Reproductive

Hormonal contraceptives borrow the ovary’s own feedback signals. Steady estrogen plus a progestin suppresses GnRH, FSH and LH, so no follicle matures and the mid-cycle LH surge never comes; the progestin also makes cervical mucus hostile to sperm. Estrogen raises hepatic clotting-factor synthesis, which is why combined methods carry the VTE risk and the smoking boxed warning. Progestin-only methods vary in how fully they block ovulation, the medroxyprogesterone injection lowers serum estrogen and bone density, and emergency contraception works mainly by delaying ovulation.

After menopause, estradiol from the ovarian follicle gives way to estrone made in fat and other peripheral tissues, and LH and FSH rise. Estrogen therapy relieves hot flashes and genitourinary symptoms through nuclear estrogen receptors, but unopposed it drives the endometrium toward hyperplasia and cancer, so a woman with a uterus also takes a progestin or bazedoxifene. Oral estrogen raises hepatic clotting factors; the WHI defined the boxed risks. Mifepristone blocks the progesterone receptor, and fezolinetant blocks NK3 receptors in the hypothalamic thermoregulatory center.

SERMs bind the estrogen receptor and act as agonists in some tissues and antagonists in others. Tamoxifen blocks estrogen in breast tissue but acts like estrogen in bone and the uterus, so it treats and prevents ER-positive breast cancer while raising endometrial cancer and clot risk; it needs CYP2D6 to make its potent metabolite endoxifen. Clomiphene blocks hypothalamic estrogen feedback so gonadotropins rise and ovulation follows; ospemifene is an endometrial agonist used for painful intercourse after menopause; toremifene prolongs the QT interval.

Aromatase, a cytochrome P450 enzyme, makes estrogens from androgens. After menopause the ovary is no longer the main source, and estrogen comes from aromatase in peripheral tissues such as fat — so blocking the enzyme lowers estrogen and treats hormone receptor-positive breast cancer. Anastrozole and letrozole bind noncovalently and can be displaced; exemestane, a steroidal false substrate, inactivates the enzyme for good. Before menopause the falling estrogen raises gonadotropins and the ovary escapes, which is why the labels are for postmenopausal women.

Parathyroid hormone (PTH) raises serum calcium through bone, kidney and, via calcitriol, the gut. Given continuously it resorbs bone, but intermittent PTH-receptor stimulation by teriparatide or abaloparatide builds it. Romosozumab builds bone by blocking sclerostin, a brake on Wnt signaling. Denosumab blocks RANKL, so its effect fades and turnover rebounds when it is stopped. Raloxifene is an estrogen agonist in bone and an antagonist in breast and uterus. Cinacalcet sensitizes the parathyroid calcium-sensing receptor, and calcitriol replaces the active vitamin D that failing kidneys cannot make. (on the Endocrine pages)

GnRH reaches the pituitary in pulses and acts on a Gq-coupled receptor to release LH and FSH. A long-acting agonist first stimulates the receptor, then — because exposure is continuous — downregulates it, so LH, FSH and gonadal steroids fall after an initial flare. Antagonists block the receptor competitively and suppress at once, with no flare. The result is medical castration in prostate cancer, a hypoestrogenic state for endometriosis and fibroids, a halt to central precocious puberty, and no premature LH surge in fertility treatment.

Three anterior-pituitary levers. Somatostatin switches off growth hormone, insulin, glucagon, TSH and gut hormones; its long-acting analogs octreotide and lanreotide treat acromegaly, carcinoid and VIPoma — and, like a somatostatinoma, cause gallstones and glucose swings. Growth hormone acts through IGF-1: somatropin replaces it, while pegvisomant blocks its receptor and is judged by IGF-1 alone. Dopamine tonically inhibits prolactin, so the ergot D2 agonists cabergoline and bromocriptine treat prolactinomas and hyperprolactinemia, at the price of valve and fibrosis risks. (on the Endocrine pages)

GnRH drives pituitary LH and FSH; LH makes Leydig cells produce testosterone, which feeds back to shut the axis down. Testosterone acts directly and through two conversions — 5α-reductase makes DHT, aromatase makes estradiol. Replacement treats primary hypogonadism (LH and FSH high) and hypogonadotropic hypogonadism (LH and FSH low or normal). Because exogenous testosterone also feeds back, it suppresses LH and FSH and with them spermatogenesis. Danazol, a weak androgen, suppresses the pituitary-ovarian axis.

Androgen signaling has three drug targets. 5α-reductase turns testosterone into DHT, the androgen that builds male external genitalia and drives prostate growth and male pattern baldness — finasteride and dutasteride block it, shrinking the prostate, halving PSA, and threatening a male fetus if a pregnant woman is exposed. The androgen receptor itself is blocked by flutamide, bicalutamide and nilutamide and by the newer enzalutamide, apalutamide and darolutamide. Abiraterone stops androgen synthesis at CYP17, raising mineralocorticoids, and is given with a corticosteroid.

Two routes to the same channel: mineralocorticoid-receptor antagonists (spironolactone, eplerenone) and ENaC blockers (amiloride, triamterene). Both shut down electrogenic sodium entry in the aldosterone-sensitive distal nephron, so K⁺ and H⁺ secretion fall. (on the Cardiovascular pages)

Sexual stimulation releases nitric oxide in the corpus cavernosum; NO activates guanylate cyclase, cGMP rises and smooth muscle relaxes so blood flows in. PDE5 inhibitors stop cGMP breakdown, amplifying that signal — they do nothing without it. The same mechanism explains the main danger: nitrates and guanylate cyclase stimulators raise cGMP from the other side, so the combination causes severe hypotension. Selectivity matters too: weaker selectivity over retinal PDE6 is thought to underlie color-vision changes.

Antagonists of Gq-coupled α1 receptors (vascular and prostatic smooth muscle) and, for the nonselective agents, of the Gi-coupled α2 brake on norepinephrine release. Selectivity decides the reflex tachycardia; the α1A preference of tamsulosin and silodosin targets the prostate. Metyrosine instead blocks catecholamine synthesis at tyrosine hydroxylase. (on the Autonomics pages)

Pulmonary arterial hypertension drugs correct three endothelial signals: endothelin receptor antagonists block endothelin-1 at ETA (with or without ETB) receptors; PDE-5 inhibitors and the sGC stimulator riociguat raise cGMP; epoprostenol and treprostinil raise cAMP through the IP receptor. The signature hazards follow from those mechanisms — ERA and riociguat teratogenicity, cGMP-stacking hypotension with nitrates, PDE-6 color-vision changes, and rebound when a short-lived prostacyclin stops. (on the Cardiovascular pages)

Oxytocin is the hypothalamic nonapeptide released from the posterior pituitary that contracts the uterus and ejects milk. It acts on myometrial G protein–coupled receptors that raise intracellular calcium, and those receptors multiply through pregnancy, so the uterus at term is far more sensitive. Given as an IV infusion it induces or strengthens labor and controls postpartum bleeding; too much causes hyperstimulation, and its antidiuretic effect can cause water intoxication.

Beyond oxytocin, two pharmacologic families move the uterus. Methylergonovine, an ergot alkaloid, gives a sustained contraction but also constricts vessels, so hypertension is a contraindication. The prostaglandin analogs act on their own G protein–coupled receptors: carboprost (PGF2α) contracts the uterus and the bronchi, dinoprostone (PGE2) ripens the cervix and sensitizes the myometrium to oxytocin, and misoprostol (PGE1) protects the stomach but contracts the pregnant uterus.

Magnesium sulfate is the first-line drug to prevent and control seizures in preeclampsia and eclampsia. Magnesium blocks neuromuscular transmission by cutting acetylcholine release, competes with calcium at voltage-gated channels and blocks the NMDA receptor. It is not metabolized and leaves only through the kidneys, so toxicity — lost reflexes, then respiratory paralysis, then heart block and arrest — follows renal impairment, and IV calcium is the antidote.

Myometrial contraction runs on calcium: calcium entry activates calmodulin and myosin light chain kinase. Tocolytics quiet it by different mechanisms — terbutaline raises cAMP through β2 receptors, nifedipine blocks calcium entry, and indomethacin cuts prostaglandin production. None is FDA-approved for tocolysis, and the aim is only a short delay, two to seven days, for antenatal corticosteroids and transfer. Each drug’s off-target action is its hazard: β1 cardiac effects and metabolic shifts with terbutaline, hypotension with nifedipine, the fetal ductus with indomethacin.

Vasopressin (ADH) acts on two receptors: V2 on the collecting duct (Gs → cAMP → aquaporin-2 insertion → water reabsorption) and V1 on vascular smooth muscle (Gq → calcium → vasoconstriction). Desmopressin is a V2-selective analog with little pressor effect — it replaces ADH in central diabetes insipidus, distinguishes central from nephrogenic DI, and releases von Willebrand factor and factor VIII; its defining risk is water intoxication. Vasopressin itself is a V1 pressor for vasodilatory shock. (on the Renal pages)

Potassium sets the resting membrane potential and shifts between cells and plasma with insulin, β-adrenergic stimulation and pH; both extremes show on the ECG. Magnesium is the cofactor that lets cells hold potassium and the drug that reverses torsades, but in excess it blocks the neuromuscular junction. Calcium stabilizes the heart in hyperkalemia, and tonicity decides where an IV fluid’s water goes. (on the Renal pages)

Glucocorticoids diffuse into cells and bind a cytoplasmic receptor that moves to the nucleus: it switches on anti-inflammatory genes such as lipocortin-1, which inhibits phospholipase A2, and switches off inflammatory transcription factors such as NF-κB. The same genomic action raises glucose, breaks down muscle and bone, and feeds back on the HPA axis, so long courses suppress ACTH and must be tapered. The drugs differ mainly in duration and in how much they also stimulate the mineralocorticoid receptor — cortisol about equally, the synthetic steroids hardly at all. (on the Endocrine pages)