Estrogen replacement therapy and cardiac function under metabolic syndrome: a treacherous art.

Regardless of age, race, and ethnicity, cardiovascular disease is the number 1 cause of death for women, and its prevalence rises rapidly after menopause.1–4 This postmenopausal increase is believed to result from the loss of endogenous estrogen. Although estrogen replacement therapy (ERT) has long been thought to protect against menopauseassociated cardiovascular anomalies, osteoporosis, hot flashes, and thinning of the vaginal epithelium,3–5 findings from the Heart and Estrogen/Progestin Replacement Study and the Women’s Health Initiative Study5 do not support the notion that ERT protects the cardiovascular system. Instead, the data indicate just the opposite, that is, increased risk of cardiovascular disease, in addition to the apparent higher risk of breast cancer and deep vein thrombosis.1,2,4 Although results from clinical trials have substantiated the beneficial role of ERT in the management of menopausal symptoms, the unexpected finding of exacerbated cardiovascular function after ERT has made women hesitant to initiate ERT after menopause.1 Further analysis of the clinical trials revealed that the age of a woman and especially the number of years after menopause onset may be primary factors that contribute to the ultimate cardiovascular outcome of ERT. Although estrogen-progesterone therapy was found beneficial in young postmenopausal women, it increased cardiovascular risk when initiated in older postmenopausal women with established coronary artery disease.2,4 It is, thus, recommended that ERT be limited to the shortest duration consistent with treatment goals (eg, relief of menopausal symptoms).1 In contrast to the generalized recommendation for short duration of menopausal hormone treatment,2,4 careful scrutiny of the data from the Women’s Health Initiative Estrogen Plus Progestin Trial reveal a reduced coronary heart disease risk after 5 to 6 years of ERT treatment. Accordingly, the overall effect of ERT on cardiovascular health in postmenopausal women is controversial, making it difficult to evaluate individualized care based on the risk:benefit ratio. A number of studies have reported a potential link between reduced estrogen and the prevalence of metabolic syndrome, a complex, debilitating disorder that includes hypertension, diabetes mellitus, and dyslipidemia.3 However, a reduced incidence of type 2 diabetes mellitus and obesity was noted in otherwise healthy postmenopausal women who received estrogen.3 This inverse correlation between estrogen and metabolic syndrome suggests that estrogen deficiency that accompanies menopause may play a role in the onset and development of metabolic syndrome. Thus, despite the controversies regarding ERT, it appears that younger postmenopausal women with metabolic syndrome may benefit from ERT. However, there are still major gaps in our knowledge base. The pathophysiology of metabolic syndrome in perimenopausal and postmenopausal women is still not well understood, although ambient reproductive hormone levels are believed not to be the only variables that affect the frequency and severity of metabolic syndrome in women. It is particularly worrisome that some studies have indicated a potential tie between severity of menopausal syndrome (eg, hot flashes) and increased cardiovascular risk,1,3 suggesting that younger postmenopausal women with metabolic syndrome who most need ERT for symptom relief may be at a greater risk of adverse effects from ERT. In this issue of Hypertension, Murase et al6 examined the effect of ERT on obesity, cardiac geometry and contractile function using a new model of metabolic syndrome, the DahlS.Z-Lepr/ Lepr (DS/obese) rats derived from a cross between Dahl salt-sensitive and Zucker rats.6 Animals ovariectomized at 7 weeks of age received an estrogen pellet or placebo at 8 weeks. Age-matched female homozygous lean littermates (DahlS.Z-Lepr /Lepr or DS/lean rats) of DS/ obese rats served as controls. Ovx-DS/obese rats manifested hypertension at 7 weeks of age and thereafter and exhibited left ventricular fibrosis and diastolic dysfunction at 13 weeks of age. ERT attenuated hypertension in Ovx-DS/obese rats without affecting blood pressure in ovariectomized DS/lean (Ovx-DS/lean) rats. ERT exacerbated left ventricular fibrosis and diastolic dysfunction and further increased cardiac oxidative stress and inflammation in Ovx-DS/obese and OvxDS/lean rats. Consistent with the reported beneficial effect of estrogen on metabolic syndrome,3 ERT reduced food intake, body weight, and visceral fat content in both Ovx-DS/obese and Ovx-DS/lean rats. These authors concluded that ERT may attenuate hypertension and obesity but exacerbated cardiac fibrosis and diastolic dysfunction in Ovx-DS/obese The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Center for Cardiovascular Research and Alternative Medicine (A.S., J.R.), University of Wyoming College of Health Sciences, Laramie, WY; Shanghai Institute of Cardiovascular Diseases (A.S.), Zhongshan Hospital, Fudan University, Shanghai, China. Correspondence to Jun Ren, Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071. E-mail [email protected] (Hypertension. 2012;59:552-554.) © 2012 American Heart Association, Inc.