Evidence of masculinization in the clinical application of anabolic steroids poses the most serious limitation on their widespread clinical usefulness. The virilizing effects commonly observed include increased hair growth (hirsutism), clitoral enlargement, deepening of the voice, menstrual irregularities, and acne. Electrolyte imbalance, notably the retention of sodium chloride leading to edema, is also considered to be a
major side effect for certain of the anabolic agents. The incidence and severity of these side effects vary with the individual and as such make the estimation of androgenic activity in man somewhat more difficult than in laboratory animals. Female patients and young children are the most sensitive to the virilizing side effects. The effect of androgens on epiphyseal closure is also a major concern in the use of anabolic agents in children (71a).
The estimation of the androgenic activity of an anabolic agent in terms of the clinical situations wherein it will be employed constitutes the final and most meaningful approach. Thus, the clinical evaluation of an anabolic agent should be directed toward the estimation of the degree of anabolic effect achieved with dosage levels which are not androgenic or, at most, weakly so. This approach permits the maximum use to be made of the anabolic agents presently available which are claimed to have, it must be recognized, a relative but not absolute separation of anabolic and androgenic activities.
426 AARON ARNOLD AND GORDON O. POTTS V I . LIMITATIONS OTHER THAN ANDROGENICITY
A. Experimental Evaluation
While the androgenicity of testosterone, its esters, and methyltestos-terone restrict the potential usefulness of these steroids for their anabolic effects, many of the synthetic steroids have additional limitations. Potts et al. (44a) described steroids whose estrogenic effects prevented their experimental evaluation in the rat nitrogen assay. Arnold and Potts (25) reported that two of the 19-nortestosterones could be only partially as-sessed for their ability to promote nitrogen retention in rats due to their adverse effect on feed consumption.
Junkmann and Suchowsky (44) graphically presented the hormonal profile of twelve steroids which included, in addition to the myotrophic effects (based on the levator ani response) and androgenic effects (based on the ventral prostate and the seminal vesicle responses), the pro-gestational effects, the antiestrogen effects (in ovariectomized female rats maintained with an estrogen) and pituitary-inhibitory effects in reproductively mature male or female rats.
These results emphasize the importance of a complete evaluation of the hormonal profile of an anabolic agent in addition to its ana-bolic: androgenic activities. This is especially germane in the study of the newer steroids where it has been demonstrated that a single com-pound may possess estrogenic, anabolic, androgenic, and progestational activities (72). Thus, it may be desirable that the anabolic agents of interest should be assessed also for estrogenic (71, 73, 74), progestational (71, 75-78), and pituitary-inhibitory properties (71). This permits cor-relation of these activities with the anabolic: androgenic profile.
B. Clinical Evaluation
Fox et al. (30) have noted that some synthetic anabolic agents increase the bromsulphalein (BSP) retention time, an index of deranged
hepatic function, when they are given at elevated dosages or, it may be added, when given for prolonged periods. Elevated serum transaminase levels have also been noted. Kory et al. (79) presented evidence that functional liver derangement was not accompanied by injury of liver cells. Furman et al. (80) found that the androgenicity of some agents led to a decreased ^/^-lipoprotein ratio. The significance of this latter observation is not clear at this time.
V I I . SOME REPRESENTATIVE ASSESSMENTS OF THE DEGREE OF DISSOCIATION OF ANABOLIC AND ANDROGENIC EFFECTS
Reports in the literature are rapidly multiplying on the relative anabolic and androgenic properties of this group of steroids. In order
T A B L E X I
ANABOLIC AND ANDROGENIC DISSOCIATION OF SOME REPRESENTATIVE ORALLY EFFECTIVE ANABOLIC STEROIDS
(Relative to Methyltestosterone) Anabolic Androgenic
Steroid activity activity Ratio Reference
Methyltestosterone 1.0 1.0 1.0 —
Androisoxazole 1.55« 0.22* 7.0 (27)
Androisoxazole c — 1.7 (44)
Androstanolone e — 0.8 (44)
Androstanolone 0.13° 0.50* 0.26 (28)
4-Chloromethyltestosterone 0.50c 0.15* 3.3 (45) 4-Chloromethyltestosterone 0 . 5 0c 0.10* 5.0 (45) 7,17-Dimethyltestosterone 5.75e 3* 1.9 (19) 7,17-Dimethyltestosterone 4.2* 1.3* 3.2 (24)
Ethylestrenol 4 . 2 1c 0.22* 19 (46, 47) 4-Hydroxymethyltestosterone 1.8* 0.36* 5.0 (24) 4-Hydroxymethyltestosterone 1.8» — — (30) Methandrostenolone 0 . 8 9c 0.45* 1.97 (47)
428 AARON ARNOLD AND GORDON O. POTTS
activity Ratio Reference
Norethandrolone 0.75c 0.22 3.4 (2)
a Rat nitrogen retention method.
h Androgenic evaluation based on ventral prostate weight increase.
e Rat myotrophic procedure.
d Androgenic evaluation based on seminal vesicle weight increase.
• Nitrogen balance evaluation with the ovariectomized monkey.
f Clinical nitrogen balance evaluation.
0 Clinical nitrogen utilization method; testosterone propionate reference.
to follow the significant advances being reported, it is important to have a background of information on the comparative anabolic and andro-genic effects together with the relative dissociations of these effects.
With this need in mind, a summary of recently published comparisons is given in Table XI.
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