Selective Estrogen Receptor Modulators

Selective oestrogen receptor modulators (SERMs) bind oestrogen receptors and act as agonists in some tissues and antagonists in others. Clomifene induces ovulation, tamoxifen treats and prevents breast cancer, raloxifene prevents and treats postmenopausal osteoporosis, and ospemifene treats painful intercourse after menopause.

The balance of benefit and harm differs between agents, so the indication determines the choice.

Mechanism. Each SERM changes the shape of the oestrogen receptor and recruits different co-regulators in each tissue. Tamoxifen blocks breast tissue and stimulates endometrium and bone. Raloxifene blocks breast and endometrium and stimulates bone. Clomifene blocks hypothalamic receptors and raises gonadotropin release.

Pharmacokinetics. All are absorbed orally and metabolised in the liver. Tamoxifen is a prodrug converted by CYP2D6 to endoxifen; half-life of the parent is 5 to 7 days. Raloxifene has low bioavailability (2%) and a half-life of 28 hours. Clomifene has a half-life of 5 to 7 days.

Effects on tissue.

• Bone: raloxifene and tamoxifen preserve density in postmenopausal women; raloxifene lowers vertebral fracture risk by about 30 to 50% but not hip fracture.
• Breast: tamoxifen and raloxifene reduce oestrogen receptor positive breast cancer risk in high-risk women.
• Endometrium: tamoxifen causes polyps, hyperplasia and cancer; raloxifene does not.

Tamoxifen and CYP2D6. Strong CYP2D6 inhibitors (paroxetine, fluoxetine, bupropion) lower endoxifen levels and should be avoided; venlafaxine, citalopram and sertraline are weaker inhibitors and are usually preferred for hot flushes or mood.

• First-line. Tamoxifen for premenopausal oestrogen receptor positive breast cancer; raloxifene for osteoporosis in postmenopausal women with a high vertebral fracture and breast cancer risk; clomifene or letrozole for ovulation induction.
• Alternative. Aromatase inhibitors for postmenopausal breast cancer; bisphosphonates for osteoporosis; letrozole before clomifene in polycystic ovary syndrome.
• Specialist. Breast cancer prevention in women with strong family history or atypical hyperplasia; male infertility (off-label clomifene); gynaecomastia treatment.
• Emergency. None.

Selection. For breast cancer prevention in postmenopausal women, raloxifene has fewer endometrial effects than tamoxifen. Women with a uterus on tamoxifen should report any abnormal vaginal bleeding at once.

Contraindications. Pregnancy (all); history of venous thromboembolism, pulmonary embolism or stroke (tamoxifen, raloxifene); undiagnosed vaginal bleeding; active liver disease; hypersensitivity; clomifene with ovarian cysts or hormone-dependent tumours; ospemifene with breast cancer.

Serious adverse effects.

• Venous thromboembolism (2 to 3 times higher), stroke, cataract.
• Endometrial hyperplasia and cancer (tamoxifen).
• Hot flushes, vaginal discharge, leg cramps, mood change, visual disturbance (clomifene).
• Multiple pregnancy and ovarian hyperstimulation (clomifene).

Major interactions. Strong CYP2D6 inhibitors with tamoxifen (reduced effect); warfarin (raised INR with tamoxifen); colestyramine lowers raloxifene absorption; oestrogen therapy with tamoxifen or raloxifene works against each drug; rifampicin lowers levels.

Common prescribing errors.

• Prescribing paroxetine or fluoxetine with tamoxifen.
• Missing endometrial symptoms on tamoxifen.
• Using raloxifene for hot flushes (it can worsen them).
• Continuing clomifene beyond 6 ovulatory cycles.
• Giving SERMs to premenopausal women for osteoporosis.

Special groups.

• Pregnancy: contraindicated; stop clomifene once pregnant.
• Breastfeeding: avoid.
• Children and adolescents: not used.
• Older adults: raloxifene is for women after menopause; stroke risk needs review.
• Kidney: no adjustment.
• Liver: avoid in active disease.
• East Africa: tamoxifen is the main affordable endocrine therapy for breast cancer; many breast cancers present at a younger age, so premenopausal use is common; check for interactions with antidepressants and antimalarials that inhibit CYP2D6.

Monitoring. Gynaecological symptoms yearly on tamoxifen; bone density with raloxifene; blood pressure; leg symptoms; liver tests when clinically indicated; ultrasound in clomifene cycles.

Referral and escalation. Postmenopausal bleeding; unilateral leg swelling, breathlessness or neurological symptoms; visual change; pregnancy; no ovulation after 3 cycles of clomifene.

Comparison with alternative classes. SERMs are oral and affordable, and offer tissue-selective effects, but raise thrombosis risk. Aromatase inhibitors are more effective in postmenopausal breast cancer and for ovulation induction, with other adverse effect profiles.