Sex Hormones & Related Drugs

A high-yield endocrine pharmacology block covering oestrogens, progestogens, androgens, the SERMs (tamoxifen, raloxifene), antiestrogens (clomiphene), aromatase inhibitors, GnRH analogues, and the practical pharmacology of combined oral contraceptives, hormone replacement therapy, and PCOS therapy. NEET PG loves mechanism + tissue-selectivity + contraindications here.

Overview & classification

Gonadal steroids are synthesised from cholesterol via the steroidogenic pathway (cholesterol → pregnenolone via desmolase, the rate-limiting CYP11A1 step) and act on intracellular nuclear receptors (ER-α, ER-β, PR, AR) that function as ligand-activated transcription factors. Drugs in this group either replace, mimic, block, or modulate these hormones.

Class	Examples	Core action
Oestrogens	Ethinylestradiol, estradiol valerate, conjugated equine oestrogens, mestranol	ER agonist
Progestogens	Progesterone (micronised), levonorgestrel, desogestrel, drospirenone, dienogest, medroxyprogesterone acetate (MPA)	PR agonist
Androgens	Testosterone (esters/gel), methyltestosterone, danazol, nandrolone, stanozolol	AR agonist (anabolic)
Antiestrogens / SERMs	Clomiphene, tamoxifen, raloxifene, ospemifene, bazedoxifene	Tissue-selective ER agonist/antagonist
Antiprogestins	Mifepristone, ulipristal	PR antagonist (also GR)
Antiandrogens	Cyproterone, flutamide/bicalutamide, spironolactone, finasteride/dutasteride	AR block / 5α-reductase inhibition
Aromatase inhibitors	Letrozole, anastrozole (non-steroidal); exemestane (steroidal)	Block androgen→oestrogen conversion
GnRH analogues	Leuprolide, goserelin, nafarelin (agonists); cetrorelix, ganirelix, degarelix (antagonists)	Modulate pituitary FSH/LH

High-yield: Ethinylestradiol differs from natural estradiol by an ethinyl group at C17, which blocks first-pass hepatic metabolism, making it orally potent and long-acting — the workhorse oestrogen of combined pills.

Oestrogens

Physiological & pharmacological actions

• Growth of female secondary sex characters, endometrial and breast proliferation, fusion of epiphyses.
• Maintain bone mass by inhibiting osteoclastic resorption (decrease IL-1, IL-6, TNF; promote osteoclast apoptosis).
• Hepatic effects: increase HDL, decrease LDL; increase clotting factors (II, VII, IX, X) and decrease antithrombin III → pro-thrombotic; increase CBG, TBG, SHBG, angiotensinogen.
• Favourable lipid effect but net cardiovascular risk depends on age/route (see HRT).

Therapeutic uses

Contraception, HRT for menopausal vasomotor symptoms and urogenital atrophy, hypogonadism/Turner syndrome, and (historically) prostate cancer (rarely now).

High-yield: Oestrogen's adverse effects to memorise = nausea (most common early), VTE, endometrial carcinoma (unopposed), gallstones, hypertension, breast tenderness, migraine. Unopposed oestrogen in a woman with intact uterus → endometrial hyperplasia/cancer, hence always add a progestogen.

Progestogens

• Secretory transformation of endometrium, support pregnancy, suppress ovulation (negative feedback on LH surge), thicken cervical mucus.
• 19-nortestosterone derivatives (levonorgestrel, norethindrone) have androgenic activity → acne, hirsutism; newer agents (desogestrel, drospirenone, dienogest) are less androgenic.
• Drospirenone is unique: it is an analogue of spironolactone → antimineralocorticoid + antiandrogenic; risk of hyperkalaemia (avoid with ACEi/ARB/K-sparing diuretics).

High-yield: Cyproterone acetate and drospirenone are the progestins with antiandrogenic action — preferred in COCs for acne/hirsutism/PCOS.

Combined oral contraceptives (COC)

Mechanism — the layered contraceptive effect

Oestrogen suppresses FSH → no dominant follicle. Progestogen suppresses the LH surge → no ovulation (primary mechanism), thickens cervical mucus (blocks sperm), and renders endometrium non-receptive.

Flow: Daily oestrogen + progestin → negative feedback on hypothalamus/pituitary → ↓FSH & ↓LH → no LH surge → no ovulation → + hostile cervical mucus + atrophic endometrium → contraception.

Efficacy — Pearl Index

Method	Perfect-use failure	Typical-use failure
COC	0.3%	~9%
Progestin-only pill	0.3%	~9%
DMPA injection	0.2%	~6%
Copper IUCD	0.6%	0.8%
LNG-IUS (Mirena)	0.2%	0.2%
Etonogestrel implant	0.05%	0.05%
Male condom	2%	~18%
Tubal ligation	0.5%	0.5%

High-yield: The etonogestrel subdermal implant (Implanon/Nexplanon) has the lowest failure rate of all reversible methods (Pearl index ~0.05). LNG-IUS is next.

Non-contraceptive benefits

Reduced risk of ovarian and endometrial cancer (protective, lasts years after stopping), benign breast disease, ovarian cysts, ectopic pregnancy, PID; improves dysmenorrhoea, menorrhagia, acne, and PCOS hirsutism.

Adverse effects & risks

• Venous thromboembolism — the most important. Third-generation progestins (desogestrel, gestodene) and drospirenone carry higher VTE risk than levonorgestrel (2nd gen).
• Increased risk of cervical and (slightly) breast cancer; hepatic adenoma.
• Hypertension, migraine, cholestasis, weight gain, breakthrough bleeding.

Contraindications (WHO MEC category 4 — "do NOT use")

High-yield — COC absolute contraindications: History of/active VTE or thrombophilia, migraine with aura, smoker >35 years (≥15 cigarettes/day), breast cancer, active liver disease/tumour, uncontrolled hypertension (≥160/100), ischaemic heart disease/stroke, <6 weeks postpartum if breastfeeding, known prothrombotic mutation, complicated diabetes, oestrogen-dependent tumour.

Mnemonic for COC contraindications — "My Very Best Heart Loves Strong Coffee": Migraine with aura, VTE, Breast cancer, Hypertension uncontrolled, Liver disease, Smoker >35y, Coronary/Cerebro-vascular disease.

Drug interactions

Enzyme inducers reduce efficacy: rifampicin, phenytoin, carbamazepine, phenobarbitone, St John's wort, some antiretrovirals → use backup or alternative method. Antibiotics other than rifamycins generally do NOT reduce COC efficacy (myth previously taught).

Emergency contraception

Method	Window	Mechanism
Levonorgestrel 1.5 mg	≤72 h (up to 120 h, less effective)	Delays/inhibits ovulation
Ulipristal acetate 30 mg	≤120 h	Selective PR modulator — delays ovulation even after LH starts rising
Copper IUCD	≤5 days	Spermicidal + prevents implantation — most effective EC

High-yield: Copper IUCD is the most effective emergency contraceptive (failure <0.1%) and provides ongoing contraception. Ulipristal is more effective than LNG, especially in obese women and later in the cycle.

Hormone replacement therapy (HRT)

• Oestrogen alone if hysterectomised; oestrogen + progestogen if uterus intact (progestogen protects endometrium).
• Best for vasomotor symptoms and urogenital atrophy; benefit on osteoporosis but not first-line for it.

The WHI lessons

High-yield (WHI trial): Combined oestrogen + progestin HRT increased risk of breast cancer, coronary events, stroke, and VTE; oestrogen-only arm increased stroke/VTE but did not increase (and may reduce) breast cancer and reduced fractures. HRT is not recommended for cardiovascular protection. "Timing hypothesis": starting near menopause (<60 y / <10 y since menopause) is safer than late initiation.

SERMs — selective oestrogen receptor modulators

SERMs are the classic NEET PG tissue-selectivity question: agonist in some tissues, antagonist in others, depending on the co-activator/co-repressor recruitment in that tissue.

Drug	Breast	Bone	Endometrium	Lipids/Other	Main use
Tamoxifen	Antagonist	Agonist (protects)	Agonist (↑ Ca risk)	Favourable lipids	ER+ breast cancer (pre & post-menopausal)
Raloxifene	Antagonist	Agonist	Neutral (no endometrial risk)	—	Postmenopausal osteoporosis; reduces breast Ca risk
Clomiphene	Antagonist (hypothalamus)	—	—	—	Ovulation induction
Ospemifene	—	—	Agonist	Agonist on vagina	Dyspareunia from vulvovaginal atrophy

High-yield: Tamoxifen = ER antagonist in breast but agonist in endometrium and bone → increases risk of endometrial carcinoma and VTE, but protects bone. Raloxifene is antagonist in breast AND neutral in endometrium → used for osteoporosis with bonus breast-cancer risk reduction and no endometrial cancer risk.

• Tamoxifen is metabolised by CYP2D6 to active endoxifen; poor metabolisers / strong CYP2D6 inhibitors (paroxetine, fluoxetine) reduce efficacy.
• Tamoxifen adverse effects: hot flushes, endometrial cancer, VTE, cataracts, retinopathy.

Aromatase inhibitors

Block CYP19 (aromatase) → halt peripheral conversion of androgens to oestrogens. Effective only in postmenopausal women (in premenopausal women, ovarian aromatase is gonadotropin-driven and not adequately suppressed).

• Letrozole, anastrozole (reversible, non-steroidal); exemestane (irreversible, steroidal "suicide" inhibitor).
• Use: adjuvant therapy of postmenopausal ER+ breast cancer (superior to tamoxifen in this group), and letrozole is now first-line for ovulation induction in PCOS.
• Adverse: osteoporosis/fractures and arthralgia (because they remove protective oestrogen), unlike tamoxifen which protects bone.

High-yield: Letrozole has overtaken clomiphene as first-line for ovulation induction in PCOS (higher live-birth rate, lower multiple-pregnancy rate). Letrozole is teratogenic — used only in early follicular phase before conception.

Clomiphene (ovulation induction)

Mechanism: SERM that blocks oestrogen receptors at the hypothalamus → brain perceives low oestrogen → ↑GnRH pulses → ↑FSH/LH → follicular development and ovulation.

Flow: Clomiphene blocks hypothalamic ER → loss of negative feedback → ↑GnRH → ↑FSH/LH → ovulation.

• Given days 2–6 of cycle. Adverse: hot flushes, ovarian hyperstimulation, multiple pregnancy (~8%), antiestrogenic effect on cervical mucus/endometrium (a reason letrozole may give better pregnancy rates).

Androgens & anabolic steroids

• Testosterone given parenterally (esters, depot) or transdermally; oral methyltestosterone is hepatotoxic (17-alkylated).
• Uses: male hypogonadism, delayed puberty, certain anaemias (historical), hereditary angioedema (danazol/stanozolol).
• Danazol — weak androgen + inhibits gonadotropin release; used in endometriosis, fibrocystic breast disease, hereditary angioedema. Adverse: virilisation, weight gain, hepatic dysfunction.
• Anabolic steroid abuse → testicular atrophy, gynaecomastia (aromatisation), dyslipidaemia, hepatic tumours, aggression.

Antiandrogens (PCOS / hirsutism relevance)

Drug	Mechanism	Note
Spironolactone	AR antagonist + weak 5α-reductase inhibition	Common for hirsutism; hyperkalaemia
Cyproterone acetate	AR antagonist + progestin	In COC for acne/hirsutism
Flutamide/bicalutamide	Non-steroidal AR blocker	Prostate cancer; flutamide hepatotoxic
Finasteride (5αR type 2), Dutasteride (type 1&2)	Block testosterone→DHT	BPH, male-pattern baldness; teratogenic to male foetus

GnRH analogues

• Agonists (leuprolide, goserelin, nafarelin): continuous (non-pulsatile) administration → initial flare (↑LH/FSH for ~1–2 weeks) → then downregulation/desensitisation of pituitary GnRH receptors → medical castration (↓FSH/LH/sex steroids).
• Antagonists (cetrorelix, ganirelix, degarelix): immediate suppression without flare.
• Uses: prostate cancer (with anti-androgen cover initially to prevent tumour flare), endometriosis, uterine fibroids, central precocious puberty (paradoxically restores normal pulses), IVF protocols.
• Pulsatile GnRH (gonadorelin pump) actually stimulates the axis (used in hypogonadotropic hypogonadism/infertility) — the route/pattern determines stimulation vs suppression.

High-yield: GnRH agonists cause a transient testosterone/tumour "flare" → cover with an antiandrogen (e.g. flutamide/bicalutamide) for the first weeks in metastatic prostate cancer. GnRH antagonists (degarelix) avoid this flare entirely.

PCOS pharmacotherapy

Stepwise approach by goal:

1. Lifestyle/weight loss — first-line for all.
2. Menstrual regulation + hirsutism/acne → COC (preferably with antiandrogenic progestin, e.g. drospirenone/cyproterone).
3. Insulin resistance / metabolic → metformin (helps cycles, modest weight effect).
4. Hirsutism (refractory) → add spironolactone (with contraception, as it is teratogenic).
5. Fertility desired → letrozole first-line (then clomiphene); gonadotropins/ovarian drilling if resistant.

High-yield: In PCOS wanting pregnancy → letrozole (first-line ovulation induction). In PCOS wanting cycle control/hirsutism → COC ± spironolactone. Metformin for the metabolic/insulin-resistance component.

Antiprogestins

• Mifepristone (RU-486): PR + GR antagonist. Uses: medical abortion (with misoprostol), Cushing syndrome (GR block), emergency contraception (high dose).
• Ulipristal: SPRM — emergency contraception and (formerly) uterine fibroids.

High-yield: Medical termination regimen = mifepristone followed 24–48 h later by misoprostol (a PGE1 analogue causing uterine contraction).

Key differentials / commonly confused pairs

• Tamoxifen vs Raloxifene: both antagonise breast ER and agonise bone; tamoxifen is endometrial agonist (cancer/VTE risk) while raloxifene is endometrium-neutral. Raloxifene cannot treat established breast cancer (used for prevention/osteoporosis); tamoxifen treats it.
• Aromatase inhibitor vs Tamoxifen on bone: AIs worsen bone (cause osteoporosis); tamoxifen protects bone.
• GnRH agonist vs antagonist: agonist = initial flare then suppression; antagonist = immediate suppression.
• Clomiphene vs Letrozole: both induce ovulation; letrozole = aromatase inhibitor (now first-line, better live births in PCOS); clomiphene = SERM with antiestrogenic endometrial effect.
• Levonorgestrel vs Drospirenone progestins: levonorgestrel (lower VTE, androgenic); drospirenone (antiandrogenic, hyperkalaemia risk, slightly higher VTE).

Recently asked / exam angle

• "Most effective reversible contraceptive" → etonogestrel implant (lowest Pearl index); "most effective emergency contraceptive" → copper IUCD.
• "SERM agonist in endometrium" → tamoxifen (endometrial cancer risk).
• "SERM used in osteoporosis without endometrial risk" → raloxifene.
• "First-line ovulation induction in PCOS" → letrozole.
• "Drug causing flare in prostate cancer / needs antiandrogen cover" → GnRH agonist (leuprolide/goserelin).
• "Progestin causing hyperkalaemia" → drospirenone (spironolactone analogue).
• "Active metabolite of tamoxifen / CYP2D6" → endoxifen; paroxetine reduces efficacy.
• "Mechanism of clomiphene" → blocks hypothalamic ER, raises FSH/LH.
• WHI trial conclusions on combined HRT (↑breast Ca, ↑CHD, ↑stroke, ↑VTE).
• "Why ethinylestradiol orally active" → C17 ethinyl group resisting first-pass metabolism.
• Steroidal aromatase inhibitor (suicide inhibitor) → exemestane.
• Mifepristone mechanism → progesterone (and glucocorticoid) receptor antagonist.

Rapid revision

1. Ethinylestradiol's C17 ethinyl group → oral activity (escapes first-pass).
2. COC primary mechanism = progestin suppresses LH surge → no ovulation.
3. Most effective reversible contraceptive = etonogestrel implant; most effective EC = copper IUCD.
4. COC absolute contraindications: VTE, migraine with aura, smoker >35y, breast cancer, uncontrolled HTN, liver disease.
5. 3rd-gen progestins & drospirenone → higher VTE risk than levonorgestrel.
6. Drospirenone = spironolactone analogue → antiandrogenic + hyperkalaemia.
7. Tamoxifen = breast antagonist, endometrium + bone agonist → endometrial Ca & VTE risk; active metabolite endoxifen (CYP2D6).
8. Raloxifene = breast antagonist, bone agonist, endometrium neutral → osteoporosis.
9. Aromatase inhibitors (letrozole/anastrozole/exemestane) → postmenopausal ER+ breast Ca; cause osteoporosis/arthralgia.
10. Letrozole = first-line ovulation induction in PCOS; clomiphene blocks hypothalamic ER.
11. GnRH agonist → initial flare then downregulation (cover with antiandrogen in prostate Ca); antagonist → no flare.
12. WHI: combined HRT raises breast cancer, CHD, stroke, VTE — not for cardioprotection.