GnRH agonist decreases endothelial nitric oxide synthase (eNOS) expression in leiomyoma.

UNLABELLED: OBJECTIVES To define the effect of GnRH agonist (GnRHa) treatment on endothelial nitric oxide synthase (eNOS) expression in leiomyoma. As eNOS expression is more pronounced in leiomyoma compared to parental myometrium, we hypothesized that the mechanism(s) of tumor shrinkage by GnRHa may be due to decreased nitric oxide (NO) production in leiomyoma. METHODS: Eleven patients with leiomyoma were operated for myoma enucleation by laparatomy. Six of them were treated with GnRHa every 28 days, three times before the operation. The remaining five patients who had no treatment prior to operation formed the control group. Blood was drawn from the patients before treatment and on the day of operation for the assay of serum estradiol (E(2)). Immunohistochemical localization of eNOS expression in leiomyoma and myometrium in treated patients, and in leiomyoma in the control group, was performed using monoclonal antibodies specific to eNOS. RESULTS: All treated subjects showed a significant reduction of fibroid volume at the end of therapy. eNOS-positive cells were localized primarily within the vascular endothelium and smooth muscle cells, but had weak expression in fibroid and myometrial muscle cells in the treated group. The immunoreactivity was similar for both the leiomyoma and myometrium (P > 0.05). In contrast to this, the control group had shown strong expression in leiomyoma muscle cells (P < 0.005) in addition to the vascular endothelium and smooth muscle cells. CONCLUSION: GnRHa-induced tumor shrinkage should be due to diminished eNOS expression, most probably by lowering estrogen secretion.

Endothelial nitric oxide synthase expression in leiomyoma and parental myometrium.

The aim of this study was to determine the expression of endothelial nitric oxide synthase (eNOS) in leiomyomatous tissue as a possible mediator of the growth process. Nine patients had myoma enucleation during the follicular phase. The myomata and adjacent myometrial tissues were fixed in formol until study. Immunohistochemical localization of leiomyomatous and myometrial tissue eNOS expression was performed using specific monoclonal antibodies to eNOS. Statistical comparisons were made using the Mann-Whitney Wilcoxon rank-sum test for the expression of eNOS. The test was considered significant when p values were <0.05. Immunostaining for eNOS was seen in the cytoplasm of myometrial endothelial and smooth muscle cells in both tissue sections. eNOS expression was significantly higher in the smooth muscle cells of leiomyomata, compared to parental myometrium (p < 0.0005). The expression of eNOS in vascular endothelial cells was not different in the leiomyoma and myometrium (p > 0.05). To our knowledge, this is the first study to document marked expression of eNOS in leiomyomatous tissue, compared to parental myometrium. We also conclude that the mechanism(s) of the growth-promoting effect of estrogen on leiomyomata is mediated by more synthesis of NO.