Androgen target tissues

Circulating testosterone serves as a precursor for the formation of two types of active metabohtes (see Figure 53-3). Through the actions of 5a-reductase, 6%-8% of testosterone is converted to DHT. Alternatively, testosterone and androstenedione can be converted to estrogens ( 0.3%) through aromatase. DHT is formed in androgen target tissues, such as the skin and prostate, whereas aromatization... 

In androgen target tissues that contain 5Q -reductase, testosterone is converted to DHT, which activates the AR-ARE sequence leading to an androgenic response. DHT undergoes inactivation when it dissociates from... 

Fig. 1.1. General mechanism of action of steroid hormones. Steroid hormones cross through the plasmatic membrane without apparent difficulty favored by gradient. Some, which can be considered prohormones, are metabolized and transformed into more active products. This is the case with testosterone, which becomes dihydrotestosterone (DHT) in the target tissues of androgens, through the 5-alfa-reductase enzyme. The hormone binds to the receptor, a soluble protein of the cellular cytosol that, in the absence of hormone, is found associated with other proteins (hsp90 and others) that maintain the receptor in an inactive state. The hormone-receptor bond causes the other proteins to separate and a homodimer to be formed. The homodimer is the activated form of the receptor since it is capable of recognizing the genes that depend on that steroid hormone as well as of activating its expression, which leads to the synthesis of specific proteins...

Non-sex accessory tissues also are targets for the protein anabolic actions of androgens. These tissues possess lower levels of endogenous hormone, minimal 5a-reductase activity, and lower concentrations of specific androgen receptors. The protein anabolic actions are probably mediated by an interaction with the androgen receptor. 

In many target tissues, testosterone is converted to dihydrotestosterone by 5a-reductase. In these tissues, dihydrotestosterone is the major active androgen. The conversion of testosterone to estradiol by P450 aromatase also occurs in some tissues, including adipose tissue, liver, and the hypothalamus, where it may be of importance in regulating gonadal function. 

Spironolactone, a competitive inhibitor of aldosterone (see Chapter 15), also competes with dihydrotestosterone for the androgen receptors in target tissues. It also reduces 17a-hydroxylase activity, lowering plasma levels of testosterone and androstenedione. It is used in dosages of 50-200 mg/d in the treatment of hirsutism in women and appears to be as effective as finasteride, flutamide, or cyproterone in this condition. 

All classes of steroid hormones bind to specific cytoplasmic receptors in their respective target tissues, and are then translocated to the nucleus. For example, testosterone, a lipid-soluble substance, enters the cell and is enzymatically reduced to dihydrotestosterone by 5-a reductase. Dihydrotestosterone then becomes bound to a specific androgen receptor site located in the cytoplasm. This complex becomes activated and is then translocated to the nucleus, where it binds to the chromatin acceptor site consisting of DNA and nonhistone chromosomal proteins. This interaction results in the transcription of a specific messenger RNA that is then relocated to the cytoplasm and translated on the cytoplasmic ribosomes, resulting in the synthesis of a new protein that sponsors the androgenic functions (Figure 61.6). 

Spironolactone, a competitive inhibitor of aldosterone (see Chapter 15 Diuretic Agents), also competes with dihydrotestosterone for the androgen receptors in target tissues. It also reduces 17a-... 

Steroid hormones achieve their effects on target tissues through intracellular receptor proteins. According to recent views, oestrogen and progestin receptors are localized in the nuclear compartment of the cells, whereas glucocorticoid receptors may reside in both the cytoplasm and the nucleus. Determination of the intracellular localization of androgen receptors awaits the development of (monoclonal) antibodies which will enable immunohistochemical studies. The molecular aspects of the mechanism of action of steroid hormones will be covered in other chapters [1-3] in this volume. The present chapter deals with the characterization, assay and purification of steroid receptors. 

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