Contrasting Effects of Oral Versus Transdermal Estrogen on Serum Amyloid A (SAA) and High-Density Lipoprotein–SAA in Postmenopausal Women

Abstract

Objectives-Previous studies indicated that oral estrogen increased C-reactive protein by a first-pass hepatic effect. In this study, we determine whether the route of estrogen administration influences serum amyloid A (SAA), another acute-phase protein produced by the liver, and the SAA content of the high-density lipoprotein (HDL-SAA) in postmenopausal women. Methods and Results-In 29 postmenopausal women without coronary heart disease, we conducted a randomized crossover placebo-controlled study to compare effects of transdermal versus oral estrogen on SAA and HDL-SAA. SAA, apolipoprotein A-I, HDL, and HDL-SAA were measured before and after 8 weeks of transdermal estradiol (100 g per day), oral-conjugated estrogens (0.625 mg per day), or placebo. We found that oral estrogen significantly increased levels of SAA, HDL, and HDL-SAA, whereas transdermal estrogen reduced both SAA and HDL-SAA but had no effect on HDL in the same women. Conclusions-Oral estrogen increased SAA and altered HDL composition to contain a higher level of SAA by a first-pass hepatic mechanism. Because elevated SAA levels predict adverse prognosis in healthy postmenopausal women, and elevated HDL-SAA levels have been shown to interfere with HDL function, the route of administration may be an important consideration in minimizing side effects of estrogen replacement therapy on cardiovascular outcomes. Key Words: hormones Ⅲ inflammation Ⅲ serum amyloid A Ⅲ menopause Ⅲ HDL T he role of inflammation in the development of atherosclerosis is firmly established. Among markers of systemic inflammation, C-reactive protein (CRP) is one of the most important acute-phase proteins known to be independent predictors of adverse cardiovascular events in otherwise healthy women. 1 Recent studies by our group and others indicated that oral estrogen replacement therapy (ERT) caused a sustained increase in CRP, which may explain the increased risks of cardiovascular events of ERT in clinical trials. 2,3 This increase in CRP was avoided by transdermal estrogen, implicating a first-pass hepatic effect. See page 1741Serum amyloid A (SAA) is another acute-phase protein that determines long-term cardiovascular prognosis in women. 1 Like CRP, SAA is produced by the liver and has been shown to directly promote atherosclerosis and vascular inflammation. 4 However, unlike CRP, SAA can form a complex with high-density lipoprotein (HDL) in the plasma, and the elevated SAA content of the HDL particle (HDL-SAA) has been shown to interfere with antiatherogenic, antioxidative, and anti-inflammatory HDL function. 5 Although the influence of estrogen on CRP has been studied extensively, effects of estrogen administration on SAA are still unknown. The purpose of our present study is not only to determine whether the route of estrogen administration influences SAA levels but also HDL-SAA in postmenopausal women. MethodsThe study was approved by the institutional review board of the University of Texas Southwestern Medical Center at Dallas. After informed written consent was obtai...

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