Selective
progesterone receptor modulators are a class of drugs with
progesterone antagonist activity that may confer therapeutic benefit for reproductive disorders in premenopausal women. Endometrial structure, which is dynamically controlled by circulating
sex hormones, is likely to be perturbed by
progesterone receptor modulators through their
progesterone antagonist properties. We examined endometrial histology in 58 premenopausal women treated with the
progesterone receptor modulator
CDB-4124 (also known as
Proellex) for
endometriosis or uterine leiomyomata in two clinical trials. Endometrial biopsies obtained after 3 or 6 months with doses of 12.5, 25, or 50 mg daily oral
CDB-4124 were reviewed independently by three pathologists. Consensus diagnoses using the World Health Organization
hyperplasia scoring system, comments on specific histologic features, and clinical annotation were collected and analyzed. The majority of the endometrial biopsies (103 of 174 biopsies) contained histologic changes that are not seen during normal menstrual cycles. The histology of CDB-4124-treated patients was generally inactive or atrophic, and less frequently, proliferative or secretory, superimposed upon which were novel changes including formation of cystically dilated glands, and secretory changes coexisting with mitoses and apoptotic bodies. With increasing treatment dose and duration, the
cysts became predominant and their lining inactive or atrophic. Cystic glands in the CDB-4124-treated subjects correlated with increased endometrial thickness by ultrasound. None of the CDB-4124-treated patients developed
endometrial carcinoma or
hyperplasia while on
therapy.
CDB-4124 therapy for 3-6 months produces histologic changes that are sufficiently novel that they might easily be misinterpreted by pathologists, particularly as disordered proliferative or hyperplastic endometrium. Knowledge of the constellation of endometrial changes associated with this agent and other
progesterone receptor modulators, including cystic architecture and mixed non-physiologic epithelial changes will prevent misdiagnosis.