Use and abuse of anabolic-androgenic steroids and androgen precursors
1. What are anabolic-androgenic steroids (AASs)?
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.
3. Summarize the biologic effects of AASs.
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).
4. How does testosterone mediate effects via estradiol?
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.
5. How do AAS levels change with age?
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.
6. How do AASs exert their effects?
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.
7. How are androgens metabolized, and why is it necessary to modify testosterone for administration?
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.
