Significance of progesterone receptors (PR-A and PR-B) expression as predictors for relapse after successful therapy of endometrial hyperplasia: a retrospective cohort study

This is the peer reviewed version of the following article: Sletten, E.T., Arnes, M., Lyså, L.M., Larsen, M. & Ørbo, A. (2019). Significance of progesterone receptors (PR-A and PR-B) expression as predictors for relapse after successful therapy of endometrial hyperplasia: a retrospective cohort study. BJOG: an International Journal of Obstetrics and Gynaecology, 126(7), 936-943, which has been published in final form at https://doi.org/10.1111/1471-0528.15579. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.Objective - After successful progestin therapy for endometrial hyperplasia (EH), the risk of relapse remains. We aimed to assess if immunohistochemical (IHC) expression of progesterone receptor isoforms, PR‐A and PR‐B, in endometrial glands and stroma in pre‐treatment endometrial biopsies was related to relapse of EH. Design and setting - Biopsy material originated from women with low‐risk and medium‐risk EH recruited to a recent Norwegian multicentre randomised trial. Participants (n = 153) had been treated for 6 months with three different progestin regimens. Population - One hundred and thirty‐five of the 153 women achieved therapy response and underwent follow up for 24 months after therapy withdrawal. Fifty‐five women relapsed during follow up. Pre‐treatment endometrial biopsies from 94 of the 135 responding women were available for IHC staining. Methods - Immunohistochemical staining was performed separately for PR‐A and PR‐B and IHC expression was evaluated in endometrial glands and stroma by a histological score (H‐score) using light microscopy. Main outcome measure - Immunohistochemical expression of PR‐A and PR‐B in endometrial glands and stroma in women with or without relapse of EH. Results - Low PR‐A in endometrial glands (P = 0.013) and stroma (P 1 (19%; P < 0.001). Conclusion - Immunohistochemical expression of PR‐A and PR‐B in pre‐treatment endometrial biopsy proves valuable as a predictor of relapse in EH

HE4 is a novel tissue marker for therapy response and progestin resistance in medium- and low-risk endometrial hyperplasia

Background: The aim of the present study was to investigate whether changes in the tissue expression of human epididymisspecific protein 4 (HE4) could predict therapy resistance and relapse after progestin hormone therapy for medium- and low-risk endometrial hyperplasia. Methods: Endometrial biopsies were obtained from women participating in a multicentre RCT performed according to the CONSORT guidelines; the women were randomly assigned to either LNG-IUS; 10 mg of oral medroxyprogesterone acetate (MPA) administered for 10 days per cycle; or 10 mg of oral MPA administered daily for 6 months. Of the 153 women who completed therapy, 141 had adequate material for immunohistochemistry in pre- and post-treatment biopsies. An antibody to HE4 (clone 12A2 monoclonal IgG1 antibody, Fujirebio Diagnostics, Inc.) was used for the immunohistochemical staining of the pre- and post-treatment biopsies from each participant. The expression of HE4 staining was evaluated by the histological score (H-score) using light microscopy. Results: Changes in the expression of HE4 (H-score) during therapy were related to the therapy group (Po0.001) and therapy response (Po0.001) of the individuals but could not predict relapse (P40.05). Changes in the intracellular bodies were shown to predict both the therapy response (P ¼ 0.038) and relapse (P ¼ 0.014). Conclusions: Changes in the expression of HE4 during progestin therapy regimens can predict therapy response or indicate progestin resistance for medium- and low-risk endometrial hyperplasia