Effect of ulipristal acetate on proliferation and apoptosis In uterine leiomyoma tissue

Abstract

Uterine leiomyoma is one of the commonest benign tumor in the female genital tract. Ulipristal acetate (UPA), at a dose of 5mg daily for 12 weeks, is recognized as an effective treatment to reduce size of uterine leiomyoma and improve the accompanying symptoms before surgery. However, studies about cellular changes related to proliferation and apoptosis that can be induced by UPA in leiomyoma tissue and the molecular mechanisms behind are limited and not consistent. The aims of the present study were to (1) detect the in-vivo effect of UPA on the proliferation and apoptosis of uterine leiomyoma tissue and (2) analyze the effect of UPA on apoptosis-related markers in leiomyoma tissue. A cohort of 12 premenopausal patients with symptomatic leiomyomas (most with menorrhagia) was recruited from Queen Mary Hospital, Hong Kong, and they were randomly assigned to the treatment group (n=7) or the control group (n=5). Patients in the treatment group received 5mg UPA orally once daily for 12 weeks, while those in the control group took placebo once daily for 12 weeks before their planned surgeries. The proliferative and apoptotic indices in the leiomyoma cells were globally assessed by Ki67 immunostaining and the TUNEL method respectively. Expression of Bax, Bcl-2 and c-Myc was assessed at protein and mRNA levels using immunohistochemical staining and real-time qualitative polymerase chain reaction (RT-qPCR) respectively. Immunostaining was analyzed on a blinded basis by two independent investigators. There was significantly lower Ki67 positivity in leiomyoma tissues in the UPA treatment group compared to the control group (P = 0.0101), while the overall apoptotic index by TUNEL method was significantly higher in leiomyoma tissue in the UPA treatment group compared to the control group (P = 0.0480). There was no significant difference in Bax, Bcl-2 and c-Myc expression either at protein level or mRNA level between the UPA treatment group and control group (P > 0.05). In conclusion, cell proliferation was decreased while apoptosis was increased in the leiomyoma of patients after UPA treatment. This indicated that UPA worked as an inhibitor of cell proliferation and a promotor of cell apoptosis in leiomyoma tissue. UPA may exert its pro-apoptotic effects by pathways other than the Bax/Bcl-2 pathway.