Progestin therapy (medroxyprogesterone acetate or LNG-IUD) for Grade 1 endometrial carcinoma confined to the endometrium (Stage IA) in a young woman desiring fertility works by which molecular mechanism?

• A Upregulation of estrogen receptor alpha expression on endometrial cells
• B Activation of progesterone receptors leading to downregulation of estrogen receptors, pro-apoptotic effects, and reduced glandular proliferation ✓
• C Inhibition of aromatase in the endometrium reducing local estrogen
• D PD-L1 upregulation promoting immune tolerance of tumor cells

Explanation

Progestins act via progesterone receptors (PR-A and PR-B) in endometrial glands to downregulate estrogen receptor expression, reduce glandular proliferative activity, induce secretory transformation and decidualization, and promote apoptosis of endometrial cells. This reverses the unopposed estrogen-driven proliferation underlying most Type I (endometrioid) endometrial carcinomas. Response to progestin therapy requires PR positivity, which is typically preserved in well-differentiated (Grade 1) tumors.

Reference: Shaw's Textbook of Gynaecology, 17th ed.

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