Nongenomic effects of androgens

Most androgenic hormone action is thought to go through direct activation of DNA transcription via high affinity interactions with the androgen receptor. Information on the physiology and pathophysiology of these receptor actions will be given in the next chapters. In this section, complementary non-genomic effects of androgens will be discussed shortly.

In recent years, a variety of rapid "non-genomic" effects of sex steroids has been documented for these "nuclear-oriented" ligands (reviewed by Simoncini and Genazzani 2003). Androgens can also activate transcription-independent signalling pathways (Heinlein and Chang 2002). Rapid effects of androgens have been shown on calcium fluxes (Guo et al. 2002) and on intracellular phosphorylation cascades such as the Map-kinase pathway (Castoria et al., 2003). Membrane effects of androgens have also been implicated in functional responses such as rapid secretion of the prostate specific antigen (PSA) by prostatic cells (Papakonstanti et al. 2003) and the secretion of GnRH by pituitary cells (Shakil et al. 2002). In NIH 3T3 cells DNA synthesis is triggered after association between the androgen receptor and the membrane components has occurred under the influence of nanomolar concentrations of androgens. It appears that in these cells the very low density of androgen receptors is not sufficient to stimulate gene transcription (Castoria et al. 2003). Androgen-stimulated gene transcription only occurs when the intracellular receptor concentration is elevated. The membranous effects of low concentrations of "nuclear oriented" receptors could represent a more general mode for steroid action in general. More investigations in this direction are required.

Not all the membrane effects of androgens (and other sex steroids) are mediated by the classical receptor. There are several good indications that other steroid-binding proteins localised in the plasma membrane are essential for signal trans-duction, but for many years the structure of these proteins could not be elucidated and therefore it was not popular to study this subject. Recently an alternative receptor for membrane effects of progestins has been cloned (Zhu et al. 2003a). The protein has seven transmembrane domains and has similarities with G proteincoupled receptors. Hybridisation analyses have revealed that many mRNAs are present in a variety of human tissues (Zhu etal. 2003b). Although a similar protein has not been identified for androgens, it is known that humans can smell very small amounts of androstenone (16 ene-5a-androsten-3-one) as a volatile compound. Since only a very few isomers (but not testosterone) can be detected by the olfactory system, it is very likely that the smell is triggered by specific membrane receptors for androstenone in the olfactory sensory neurons (Snyder etal. 1988). It is known that all olfactory receptors are classical G protein-coupled proteins and since the alternative membrane receptor for progestins is homologous with G coupled-receptors, it is not unlikely that alternative androgen receptors in the olfactory system have a similar structure.

Recently, effects of testosterone on calcium mobility through cell membranes of T cells were reported (Benten etal. 1997). Since T cells do not possess the classical androgen receptors, this biological response also indicates the involvement of unconventional plasma membrane receptors for the expression of these androgen effects. Another example of the involvement of alternative androgen receptors can be found in eels. In eels nanomolar concentrations of 11-ketotestosterone, for which no nuclear receptor has been found, are essential for maintaining sper-matogenesis in vitro. Under these conditions high concentrations of testosterone or dihydrotestosterone were inactive (Miura etal. 1991).

Growth factors Testosterone Testosterone

5a reductase

Phosphorylation cascades

DHT Phosphorylation cascades

Nuclear receptor —

Gene expression

Fig. 1.8 Genomic and non-genomic actions of testosterone.

The dependence of spermatogenesis on high levels of testosterone can not be explained by properties of the classical nuclear receptor. Since the levels of testosterone required for maintaining normal spermatogenesis are much higher than the saturation level of the high-affinity androgen receptor, an alternative sensing system with a lower affinity has been postulated to operate (Rommerts 1988 and 1992) and later identified (Lyng etal. 2000). In this connection it is striking to note that the alternative membrane receptor for progestins mentioned earlier also has a 10 fold lower affinity than the classical progesterone receptor.

So far the non-genomic effects of steroids have received much less attention than the genomic effects. Increasing evidence collected in the last 5 years strongly suggests that the nucleus may not be the prime target for steroid actions. More and more we discover that biological systems in general are fine-regulated by networks of molecules and each day new signalling pathways and connections between these pathways are revealed. The importance of external regulatory networks for the outcome of steroid hormone action in the nucleus was stressed by O'Malley et al. (1995) when he proposed that membrane transduction pathways, activated by growth factors that interact with the nuclear receptor via intracellular phospho-rylation cascades may "set the nuclear receptor thermostat" for proper responses to steroids. In a similar fashion the signal transduction pathways activated by the membrane effects of steroids could also influence its genomic actions, indicating that nuclear and membrane effects of steroids are probably more closely linked than previously thought (see Fig. 1.8).

1.8 Key messages

• Steroidogenesis is the cleavage of the carbon chain of cholesterol inside the mitochondria with formation of the biologically inactive steroid pregnenolone as endproduct. Specific enzymes in the endoplasmic reticulum of the Leydig cells form a metabolic network to catalyse the transformation of pregnenolone into biologically active testosterone.

• LH regulates the transport of cholesterol to the inside of the mitochondria (short-term regulation of steroidogenesis) as well as the profile and activities of the pregnenolone-metabolising enzymes (long-term regulation of steroidogenesis).

• The physiological role of specific paracrine factors for regulation of Leydig cell steroidogenesis is less clear than the role of LH.

• For extracellular and intracellular transport of cholesterol, specific transport systems are required. In contrast, steroids diffuse through tissues without specific transport systems and, as a result, all cells in the body "see" roughly the same concentration of unbound testosterone.

• In target cells transformations of testosterone into more active ligands can take place when the rate of inactivation is low.

• The response of target cells depends on the occupancy of the receptors that in turn depends on the intracellular concentration of unbound active androgens.

• In addition to genomic effects of androgens through the nuclear receptor, androgens can also stimulate non-genomic effects through interactions with receptors in the cell membrane.

• Disturbances in the biosynthesis of androgens through enzyme defects or in the actions of androgen are often the cause of abnormal sexual differentiation.

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