Gonadal Pharmacology · Module 5 of 5

Androgen Pharmacology

Testosterone · 5-Alpha-Reductase Inhibitors · Anti-Androgens · Anabolic Steroids

Testosterone and dihydrotestosterone are not interchangeable — testosterone mediates muscle growth, erythropoiesis, bone density, and libido through direct androgen receptor (AR) activation, while DHT (produced by 5-alpha-reductase in prostate, skin, and scalp) has 3–5 times greater AR affinity and drives prostate growth, androgenetic alopecia, and virilization of external genitalia; 5-alpha-reductase inhibitors exploit this distinction by reducing DHT without meaningfully reducing testosterone-dependent effects.
PSA is suppressed approximately 50% by 5-alpha-reductase inhibitors — a PSA value measured on finasteride or dutasteride must be doubled before clinical interpretation; failing to adjust risks missing a rising PSA that would otherwise trigger biopsy in a patient at risk for prostate cancer.
Anti-androgens span a mechanistic spectrum from mineralocorticoid receptor antagonism (spironolactone) to steroidal progestins with anti-gonadotropic effects (cyproterone acetate) to highly selective second-generation AR antagonists that block nuclear translocation and DNA binding (enzalutamide); enzalutamide's GABA-A receptor modulation produces clinically meaningful seizure risk (~0.5% per year) and is a prescribing caution in patients with prior seizure history.
Oral anabolic-androgenic steroids are C17-alpha-alkylated to resist hepatic oxidation at the C17-beta hydroxyl position — this modification allows oral bioavailability but causes hepatocyte accumulation, producing a cholestasis-to-carcinoma progression risk that is entirely absent with injectable AAS, which undergo normal ester cleavage to natural testosterone.
Testosterone replacement therapy reliably suppresses the HPG axis — LH and FSH fall, intratesticular testosterone drops below the threshold for spermatogenesis, and azoospermia develops over months; coadministration of hCG (which mimics LH at the testis) maintains intratesticular testosterone and preserves spermatogenesis in men who desire future fertility.

Abbreviations: DHT = dihydrotestosterone · AR = androgen receptor · 5AR = 5-alpha-reductase · PSA = prostate-specific antigen · BPH = benign prostatic hyperplasia · PCOS = polycystic ovary syndrome · HPG = hypothalamic-pituitary-gonadal · hCG = human chorionic gonadotropin · LH = luteinizing hormone · AAS = anabolic-androgenic steroids · LVH = left ventricular hypertrophy · VTE = venous thromboembolism · TRT = testosterone replacement therapy · MR = mineralocorticoid receptor · mCSPC = metastatic castration-sensitive prostate cancer · AR-V7 = androgen receptor splice variant 7 · CAD = coronary artery disease

Testosterone vs. Dihydrotestosterone — Tissue-Selective Actions

Testosterone — Direct AR Actions

Muscle, Bone, Erythropoiesis, Libido

Skeletal muscle protein synthesis and mass
Bone mineral density maintenance
Erythropoiesis stimulation via EPO and direct erythroid progenitor effects
Libido, mood, and cognitive function
Aromatized to estradiol in adipose tissue → bone protection and gonadotropin feedback
Excess aromatization → gynecomastia, fluid retention

DHT — Via 5-Alpha-Reductase (Types 1 & 2)

Prostate, Scalp, Skin, External Genitalia

Prostate growth — BPH and androgen-driven prostate cancer
Male-pattern hair loss (androgenetic alopecia) at scalp
Beard and body hair development; sebaceous gland activity → acne
External genital virilization during fetal development
3–5× greater AR affinity than testosterone — not aromatized to estradiol
5-alpha-reductase deficiency: absent DHT → ambiguous genitalia at birth despite normal testosterone

5-Alpha-Reductase Inhibitors

Drug	Isoform Selectivity	Approved Uses	PSA Effect	Key Safety
Finasteride	Type 2 selective	BPH (5 mg); androgenetic alopecia (1 mg)	Reduces ~50% — must double measured PSA before interpretation	Sexual dysfunction (libido, erectile, ejaculatory); Post-Finasteride Syndrome; teratogenic (male fetus)
Dutasteride	Dual type 1 + type 2	BPH	Reduces ~50% — must double measured PSA before interpretation	Same sexual effects; drug persists in semen up to 6 months after stopping; teratogenic (male fetus)

Anti-Androgens Compared

Drug	Mechanism	Clinical Use	Key Adverse Effects / Notes
Spironolactone	MR antagonist; AR antagonist at high doses	PCOS hirsutism; gender-affirming (feminizing); hyperaldosteronism	Hyperkalemia — monitor K⁺ especially with ACE inhibitors or ARBs; teratogenic (male fetus); menstrual irregularity
Bicalutamide	High-affinity non-steroidal AR antagonist; no HPG axis suppression	Prostate cancer (combined with GnRH agonist/antagonist); hirsutism	Hepatotoxicity — monitor LFTs; gynecomastia (LH feedback intact → testosterone rises ~1.5×)
Enzalutamide	2nd-generation AR antagonist — blocks ligand binding, nuclear translocation, and DNA binding	Castration-resistant prostate cancer; mCSPC	Seizure risk (~0.5%/yr, GABA-A modulation); AR-V7 splice variant → resistance; fatigue, cognitive effects
Cyproterone acetate	Steroidal AR antagonist + progestin + anti-gonadotropic (not US-approved)	Prostate cancer; hirsutism; gender-affirming (outside US)	Meningioma (dose- and duration-dependent risk); VTE; hepatotoxicity

Anabolic-Androgenic Steroid Toxicity

Oral AAS — C17-Alpha-Alkylated

Hepatotoxicity: Not Seen with Injectables

C17-alpha methyl group blocks hepatic oxidation at C17-beta hydroxyl → oral bioavailability
Steroid accumulates in hepatocytes → cholestasis, peliosis hepatis
Progression: cholestasis → peliosis hepatis → hepatic adenoma → hepatocellular carcinoma
Injectable AAS (nandrolone decanoate, testosterone enanthate): undergo normal ester cleavage → no hepatotoxicity

All Routes — Systemic Toxicity

Cardiovascular, Endocrine, Psychiatric

Cardiovascular: pathological LVH, HDL markedly reduced, premature CAD — LV dysfunction persists years after cessation
Erythrocytosis → elevated VTE risk
HPG suppression → testicular atrophy, azoospermia (recovery 6–24 months)
Gynecomastia from excess aromatization to estradiol
Acne, tendon rupture (collagen synthesis impaired)
Psychiatric: aggression and hypomania during use; withdrawal dysphoria and depression

Chapter Complete — Gonadal Pharmacology (GOND) · Key Clinical Rules

PSA suppression by 5-alpha-reductase inhibitors is approximately 50% — always double the measured PSA value before clinical interpretation on finasteride or dutasteride. A failure to apply this correction can mask a rising PSA and delay prostate cancer diagnosis.

Testosterone replacement therapy reliably suppresses HPG axis function and eliminates spermatogenesis. Men who desire future fertility should receive coadministered hCG (mimics LH at the testis) to maintain intratesticular testosterone above the threshold required for sperm production. Clomiphene is an alternative for preservation of the HPG axis in hypogonadal men who wish to remain fertile.

Oral anabolic-androgenic steroids (C17-alpha-alkylated) cause hepatotoxicity through hepatocyte accumulation — cholestasis, peliosis hepatis, adenoma, and carcinoma are all documented. Injectable AAS do not carry this risk because ester cleavage restores normal testosterone.

Enzalutamide carries a clinically significant seizure risk (~0.5% per year) through GABA-A receptor modulation; use with caution in patients with a seizure history or concurrent medications that lower the seizure threshold.

AR-V7 (androgen receptor splice variant 7) confers resistance to all AR-targeted agents — enzalutamide, abiraterone, and related drugs — because the ligand-binding domain is absent. Detection of AR-V7 in circulating tumor cells should prompt switch to taxane-based chemotherapy (docetaxel or cabazitaxel).

Suggested References

Author / Source	Title	Publication
Katzung BG, ed.	Basic and Clinical Pharmacology, 15th ed. — Chapter 40: Estrogens, Progestins, and the Female Reproductive Tract	McGraw-Hill; 2021
Brunton L, Knollmann B, Hilal-Dandan R, eds.	Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed. — Chapter 44: Estrogens and Progestins	McGraw-Hill; 2023
Mooradian AD, Morley JE, Korenman SG.	Biological actions of androgens	Endocr Rev. 1987;8(1):1–28
Bhasin S, Cunningham GR, Hayes FJ, et al; Endocrine Society.	Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline	J Clin Endocrinol Metab. 2010;95(6):2536–2559
Imperato-McGinley J, Guerrero L, Gautier T, Peterson RE.	Steroid 5alpha-reductase deficiency in man: an inherited form of male pseudohermaphroditism	Science. 1974;186(4170):1213–1215
Lincoff AM, Bhasin S, Flevaris P, et al; TRAVERSE Study Investigators.	Cardiovascular safety of testosterone-replacement therapy	N Engl J Med. 2023;389(2):107–117
Hsieh TC, Pastuszak AW, Hwang K, Lipshultz LI.	Concomitant intramuscular human chorionic gonadotropin preserves spermatogenesis in men undergoing testosterone replacement therapy	J Urol. 2013;189(2):647–650
Thompson IM, Goodman PJ, Tangen CM, et al.	The influence of finasteride on the development of prostate cancer	N Engl J Med. 2003;349(3):215–224
Huggins C, Hodges CV.	Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate	Cancer Res. 1941;1(4):293–297
Beer TM, Armstrong AJ, Rathkopf DE, et al; PREVAIL Investigators.	Enzalutamide in metastatic prostate cancer before chemotherapy	N Engl J Med. 2014;371(5):424–433
Pope HG Jr, Wood RI, Rogol A, et al.	Adverse health consequences of performance-enhancing drugs: an Endocrine Society scientific statement	Endocr Rev. 2014;35(3):341–375
Baggish AL, Weiner RB, Kanayama G, et al.	Long-term anabolic-androgenic steroid use is associated with left ventricular dysfunction and premature coronary artery disease in abusers of illicit drugs	Circ Heart Fail. 2010;3(4):472–476