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Figure 42-2)

A. Hypothalamus
As the integrative center of the HPG axis, the hypothalamus receives neuronal input from many brain centers, including the amygdala, thalamus, pons, retina, and cortex, and is the pulse generator for the cyclical secretion of pituitary and gonadal hormones. It is anatomically linked to the pituitary gland by both a portal vascular system and neuronal pathways. By avoiding the systemic circulation, the portal vascular system provides a direct mechanism for the delivery of hypothalamic hormones to the anterior pituitary. Of the several hypothalamic hormones that act on the pituitary gland, the most important one for reproduction is gonadotropin-releasing or LH-releasing hormone (GnRH or LHRH), a 10-amino acid peptide secreted from the neuronal cell bodies in the preoptic and arcuate nuclei. At present, the only known function of GnRH is to stimulate the secretion of LH and FSH from the anterior pituitary. Once secreted into the pituitary portal circulation, GnRH has a half-life of approximately 5-7 min, almost entirely removed on the first pass through the pituitary either by receptor internalization or enzymatic degradation.

GnRH secretion by the hypothalamus results from integrated input from a variety of influences, including the effects of stress, exercise, and diet from higher brain centers, gonadotropins secreted from the pituitary, and circulating gonadal hormones. Known substances that regulate GnRH secretion are listed in

Table 42-1.

GnRH secretion is pulsatile in nature. This secretory pattern governs the concomitant cyclic release of the gonadotropins LH and FSH (to a lesser extent) from the pituitary. The pulse frequency appears to vary from once hourly to as seldom as once or twice in 24 h. The importance of the pulsatile GnRH secretory pattern in normal reproductive function is aptly demonstrated by the ability of the exogenously given GnRH agonists Lupron or Zoladex (leuprolide acetate) to halt testosterone production within the testicle by changing the pituitary exposure to GnRH from a cyclic to a constant pattern.

B. Anterior Pituitary
The anterior pituitary gland, located within the bony sella turcica of the cranium, is the site of action of GnRH. GnRH stimulates the production and release of FSH and LH by a calcium flux-dependent mechanism. These peptide hormones were named after their elucidation in the female, but it is recognized that they are equally important in the male. The sensitivity of the pituitary gonadotrophs for GnRH varies with patient age and hormonal status.

LH and FSH are the primary pituitary hormones that regulate testis function. They are both glycoproteins composed of 2 polypeptide chain subunits, termed α and β, each coded by a separate gene. The α subunit of each hormone is identical and is similar to that of all other pituitary hormones; biologic and immunologic activity are conferred by the unique β subunit. Both subunits are required for endocrine activity. Sugars linked to these peptide subunits, consisting of oligosaccharides with sialic acid residues, differ in content between FSH and LH and may account for differences in signal transduction and plasma clearance of these hormones.

Secretory pulses of LH vary in frequency from 8 to 16 pulses in 24 h and vary in amplitude by 1- to 3-fold. These pulse patterns generally reflect GnRH release. Both androgens and estrogens regulate LH secretion through negative feedback. On average, FSH pulses occur approximately every 1.5 h and vary in amplitude by 25%. The FSH response to GnRH is more difficult to measure than that of LH because of a smaller amplitude response and a longer serum half-life. The recently discovered gonadal proteins inhibin and activin may exert significant effects on FSH secretion and are thought to account for the relative secretory independence of FSH from GnRH secretion. They will be discussed in the Testis section.

The only known effects of FSH and LH are in the gonads. They activate adenylate cyclase, which leads to increases in intracellular cAMP. In the testis, LH stimulates steroidogenesis within Leydig cells by inducing the mitochondrial conversion of cholesterol to pregnenolone and testosterone. FSH binds to Sertoli cells and spermatogonial membranes within the testis and is the major stimulator of seminiferous tubule growth during development. FSH is essential for the initiation of spermatogenesis at puberty. In the adult, the major physiologic role of FSH is to stimulate quantitatively normal levels of spermatogenesis.

A third anterior pituitary hormone, prolactin, can also have effects on the HPG axis and fertility. Prolactin is a large, globular protein of 199 amino acids (23 kDa) that is known to affect milk synthesis during pregnancy and lactation in women. The normal role of prolactin in men is less clear, but it may increase the concentration of LH receptors on the Leydig cell and help sustain normal, high intratesticular testosterone levels. It may also potentiate the effects of androgens on the growth and secretions of the male accessory sex glands. Normal prolactin levels may be important in the maintenance of libido. Although low prolactin levels are not necessarily pathologic, evidence suggests that hyperprolactinemia abolishes gonadotropin pulsatility by interfering with episodic GnRH release.

C. The Testis
Normal male virility and fertility requires the collaboration of both the exocrine and endocrine testis. Both units are under the direct control of the HPG axis. The interstitial compartment, composed mainly of Leydig cells, is responsible for steroidogenesis. The seminiferous tubules have an exocrine function with spermatozoa as the product.

1. Endocrine testis - Normal testosterone production in men is approximately 5 g/d, and secretion occurs in a damped, irregular, pulsatile manner. In normal men, approximately 2% of testosterone is “free” or unbound and considered the biologically active fraction. The remainder is almost equally bound to albumin or sex hormone-binding globulin (SHBG) within the blood. SHBG can also bind estradiol in the peripheral blood, but the binding affinity is lower than that of testosterone. Several pathologic conditions can alter SHBG levels within the blood and, as a consequence, change the amount of free or bioactive testosterone available for tissues. Elevated estrogens and thyroid hormone decrease plasma SHBG and therefore increase the free testosterone fraction, whereas androgens, growth hormone, and obesity increase SHBG levels and decrease the active androgen fraction. Testosterone is a profound regulator of its own production through negative feedback on the HPG axis.

Testosterone is metabolized into 2 major active metabolites in the target tissue: (1) the major androgen dihydrotestosterone (DHT) from the action of 5 α-reductase and (2) the estrogen estradiol through the action of aromatases. DHT is a much more potent androgen than is testosterone. In most peripheral tissues, testosterone reduction to DHT is required for androgen action, but in the testis and probably skeletal muscle, conversion to DHT is not essential for hormonal activity.

2. Exocrine testis - The primary site of FSH action is on Sertoli cells within the seminiferous tubules. In response to FSH binding, Sertoli cells are stimulated to make a host of secretory products important for germ cell growth, including androgen-binding protein (an effect augmented by testosterone), transferrin, lactate, ceruloplasmin, clusterin, plasminogen activator, prostaglandins, and several growth factors. Through these FSH-mediated actions, seminiferous tubule growth is stimulated during development and sperm production is initiated during puberty. In adults it is thought that FSH is required for normal spermatogenesis.

3. Inhibin and activin - Inhibin is a 32-kDa protein derived from Sertoli cells that specifically inhibits FSH release from the pituitary. Within the testis, inhibin production is stimulated by FSH and acts by negative feedback at the pituitary or hypothalamus. Recently, activin, a protein hormone with close structural homology to transforming growth factor-β, has also been purified and cloned and appears to exert a stimulatory effect on FSH secretion. Activin consists of a combination of 2 of the same β subunits found in inhibin and is also derived from the testis. Activin receptors are found in a host of extragonadal tissues, suggesting that this hormone may have a variety of growth factor or regulatory roles in the body.