Androgenic activity modifications

Chemical modifications of testosterone have led to some synthetic compounds which show a satisfactory dissociation between anabolic and androgenic properties. Many attempts have also been made to find orally active anabolic steroids without androgenic activity since orally active compounds would have a much greater clinical application than intramuscularly administered drugs. 

Several modifications of 17a-methyltestosterone lead to potent, orally active anabolic agents. Two hydroxylated analogs Include oxymesterone (Fig. 45.9) and oxymetholone (Fig. 45.10). These drugs have at least three times the anabolic and half the androgenic activity of testosterone (73). 

In spite of the fact that certain chemical modifications were highly successful in bringing about a favorable anabolic-androgenic ratio, it is not possible as yet to make generalizations about what kind of chemical modification will enhance the anabolic activity with a simultaneous repression of androgenic properties. 

One of the earliest and most important observations was the result of a molecular modification study which produced a totally unexpected result. In 1938, Inhoffen found that 17-ethinylestradiol was a more effective oral estrogen than estradiol itself (51). When this modification was applied to testosterone (VIII, R = CH3, X = H), in an effort to prepare an orally active androgen, the 17-ethinytestosterone (XV) so produced (58, 88) was found instead to be a potent oral progestogen, and is still used clinically in this field. 

Ethisterone (Fig. 46.14), a 17a-ethynyl derivative of testosterone, is one of the first synthetic progestins to be used therapeutically. In 1937, this agent was synthesized from male sex hormones (androstanes) in an attempt to find an orally active androgen (53). Ethisterone later proved to be an effective oral progestin and became useful in the treatment of menstrual dysfunctions (49). Several molecular modifications... 

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