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

Area of Science:

• Reproductive Endocrinology
• Gynecologic Pathology
• Pharmacology

Background:

• Selective progesterone receptor modulators (SPRMs) possess progesterone antagonist activity, offering potential therapeutic benefits for premenopausal women's reproductive disorders.
• Endometrial structure is sensitive to hormonal fluctuations, making it susceptible to alterations by SPRMs.

Purpose of the Study:

• To investigate the endometrial histology in premenopausal women treated with the SPRM CDB-4124 (Proellex).
• To characterize the novel histologic changes induced by CDB-4124 and assess their potential for misinterpretation.

Main Methods:

• Analysis of endometrial biopsies from 58 premenopausal women in two clinical trials of CDB-4124 (12.5-50 mg daily for 3-6 months).
• Independent review of biopsies by three pathologists using WHO hyperplasia scoring and detailed feature analysis.
• Correlation of histologic findings with clinical data and ultrasound measurements.

Main Results:

• The majority of biopsies (103/174) exhibited non-physiologic changes.
• Histology was predominantly inactive/atrophic, with novel features like cystic glands and coexisting mitoses/apoptosis.
• Cystic changes increased with dose/duration and correlated with endometrial thickness; no hyperplasia or carcinoma developed.

Conclusions:

• CDB-4124 induces unique endometrial histologic changes, including cystic glands and mixed epithelial alterations.
• These novel changes may be misinterpreted as disordered proliferative or hyperplastic endometrium.
• Awareness of these SPRM-associated changes is crucial for accurate pathologic diagnosis and to prevent misdiagnosis.