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

The use of agonistic analogues of luteinizing hormone releasinghormone (LHRH) is an established therapy for hormone-dependentmetastatic pre-menopausal breast cancer. Their mechanism ofaction in this disease is the suppression of ovarian oestrogenproduction (medical castration). In the treatment of post-menopausalmetastatic breast cancer, LHRH agonists alsohave some effect,although minor, probably through a suppression of ovarian androgenproduction. Convincing evidence has been accumulated that LHRHanalogues can directly inhibit the proliferation of breast cancercells in vitro. The clinical impact of these findings, however,is still controversial. Experimental data and several pilotclinical trals suggest that in epithelial ovarian cancer andsex-cord-stromal tumours of the ovary, LHRH agonists might haveantitumour activity through the suppression of gonadotrophinsecretion (selective medical hypophysectomy). Phase III clinicaltrials, evaluating this hypothesis, are in progress. Directantiproliferative effects of LHRH analogues on epithelial ovariancancer cells have been demonstrated in vitro. In endometrialcnacer, experimental and early clinical results support theconcept of a direct antiproliferative activity of LHRH analogues.Recently, potent antagonistic analogues of LHRH, devoid of relevantside-effects have become available for clinical testing. Thesenew antagonists might be superior to agonistic LHRH analogueswith respect to the rapidity and efficacy of selective medicalhypophysectomy and medical castration. Modern LHRH antagonistsmight also permit a better exploitation of direct antitumoureffects. A further therapeutic improvement in gynaecologicaloncology might result from a combination of LHRH agonists orantagonists with other peptide hormone anlogues such as agonistsof somatostatin or antagonists of bombesin/gatrin releasingpeptide which have antitumour activity. Since 50% of breastcancers and 80% of epithelial ovarian cancers and endometrialcancers have high affinity binding sites for LHRH, cytotoxicLHRH analogues might provide a targeted chemotherapy, whichwould be more efficacious and less toxic than conventional regimens.