Anti-oestrogens

Anti-oestrogens

The selective oestrogen receptor modulators (SERMs) are non-steroidal anti-oestrogenic agents. Their anti-oestrogenic effects may be related to their ability to compete with oestrogen for binding sites in target tissues such as breast tissue. These agents block oestrogen effects in breast tissue, inhibit bone resorption, produce an oestrogen-like effect on the cardiovascular system, and barely, if at all, stimulate tissue in the breast or the uterus. The two common examples of anti-oestrogens are tamoxifen and clomiphene, though both possess oestrogenic as well as anti-oestrogenic effects. Clomiphene citrate is a non-steroidal ovulatory stimulant. Other examples of SERMs include drolox-ifene, levormeloxifene, raloxifene and toremifene.

Tamoxifen is mainly used in the treatment of breast cancer, while clomiphene is useful in treating female infertility. The approved indication for tamoxifen is for the treatment of node-positive breast cancer in post -menopausal women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. Tamoxifen is the first-line therapy in advanced breast cancer for post-menopausal women. It is used as an alternative to oophorectomy or ovarian irradiation in pre-menopausal women with metastatic breast cancer. Toremifene is indicated for the treatment of metastatic breast cancer in post-menopausal women with oestrogen-receptor positive or unknown tumours. It binds to oestrogen receptors and may have oestrogenic, anti-oestrogenic, or both properties, depending upon the duration of treatment. Clomiphene is indicated for the treatment of ovulatory failure in patients desiring pregnancy.

Clomiphene can cause the following adverse effects: ovarian enlargement, abdominal pain, nausea and vomiting, vasomotor flushing, blurred vision, breast discomfort, depres-sion, nervousness, insomnia, dizziness, and headache. Elevated transaminases, as well as occasional reports of hepatitis, have been reported. Additionally, various liver neoplasms have been reported, but the causal relationship remains uncertain. Ovarian hyperstimulation syndrome has been reported after therapeutic use of clomiphene. Early effects may include nausea, vomiting, diarrhoea and weight gain. In severe cases, effects may include gross ovarian enlargement, ascites, dyspnoea, oliguria, pleural effusion, pericardial effusion, anasarca, acute abdomen, hypo-tension, renal failure, pulmonary oedema, intraperitoneal and ovarian haemorrhage, ovarian torsion, deep venous thrombosis, respiratory distress, electrolyte imbalances, hypovolaemia, hypoproteinaemia, haemoconcentration, and shock. Symptoms of overdose (e.g. nausea, vomiting, vasomotor flashes, visual blurring, spots or flashes, scotomata, ovarian enlargement with pelvic or abdominal pain) following inadvertent use of more than the recommended dose appear to be an extension of adverse effects. Treatment consists of supportive and sympto-matic measures. Due to the large molecular weight of clomi-phene (approximately 580), dialysis and similar techniques are not anticipated to be beneficial.

Tamoxifen can cause the following adverse effects: hot flushes, oedema, GI upset, vertigo, rash, pruritis vulvae, vaginal bleeding, thromboembolic phenomena, leucopenia, thrombo-cytopenia,. In patients with bone metastases, tamoxifen can cause dangerous hypercalcaemia. Corneal changes, cataracts, glaucoma, abnormal vision/diplopia, and retinopathy have been observed in patients receiving therapeutic tamoxifen or toremifene. Myocardial infarction has been reported with chronic therapeutic use. Tamoxifen has been associated with changes in liver enzyme levels, and on rare occasions, more severe liver damage including fatty liver, cholestasis, hepatitis and hepatic necrosis. A few of these serious cases included deaths. A causal relationship is unclear. Steatohepatitis progressing to cirrhosis has been reported in some women with breast cancer following long-term (3 to 5 years) adjunctive therapy with tamoxifen. In some clinical studies, toremifene administration was associated with angina and arrhythmias during therapeutic use. Thromboembolic events, including pulmonary embolism, thrombosis and thrombophlebitis, have been associated with tamoxifen and toremifene. Tamoxifen may cause developmental abnormalities of the genital tract in humans and an interval of many years between in utero exposure and clinical manifestations could exist. Results from animal studies using tamoxifen are similar to those using diethylstilbestrol (DES) under similar conditions. Based on a literature review, the incidence of endometrial cancer is increased in women after receiving tamoxifen therapy.

Although a small risk, data suggests it may act as a tumour promoter in human endometrium. There is little information regarding overdose in humans. At doses at least 6 times (400 mg/m2) the recommended dose (20 to 40 mg daily), neurotox-icity (seizures, tremor, hyperreflexia, unsteady gait and dizzi-ness) and electrocardiographic changes (prolonged QT interval) were noted. Treatment consists of symptomatic and supportive measures. Monitor liver function tests following acute over-dose. Consider administration of activated charcoal after a potentially toxic ingestion. Gastric lavage may be done with a large-bore orogastric tube after a potentially life-threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes). Monitor ECG for QT prolongation and arrhythmias. Obtain periodic complete blood counts, including platelet counts. Monitor for signs of tremor, hyperreflexia, unsteady gait, dizziness and seizures.