exposure to gonadal steroids (mainly estradiol) ultimately causes epiphyseal closure and limits further bone growth.
Regulation of the Hypothalamic-Pituitary-Testis Axis in Adult Men
Hypothalamic GnRH regulates the production of the pituitary gonadotropins LH and FSH (Fig. 346-2). GnRH is released in discrete pulses approximately every 2 hours, resulting in corresponding pulses of LH and FSH. These dynamic hormone pulses account in part for the wide variations in LH and testosterone even within the same individual. LH acts primarily on the Leydig cell to stimulate testosterone synthesis. The regulatory control of androgen synthesis is mediated by testosterone and estrogen feedback on both the hypothalamus and the pituitary. FSH acts on the Sertoli cell to regulate spermatogenesis and the production of Sertoli products such as inhibin B, which acts to suppress pituitary FSH selectively. Despite these somewhat distinct Leydig and Sertoli cell–regulated pathways, testis function is integrated at several levels: ...