Elucidating the Effect of Progesterone Resistance in the Pathogenesis of Endometriosis

Abstract

Until today, the pathogenesis of endometriosis is unclear resulting in no ideal treatment available as patients exhibit a variable response to the current strategy. Progestin, which acts via progesterone receptor (PR) is a modality of treatment for endometriosis. We investigated the perturbations of PR isoforms A and B in endometriosis patients and its relationship with pain score and serum CA-125 after endometriosis surgery. A prospective, case control study was conducted in UKM medical centre. Total RNA was extracted from the endometrioma lining and endometrial tissue to measure the transcript level of PR mRNA using qPCR. Serum was collected for the measurement of CA-125. Visual analogue scale (VAS) for pain was recorded at pre- and post-treatment. Primary endometrial cell culture with treatment using progestin and anti-progesterone was performed. Whole exome sequencing of endometrial tissues from eutopic and ectopic endometrial samples was conducted. Thirty-six endometriosis and 30 control patients were recruited. PR-B/PR- A mRNA expression ratio was significantly lower in ectopic and eutopic of

endometriosis samples compared to the control (P<0.05). PR-A/GAPDH mRNA expression ratio was significantly higher in eutopic compared to the control (P<0.05). PR-B/GAPDH mRNA expression ratio did not show any significant difference between all groups. Serum CA-125 and VAS score were significantly lower in the endometriosis group post- compared to pre-surgery (P<0.05). There was no significant correlation seen between improvement of VAS scores post-surgery in eutopic or ectopic samples. In vitro treatment of eutopic and ectopic endometrial cells with mifepristone showed no significant difference in PR-A/GAPDH, however there was significant difference in PR-B/GAPDH mRNA expression ratios between ectopic group compared to healthy and eutopic group (P<0.05). Two single nucleotide polymorphisms in two separate genes, which were detected in 75% of endometriosis samples. This study confirmed that there was perturbation in the mRNA expression ratio of PR-B/PR-A in endometriosis patients. This is most likely due to the elevation of PR-A/GAPDH expression and not PR-B/GAPDH expression. Our findings indicated that surgery improved serum CA-125 levels and also pain score using VAS, which may be a useful tool for monitoring the disease. However, we could not find any correlation between PR isoform ratios and these improvements of pain score. Our in vitro culture did not confirm our hypothesis of higher PR-B/PR-A ratio with mifepristone treatment. The significant increase in PR-B/GAPDH expression in ectopic samples may suggest that only PR-B is important for clinical improvement.

Endometriosis has a multifactorial aetiology. Our findings of the reduction in PR- B/PR-A ratio appears to cause progesterone resistance that contributes to the development of endometriosis, along with the presence of two potential SNPs for the two genes. The mechanism of action of mifepristone in improving endometriosis appears to increase PR-B only without affecting the PR-B/PR-A ratio.