Critchley H O, Wang H, Kelly R W, Gebbie A E, Glasier A F
Department of Obstetrics and Gynaecology, University of Edinburgh, Centre for Reproductive Biology, UK.
Hum Reprod. 1998 May;13(5):1210-7. doi: 10.1093/humrep/13.5.1210.
This study has examined endometrial tissue in 14 normal women prior to insertion of a levonorgestrel-releasing intrauterine system (LNG-IUS) and thereafter longitudinally for up to 12 months post-insertion. The specific endpoints examined by immunohistochemistry were progesterone receptor (PR) subtypes A + B, oestrogen receptor (ER) and prostaglandin dehydrogenase (PGDH). Two antiprogesterone receptor antibodies, one specific to PR(B) subtype and the other to PR subtype A + B, were employed to examine the localization of both PR isoforms. The activity of PGDH, a progesterone dependent enzyme, was also measured. ER and PR(A+B) and PR subtype B were significantly down-regulated in glands and stroma in the presence of continuous intrauterine LNG delivery. There was an apparent increase in PR(A) immunoreactivity in endometrial glands between 6 and 12 months post-insertion. Consistent with down-regulation of both isoforms of PR was reduced glandular PGDH immunostaining following LNG-IUS insertion, and PGDH activity (as measured by metabolism of excess substrate in vitro). Furthermore, PGDH activity, known to be localized in the glands, significantly increased (P < 0.05) at 12 months post-insertion, coinciding with the observed increase in glandular PR(A+B) immunoreactivity at this time. Since the LNG-IUS suppresses the PR(B) so strongly, PR(A) is likely to be the subtype that mediates long term LNG action in the endometrium. PR(B) is the more suppressed of the two subtypes, and only PR(A) rises along with PGDH activity. Alterations to normal endometrial morphology and function, e.g. perturbation of normal sex steroid receptor expression, following exposure to high concentrations of local LNG, may play a role in the aetiology of bleeding disorders associated with the LNG-IUS. Further elucidation of local uterine mediators involved in the mechanism of bleeding problems is required.
本研究对14名正常女性在插入左炔诺孕酮宫内节育系统（LNG-IUS）之前以及插入后长达12个月的时间内进行了子宫内膜组织的纵向研究。通过免疫组织化学检测的特定终点指标为孕激素受体（PR）A + B亚型、雌激素受体（ER）和前列腺素脱氢酶（PGDH）。使用两种抗孕激素受体抗体，一种对PR（B）亚型具有特异性，另一种对PR A + B亚型具有特异性，来检测两种PR异构体的定位。还测量了孕激素依赖性酶PGDH的活性。在持续宫内输送LNG的情况下，腺体和基质中的ER、PR（A + B）和PR B亚型均显著下调。插入后6至12个月，子宫内膜腺体中PR（A）免疫反应性明显增加。与PR两种异构体的下调一致，LNG-IUS插入后腺体PGDH免疫染色减少，并且PGDH活性（通过体外过量底物代谢测量）降低。此外，已知定位于腺体的PGDH活性在插入后12个月时显著增加（P < 0.05），此时观察到腺体PR（A + B）免疫反应性增加。由于LNG-IUS强烈抑制PR（B），PR（A）可能是介导LNG在子宫内膜中长期作用的亚型。PR（B）是两种亚型中受抑制程度更高的，只有PR（A）随PGDH活性升高。暴露于高浓度局部LNG后，正常子宫内膜形态和功能的改变，例如正常性类固醇受体表达的扰动，可能在与LNG-IUS相关的出血性疾病的病因中起作用。需要进一步阐明参与出血问题机制的局部子宫介质。
