Step 1 · Reproductive

Reproductive Pharmacology

Name: Reproductive Pharmacology
Creator: Veli Bakalov, MD

Tissue-specific hormones: the contraceptives, SERMs, and analogs boards love

Reproductive·Pharmacology·6 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Combined contraceptives suppress GnRH → LH/FSH so there is no LH surge or ovulation; estrogen causes VTE, so avoid in smokers over 35, migraine with aura, prior VTE or estrogen-sensitive cancer.
Combined contraceptives lower ovarian and endometrial cancer risk; progestin-only methods are safe after VTE, in lactation and in smokers over 35, but DMPA causes reversible bone loss and delayed fertility.
Tamoxifen is a breast antagonist but an endometrial and bone agonist: endometrial cancer and VTE risk; raloxifene is an endometrial antagonist (no endometrial cancer) that treats osteoporosis but still causes VTE.
Aromatase inhibitors (anastrozole, letrozole, exemestane) block peripheral androgen → estrogen conversion; first-line for postmenopausal ER-positive breast cancer, ineffective alone premenopause, cause osteoporosis and arthralgia.
Clomiphene blocks hypothalamic estrogen receptors, lifting negative feedback to raise GnRH, FSH and LH and induce ovulation; risks are multiple gestation, ovarian hyperstimulation and visual changes (letrozole now often preferred in PCOS).
Leuprolide is stimulatory when pulsatile and suppressive when continuous (prostate cancer, endometriosis, fibroids, precocious puberty); cover the initial testosterone flare with an antiandrogen, or use degarelix for no flare.
Finasteride inhibits 5α-reductase (testosterone → DHT), shrinking the prostate and halving PSA; flutamide and bicalutamide block the androgen receptor.
PDE5 inhibitors raise cGMP to sustain erection and treat pulmonary hypertension; nitrates are an absolute contraindication, and sildenafil blue-tinted vision reflects PDE6 inhibition.
Tocolytics (nifedipine, terbutaline, indomethacin under 32 weeks, MgSO4) buy about 48 hours for betamethasone; oxytocin is first-line for postpartum hemorrhage, and unopposed estrogen with an intact uterus causes endometrial cancer.

Hormonal contraception

Combined estrogen–progestin contraceptives. Pills, patch and ring suppress hypothalamic GnRH and therefore pituitary LH and FSH: estrogen blunts FSH-driven follicle development, and progestin abolishes the midcycle LH surge, so ovulation does not occur. Progestin also thickens cervical mucus and thins the endometrium, adding backup protection. Benefits include a lower risk of ovarian and endometrial cancer, lighter and more regular menses, and improved acne (estrogen raises SHBG, lowering free testosterone).

Estrogen drives the danger. Estrogen increases hepatic synthesis of clotting factors, so venous thromboembolism (VTE) is the main risk. Combined methods are contraindicated in smokers over 35 (MI and stroke), migraine with aura, prior VTE, and estrogen-sensitive cancer.

Progestin-only methods. The minipill, etonogestrel implant, levonorgestrel IUD and depot medroxyprogesterone acetate (DMPA) all thicken cervical mucus; the minipill and IUD rely mainly on this local effect, whereas the implant and DMPA also reliably suppress ovulation. Without estrogen they are safe with a VTE history, during lactation, and in smokers over 35. DMPA causes reversible bone mineral density loss and delayed return of fertility.

Combined vs progestin-only contraception

Feature	Combined (estrogen + progestin)	Progestin-only
Main mechanism	↓GnRH → ↓LH/FSH; no LH surge, no ovulation	Thick cervical mucus (implant and DMPA also block ovulation)
Main risk	VTE (estrogen)	Irregular bleeding; DMPA bone loss
Usable after VTE, while breastfeeding, or smoker >35	No	Yes
Cancer effect	↓Ovarian and endometrial cancer	—

SERMs and aromatase inhibitors

Tamoxifen. Selective estrogen receptor modulators (SERMs) are agonists in some tissues and antagonists in others. Tamoxifen is an antagonist in breast, so it treats and prevents ER-positive breast cancer and can be used before menopause. It is an agonist in endometrium (endometrial hyperplasia and carcinoma), in bone (protective), and on hepatic clotting factors (VTE). It is a prodrug activated by CYP2D6, and hot flashes are common.

Raloxifene is an antagonist in both breast and endometrium and an agonist in bone; unlike tamoxifen, it does not raise endometrial cancer risk. It treats postmenopausal osteoporosis and reduces breast cancer risk, but it still raises VTE risk and can cause hot flashes and leg cramps.

Aromatase inhibitors. Anastrozole and letrozole (reversible, nonsteroidal) and exemestane (irreversible, steroidal) block aromatase, which converts adrenal and peripheral androgens to estrogen in fat and other tissues. After menopause this peripheral conversion is the main estrogen source, so aromatase inhibitors are first-line adjuvant therapy for ER-positive breast cancer in postmenopausal women. They are ineffective alone before menopause, because the falling estrogen releases gonadotropins that drive ovarian estrogen production. Toxicity comes from estrogen deprivation: osteoporosis and arthralgia.

Estrogen-modulating drugs in breast and bone

Drug	Breast	Endometrium	Bone	Key uses and risks
Tamoxifen	Antagonist	Agonist → cancer risk	Agonist (protective)	ER+ breast cancer, any menopausal status; VTE
Raloxifene	Antagonist	Antagonist (no ↑ cancer)	Agonist (protective)	Postmenopausal osteoporosis, breast cancer prevention; VTE
Aromatase inhibitors	↓Estrogen synthesis	No stimulation	Bone loss	Postmenopausal ER+ breast cancer; arthralgia

Ovulation induction and GnRH analogs

Clomiphene. This SERM antagonizes estrogen receptors in the hypothalamus. The brain senses "low estrogen," negative feedback is lifted, and GnRH, FSH and LH rise to drive follicle development and ovulation in anovulatory infertility such as PCOS. Risks are multiple gestation, ovarian hyperstimulation, hot flashes and visual changes. Letrozole, which lowers estrogen feedback by blocking aromatase, is now often preferred for ovulation induction in PCOS.

GnRH agonists. Leuprolide and goserelin mimic GnRH. Pulsatile dosing reproduces physiology and stimulates LH and FSH (used for infertility). Continuous dosing downregulates pituitary GnRH receptors, suppressing LH, FSH and sex steroids (prostate cancer, endometriosis, uterine fibroids, central precocious puberty). The resulting hypogonadal state causes hot flashes, decreased libido and bone loss.

First 1–2 weeks: flareContinuous agonist first stimulates LH, raising testosterone (bone pain, urinary obstruction in prostate cancer); an antiandrogen such as flutamide blocks it
Receptor downregulationPituitary GnRH receptors desensitize and LH/FSH fall
Castrate sex-steroid levelsSustained medical castration while dosing continues

GnRH antagonists. Degarelix and relugolix block the receptor directly, suppressing gonadotropins immediately with no flare and no need for antiandrogen cover.

Androgen-pathway and erectile drugs

Finasteride. By inhibiting 5α-reductase, finasteride lowers conversion of testosterone to dihydrotestosterone (DHT). The prostate shrinks over months in BPH, PSA falls by about 50% (so measured values must be doubled when screening), and male-pattern baldness improves. Side effects are gynecomastia, decreased libido and sexual dysfunction; it is teratogenic to a male fetus, so pregnant women should not handle crushed tablets. The α₁-blocker tamsulosin relieves BPH symptoms faster but does not shrink the gland.

Androgen receptor antagonists. Flutamide and bicalutamide competitively block the androgen receptor in prostate cancer, classically paired with a GnRH agonist to cover the flare; gynecomastia is common, and flutamide is hepatotoxic.

PDE5 inhibitors. Sexual stimulation releases nitric oxide, which activates guanylyl cyclase and generates cGMP, relaxing corpus cavernosum smooth muscle. Sildenafil, tadalafil and vardenafil inhibit PDE5, which degrades cGMP, so they sustain vasodilation and erection; they also treat pulmonary hypertension. Combined with nitrates they cause severe hypotension, an absolute contraindication. Headache, flushing and dyspepsia are common, and sildenafil can cause blue-tinted vision through retinal PDE6 inhibition.

Obstetric drugs: tocolytics and uterotonics

Tocolytics relax the uterus to delay preterm labor about 48 hours, a window used for maternal transfer and for betamethasone, which accelerates fetal lung maturity (surfactant production), typically between 24 and 34 weeks. Magnesium sulfate also gives fetal neuroprotection; its toxicity (areflexia, then respiratory depression) is reversed with calcium gluconate.

Uterotonics do the opposite. Oxytocin induces or augments labor and is first-line to prevent and treat postpartum hemorrhage; at high doses its ADH-like effect can cause water intoxication. Misoprostol (PGE₁) ripens the cervix and treats hemorrhage. Methylergonovine treats hemorrhage but is contraindicated in hypertension, and carboprost (PGF_2α) is avoided in asthma.

Drugs that relax vs contract the uterus

Drug	Class	Role	Key caution
Nifedipine	Calcium channel blocker	Tocolytic	Maternal hypotension, reflex tachycardia
Terbutaline	β₂ agonist	Tocolytic	Tachycardia, hyperglycemia, hypokalemia
Indomethacin	NSAID	Tocolytic (<32 weeks)	Premature ductus closure, oligohydramnios
Magnesium sulfate	Ca²⁺ antagonist	Tocolytic; fetal neuroprotection	Areflexia → respiratory depression
Oxytocin	Oxytocin receptor agonist	Induction; first-line hemorrhage	Water intoxication, hyperstimulation
Misoprostol	PGE₁ analog	Cervical ripening; hemorrhage	Abortifacient
Methylergonovine	Ergot alkaloid	Hemorrhage	Contraindicated in hypertension

Menopausal hormone therapy

Indications. Estrogen is the most effective treatment for vasomotor symptoms (hot flashes) and vaginal atrophy, and it prevents postmenopausal bone loss; isolated vaginal symptoms can be treated with low-dose vaginal estrogen.

Always oppose estrogen when the uterus is present. Unopposed estrogen causes endometrial hyperplasia and carcinoma, so a progestin is added whenever the uterus is intact; after hysterectomy estrogen alone is used.

Risks. The Women's Health Initiative linked combined estrogen–progestin therapy to more VTE, stroke and breast cancer, so hormone therapy is given at the lowest effective dose for the shortest necessary time and is not used to prevent cardiovascular disease.

Avoid systemic hormone therapy with a history of breast cancer, VTE or stroke, active liver disease, or unexplained vaginal bleeding.