Androgens, Anabolic Steroids, Antiandrogens
Androgens are masculinizing substances. The endogenous male gonadal hormone is the steroid testosterone from the interstitial Leydig cells of the testis. Testosterone secretion is stimulated by hypophyseal luteinizing hormone (LH), whose release is controlled by hypotha-lamic GnRH (gonadorelin, p. 242). Release of both hormones is subject to feedback inhibition by circulating testosterone. Reduction of testosterone to dihydrotestosterone occurs in most target organs; the latter possesses higher affinity for androgen receptors. Rapid intrahepatic degradation (plasma t1/2 ~ 15 min) yields androsterone among other metabolites (17-ketosteroids) that are eliminated as conjugates in the urine. Because of rapid hepatic metabolism, testosterone is unsuitable for oral use. Although it is well absorbed, it undergoes virtually complete pre-systemic elimination.
Testosterone (T.) derivatives for clinical use. T. esters for i.m. depot injection are T. propionate and T. heptanoate (or enanthate). These are given in oily solution by deep intramuscular injection. Upon diffusion of the ester from the depot, esterases quickly split off the acyl residue, to yield free T. With increasing lipophilicity, esters will tend to remain in the depot, and the duration of action therefore lengthens. A T. ester for oral use is the undecanoate. Owing to the fatty acid nature of undecanoic acid, this ester is absorbed into the lymph, enabling it to bypass the liver and enter, via the thoracic duct, the general circulation. 17-a Methyltestosterone is effective by the oral route due to its increased metabolic stability, but because of the hepatotoxicity of C17-alkylated andro-gens (cholestasis, tumors) its use should be avoided. Orally active mesterolone is 1 a-methyl-dihydrotestosterone. Transdermal delivery systems for T. are also available.
Indications. For hormone replacement in deficiency of endogenous T.
production and palliative treatment of breast cancer, T. esters for depot injection are optimally suited. Secondary sex characteristics and libido are maintained; however, fertility is not promoted. On the contrary, spermatogenesis may be suppressed because of feedback inhibition of hypothalamohypophyseal gonadotropin secretion.
Stimulation of spermatogenesis in gonadotropin (FSH, LH) deficiency can be achieved by injection of HMG and HCG. HMG or human menopausal gonadotropin is obtained from the urine of postmenopausal women and is rich in FSH activity. HCG, human chorionic gonadotropin, from the urine of pregnant women, acts like LH.
Anabolics are testosterone derivatives (e.g., clostebol, metenolone, nan-drolone, stanozolol) that are used in debilitated patients, and misused by athletes, because of their protein anabolic effect. They act via stimulation of androgen receptors and, thus, also display an-drogenic actions (e.g., virilization in females, suppression of spermatogene-sis).
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