Endometrial changes from short-term therapy with CDB-4124, a selective progesterone receptor modulator

Abstract

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 Proellext) 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.

CDB-4124, a Progesterone Receptor Modulator, Inhibits Mammary Carcinogenesis by Suppressing Cell Proliferation and Inducing Apoptosis

“…The apparent relationship between mammary gland architecture and cyst formation that may have ductal or lobular origin is apparently a consequence of decreased functional activity of MECs as result of CDB-4124 treatment. This has also been observed in the endometrium of women treated for uterine fibroids and endometriosis with the same agent (30). The inhibitory effect of CDB-4124 on cell proliferation we see in both, long-and short-term (3 month) treatments correlates well with recent data from a clinical trial with mifepristone (RU-486).…”

Progesterone receptor modulators in breast cancer

“…At the same time, women on PRMs should retain tonic levels of estrogen in the absence of progesterone. While this might suggest the establishment of a state of unopposed estrogen, the direct effect of PRMs on the endometrium producing PAEC (Ioffe et al, 2009) avoids unopposed estrogenic stimulation.…”

“…In a recent study 58 premenopausal women with endometriosis or uterine leiomyomas were treated for 3 or 6 months with different doses of CDB-4124. Endometrial biopsies were taken and were independently examined by 3 pathologists (Ioffe et al, 2009). They confirmed previous observations for cystic formations among endometrial glands and reported lack of endometrial hyperplasia or carcinomas in treated patients.…”

Progesterone Resistance and Targeting the Progesterone Receptors: A Therapeutic Approach to Endometriosis

“…More recently, an additional concern has emerged following histological evaluations of subjects dosed for more than 3 months on steroidal PRAs. The endometrium of these individuals undergoes a characteristic cystic histological change which may be difficult to distinguish from endometrial hyperplasia without specialist evaluation (Ioffe et al, 2009;Mutter et al, 2008;Williams et al, 2007).…”