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Differential effects of estradiol on carotid artery inflammation when administered early versus late after surgical menopause

Sophonsritsuk, Areepan MD, PhD1,2; Appt, Susan E. DVM1; Clarkson, Thomas B. DVM1; Shively, Carol A. PhD1; Espeland, Mark A. PhD3; Register, Thomas C. PhD1

doi: 10.1097/gme.0b013e31827461e0
Original Articles

Objective The aim of this study was to determine the effects of estrogen therapy (ET) on carotid artery inflammation when initiated early and late relative to surgical menopause.

Methods Female cynomolgus macaques consuming atherogenic diets were ovariectomized and randomized to control or oral estradiol (E2; human equivalent dose of 1 mg/d micronized E2) initiated at 1 month (early menopause, n = 24) or 54 months (late menopause, n = 40) after ovariectomy. The treatment period was 8 months. Carotid artery expression of the markers of monocyte/macrophages (CD68 and CD163), dendritic cells (CD83), natural killer cells (neural cell adhesion molecule-1), and interferon-γ was significantly lower in E2-treated animals in the early menopause group but not in the late menopause group (P < 0.05). In contrast, carotid artery transcripts for T-cell markers (CD3, CD4, CD8, and CD25), interleukin-10, type I collagen, monocyte chemoattractant protein-1, matrix metalloproteinase-9, and tumor necrosis factor-α were lower in E2-treated monkeys regardless of menopausal stage (P < 0.05).

Conclusions ET initiated soon after menopause inhibits macrophage accumulation in the carotid artery, an effect that is not observed when E2 is administered after several years of estrogen deficiency. No evidence for pro-inflammatory effects of late ET is observed. The results provide support for the timing hypothesis of postmenopausal ET with implications for the interpretation of outcomes in the Women’s Health Initiative.

From the 1Section on Comparative Medicine, Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC; 2Reproductive Endocrinology and Infertility Unit, Department of Obstetrics and Gynecology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; and 3Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC.

Received March 16, 2012; revised and accepted September 13, 2012.

Funding/support: This project was supported by National Institutes of Health grants AG18170 (T.C.R.), AG 28641 (T.C.R.), and HL 45666 (T.B.C.), and by the Wake Forest University Claude D. Pepper Older Americans Independence Center (P30-AG21332).

Financial disclosure/conflicts of interest: None reported.

Address correspondence to: Thomas C. Register, PhD, Section on Comparative Medicine, Department of Pathology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1040. E-mail:

© 2013 by The North American Menopause Society.