Testosterone alkylated androgens

Testosterone (T.) derivatives for clinical use. T. esters for im. 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. 17-0 Methyltestosterone is effective by the oral route due to its increased metabolic stability, but because of the hepatotoxicity of Cl 7-alkylated androgens (cholestasis, tumors) its use should be avoided. Orally active mesterolone is 1 a-methyl-dihydrotestosterone. Trans-dermal delivery systems for T. are also available. 

ALKYLATED ANDROGENS Adding an alkyl group to the 17a position of testosterone (Figure 58-5) retards its hepatic metabolism. Consequently, 17a-alkylated androgens are androgenic when administered orally however, they are less androgenic than testosterone itself and cause hepatotoxicity, whereas native testosterone does not. 

Isotestosterone and 8a, 1 Oa-testosterone can be considered as substituted testosterone derivatives where the 8-H is substituted by an alkyl group. In the case of 8a,10a-testosterone other structural features are prohibitive for biological activity. However, 8-isotestosterone displays decreased, but definite androgenic and anabolic properties. Nagata [160] prepared some 8/3-substituted testosterone homologs —8-methyl-testosterone (E-30) and others. In all cases decreased androgenic and anabolic potencies were observed. These facts point to the importance of /3-face attachment to the receptor at carbon-8. 

Nitrogen retention evaluation [251] was as good with ]7a-ethylnor-testosterone as with testosterone propionate (subcutaneous administration) or 17a-methyltestosterone (oral administration) [250]. The calcium and phosphorus retention was also favorably affected but as a side effect, mild cholestatic jaundice was observed [256]. Also a marked increase in bromsulfalein retention was observed in humans by administration of 17a-ethylnortestosterone [257]. Other 17o -alkyl substitutions (propyl, allyl, methallyl, ethynyl) caused a decrease of the anabolic activity. A new type of derivatives of 19-nortestosterone was prepared by etherification of the 17/3-hydroxy group [12,143,258]. Among these compounds, 19-nortestosterone-17-(cyclopent-l -enyl) ether (N-81) possesses a favorable anabolic-androgenic ratio without the undesirable side effects. 

Injected as an oil, androgens are so quickly absorbed, metabolized, and excreted that the effect is very small. Esters of testosterone are more slowly absorbed and are more effective. The majority of the androgens is inactivated primarily in the liver and involves oxidation of the hydroxy groups and reduction of the steroid ring. Alkylation at the 17-position retards hepatic metabolism and hence is effective orally. 

Androgens with an alkyl group (ethinyl- or methyl-) added to carbon-17 of the steroid nucleus are likely to have which property relative to natural testosterone ... 

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