Progestin receptor isoforms and prostaglandin dehydrogenase in the endometrium of women using a levonorgestrel-releasing intrauterine system

This study has examined endometrial tissue in 14 normal women prior toinsertion of a levonorgestrel-releasing intrauterine system (LNG-IUS) andthereafter longitudinally for up to 12 months post-insertion. The specificendpoints 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 thelocalization of both PR isoforms. The activity of PGDH, a progesteronedependent enzyme, was also measured. ER and PR(A+B) and PR subtype B weresignificantly down-regulated in glands and stroma in the presence ofcontinuous intrauterine LNG delivery. There was an apparent increase inPR(A) immunoreactivity in endometrial glands between 6 and 12 monthspost-insertion. Consistent with down- regulation of both isoforms of PR wasreduced glandular PGDH immunostaining following LNG-IUS insertion, and PGDHactivity (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) immunoreactivityat this time. Since the LNG-IUS suppresses the PR(B) so strongly, PR(A) islikely to be the subtype that mediates long term LNG action in theendometrium. PR(B) is the more suppressed of the two subtypes, and onlyPR(A) rises along with PGDH activity. Alterations to normal endometrialmorphology and function, e.g. perturbation of normal sex steroid receptorexpression, following exposure to high concentrations of local LNG, mayplay a role in the aetiology of bleeding disorders associated with theLNG-IUS. Further elucidation of local uterine mediators involved in themechanism of bleeding problems is required.