Data are from Djerassi, C., Miramontes, L., Rosenkranz, G., et al.: Steroids. LIV. Synthesis of 19-Nor-17a-ethynyltestosterone and 19-Nor-17a-methyltestosterone. J. Am. Chem. Soc. 76:4092-4094, 1954.

Data are from Djerassi, C., Miramontes, L., Rosenkranz, G., et al.: Steroids. LIV. Synthesis of 19-Nor-17a-ethynyltestosterone and 19-Nor-17a-methyltestosterone. J. Am. Chem. Soc. 76:4092-4094, 1954.

action, although some activities at AR are retained. A disadvantage of the 17a-methyl testosterones is hepatotoxicity. Hepatic disturbances, jaundice (occasionally), and death (in rare cases) may occur, particularly in the high doses often used by athletes (see next section).

Table 25.5 illustrates some structure-activity effects of the androgens, such as the greatly decreased activity of the 17a-ol isomer of testosterone (epitestosterone). A carbonyl group at C3 and a 17^-OH on a steroid backbone are key structural features required for high affinity at the AR. Hundreds of different AAS have been synthesized and studied. The goal of many synthetic programs was to make a compound that possessed the anabolic properties of testosterone but lacked its androgenic actions. Although numerous compounds were prepared that did display improved anabolic/androgenic ratios in vitro, no compounds completely lacked androgenic action.117 Also, the high anabolic/androgenic ratios did not appear to be maintained when these drugs were used in humans. Despite the inability to prepare a strictly anabolic steroid, several trends were noticed in the structure-activity relationships for the hundreds of AAS that have been prepared.111 Removal of the C19 methyl, 5a-reduction, and replacement of C2 with an oxygen are all structural changes that tend to increase anabolic activity. Although most of the androgens have a carbonyl at C3, stanozolol (Fig. 25.22) represents an "anabolic" steroid that lacks the C3 carbonyl, but still is active. As with other compounds that have been discussed, OH groups in the testosterones are often converted to the corresponding esters to prolong activity or to provide some protection from oxidation.

Therapeutic Uses of Anabolic Androgenic Steroids

The primary use of AAS is in androgen replacement therapy in men, either at maturity or in adolescence. The cause of

Stanozolol Tetrahydrogestrinone (THG) Danazol

Figure 25.22 • Testosterone and synthetic anabolic androgenic steroids.

testosterone deficiency may be either hypogonadism or hypopituitarism.

The use of the AAS for their anabolic activity or for uses other than androgen replacement has been limited because of their masculinizing actions. This has greatly limited their use in women and children. Although anabolic activity is often needed clinically, especially in patients with AIDS, none of the products presently available is free of significant androgenic side effects.

The masculinizing (androgenic) side effects in females include hirsutism, acne, deepening of the voice, clitoral enlargement, and depression of the menstrual cycle. Furthermore, AAS generally alter serum lipid levels and increase the probability of atherosclerosis, characteristically a disease of men and postmenopausal women.

The masculinizing effects of the AAS preclude their use in most circumstances in women. Secondary treatment of advanced or metastatic breast carcinoma in selected patients is generally considered to be the only indication for large-dose, long-term androgen therapy in women. In lower doses, androgen replacement therapy is more often being considered for use in menopausal and postmenopausal women for the positive effects on libido, mood, vasomotor symptoms, and muscle mass, all areas negatively affected by decreased testosterone levels in aging women.118

Androgens are also used to relieve bone pain associated with osteoporosis and to treat certain anemias, although this use has greatly decreased because of the availability of erythropoietin. In all cases, use of these agents requires caution.

Androgens and Sports

The use of androgens for their anabolic effects (hence the term anabolic steroids) by athletes began in the late 1940s and has, at times, been widespread.119 Prior to urine testing requirements, it was estimated that up to 80% of competitive weight lifters and about 75% of professional football players used these drugs, along with various other athletes. Despite the growing awareness of the dangers of anabolic steroid use over the past 20 years, abuse of steroids is still a problem in many competitive sports. The recent Bay Area Laboratory Co-Operative (BALCO) scandal involving professional athletes in baseball, football, and track, and the continuing steroid problems seen in cycling illustrate this phenomenon all too well.

Some of the specific risks associated with the use/abuse of AAS are120:

In both sexes

Increased risk of coronary heart disease, stroke, or obstructed blood vessels

Increased aggression and antisocial behavior (known as

"steroid rage") Liver tumors, peliosis hepatis (blood-filled cysts), and jaundice (for 17a-alkylated androgens only) In men

Testicular atrophy with consequent sterility or decreased sperm count and abnormal motility and morphology Impotence Enlarged prostate

Breast enlargement (for androgens that can be converted to estrogens) In women Clitoral enlargement Facial and body hair growth Baldness Deepened voice Breast diminution

Because of these risks, the International Olympic Committee, numerous professional sports organizations, and the National Collegiate Athletic Association (NCAA) banned all anabolic drugs. Testing of elite athletes for performance-enhancing drugs of all types, as mentioned previously, is now commonplace.

Although numerous anabolic steroids have been synthesized and used/abused by athletes, most likely all of the androgens have been used by athletes in an attempt to improve strength and increase muscle mass. In the early years, the 17a-alkylated steroids with high anabolic/androgenic ratios in vitro were used with the belief that the anabolic properties of these drugs were greater than those of other androgens such as testosterone. With the ban on the use of steroids in most sports and the prevalence of drug testing, however, the 17a-alkylated steroids have fallen out of favor because of the ease of detecting these compounds by mass spectrometry. This has led to a greater use of testosterone and its esters, as well as the androgen precursors an-drostenedione ("andro"), androstenediol, androstanediol, and DHEA. The belief is that because these steroids all occur naturally, detecting them will be much more difficult. Although it is true that assays for the endogenous steroids must now discriminate deviations from normal ratios, it is possible to detect the abuse of these compounds. Pharmaceutical testosterone, for example, can be detected by a urine test examining the ratio of testosterone glu-curonide to epitestosterone glucuronide and by determining the carbon isotope ratio that can distinguish between synthetic and natural testosterone.121 Another approach to avoid detection is the synthesis and use of designer steroids, chemicals that have not been previously described and therefore are not actively pursued in drug screens. Tetrahydrogestrinone (THG) (see Figure 25.22) is a designer steroid associated with the BALCO scandal. THG is a derivative of the progestin, gestrinone, that was unknown prior to 2003.122 In 2004, THG and the testosterone precursors (except DHEA) were reclassified as Schedule III controlled substances.

Many studies have attempted to determine if taking anabolic steroids improves athletic performance.123,124 Some failed to use controls (athletes who trained in an identical manner but did not take anabolic steroids). Others failed to use placebos in at least a single-blind research design (neither the treated nor control groups knowing that they were taking).

An additional problem with many of the studies has been that typical therapeutic doses have been tested for their anabolic properties in clinical settings, whereas athletes typically use much higher doses.117 Although short-term enhancements in strength and increases in muscle mass have been observed, many negative side effects can be expected with long-term steroid use. It would be fair to say, therefore, that the benefit of anabolic steroids to athletic performance is uncertain. The risks of using these drugs appear to outweigh their benefits.

Anabolic Androgenic Steroid Products

Therapeutic uses of the androgens are discussed previously. 17^-Esters and 17a-alkyl products are available for a complete range of therapeutic uses. These drugs are contraindi-cated in men with prostate cancer; in men or women with heart, kidney, or liver disease; and in pregnancy. Diabetics using the androgens should be carefully monitored. Androgens potentiate the action of oral anticoagulants, causing bleeding in some patients, and they may also interfere with some laboratory tests. Female patients may develop vir-ilization side effects, and doctors should be warned that some of these effects may be irreversible (e.g., voice changes). All the anabolic agents currently commercially available (oxymetholone, oxandrolone, nandrolone decanoate) have significant androgenic activity; hence, virilization is a potential problem for all women patients. Many of the anabolic agents are orally active, as one would predict by noting a 17a-alkyl group in many of them (see Fig. 25.22). Those without the 17a-alkyl (nandrolone decanoate) are active only intramuscularly. The 17a-alkyl products may induce liver toxicity in some patients.

Testosterone, USP. Testosterone, 17^-hydroxyandrost-4-en-3-one, is a naturally occurring androgen in men. In women, it mainly serves as a biosynthetic precursor to estra-diol but also has other hormonal effects. It is rapidly metabolized to relatively inactive 17-ones (see Fig. 25.21), however, preventing significant oral activity. Testosterone is available in a transdermal delivery system (patch), a gel formulation, a buccal system, and as implantable pellets. Testosterone 17^-esters are available in long-acting IM depot preparations illustrated in Figure 25.22, including the following:

• Testosterone cypionate, USP: Testosterone 17^-cyclopentylpropionate

• Testosterone enanthate, USP: Testosterone 17^-heptanoate

• Testosterone propionate, USP: Testosterone 17^-propionate

In addition, a NDA for testosterone undecanoate (Nebido) was filed in 2007 for approval as a long-acting preparation for the treatment of male hypogonadism. It is already approved for this use in Europe.

Methyltestosterone, USP. Methyltestosterone, 17^-hydroxy-17-methylandrost-4-en-3-one, is only about half as active as testosterone (intramuscularly), but it has the great advantage of being orally active.

Fluoxymesterone, USP. Fluoxymesterone, 9a-fluoro-11j6,17jS-dihydroxy-17-methylandrost-4-en-3-one, is a highly potent, orally active androgen, about 5 to 10 times more potent than testosterone. It can be used for all the indications discussed previously, but its great androgenic activity has made it useful primarily for treatment of the androgen-deficient male.

Oxymetholone, USP. Oxymetholone, 17j8-hydroxy-2-(hydroxymethylene)-17-methylandrostan-3-one, is approved for the treatment of various anemias.

Oxandrolone, USP. Oxandrolone, 17j8-hydroxy-17-methyl-2-oxaandrostan-3-one, is approved to aid in the promotion of weight gain after weight loss following surgery, chronic infections, or severe trauma and to offset protein ca-tabolism associated with long-term corticosteroid use. Oxandrolone is also used to relieve bone pain accompanying osteoporosis. It has been used to treat alcoholic hepatitis and HIV wasting syndrome.

Nandrolone Decanoate, USP. Nandrolone decanoate, 17j8-hydroxyestr-4-en-3-one 17-decanoate, has been used in the management of certain anemias, but the availability of erythropoietin has greatly reduced this use.

Danazol and Endometriosis

Danazol, USP. Danazol, 17a-pregna-2,4-dien-20-yno-[2,3-d]isoxazol-17-ol, is a weak androgen that, in spite of the 17a-ethinyl group, has little estrogenic or progesto-genic activity. Danazol has been called a synthetic steroid with diverse biological effects.125 Danazol binds to sex hormone-binding globulin (SHBG) and decreases the hepatic synthesis of this estradiol and testosterone carrier. Free testosterone thus increases. Danazol inhibits FSH and LH production by the hypothalamus and pituitary. It binds to PRs, GRs, ARs, and ERs. Although the exact mechanism of action is unclear, danazol alters endometrial tissue so that it becomes inactive and atrophic, which allows danazol to be an effective treatment for endometriosis. Danazol is also used to treat hereditary angioedema and fi-brocystic breast disease.


Various compounds (Fig. 25.23) have been intensively studied as AR antagonists, or antiandrogens.126,127 Antiandrogens are of therapeutic use in treating conditions of hyperan-drogenism (e.g., hirsutism, acute acne, and premature baldness) or androgen-stimulated cancers (e.g., prostatic carcinoma). The ideal antiandrogen would be nontoxic, highly active, and devoid of any hormonal activity. Both steroidal and nonsteroidal antiandrogens have been investigated, but only nonsteroidal antiandrogens have been approved for use in the United States. Cyproterone acetate, a steroidal antiandrogen, is used in Europe. The steroidal antiandrogens typically have actions at other steroid receptors that limit their use. The nonsteroidal antiandrogens, while lacking hormonal activity, bind with lower affinity to the AR than the endogenous hormones.


Three nonsteroidal antiandrogens are in clinical use in the United States—flutamide, bicalutamide, and nilutamide (Fig. 25.23). They are mainly used in the management of prostate cancer. Flutamide was the first of these compounds approved for use by the FDA, but liver toxicity and thrice-daily dosing offered room for improvement. It was also determined that a metabolite of flutamide, hydroxyflutamide, had greater antiandrogen action than the parent. Bicalutamide, which has greater potency than flutamide, incorporates an OH into its structure at the same relative position as in hydroxyflutamide. Bicalutamide is dosed once a day and has less toxicity than flutamide and nilutamide, making it a preferred choice when initiating therapy.

Prostate cancer is strongly androgen sensitive, so by blocking AR, the cancer can be inhibited or slowed. Studies have shown that these drugs completely inhibit the action of testosterone and other androgens by binding to AR. In clinical trials when given as a single agent for prostate cancer, serum testosterone and estradiol increase. But when given in combination with a GnRH agonist, such as gosere-lin or leuprolide, bicalutamide and flutamide do not affect testosterone suppression, which is the result of GnRH. GnRH agonists greatly decrease gonadal function—the medical equivalent of castration in men. Thus, the combination of GnRH with bicalutamide or flutamide blocks the production of testosterone in the testes and AR in the prostate.

Antiandrogen Products

Flutamide, USP. Flutamide, 2-methyl-N-[4-nitro-3-(tri-fluoromethyl)phenyl]propanamide, is dosed 3 times daily (250-mg dose; 750-mg total daily dose). A major metabolite of flutamide, hydroxyflutamide, is a more potent AR antagonist than the parent compound. This metabolite, which is present at a much higher steady-state concentration than is flutamide, contributes a significant amount of the

Figure 25.23 • Antiandrogens.

Figure 25.23 • Antiandrogens.

antiandrogen action of this drug. A limiting factor in the use of flutamide is hepatotoxicity in from 1% to 5% of patients. Although the hepatotoxicity usually is reversible following cessation of treatment, rare cases of death associated with hepatic failure have been reported to be associated with flutamide therapy. Diarrhea is also a limiting side effect with flutamide therapy for some patients.

Bicalutamide, USP. Bicalutamide, N-4-cyano-3-(triflu-oromethyl)phenyl-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-

2-methyl-propanamide (Casodex), is more potent than flutamide and has a much longer half-life (5.9 days vs. 6 hours for hydroxyflutamide). Because of the longer half-life, bicalutamide is used for once-a-day (50 mg) treatment of advanced prostate cancer. Bicalutamide is available as a racemic mixture, but both animal and human studies with the AR show that the R-enantiomer has higher affinity for the AR than the S-enantiomer.128

Nilutamide, USP. Nilutamide, 5,5-dimethyl-3-[4-nitro-

3-(trifluoromethyl)phenyl]-2,4-imidazolidinedione, is used in combination with surgical castration for the treatment of metastatic prostate cancer. Nilutamide, which has an elimination half-life of approximately 40 hours, can also be used in once-daily dosing, but it has side effects that limit its use—visual disturbances, alcohol intolerance, and allergic pneumonitis.

Inhibition of 5a-Reductase

5a-DHT is important for maintaining prostate function in men. The formation of DHT is mediated by 5a-reductase, an enzyme that has two distinct forms, type I and type II.129,130 The type I enzyme is located in the liver and some peripheral tissues and is involved mainly in the metabolism of testosterone and other A-ring enones. The type II enzyme is located in the prostate gland and testes and is responsible for the conversion of testosterone to DHT for androgenic action. Blocking this enzyme is one approach for controlling androgen action. The review by Harris and Kozarich provides an excellent background and details the development of finasteride, the first 5a-reductase inhibitor approved for use in the United States (Fig. 25.24).131

DHT also plays a major role in the pathogenesis of benign prostatic hyperplasia (BPH). Finasteride, (5a,17jS)-N-(1,1-dimethylethyl)-3-oxo-4-azaandrost-1-ene-17-carbox-amide (Proscar, Propecia), is a potent, slow, tight-binding inhibitor of 5a-reductase that functions by a unique mechanism. Finasteride is activated by the enzyme and irreversibly binds to the NADP cofactor, yielding a finasteride-NADP complex that is only slowly released from the enzyme active site, producing essentially irreversible inhibition of the enzyme (Fig. 25.25).132 The turnover from the finasteride-5a-reductase complex is very slow (t1/2—30 days).

Finasteride is a relatively selective inhibitor of type II 5a-reductase. This enzyme is present in high levels in the prostate and at lower levels in other tissues. Because of the strong connection to the formation of DHT in the prostate, it was theorized that specific inhibition of this isoform would yield the greatest therapeutic effect. Other studies suggest, however, that the type I isoform may also play a role in the progression of hormone-dependent prostate cancer.133 Because of this, dual 5a-reductase inhibitors have been developed. Dutasteride, (5a,17j8)-N-{2,5

Finasteride (Proscar, Propecia)
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