Info

Dehydroepiandrosterone

Dehydroepiandrosterone

FIGURE 12-5 Structure of the important steroid hormones for the male (see also Figure 2-22).

(see Figure 2-35), which are in turn conjugated to either glucuronic acid or sulfate to yield a water-soluble form amenable to urinary excretion.

The two principal androgens present in target cells are testosterone (T) and 5a-dihydrotestosterone (DHT). While both T and DHT are produced by the testes and circulate in the plasma, there is also significant target organ metabolism of T to DHT. Both T and DHT are potent activators of the androgen nuclear receptor. It is not yet clear whether T or DHT is the predominant initiator of gene transcriptors, although both bind very effectively to the androgen nuclear receptor. Thus, the mechanism by which two different steroid hormones bind to the same receptor but achieve different biological functions is not yet known.

a. Testosterone 5a-Reductase

The major site of nontesticular production of DHT is in the prostate, but there is also evidence of its production in other target tissues. The enzyme responsible for the conversion of T into DHT is a A3-ketosteroid-5a-oxidoreductase that requires NADPH as a cofactor.

It is now known from molecular biological studies that there are two genes for both the rat and the human 5o;-reductase. Both genes code for 24.9-kDa proteins that share a 50% amino acid homology, but have somewhat different kinetic properties.

The tissue distribution of the mRNA for the two 5a-reductase proteins is different. The type I enzyme, which has been postulated to be involved in the catabo-

TABLE 12-2 Production Rates, Metabolie Clearance, and Plasma Levels of Sex Steroids in the Human Male

Steroid Plasma concentration (ng/100 ml) Testes secretion rate (yxg/day) Metabolic clearance rate" (liters/day)

Testosterone 300-1100 5000 980

Dihydrotestosterone (DHT) 25-75 500-100" 500

Androstenedione 50-200 2500 2300

Androstane-3a,17/3-diol 130 200 >1200

Estradiol 2-3 10-15c 1700

" Metabolic clearance rate (MCR) is an estimation of the rate at which the steroid is irreversibly removed from the plasma by inactivation (further metabolism). The plasma flow through the liver is —1500 liters/day. Abstracted from Makin, H. T. J. (ed.) (1975). "Biochemistry of Steroid Hormones." William Clowes & Sons, Ltd., London, UK.

b Approximately 300-400 /xg of DHT is estimated to be synthesized outside the testes. c Most blood estradiol in the male is derived from peripheral aromatization of secreted testosterone.

lism (i.e., inactivation) of testosterone, is found in highest concentrations in the liver, kidney, intestine, brain, adrenal, and lung of the rat. In contrast, the type II 5a-reductase, which is believed to be involved in the generation of "active androgen," is found in typical androgen target tissues such as the prostate, seminal vesicles, epididymis, and liver. There is also evidence that the type I 5a-reductase is associated with microsomal membranes of the cell, while the type II enzyme is associated with the cell nucleus.

Because of the importance of the 5a-reductase in determining the response of a tissue to dihydrotestos-terone, there has been a search to identify synthetic inhibitors of this enzyme. As a consequence of these efforts, several drug candidates have been identified; these include the orally active finasteride and 17/3-(N,N-diethylcarbamoyl)-4-aza-5a-androstan-3-one (4-MA). The hope is that these drugs may allow the selective treatment of DHT-dependent clinical disorders, such as benign prostatic hyperplasia, alopecia, hirsutism, and acne.

An extensive series of studies has documented that mutations in the 5a-reductase gene result in the appearance of several clinical disorders, including some cases of male pseudohermaphroditism (see Section V). Not only do these studies provide a molecular description of several clinical diseases, but they also emphasize that dihydrotestosterone may be the "active androgen."

The biological responses of the androgens are summarized in Table 12-3. They may be divided into four categories: (1) a growth-promoting or androgenic effect on the male reproductive tract; (2) a stimulatory or anabolic effect on body weight (skeletal muscle) and nitrogen balance; (3) development of male secondary sex characteristics; and (4) actions in the central nervous system and brain.

While it is clear that both T and DHT are the predominant androgens, it has not been possible to un equivocally determine which steroid is the primary or sole initiator of biological responses in which tissues; however, Table 12-3 includes some proposed assignments. Certainly it is not true that DHT is the only active androgen. Whether DHT or T is the primary androgenic initiator presumably is a reflection of the tissue distribution of the 5a-reductase.

TABLE 12-3 Biological Responses of the Androgens
Cure Tennis Elbow Without Surgery

Cure Tennis Elbow Without Surgery

Everything you wanted to know about. How To Cure Tennis Elbow. Are you an athlete who suffers from tennis elbow? Contrary to popular opinion, most people who suffer from tennis elbow do not even play tennis. They get this condition, which is a torn tendon in the elbow, from the strain of using the same motions with the arm, repeatedly. If you have tennis elbow, you understand how the pain can disrupt your day.

Get My Free Ebook


Post a comment