Antiandrogens & 5α-Reductase Inhibitors

DHT is the most potent androgen and a pure androgen — it cannot be converted to estrogen. It is made mainly in target tissues, where 5α-reductase reduces testosterone; compared with testosterone, DHT has about double the binding affinity for the androgen receptor and dissociates about five times more slowly. DHT binds the androgen receptor in the cytoplasm, and the ligand–receptor complex moves to the nucleus to act as a transcription factor.

There are two main isoenzymes. Type 1 sits in skin — sebaceous glands, sweat glands and keratinocytes — and makes about a third of circulating DHT; type 2 sits in the male genital tract, including the prostate, and makes about two thirds. Before birth, DHT forms the penis, scrotum and prostate; males with 5α-reductase deficiency are born with underdeveloped genitalia and a small or absent prostate. Through adolescence and adulthood, DHT promotes prostate growth, sebaceous gland activity, body and facial hair, and male pattern baldness, while it has no significant role in normal female physiology. (Testosterone replacement and its two conversions are taught on the Androgens page.)

Finasteride inhibits type II 5α-reductase and slowly forms a stable enzyme complex; dutasteride inhibits types 1 and 2. In men with BPH, finasteride lowered prostatic DHT by about 80% while tissue testosterone rose up to tenfold, and prostate volume fell by about 20% — returning toward baseline about three months after stopping. Symptom relief is gradual, over several months. In male pattern hair loss, the balding scalp holds more DHT, and finasteride lowers scalp and serum DHT (Propecia).

The PSA consequence is a label point: these drugs lower serum PSA by about 50%, even when prostate cancer is present. A new baseline is set after several months, any confirmed rise from the lowest value is evaluated, and with dutasteride an isolated PSA is doubled for comparison with untreated men. They may also increase the risk of high-grade prostate cancer. Because DHT shapes male genitalia, women who are or may be pregnant must not handle crushed or broken finasteride tablets or leaking dutasteride capsules — dutasteride is absorbed through skin — and men on dutasteride wait 6 months after the last dose before donating blood, so a pregnant transfusion recipient is not exposed. Alpha-blockers, the other BPH drug class, are taught on the Alpha-Adrenergic Antagonists page.

Flutamide was the first nonsteroidal antiandrogen, followed by nilutamide and bicalutamide; StatPearls calls enzalutamide, apalutamide, darolutamide and abiraterone the newer, second-generation antiandrogens, which often work even when initial hormonal therapy has failed. Flutamide, bicalutamide and nilutamide block androgen at the receptor — bicalutamide competitively at cytosolic receptors — and are used with castration: a GnRH agonist suppresses testicular androgen by inhibiting LH, and the receptor blocker complements it. Receptor blockade also removes androgen feedback at the pituitary: nilutamide raised LH in rats (but not in castrated men), and flutamide raises plasma testosterone and estradiol. Enzalutamide, apalutamide and darolutamide also block the receptor’s nuclear translocation, and enzalutamide and apalutamide its interaction with DNA.

Flare protection. When a GnRH agonist starts, testosterone rises about 50% above baseline in the first weeks (tumor flare, GnRH Agonists & Antagonists page). Starting an antiandrogen such as bicalutamide first blocks the clinical response to that surge; it is not needed with degarelix or relugolix, which cause no surge. When disease progresses on an antiandrogen, stopping it can itself lower PSA or improve symptoms — the antiandrogen withdrawal phenomenon. Spironolactone, a potassium-sparing diuretic, also has antiandrogenic effects (Potassium-Sparing Diuretics page).

Both boxed toxicities have a chemical explanation or parallel. Flutamide’s boxed liver injury is cholestatic hepatitis from mitochondrial toxicity of its major metabolite, hydroxyflutamide, which blocks the hepatocyte electron transport chain; another metabolite is an aniline, causing methemoglobinemia and hemolytic anemia in susceptible patients such as those with G6PD deficiency. Nilutamide’s boxed interstitial pneumonitis and its hepatitis resemble the effects of nitrofurantoin, another nitroaromatic compound; both are metabolized in vitro to nitroanion free radicals in lung and liver. Bicalutamide also carries a hepatitis warning, so transaminases are checked on a labeled schedule for all three, and each is stopped for jaundice or an ALT above twice normal. Hot flashes, impotence and loss of libido are the effects of low androgen.

Enzalutamide causes seizures (0.6%, and 2.2% with predisposing factors) and PRES, and enzalutamide and apalutamide cause falls and fractures — so fall and fracture risk is assessed and bone-targeted agents are considered. Both are strong CYP3A4 inducers that lower levels of many other drugs.

CYP17 (17α-hydroxylase/C17,20-lyase) catalyzes two steps toward androgens: 17α-hydroxylation of pregnenolone and progesterone, then formation of DHEA and androstenedione. It is expressed in the testes, adrenal glands and prostate tumor, so abiraterone cuts androgen synthesis at all three, alongside a GnRH analog or orchiectomy. Blocking it also raises adrenal mineralocorticoid production, causing hypertension, hypokalemia and fluid retention; hypokalemia has led to QT prolongation and torsades de pointes.

Abiraterone is labeled with a corticosteroid — prednisone for Zytiga, methylprednisolone for Yonsa — and blood pressure and potassium are controlled before and monitored during treatment. Stopping the steroid, infection or stress can unmask adrenocortical insufficiency, whose signs mineralocorticoid excess may hide (glucocorticoids are taught on the Corticosteroids page). Abiraterone can also cause fatal hepatotoxicity, and adding radium Ra 223 increased fractures and deaths.