Male Reproduction 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.
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
