Hormonal contraceptives and HRT
Hormonal drugs: contraceptives, HRT, ovulation induction, GnRH analogues and antiprogestogens
Nearly every hormonal drug in gynaecology works by changing feedback on the hypothalamus and pituitary or by acting directly on oestrogen, progesterone or androgen receptors in target tissues. Once the receptor and the feedback loop are clear, the uses, side effects and contraindications follow. CPSP asks mechanisms, thrombosis and cancer risks, drug interactions and emergency contraception.
One of the most tested topics in past papers
Combined hormonal contraception
- Ethinylestradiol suppresses FSH (no follicle selection) and stabilises the endometrium for predictable withdrawal bleeds; the progestogen blocks the mid-cycle LH surge, thickens cervical mucus and thins the endometrium.
- Benefits: lower risk of ovarian, endometrial and colorectal cancer; less dysmenorrhoea (anovulation and thin endometrium cut prostaglandin), menorrhagia and functional cysts.
- Venous thrombosis: ethinylestradiol on the liver raises clotting factors (fibrinogen, II, VII, X) and lowers antithrombin and protein S. This happens by any route, so the patch and ring carry the same risk as the pill.
- Contraindications: migraine with aura (ischaemic stroke), previous VTE or known thrombophilia, smoker over 35, severe hypertension, current breast cancer, active liver disease, early postpartum.
- Missed pills at the start of a pack lengthen the hormone break, letting a follicle grow and ovulate.
- Enzyme inducers (rifampicin, carbamazepine, phenytoin, St John's wort) speed clearance and cause pill failure; use a copper IUD, LNG-IUS or depot injection. Oestrogen in turn induces glucuronidation, halving lamotrigine levels.
| Progestogen | Property | Consequence |
|---|---|---|
| Levonorgestrel, norethisterone | 19-nortestosterone derivatives, mildly androgenic | Acne, hirsutism; lowest VTE risk among pills |
| Desogestrel, gestodene | Less androgenic | About double the VTE risk of levonorgestrel pills |
| Drospirenone | From spironolactone: antimineralocorticoid, anti-androgen | Hyperkalaemia with ACE inhibitors or CKD |
| Cyproterone acetate | Anti-androgen | Used for acne and hirsutism |
| Norethisterone (high dose) | About 1% converted to ethinylestradiol | Caution after VTE when used at 10–15 mg daily |
Progestogen-only and intrauterine methods
| Method | Main action | Points tested |
|---|---|---|
| Traditional POP (norethisterone, levonorgestrel) | Thick cervical mucus; ovulation stopped in about half | 3-hour window; safe in breastfeeding |
| Desogestrel POP | Inhibits ovulation | 12-hour window |
| Etonogestrel implant | Inhibits ovulation | 3 years; irregular bleeding |
| Depot medroxyprogesterone | Inhibits ovulation | Every 13 weeks; bone loss, weight gain; fertility returns after 6–12 months |
| LNG intrauterine system | Local endometrial atrophy, thick mucus | Treats heavy painful periods; contraindicated in current breast cancer |
| Copper IUD | Copper ions toxic to sperm and ova, sterile endometrial inflammation | Heavier periods (more prostaglandin and fibrinolysis); most effective emergency method |
- Progestogen-only methods do not raise clotting factors, so they are used after VTE; irregular bleeding is the commonest reason for stopping them.
- Sugammadex binds progestogens, acting like a missed pill.
Emergency contraception
| Method | Time limit | Mechanism |
|---|---|---|
| Copper IUD | 5 days | Prevents fertilisation and implantation |
| Ulipristal 30 mg | 120 hours | Progesterone receptor modulator; delays follicle rupture even after the LH rise begins |
| Levonorgestrel 1.5 mg | 72 hours | Delays ovulation; useless after the LH surge; double dose with enzyme inducers |
- Hormonal emergency contraception is not abortifacient. After ulipristal, wait 5 days before starting a progestogen, which would compete at the receptor.
Hormone replacement and SERMs
- Oestrogen relieves vasomotor symptoms, vaginal atrophy and prevents osteoporosis. A woman with a uterus needs a progestogen to prevent endometrial hyperplasia and carcinoma from unopposed oestrogen.
- Risks: breast cancer (greater with combined HRT), VTE and stroke with oral oestrogen, gallbladder disease.
- Oral oestrogen reaches the liver at high concentration (first pass), raising VLDL and triglycerides, SHBG and clotting factors; transdermal oestradiol has little hepatic effect.
| SERM | Breast | Endometrium | Bone | Main uses and risks |
|---|---|---|---|---|
| Tamoxifen | Antagonist | Agonist | Agonist | Breast cancer; endometrial hyperplasia and carcinoma, VTE, hot flushes |
| Raloxifene | Antagonist | Antagonist | Agonist | Postmenopausal osteoporosis with lower breast cancer risk; VTE, hot flushes |
| Clomiphene | Hypothalamic antagonist | Antagonist | Little | Ovulation induction |
Ovulation induction
- Clomiphene blocks hypothalamic oestrogen receptors, removing negative feedback so GnRH, FSH and LH rise. Peripheral anti-oestrogen effects thin the endometrium and thicken mucus; risks are multiple pregnancy and visual symptoms.
- Letrozole, an aromatase inhibitor, lowers oestradiol and so releases FSH, without peripheral anti-oestrogen effects; preferred in PCOS. In postmenopausal breast cancer it blocks oestrogen made by aromatisation of adrenal androgens in fat.
- Gonadotrophins: FSH drives granulosa cells to aromatise androgen made by theca cells under LH (two-cell theory), so hypogonadotrophic women need LH activity too. hCG shares the α subunit and binds the LH receptor, triggering ovulation about 36 hours later; its long action drives ovarian hyperstimulation syndrome.
GnRH analogues, antiprogestogens and others
- GnRH agonists (goserelin, leuprorelin) given continuously first cause a flare of LH and FSH for 1–2 weeks, then desensitise and downregulate pituitary receptors, producing a reversible menopause. Uses: endometriosis, shrinking fibroids before surgery, precocious puberty, IVF, prostate and breast cancer. Side effects: hot flushes and bone loss (add-back HRT).
- GnRH antagonists (cetrorelix, ganirelix, degarelix) suppress at once, with no flare; used to prevent a premature LH surge in IVF.
- Mifepristone blocks progesterone and glucocorticoid receptors: medical abortion with misoprostol; raise steroid cover in adrenal insufficiency.
- Ulipristal 5 mg daily shrank fibroids but was restricted after severe liver injury.
- Danazol, an ethisterone derivative, suppresses gonadotrophins; androgenic effects include acne, hirsutism and irreversible voice deepening, and it virilises a female fetus.
- Tranexamic acid blocks lysine binding sites on plasminogen, preserving endometrial clots and halving menstrual loss; avoid with active thrombosis.
Remember Pulsatile GnRH stimulates the pituitary; continuous GnRH shuts it down after a brief flare.
Exam trap Tamoxifen protects the breast but stimulates the endometrium; raloxifene does not stimulate the endometrium.
Exam trap Migraine with aura is an absolute contraindication to combined hormonal contraception.
Test yourself on this topic
5 of the 43 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A 38-year-old woman with heavy but regular periods and a normal uterus is given oral tranexamic acid on the heaviest days. Her blood loss halves. At the molecular level, how does the drug act?
Answer: Blocks lysine sites on plasminogen
The endometrium has high fibrinolytic activity at menstruation, and in heavy menstrual bleeding plasminogen activators are increased. Tranexamic acid is a synthetic lysine analogue that blocks the lysine-binding sites on plasminogen, preventing it from binding fibrin and being converted to plasmin. Clots in the spiral arterioles are preserved, reducing loss by about 40 to 50%. It does not affect the cycle and is taken only during bleeding.
Tranexamic acid
- Synthetic lysine analogue
- Blocks plasminogen binding to fibrin
- Preserves endometrial clots
- Blood loss falls by 40–50%
Remember Stop plasmin, keep the clot.
Exam trap It is avoided in women with active thromboembolic disease.
Why the other options are wrong
- Inhibits cyclo-oxygenase in endometrium COX inhibition is the action of mefenamic acid.
- Activates platelet glycoprotein IIb/IIIa It does not act on platelet receptors.
- Increases synthesis of factor VIII It does not change factor VIII synthesis.
- Constricts the spiral arterioles It does not constrict vessels.
A woman with Addison disease on hydrocortisone replacement requests medical termination at 7 weeks. The gynaecologist plans to increase her steroid dose while she takes mifepristone. What is the reason?
Answer: Mifepristone also blocks glucocorticoid receptors
Mifepristone is a progesterone receptor antagonist but also a potent glucocorticoid receptor antagonist; at higher doses it is used to treat Cushing syndrome. In a woman dependent on replacement steroids, blocking glucocorticoid receptors can precipitate adrenal insufficiency, so the glucocorticoid dose is increased. Long-term systemic steroid use, which may also lose effect, and chronic adrenal failure are relative contraindications.
Mifepristone receptor actions
- Blocks progesterone receptors
- Also blocks glucocorticoid receptors
- Risk in adrenal insufficiency
- Higher doses used in Cushing syndrome
Remember Mifepristone blocks cortisol too.
Exam trap Asthma treated with steroids may also be harder to control after mifepristone.
Why the other options are wrong
- Mifepristone induces hepatic cortisol breakdown Its main issue is receptor block, not induction of cortisol breakdown.
- Mifepristone suppresses ACTH release It does not suppress ACTH; it tends to raise it in people with intact adrenals.
- Misoprostol inhibits cortisol synthesis Misoprostol does not inhibit cortisol synthesis.
- Mifepristone blocks the mineralocorticoid receptor It has little mineralocorticoid receptor action.
Ulipristal acetate 5 mg daily was used to shrink uterine fibroids before surgery, but its use was later restricted after reports of a serious adverse effect. Which effect led to the restriction?
Answer: Severe drug-induced liver injury
Ulipristal acetate is a selective progesterone receptor modulator that reduces fibroid size and bleeding. Rare but severe drug-induced liver injury, some cases needing transplantation, was reported with long-term 5 mg use, so its use for fibroids was restricted, with liver function monitoring where it is still used. The single 30 mg dose for emergency contraception has not been linked to this problem.
Ulipristal for fibroids
- Progesterone receptor modulator
- Shrinks fibroids, less bleeding
- Restricted for liver injury
- Single EC dose not affected
Remember Long-term ulipristal: watch the liver.
Exam trap Ulipristal causes benign endometrial changes that should not be mistaken for hyperplasia.
Why the other options are wrong
- Irreversible loss of bone density Bone loss is a feature of GnRH agonists, not ulipristal.
- Ischaemic stroke in young women Stroke was not the concern.
- Endometrial adenocarcinoma SPRMs cause benign endometrial changes, not carcinoma.
- Agranulocytosis with sepsis Agranulocytosis was not the concern.
A 28-year-old woman who cannot use hormones has a copper intrauterine device fitted. By which mechanism does it mainly prevent pregnancy?
Answer: Copper ions are toxic to sperm and ova
The copper IUD releases copper ions into the uterine and tubal fluid. Copper is toxic to sperm and ova, impairing sperm motility and survival and preventing fertilisation, and the device also provokes a sterile inflammatory reaction in the endometrium with leucocytes and prostaglandins. If fertilisation does occur, implantation is prevented, which is why it works as emergency contraception up to 5 days after intercourse.
Copper IUD
- Copper ions toxic to sperm and ova
- Sterile endometrial inflammation
- Prevents fertilisation mainly
- Also blocks implantation (emergency use)
Remember Copper kills sperm; ovulation continues.
Exam trap Because ovulation continues, a copper IUD does not help ovarian or hormonal symptoms.
Why the other options are wrong
- It releases progestogen that thickens mucus Progestogen release is the mechanism of the levonorgestrel IUS.
- It suppresses the LH surge and ovulation Ovulation continues normally with a copper IUD.
- It blocks the tubal ostia mechanically It does not block the tubal ostia.
- It induces endometrial atrophy Endometrial atrophy is caused by the levonorgestrel IUS.
A 22-year-old woman starting her first combined oral contraceptive pill wants the type with the lowest risk of venous thromboembolism. Which progestogen should her pill contain?
Answer: Levonorgestrel
All combined pills raise venous thrombosis risk because ethinylestradiol increases hepatic synthesis of clotting factors and reduces natural anticoagulants. The progestogen modifies this: more androgenic progestogens such as levonorgestrel partly counteract the oestrogen's hepatic effect, so pills containing levonorgestrel (or norethisterone) carry about half the risk of those with desogestrel, gestodene, drospirenone or cyproterone. They are therefore the usual first choice.
Progestogen and VTE risk
- Ethinylestradiol raises clotting factors
- Levonorgestrel partly offsets this
- Desogestrel, gestodene, drospirenone: about double
- First choice: levonorgestrel pill
Remember Lowest VTE risk pill: levonorgestrel.
Exam trap Even the safest combined pill raises VTE risk; pregnancy raises it far more.
Why the other options are wrong
- Desogestrel Desogestrel pills carry about twice the risk of levonorgestrel pills.
- Gestodene Gestodene pills carry about twice the risk.
- Drospirenone Drospirenone pills carry a higher risk.
- Cyproterone acetate Cyproterone pills carry a higher risk and are for acne and hirsutism.
Where this sits in the CPSP syllabus
- Obstetrics & Gynaecology, Paper 2: Drugs in obstetrics and gynaecology, Hormonal drugs: contraceptives, HRT, ovulation induction, GnRH analogues, antiprogestogens
Read next
Drug dose pages
Doses, cautions and practical tips for drugs in this chapter.