Molecular Actions

A. Production of Steroid Hormones

1. Steroid Biosynthesis—Actions ofLH

The molecular actions of LH to stimulate steroidogenesis and the production of testosterone by the Ley-dig cell are analogous to those discussed in Chapter 10 for the action of ACTH (see Figure 10-9). The mechanism involves the production of cAMP as a consequence of the binding of LH to the Ley dig cell plasma membrane. The cAMP then activates protein kinases, which phosphorylate as yet unidentified proteins, causing increased protein synthesis and ultimately in creased rates of hydrolysis of cholesterol esters into cholesterol. Cholesterol is then subjected to side chain cleavage in the mitochondria to yield pregnenolone, which is the rate-limiting step in androgen biosynthesis (see Figure 2-20). The subsequent steps in the generation of androgens are reviewed in Figure 2-22.

B. Cellular Mechanisms of Action(s) of Androgens

1. Androgen Receptor

The biological effects mediated by the androgenic steroids in the male reproductive system, as well as in those tissues associated with the secondary sex characteristics (see Table 12-3), are all believed to occur as a consequence of the association of the appropriate androgen with a cytoplasmic receptor in a given target tissue. Table 12-6 tabulates the tissue distribution of androgen receptors-binding proteins. As discussed earlier in some tissues dihydrotestosterone has been

TABLE 12-6 Tissue Distribution of Androgen Receptor"

Category of response

Androgenic effects

Male reproductive tract

Secondary sex characteristics

Brain

Anabolic effects Other responses

Tissue

Testes, prostate, seminal vesicle, epididymus Skin, hair follicle, cockerel comb, and wattles Hypothalamus, pituitary preoptic area, cortex Levator ani muscle, thigh muscle Sebaceous and preputial gland, androgen-sensitive tumor, kidney, uterus, liver

" Most of the entries were derived from experimental studies in either the rodent or adult chicken, where either the androgen receptor mRNA or protein was quantitated. Information for this table was abstracted from Quigley, C. A., DeBellis, A., Marschke, K. B., El-Awady, M. K., Wilson, E. M., and French, F. S. (1995). Androgen receptor defects: Historical clinical and molecular perspectives. En-docr. Rev. 16, 271-321.

shown to be the initiating signal, while in other tissues it is believed to be testosterone.

The human androgen receptor (AR) gene and cDNA have been cloned and evaluated (see Figure 12-12). The AR gene codes for a protein of 918 amino acids with a molecular mass of 110-114 kDa. Surprisingly, the AR gene is located on the X chromosome.

The AR has been shown to function, as do all steroid receptors, as a transcriptional regulatory protein that is essential for male sexual differentiation and development. As shown in Figure 12-12, the AR has many functional domains that participate in its activation of gene transcription. The key region is the DNA-binding domain, which interacts with the hormone response elements (HRE) of the promoters of regulated genes. The consensus sequence of the HRE for the AR is similar to the HRE for the glucocorticoid and progesterone receptors (see Table 1-10). For these three receptors, the HRE is AGAACAnnnTGTTCT. Although the AR has a partial palindrome-like HRE, which is compatible with the formation of a functional dimer as has been shown for the retinoid X, la,25(OH)2D3 and thyroid receptors, no evidence of a dimer of the AR has been reported.

The ligand-binding domain of the androgen receptor, which represents 30% of the protein, has a high specificity for its ligand (see Table 12-7). Both testosterone and dihydrotestosterone display the highest affinity for the AR, which is consistent with their designation as "active" androgens.

The AR receptor is localized in the cytoplasmic-nuclear portion of the target cell and, when occupied with ligand (usually testosterone or dihydrotestoster-

X chromosome qli-i2

Gene

cDNA Exons

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