Mol. Hum. Reprod. Advance Access originally published online on August 11, 2009
Molecular Human Reproduction 2009 15(10):633-643; doi:10.1093/molehr/gap063
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This article appears in the following Molecular Human Reproduction issue: Special Issue: Mechanisms of Endometriosis [View the issue table of contents]
Progestins inhibit expression of MMPs and of angiogenic factors in human ectopic endometrial lesions in a mouse model
1Institute of Molecular Biology, University Hospital Essen, 45122 Essen, Germany 2Solvay Pharmaceuticals Research Laboratories, 30173 Hannover, Germany 3Department of Gynecology, University Hospital Essen, 45122 Essen, Germany 4Institute of Pathology and Neuropathology, University Hospital Essen, 45122 Essen, Germany
5 Correspondence address: Tel: +49-201-7231636; Fax: +49-201-7235974; E-mail: ruth.gruemmer{at}uk-essen.de
Progestins are successfully used in the treatment of endometriosis; however, the exact mechanisms of their action are still unsolved. We here focused on the effect of different progestins on parameters of extracellular matrix degradation and angiogenesis involved in the establishment and maintenance of ectopic endometrial lesions. Human endometrium was intraperitoneally transplanted into nude mice. After 7 and 28 days of treatment with progesterone, dydrogesterone, or its metabolite dihydrodydrogesterone, respectively, ectopic lesions were evaluated for proliferation and apoptosis. Expression of estrogen receptor 
, progesterone receptor-AB, the angiogenetic factors, cysteine-rich angiogenic inducer (CYR61), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGFA) and the matrix metalloproteinase (MMP)-2, -3, -7 and -9 was investigated. Functional impact on angiogenesis was evaluated by density of microvessels and of vessels stabilized by pericytes within the ectopic lesions. Although dydrogesterone significantly reduced proliferation of endometrial stromal cells after 28 days, suppression of apoptosis was independent from progestins. Expression of MMP-2 was significantly reduced by all progestins and MMP-3 by dydrogesterone. In the grafted endometrial tissue, transcription of bFGF was suppressed by progesterone and dihydrodydrogesterone, and VEGFA and CYR61 by dihydrodydrogesterone and dydrogesterone. In parallel, microvessel density was slightly suppressed by progestins, whereas number of stabilized vessels increased. Thus, progestins regulate factors important for the establishment and maintenance of ectopic endometrial lesions.
Key words: progestins/dydrogesterone/MMP/angiogenesis/endometriosis
Submitted on May 4, 2009; resubmitted on July 27, 2009; accepted on July 29, 2009.