PharmacologyTier 1Medical Sciences concept

Selective estrogen receptor modulator (tamoxifen) effects and adverse effects

Core concept

A SERM is agonist in some tissues, antagonist in others - the effect depends on which coregulator the ligand-receptor complex recruits in that tissue
- Coactivator recruited -> agonist; corepressor recruited -> antagonist
Tamoxifen is a prodrug
- CYP2D6 -> endoxifen, the active metabolite (~100x the parent affinity)

Tissue	Tamoxifen	Raloxifene	Clomifene
Breast	Antagonist	Antagonist	-
Endometrium	Agonist (inc cancer)	Antagonist/neutral	-
Bone	Agonist (dec fracture)	Agonist	-
Hypothalamus	Antagonist (hot flushes)	Antagonist	Antagonist
Liver/coagulation	Agonist -> inc VTE	inc VTE	-

Clomifene - hypothalamic ER antagonist -> blocks oestrogen negative feedback -> inc GnRH -> inc LH/FSH -> inc endogenous testosterone or ovulation induction
- Preserves spermatogenesis, unlike exogenous testosterone

Adjuvant tamoxifen 5 years -> ~dec 30-40% recurrence, dec ~30% breast cancer mortality; 10 years better in higher risk
Adverse effects
- Endometrial hyperplasia, polyps and carcinoma (RR ~2-3, postmenopausal women only)
- VTE (RR ~2), rising perioperatively
- Hot flushes, vaginal discharge, cataracts, deranged LFTs, hepatic steatosis
- Bone: protective after menopause, mildly bone-losing before it
Any postmenopausal bleeding on tamoxifen requires investigation - TVUS thickness thresholds are unreliable on tamoxifen, go to hysteroscopy and biopsy
CYP2D6 interaction - avoid strong inhibitors
- Avoid paroxetine and fluoxetine (potent CYP2D6 inhibitors -> dec endoxifen -> possible loss of efficacy)
- Use venlafaxine, citalopram or escitalopram for hot flushes instead
- CYP2D6 poor metabolisers generate less endoxifen
Tamoxifen vs aromatase inhibitor
- AIs (anastrozole, letrozole, exemestane) block peripheral aromatisation - postmenopausal only, more effective, but inc bone loss, arthralgia, dyslipidaemia, and no endometrial or VTE risk
- Premenopausal: tamoxifen, or ovarian suppression + AI
Fulvestrant is not a SERM - it is a SERD, a pure antagonist causing receptor degradation

ER+ breast cancer, adjuvant and metastatic; also risk reduction in high-risk women
Raloxifene - postmenopausal osteoporosis with a bonus reduction in invasive breast cancer; no benefit for hip fracture, and inc fatal stroke
Stop tamoxifen before major surgery and during prolonged immobility (VTE)
Clomifene - ovulation induction in PCOS (though letrozole is now preferred), and male hypogonadism where fertility must be preserved
Tamoxifen flare - transient inc bone pain and hypercalcaemia in metastatic disease, a sign of response, not progression

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