Enhanced deoxyribonucleic acid damage and repair but unchanged apoptosis in uterine leiomyomas treated with gonadotropin-releasing hormone agonist.

Abstract

Our purpose was to investigate the histopathologic changes in uterine leiomyomas in cell proliferation, proliferating cell nuclear antigen expression, angiogenesis, and apoptosis after treatment with gonadotropin-releasing hormone agonist. Fifteen consecutive patients who had undergone gonadotropin-releasing hormone agonist treatment before surgery and 44 patients who did not were studied. The volumes of myomas were determined ultrasonographically, and in patients receiving gonadotropin-releasing hormone agonist therapy measurements were done again after administration of the gonadotropin-releasing hormone agonist to evaluate the response to treatment. Paraffin sections were stained with hematoxylin and eosin, PC 10 for proliferating cell nuclear antigen expression, MIB 1 for measurement of cell proliferation, ApopTag for apoptosis, and factor VIII for quantitation of microvessel density. A deoxyribonucleic acid fragmentation test was also done on nine cases with available frozen tissues. Most of the leiomyomas showed substantial expression of proliferating cell nuclear antigen. Gonadotropin-releasing hormone agonist therapy further induced significant overexpression of proliferating cell nuclear antigen (p = 0.0004, chi 2 test). All three leiomyomas that failed to respond to therapy showed less proliferating cell nuclear antigen staining compared with the good responders. In contrast, data from MIB 1 immunostaining showed that < 0.3% of leiomyoma cells were proliferating. However, positive-staining cells were more frequently detected in the treatment group (0.075% +/- 0.091% vs 0.002% +/- 0.010%, p = 0.0002, Mann-Whitney U test). Apoptosis developed spontaneously in leiomyoma cells independent of gonadotropin-releasing hormone agonist therapy. No significant change in apoptosis but a significant increase in microvessel density was observed in the treatment group compared with the control group. Enhanced deoxyribonucleic acid damage or repair with cell growth arrest may be responsible for the action of gonadotropin-releasing hormone agonist in shrinking uterine leiomyomas. Moreover, the extent of proliferating cell nuclear antigen expression seems to be associated with the response to gonadotropin-releasing hormone agonist therapy.