Progesterone receptor modulators and the endometrium: changes and consequences†

Progesterone receptor modulators (PRMs) have been used for contraceptive research, as well as for treatment of fibroids, endometriosis and heavy or irregular menstrual bleeding. Long-term treatment with these compounds results in changes to the endometrium resulting in potential confusion in trying to characterize endometrial biopsies. A meeting was held to discuss the properties of PRMs, the effects of perturbed hormonal control of the endometrium and the need for further understanding of the biology of progesterone receptor action to facilitate the development of new PRMs. A panel of pathologists was convened to evaluate endometrial changes associated with a minimum of three months of chronic treatment with PRMs. Four different agents were used in the treatment regimens but the pathologists were blinded to treatment regimen or agent. The panel agreed that the endometrial biopsies did not fit into a classification of either proliferative or secretory endometrium but exhibited an unusual architecture that could be characterized as glandular dilatation. There was little evidence of mitosis, consistent with a proposed anti-proliferative effect of PRMs. The panel concluded that the biopsies did not reveal evidence of safety concern and that pathologists and investigators familiar with endometrial effects of chronic PRM exposure should consider working with pharmaceutical companies and regulatory agencies to develop standard descriptions of PRM-associated endometrial changes as well as the types of histologic changes that would signal a need for intervention.