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 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 prostagland in dehydrogenase (PGDH), Two antiprogesterone receptor antibodies, one specific to PRB subtype and the other to PR subtype A + B, were emplo yed to examine the localization of both PR isoforms, The activity of P GDH, a progesterone dependent enzyme, was also measured. ER and PRA+B and PR subtype B were significantly down-regulated in glands and strom a in the presence of continuous intrauterine LNG delivery. There was a n apparent increase in PRA immunoreactivity in endometrial glands betw een 6 and 12 months post-insertion. Consistent with down-regulation of both isoforms of PR was reduced glandular PGDH immunostaining followi ng LNG-IUS insertion, and PGDH activity las measured by metabolism of excess substrate in vitro). Furthermore, PGDH activity, known to be lo calized 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, PRA is likely to be the subtype that mediates long term LNG action in the endometrium, PRB is the more suppressed of the two subtypes, and only PRA rises along with PGDH activity. Alterations to normal endometrial morphology and function, e.g. perturbation of norma l sex steroid receptor expression, following exposure to high concentr ations of local LNG, may play a role in the aetiology of bleeding diso rders associated with the LNG-IUS, Further elucidation of local uterin e mediators involved in the mechanism of bleeding problems is required .