AASs are a group of steroid hormones derived from chemical modification of testosterone. The precursor to testosterone is cholesterol; endogenous synthesis is limited by cholesterol delivery to mitochondria for modification. After synthesis and secretion, testosterone is further converted to strong androgens to include dihydrotestosterone (DHT) via 5α-reductase, and weak androgens to include dehydroepiandrosterone (DHEA) and androstenedione. Testosterone is also converted via aromatase to estradiol, an active metabolite, although not an AAS. The terms anabolic and androgenic derive from their ability to promote positive nitrogen balance and accretion of lean body mass, as well as masculinization.

In men, androgens are made in the Leydig cells of the testes. In women, androgens are made in the corpus luteum of the ovary. The adrenal cortex is the main site of DHEA synthesis. Peripheral conversion of testosterone into DHT occurs in the skin, prostate, and external genitalia and into estradiol by liver and adipose tissue.

Endogenous AASs have diverse effects with three distinct physiologic surges. The most prominent are effects on male sexual differentiation starting during the fetal period at weeks 6 through 8 of gestation, when AASs promote the development of male genitalia. The second surge occurs during the neonatal period, when AASs are involved in the growth of the phallus to normal size, in testicular descent, and in spermatogonial development. The final surge assists with secondary sexual characteristics during puberty, including growth and development of the prostate, seminal vesicles, penis, and scrotum. Pubertal changes in hair growth and sebaceous glands result in the male pattern of hair growth on the chin, pubic area, chest, and axillary regions, as well as acne provocation via increased sebum production. Vocal cords begin to thicken along with enlargement of the larynx, with resulting voice deepening. Data indicating decreased urinary nitrogen levels support AAS effects on protein anabolism that lead to an increase in lean body mass, specifically in the upper girdle, and alterations of fat distribution. Further structural changes occur with increases in bone mineral density and long bone growth, as well as closure of the epiphyses. Neurologic changes include increased libido and spontaneous erections. Other effects include assistance with wound healing, stimulation of liver release of clotting factors and erythropoietin with a secondary increase in hematocrit, and suppression of high-density lipoprotein (HDL) synthesis (Box 50-1).

During puberty, when testosterone levels surge to stimulate bone growth, peripheral androgen conversion via aromatase also peaks. Newly synthesized estradiol promotes epiphyseal closure during puberty, thus counteracting the effects of testosterone. In patients with aromatase deficiency or estradiol receptor dysfunction, long bones continue to grow, with resultant osteoporosis secondary to continued and unmonitored growth. This mechanism is different from estrogen’s effect on osteoclasts and osteoblasts associated with osteoporosis in postmenopausal women.

Total, free, and bioavailable testosterone levels decrease with age. This change contributes to the decrease in muscle mass, increase in fat, decrease in libido, increase in fatigue, and minor decreases in cognitive function seen in elderly persons.

Approximately 50% of circulating testosterone is strongly bound to sex hormone–binding globulin (SHBG); 40% is weakly bound to albumin; and 2% is unbound or free. The albumin-bound and unbound forms constitute the “bioavailable” and thus active forms of testosterone. AASs act by binding to specific intracellular androgen receptors located throughout the body; this interaction mediates the androgenic and anabolic effects of androgens. Dihydrotestosterone, being a strong androgen, has very high affinity for androgen receptors. Estradiol, formed by aromatase conversion of testosterone, exerts its effects by binding to estrogen receptors throughout the body.

Because AASs are rapidly metabolized by the first-pass effect through the gut and liver, oral testosterone supplements are highly ineffective in the absence of modification. Alkylation of testosterone confers resistance to hepatic metabolism and results in AASs that can be administered orally. Esterification of testosterone emulsifies testosterone for intramuscular injection. Addition of carbon chains to the ring structure of testosterone increases fat solubility and extends the duration of action.

Patients with low androgen levels may complain of fatigue, hypoactive sexual desire, erectile dysfunction, diminished pubic and/or facial hair, and testicular atrophy. Other findings include diminished prostate size, abnormal sperm morphology, absent motility of sperm, and hypoproliferative normochromic anemia. Patients with elevated levels may complain of resistant acne or sudden-onset acne. Women in particular complain of hirsutism and irregular menses.

AASs are indicated for use in male hypogonadism and constitutional delay of growth and puberty. Use for stimulation of growth is cautioned because it may also concomitantly accelerate epiphyseal closure and thereby limit ultimate height achievement. Androgens are also used as prophylaxis in hereditary angioneurotic edema and as second-line therapies for osteoporosis and aplastic or hypoplastic anemias. Gynecologic uses include treatment of endometriosis with weak androgens, reduction of postpartum breast engorgement in conjunction with estrogen, and elimination of estrogen-mediated menstrual bleeding for postmenopausal women undergoing hormone replacement. Oncologically, androgens can be used to suppress some breast tumors in premenopausal women.

AASs may help elderly men by increasing body weight and muscle mass, preventing bone loss (vertebral but not femoral bone density), and improving the hematocrit; however, AASs are not without side effects. In addition, research has used androgens as male contraceptives, in chronic obstructive pulmonary disease, and in other hypogonadal wasting syndromes such as human immunodeficiency virus (HIV)–related muscle wasting and glucocorticoid muscle and bone wasting. All these uses are still under investigation.

5α-Reductase inhibitors are used to diminish testosterone conversion to DHT in peripheral tissues, most importantly the prostate gland and hair follicles. They are approved by the Food and Drug Administration (FDA) for treatment of benign prostatic hyperplasia and to combat early male pattern baldness. Androgen antagonists are also used for metastatic prostate cancer and female hirsutism.

First noted in the 1950s, AAS abuse was mostly limited to bodybuilders, other muscle building enthusiasts, and various professional athletes. It is now known that AAS abuse is far more widespread. According to the results of a 2003 monitoring study, 60% of high school seniors (male and female) have a history of AAS use, with a dramatic increase in female adolescents over the past few years. The National Institute of Drug Abuse (NIDA) report in 2007 noted use in 2.3% of boys versus 0.6% of girls. The NIDA more recently estimated that more than half a million eighth through tenth grade students are abusing AASs. Another study found that 1,084,000 Americans, or 0.5% of the adult population, have admitted to using AASs.

In the world of competitive athletics, bodybuilders are the biggest offenders with regard to AAS abuse. Because AASs increase the hematocrit through enhanced erythropoietin production, these substances may also be used by athletes participating in endurance-oriented sports. Nonathletes may use AASs solely to improve appearance. Surveys have shown the percentage of students who reported lifetime AAS use has increased from 2.7% to 6.1% since 2000. Most users are men, although up to 2% may be women. Other risk factors include involvement in school sports and the use of other illicit drugs, alcohol, or tobacco.

Both athletes and coaches are likely to answer unequivocally, “Yes.” AASs used in conjunction with adequate protein and carbohydrate intake, and proper training, in experienced athletes seem to induce greater and more rapid gains. A study comparing supraphysiologic doses of testosterone enanthate with placebo in eugonadal men found clear increases in muscle size and strength, with or without weight-training exercise. Studies of AASs in athletes have shown an increase in body weight and lean body mass, but no significant decrease in the percentage of body fat. Not only do muscle fibers gain in cross-sectional diameter with anabolic steroid use, but also new muscle fibers are formed. The upper regions of the body are the most susceptible to gains from AAS because of the relatively larger number of androgen receptors in these areas.

Doses used for illicit purposes are markedly higher (10-fold or more) than physiologic and therapeutic doses. Furthermore, multiple agents are often used in so-called stacking regimens or arrays in which multiple steroids at increasing doses are used to derive further effects. The drugs are often taken in 6- to 12-week cycles with variable periods off the drugs, but some athletes may use them as long as 1 year or more. Human chorionic gonadotropin may be used at the end of a cycle to stimulate gonadal function. Little is known about precise doses or stacking regimens; however, some anecdotal information is available.

Many different side effects have occurred with AAS use and abuse. Abuse is associated with increased rates of morbidity and mortality. Fortunately, most side effects are temporary and reversible with cessation of AASs (Table 50-1). The most common side effects are hepatic dysfunction, including cholestatic jaundice and development of hepatic neoplasms; most worrisome is peliosis hepatis, rupture of which can result in death. Other common side effects include gynecomastia, acne, male pattern baldness, increased aggression, and alterations in the cholesterol profile including an increase in low-density lipoprotein (LDL) and a decrease in HDL. Long-term AAS use is associated with a reduction in the production of natural sex hormones that is usually reversible but may take more than a year to resolve. There is also an increase in cardiovascular disease because of fluid retention, exacerbation of hypertension, increased liver synthesis of clotting factors, development of polycythemia, and vasospasm induction via effects on vascular nitric oxide. Men may be at increased risk for development of prostate problems in previously benign or local disease, impotence, and testicular atrophy resulting in infertility. Women may experience menstrual irregularities such as oligomenorrhea or amenorrhea and virilizing effects such as hirsutism, clitoromegaly, and deepening of the voice. In adolescents, one must be cautious of premature epiphyseal closure leading to a reduction in final adult height and psychological dysfunction resulting from androgen effects on brain development (see Table 50-1).

Urine samples are evaluated via mass spectroscopy and gas chromatography, in which direct confirmation comes from measurement of protein kinase C (PKC). PKC reflects an endogenous synthetic origin and rules in or out a potential physiologic anomaly. An increased ratio of urine testosterone to epitestosterone (>6:1) is also confirmatory of AAS use. Furthermore, urine samples with a high ratio of testosterone to leuteinizing hormone (LH) greater than 30 suggest AAS abuse because LH secretion is suppressed in subjects using testosterone.

These are products or supplements advertised to be metabolized to testosterone or other active metabolites. In 2004, the U.S. Congress passed the Anabolic Steroid Control Act, which banned prohormones indefinitely.

Mixed data since 2000 have shown that acute oral ingestion of greater than or equal to 200 mg daily of androstenedione or androstenediol modestly increases serum testosterone and circulating estrogen concentrations in men and women. However, doses lower than 300 mg taken for up to 12 weeks have shown no effect on body composition or physical performance.

Yes, the literature suggests that use of suprapharmacologic doses can be anabolic in certain situations. However, the situations and mechanisms of action are unclear, and side effects similar to those for AAS occur.