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.
PIP: The effects of a levonorgestrel-releasing intrauterine system (LNG-IUS) on endometrial tissue were investigated in 14 UK women who were followed for 12 months after its insertion. Of particular interest was the etiology of menstrual aberration associated with progestogen-only contraception. In the presence of continuous intrauterine LNG delivery, estrogen receptor and progesterone receptor (PR) subtype A + B and subtype B were significantly downregulated in the endometrial glands and stroma. There was no apparent increase in PR subtype A immunoreactivity in endometrial glands 6-12 months after LNG-IUS insertion. Also observed was reduced glandular prostaglandin dehydrogenase (PGDH) staining and activity. PGDH activity significantly increased at 12 months post-insertion coinciding with the increase in glandular PR subtype A + B. Since the LNG-IUS suppresses the PR subtype B so strongly and only PR subtype A rises along with PGDH activity, PR A is likely the subtype that mediates long-term LNG action in the endometrium. Perturbation of normal sex steroid receptor expression after exposure to high concentrations of local LNG may play a role in the bleeding disorders associated with use of the LNG-IUS. Examination of more local mechanisms in endometrium exposed to an LNG-IUS should help elucidate some of the potential mechanisms regulating endometrial bleeding.