T

a T, testosterone; DHT, dihydrotestosterone; E, estradiol. The proposed mediator assignments were made on the basis of the ligand selectivity of the receptor-binding protein present in the tissue in question.

a T, testosterone; DHT, dihydrotestosterone; E, estradiol. The proposed mediator assignments were made on the basis of the ligand selectivity of the receptor-binding protein present in the tissue in question.

The effects of androgens on the brain and central nervous system are complex and believed to occur as a consequence of the metabolism of testosterone into both DHT as well as estradiol. The 5a-reductase is present in the hypothalamus, midbrain, amygdala, hippocampus, cerebellum, and cerebral cortex. As yet the specific function of the localized DHT is not known; conceivably it may play a role in the development of the brain and the initiation of puberty. In addition, T, but not DHT, can be converted into estradiol in specific neurons by aromatization.

2. Estrogens

As documented in Table 12-2, there are finite levels of estradiol and estrone present in the male. Approximately 10-20% of these are generated by the testes; the remainder is produced in a variety of nonendocrine tissues including brain, liver, fat, and skin, all of which have low levels of the cytochrome P450 aromatase necessary to transform androgens into estrogens (see Figure 2-23). With the exception of the effects of testosterone-derived estradiol in the male brain, the biological role of estrogens in the male is not well delineated.

B. Steroid Hormone-Binding Globulin

Following their secretion from the tissue of origin, all steroid hormones are bound to one or more plasma proteins. For the sex steroids there is one plasma (i-globulin protein that serves to transport both selected androgens as well as estrogens. This protein, termed steroid hormone-binding globulin (SHBG), has been isolated and purified and is a dimeric glycosylated protein with a molecular mass of 84 kDa (see Chapter 2, Table 2-7). SHBG has a preference for steroids with a 170-hydroxyl [Kd « (1-5) X 10 10 M]; accordingly, it binds T, DHT, and estradiol, but not progesterone or Cortisol, with high affinity. SHBG is synthesized by the liver, and its plasma levels, which are 2-fold greater in normal women than in men, are increased in pregnancy and hyperthyroidism.

The functions of SHBG are not clear. Since its ligands are reasonably water soluble, it cannot function simply as a means of steroid solubilization. SHBG also is not believed to participate directly in the mode of action of either androgens or estrogens. It has been suggested that an important function of SHBG is to provide a "reservoir" of bound hormone that could effectively dampen oscillations in the free concentrations.

C. Peptide Hormones

1. Gonadotropins

The chemistry of luteinizing hormone (LH), which was formerly designated in the male as interstitial cell-stimulating hormone (ICSH), and follicle-stimulating hormone (FSH) is discussed in detail in Chapter 5. Both FSH and LH are secreted by the adenohypophy-sis; their release is governed in a complex fashion by gonadotropin-releasing hormone (GnRH), the blood level of steroid hormones, and possibly other as yet uncharacterized factors.

a. Luteinizing Hormone

The production and secretion of testosterone by the Leydig cells is under the control of LH in the adult male and by chorionic gonadotropin (hCG) in the developing male fetus. The secretion of LH is reciprocally related to the blood levels of testosterone and estradiol.

The actions of LH on the Leydig cells to stimulate testosterone production are produced as a consequence of its interaction with a membrane receptor that stimulates cAMP production; this in turn activates a cholesterol side chain cleavage pathway. A similar mechanism for LH is operative in the female corpus luteum and in both the male and female in the adrenal cortex, where ACTH stimulates the production of the glucocorticoids (see Figure 2-20) (see later discussion).

b. Follicle-Stimulating Hormone

FSH in the male, in conjunction with testosterone, acts on the Sertoli cells of the seminiferous tubule at the time of puberty to initiate sperm production. In the rat once the germinal epithelium differentiative process is established, testosterone alone can maintain viable sperm production; it is not yet certain whether this is also true in the primate. FSH interacts on the Sertoli cell with a membrane receptor, which results in a concomitant increase in cAMP. This in turn stimulates additional metabolic processes related to spermatogenesis. The biological actions of FSH in the male are summarized in Table 12-4.

c. GnRH

The secretion by the pituitary adenohypophysis of the gonadotropins FSH and LH is governed by the central nervous system hypothalamus-mediated reTABLE 12-4 Biological Actions of Follicle-Stimulating Hormone (FSH) in the Male

Cell Action

Mature Sertoli cell Initiate spermatogenesis

Initiate synthesis of inhibin Stimulate production of new proteins, including androgen-binding protein (ABP), GnrH-like peptide, Mullerian inhibiting factor (MIF), Plasminogen activator, transferrin

Immature Sertoli cell Stimulate mitotic division

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