[Antiandrogens. Mechanisms and paradoxical effects].
Antiandrogens can be distinguished into three categories: those realizing a biochemical castration, those acting only at the target cell level by competitive inhibition of androgen binding to their receptor, and those doing both. In the first category enter mainly LHRH agonists and steroidogenesis inhibitors. LHRH agonists act through pituitary desensitization and have the inconvenient of an initial stimulation (flare-up) resulting in a lag before efficiency can be obtained. In addition, they do not suppress adrenal androgens. Steroidogenesis enzymes inhibitors can never realize a complete block and, due to negative feed-back control, circulating androgens progressively increase again after a while. Non steroidal antiandrogens interact with the androgen receptor thus preventing androgen action by competitive inhibition. However, as they also interact with the androgen receptor at the hypothalamic level, the resulting progressive increase in circulating androgens may overcome the peripheral inhibition at the receptor level. Their use is therefore restricted to castrated (surgically of biochemically) subjects, to suppress the effects of adrenal androgens or of the initial flare-up under LHRH agonists. As they have no antigonadotropic action, they must be associated in women with some kind of contraception. In contrast, the main progestational antiandrogen used, cyproterone acetate (CPA), has antigonadotropic effects which suppress androgen production and realizes at the same time an efficient contraception in women. It interacts with the androgen receptor and thus inhibits the action at the target cell site of any remaining androgens. In addition, it lowers the androgen dependent 5 alpha-reductase of human skin and has a weak agonist effect on liver protein synthesis resulting in an increased metabolic clearance rate of testosterone. In conclusion, CPA which by itself suppresses testosterone production, increases testosterone elimination and prevents testosterone action, seems at the present time the more complete available antiandrogen.
Mowszowicz
I
I
Laboratoire de Biochimie B, Hôpital Necker, Paris.
D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists / Q000378:metabolism / Q000494:pharmacology; D000728:Androgens / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D002927:Cimetidine; D003534:Cyproterone / Q000031:analogs & derivatives / Q000494:pharmacology; D017373:Cyproterone Acetate; D005485:Flutamide / Q000494:pharmacology; D006801:Humans; D009570:Nitriles; D013148:Spironolactone / Q000494:pharmacology; D014105:Tosyl Compounds
D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D009570:Nitriles; D014105:Tosyl Compounds; D013148:Spironolactone; D017373:Cyproterone Acetate; D005485:Flutamide; D002927:Cimetidine; C053541:bicalutamide; D003534:Cyproterone
Les antiandrogènes. Mécanismes et effets paradoxaux.