Effect of Hormone Replacement Therapy on Plasma Levels of the Cardiovascular Risk Factor Asymmetric Dimethylarginine: A Randomized, Placebo-Controlled 12-Week Study in Healthy Early Postmenopausal Women

Post, Marinka S.; Verhoeven, Marieke O.; Mooren, M.J. van der; Kenemans, P.; Stehouwer, Coen D.A.; Teerlink, Tom

doi:10.1210/jc.2003-030584

Cited by 60 publications

(45 citation statements)

References 40 publications

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“…[23][24][25][26][27] In the present study, the treatment characteristics and lifestyles of patients were similar, excluding the possible effects of confounding factors on these results.…”

Section: Discussionsupporting

confidence: 51%

Short Term Fluvastatin Treatment Lowers Serum Asymmetric Dimethylarginine Levels in Patients With Metabolic Syndrome

Oğuz

Uzunlulu

2008

Int. Heart J.

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SUMMARYElevated concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are associated with endothelial dysfunction. Metabolic syndrome (MetS) is also a condition associated with impaired endothelial function. To test the hypothesis that lipid lowering treatment with a statin lowers ADMA levels, we investigated the effect of fluvastatin treatment on serum ADMA levels in patients with MetS.A total of 85 hypercholesterolemic MetS patients (53 females, 32 males; mean age, 55.8 ± 9.1 years) were included in this prospective, randomized, controlled study. Patients were randomly assigned to either the treatment (n = 42) or control group (n = 43). Recommendations for lifestyle modification were provided to both groups. In addition, the patients in the treatment group received fluvastatin, extended release tablets, 80 mg/day, orally for 6 weeks. Serum levels of ADMA and lipids were assessed at baseline and at the completion of treatment. High performance liquid chromatography was used to measure serum ADMA concentrations.In the fluvastatin group, there was a significant reduction in serum ADMA levels compared to baseline (from 1.57 ± 1.07 µmol/L to 1.17 ± 1.41 µmol/L, P < 0.05), whereas in the control group no significant change was observed (from 1.06 ± 0.46 µmol/L to 1.24 ± 1.38 µmol/L, P > 0.05). There was a statistically significant difference between the groups in terms of mean percent change from baseline (P = 0.047). Fluvastatin treatment for hypercholesterolemia in patients with MetS is associated with a decrease in serum ADMA levels at 6 weeks. This finding is consistent with known beneficial effects of statin treatment on endothelial function in hypercholesterolemic patients. (Int Heart J 2008; 49: 303-311) Key words: Asymmetric dimethylarginine, Fluvastatin, Metabolic syndrome METABOLIC syndrome (MetS) is characterized by a cluster of cardiometabolic risk factors including hypertension, atherogenic dyslipidemia, hyperglycemia, and prethrombotic/proinflammatory conditions, 1) and represents a significant risk factor for the development of coronary heart disease, myocardial inFrom the

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“…[23][24][25][26][27] In the present study, the treatment characteristics and lifestyles of patients were similar, excluding the possible effects of confounding factors on these results.…”

Section: Discussionsupporting

confidence: 51%

Short Term Fluvastatin Treatment Lowers Serum Asymmetric Dimethylarginine Levels in Patients With Metabolic Syndrome

Oğuz

Uzunlulu

2008

Int. Heart J.

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“…For instance, plasmatic ADMA concentrations are lower before than after menopause, suggesting an effect of estrogens in ADMA metabolism (Schulze et al, 2005). Indeed, in some studies, hormone replacement therapy significantly reduced plasma concentrations of the cardiovascular risk factor ADMA in healthy postmenopausal women (Post et al, 2003) and raised levels of NO (Saitta et al, 2001) which could lead to an increase in endothelium-dependent flow-mediated dilation observed during oral hormone replacement therapy (Vehkavaara et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Estradiol, acting through estrogen receptor alpha, restores dimethylarginine dimethylaminohydrolase activity and nitric oxide production in oxLDL-treated human arterial endothelial cells

Novella

Laguna-Fernández

Lázaro-Franco

et al. 2013

Molecular and Cellular Endocrinology

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a b s t r a c tAsymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase. ADMA accumulation, mainly due to a decreased dimethylarginine dimethylaminohydrolase (DDAH) activity, has been related to the development of cardiovascular diseases. We investigate whether estradiol prevents the changes induced by oxidized low density lipoprotein (oxLDL) on the DDAH/ADMA/NO pathway in human umbilical artery endothelial cells (HUAEC). HUAEC were exposed to estradiol, native LDL (nLDL), oxLDL and their combinations for 24 h. In some experiments, cells were also exposed to the unspecific estrogen receptor (ER) antagonist ICI 182780, the specific ERa antagonist MPP or specific agonists for ERa, ERb and GPER. ADMA concentration was measured by HPLC and concentration of NO by amperometry. Protein expression and DDAH activity were measured by immunoblotting and an enzymatic method, respectively. oxLDL, but not nLDL, increased ADMA concentration with a concomitant decrease on DDAH activity. oxLDL reduced eNOS protein and NO production. Estradiol alone had no effects on DDAH/ADMA/NO pathway, but increased the attenuated endothelial NO production induced by oxLDL by reduction in ADMA and preventing loss of eNOS protein levels. ICI 182780 and MPP completely abolished these effects of estradiol on oxLDL-exposed cells. ERa agonist, but not ERb and GPER agonists, mirrored estradiol effects on NO production. In conclusion, estradiol restores (1) DDAH activity, and therefore ADMA levels, and (2) NO production impaired by oxLDL in HUAEC acting through ERa.

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“…Oral contraceptives (OCs) are known to lower ADMA concentrations significantly in women with PCOS (9), and orally administered hormone replacement therapy (HRT) also has an effect on circulating ADMA levels (13)(14)(15). Our own studies and those of others have shown that during normal pregnancy, when there are high circulating estrogen levels, ADMA and SDMA concentrations are significantly decreased compared to the levels of non-pregnant women (10,16,17).…”

Section: Introductionmentioning

confidence: 99%

ADMA concentration changes across the menstrual cycle and during oral contraceptive use: the Cardiovascular Risk in Young Finns Study

Valtonen

Punnonen²,

Saarelainen³

et al. 2010

European Journal of Endocrinology

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Objective: The aim of this study was to evaluate changes in the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) levels during different menstrual cycle phases in young adult women with or without oral contraceptive (OC) use. Design and methods: The subjects (nZ1079) originated from a large population-based, prospective cohort study conducted in Finland. Plasma ADMA, symmetric dimethylarginine (SDMA), L-arginine, C-reactive protein, creatinine, and brachial artery flow-mediated dilatation (FMD) were measured. The use of OCs and menstrual cycle phase were determined from a questionnaire. Results: In non-OC users, ADMA (PZ0.017), L-arginine (PZ0.002), and ADMA/SDMA ratio (P!0.001) were significantly lower in the luteal phase than in the follicular phase of the menstrual cycle. Non-OC users also had significantly higher ADMA and SDMA concentrations (P!0.001) and lower L-arginine concentrations (P!0.001) compared to OC users of estrogen-containing pills. Progestin-only contraceptive pills (POPs) did not lower the ADMA level, but maintained it at the same level as in non-OC users. In OC users, there were no significant differences found in ADMA, FMD, or FMD% across menstrual cycle, whereas brachial artery diameter was significantly more decreased in the luteal phase (PZ0.013) than in the follicular phase. Conclusion: We observed that the circulating ADMA concentration varies across the menstrual cycle in young women not using OCs, and women on OCs displayed significantly lower circulating ADMA concentrations than non-OC users, though this was not the case with POP contraception.

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Effect of Hormone Replacement Therapy on Plasma Levels of the Cardiovascular Risk Factor Asymmetric Dimethylarginine: A Randomized, Placebo-Controlled 12-Week Study in Healthy Early Postmenopausal Women

Cited by 60 publications

References 40 publications

Short Term Fluvastatin Treatment Lowers Serum Asymmetric Dimethylarginine Levels in Patients With Metabolic Syndrome

Short Term Fluvastatin Treatment Lowers Serum Asymmetric Dimethylarginine Levels in Patients With Metabolic Syndrome

Estradiol, acting through estrogen receptor alpha, restores dimethylarginine dimethylaminohydrolase activity and nitric oxide production in oxLDL-treated human arterial endothelial cells

ADMA concentration changes across the menstrual cycle and during oral contraceptive use: the Cardiovascular Risk in Young Finns Study

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