Histological and immunohistochemical characteristics of superficial peritoneal endometriotic lesions of clinical responders and non-responders to dienogest treatment

STUDY QUESTION Are there histological and immunohistochemical patterns of superficial peritoneal endometriotic lesions of symptomatic patients that characterize non-response to dienogest treatment and may suggest progesterone resistance?SUMMARY ANSWER No significant histological or immunohistochemical differences were observed in superficial peritoneal endometriotic lesions between clinical responders and non-responders to dienogest treatment.WHAT IS KNOWN ALREADY Progestogens are effective in reducing pelvic pain symptoms in approximately two-thirds of patients with endometriosis. Treatment failure can be reasonably explained by progesterone resistance, but the available evidence is not definitive.STUDY DESIGN, SIZE, DURATION A prospective, single-centre, single-arm, observational study was conducted between January 2023 and January 2024 in 55 women treated with dienogest, 2 mg/day, before laparoscopic surgery for endometriosis.PARTICIPANTS/MATERIALS, SETTING, METHODS All the participants had histologically confirmed endometriosis. Patients were classified as clinical responders (n = 36) or non-responders (n = 19) based on the self-reported 7-point Patient Global Impression of Change scale. In addition, pain severity was dichotomized as either 'absent/mild' (0-3 points) or 'moderate/severe' (4-10 points) across individual pain domains, using a 0-10-point numerical rating scale. The histological morphology and the immunohistochemical expression of progesterone receptors, oestrogen receptors, and CD15 were evaluated in the excised superficial peritoneal lesions. Tissue analyses were all performed by the same blinded pathologist.MAIN RESULTS AND THE ROLE OF CHANCE A histological morphological response to chronic progestogen treatment, defined by the presence of stromal atrophy and absence of active glands, was observed in 29/36 (80.5%) clinical responders and 16/19 (84.2%) non-responders. Furthermore, no statistically significant between-group differences were observed in progesterone receptor (PR), oestrogen receptor (ER), and CD15 expression. At univariate logistic regression analysis, no significant associations were identified between clinical response to dienogest therapy and several individual variables (i.e. body mass index, age at diagnosis, duration of therapy, histological morphological response, phenotypic subtypes of peritoneal endometriotic lesions, and presence of adenomyosis or deep endometriosis). Exploratory analyses based on pain severity categorization yielded results broadly consistent with the main findings. However, patients with moderate/severe deep dyspareunia showed a significantly lower proportion of high-intensity glandular ER expression in comparison to those with absent/mild deep dyspareunia. In addition, a significantly lower glandular PR expression was detected in patients with moderate/severe dyschezia symptoms compared with those with absent/mild dyschezia.LIMITATIONS, REASONS FOR CAUTION Only superficial peritoneal endometriotic lesions were evaluated, and no information was collected on ovarian endometriotic cysts or deep infiltrating endometriosis. In addition, due to the limited sample size, a type II error cannot be excluded. Moreover, receptor isoforms, including progesterone receptor isoforms A and B (PR-A, PR-B) and oestrogen receptor isoforms alpha and beta (ER alpha, ER beta) were not assessed. However, the clinical relevance of the variance of molecular expression of progesterone and oestrogen receptors in the pathogenesis of pelvic pain symptoms remains difficult to interpret.WIDER IMPLICATIONS OF THE FINDINGS Considering that the vast majority of lesions excised from non-responders showed clear evidence of the effect of dienogest, this study does not support the notion that intrinsic progesterone resistance may represent the sole or prominent mechanism underlying clinical non-response to dienogest treatment in women with endometriosis. However, analyses based on pain intensity dichotomization suggest that the severity of deep dyspareunia and dyschezia may be influenced by ER and PR glandular expression in superficial peritoneal endometriotic lesions. Though larger studies are warranted to further clarify these aspects, mechanisms beyond tissue-level progesterone resistance, including central sensitization, should be explored as potential contributors to symptomatic non-response to dienogest.STUDY FUNDING/COMPETING INTEREST(S) This study was partially funded by the Italian Ministry of Health, Current research IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan. N.B. and P.V. have received royalties from Wolters Kluwer for chapters on endometriosis management in the clinical decision support resource UpToDate, and both maintain a private gynaecological practice. P.V. is a member of the Editorial Board of Human Reproduction Open, the Journal of Obstetrics and Gynaecology Canada, and the International Editorial Board of Acta Obstetricia et Gynecologica Scandinavica. All other authors declare no conflicts of interest.