Metabolism of testosterone

The steady state level of biologically active steroids in the body as a whole is determined by the rate of synthesis and the rate of degradation. To maintain a steady state concentration of active steroids in a target cell a similar balance between the supply and removal must be maintained. The supply side of the balance is determined by the rate of inward transport of active steroid, sometimes in combination with activation through metabolism of the precursor. Similarly, factors that control removal are the rate of outward transport and the rate of degradation. A network of different factors contributes to the control of the level of a particular steroid in the target cell. Outside the target cell: flow rate of biological fluid (blood or lymph), release from binding proteins, transport through membranes, connective tissue, cell layers, in which sometimes inactivation of steroid can occur during transport. Inside the target cell: local activation or inactivation reactions and outward transport. Alterations in the rate of degradation of androgens induced by disease, ageing, treatment with drugs etc. are therefore as important as changes in the rate of the testicular synthesis. As an example, it could be possible that altered androgen metabolism during ageing may be responsible for a local hyperandrogenic state in the prostate leading to benign prostatic hyperplasia (Ishimaru etal. 1977).

There are several possibilities for the metabolism of testosterone (see Figure 1.7). Aromatization or reduction of the A4bond of testosterone give rise to 17^-estradiol and 5a-dihydrotestosterone, respectively. These steroids have completely different biological activities since they interact with discrete receptors in the cell. Actions of testosterone on target tissues are therefore significantly modulated by metabolic reactions. When a target cell is estrogen-dependent, the aromatase activity in target cells and the supply of androgen substrate are of major importance for determining the rate of synthesis of estrogens. In humans the aromatase cytochrome P450 enzyme (p450arom or CYP19) is encoded by a single gene. This gene is expressed in many tissues including the placenta, ovary, testis, fat tissue, liver, brain, hair, follicles and the brain. A very few cases of complete aromatase deficiency due to a gene defect have been noted (Morishima et al. 1995; Bulun 1996). The activity of 17^HSD, especially the type 2 isoform that favours oxidative reactions, determines how much of the active oestradiol is converted to the biological inactive estron (Andersson and Moghrabi 1997). The importance of estrogens in males is reviewed by De Ronde etal. (2003).

For proper action of androgens it is sometimes necessary to convert testosterone into 5a-dihydrotestosterone before it can fully activate the androgen receptor. Two

Testosterone Metabolism
Fig. 1.7 Various possibilities for metabolism of testosterone.

isoforms of5a-reductase exist and isoform 2 is most important because deficiencies of reductase type 2 are correlated with abnormal clinical manifestations (Wilson etal. 1993). To establish a critical steady state concentration ofDHT, not only the activity of the 5a reductase must be high enough, but also the metabolism ofDHT must be low. In the prostate of the dog the activity of the reductive 3a/3^- steroid dehydrogenase activities are low, and this favours the formation ofDHT. The low rate of metabolism through the 3a/3^- dehydrogenase pathway may be the consequence of a low expression of one or both of these enzymes in the prostate, but it may also be possible that within one cell there is a balance between oxidative and reductive actions of two different iso-enzymes. Support for this hypothesis is a report showing that rat and human prostate contain an oxidative 3a-hydroxysteroid dehydrogenase that can convert 5a-androstane-diol back to dihydrotestosterone (Biswas and Russell 1997). This could explain why 5a-androstane-3a, 17p-diol is a more potent androgen for maintaining epididymis function than dihydrotestosterone or testosterone (Lubicz-Nawrocki 1973). Prostate tissue also contains the type 2, 17^ hydroxysteroid dehydrogenase that is primarily oxidative in nature. This enzyme does not metabolise DHT but it does convert testosterone in androstenedione, especially when 5a reductase is inhibited (George 1997). In muscle there is a high activity of 3aHSD and a low 5a-reductase (Luke and Coffey 1994). This combination of enzymes seems to operate to optimise the amount of testosterone for testosterone-dependent receptor stimulation in this cell type. In other target cells such as the skin and the hair follicle, the level of DHT, as the most active ligand, can depend on the supply of testosterone and conversion to DHT on one hand, balanced by the catabolism of DHT via reducing 3a/3ß- steroid dehydrogenases and glucuronidation on the other hand (Rittmaster 1994). Oxidizing activities of 3a-steroid dehydrogenases may, however, offset this inactivation of DHT (Penning 1997). Thus the pattern of active and inactive androgen metabolites depends on a network of steroid-metabolising enzyme activities. Owing to these local conversions, the peripheral plasma concentrations of androgens are only a rough indicator for their biological activities. It has already been known for many years how androgen action in certain tissues can be amplified by enzymes that favour DHT formation. Much less is known about the regulation of these enzymes under physiological conditions. For instance, how does ageing affect the true levels of active androgens within the target cells? It is known that in the kidney, cortisol can be completely inactivated by oxidative actions of 11ß-hydroxysteroid dehydrogenase in cell layers that surround the target cells for aldosterone (White etal. 1997). Thus a "metabolic shield" protects the receptors for mineralocorticoids in the target cells from unwanted actions of glucocorticoids. The reverse is also possible; local amplification of glucocorticoid action can occur by reducing inactive cortisone to cortisol. This can occur in liver, fat cells and in the brain and has enormous implications for the slow development of diseases such as diabetes type 2 (reviewed by Seckl and Walker 2001). Altogether these new observations have stimulated investigators to study further the details of corticosteroid metabolism. Although a "metabolic shield" for protecting cells from actions of androgens has not been shown, the physiological implications of interacting androgen metabolising enzymes requires more attention. Over the past years we have learned a lot from knock out studies or from over-expression of enzyme activities in tissues and cells. Now it is time to study the detailed interactions between the natural enzyme activities under different physiological conditions, for instance during ageing.

Although the balance of specific "activating" and "inactivating" steroid conversions is of great importance for the manipulation of the androgen response of the target cells, they are less important for the overall degradation and clearance of androgens. The pathway for degradation of androgens in various tissues is determined by the profile of enzymes involved in the inactivation process. Enzymes that are active in degrading androgens are 5a- and 5ß-steroid reductases, 17ß-hydroxysteroid dehydrogenase and 3a- and 3ß-hydroxysteroid dehydrogenases. In addition to these enzymes that convert existing functional groups, androgens can also be hydroxylated at the 6, 7, 15 or 16 positions (Träger 1977). Most of these androgen metabolites are intrinsically inactive. However, some steroids such as 5a-androstanediol can be "reconverted" to dihydrotestosterone and these steroids may therefore be considered as potentially active androgens. The androgenic effects will depend on the degree of metabolism. The 5^-androgenic metabolites are a special group of compounds that stimulate the production ofheme inbone marrow and liver (Besa and Bullock 1981). These biological effects are not mediated by the classical androgen receptor. Thus steroid metabolites that cannot bind to nuclear steroid receptors can still express biological activity (see also next section). Metabolism or even catabolism should therefore not always be considered as an inactivating pathway, preparing a steroid for excretion. Androsterone (3a-hydroxy-5a-androstane-17-one) and etiocholanolone (3a-hydroxy-5^-androstane-17-one) are the most abundant urinary androgen metabolites. Some androgen metabolites are excreted as free steroids, whereas others are conjugated. These conjugated steroids carry a charged group such as a sulphate or a glucuronide group on the 3- or 17-position. Dehydroepiandrosterone-sulphate is a well-known example of a conjugated steroid which is produced by the adrenal cortex and that is present in the circulation at micromolar levels without a clear physiological function. In adult men, glu-curonides of the 5^-androstane compounds are most abundant. The majority of the catabolic reactions take place in the liver but the prostate and the skin also contribute significantly to the metabolism of androgens. All the steroid-metabolising enzymes together constitute a network for transforming androgens into secretion products that finally leave the body via the urine or the skin. The flux through this network is great because the overall halflife of testosterone in men is only 12 minutes. It is clear that to maintain of a constant level of testosterone in the body, this breakdown must be balanced by a continuous supply from the testis.

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