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Chapter: Basic & Clinical Pharmacology : The Gonadal Hormones & Inhibitors

Metabolism - The Testis

In many target tissues, testosterone is converted to dihydrotestos-terone by 5α-reductase.


In many target tissues, testosterone is converted to dihydrotestos-terone by 5α-reductase. In these tissues, dihydrotestosterone is the major active androgen. The conversion of testosterone to estradiol by P450 aromatase also occurs in some tissues, including adipose tissue, liver, and the hypothalamus, where it may be of importance in regulating gonadal function.

The  major  pathway  for  the  degradation  of  testosterone  in humans occurs in the liver, with the reduction of the double bond and ketone in the A ring, as is seen in other steroids with a 4-ketone configuration in the A ring. This leads to the produc-tion  of  inactive  substances  such  as  androsterone  and  etiocholanolone that are then conjugated and excreted in the urine.

Androstenedione, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS) are also produced in significant amounts in humans, although largely in the adrenal gland rather than in the testes. They contribute slightly to the normal maturation process supporting other androgen-dependent pubertal changes in the human, primarily development of pubic and axillary hair and bone maturation. As noted, some studies suggest that DHEA and DHEAS may have other central nervous system and metabolic effects and may prolong life in rabbits. In men they may improve the sense of well-being and inhibit atherosclerosis. In a placebo-controlled clinical trial in patients with systemic lupus erythematosus, DHEA demonstrated some beneficial effects (see Adrenal Androgens). Adrenal androgens are to a large extent metabolized in the same fashion as testosterone. Both steroids—but particularly androstenedione— can be converted by peripheral tissues to estrone in very small amounts (1–5%). The P450 aromatase enzyme responsible for this conversion is also found in the brain and is thought to play an important role in development.

Physiologic Effects

In the normal male, testosterone or its active metabolite 5α-dihydrotestosterone is responsible for the many changes that occur in puberty. In addition to the general growth-promoting properties of androgens on body tissues, these hormones are responsible for penile and scrotal growth. Changes in the skin include the appearance of pubic, axillary, and beard hair. The sebaceous glands become more active, and the skin tends to become thicker and oilier. The larynx grows and the vocal cords become thicker, leading to a lower-pitched voice. Skeletal growth is stimulated and epiphysial closure accelerated. Other effects include growth of the prostate and seminal vesicles, darkening of the skin, and increased skin circulation. Androgens play an impor-tant role in stimulating and maintaining sexual function in men. Androgens increase lean body mass and stimulate body hair growth and sebum secretion. Metabolic effects include the reduc-tion of hormone binding and other carrier proteins and increased liver synthesis of clotting factors, triglyceride lipase, α1-antitrypsin, haptoglobin, and sialic acid. They also stimulate renal erythropoi-etin secretion and decrease HDL levels.

Synthetic Steroids with Androgenic & Anabolic Action

Testosterone, when administered by mouth, is rapidly absorbed. However, it is largely converted to inactive metabolites, and only about one sixth of the dose administered is available in active form. Testosterone can be administered parenterally, but it has a more prolonged absorption time and greater activity in the propionate, enanthate, undecanoate, or cypionate ester forms. These derivatives are hydrolyzed to release free testosterone at the site of injection. Testosterone derivatives alkylated at the 17 position, eg, methyltes-tosterone and fluoxymesterone, are active when given by mouth.

Testosterone and its derivatives have been used for their ana-bolic effects as well as in the treatment of testosterone deficiency.

Although testosterone and other known active steroids can be isolated in pure form and measured by weight, biologic assays are still used in the investigation of new compounds. In some of these studies in animals, the anabolic effects of the compound as measured by trophic effects on muscles or the reduction of nitrogen excretion may be dissociated from the other androgenic effects. This has led to the marketing of compounds claimed to have anabolic activity associated with only weak androgenic effects. Unfortunately, this dissociation is less marked in humans than in the animals used for testing (Table 40–5), and all are potent androgens.

Pharmacologic Effects

A. Mechanism of Action

Like other steroids, testosterone acts intracellularly in target cells. In skin, prostate, seminal vesicles, and epididymis, it is converted to 5α-dihydrotestosterone by 5α-reductase. In these tissues, dihy-drotestosterone is the dominant androgen. The distribution of this enzyme in the fetus is different and has important developmental implications.

Testosterone and dihydrotestosterone bind to the intracellular androgen receptor, initiating a series of events similar to those described above for estradiol and progesterone, leading to growth, differentiation, and synthesis of a variety of enzymes and other functional proteins.

B. Effects

In the male at puberty, androgens cause development of the sec-ondary sex characteristics (see above). In the adult male, large doses of testosterone—when given alone—or its derivatives sup-press the secretion of gonadotropins and result in some atrophy of the interstitial tissue and the tubules of the testes. Since fairly large doses of androgens are required to suppress gonadotropin secre-tion, it has been postulated that inhibin, in combination with androgens, is responsible for the feedback control of secretion. In women, androgens are capable of producing changes similar to those observed in the prepubertal male. These include growth of facial and body hair, deepening of the voice, enlargement of the clitoris, frontal baldness, and prominent musculature. The natural androgens stimulate erythrocyte production.

The administration of androgens reduces the excretion of nitro-gen into the urine, indicating an increase in protein synthesis or a decrease in protein breakdown within the body. This effect is much more pronounced in women and children than in normal men.

Clinical Uses

A. Androgen Replacement Therapy in Men

Androgens are used to replace or augment endogenous androgen secretion in hypogonadal men (Table 40–6). Even in the presence of pituitary deficiency, androgens are used rather than gonadotropin except when normal spermatogenesis is to be achieved. In patients with hypopituitarism, androgens are not added to the treatment regimen until puberty, at which time they are instituted in gradually increasing doses to achieve the growth spurt and the development of secondary sex characteristics. In these patients, therapy should be started with long-acting agents such as testosterone enanthate or cypionate in doses of 50 mg intramuscularly, initially every 4, then every 3, and finally every 2 weeks, with each change taking place at 3-month intervals. The dose is then doubled to 100 mg every 2 weeks until maturation is complete. Finally, it is changed to the adult replacement dose of 200 mg at 2-week intervals.

Testosterone propionate, though potent, has a short duration of action and is not practical for long-term use. Testosterone unde-canoate can be given orally, administering large amounts of the steroid twice daily (eg, 40 mg/d); however, this is not recom-mended because oral testosterone administration has been associ-ated with liver tumors. Testosterone can also be administered transdermally; skin patches or gels are available for scrotal or other skin area application. Two applications daily are usually required for replacement therapy. Implanted pellets and other longer-acting preparations are under study. The development of polycythemia or hypertension may require some reduction in dose.

B. Gynecologic Disorders

Androgens are used occasionally in the treatment of certain gyne-cologic disorders, but the undesirable effects in women are suchthat they must be used with great caution. Androgens have been used to reduce breast engorgement during the postpartum period, usually in conjunction with estrogens. The weak androgen danazol is used in the treatment of endometriosis (see above).

Androgens are sometimes given in combination with estrogens for replacement therapy in the postmenopausal period in an attempt to eliminate the endometrial bleeding that may occur when only estrogens are used and to enhance libido. They have been used for chemotherapy of breast tumors in premenopausal women.

C. Use as Protein Anabolic Agents

Androgens and anabolic steroids have been used in conjunction with dietary measures and exercises in an attempt to reverse pro-tein loss after trauma, surgery, or prolonged immobilization and in patients with debilitating diseases.

D. Anemia

In the past, large doses of androgens were employed in the treatment of refractory anemias such as aplastic anemia, Fanconi’s anemia, sickle cell anemia, myelofibrosis, and hemolytic anemias. Recombinant erythropoietin has largely replaced androgens for this purpose.

E. Osteoporosis

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, bisphos-phonates have largely replaced androgen use for this purpose.

F. Use as Growth Stimulators

These agents have been used to stimulate growth in boys with delayed puberty. If the drugs are used carefully, these children will probably achieve their expected adult height. If treatment is too vigorous, the patient may grow rapidly at first but will not achieve full predicted final stature because of the accelerated epiphysial closure that occurs. It is difficult to control this type of therapy adequately even with frequent X-ray examination of the epiphyses, since the action of the hormones on epiphysial centers may con-tinue for many months after therapy is discontinued.

G. Anabolic Steroid and Androgen Abuse in Sports

The use of anabolic steroids by athletes has received worldwide attention. Many athletes and their coaches believe that anabolic steroids—in doses 10–200 times larger than the daily normal physiologic production—increase strength and aggressiveness, thereby improving competitive performance. Such effects have been unequivocally demonstrated only in women. Furthermore, the adverse effects of these drugs clearly make their use inadvisable.

H. Aging

Androgen production falls with age in men and may contribute to the decline in muscle mass, strength, and libido. Preliminary studies of androgen replacement in aging males with low andro-gen levels show an increase in lean body mass and hematocrit and a decrease in bone turnover. Longer studies will be required to assess the usefulness of this therapy.

Adverse Effects

The adverse effects of these compounds are due largely to their masculinizing actions and are most noticeable in women and pre-pubertal children. In women, the administration of more than 200–300 mg of testosterone per month is usually associated with hirsutism, acne, amenorrhea, clitoral enlargement, and deepening of the voice. These effects may occur with even smaller doses in some women. Some of the androgenic steroids exert progesta-tional activity, leading to endometrial bleeding upon discontinua-tion. These hormones also alter serum lipids and could conceivably increase susceptibility to atherosclerotic disease in women.

Except under the most unusual circumstances, androgens should not be used in infants. Recent studies in animals suggest that administration of androgens in early life may have profound effects on maturation of central nervous system centers governing sexual development, particularly in the female. Administration of these drugs to pregnant women may lead to masculinization or undermasculinization of the external genitalia in the female and male fetus, respectively. Although the above-mentioned effects may be less marked with the anabolic agents, they do occur. Sodium retention and edema are not common but must be carefully watched for in patients with heart and kidney disease.

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 treat-ment, 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.

Replacement therapy in men may cause acne, sleep apnea, erythrocytosis, gynecomastia, and azoospermia. Supraphysiologic doses of androgens produce azoospermia and decrease in testicular size, both of which may take months to recover after cessation of therapy. The alkylated androgens in high doses can produce pelio-sis hepatica, cholestasis, and hepatic failure. They lower plasma HDL and may increase LDL. Hepatic adenomas and carcinomas have also been reported. Behavioral effects include psychological dependence, increased aggressiveness, and psychotic symptoms.

Contraindications & Cautions

The use of androgenic steroids is contraindicated in pregnant women or women who may become pregnant during the course of therapy.

Androgens should not be administered to male patients with carcinoma of the prostate or breast. Until more is known about the effects of these hormones on the central nervous system in develop-ing children, they should be avoided in infants and young children.

Special caution is required in giving these drugs to children to produce a growth spurt. In most patients, the use of somatotropin is more appropriate .

Care should be exercised in the administration of these drugs to patients with renal or cardiac disease predisposed to edema. If sodium and water retention occurs, it will respond to diuretic therapy.

Methyltestosterone therapy is associated with creatinuria, but the significance of this finding is not known.

Caution: Several cases of hepatocellular carcinoma have beenreported in patients with aplastic anemia treated with androgen anabolic therapy. Erythropoietin and colony-stimulating factors  should be used instead.

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