Effects of Hormone Replacement Therapy on Plasma Homocysteine and C-Reactive Protein Levels

Yildirir, Aylin; Aybar, F.; Tokgözoğlu, Lâle; Yaralı́, Hakan; Kabakçı, Giray; Bükülmez, Orhan; Sinici, İncilay; Oto, Ali̇

doi:10.1159/000049412

Cited by 27 publications

(21 citation statements)

References 21 publications

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“…Despite previous studies that suggest that female sex hormones have the ability to effect hs-CRP, homocysteine, and lipid concentrations (9,26,45,55), no differences were observed in these variables in the present study. Treatment of postmenopausal women with oral conjugated equine estrogen has been shown to increase hs-CRP, but no change in hs-CRP has been observed with the use of transdermal estrogen (20), suggesting that the lack of change in hs-CRP across hormone treatments in this study may be due to the transdermal route of estrogen delivery.…”

Section: Discussioncontrasting

confidence: 99%

Estrogen, medroxyprogesterone acetate, endothelial function, and biomarkers of cardiovascular risk in young women

Meendering¹,

Torgrimson²,

Miller³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Meendering JR, Torgrimson BN, Miller NP, Kaplan PF, Minson CT. Estrogen, medroxyprogesterone acetate, endothelial function, and markers of cardiovascular risk in young women. Am J Physiol Heart Circ Physiol 294: H1630-H1637, 2008. First published February 15, 2008 doi:10.1152/ajpheart.01314.2007.-Medroxyprogesterone acetate (MPA) is widely known for its use in combination hormone therapy for postmenopausal women. However, MPA is also commonly used in young women for contraception and treatment of a number of gynecological conditions. Despite its widespread use, the cardiovascular effects of MPA in young women are unclear. Therefore, the purpose of this study was to determine the acute effects of MPA when used in combination with estradiol on markers of cardiovascular risk in young women. We suppressed endogenous estrogens and progesterone in 10 premenopausal women using a gonadotropin-releasing hormone antagonist (GnRHa) for 10 days. On day 4 of GnRHa subjects received 0.1 mg of estradiol (GnRHaϩE2), and on day 7 5 mg of MPA was added (GnRHaϩE2ϩMPA). Endothelium-dependent vasodilation and endothelium-independent vasodilation of the brachial artery, lipids, homocysteine, high-sensitivity C-reactive protein, and endothelin-1 were assessed during treatment with GnRHa, GnRHaϩE2, and GnRHaϩE2ϩMPA. Four additional subjects were tested to validate the efficacy of the GnRHa model and confirm the findings. Endothelium-dependent vasodilation was greater during GnRHaϩE2 than during GnRHa or GnRHaϩE2ϩMPA (P ϭ 0.006). Endothelin-1 was lower during GnRHaϩE2 than GnRHa alone (P ϭ 0.039). Endothelin-1 increased with the addition of MPA and was not significantly different from GnRHa alone. There were no differences in the other markers of cardiovascular risk between hormone treatment days. These data suggest that acute MPA administration negates the beneficial effects of estradiol on endothelium-dependent vasodilation in young women. In addition, these data suggest that estradiol decreases endothelin-1 concentrations and the addition of MPA may counteract the effect of estradiol on endothelin-1. endothelium; hormones; flow-mediated vasodilation; endothelin-1; progestins THERE IS SUBSTANTIAL EVIDENCE to suggest that estrogens have a cardioprotective influence in women by improving endothelial function (11,14,19,24) and low-density lipoprotein (LDL) concentrations (45) while decreasing concentrations of endothelin-1 (ET-1) (4,26,31,32,56) and homocysteine (9). In contrast, medroxyprogesterone acetate (MPA) has been shown to counteract the beneficial effects of estrogens in animals (1, 52) and in some studies in postmenopausal women (18,44,49). Recently, the estrogen plus MPA arm of the Women's Health Initiative clinical trial was terminated because of a trend toward negative cardiovascular outcomes (37). These findings raise questions about the use of progestins, and specifically MPA, in hormone treatments.In addition to postmenopausal women, premenopausal women are also commonly prescribed MPA. MPA is used in the injectable prog...

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Section: Discussioncontrasting

confidence: 99%

Estrogen, medroxyprogesterone acetate, endothelial function, and biomarkers of cardiovascular risk in young women

Meendering¹,

Torgrimson²,

Miller³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

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“…Although this finding is contrary to the observation of Cushman et al 4 in the Postmenopausal Estrogen/Progestin Interventions (PEPI) study, similar data have been reported by another group, 5 suggesting to these investigators that the addition of a progestin might attenuate otherwise proinflammatory effects of estrogen and thus provide a more atheroprotective form of hormone therapy. However, this combination hormone therapy did not reduce cardiovascular risk in the Heart Estrogen/progestin Replacement Study (HERS).…”

Section: Responsecontrasting

confidence: 59%

Statin Attenuates Increase in C-Reactive Protein During Estrogen Replacement Therapy in Postmenopausal Women

2002

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In their interesting study, Koh et al 1 demonstrated that 0.625 mg of conjugated equine estrogen (CEE) daily for 6 weeks caused an increase in plasma C-reactive protein (CRP), whereas the combination of simvastatin 10 mg daily with CEE for 6 weeks reduces the estrogen-induced increase in CRP. The antiinflammatory effect of HMG-CoA reductase inhibitors (statins) may reduce the estrogen-induced increase in plasma concentrations of CRP. The Heart and Estrogen/ Progestin Replacement Study (HERS) demonstrated that estrogen and progestin therapy did not reduce the overall rate of coronary events in postmenopausal women with established coronary disease. 2 Because elevated CRP may be associated with plaque destabilization and rupture, a proinflammatory effect of estrogen might explain the increased number of cardiovascular events demonstrated in women with existing cardiovascular disease during the first year of the HERS trial. Accordingly, a combination of statin therapy may lead to a reduction in the incidence of coronary events in women with coronary artery disease. However, combination therapy did not completely reverse the increase in CRP concentrations. In contrast to oral estrogen replacement therapy (ERT), transdermal ERT has been reported to decrease CRP concentrations. 3 Because estrogen directly passes hepatic circulation when administered orally, estrogen's hepatic stimulation may result in an increased production of CRP. Because of less hepatic stimulation, transdermal ERT may decrease CRP concentrations.We previously demonstrated that the addition of clinically determined doses of medroxyprogesterone acetate (MPA) to estrogen inhibited the increase in CRP to the baseline level. 4 Because androgens have been reported to have antiinflammatory effects 5 and because synthetic progestins such as MPA also have androgenic effects, MPA may reduce CRP concentrations. Thus, transdermal administration of estrogen or the addition of MPA to estrogen decreases CRP concentrations effectively. Further studies are needed to investigate whether CRP reduction can prevent early increases in coronary events in women with coronary artery disease, as demonstrated in the HERS trial.

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“…Homocysteine levels rise in postmenopausal women, 38 and hormone replacement therapy results in a decrease in homocysteine levels. 39 Low-dose estrogen therapy, 0.5 to 2.0 mg of oral 17␤ estradiol, has also been shown to reduce homocysteine levels in elderly men. 40 Menopause is associated with a 10% to 30% increase in plasma levels of lipoprotein(a), which falls with estrogen therapy 41,42 ; one trial in elderly men did not show any changes in lipoprotein(a) with oral estradiol supplementation.…”

Section: Discussionmentioning

confidence: 99%

Endogenous Estrogens Influence Endothelial Function in Young Men

Lew

Komesaroff

Williams

et al. 2003

Circulation Research

100

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Abstract-Males produce endogenous estrogen from testosterone via the enzyme aromatase. Previous studies have suggested a role for endogenous estrogens in cardiovascular function in men. We examined the effects of endogenous estrogen suppression via aromatase inhibition on endothelial function, systemic arterial compliance, and lipoprotein levels in healthy young men. Using a placebo-controlled double-blind randomized design, 20 healthy men, aged 18 to 32 years, were randomized to receive either the aromatase inhibitor anastrozole (1 mg) or matching placebo. Hormone, lipid levels, C-reactive protein (CRP), and homocysteine were measured. Endothelial function, determined by flow-mediated dilation of the brachial artery, and systemic arterial compliance were assessed at baseline and after 6 weeks of treatment. There was a significant decrease in 17␤-estradiol concentrations with aromatase inhibition, from 85.4Ϯ4.2 to 64.3Ϯ8.1 pmol/L (meanϮSD, Pϭ0.042). Compared with baseline, a significant decrease in flow-mediated dilation was observed in subjects taking anastrozole [median, 6.1% (range, 5.2 to 13.4) to 3.5% (2.0 to 5.7), Pϭ0.034] but not in the placebo group. No changes were observed in nitroglycerin-induced endothelium-independent dilation in either group. There was no change in systemic arterial compliance with either aromatase therapy or placebo. There were no significant changes in lipoproteins, testosterone, DHEA, CRP, or homocysteine levels in either the anastrozole or placebo group. We conclude that suppression of endogenous estrogens with an aromatase inhibitor resulted in impairment of flow-mediated dilation without significant changes in lipoproteins, homocysteine, or CRP. Our results suggest that endogenous estrogens play a direct regulatory role in endothelial function in young healthy men.

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Effects of Hormone Replacement Therapy on Plasma Homocysteine and C-Reactive Protein Levels

Cited by 27 publications

References 21 publications

Estrogen, medroxyprogesterone acetate, endothelial function, and biomarkers of cardiovascular risk in young women

Estrogen, medroxyprogesterone acetate, endothelial function, and biomarkers of cardiovascular risk in young women

Statin Attenuates Increase in C-Reactive Protein During Estrogen Replacement Therapy in Postmenopausal Women

Endogenous Estrogens Influence Endothelial Function in Young Men

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