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

Abstract

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.

Oral contraceptives modify DNA methylation and monocyte-derived macrophage function

“…Although the absolute reduction of this endogenous inhibitor of nitric oxide synthase was small, the biological variation in the plasma asymmetric dimethylarginine/arginine ratio is also very low and even a slight increase in the asymmetric dimethylarginine/arginine ratio is associated with an elevated risk of acute coronary events [12]. The reduction in the asymmetric dimethylarginine/arginine ratio is in line with the results of Valtonen et al [11]. Notably, the ratio increase was mainly sustained by a decrease in arginine.…”

“…Notably, the ratio increase was mainly sustained by a decrease in arginine. The decrease in arginine is not a universal finding [11], and the reasons for this discrepancy are not well understood, but a decrease in arginine has been reported after oral hormonal replacement therapy [42]. …”

“…In addition, OCs can induce subclinical abnormalities in carbohydrate metabolism [7,8], can modify lipid metabolism [9], and are associated with elevation of C-reactive protein [10]. OCs decrease symmetric methylarginine and asymmetric dimethylarginine [11], the latter being an inhibitor of nitric oxide and an index of endothelial dysfunction [12]. OC-induced variations may increase the risk of venous thromboembolism [13,14] and elevate the prevalence of atherosclerosis and its complications in young, apparently healthy women [15,16].…”

“…Macrophages play crucial roles in atherosclerosis and immunity [17,18] and are uniquely dependent on the milieu to which they are exposed [19], which, as already mentioned, can in turn be modified by OCs [5,6,9-11,13,14]. Importantly, monocyte-derived macrophages (MDMs) express estrogen and androgen receptors [20].…”

The correlation of serum asymmetric dimethylarginine and anti‐Müllerian hormone in primary dysmenorrhea

“…Changes in serum ADMA levels have also been investigated during normal menstrual periods. The menstrual cycle is divided into follicular and luteal phases and is regulated by hormones [4]. Estrogen and progesterone levels are lower in the early period of the follicular phase, but start to increase toward the end of the follicular phase, peaking during the surge of luteinizing hormone and follicle‐stimulating hormone.…”