The androgen axis compared — testosterone, 5α-reductase inhibitors, antiandrogens, abiraterone, GnRH agents and PDE5 inhibitors

GnRH from the hypothalamus drives pituitary LH and FSH; LH makes Leydig cells produce testosterone, which feeds back to shut the axis down. In target tissues, 5α-reductase converts testosterone to DHT, the more potent androgen, and both act through the intracellular androgen receptor.

The drugs act at each step. GnRH agonists downregulate the pituitary receptor after an initial stimulation, and antagonists block it at once. Abiraterone inhibits CYP17, the enzyme of androgen synthesis in the testes, adrenal glands and prostate tumor. Finasteride and dutasteride block the conversion to DHT. Flutamide, bicalutamide and nilutamide, and the newer enzalutamide, apalutamide and darolutamide, block the receptor — and spironolactone, a mineralocorticoid receptor antagonist, also binds androgen receptors. Testosterone itself replaces the hormone. PDE5 inhibitors sit outside the axis: they preserve cGMP made in response to nitric oxide, so they work only with sexual stimulation.

Exogenous testosterone suppresses LH and, at large doses, FSH through feedback inhibition, so spermatogenesis falls — azoospermia and reduced fertility that may not reverse — and the testes shrink in men who misuse it. A GnRH agonist first stimulates the receptor, so testosterone rises about 50% above baseline in the first weeks; in prostate cancer that surge can cause tumor flare, which is why an antiandrogen such as bicalutamide is started first, or an antagonist (degarelix, relugolix), which causes no surge, is used instead.

Blocking the receptor also blocks feedback: nilutamide raised LH in rats, though not in castrated men, and flutamide raises plasma testosterone and estradiol, and the labels pair the receptor blockers with medical or surgical castration.

Testosterone raises hematocrit, which is checked before treatment, can raise blood pressure, and the higher red cell mass may raise the risk of thromboembolic events; gels carry a boxed warning for secondary exposure, after children who touched application sites were virilized. Finasteride and dutasteride lower PSA by about half and must not be handled by pregnant women, because DHT forms male external genitalia. Flutamide has a boxed warning for hepatic injury and nilutamide for interstitial pneumonitis; enzalutamide causes seizures, and enzalutamide and apalutamide cause falls and fractures.

Abiraterone raises adrenal mineralocorticoid production — hypertension, hypokalemia and fluid retention — and is labeled with prednisone or methylprednisolone. GnRH agents bring androgen-deprivation warnings: QT prolongation with agonists and antagonists, and hyperglycemia and cardiovascular events on the agonist labels. PDE5 inhibitors are contraindicated with nitrates in any form and with guanylate cyclase stimulators such as riociguat, because the added cGMP causes severe hypotension. Spironolactone’s androgen-receptor binding causes gynecomastia.