Antioestrogens

Selective antagonists of the oestrogen receptor are used either to induce gonadotrophin release in anovulatory infertility, or to block stimulation of oestrogen-receptor-positive carcinomas of the breast

Clomifene is structurally related to stilboestrol; it is a weak oestrogen agonist having less activity than natural oestrogens, so that its occupation of receptors results in antagonism, i.e. it is a partial agonist. Clomifene blocks hypothalamic oestrogen receptors so that the negative feedback of natural oestrogens is prevented and the pituitary responds by increased secretion of gonadotrophins, which may induce ovulation. Clomifene is administered during the early follicular phase of the menstrual cycle (50 mg daily on days 2-6) and is successful in inducing ovulation in about 85% of women. Multiple ovulation with multiple pregnancy may occur and this is its principal adverse effect. There have also been reports of an increased incidence of ovarian carcinoma following multiple exposure, and the number of consecutive cycles for which clomiphene may be used to stimulate ovulation should be limited to 12.

Cyclofenil acts similarly to clomiphene.

Tamoxifen is a nonsteroid competitive oestrogen antagonist on target organs. Although available for anovulatory infertility (20 mg daily on days 2, 3, 4 and 5 of the cycle) its main use now is in the treatment of oestrogen-dependent breast cancer. Treatment with tamoxifen delays the growth of metastases and increases survival; if tolerated it should be continued for 5 years.

Tamoxifen is also the hormonal treatment of choice in women with oestrogen-receptor-positive metastatic breast cancer. Approximately 60% of such patients respond to initial hormonal manipulation, whereas less than 10% of oestrogen-receptor-negative tumours respond.

Severe adverse effects are unusual with tamoxifen but patients with bony metastases may experience an exacerbation of pain, sometimes associated with hypercalcaemia; this reaction com monly precedes tumour response. Amenorrhoea commonly develops in premenopausal women. Patients should be told of the small risk of endometrial cancer and encouraged to report relevant symptoms early. They can be reassured that the benefits of treatment far outweigh the risks.

Progesterone {il/2 5 min) is produced by the corpus luteum and converts the uterine epithelium from the proliferative to the secretory phase. It is thus necessary for successful implantation of the ovum, and is essential throughout pregnancy in the last two-thirds of which it is secreted in large amounts by the placenta. It acts particularly on tissues that are sensitised by oestrogens. Some synthetic progestogens are less selective, having varying oestrogenic and androgenic activity, and these may inhibit ovulation, though not very reliably. Progestogens are of two principal kinds:

• Progesterone and its derivatives: dydrogesterone, hydroxyprogesterone, medroxyprogesterone 28 h), etc.

• Testosterone derivatives: norethisterone and its prodrug ethynodiol (t'/210 h), levonorgestrel, desogestrel, gestodene, gestronol, norgestimate.

All can virilise directly or via metabolites (except progesterone and dydrogesterone) and fetal virilis-ation to the point of sexual ambiguity has occurred with vigorous use during pregnancy (see also Contraception, p. 721).

Megestrol is used only in cancer; it causes tumours in the breasts of beagle dogs.

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