Androgen, Antiandrogen & Uterotonic Pharmacology

Androgens: testosterone and danazol

Testosterone replacement. Testosterone is given as intramuscular esters (cypionate, enanthate), transdermal gel or patch, or orally as the 17α-alkylated methyltestosterone, mainly for male hypogonadism and delayed puberty. It acts on the androgen receptor (AR) directly, is converted by 5α-reductase to dihydrotestosterone (DHT), and is aromatized to estradiol in fat.

Feedback suppression. Exogenous androgen inhibits GnRH, LH and FSH. Without LH, Leydig cells stop making the high intratesticular testosterone that spermatogenesis needs, and Sertoli support falls without FSH: the testes shrink and oligospermia or azoospermia follows, the classic picture in anabolic steroid users. A hypogonadal man who wants children therefore receives hCG (LH-like) with or without FSH, not testosterone.

• Erythrocytosis, the most common dose-limiting effect: hold therapy if the hematocrit exceeds 54%.
• Lipids and skin: HDL falls, LDL rises; acne and oily skin.
• Gynecomastia from aromatization to estradiol; the same estradiol causes premature epiphyseal closure in adolescents.
• Virilization in women: hirsutism, clitoromegaly, deep voice.
• Oral 17α-alkylated androgens: cholestatic jaundice, peliosis hepatis (blood-filled hepatic cysts), hepatic adenoma.

Testosterone is contraindicated in prostate cancer and male breast cancer.

Danazol. A derivative of ethisterone (17α-ethinyl testosterone), danazol is a weak AR agonist and antigonadotropin that blunts the midcycle LH/FSH surge; the resulting anovulation and low-estrogen, mildly androgenic state shrinks endometrial implants in endometriosis. Attenuated androgens also raise hepatic C1-esterase inhibitor production, the historic basis for hereditary angioedema prophylaxis. Adverse effects are androgenic (weight gain, edema, acne, hirsutism, a deepened voice that may be permanent, ↓HDL) plus hepatotoxicity and pseudotumor cerebri. It is teratogenic, virilizing a female fetus.

Antiandrogens in prostate cancer

Androgen signaling can be cut at four checkpoints: the pituitary GnRH receptor, CYP17A1 in steroid synthesis, 5α-reductase, and the AR itself. Androgen deprivation therapy (ADT) is the backbone of advanced prostate cancer treatment and as a class causes hot flashes, ↓libido and bone loss.

GnRH agonists vs antagonists. Continuous leuprolide or goserelin first stimulates LH, causing a testosterone flare for 1–2 weeks (bone pain, urinary obstruction, spinal cord compression in metastatic disease) before receptor downregulation reaches castrate levels in about 2–4 weeks; an AR antagonist such as bicalutamide covers the flare. Degarelix (SC) and relugolix (oral) competitively block the receptor and reach castrate testosterone within days, with no flare and no need for antiandrogen cover, which suits urgent situations such as impending cord compression.

AR antagonists. Flutamide and bicalutamide are nonsteroidal competitive antagonists paired with GnRH agonists. They cause gynecomastia and breast tenderness, hot flashes and ↓libido; gynecomastia arises because hypothalamic AR blockade lifts feedback, so LH, testosterone and aromatized estradiol all rise. Flutamide carries a boxed warning for hepatotoxicity (monitor liver tests) and causes diarrhea. The second-generation agents enzalutamide, apalutamide and darolutamide bind with higher affinity, lack partial agonism, and also block AR nuclear translocation and DNA binding; they are used in castration-resistant and castration-sensitive disease. Enzalutamide lowers the seizure threshold (off-target GABA-A inhibition), causes fatigue, hypertension and falls, and strongly induces CYP3A4.

Abiraterone. Abiraterone inhibits CYP17A1 (17α-hydroxylase and 17,20-lyase), shutting androgen synthesis in testes, adrenals and tumor. Cortisol falls too, so ACTH rises and upstream steroids accumulate, above all the mineralocorticoid 11-deoxycorticosterone, causing hypertension, hypokalemia and edema. Low-dose prednisone suppresses ACTH to prevent this; liver tests are monitored.

Abiraterone recreates 17α-hydroxylase-deficiency congenital adrenal hyperplasia: hypertension, hypokalemia and low sex steroids.

Antiandrogens for hirsutism

Spironolactone blocks both mineralocorticoid and androgen receptors and modestly lowers androgen production. It treats hirsutism and acne (for example in PCOS), usually alongside an oral contraceptive because it can feminize a male fetus; hyperkalemia, menstrual irregularity and, in men, gynecomastia are its adverse effects. Ketoconazole inhibits steroidogenic CYPs (side-chain cleavage, 17,20-lyase, 11β-hydroxylase), lowering androgens and cortisol, but hepatotoxicity and CYP3A4 inhibition limit oral use. Combined oral contraceptives remain first-line for hirsutism: estrogen raises SHBG and the progestin suppresses LH-driven ovarian androgens.

Uterotonics and postpartum hemorrhage

Oxytocin. Released from the posterior pituitary, oxytocin acts on Gq-coupled receptors (PLC → IP₃ → Ca²⁺ → myosin light-chain kinase) that estrogen upregulates toward term; it also contracts breast myoepithelium (milk letdown). It is used for labor induction and augmentation and, with fundal massage, is first-line for preventing and treating atonic postpartum hemorrhage. Hazards: tachysystole (more than 5 contractions in 10 minutes, averaged over 30 minutes) with fetal heart rate decelerations or uterine rupture; water intoxication, because oxytocin differs from ADH by two amino acids and at high doses in hypotonic fluid activates V2 receptors → hyponatremic seizures; and hypotension with rapid IV push.

Second-line agents are chosen by contraindication. Methylergonovine, an ergot alkaloid acting on α-adrenergic and serotonergic receptors, causes tetanic contraction plus vasoconstriction; it is avoided in hypertension, preeclampsia and coronary disease and with strong CYP3A4 inhibitors (protease inhibitors, clarithromycin, azoles) that precipitate ergotism. Tranexamic acid, an antifibrinolytic, is added within 3 hours of birth.

Cervical ripening and medical abortion

PGE analogs. Dinoprostone (PGE₂; vaginal insert or gel) and misoprostol (PGE₁; vaginal or oral) remodel cervical collagen and stimulate contractions, ripening a low-Bishop-score cervix before induction; the dinoprostone insert can be removed if tachysystole develops. Misoprostol is avoided for induction after prior cesarean or major uterine surgery (rupture risk). It also prevents NSAID-induced ulcers, a use contraindicated in pregnancy because it is an abortifacient.

Mifepristone. This competitive progesterone-receptor antagonist causes decidual breakdown, cervical softening and increased myometrial prostaglandin sensitivity; misoprostol 24–48 hours later expels the pregnancy. The regimen is approved through 70 days of gestation and also manages early pregnancy loss; heavy bleeding and, rarely, serious infection are the main risks. Contraindications: ectopic pregnancy, an IUD in place, chronic adrenal failure or long-term corticosteroids, and bleeding disorders or anticoagulation. At high doses it also blocks glucocorticoid receptors, treating hyperglycemia in Cushing syndrome.

Magnesium sulfate

Uses and mechanism. Magnesium sulfate is first-line seizure prophylaxis in preeclampsia with severe features and treats eclamptic seizures, outperforming phenytoin and diazepam at preventing recurrence. Given when birth before 32 weeks is imminent, it lowers the risk of cerebral palsy; tocolytics such as nifedipine, indomethacin and terbutaline lack this benefit. Magnesium antagonizes calcium (NMDA blockade, ↓acetylcholine release at the neuromuscular junction, cerebral vasodilation) and is renally cleared, so oliguria raises levels quickly.

Toxicity. Hypermagnesemia progresses from flushing and nausea to loss of deep tendon reflexes (the earliest reliable sign), then respiratory depression, then cardiac conduction block and arrest. Patellar reflexes, respiratory rate and urine output are monitored during infusion.

Absent reflexes or slowed breathing on magnesium: stop the infusion and give IV calcium gluconate (1 g as 10 mL of a 10% solution).