Apoptosis, proliferation, and sex steroid receptors in postmenopausal endometrium before and during HRT

OBJECTIVES: Endometrial homeostasis, indicated as the balance between apoptosis and proliferation, was studied with regard to endometrial safety and bleeding disturbances. MATERIALS AND METHODS: The quantitatively sufficient endometrial biopsies of 92 postmenopausal women enrolled in the study were investigated. The participants were divided into two groups, each receiving a continuous combined HRT regimen with either conjugated estrogen (CE) 0.625 mg + 5 mg medroxyprogesterone acetate (MPA) (=CE/MPA) or 17-beta-estradiol (E2) 2 mg + 1 mg norethisterone acetate (NETA) (=E2/NETA). These were evaluated according to apoptotic index (Ai) and proliferation marker Ki-67 index. Estrogen receptor alpha (ER) and progesterone receptor (PR) expression were also monitored, as well as endometrial thickness. Quantitative in situ techniques were used. RESULTS: Ai and Ki-67 index were unchanged in epithelial glands of endometrium from baseline to second biopsy obtained after 1 year of combined continuous HRT. In stromal tissue, Ki-67 index was increased, while Ai was on the same level. PR expression in both epithelium and stroma was unchanged. Endometrial thickness was unaffected during therapy, and the histopathological evaluation showed no development of hyperplasia or carcinoma. CONCLUSIONS: The unaffected homeostasis in endometrial epithelium contributes to endometrial safety and is in accordance with the histopathological findings of no hyperplasia. The homeostasis of stroma was transformed to be more proliferative. Increased stromal proliferation may be of importance for stromal support of the veins and for decreasing breakthrough bleeding during HRT. The increased stromal proliferation, as well as the decreased ER expression both in epithelium and stroma, could be an effect of progesterone.