THE USE OF LUTEINIZING-HORMONE-RELEASING HORMONE AGONISTS AND ANTAGONISTS IN GYNECOLOGICAL CANCERS

The use of agonistic analogues of luteinizing hormone releasing hormon e (LHRH) is an established therapy for hormone-dependent metastatic pr e-menopausal breast cancer. Their mechanism of action in this disease is the suppression of ovarian oestrogen production (medical castration ). In the treatment of post-menopausal metastatic breast cancer, LHRH agonists also have some effect, although minor, probably through a sup pression of ovarian androgen production. Convincing evidence has been accumulated that LHRH analogues can directly inhibit the proliferation of breast cancer cells in vitro. The clinical impact of these finding s, however, is still controversial. Experimental data and several pilo t clinical trials suggest that in epithelial ovarian cancer and sex-co rd-stromal tumours of the ovary, LHRH agonists might have antitumour a ctivity through the suppression of gonadotrophin secretion (selective medical hypophysectomy). Phase III clinical trials, evaluating this hy pothesis, are in progress. Direct antiproliferative effects of LHRH an alogues on epithelial ovarian cancer cells have been demonstrated in v itro. In endometrial cancer, experimental and early clinical results s upport the concept of a direct antiproliferative activity of LHRH anal ogues. Recently, potent antagonistic analogues of LHRH, devoid of rele vant side-effects have become available for clinical testing. These ne w antagonists might be superior to agonistic LHRH analogues with respe ct to the rapidity and efficacy of selective medical hypophysectomy an d medical castration. Modern LHRH antagonists might also permit a bett er exploitation of direct antitumour effects. A further therapeutic im provement in gynaecological oncology might result from a combination o f LHRH agonists or antagonists with other peptide hormone analogues su ch as agonists of somatostatin or antagonists of bombesin/gastrin rele asing peptide which have antitumour activity. Since 50% of breast canc ers and 80% of epithelial ovarian cancers and endometrial cancers have high affinity binding sites for LHRH, cytotoxic LHRH analogues might provide a targeted chemotherapy, which would be more efficacious and l ess toxic than conventional regimens.