Dihydrotestosterone metabolism

Dihydrotestosterone—Metabolic conversion of testosterone by 5a reductase produces dihydrotestosterone. This is the primary androgen stimulant of prostate cell growth. 

The most significant metabolic product of testosterone is DHT, since in many tissues, including prostate, external genitalia, and some areas of the skin, this is the active form of the hormone. The plasma content of DHT in the adult male is about one-tenth that of testosterone, and approximately 400 ig of DHT is produced daily as compared with about 5 mg of testosterone. About 50-100 ig of DHT are secreted by the testes. The rest is produced peripherally from testosterone in a reaction catalyzed by the NADPH-depen-dent 5oi-reductase (Figure 42-6). Testosterone can thus be considered a prohormone, since it is converted into a much more potent compound (dihydrotestosterone) and since most of this conversion occurs outside the testes. Some estradiol is formed from the peripheral aromatization of testosterone, particularly in males. 

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...

Testosterone (T.) derivatives for clinical use. T. esters for im. depot injection are T. propionate and T. heptanoate (or enanthate). These are given in oily solution by deep intramuscular injection. Upon diffusion of the ester from the depot, esterases quickly split off the acyl residue, to yield free T. With increasing lipophilicity, esters will tend to remain in the depot, and the duration of action therefore lengthens. A T. ester for oral use is the undecanoate. Owing to the fatty acid nature of undecanoic acid, this ester is absorbed into the lymph, enabling it to bypass the liver and enter, via the thoracic duct, the general circulation. 17-0 Methyltestosterone is effective by the oral route due to its increased metabolic stability, but because of the hepatotoxicity of Cl 7-alkylated androgens (cholestasis, tumors) its use should be avoided. Orally active mesterolone is 1 a-methyl-dihydrotestosterone. Trans-dermal delivery systems for T. are also available. 

Cimetidine inhibits binding of dihydrotestosterone to androgen receptors, inhibits metabolism of estradiol, and increases serum prolactin levels. When used long-term or in high doses, it may cause gynecomastia or impotence in men and galactorrhea in women. These effects are specific to cimetidine and do not occur with the other H2 antagonists. 

Saw palmetto relieves urinary symptoms and flow measures associated with an enlarged prostate it does not reduce the enlargement. Saw palmetto is chiefly employed to manage prostatic enlargement or benign prostatic hyperplasia (BPH). A hexane extract inhibits 5-alpha reductase, the enzyme needed for the conversion of testosterone into dihydrotestosterone (DHT). Saw palmetto further antagonizes DHT binding at prostatic receptor sites, which increases the metabolism and excretion of DHT. It is also used to treat BPH-related inflammation (see Chapter 55). 

It can be seen that androstane-17 8-ol-3-one (dihydrotestosterone) is 2 to 2)4 times as active as testosterone on the seminal vesicles and ventral prostate indices, but the rest of the compounds are all less active than testosterone. Thus metabolic inactivation is a very important factor to be considered. 

The most important function of the 4,5-double bond seems to be the protection of the 3-carbonyl function against metabolic inactivation. It is known that 5a-dihydrotestosterone is a more powerful androgen than testosterone, especially when measured by the ventral prostate index. 

However, the 3-carbonyl function is metabolized much faster in 5a-dihydrotestosterone than in testosterone where the 4,5-double bond has a rate-limiting effect, i.e., the metabolic inactivation of 3-carbonyl group is much faster than the reduction of 4,5-double bond [168,221]. 

The metabolism of DHEA was studied by means of human prostate homogenates [80], as well as human and rat liver microsomal fractions [81-82]. Using human prostate homogenates, androst-5-ene-3P,17P-diol (major component), androst-4-ene-3,17-dione, testosterone, 5a-dihydrotestosterone, androsterone, and 7a-hydroxy-DHEA were identified as metabolites of DHEA [80]. By means of liver microsomal fractions, 16a-hydroxy-DHEA, 7a-hydroxy-DHEA, and 7-oxo-DHEA were identified by Fitzpatrick et al. [81], while in total 19 DHEA metabolites were reported by Marwah et al. [82]. Some of these metabohtes were characterized for the first time. (Quantitative analysis of 5a-androstane-3p,17P-diol in plasma was recently reported by Reddy et al. [83]. 

Current medical theory suggests that the primary cause of prostatic swelling is an increased production of the potent androgen dihydrotestosterone (DHT). While testosterone levels drop with increased age, follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, and estradiol steadily increase. The elevated levels of estrogens decrease metabolism of DHT, and increased prolactin also raises the levels of DHT in the... 

P. O. Gisleskog, D. Hermann, M. Hammarlund-Udenaes, and M. O. Karlsson, A model for the turnover of dihydrotestosterone in the presence of the irreversible 5 alpha-reductase inhibitors Gil98745 and finasteride. Clin Pharmacol Ther 64 636-647 (1998). M. Pirmohamed and B. K. Park, in Elandbook of Drug Metabolism, T.F. Woolf (Ed.). Marcel Dekker, New York, 1999, pp. 443 76. 

Testosterone (T), the male hormone par excellence, is primarily produced in the testis. It is metabolized to the more potent dihydrotestosterone (DHT). Physiological T concentrations reflect the balance between biosynthesis and metabolism. Therefore, T is a prime... 

Two recently developed classes of drug show promise, and these act by inhibiting the production of testosterone from cholesterol or its metabolism by the enzyme 5-cc-reductase. Attempts to control benign prostatic hyperplasia provided the incentive for the development of 5-a-reductase inhibitors. It has been known for some time that there is a genetic condition that is manifested by a deficiency of this enzyme. Men who have this gene defect have normal external genitalia but only a very small prostate and additionally, they do not develop acne or exhibit the typical male pattern of hair loss. All of these processes are under the control of 5- -reductase, which controls the conversion of testosterone to another steroid, dihydrotestosterone, and it is an imbalance in the ratio of these two steroids that leads to acne, male-pattern baldness, prostatic hyperplasia and probably prostatic cancer. Several... 

Methyltestosterone is metabolized in the liver via the same pathways as testosterone and is converted to 5alpha-dihydrotestosterone and its glucuronide and sulfate conjugates. 

Testosterone is metabohzed in the liver to androsterone and etiocholanolone (Figure 58-3), which are biologically inactive. Dihydrotestosterone is metabolized to androsterone, androstane-dione, and androstanediol. 

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