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.