Steroids regulate CXCL4 in the human endometrium during menstruation to enable efficient endometrial repair

Context: Repair of the endometrial surface at menstruation must be efficient to minimize blood loss and optimize reproductive function. The mechanism and regulation of endometrial repair remain undefined.

Objective: To determine the presence/regulation of CXCL4 in the human endometrium, as a putative repair factor at menses.

Patients/Setting: Endometrium was collected throughout the menstrual cycle from healthy women attending the gynecology department. Menstrual blood loss was objectively measured in a subset and heavy menstrual bleeding (HMB) defined as >80ml/cycle. Monocytes were isolated from peripheral blood.

Design: CXCL4 mRNA and protein were identified by RT-qPCR and immunohistochemistry. The function/regulation of endometrial CXCL4 was explored by in vitro cell culture.

Results: CXCL4 mRNA concentrations were significantly increased during menstruation. Intense staining for CXCL4 was detected in late secretory and menstrual tissue, localized to stromal, epithelial and endothelial cells. Co-localization identified positive staining in CD68+ macrophages. Treatment of human endometrial stromal (hESC) and endothelial (HEEC) cells with steroids revealed differential regulation of CXCL4. Progesterone withdrawal resulted in significant increases in CXCL4 mRNA and protein in hESCs, whereas cortisol significantly increased CXCL4 in HEECs. In women with HMB, CXCL4 was reduced in endothelial cells during the menstrual phase when compared to women with normal menstrual bleeding. Cortisol exposed macrophages displayed increased chemotaxis towards CXCL4 compared to macrophages incubated with estrogen or progesterone.

Conclusions: Our data implicate CXCL4 in endometrial repair post menses. Reduced cortisol at time of menses may contribute to delayed endometrial repair and HMB, in part by mechanisms involving aberrant expression of CXCL4.