Endometrial effects of SPRMs

Progesterone receptor modulators (PRMs) are a family of compounds binding to progesterone receptors. These are usually pure agonists such as progestins but selective progesterone receptor modulators (SPRMs) on the other hand have mixed agonist-antagonist properties and have a wide range of potential clinical applications. They are also known have an impact on the endometrium and this was the focus of Christine Bergeron’s presentation on day 3 of ESG.

SPRMs are thought to have a number of different effects on the endometrium including control of endometrial bleeding, decrease in uterine blood flow and PR-mediated antiproliferative effect. For this reason there has been an importance placed on looking at the pathology induced by SPRMs. Surprisingly data showed that SRPMs actually had an antiproliferative effects. Treatment partly suppressed the mitotic activity in the glands and impacted the paradoxal. It is thought they may be induced via androgens receptors.

Studies have looked at the PRM associated endometrial change PAEC with use of ulipristal acetate (UPA). Data from the Pearl I and Pearl II studies showed that benign and reversible changes in the endometrium were observed in 65-75% of patients treated within UPA for 2 months but that these PAEC changes were reversible after treatment. Both studies found hyperplasia, but in very small amounts, which showed there was no safety problem with the use of ulipristal acetate.  The PEARL III extension study also showed there was no hyperplasia after four cycles of UPA (Donnez et al 2014. Fertil. Steril). PAEC was found in one course but at a much lower percentage than in PEARL I and II as the biopsy was done after menstruation. From the three PEARL studies we can conclude that when a patient is on a long term treatment (4 continuous cycles) of UPA it doesn’t introduce PAEC but patient’s may get regression if you treatment is stopped.

Christine also shared a Spanish hysterectomy study that retrospectively looked at 100 hysterectomies. Results from this study showed 8 cases of diffuse PAEC after 1 month of treatment, this only occurred in immediate or recently resected specimen. By contrast the data also showed that Focal PAEC is non-specific and may not be related to UPA.

This data further compounds thoughts that PRMs present a new group of agents with considerable therapeutic potential in treatment of fibroids, endometriosis and contraception, this is associated with a histological transformation of the endometrium (that should not be confused with endometrial hyperplasia) in which non-physiological secretory appearances and cystic glandular dilation are common symptoms. We look forward to seeing more data about PRMs being used for therapeutic potential in upcoming conferences in 2018 now that safety has been demonstrated!