The History and Present Status of the Drug Development of Anabolic Steroids

Table of Contents

• Abstract
• The Discovery of Testosterone
• The Development of Analogues and Derivatives
• Presently Known Clinical Activities of Testosterone
• Structure Activity Relationships
• The Creation of Oxandrolone
• Uses of Oxandrolone Today
• Other Steroids for Anabolic Use Exhibiting High Anabolic / Androgenic Dissociation
• Testosterone Drug Products
• Testosterone Analogues of Value for Reasons Other Than Anabolism
• Views Regarding Future Development
• References

Abstract

Approximately 75% of all health care expenditures in the United States are for treatment of diseases showing preference or distinction in effects between the sexes: for example, cardiovascular disease and many forms of cancer. Yet a comprehensive understanding of the diverse physiological actions of sex hormones and their drug analogues is still elusive, as is a clear set of principles for anabolic/androgenic hormone therapy and drug design. This is particularly remarkable considering that anabolic/androgenic steroids (AAS) have been available for over 40 years, and over one million Americans have used these drugs. Largely because of this lack of knowledge, American physicians have generally been reluctant to prescribe these compounds. Pharmaceutical companies have largely abandoned research in this area, as evidenced by the fact that no new types of these drugs have been developed in the United States in over 20 years. Another concern of physicians is that certain of these drugs have shown evidence of hepatotoxicity.

However, recent research findings indicate that certain of these drugs indeed can be used safely and effectively. Better measurement of desired vs. undesired effects of experimental compounds may make possible the design of superior drugs. Existing drugs are proving useful for many diseases. Danazol has been effective for endometrial cancer, benign breast disease, menorrhagia, mixed connective tissue disease, autoimmune hemolytic anemia, thrombocytopenic diseases, and osteoporosis, for example. Stanozolol, oxandrolone, and tibolone are also proving useful for several conditions, and certain testosterone analogues, particularly oxandrolone, methenolone, and nandrolone, now appear to be well established as safe and effective for improvement of protein anabolism in debilitated or traumatized patients. AIDS patients in particular may benefit greatly from such a treatment, and in fact oxandrolone was recently re-released to the market for this purpose. And the pharmaceutical delivery of testosterone has recently been greatly improved by the development of transdermal patches, which are expected to be a potential billion-dollar market.

The history of the development of testosterone from its discovery to these and other current uses is described in this paper.

The Discovery of Testosterone

It had been known since ancient times that the testicles were required for the development and maintenance of male sexual characteristics. Early scientific ideas held that the mechanism of action was through the nervous system. The modern concept of hormone action through the blood was not established until Berthold’s experiments in 1849 with cockerels. Removal of the testes from these birds caused comb shrinkage and loss of color and sexual function. Berthold found that if the testicles were transplanted to the abdomen, the virility of the birds remained unaffected. Dissection showed that no nervous connections were formed, but extensive capillarization had taken place.¹ He concluded that “the testes act upon the blood, and the blood acts correspondingly upon the entire organism.”² This work was the foundation stone of endocrinology. The “capon test” of changes in comb measurement became an important assay for activity of male hormone extracts, although it is today obsolete.

Use of this assay enabled Koch’s development in 1929 of a procedure to produce an extract of potent activity from bull’s testicles. This was followed by a complete purification in 1935 by Laquer. A year later, Ruzicka achieved the synthesis of the identical compound, testosterone, from cholesterol, as did Butenandt and Hanisch.³

In 1936, Kochakian succeeded in demonstrating that use of testosterone or testosterone acetate reduced urinary nitrogen excretion of the castrated dog and increased body weight.⁴ Kenyon later showed that testosterone was a potent anabolic substance in man as well.

The Development of Analogues and Derivatives

Kochakian states in (9) that his work with the mouse, showing that androstane-3a,17ß-diol was preferentially renotrophic while androstenedione preferentially increased the size of the seminal vesicles and prostate, together with findings that 19-nortestosterone (nandrolone) had a preferential effect on the levator ani muscle of the rat, served as an impetus for the development of drugs that might be exclusively or largely protein anabolic for use in debilitated patients.

Between 1948 and 1955, chemists at Searle had synthesized more than a thousand different testosterone derivatives and analogues. Using an assay developed by Hershberger which measured the effect of a test compound both on the prostate and levator ani of the castrated rat, these compounds were screened both orally and parenterally under the direction of Saunders and Drill.¹ It was implicitly assumed that activity on the levator ani would be indicative of a drug’s therapeutic effects, while activity on the castrated rat prostate would be a sufficient and accurate predictor of all of a drug’s numerous and varied potential “androgenic” side effects on humans of both sexes. It was a particular research goal of this project to find drugs which would be effective orally, since testosterone itself was not very potent via that route of administration.

One compound, a 17-ethylated, 19-normethyl analogue of testosterone, appeared to be superior to others. By Hershberger’s assay method, it was found to be only 1/16 as “androgenic” (prostatotrophic) than it was “anabolic” (potent in inducing growth in the rat levator ani, a sex-specific muscle). Other workers obtained myotrophic: androgenic dissociation ratios of 2:1, 3.5:1, 20:1, 1.3:1, 4:1, 3.1:1, and 7.1 relative to testosterone.⁵ These values are clearly inconsistent but such was typical with this assay method.

Searle’s animal tests indicated no significant toxicity to the drug, which they named Nilevar (norethandrolone). In clinical tests, the drug was found beneficial for nutritionally depleted cardiac patients, gastrectomy patients, chronically underweight men, women, and children, and some doctors even used norethandrolone “almost routinely to hasten the convalescence of hospitalized children.”⁴ The drug was FDA approved in 1956 and still sees some use today, although it has been shown to be slightly hepatotoxic.⁶

Numerous other drugs were developed which, like norethandrolone, were simple modifications of the testosterone structure. Only two, which shall be described later, appear clearly superior to norethandrolone for use as a protein anabolic where minimization of virilizing side effects is desired. Many are similar, and many are worse as regards toxicity and/or clinical androgenicity and other side effects. Certain more substantially modified structures, to be described, have properties extending beyond protein anabolism which make them therapeutically useful for treatment of several diseases.

Presently Known Clinical Activities of Testosterone

In the human, testosterone is known to improve protein anabolism in depleted individuals, and at supraphysiological levels, it can increase protein anabolism in healthy individuals. It can also maintain or improve bone density. These properties are classified as anabolic.

Androgenic properties include, for the male, development and maintenance of male sexual characteristics, induction or acceleration of development of male pattern baldness, and enlargement of the prostate. In the female, they can include induction of hirsutism, hoarsening and lowering of the voice, change in skin texture, menstrual irregularities, growth of cartilage of the nose, and enlargement of the clitoris. Other effects which may be experienced by either sex include acne, increased aggression, increased libido, or other mood changes. Many of the tissues experiencing these effects have high levels of 5a-reductase, an enzyme which converts testosterone to dihydrotestosterone (DHT).

Other effects, not readily categorizable as either anabolic or androgenic, include edema, suppression of LH/FSH, gynecomastia in the male, hypertension, and maturation of immature epiphyseal plates. These effects may be caused partly or entirely by the conversion of testosterone to estradiol in the body, accomplished principally by CYP 19 aromatase. Other effects include hypertension, reduction of HDL blood lipid, decreased blood clotting time, enlarged heart, CNS stimulation which may lead to insomnia or headaches, and reversible reduction or loss of fertility in the male. Testosterone is also known to modulate the immune system⁷ and to have other metabolic effects not discussed here.

These activities appear to be primarily the result of the ability of testosterone or certain of its metabolites, particularly DHT, to bind to the androgen receptor (AR) of cells. The AR then binds to DNA and increases the transcription of certain genes; this concept was proposed by Jensen and Jacobsen in 1963. There also appear to be effects at the translational level.⁸

Despite the list of undesirable potential effects, the fact remains that testosterone is normal and necessary to functioning of individuals of both sexes. The complications listed above should be considered to be potential results of abnormal use of testosterone.

Structure Activity Relationships

Prostate tissues contain high levels of 5a-reductase, which converts testosterone to DHT, and DHT was shown to be the active androgen in this tissue. Skeletal muscle, on the other hand, contains little or none of this enzyme, and so it seemed a plausible hypothesis that DHT was perhaps responsible for androgenic effects, and testosterone responsible for anabolic effects. In fact, however, muscle androgen receptors were found to bind DHT even better than testosterone, and the receptors of the two tissue types were indistinguishable.⁹

While it has been shown that shorter and longer length isoforms of the same AR do exist,¹⁰ they have the same binding site and no distinct difference in action has been found. The preponderance of evidence is that there is only one AR, and that differences in activity are a result either of difference in the length of time in which the AAS molecule remains bound to the receptor, or to differences resulting from tissue-specific metabolism of the drugs.¹¹

Accordingly, here structure activity relationship (SAR) shall be considered only as it concerns binding to the AR, and metabolism.

Three-dimensional shape is the primary consideration for determining the activity of a steroid molecule. Comparison of the shapes of testosterone and DHT vs. estradiol, an otherwise similar molecule, illustrates this point.

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The stereochemistry of the steroid skeleton must be identical to testosterone, as shown above, or the resulting change in three dimensional shape results in loss of activity.

The ß (lower) face of the steroid clearly binds to the AR.¹² The extent of a face binding is unclear, as is the manner in which the -3 keto exerts its influence.¹² A number of compounds do bind strongly to the AR while lacking -3 substitution; therefore, a -3 keto is not required.

Understanding of the binding is complicated by the fact that SAR studies have involved bioassays, in which binding to carrier protein is also a factor. The carrier protein (ABP) prefers saturation, as with DHT, to the D4 double bond, as with testosterone, but this structural feature has little to do with binding to the AR. Presence of a hydroxyl oxygen at -17 enhances binding at the AR, but not to ABP. Removal of the 19 methyl, as with nandrolone, reduces ABP binding, but does not impair AR binding.

Substitutions made which have still allowed full activity of a derivative or analogue include: 4-chloro; 6-chloro; 6a-chloro or fluoro; 6a or ß-methyl; various 7a substitutions; 9a-fluoro or chloro; 11-keto; 11-hydroxy, chloro, or fluoro; 11-keto; 17a-methyl or ethyl; saturation of D4; desaturation of D1, D5, D6, D10, or D11; various substitutions at -1, -2, and -3, and 13; and derivatization of the -17 hydroxyl.¹³

Substitutions which can eliminate or greatly reduce activity include 1a-ethyl; 2ß-fluoro; 3-methyl; 4-ethyl; 4,4-dimethyl; 5a-methyl; 10-cyano; 11ß-methyl; 13a-methyl; and bulky 17a substituents.¹³

A computer program has been developed which, reportedly, accurately predicts binding of steroids not only to the AR, but also to the estrogen, progesterone, and gluco- and mineralocorticoid receptors.¹⁴

Important considerations for metabolism include whether or not the 17 position is accessible for oxidation. If it is, then the drug generally cannot be given orally. Methyl substitution at this position will solve this problem, but results in some degree of hepatotoxicity, except with oxandrolone, and is correlated with a reduction in HDL blood lipid levels. The presence of C19 is also correlated with reduction of these lipid levels. Another characteristic of major importance is the A ring’s ability to be oxidized to aromaticity. If it is aromatized, the molecule acquires estrogenic activity. This factor must be considered in the design of these drugs, since conversion to estrogen is an undesired side effect.

The availability of a D4 double bond to be enzymatically reduced, and the activity of any such reduced metabolite relative to the unmetabolized drug, has been discovered to be of prime importance in determining a molecule’s dissociation between anabolic and androgenic effects. It has been shown recently that, unlike testosterone, nandrolone (19-nortestosterone) becomes less potent when it is metabolized to the dihydro from by 5a-reductase.¹⁵ This can explain the observed differential in levator ani:prostate activity in the rat. The potency of testosterone is increased in the prostate via metabolism, whereas the potency of nandrolone is decreased in the prostate by the analogous biotransformation.This principle may well apply to other AAS, and therefore the designer of drugs of this type must consider the results of activity of 5a-reductases not only in the prostate, but in the scalp and other tissues.

Unfortunately, binding to carrier proteins seems to be poorly understood. There may be important SAR relationships to be discovered in this area, perhaps significantly affecting the action of AAS, and offering the drug designer a means of achieving a greater selectivity of action.

The Creation of Oxandrolone

After the development of norethandrolone, Pappo, at Searle, became interested in the concept of developing testosterone analogues with a heteroatom in the steroid skeleton. Substitution of an oxygen for C2 seemed convenient and reasonable. The first compound produced had slight activity, which disproved the previously held theory that the fundamental steroid skeleton must remain unchanged. This was enough reason to justify further work. Together with Jung, Pappo later synthesized oxandrolone (17a-methyl-2-oxa-5a -androstan-17ß-ol-3-one).¹

Given orally to the rat, oxandrolone was found effective in decreasing urinary nitrogen excretion, but with no observed increase in the weight of the seminal vesicles or prostate. Toxicity was demonstrated to be of a very low order. Tests for estrogenicity, estrogen antagonism, progestational activity, progesterone antagonism, anti-inflammatory activity, and anti-desoxycorticosterone activity showed oxandrolone to exhibit none of these potential side effects.¹⁶

Human trials were performed on subjects on constant dietary intakes, and urinary nitrogen excretion was measured. Nitrogen sparing activity was observed with doses as low as 0.6 mg/day. Progressively greater responses were observed, with log response, as the dose was increased to 20 mg/day. The anabolic potency appeared to be 3.8-10.6 times that of methyltestosterone (95% confidence interval) with the mean estimate being 6.3 times the effectiveness.¹⁶

At dosages of up to 40 mg/day, oxandrolone had no effect on the excretion of sodium. Urinary hydroxycorticosteroids were not affected by oxandrolone, indicating no direct ACTH-suppressing activity. Effect on circulating eosinophiles was studied at 5 and 20 mg/day: oxandrolone exhibited no effect.¹⁶

Fox et al. point out that structurally the only difference between oxandrolone and methyldihydrotestosterone is the substitution of oxygen for carbon at the C2 position, and therefore oxandrolone’s improved potency is due solely to the introduction of the oxygen atom.¹⁶ However, in other molecules, generally no improvement is seen by this substitution.¹³

Uses of Oxandrolone Today

Oxandrolone is unique among the 17-methylated anabolic steroids in that it has minimal or no liver toxicity. Its safety may be due to the fact that it is largely excreted unchanged. BioTechnology General, which has recently re-released the drug, states that unlike other AAS, oxandrolone is primarily metabolized extrahepatically, and much is excreted unchanged.¹⁷

Uses include treatment of Turner’s Syndrome in girls,⁹ constitutionally delayed growth or puberty of boys,^18,19 and alcoholic hepatitis.²⁰ It is the only anabolic steroid approved by the FDA for the treatment of chronic underweight condition. The recent re-release of the drug was largely with a view towards use in the AIDS market for AIDS wasting syndrome.

The drug has also been found to change body fat patterns in obese men, producing proportionately more reduction of abdominal body fat relative to total body fat than is seen without the drug. This may be a health benefit.²¹

Oxandrolone is incapable of being aromatized, because of the presence of the oxygen atom in the A ring, and therefore has no metabolites of estrogenic activity. Anecdotally, it is known as being one of only two oral anabolic steroids of high safety with minimal side effects. (The other, methenolone, is not available in the United States.)

Other Steroids for Anabolic Use Exhibiting High Anabolic / Androgenic Dissociation

Nandrolone (IM) “Deca-Durabolin”

As described previously, this compound loses potency upon reduction, which provides a logical explanation for its observed improvement in anabolic/androgenic dissociation. It is effective for the treatment of osteoporosis,²² including corticosteroid-induced osteoporosis;²³ to augment total parenteral nutrition of the malnourished; in treatment of malnutrition of continuous ambulatory peritoneal dialysis (CAPD) patients;²⁴ for chronic obstructive pulmonary disease;²⁵ and can be of some value in stimulating erythropoesis. Nandrolone is of value in the treatment of anemia resulting from renal failure or other causes. There are anecdotal reports from physicians treating AIDS patients that nandrolone can effect a significant improvement in cell mediated immune function that manifests itself as increased CD8+ t-cells.²⁶ Increases in p24 antibodies have been noted.²⁷ As mentioned above, there are ongoing trials for the use of nandrolone in AIDS wasting,²⁸ including via transdermal delivery.

Nandrolone, at therapeutic doses, does not cause an unfavorable decrease in HDL blood lipid levels.²⁹ It is perhaps an interesting note that nandrolone has been found to be a natural product, found in horses, cattle, and boars.³⁰

Methenolone (I.M., oral) “Primobolan”

This drug is mentioned because of its successful use in Europe. This, oxandrolone, and testosterone undecanoate are the only oral steroids used for purposes of anabolism which demonstrate no clinically significant hepatotixicty. This drug is also considered to be the least virilizing of all the AAS, although oxandrolone may be comparable in this regard. Methenolone might plausibly be superior to nandrolone for treatment of women for any or all of the conditions for which nandrolone is used, but this drug is not available in the United States. Manufactured by Schering A.G., it is widely used elsewhere.

Testosterone Drug Products

Esterification of the -17 hydroxyl of testosterone produces a drug for I.M. injection with favorable pharmacodynamic properties. The resulting increase in partition coefficient causes most of the drug to be dissolved in lipid at any given time, with slow release to blood serum. Cypionate, enanthate, and undecanoate esters are common, with the longer chain esters having longer half lives. These may be in excess of one week.³¹

Use of testosterone esters includes hormone replacement therapy in males. Testosterone esters are also being researched as a means of contraception.³²

Testosterone undecanoate is also available in an oral formulation, which is absorbed directly into the lymphatic system and thus is not immediately oxidized by the liver, as would generally be the case with a non-17-alkylated testosterone. The oral formulation has a half life of a few hours, and clinically does not result in the significant inhibition of LH/FSH that is seen with I.M. testosterone esters, perhaps because of pharmacodynamic differences. One study found no liver problems in subjects that had used the drug for 10 years or more. Testosterone undecanoate has been used successfully in treating growth problems in boys,¹⁹ and, remarkably, has been shown to improve the serum lipid profile of older men,³³ and to be therapeutic to elderly male patients with myocardial ischemia, relieving angina pectoris and improving ECG and Holter recordings.

However, the clinically useful dosage is typically 240 mg/day, indicating low bioavailability of this formulation.

Testosterone patches have been developed, and recently improved so that they may be applied to the skin of the back rather than of the scrotum. The makers of this product (Androderm) consider the male hormone replacement therapy market to be worth approximately $800,000,000, of which they hope to obtain 10%. Patches are also being tested for use in AIDS wasting syndrome.³⁴

Sublingual testosterone cyclodextrin is another new product, and results in less suppression of LH/FSH than testosterone enanthate administered by I.M. injection. Half life is approximately one hour. This product is thought to be suitable for treatment of boys with delayed puberty, and for older men with androgen deficiency.³⁵

Researchers point out that testosterone, though at a lower concentration, is also normal to the female physiology, and older women may also suffer from androgen deficiency, resulting in loss of energy, depression, impairment of sexual functioning, and headaches. Returning testosterone levels to normal female physiological values, in combination with estradiol therapy, has been found beneficial. It is felt that this is a neglected area of medical practice, and further research is needed.³⁶

Dihydrotestosterone (Transdermal, I.M.)

DHT has proven effective in the treatment of microphallus, applied topically,³⁷ and has been shown to be of value in the treatment of elderly hypogonadal men. Within the prostate, exogenously supplied testosterone is enzymatically converted to DHT, a more potent agonist of the AR, and also to estradiol. Prostate enlargement is a common side effect of testosterone use, perhaps for these reasons. However, it has been found that when DHT itself is supplied to elderly hypogonadal men, reduction of prostate size occurs.³⁸ This appears to be due to inhibition of endogenous testosterone, estradiol, and aromatase. Furthermore, DHT is more potent than testosterone in most tissues (perhaps excepting muscle, as a result of enzymatic conversion to the diol) whereas testosterone is effectively less potent to those tissues lacking 5a-reductase. DHT can therefore be given in a lower dose than testosterone to achieve the same effect in target tissues, and therefore, less DHT, less testosterone, and less estradiol reach the prostate when DHT itself is given as the drug. However, DHT has not been studied much for use in replacement hormone therapy.

Derivatives of DHT, such as dromostanolone, may be of interest as well.

Testosterone Analogues of Value for Reasons Other Than Anabolism

Danazol (Oral) “Danacrit”

Danazol is the drug of choice for long term prophylaxis of hereditary angioedema. It is among the front line drugs for treatment of endometriosis.³⁹ Plausible mechanisms for which there is evidence for activity in this area include suppression of the midcycle surge of LH/FSH at the hypothalamic level,⁴⁰ inhibition of the transcription of the gene for the estrogen receptor in monocytes,⁴¹ inhibition of estrone sulfatase (required to convert estrone sulfate to estradiol),⁴² and stimulation of B cells.⁴³ Danazol therapy is also anti-osteoporotic, whereas many other drugs for endometriosis cause loss of bone mass.⁴⁴

A disadvantage of danazol therapy is that approximately 10% of patients experience hepatocellular damage, and virilizing side effects are frequent at therapeutic doses for treatment of endometriosis.⁴⁵ However, application via a vaginal suppository has proven an effective way to target the drug for treatment of endometriosis, which should reduce side effects.

Danazol has also been useful for treatment of fibrocystic myopathy of the breast,⁴⁶ mastalgia,⁴⁷ idiopathic thrombocytopenic purpurea,^47,48 mixed tissue disease with protein S deficiency,⁴⁹ autoimmune hemolytic anemia,^50,51 menorrhagia,⁵² and “severe PMS.”^53,54

Danazol binds to low affinity glucocorticoid binding sites (LAGS) in the liver.⁵⁵

Plasma fibrinogen and lipoprotein (a) levels decrease with danazol treatment, and plasminogen levels rise, thus inhibiting the process of thrombosis.

Stanozolol (Oral or I.M.) “Winstrol”

This drug is a potent anabolic, but also binds to the progesterone receptor⁵⁶ and to LAGS in the liver.⁵⁵ In muscle tissue, it has been found to stimulate immediate-early gene expression by a means independent of the AR.⁵⁷ Stanozolol can stimulate the production of prostaglandin E2 and the matrix metalloproteases collegenase and stromelysin in skin fibroblasts. It has been found to inhibit growth factor stimulated DNA synthesis and fibroblasts.⁵⁶ The drug has substantial fibrinolytic properties, and has been effective in the treatment of urticaria, Raynaud’s phenomenon, cryptofibrinogenemia, and lipodermatosclerosis.⁵⁸ It has also effected cures of osteonecrosis in cases resistant to all other therapy.⁵⁹ Stanozolol has been used successfully in treatment of AIDS wasting syndrome.⁶⁰

This drug is also useful in treatment of hereditary angioedema. It is somewhat hepatotoxic,⁶¹ but less so than many other oral anabolic steroids. It influences some immunological processes. Stanozolol has been found to increase lymphocyte count and CD8+ cell numbers, but to decrease CD4+ and CD3+ in postmenopausal women using it for osteoporosis.⁶² This effect would plausibly be useful for treatment of autoimmune disorders.

Stanozolol also lowers lipoprotein (a).⁶³

Tibolone (Oral) “Livial”

Tibolone shows weak estrogenic, progestogenic, and AR agonist properties.⁶⁴ It has been used in postmenopausal women and found to be effective in relieving climacteric symptoms and in maintaining skeletal integrity. It can reduce vasomotor symptoms and reduce vaginal dryness,⁵⁶ and improve peripheral microcirculation.⁶⁵ It has been found to improve sexual desire.⁶⁶ Tibolone has been seen to lower lipoprotein (a), triglycerides, and LDL blood lipids.⁶⁷

It has been argued that, unlike estradiol, tibolone will not stimulate estrogen-sensitive tumors, nor does it stimulate the endometrium, and therefore will not induce vaginal bleeding. (Nonetheless, in some clinical cases vaginal bleeding has been observed.) Only 2.5 mg/day is required. Further study of its suitability as a component in hormone replacement therapy for postmenopausal and perhaps elderly women seems called for.

Views Regarding Future Development

This class of drugs has been developed to date without assays that were ever proven to correlate accurately with therapeutic value or side effects of importance in the human, nor with any knowledge of the effects of enzymatic conversion of the drugs within each tissue. Perhaps most seriously, the entire concept of “androgenicity” being a single property of a steroid, in contrast to an “anabolic” property, was fundamentally incorrect. This is not to say that previous workers were incorrect to attempt to maximize the differences in activity which they could measure. It is simply that the means were not then available to adequately understand these drugs, and indeed the means are only developing now.

The acquisition of better understanding of structure activity relationships and the development of assays using cultured, differentiated human cells directly demonstrating desired therapeutic activity, as well as specific undesired side effects, should give the drug designer the tools necessary to design a new generation of anabolic/androgenic steroids of superior selectivity and safety. As an illustration, assays measuring ratios between levator ani myotrophic activity versus prostatotrophic activity in the castrated rat (the primary assay used in past development) could not reasonably be expected to of much value in identifying compounds of maximal therapeutic potency with minimal side effects for human female osteoporotic patients, whereas assays with cultured human cells might plausibly be very predictive of clinical properties.

Today, rational drug design which accounts for enzymatic biotransformations of steroid drugs is possible. For example, aromatization is generally an undesired side effect, and a number of obvious means may be employed specifically to defeat aromatase. At least several of these possibilities have never been made, but could readily be synthesized today.

Organic synthesis techniques today are considerably more versatile than they were in the 1950s and 1960s. At that time, synthesis of test compounds was, of necessity, generally limited to making whatever modifications could be made with the available techniques, which were limited. Quite a number of successful substitutions were made only in combination with each other, and never individually, because of this limitation. Perhaps some useful, even superior, drugs exist which possess only one of those substitutions. The probability of finding a useful drug by this method may be relatively high.

The power and universality of hormones in the body are such that, regardless of any improved separation of effects, these drugs shall always have to be approached with caution. Levels of drug which are supraphysiological in activity, relative to the sex of the patient, will always be a problem, although males can tolerate much more excess than females. Indeed, with males, the toxicity of overdose of AAS is, relative to almost all other drugs, outstandingly low. Nonetheless, undesired side effects do occur with supraphysiological levels of drug.

It seems inevitable that hormone replacement therapy for those leaving middle age shall become a large market. Unfortunately, the optimal set of levels of hormones for this population is something that is not known. Artificial restoration of hormone levels to more youthful values may well not be optimal.

For male hormone replacement therapy, testosterone itself or ester derivatives of it are today by far the predominant drug, though synthetic anabolic steroid drugs were developed precisely in order to provide a safer alternative. It is ironic that the same generation which recently banned anabolic steroids is now demanding testosterone for themselves. Many lawmakers or other eminent persons receive testosterone from their doctors, but most would probably deny that they are anabolic steroid users. Another consideration is that many doctors are extremely reluctant for perceived legal reasons to prescribe oxandrolone, methenolone, nandrolone, or other synthetics to their patients instead of testosterone.

It is to be hoped that such non-medical factors will not prevail. Testosterone itself has numerous disadvantages for the older male: it is likely to enlarge the prostate and may worsen blood lipid profiles, for example, and results in a relatively high degree of suppression of LH./FSH. That is not to say that it is obvious exactly what drugs should be used – if any – or in what manner. But it seems clear that synthetic analogues and derivatives should have important roles, for some of them offer real advantages.

Therapy for post-menopausal and elderly women has overlooked the fact that “androgens” are a normal part of the female physiology. At normal female physiological levels they do not result in virilization, but rather, their activity is to contribute to normal female function and health. Hormone replacement therapy for these women should not overlook this fact. Again, synthetics, particularly oxandrolone, methenolone, tibolone, and perhaps nandrolone, probably offer advantages relative to testosterone itself.

The hormonal milieu of the body is complex. It seems unlikely that simple solutions to problems of hormonal deficiency or to disease states that may be affected by hormones will ever yield optimal results. However, considerable progress has been made in the last few years in understanding the actions and effects of anabolic/androgenic steroids, and the exploding market for these products might soon motivate pharmaceutical firms to sponsor further research in this field.