Androgenic-Anabolic Agents

Mibolerone (9-6) is approved for preventing estrus in female dogs. Significant amounts of this orally active anabolic agent are diverted for use by body builders and athletes. This use is specifically proscribed by the DEA. 

Trenbolone (12-2) is another androgenic-anabohc agent approved for veterinary use. The drug is administered to cattle during shipment in order to minimize weight loss causes by stress. 

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In Table I are fisted the various names for the most widely available androgenic-anabolic agents. Testosterone itself was synthesized before it was known to be the major hormone produced by the testis. The myriads of synthetic routes to this material have been reviewed frequently, and the agent itself and its esters are so abundantly available at reasonable prices that the synthesis will not be considered here. 

Much has been written about the favorable effects of androgenic-anabolic agents on calcium balance, for which they have been widely used. A recent report combined both calcium balance and radioactive calcium turnover studies (25). It again showed the favorable effects of the steroids, which these authors attributed to a decrease in resorption of bone. 

Anabolic Agents—includes anabolic androgenic steroids such as stanozolol and other... 

Androgens and anabolic agents have been used in the treatment of osteoporosis, either alone or in conjunction with estrogens. With the exception of substitution therapy in hypogonadism, bisphosphonates have largely replaced androgen use for this purpose. 

Most of the synthetic androgens and anabolic agents are 17-alkyl-substituted steroids. Administration of drugs with this structure is often associated with evidence of hepatic dysfunction. Hepatic dysfunction usually occurs early in the course of treatment, and the degree is proportionate to the dose. Bilirubin levels may increase until clinical jaundice is apparent. The cholestatic jaundice is reversible upon cessation of therapy, and permanent changes do not occur. In older males, prostatic hyperplasia may develop, causing urinary retention. 

Estradiol-17 is given to animals in form of a subcutaneous implant in the ear, alone or in combination with other hormonally active compounds such as progesterone or trenbolone acetate. Estradiol-17 is used in steers, to best advantage, but also exhibits some anabolic effects in heifers and veal calves. It works best in lambs in conjunction with androgens, but is not effective as an anabolic agent in pigs. It has been used in many forms in the past including the benzoate, dipropionate, hemisuccinate, heptanoate, propionate, undecanoate, and valerate esters. 

Caution Several cases of hepatocellular carcinoma have been reported in patients with aplastic anemia treated with androgen anabolic therapy. Colony-stimulating factors (Chapter 33 Agents Used in Anemias Hematopoietic Growth Factors) should be used instead. 

The aim of this work is to review the structure-activity theories in the field of androgens and anabolic agents. It is written primarily for medicinal chemists and pharmacologists, but other research scientists, such as endocrinologists and biochemists, may also find it of value. 

In Chapter 4 the therapeutic action of androgens and anabolic agents is examined. In Chapter 5 some 650 androgens and anabolic agents are compiled. The literature is covered through 1967. Some compounds could not be incorporated into the tables owing to the lack of biologic data. 

Excellent accounts of the biological effects and clinical application of anabolic steroids, by Kriiskemper [5], and of the pharmacology of anabolic steroids, by Overbeek [50], are available. It is the aim of this book to examine the chemical structure-biological activity relationship of androgens and anabolic agents. A new theory of steroid-receptor interaction is also advanced, based on a new approach to the chemical structure-biological activity relationship. 

The natural androgen testosterone and a large number of other androgens and anabolic agents possess the 4,5-double bond, while the majority of metabolic products lack this unsaturation. The hypothesis was put forward that the reduction of the 4,5-double bond in the liver may represent the rate-limiting step in the inactivation of these hormones [168,221]. Upon hydrogenation of the double bond, the 5-carbon becomes asymmetric and therefore two possible isomers could result, the 5a-isomer (trans... 

Since the 5j8-dihydro derivatives, compounds in which rings A and B possess a cis junction, are inactive as androgens or anabolic agents, the ratio of products formed in the reduction becomes important. 

Reduction of the 3-ketone group can give rise to 3a- or 3/3-hydroxy compounds, with the former dominating in men. Of the two epimers, the 3a-hydroxy compounds are usually the more potent androgens and anabolic agents. A contrary example was given by Dorfman [241] ... 

The 2a-methyl substitution decreases the androgenic activity and increases the anabolic activity of the parent steroid. 2a-Methyldihy-drotestosterone was found to be as active orally as 17a-methyltes-tosterone as an anabolic agent and to have very low androgenicity. 2a,17a-Dimethyldihydrotestosterone possesses 20% of the androgenic and 400% of the anabolic activity of 17a-methyltestosterone when administered orally. 

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