Increased C-reactive Protein Levels during Short-term Hormone Replacement Therapy in Healthy Postmenopausal Women

Baal, W.M. van; Kenemans, P.; Mooren, M.J. van der; Kessel, H. Van; Emeis, J.J.; Stehouwer, Coen D.A.

doi:10.1055/s-0037-1614600

Cited by 130 publications

(75 citation statements)

References 14 publications

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“…However, this is unlikely because previous studies indicated that oral estrogen has been shown to consistently increase acute phase protein CRP regardless of specific preparations (ie, oral-conjugated estrogens or oral 17␤-estradiol, or estradiol valerate). 11,12 Our observation may have important clinical implication for several reasons. First, elevated SAA levels are independently associated with adverse cardiovascular events in women, 1 possibly by their direct proinflammatory and proatherogenic effects.…”

Section: Discussionmentioning

confidence: 83%

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

Abbas¹,

Fadel²,

Wang³

et al. 2004

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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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Section: Discussionmentioning

confidence: 83%

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

Abbas¹,

Fadel²,

Wang³

et al. 2004

ATVB

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“…43 Furthermore, lowering fibrinogen levels via drugs may not have the same effect as naturally low levels. van Baal et al 44 observed an estrogen-associated 12% reduction in clottable fibrinogen but no change in fibrinogen antigen, suggesting that estrogen may act on fibrinogen clotting, not synthesis.…”

Section: Effects Of Serms On Hemostasismentioning

confidence: 99%

Cardiovascular Effects of Droloxifene, a New Selective Estrogen Receptor Modulator, in Healthy Postmenopausal Women

Herrington

Pusser

Riley

et al. 2000

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Abstract-Selective estrogen receptor modulators, like tamoxifen and related compounds, have mixed estrogen agonistic/ antagonistic effects. Tamoxifen may confer significant cardiovascular benefits without the estrogen-associated risks of endometrial and breast cancer. Droloxifene, a structural analogue of tamoxifen, has estrogen agonistic effects on bone and antagonistic effects on endometrial and breast tissue. Its cardiovascular effects in women are unknown. We enrolled 24 healthy postmenopausal women in a randomized, double-blind, 2-period crossover trial comparing the effects of droloxifene (60 mg/d) with conjugated estrogen (0.625 mg/d). Plasma lipids, coagulation and fibrinolytic factors, and brachial flow-mediated vasodilator responses were measured at the beginning and end of each treatment period. Droloxifene and estrogen resulted in 16.6% and 12.0% reductions, respectively, in low density lipoprotein cholesterol (PϽ0.001) and 13.2% and 9.5% reductions, respectively, in lipoprotein(a) (PϽ0.05). In contrast, estrogen, but not droloxifene, increased high density lipoprotein (18.5%, PϽ0.001). Droloxifene also reduced fibrinogen by 17.8% versus a 7.3% reduction with estrogen (Pϭ0.004) but produced no estrogen-like changes in plasminogen, plasminogen activator inhibitor-1, or tissue plasminogen activator. Droloxifene and estrogen produced 36.4% and 27.3% increases, respectively, in flow-mediated vasodilation (percent change from baseline, PϽ0.05 for both). Droloxifene has estrogen agonistic properties regarding low density lipoprotein and lipoprotein(a) metabolism, certain coagulation factors, and endothelium-dependent vasodilation but, unlike estrogen, has no effect on high density lipoprotein/triglyceride metabolism and the fibrinolytic cascade. It remains unknown whether droloxifene can confer a true cardiovascular benefit. Key words: droloxifene Ⅲ hormone replacement therapy Ⅲ women Ⅲ estrogen Ⅲ cardiovascular disease E strogen replacement therapy favorably influences several domains of vascular health, including lipid metabolism, endothelial function, and aspects of hemostasis. 1 However, estrogen replacement also carries an increased risk of endometrial 2 and possibly breast 3 carcinoma. The recent Heart and Estrogen/Progestin Study trial 4 also raises questions about whether the favorable effects of estrogen on the cardiovascular system may be offset by other, previously unrecognized, adverse cardiovascular effects, resulting in no overall clinical cardiovascular benefit.Selective estrogen receptor modulators (SERMs), like tamoxifen, are compounds with mixed estrogen agonistic/antagonistic effects. Other benzothiophene derivatives, such as raloxifene, and other structurally unrelated compounds, such as soy phytoestrogens and tibolone, have variable degrees of estrogen agonistic and antagonistic effects. 5 Tamoxifen lowers cholesterol, 6 and in trials in women with breast cancer, it was associated with 15% to 63% fewer cardiovascular events. 7 However, tamoxifen also increases the risk for endometrial ...

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“…The PEPI study 1 was a 3-year randomized trial, whereas Ridker et al presented cross-sectional results from the Women's Health Study (WHS). 2 In addition, the women in our study were all diabetics, and CRP levels are known to be significantly raised in diabetics. Our sample size was smaller than the American studies.…”

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confidence: 90%

C-Reactive Protein and Hormone Replacement Therapy

2000

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Two recent articles in Circulation 1,2 described increases in C-reactive protein (CRP) concentration with hormone replacement therapy (HRT) that consisted of oral estrogen or estrogen plus progestin preparations. The authors argued that such a proinflammatory effect of HRT may help to explain the increased risk of cardiovascular disease in the first year of treatment with HRT, as observed in the recent HERS trial (Heart and Estrogen-progestin Replacement Study).In contrast, in related research, we have found that in a double-blind trial of 33 women with type 2 diabetes, a combination of transdermal estradiol (80 g) and continuous oral norethisterone (1 mg) significantly reduced CRP concentrations relative to placebo after 6 months of therapy. 3 What could be the reasons for the discordant results observed?There were differences in design between the studies. The PEPI study 1 was a 3-year randomized trial, whereas Ridker et al presented cross-sectional results from the Women's Health Study (WHS). 2 In addition, the women in our study were all diabetics, and CRP levels are known to be significantly raised in diabetics. Our sample size was smaller than the American studies. Nonetheless, we propose that beyond methodological issues, there are important biological explanations for the differences in the direction of CRP after HRT.First, in our study, the estrogen component was delivered transdermally (not orally 1,2 ), thus bypassing the hepatic first-pass metabolism effect. This may be critical, because plasma CRP concentrations are thought to reflect increased hepatic synthesis rather than systemic clearance. Second, the progestogen used in our study was oral norethisterone, a 19 nortestosterone progestin. This preparation has both progestogenic and androgenic effects. This is noteworthy because both progestogens and androgens generally display antiinflammatory effects in other tissues. 4 It is conceivable that similar effects occur in the liver.Interestingly, triglyceride concentrations are also reduced with oral norethisterone (in general, the progestin effect may be triglyceride neutral, and androgens diminish circulating triglyceride concentrations), whereas oral estrogens increase hepatic triglyceride synthesis. 5 In support of a net progestogenic/androgenic hepatic effect in our study, triglyceride concentrations were significantly reduced.We suggest that not all HRTs are alike in their effect on CRP concentrations. The route of delivery of the estrogen, the relative androgenicity of the progestogen, and the chronicity of use might be important in this respect. It would be interesting to examine whether HRT preparations, which reduce CRP concentrations, avoid a transient increase in cardiovascular risk potentially associated with preparations containing oral estrogens. If so, this route of delivery might be more desirable for women with existing coronary heart disease who are considering HRT.

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Increased C-reactive Protein Levels during Short-term Hormone Replacement Therapy in Healthy Postmenopausal Women

Cited by 130 publications

References 14 publications

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

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

Cardiovascular Effects of Droloxifene, a New Selective Estrogen Receptor Modulator, in Healthy Postmenopausal Women

C-Reactive Protein and Hormone Replacement Therapy

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