Anabolic androgenic hormones

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pled to bone resorption [ 1211. In over 25 years of research with another steroid hormone system, the corticosteroids, it has so far been impossible to separate their effects on inflammatory cells from those on immune cells, two cell lines that are also closely coupled physiologically. Another vitamin D analogue that may be useful in the management of some uremic patients is one that will improve intestinal absorption of calcium without having any effects on bone. Several such compounds are at

present under investigation [98]. This search for a compound that acts on only one end-organ system of the naturally occurring hormone also reminds one of the experiences with corticosteroids; i.e., mineralocorticoid versus glucocorticoid. In closing, I think that with the judicious use of 1,25-DHCC and 25HCC, in combination with control of serum phosphate, renal osteodystrophy, as we know it today, will be eliminated by the early 1980’s.

Anabolic Androgenic Hormones N. T. SHAHIDI, M.D., University of Wisconsin Medical School, Madison, Wisconsin

Anabolic hormones are usually referred to a group of androgenic anabolic steroids whose main function is to generally stimulate the synthesis of cellular protein. To date, numerous derivatives of the parent androgen, testosterone, have been synthesized with the hope of a substantial degree of protein anabolism without androgenic property. In most cases, a satisfactory dissociation between anabolic and androgenic properties has been achieved. Unfortunately, however, none of the preparations is completely devoid of virilizing effect, particularly when given in large doses. An important class of anabolic compounds are the 17~alkylated derivatives of testosterone. The introduction of the 1-Id+alkyl substituent into the testosterone molecule prevents the metabolic inactivation through oxidation of the 17-hydroxy group to the 17-keto group. The presence of the alkyl group is also responsible for oral activation of these compounds. Another important class of anabolic steroids is made of 19-nor-testosterone derivatives. In this group of compounds, the Cl g-methyl group of testosterone has been replaced by a hydrogen atom. In 19-nortestosterone derivatives, there is an important dissociation in anabolic and androgenic activity. Several forms of 19-not-testosterone are clinically available. The structural formula of the most commonly used anabolic steroids used are shown in Figure 7. In this figure, some of the common testosterone esters are also represented. The esterification of 17&hydroxy protects against metabolic inactivation.and brings about a protracted biological effect. Erythropoietic Action of Anabolic-Androgenic SteAmong various biologic activities of androroids. genie-anabolic hormones, the stimulation of erythropoiesis has been known for many years. More recently, it has received particular attention because of its application to clinical medicine [ 122,123]. To date, androgenic-anabolic hormones remain the most useful

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nonspecific erythropoietic stimulant available. Other compounds, such as cobalt and batyl alcohol, have been completely abandoned as the result of either their extreme toxicity or their ineffectiveness. The use of erythropoietin to stimulate erythropoiesis in bone marrow failure remains experimental. Several studies have indicated that the anemia in patients with chronic renal failure maintained with hemodialysis may diminish following androgenic-anabolic steroid therapy. In a series of 15 patients treated with testosterone enanthate, there was a mean increase of 353 ml of red cell mass over the pretreatment level [ 1241. In another series of 25 patients undergoing long-term hemodialysis, administration of a mixture of testosterone esters given weekly or twice weekly by intramuscular injection produced a definite rise in the hematocrit levels in all patients [ 1251. After the androgen therapy was discontinued, the hematocrit value began to decline steadily. The treatment has been effective in bilaterally nephrectomized patients as well as those with intact kidney tissue [ 1251. More recent reports using fluoxymesterone [ 126- 1281 and intramuscular testosterone propionate have confirmed early observations of the beneficial effect of androgens in patients with chronic renal failure. A recent controlled study showed that nandrolone decanoate, an anabolic agent with markedly reduced androgen activity, may also benefit the patients with chronic renal failure undergoing maintenance hemodialysis [ 1291. In contrast to the foregoing results, when seven patients with chronic renal failure undergoing hemodialysis were treated with 100 mg of oxymetholone daily, none of the patients showed any rise in hematocrit values [ 1301. Similarly, in another study, 55 patients with chronic renal failure undergoing regular hemodialysis were treated with a daily dose of 100 mg of oxymetholone. Of these, 22 completed a double-blind crossover trial.

COMBINED SEMINAR ON THE USE OF DRUGS IN RENAL FAILURE

METHOLONE

STANOZOLOL

ACETATE

FLUOXYMESTERONE

OXYMETHOLONE

OH

DROhiOSTANOLONE

NANDROLONE

&

TESTOSTERONE

R= OH ,”

TESTOSTERONE

PROPIONATE

R= 0C&CH3

TESTOSTERONE

ENANTHATE

R= OC?CH,),CH,

TESTOSTERONE

ACETATE

R= OCf”~

4 TESTOSTERONE

Figure 7.

PHENPROPIONATE

-

The structural formula of the commonly used androgens.

It was found that after four and a half to five months of trial, only one patient who had a polycystic disease had benefitted from the administration of oxymetholone [ 1311. The lack of erythropoietic response using oxymetholone is intriguing, for this anabolic agent has proved to be one of the most potent erythropoietic stimulants available in the treatment of hypoplastic anemia. This discrepancy may be the result of the difference in the structure and biotransformation of the androgens involved. The Mechanism of Actions of Androgens on Erythropoiesis As Related to Androgen Biotransformation. Considering the metabolism of testosterone, the parent androgen, the 17-hydroxy group can be oxidized to the correspondent 17-ketosteroids. The reduction of A4 double bond would result in the formation of 56-H and 5a-H derivatives, which are very different in their spacial configuration. Among the metabolites, some of the fl-hydroxy and Saderivatives are androgens. However,

the 5&H steroids are not androgenic. Although the 5&-l steroids are produced at the site of target organs, such as prostate by 5c+reductase, the 50-H steroids are formed in the liver by 5&H reductase [ 1321. It is now known that these naturally occurring steroids and those of synthetic origin exert their erythropoietic effect in several ways. The androgenic steroids comprising most of the unsaturated and 5~H compounds exert their effect on etythropoiesis mainly indirectly by stimulating erythropoietin production [ 133- 1351. In rodents, the kidneys seem to play a major part in the stimulation of erythropoietin, for the response to androgen is completely abolished by nephrectomy [ 1361. In agreement with this observation, studies have demonstrated that rats and rabbits treated with androgens exhibit an increased amount of renal erythropoietic factor (erythrogenin) in the kidneys and that such an elevation in erythrogenin is correlated with an increased erythropoietin production seen after administration of

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testosterone [ 1371. Androgen-treated female rats exhibit definite renal hypertrophy which closely parallels an increase in red cell mass [ 1381. It has also been shown that the ribonucleic acid of the mouse kidhey is decreased by castration and increased by the administration of androgens [ 1391. In man, because of the extrarenal source of erythropoietin, the presehce of kidneys does not seem essential for androgens to stimulate erythropoiesis. Significant erythrapoietic response has been achieved after androgen therapy in nephrectomized patients undergoing long-term hemodialysis [ 126,129]. It has been suggested, however, that these patients might show an even greater erythropoietic response if one of the kidneys were still present. The renotrophic action of androgens seems to depend, as for target organs such as prostate, on the presence of specific cytoplasmic androgen receptor proteins [ 1401. 5&H steroids have been reported to stimulate hemoglobin synthesis only by their direct cellular action without stimulating erythropoletin production [ 1411443. Other studies using thymidine suicide technics have yet uncovered another cellular effect of testosterone and some of its metaboiites; namely, the triggering of colony-forming units into cell cycles [ 1451. More recent investigations measuring the colonyforming ability of erythroid cells in vitro not only have cohfirmed the direct cellular action of most @-H steroids, but have also further shown that some of the 5a-H metabolites may exert similar direct action on erythroid elements [ 146,147]. Although the erythropoietic effect of unsaturated and tne 5a-H compounds in vivo has been well documented, studies evaluating the role of 5P-H metabolites in enhancing erythropoiesis in vivo have yielded conflicting results [143,144,148]. The Side Effects of Androgenic-Anabolic Hormones. The administration of androgens in dosage used to en-

hance erythropoiesis has definite side effects. Some degree of masculinization occurs in all children and women receiving large doses of androgens regardless of the preparation used. Flushing of the skin and acne appear usually two to three months after the initiation of androgen therapy. Deepening and hoarseness of the voice follow these dermal changes. In children before puberty, changes of external genitalia and growth of pubic hair occur one to three months after therapy. In females of menstruating age, amenorrhea and moderate enlargement of the clitoris develop. Changes in libido in both sexes have also been observed. It is known that prolonged administration of large doses of androgens to children increases the rate of the skeletal maturation. However, no serious growth retardation or roenfgenologic evidence of accelerated bone maturation‘has been noted in children treated with anabolic-androgenic steroids. Treatment with 17a-alkylated androgens may cause considerable disturbance to liver function. The abnormality ranges from an increase in sulfobromophthalein retention elevation in serum transaminase to a frank picture of cholestasis. This abnormality is, however, often reversible; Other complications such as significant weight gain as a result of water retention and elevation of plasma triglycerate levels have also been noted. In addition td’their hemopoietic effect, androgens are protein anabolic steroids that result in an appreciable nitrogen retention and thereby in a decrease in the formation of intoxicating protein breakdown products. As a result, sudden withdrawal of these hormones in uremic patients may markedly increase azotemia. A significant increase in erythrocyte 2,3diphosphoglycerate after androgen administration has been observed in man and in laboratory animals [ 1221. It is well known that this organic phosphate facilitates the unloading of oxygen from hemoglobin into the tissues by decreasing the oxygen affinity for hemoglobin.

Nutritional Supplements in Renal Failure KURT H. STENZEL, M.D., Rogosin Kidney Center, The New York Hospital-Cornell

A variety of nutritional supplements are often prescribed for patients with renal disease because of the frequency of wasting syndromes, the frequency of various vitamin and mineral deficiencies, and the necessity for limiting protein intake. These additives include caloric, vitamin, mineral and amino acid supplements. Precise nutritional requirements in patients with renal disease are not known. Requirements for normal people have been determined largely by short-term balance

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studies. The efficacy of nutritional supplements depends not only on over-all balance, but also on the particular metabolic pathways used to maintain that balance. For instance, external balance of a particular nutrient may be maintained in uremia by very different mechanisms than in health. Nutritional supplements, to be effective, must first be absorbed and then metabolized in a fashion that promotes normal tissue function. Gastrointestinal disease is common in uremia and may prevent adequate