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Male Reproduction: I The Testis


Male Reproduction: I The Testis
Clinical background
Normal fertility in the male is produced by a complex interac- tion between genetic, autocrine, paracrine and endocrine function. The endocrine control of reproductive function in the male depends upon an intact hypothalamo–pituitary–testicular axis. The testis has a dual role – the production of spermatozoa and the synthesis and secretion of testosterone needed for the development and maintenance of secondary sexual characteristics and essential for maintaining spermatogenesis. These functions in turn depend upon the pituitary gonadotrophin hormones: luteinizing hormone (LH; required to stimulate testicular Leydig cells to produce testosterone); and follicle stimulating hormone (FSH; required for the development of the immature testis and a possible role in adult spermatogenesis). Gonadotrophin production occurs in response to stimulation by hypothalamic GnRH. Testosterone exerts a negative feedback on the secretion of LH and FSH and the hormone inhibin-β, also synthesized by the testis, has a specific regulatory role for FSH. Thus in primary seminiferous tubular failure, low testosterone concentrations are associated with elevated gonadotrophins whereas in the presence of hypothalamic pituitary disease the gonadotrophin concentrations are low (secondary testicular failure).

Spermatogenesis is dependent upon testosterone availability.
In primary seminiferous tubular failure androgen deficiency has a number of causes including: genetic defects in the Y chromosome and gonadotrophin receptor genes, previous testicular inflammation such as mumps orchitis and chemotherapy or radiotherapy for malignant disease. Patients exhibit signs of androgen deficiency and the azoospermia is associated with elevated gonadotrophin levels (hypergonadotrophic hypogonadism). Treatment requires androgen replacement therapy with assessment and management in a specialist fertility treatment centre.

Male Reproduction: I The Testis, Control of testis function, Testosterone biosynthesis, Testosterone mechanism of action,

The testis
The testis is the male gonad, and its primary functions are the production of spermatozoa and testosterone. The spermatozoa are produced in the seminiferous tubules and testosterone is synthesized in the Leydig cell. In the human male, the two testes are in the scrotum, each about 5 cm in length and about 2–3 cm in diameter. The testis is encapsulated within a connective tissue sheath called the tunica albuginea, and consists chiefly of a packed mass of convoluted seminiferous tubules. In each testis, these converge into the rete testis, which opens to feed ductules to the epididymis. The epididymis has a head and a tail, the latter feeding into the vas deferens.
The seminiferous tubules consist of an outer sheath of connective and smooth muscle, surrounding an inner lining containing the Sertoli cells. Embedded within and between the Sertoli cells are the germ cells which produce the spermatozoa. These are released into the lumen of the tubule and are stored in the tail of the epididymis. The Leydig cells, also called the intestitial cells, lie between the seminiferous tubules and secrete testosterone.
Control of testis function (Fig. 31a). The hypothalamus sends episodic pulses (approximately once every 90 minutes) of gonadotrophin releasing hormone (GnRH) to the anterior pituitary gonadotroph cells, which secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (Chapter 5). LH targets the Leydig cell, where it stimulates testosterone production through the cAMP second messenger system. FSH targets the Sertoli cell, where, together with testosterone, it stimulates cAMP and subsequent spermatogenesis. There is evidence that FSH, perhaps together with prolactin, increases the number of LH receptors on Leydig cells. Another hormone, inhibin, is produced by the testis, probably by the Sertoli cell. Inhibin, a polypeptide, inhibits FSH release from the pituitary gland by a negative feedback effect.
Testosterone biosynthesis in the Leydig cell is from cholesterol, which is converted to pregnenolone (Fig. 31b). In humans, most of the pregnenolone is 17-hydroxylated and then undergoes side-chain cleavage to yield the 17-ketosteroids, which are converted to testosterone. Once in the blood, appro- ximately 95% of the testosterone is bound to plasma proteins, mainly to sex hormone-binding globulin (SHBG) and to albumin. Testosterone is metabolized to inactive metabolites chiefly in the liver. These are androsterone and etiocholanolone (Fig. 31c), which are excreted as soluble glucuronides and sulphates.
Testosterone mechanism of action. Testosterone acts not only as a hormone in its own right, but also as a prohormone. In the target cell, testosterone may be reduced to its 5-α-reduced metabolite 5-α-dihydrotestosterone (DHT; Fig. 31d), and also aromatized to estradiol. In a highly androgen-dependent tissue such as the prostate, testosterone diffuses into the cell, where it is converted to 5-α-dihydrotestosterone. This is the active androgen in the prostate gland. DHT binds to an intranuclear androgen receptor which stimulates transcription. The androgen receptor is also able to bind testosterone, and, to a lesser extent, progesterone. In this regard, it is worth mentioning that the androgen receptor exhibits a high structural homology with the receptor for progesterone, although they are distinct receptor types within the larger subfamily of steroid receptors (see Chapter 4). The androgen receptor possesses a hormone-binding domain and a DNA-binding region, consisting of two zinc fingers (see Chapter 4).
Antiandrogens have been synthesized which compete with DHT for its receptor site. These antiandrogens are based on the structure of progesterone, and examples include cyproterone, cyproterone acetate (CA) and flutamide. In human males, CA causes atrophy of the prostate and seminal vesicles, and a loss of libido. CA will inhibit the progress of acne in teenagers. In women, CA has been used to treat virilization and hirsutism in patients with polycystic ovary syndrome (Chapter 29). The 5

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