Le mode d'action des androgènes et la 5α-réductase

Abstract

Les androgènes sont synthétisés par le testicule et la surrénale. Très liposolubles, ils pénètrent dans les cellules et se lient à leur récepteur intracellulaire. La testostérone et son métabolite, la dihydrotestostérone (DHT), sont de loin les plus actifs, la DHT ayant la plus forte affinité pour le récepteur et allongeant de façon importante sa demi-vie. La testostérone est convertie en DHT par la 5α-réductase ; cette activité enzymatique (dont le support protéique n’a pas encore été purifié) est élevée dans certains organes cibles des androgènes, essentiellement l’épididyme et la prostate. Il existe deux types de 5α-réductases ; le déficit en enzyme de type 2 est responsable du pseudohermaphrodisme masculin, ce qui indique l’importance de son rôle. Les deux activités 5α- réductase sont réglées de manière différente selon les tissus et le moment du développement. Des inhibiteurs spécifiques des isozymes 5α-réductases seraient utiles pour la contraception masculine et le traitement des tumeurs de la prostate.

In the male, androgens, defined as C19 steroids, are synthesized by the testis and adrenal. The high lipid solubility of androgens allows them to readily penetrate cells and bind to the intracellular androgen receptor. The two androgens that bind with high affinity to the androgen receptor are testosterone (T) and its 5alpha-reduced metabolite dihydrotestosterone (DHT); other androgens have very weak biological activity. Binding of androgens to the androgen receptor increases the half life of the receptor several fold. Though testosterone is the primary androgen found in the circulation, DHT is the steroid that binds with highest affinity to the androgen receptor. The conversion of T to DHT is mediated by 5alpha-reductase. High levels of this enzyme activity are found in some tissues where androgen action occurs, such as in the prostate and the epididymis, while it is essentially absent from others, such as the testis and muscle. Though the enzyme has not yet been purified to homogeneity, cDNAs from two different genes, encoded on different chromosomes, have been extensively used to understand the regulation of the mRNAs of 5alpha-reductase. The tissue distribution of these mRNAs differs markedly in both man and rodents; type 2 5alpha-reductase has been associated with the 5alpha-reductase deficiency syndrome. An extensive series of studies, using the rat epididymis as a model, have revealed that the two 5alpha-reductase mRNASs are regulated in different manners with respect to development, hormonal environment and longitudinal distribution in this tissue. It has been proposed that inhibition of this enzyme activity could be effective as a male contraceptive, for the treatment of alopecia and of benign prostatic hyperplasia (BPH) and prostatic cancer. Indeed, the first commercially available 5alpha-reductase inhibitor, finasteride, has been marketed for the treatment of BPH. With the advent of new drugs that affect both the androgen receptor and 5alpha-reductase, it should become possible to finely regulate androgen action. [References: 31]