Reproductive hormone drugs copy or block the natural hormones of the hypothalamic–pituitary–gonadal axis.

Estrogens (ethinyl estradiol in contraceptives; estradiol and conjugated estrogens in menopausal therapy)

• In contraceptives, estrogen suppresses follicle-stimulating hormone (FSH), so no dominant follicle develops, and it stabilizes the endometrium (fewer bleeding irregularities)
• In menopause, estrogen replaces lost ovarian estrogen, relieving hot flashes and genitourinary symptoms and slowing bone loss
• Estrogen raises hepatic production of clotting factors — the basis of the venous thromboembolism (VTE) risk

Progestins (levonorgestrel, norethindrone, norgestimate, desogestrel, drospirenone, etonogestrel, medroxyprogesterone)

• Suppress the luteinizing hormone (LH) surge → no ovulation
• Thicken cervical mucus (blocks sperm) and thin the endometrium
• With estrogen in menopausal therapy, a progestogen protects the endometrium from hyperplasia and cancer

Combined hormonal contraception (CHC) — pill, transdermal patch, vaginal ring — acts mainly by suppressing ovulation. Progestin-only methods act mainly through cervical mucus and endometrial change; some (implant, DMPA, drospirenone pill) also reliably suppress ovulation.

Emergency contraception (EC) — levonorgestrel and ulipristal (a progesterone receptor modulator) delay or prevent ovulation. They do not end an established pregnancy. The copper IUD prevents fertilization.

Androgens (testosterone) replace testosterone in male hypogonadism. Ovulation inducers: clomiphene (a selective estrogen receptor modulator that blocks negative feedback, raising FSH and LH) and letrozole (an aromatase inhibitor that lowers estrogen, raising FSH).

Typical failure with ordinary use: implant and IUDs under about 1%; DMPA about 4%; pill, patch, and ring about 7%. Only condoms protect against sexually transmitted infections.

Estrogen-related: nausea, breast tenderness, headache, fluid retention, raised blood pressure, melasma, VTE, stroke, myocardial infarction, gallbladder disease, benign liver adenoma (rare).

Progestin-related: irregular or unscheduled bleeding (the most common reason to stop progestin-only methods), mood change, acne, weight gain with DMPA. Drospirenone has antimineralocorticoid activity and can raise potassium.

DMPA: loss of bone mineral density (boxed warning; largely reversible after stopping, and not by itself a reason to deny the method), weight gain, delayed return of fertility (can take a year or more).

Implant and IUDs: unpredictable bleeding (implant); expulsion, rare uterine perforation, and pelvic inflammatory disease risk in the first weeks after IUD insertion.

Menopausal hormone therapy: VTE and stroke (lower with transdermal estradiol), gallbladder disease; breast cancer risk rises with longer use of estrogen plus progestogen; endometrial cancer with estrogen alone in a woman with a uterus.

Testosterone: increased blood pressure (class-wide label warning, FDA 2025), polycythemia (rising hematocrit), acne, sleep apnea worsening, reduced sperm production, gynecomastia; topical gel — boxed warning for secondary exposure (virilization of children and women who touch the skin). Boxed warnings also apply to oral testosterone undecanoate and the subcutaneous enanthate autoinjector (blood pressure increases that can raise the risk of major cardiovascular events — check BP before and during therapy) and to IM testosterone undecanoate (pulmonary oil microembolism and anaphylaxis — given only in certified settings under a REMS, with 30 minutes of observation after each injection).

Clomiphene and gonadotropins: hot flashes, visual disturbances (stop clomiphene), multiple pregnancy, ovarian hyperstimulation syndrome (abdominal distension, rapid weight gain, oliguria).

Combined hormonal contraception — US MEC category 4 (do not use) examples

• Age 35 or older and smoking 15 or more cigarettes a day (boxed warning: cigarette smoking increases serious cardiovascular events from CHC)
• Current or past VTE; known thrombogenic mutations
• Migraine with aura (stroke risk)
• Blood pressure 160/100 mmHg or higher; ischemic heart disease, stroke, complicated valvular disease
• Current breast cancer
• Severe (decompensated) cirrhosis, liver tumors
• Systemic lupus with positive antiphospholipid antibodies
• Less than 21 days postpartum (high VTE risk)
• Major surgery with prolonged immobilization

Progestin-only methods are generally safe when estrogen is contraindicated (smoking over 35, migraine with aura, VTE history). Current breast cancer is category 4 for all hormonal methods.

Menopausal hormone therapy contraindications: undiagnosed vaginal bleeding, known or suspected breast or estrogen-dependent cancer, active or past VTE, stroke or MI, active liver disease, pregnancy.

Testosterone: contraindicated in breast or prostate cancer and pregnancy; caution with polycythemia, untreated severe sleep apnea, uncontrolled heart failure. Men planning conception should not use it (suppresses sperm).

Pregnancy and lactation: hormonal contraceptives are stopped if pregnancy is confirmed (no proven teratogenicity from accidental early use). Progestin-only methods and IUDs are preferred while breastfeeding; CHC is delayed postpartum.

Interactions

• Enzyme inducers lower contraceptive effectiveness: rifampin and rifabutin, carbamazepine, phenytoin, phenobarbital, primidone, topiramate, oxcarbazepine, some HIV drugs, St. John's wort — recommend an IUD or DMPA, or a backup method
• Most other antibiotics do not reduce effectiveness
• CHC with the hepatitis C regimen ombitasvir/paritaprevir/ritonavir raises ALT (US MEC category 3)
• CHC lowers lamotrigine levels (seizure risk; toxicity in the hormone-free week)
• Estrogen raises thyroxine-binding globulin — a client on levothyroxine may need a higher dose
• Ulipristal and progestins reduce each other's effect (hence the 5-day wait)

1. Screen for contraindications before combined methods — measure blood pressure, ask about smoking and age, migraine with aura, clotting history, liver disease, breast cancer, current drugs (enzyme inducers)
2. Rule out pregnancy using the "reasonably certain not pregnant" criteria; a pelvic exam and Pap test are not required to start most methods
3. Backup contraception: 7 days after starting CHC or the implant unless started within 5 days of menses onset, and after DMPA or the LNG IUD unless started within 7 days (US SPR 2024); 2 days for progestin-only pills; none for the copper IUD
4. DMPA: deep IM into the deltoid or gluteal muscle; do not massage; schedule the next dose in 3 months (it may be given up to 15 weeks after the last injection without backup)
5. Implant or IUD procedures: consent, analgesia, monitor for vasovagal response after IUD placement; pressure dressing on the implant site
6. Menopausal therapy: baseline blood pressure, breast exam and current mammogram; evaluate any abnormal bleeding before starting; review the need yearly
7. Testosterone: check hematocrit at baseline, 3–12 months after starting, then yearly — the Endocrine Society advises not starting if baseline hematocrit is above 50% and stopping or reducing the dose if hematocrit exceeds 54%; blood pressure; PSA per age-based screening; confirm low morning testosterone on two tests before starting
8. Clomiphene/letrozole: follicle monitoring by ultrasound as ordered; report pelvic pain or visual change

• ACHES — combined hormonal warning signs: Abdominal pain, Chest pain or shortness of breath, Headache (severe), Eye problems (vision loss or blurring), Severe leg pain or swelling — seek care at once
• Missed combined pills: one missed (fewer than 48 hours late) → take it now and continue, no backup needed. Two or more missed → take the latest missed pill, continue daily, and use backup for 7 days; if the missed pills were in the last hormone week, skip the hormone-free week; consider EC if missed in week 1 after unprotected sex
• Progestin-only pill: same time every day; more than 3 hours late → take it, use backup for 2 days
• Patch: apply to clean, dry skin (buttock, abdomen, upper outer arm, back), not the breasts; change weekly
• Stop smoking, especially with estrogen methods
• Hormonal methods do not protect against STIs — use condoms
• DMPA: return every 3 months; calcium, vitamin D, weight-bearing exercise
• Emergency contraception: take as soon as possible; if the next period is more than 7 days late, take a pregnancy test
• Testosterone gel: wash hands after applying, let it dry, cover the site with clothing, and keep children and women from touching it; report leg swelling, breathing pauses at night, or headaches with high blood pressure
• Menopausal therapy: take the progestogen as prescribed if you have a uterus; report any vaginal bleeding

• Acute overdose of oral contraceptives is usually benign (nausea, vomiting, withdrawal bleeding in girls). No antidote; supportive care.
• Thromboembolic events are the dangerous toxicity: DVT (unilateral leg swelling, pain), pulmonary embolism (sudden dyspnea, chest pain, tachycardia), stroke (focal weakness, speech change), MI. Stop the estrogen and treat as an emergency; estrogen is usually stopped at least 4 weeks before major surgery with prolonged immobility.
• Liver: jaundice or right upper quadrant pain — stop and evaluate (cholestasis, adenoma).
• Testosterone: erythrocytosis (hematocrit above 54%) raises thrombosis risk — hold and report. Misuse at high doses causes mood changes, infertility, cardiovascular effects.
• Ovarian hyperstimulation syndrome: severe cases cause ascites, hemoconcentration, thrombosis, and kidney failure — urgent care.

• CHC suppresses ovulation; progestins thicken cervical mucus
• Smoking 15 or more cigarettes/day at age 35 or older = no combined methods (boxed warning)
• Other CHC "do not use": migraine with aura, VTE history, BP ≥ 160/100, current breast cancer, under 21 days postpartum
• ACHES = estrogen warning signs
• Two or more missed combined pills → backup 7 days
• Rifampin, enzyme-inducing antiseizure drugs, and St. John's wort reduce effectiveness; CHC lowers lamotrigine
• DMPA: every 3 months, bone density boxed warning, delayed fertility return
• Etonogestrel implant: up to 5 years (FDA 2026)
• EC: copper or LNG 52-mg IUD most effective; ulipristal within 5 days; levonorgestrel best within 72 hours
• Estrogen therapy with an intact uterus must include a progestogen
• Testosterone: hematocrit and BP monitoring; gel secondary-exposure boxed warning