Testosterone metabolic products

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. 

Horinouchi M, T Hayashi, H Koshino, T Yamamoto, T Kudo (2003a) Gene encoding the hydrolysis for the product of the mefa-cleavage reaction in testosterone metabolism by Comamonas testosteroni. Appl Environ Microbiol 69 2139-2152. 

The natural androgen testosterone and a large number of other androgens and anabolic agents possess the 4,5-double bond, while the majority of metabolic products lack this unsaturation. The hypothesis was put forward that the reduction of the 4,5-double bond in the liver may represent the rate-limiting step in the inactivation of these hormones [168,221]. Upon hydrogenation of the double bond, the 5-carbon becomes asymmetric and therefore two possible isomers could result, the 5a-isomer (trans... 

Metabolism studies. GC-MS is a powerful technique for following and identifying the metabolic products from the in vitro incubation of tissue preparations with steroid substrates. Examples of such studies include the 16a-hydroxylation of 18-hydroxydeoxycorticosterone by human adrenal gland [254], the eiromatization of 3jS,15, 16 -trihydroxy-5-androsten-17-one by placental homogenates [255], and the demonstration of 1/3, 12/3, 6a and 6/3 hydroxylase enzyme activities in microsomal preparations of human foetal hepatic tissue [256]. In the latter study, testosterone was used as substrate and in addition to the hydroxylated metabolites isolated, several other testosterone derivatives indicated the presence of 3a, 3/3 and 17/3-hydroxysteroid oxidoreductase in the adrenal gland preparation. 

Wang, C., Catlin, D.H., Starcevic, B., Leung, A., DiStefano, E., Lucas, G., Hull, L. and Swerdloff, R.S. (2004b). Testosterone metabolic clearance and production rates determined by stable isotope dilution/tandem mass spectrometry in normal men influence of ethnicity and age. J. Clin. Endocrinol. Metab., 89, 2936-2941. 

Transdermal patches of testosterone also have problems A fraction of the testosterone is metabolized in the skin and converts to dihydrotestosterone. This metabolic side product can cause swelling of the prostate gland. Testosterone patches are placed on the body where the rate of absorption is highest, but this unfortunately can cause the metabolic product, dihydrotestosterone, to create side effects. Improved patches can be placed in areas where metabolized dihydrotestosterone is minimized. Reduction of transdermal absorption by the changed application area can be overcome by the addition of an absorptive aid. 

Oral testosterone products are also available for supplementation. Unfortunately, testosterone has poor oral bioavailability and undergoes extensive first-pass metabolism. Alkylated derivatives such as methyltestosterone and fluoxymesterone have been formulated to compensate for these problems, but this modification makes them considerably more hepatotoxic. This adverse effect makes oral replacement undesirable and this route of administration should not be used. 

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...

Fig. 3. Relationship between substrate lipophilicity (log P) and ability of screened microorganisms to metabolize model substrates (AP = Aminopyrine DZ = Diazepam TE = Testosterone TH = Theophylline WF = Warfarin). Log P is the logarithm of the partition coefficient of a compound between n-octanol and a pH 7.0 aqueous buffer. Ordinates represent the % of cultures tested able to transform the substrates, independently of the extent of metabolism and number of products formed (from [185])...

Researchers discovered that MPA also had effects on men. When injected into a man, MPA accelerates the metabolism of testosterone while also suppressing its production. The result is a reduction of up to 75 percent in the amount of testosterone in the man s body, thus lowering the intensity of inappropriate sexual cravings and the frequency of unacceptable erotic pre-... 

C. In adolescent males, testicular testosterone production dramatically rises from prepuberal levels and then declines into adulthood. However, with advancing adulthood there is a drop in the metabolic clearance rate of testosterone, increasing the length of time that testosterone remains in the serum. Evidence of a relatively constant level of serum testosterone is seen in the relative constant levels of urinary 17-ketosteroids, a metabolite of testosterone, from the second to the fifth decade of life. 

Two female sex hormones, estradiol-17 and progesterone, and one male sex hormone, testosterone, are used as growth promoters on beef cattle (Fig. 7.1). By nature, they are all endogenous products playing an important role in controlling reproductive functions in humans and animals. When applied exogenously they will enter the same metabolic pathways as the endogenously produced molecules. 

In all species, metabolism of testosterone leads to its biological deactivation. In sheep and cattle, this biological deactivation leads mainly to formation of epitestosterone, whereas in nonruminants it leads to androsterone, etiocholano-lone, and dehydroepiandrosterone (7-9). Residues of endogenous testosterone are usually highest in the kidneys of animals such as heifers witli a low testosterone production rate, and highest in fat of animals such as bulls, with a high production rate. 

Severe consequences can occur from defective syn- thesis of a steroid hormone, as is the case in several metabolic diseases. Patients who have 21-hydroxylase deficiency are unable to convert progesterone to aldosterone and cortisol. Instead the progesterone is directed to an excess production of testosterone. In the female, this results in masculinization and hirsutism (growth of hair). In the male, premature masculinization occurs. If the disease is diagnosed before the first birthday, the patient can be treated with the missing steroid hormones, which in turn suppress the synthesis of excess progesterone and, as a consequence, testosterone via feedback mechanisms. 

Bursi et al. (2001) reported two methods to calculate the stability of testosterone-like steroids. These were the use of a decision tree and molecular descriptors or quantum mechanical methods. For satisfactory accuracy, Bursi and colleagues (2001) had to use a 3-21G basis set with spin correction and equilibrium geometries. This required 12 hours of computation for reactants and products. Optimization of transition state geometry was also required. The simpler decision tree analysis approach indicated that descriptors such as the volumes and, to a lesser degree, the shape were important. Correlations of calculated and experimental rates of metabolism were reported. 

---