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

Relapse risk of endometrial hyperplasia after treatment with the levonorgestrel‐impregnated intrauterine system or oral progestogens

Objective To investigate relapse rates after the successful treatment of patients with non-atypical endometrial hyperplasia who were randomised to either a levonorgestrel-impregnated intrauterine system (LNG-IUS; Mirena ) or two regimens of oral medroxyprogesterone acetate (MPA) after primary histological response. Design A multicentre randomised trial. Setting Ten different outpatient clinics localised in hospitals and seven gynaecological private practices in Norway. Population One hundred and fifty-three women aged 30–70 years with low- or medium-risk endometrial hyperplasia met the inclusion criteria, and 153 completed the therapy. Methods Patients were randomly assigned to one of the following three treatment arms: LNG-IUS; 10 mg of oral MPA administered for 10 days per cycle for 6 months; or 10 mg of oral MPA administered daily for 6 months. The women were followed for 24 months after ending therapy. Main outcome measures Histological relapse of endometrial hyperplasia. Results Histological relapse was observed in 55/135 (41%) women who had an initial complete treatment response. The relapse rates were similar in the three therapy groups (P = 0.66). In the multivariable analyses relapse was dependent on menopausal status (P = 0.0005) and estrogen level (P = 0.0007). Conclusions The risk of histological relapse of non-atypical endometrial hyperplasia is high within 24 months of ceasing therapy with either the LNG-IUS or oral MPA. Continued endometrial surveillance and prolonging progestogen therapy should be considered

Relapse risk of endometrial hyperplasia after treatment with the levonorgestrel-impregnated intrauterine system or oral progestogens

Objective To investigate relapse rates after the successful treatment of patients with non-atypical endometrial hyperplasia who were randomised to either a levonorgestrel-impregnated intrauterine system (LNG-IUS; Mirena ) or two regimens of oral medroxyprogesterone acetate (MPA) after primary histological response. Design A multicentre randomised trial. Setting Ten different outpatient clinics localised in hospitals and seven gynaecological private practices in Norway. Population One hundred and fifty-three women aged 30–70 years with low- or medium-risk endometrial hyperplasia met the inclusion criteria, and 153 completed the therapy. Methods Patients were randomly assigned to one of the following three treatment arms: LNG-IUS; 10 mg of oral MPA administered for 10 days per cycle for 6 months; or 10 mg of oral MPA administered daily for 6 months. The women were followed for 24 months after ending therapy. Main outcome measures Histological relapse of endometrial hyperplasia. Results Histological relapse was observed in 55/135 (41%) women who had an initial complete treatment response. The relapse rates were similar in the three therapy groups (P = 0.66). In the multivariable analyses relapse was dependent on menopausal status (P = 0.0005) and estrogen level (P = 0.0007). Conclusions The risk of histological relapse of non-atypical endometrial hyperplasia is high within 24 months of ceasing therapy with either the LNG-IUS or oral MPA. Continued endometrial surveillance and prolonging progestogen therapy should be considered

Intrauterine progestin therapy as a new approach to premalignant endometrial polyps: A prospective observational study

Background/Aim: Endometrial hyperplastic polyps (EHP) may progress to endometrial carcinoma (EC) if left untreated. We aimed to prospectively investigate the efficacy of the low-dose levonorgestrel intrauterine system (LNG-IUS) as therapy for EHP with malignant potential. Patients and Methods: In total, 37 women with EHP underwent therapy with LNG-IUS containing 13.5 mg levonorgestrel for six months or 4-10 weeks depending on whether the EHP was characterized (by D-score analysis) as low- to medium-risk (n=33) or high-risk (n=4) of coexistent or future EC. Therapy response was defined as complete clearance of hyperplastic glands in post-therapy endometrial biopsy. Results: All women with low- to medium-risk EHP obtained therapy response, whereas only 1 out of 4 with high-risk EHP responded to therapy. None of the women were diagnosed with EC during the study and no serious adverse events occurred. Conclusion: Low-dose LNG-IUS represents a promising therapy for selected women with EHP

Erratum: 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 epididymis-specific 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 (P<0.001) and therapy response (P<0.001) of the individuals but could not predict relapse (P>0.05). Changes in the intracellular bodies were shown to predict both the therapy response (P=0.038) and relapse (P=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

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

Rate of elimination of gamma-hydroxybutyrate from blood determined by analysis of two consecutive samples from apprehended drivers in Norway

Aim: Gamma-hydroxybutyrate (GHB) is a common drug of abuse with an elimination half-life of 20-45 min. However, there is some evidence that GHB might exhibit saturation kinetics after ingesting high recreational doses. The aim of this study was to investigate the elimination kinetics of GHB from blood in people apprehended by the police for impaired driving and secondary to describe concentrations in all GHB-positive drivers. Methods: Two consecutive blood samples were taken about 30-40 min apart from N =16 apprehended drivers in Norway. GHB was determined in blood by an Ultra High-Performance Liquid ChromatographyTandem Mass Spectrometry (UHPLC-MS/MS) method. The changes in GHB between the two consecutive blood samples allowed estimating GHBs elimination half-life, assuming first-order and zero-order elimination kinetics. GHB concentrations are also reported for N =1276 apprehended drivers with GHB in blood. Results: The median time interval between collecting the two blood samples was 36 min (range 20 56 min). The median concentration of GHB in the first blood sample was 56.5 mg/L (range 14.1 142 mg/L) compared with 47.8 mg/L in the second sample (range 9.75 113 mg/L). The median elimination half-life was 103 min (range 21 187 min), and GHBs median zero-order elimination rate constant was 21.0 mg/L/h (range 6.71-45A mg/L/h). Back-calculation to the time of driving resulted in GHB concentrations up to 820 mg/L assuming first-order kinetics and up to 242 ma assuming zeroorder kinetics. In all drivers (N 1276), the median GHB concentration was 73.7 ma and highest was 484 mg/L. Conclusion: The elimination half-life of GHB in blood samples from apprehended drivers was longer than expected compared with results of controlled dosing studies. Zero-order kinetics seems a more appropriate model for GHB when concentrations are back-calculated. and the median elimination rate was 21 mg/L/h. (C) 2020 The Authors. Published by Elsevier B.V