Dienogest reduces proliferation, aromatase expression and angiogenesis, and increases apoptosis in human endometriosis

Abstract

Dienogest is a novel progestin that is highly selective for progesterone receptors and inhibits endometriosis. However, it remains unknown how the administration of dienogest to patients with endometriosis impacts on their lesion tissues. The aim of this study was to evaluate the in vivo effect of dienogest on endometriosis tissue. We collected endometrioma tissues from patients treated with dienogest (N = 7) or not treated (N = 11, controls). Cell proliferation, aromatase expression and blood vessel density were evaluated by staining for Ki67, aromatase and the von Willebrand factor, respectively. Apoptosis was detected using the TUNEL assay. The proportion of Ki67 and aromatase positive epithelial cells was significantly lower in the dienogest group than in controls (p < 0.05, respectively). The number of TUNEL positive cells was significantly higher in the dienogest group (p < 0.05). The density of blood vessels in endometrioma was marginally lower in the dienogest group compared with controls (p = 0.20). Our study demonstrates that endometrioma taken from patients treated with dienogest show remarkable histological features such as reduction of proliferation, aromatase expression and angiogenesis, and increase of apoptosis. This study clarified the impact of dienogest on local histological events that explain its therapeutic effect on endometriosis.

Chinese abstract

地诺孕素是一种新型的孕激素，具有孕激素受体高度选择性，可抑制子宫内膜异位症。但是，地诺孕素作用于内异症患者受损组织的机理现在仍未明确。本研究的目的在于评估地诺孕素在体内对子宫内膜异位组织的影响。我们采集经地诺孕素治疗（N = 7）与未经治疗（N = 11，对照组）的患者的子宫内膜异位组织。通过对Ki67染色、芳香化酶及von Willebrand因子的测定，评估细胞增殖、芳香化酶表达及血管密度。细胞凋亡情况通过TUNEL检验测定。结果显示，地诺孕素组的Ki67与芳香化酶阳性上皮细胞比例显著低于对照组（均为p < 0.05）。地诺孕素组的TUNEL阳性细胞数目显著高于对照组（p < 0.05）。地诺孕素组子宫内膜异位组织中血管密度略低于对照组（p = 0.20）。本研究结果表明，经地诺孕素治疗的子宫内膜异位症患者可出现显著的组织学特征改变，如降低细胞增殖、芳香化酶表达及血管生成减少及细胞凋亡增加。研究明确了地诺孕素对局部组织的影响，证实了其治疗子宫内膜异位症的效果。

• Apoptosis
• aromatase
• dienogest
• endometriosis
• proliferation

Acknowledgements

The authors thank medical colleagues in the University of Tokyo Hospital, and Dr Nobuhiro Harada in Fujita Health University for kindly providing aromatase antibody, and Dr. Kate Hale for editing the manuscript.