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Mol. Hum. Reprod. Advance Access originally published online on October 8, 2004
Molecular Human Reproduction 2004 10(12):853-860; doi:10.1093/molehr/gah113
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Molecular Human Reproduction vol. 10 no. 12 © European Society of Human Reproduction and Embryology 2004; all rights reserved

Functional characterization of somatic point mutations of the human estrogen receptor {alpha} (hER{alpha}) in adenomyosis uteri

Martin K. Oehler1,2,{dagger},*, Holger Greschik2,*, Dagmar-C. Fischer2,3, Xiaowen Tong1,2, Roland Schuele2 and Dirk G. Kieback1,2,3

1Department of Obstetrics and Gynaecology, Baylor College of Medicine, Houston, TX, USA, 2Department of Obstetrics and Gynaecology, Freiburg University Medical Center, Freiburg, Germany and 3Department of Obstetrics and Gynaecology, Maastricht University Medical Center, Maastricht, The Netherlands

Endometriosis and adenomyosis uteri are chronic, benign diseases caused by the presence of endometrial tissue in ectopic locations, e.g. peritoneal or deep inside the myometrial wall of the uterus and/or in the rectovaginal septum. Although adenomyosis might be considered as a special form of endometriosis, both conditions differ with respect to clinical symptoms and treatment. Induction of a hypo-estrogenic state alone or in combination with surgical removal of the extra-uterine lesion is mostly sufficient for treatment of peritoneal endometriosis. By contrast, adenomyosis uteri rarely responds to hormonal therapy and usually requires a hysterectomy for cure. Consequently, the role of steroid hormone receptors with respect to the aetiology of either condition is still a matter of discussion. Using PCR/single strand conformation polymorphism analysis, we identified somatic estrogen receptor (ER) {alpha} gene mutations in three out of 55 samples from adenomyosis uteri. Functional characterization revealed that two of the mutant ER{alpha} proteins display severely impaired DNA-binding and transactivation properties secondary to an altered response to estrogens or changes in epidermal growth factor-mediated ligand-independent activation. Although the exact mechanism remains unknown, we suggest that mutation-related silencing of estrogen responsiveness might render endometriotic cells resistant to hypo-estrogenic conditions thereby accounting for failure of estrogen-ablative therapy in adenomyosis.

Key words: adenomyosis uteri/endometriosis/human estrogen receptor alpha/somatic mutation/steroid receptor

{dagger}Present address: Prince Henry's Institute of Medical Research, Monash Medical Center, Clayton, Victoria, Australia

* M.K.O. and H.G. contributed equally


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