The use of luteinizing hormone releasing hormone agonists and antagonists in gynaecological cancers

The use of agonistic analogues of luteinizing hormone releasing hormone (LHRH) is an established therapy for hormone-dependent metastatic pre-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 alsohave some effect, although minor, probably through a suppression 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 findings, however, is still controversial. Experimental data and several pilot clinical trals suggest that in epithelial ovarian cancer and sex-cord-stromal tumours of the ovary, LHRH agonists might have antitumour activity through the suppression of gonadotrophin secretion (selective medical hypophysectomy). Phase III clinical trials, evaluating this hypothesis, are in progress. Direct antiproliferative effects of LHRH analogues on epithelial ovarian cancer cells have been demonstrated in vitro. In endometrial cnacer, experimental and early clinical results support the concept of a direct antiproliferative activity of LHRH analogues. Recently, potent antagonistic analogues of LHRH, devoid of relevant side-effects have become available for clinical testing. These new antagonists might be superior to agonistic LHRH analogues with respect to the rapidity and efficacy of selective medical hypophysectomy and medical castration. Modern LHRH antagonists might also permit a better exploitation of direct antitumour effects. A further therapeutic improvement in gynaecological oncology might result from a combination of LHRH agonists or antagonists with other peptide hormone anlogues such as agonists of somatostatin or antagonists of bombesin/gatrin releasing peptide which have antitumour activity. Since 50% of breast cancers 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 less toxic than conventional regimens.