Androgens

Testosterone and its metabolite dihydrotestosterone (DHT) drive the growth of the male sex organs and maintain secondary sex characteristics — male hair distribution, a deeper voice, muscle and fat distribution. In many tissues testosterone acts after reduction to DHT, which binds an intracellular receptor and changes gene transcription.

The products are labeled for testosterone replacement in adult males with a deficiency or absence of endogenous testosterone: primary hypogonadism (testicular failure, with gonadotropins above the normal range) and hypogonadotropic hypogonadism (gonadotropin or LHRH deficiency, or pituitary-hypothalamic injury, with gonadotropins normal or low). Before starting, the diagnosis is confirmed by morning serum testosterone measured on at least two separate days. Safety and efficacy in “age-related hypogonadism” have not been established, and the products are not indicated for women.

Exogenous androgens inhibit the body’s own testosterone release through feedback inhibition of pituitary LH, and at large doses they also suppress spermatogenesis through feedback inhibition of pituitary FSH. The labels warn that this may lead to azoospermia, that reduced fertility is seen in some men on replacement therapy, and that the impact on fertility may be irreversible.

Testosterone gel (Testim) is applied to the shoulders and upper arms; the skin acts as a reservoir. Its boxed warning concerns secondary exposure: virilization has been reported in children who contacted unwashed or unclothed application sites, so hands are washed, the site is covered once dry, and the site is washed before skin-to-skin contact.

Injections include testosterone cypionate (Depo-Testosterone), given deep in the gluteal muscle, and testosterone enanthate (Xyosted), self-injected subcutaneously in the abdomen. Testosterone undecanoate comes as an oral capsule taken with food (Jatenzo) and as a long-acting intramuscular injection (Aveed), whose boxed warning covers pulmonary oil microembolism (POME) and anaphylaxis: it is given only in certified settings under a REMS, and the patient is observed for 30 minutes after each injection. Methyltestosterone, an oral 17-α-alkylated androgen, is less extensively metabolized by the liver than oral testosterone, but cholestatic hepatitis and jaundice occur with 17-α-alkylandrogens at a relatively low dose.

Androgens stimulate red cell production, so hematocrit rises; an increase in red cell mass may increase the risk of thromboembolic events, and venous thromboembolism has been reported. Testosterone can increase blood pressure, which can increase cardiovascular risk over time; it is not recommended in uncontrolled hypertension. Men with benign prostatic hyperplasia may worsen, and androgens may increase prostate cancer risk, so the prostate is evaluated before and during treatment.

Testosterone is a Schedule III controlled substance. It has been abused, typically at higher doses with other anabolic steroids, which can cause serious cardiovascular and psychiatric reactions, testicular atrophy and infertility.

Danazol is a synthetic steroid derived from ethisterone. It suppresses the pituitary-ovarian axis, lowering FSH and LH output, and its only other demonstrable hormonal effect is weak androgenic activity. In endometriosis it makes normal and ectopic endometrium inactive and atrophic. In hereditary angioedema it prevents attacks and raises the deficient C1 esterase inhibitor. It is labeled for endometriosis amenable to hormonal management and for prevention of attacks of angioedema of all types; its use in fibrocystic breast disease is off-label.

Its boxed warning covers four hazards: use in pregnancy is contraindicated (androgenic effects on the female fetus); thromboembolism, including sagittal sinus thrombosis and fatal strokes; peliosis hepatis and benign hepatic adenoma with long-term use, which can be silent until intra-abdominal hemorrhage; and benign intracranial hypertension (pseudotumor cerebri).