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

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 (n=1079) 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 (P=0.017), L-arginine (P=0.002), 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 (P=0.013) 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.

[1]  M. Doğanay,et al.  Effect of non-oral estrogen on risk markers for metabolic syndrome in early surgically menopausal women , 2010, Climacteric : the journal of the International Menopause Society.

[2]  E. Giltay,et al.  Differential effects of cross-sex hormonal treatment on plasma asymmetric dimethylarginine (ADMA) in healthy male-to-female and female-to-male transsexuals. , 2009, Atherosclerosis.

[3]  T. Lehtimäki,et al.  Use of combined oral contraceptives alters metabolic determinants and genetic regulation of C‐reactive protein. The Cardiovascular Risk in Young Finns Study , 2009, Scandinavian journal of clinical and laboratory investigation.

[4]  Risto Telama,et al.  Cohort profile: the cardiovascular risk in Young Finns Study. , 2008, International journal of epidemiology.

[5]  T. Laitinen,et al.  Serum L-homoarginine concentration is elevated during normal pregnancy and is related to flow-mediated vasodilatation. , 2008, Circulation journal : official journal of the Japanese Circulation Society.

[6]  T. Ozgurtas,et al.  Metformin and oral contraceptive treatments reduced circulating asymmetric dimethylarginine (ADMA) levels in patients with polycystic ovary syndrome (PCOS). , 2008, Atherosclerosis.

[7]  E. Brindle,et al.  C-reactive protein across the menstrual cycle. , 2008, American journal of physical anthropology.

[8]  R. Huupponen,et al.  Adulthood : The Cardiovascular Risk in Young Finns Study Risk Factors Identified in Childhood and Decreased Carotid Artery Elasticity in , 2005 .

[9]  P. Kenemans,et al.  Effects of intranasal versus oral hormone therapy on asymmetric dimethylarginine in healthy postmenopausal women: a randomized study. , 2007, Atherosclerosis.

[10]  T. Laitinen,et al.  Brachial Artery Flow-Mediated Dilation and Asymmetrical Dimethylarginine in the Cardiovascular Risk in Young Finns Study , 2007, Circulation.

[11]  T. Teerlink,et al.  HPLC analysis of ADMA and other methylated L-arginine analogs in biological fluids. , 2007, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[12]  D. Talwar,et al.  Biological variation of asymmetric dimethylarginine and related arginine metabolites and analytical performance goals for their measurement in human plasma , 2007, European journal of clinical investigation.

[13]  G. Reaven,et al.  ADMA is independently related to flow‐mediated vasodilation in subjects at low cardiovascular risk , 2007, European journal of clinical investigation.

[14]  N. Bersinger,et al.  Serum leptin and C-reactive protein levels in the physiological spontaneous menstrual cycle in reproductive age women. , 2006, European journal of endocrinology.

[15]  J. Bełtowski,et al.  Asymmetric dimethylarginine (ADMA) as a target for pharmacotherapy. , 2006, Pharmacological reports : PR.

[16]  T. Yurdun,et al.  Plasma markers of NO synthase activity in women after ovarian hyperstimulation: influence of estradiol on ADMA , 2006, Vascular medicine.

[17]  P. Kenemans,et al.  Oral, more than transdermal, oestrogen therapy lowers asymmetric dimethylarginine in healthy postmenopausal women: a randomized, placebo‐controlled study , 2006, Journal of internal medicine.

[18]  J. Viikari,et al.  Distribution and determinants of serum high‐sensitive C‐reactive protein in a population of young adults. The Cardiovascular Risk in Young Finns Study , 2005, Journal of internal medicine.

[19]  E. Schwedhelm,et al.  Determination of a reference value for NG, NG‐dimethyl‐L‐arginine in 500 subjects , 2005, European journal of clinical investigation.

[20]  J. Viikari,et al.  The 21‐year follow‐up of the Cardiovascular Risk in Young Finns Study: risk factor levels, secular trends and east–west difference , 2004, Journal of internal medicine.

[21]  J. Cooke NO and angiogenesis. , 2003, Atherosclerosis. Supplements.

[22]  S. Nussey,et al.  Estrogen Stimulates Dimethylarginine Dimethylaminohydrolase Activity and the Metabolism of Asymmetric Dimethylarginine , 2003, Circulation.

[23]  C. Stehouwer,et al.  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. , 2003, The Journal of clinical endocrinology and metabolism.

[24]  C. Stehouwer,et al.  Oestrogen replacement therapy lowers plasma levels of asymmetrical dimethylarginine in healthy postmenopausal women. , 2003, Clinical science.

[25]  A. Hingorani,et al.  Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia , 2003, The Lancet.

[26]  E. Terán,et al.  Physiological changes in platelet aggregation and nitric oxide levels during menstrual cycle in healthy women. , 2002, Nitric oxide : biology and chemistry.

[27]  J. Jespersen,et al.  Hormone replacement therapy: estrogen and progestin effects on plasma C-reactive protein concentrations. , 2002, American journal of obstetrics and gynecology.

[28]  R. Nijveldt,et al.  Determination of arginine, asymmetric dimethylarginine, and symmetric dimethylarginine in human plasma and other biological samples by high-performance liquid chromatography. , 2002, Analytical biochemistry.

[29]  M. Giusti,et al.  Circulating nitric oxide changes throughout the menstrual cycle in healthy women and women affected by pathological hyperprolactinemia on dopamine agonist therapy , 2002, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[30]  P. Vallance Importance of asymmetrical dimethylarginine in cardiovascular risk , 2001, The Lancet.

[31]  T. Lehtimäki,et al.  Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine , 2001, The Lancet.

[32]  C. Zoccali,et al.  Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study , 2001, The Lancet.

[33]  M. Denton,et al.  Dimethylarginines in chronic renal failure , 2001, Journal of clinical pathology.

[34]  R. Karas,et al.  The protective effects of estrogen on the cardiovascular system. , 2002, The New England journal of medicine.

[35]  S. Nussey,et al.  Plasma concentrations of asymmetric dimethylarginine, a natural inhibitor of nitric oxide synthase, in normal pregnancy and preeclampsia. , 1998, American journal of obstetrics and gynecology.

[36]  M. H. Gault,et al.  Prediction of creatinine clearance from serum creatinine. , 1975, Nephron.