Anti-oestrogens (Clomifene and Tamoxifen)

Clomifene is an oestrogen receptor antagonist that prevents negative feedback of oestrogen at the hypothalamus, leading to increased secretion of FSH and LH. This is used to induce ovulation in anovulatory infertility.

Tamoxifen similarly blocks oestrogen receptors but also has partial agonist properties. It is widely used as adjunctive hormone treatment in women with oestrogen-receptor positive early breast cancer.

Treatment of female infertility due to oligomenorrhoea or secondary amenorrhoea

• Tamoxifen should be first line treatment to induce ovulation, where infertility is likely to derive from hypothalamic-pituitary dysfunction (predominantly polycystic ovary syndrome - PCOS) - use up to 12 months of clomifene (or tamoxifen).¹
• About 60-85% anovulatory women ovulate in response to clomifene with 30-50% becoming pregnant following treatment.²
• In those with unexplained infertility, such treatment may increase their chances of pregnancy but this should be balanced against the risks (eg. multiple birth).¹
• Adjunctive hormonal treatment of oestrogen-receptor positive (ER-positive) breast cancer.³

Breast cancer

• Tamoxifen has an established role in the treatment of early breast cancer. It delays oestrogen-driven tumour growth and metastases and reduces recurrence risk, increases survival, irrespective of age, menopausal status, nodal involvement or chemotherapy in ER-positive tumours. If tolerated, it should be given for 5 years, usually following surgical treatment. It also reduces the risk of developing cancer in the other breast by about half. For women with ER-negative disease, the risk: benefit ratio is less clear with most deriving little benefit.⁴
• Tamoxifen remains the first-line adjuvant treatment for ER-positive early breast cancer in post-menopausal women despite the development of aromatase inhibitors. There is evidence of a marginal increase in efficacy with anastrazole compared to tamoxifen but this is outweighed as yet by concerns regarding unknown long-term side-effects and whether or not there is benefit to overall survival. Anastrazole offers an alternative when tamoxifen is contraindicated or unsuitable because of high risk of venous thromboembolism (VTE) or endometrial abnormality.⁵
• Tamoxifen is also used in post-menopausal women with ER-positive advanced breast cancer with long disease-free intervals following treatment for early disease and disease limited to bone and soft tissues although aromatase inhibitors are now regarded as preferred treatment.⁵
• Evidence suggests that tamoxifen prophylaxis can reduce ER-positive breast cancer in women at the highest risk of developing the disease however this preventative strategy is not yet recommended due to the risk of side-effects. It may possible to identify a sub-group of high-risk, healthy women for whom the risk-benefit ratio is sufficiently positive however.⁶

Treatment of mastalgia

This is an unlicensed indication:⁷

• There is limited RCT evidence that tamoxifen is more effective than placebo in reducing breast pain. Serious causes of mastalgia should be ruled out and simple analgesia etc. used in the first instance.
• Consensus is to use only under expert supervision and for no more than 6 months, usually limiting to days when symptoms are predicted (i.e. days 15-25 of standard menstrual cycle) and with non-hormonal contraception
• Its usefulness is limited by the high incidence of adverse effects.

• Possible effects on fetal development - avoid in pregnancy.²
• Abnormal uterine bleeding of undetermined cause
• Hepatic disease - avoid clomifene in severe liver disease
• Ovarian cysts - polycystic cysts may enlarge during treatment
• Breast-feeding is suppressed by tamoxifen so avoid unless potential benefit outweighs risk. Clomifene will also suppress lactation
• A personal or family history of venous thromboembolism (tamoxifen).

Side-effects include:

Clomifene

• Hot flushes, nausea, depression and breast tenderness (common).
• Blurred vision (increased pressure in anterior chamber of the eye) - stop immediately.
• Multiple pregnancy (usually 2 embryos but occasionally more) in 2-13% of induced pregnancies compared to 1-2% natural multiple birth rate (within European and north American populations).⁸
• Ovarian hyperstimulation syndrome - tends to be mild and a rare complication of clomifene treatment⁸ but potentially life-threatening.
• Possible increased risk of ovarian cancer based on a cohort study of infertile women.⁹ There was an 11-fold increase in risk of ovarian cancer in those using clomifene for 12 or more cycles (RR11.1, 95% CI 1.5-82.3). Subsequent cohort and case-control studies have not confirmed this association.⁸

Tamoxifen

• Hot flushes and other menopausal symptoms.
• Thromboembolism 11% - The International Breast Cancer Intervention Study^10,11 showed that women treated with tamoxifen had an approximately 2.3x increased risk of venous thromboembolism (VTE). Risk was highest within 3 months of surgery and following immobility. The risk is also increased when tamoxifen is used in combination with cytotoxics.
• Endometrial changes - endometrial hyperplasia, polyps, endometrial carcinoma and sarcoma. CSM advises that the benefits of tamoxifen in treatment for early breast cancer greatly outweighs the increased risk of endometrial carcinoma (for 5 years - treatment with tamoxifen, estimated cumulative risk of 2 deaths per 1000 women over 10 years).³
• Nausea and vomiting - common, 10% women on tamoxifen
• Oedema
• Tumour flare with pain & rarely hypercalcaemia where bony metastatic disease
• Visual disturbances (corneal changes, cataracts, retinopathy)
• Leucopenia.

Treating infertility

• Prior to initiating treatment, women/couples should be counselled regarding the risk of multiple pregnancy, ovarian hyperstimulation, fetal reduction and possible risk of ovarian cancer.
• The need for monitoring and ultrasound (at least in the first cycle of treatment)¹ and serum endocrine tests means, in general, clomifene is started in secondary care although GPs may continue to prescribe clomifene after the appropriate dose has been established. This should be done as part of a formal shared-care agreement.²
• In general, clomifene is used first-line but tamoxifen is licensed to treat anovulatory infertility and can be used for women who experience unwanted effects with clomifene.²
• Clomifene is usually started at a dose of 50mg daily for 5 days, commencing within 5 days of onset of progesterone-induced or spontaneous menstrual bleeding. Ovulation usually occurs within 5-10 days of taking the last tablet, with approximately 2/3 of women ovulating in the first cycle and most by the third cycle.²
• Ultrasound monitoring is used to identify a dominant follicle, an indicator of likely ovulation. Some centres also monitor serial progesterone and LH concentrations. If the woman has produced more than 2 follicles, usual practice is to advise against becoming pregnant and to reduce the dose to 25mg. If ovulation has not occurred, the dose is increased to 100 or 150mg (unlicensed dose).²
• If a woman develops visual disturbance or ovarian hyperstimulation syndrome, stop treatment immediately.
• Advice on weight reduction may improve response to clomifene as overweight women are less likely to respond to clomifene than those of normal weight - even a modest weight reduction of 5% initial body weight can improve endocrine and ovulatory function in women with PCOS.¹
• There is some evidence that combination of clomifene with metformin increases pregnancy rates (compared to clomifene alone).⁸
• NICE guidance suggests that women who ovulate with clomifene therapy but do not become pregnant after 6 months of treatment should be offered continued therapy with clomifene together with intrauterine insemination.¹
• NICE recommends that up to 12 cycles of clomifene may have clinical benefit with increasing cumulative pregnancy rate¹ although the CSM recommends no more than 6 due to the possibly increased risk of ovarian cancer.

Treating breast cancer

• Check the histology report - is the tumour ER-positive and the patient likely to benefit from treatment?
• Ensure the patient is well hydrated and measure the serum calcium if she has bony metastases.
• Exclude pregnancy and advise effective non-hormonal contraception should be continued to at least 2 months following end of treatment in pre-menopausal women.
• CSM advises that a daily dose of 20mg is the most efficacious and that no further benefit has been found with higher doses.
• Current evidence does not find benefit associated with prolonging treatment beyond 5 years.³ Tamoxifen resistance can develop after prolonged treatment.
• Obtain a careful personal and family history of venous thrombo-embolism. The decision to treat should be based on overall risk-benefit balance. Use of a prophylactic anticoagulant may be justified.¹²
• Do not stop tamoxifen before surgery or long-term immobility unless the risk of tamoxifen-induced VTE outweighs the risk of stopping treatment. Patients should receive thrombosis prophylaxis under these circumstances.¹²
• If a VTE does occur, stop tamoxifen immediately and start anti-thrombosis measures. Restarting tamoxifen after such an event should depend again on overall risk: benefit balance.¹² Anastrazole offers an alternative treatment option in such circumstances.⁵
• Patients should be counselled to report abnormal vaginal bleeding, menstrual irregularities, vaginal discharge and pelvic pain during or after their treatment with tamoxifen and this requires urgent investigation to exclude endometrial carcinoma.