The Effects of Vaginal Gestrinone with Histone Deacetylase Inhibitors on Endometriosis-Related Pain and Endometrial Proliferation - A Short Study

Objective: The present study was designed to investigate the effects of valproic acid or resveratrol, together with vitamin D3 (VITD3) in Pentravan® (PTV) administered vaginally, on deep endometriosis-associated pain in patients undergoing treatment with gestrinone. Material and methods: This was an open study involving 30 patients with deep endometriosis and pelvic pain unresponsive to previous progestin-based treatment. Pain was assessed at the initial visit and after the first and third months of treatment using a visual analog scale that graded pain from 0 to 10. Hysteroscopy with endometrial biopsy (n=21) was performed at baseline and after the first treatment month to determine aromatase expression by immunohistochemistry. Patients were divided into three groups. Patients in Group I (n=16) were treated for 6 months with vaginal gestrinone (GTN) (5 mg/ml) twice weekly together with pycnogenol (100 mg) and silymarin (400 mg) administered orally once a day. In Group II (n=8), patients received the same treatment together with vaginal resveratrol (100 mg/ml) and vitamin D3 (5000 U/ml) administered daily. Patients in Group III (n=9) were treated with gestrinone together vaginal valproic acid (VPA) (250 mg) administered daily. All vaginal medications were prepared in Pentravan®. Results: There was a significant decrease in the mean pain score of patients in Group I from 9 at baseline to 3 after the first month of treatment. In Groups II and III, on the other hand, the pain score decreased from a mean of 9 to a mean of 1, a significantly greater decrease than that achieved in Group I (p=0.01). Although the reduction in pain was significant in all the groups, after the first month of treatment it was much greater in the groups treated simultaneously with histone deacetylase (HDAC) inhibitors. By the third month of treatment, all patients in all three groups were amenorrheic and pain-free, with no difference between the groups. After the first treatment month, aromatase expression remained positive in the endometrium of 8/10 women (80%) in Group I compared to only 1/8 (12%) in Group II (p=0.006) and 2/3 (66%) in Group III (p=0.04 compared to Group II but not significantly different from Group I). Conclusion: The use of HDAC inhibitors in Pentravan® potentiated the pain-relieving effects of gestrinone in patients with deep endometriosis in the first month of treatment; however, this difference disappeared in the subsequent months. This suggests that if much faster pain relief were desired in cases of deep endometriosis, then combining vaginal gestrinone with an HDAC inhibitor would be preferable to using gestrinone alone. The combined use of gestrinone with epigenetic drugs is a novel and highly effective treatment for deep endometriosis-related pain.