Steroids Regulate CXCL4 in the Human Endometrium During Menstruation to Enable Efficient Endometrial Repair.
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.



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



Endometrial tissue 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) was defined as >80 mL per cycle. Monocytes were isolated from peripheral blood.



CXCL4 messenger RNA (mRNA) and protein were identified by quantitative reverse transcription polymerase chain reaction and immunohistochemistry. The function/regulation of endometrial CXCL4 was explored by in vitro cell culture.



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. Colocalization identified positive staining in CD68+ macrophages. Treatment of human endometrial stromal and endothelial cells (hESCs and HEECs, respectively) 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 compared with women with normal menstrual bleeding. Cortisol-exposed macrophages displayed increased chemotaxis toward CXCL4 compared with macrophages incubated with estrogen or progesterone.



These data implicate CXCL4 in endometrial repair after menses. Reduced cortisol at the time of menses may contribute to delayed endometrial repair and HMB, in part by mechanisms involving aberrant expression of CXCL4.
MRC Centre for Reproductive Health, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom.
Jacqueline A
JA
Maybin
MRC Centre for Reproductive Health, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom.
Uma
U
Thiruchelvam
MRC Centre for Reproductive Health, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom.
Mayank
M
Madhra
MRC Centre for Inflammation Research, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom.
Philippa T K
PTK
Saunders
MRC Centre for Reproductive Health, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom.
Hilary O D
HOD
Critchley
D000328:Adult; D004717:Endometrium / Q000166:cytology / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008595:Menorrhagia / Q000235:genetics* / Q000378:metabolism; D008597:Menstrual Cycle / Q000235:genetics / Q000378:metabolism; D008598:Menstruation / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes; D010978:Platelet Factor 4 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology; D012333:RNA, Messenger; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000187:drug effects; D055815:Young Adult
D012333:RNA, Messenger; D010978:Platelet Factor 4; D011374:Progesterone; D004958:Estradiol; D006854:Hydrocortisone