Plasma Metabolic Profiles in Women are Menopause Dependent

Abstract

Menopause is an endocrinological transition that greatly affects health and disease susceptibility in middle-aged and elderly women. To gain new insights into the metabolic process of menopause, plasma metabolic profiles in 115 pre- and post-menopausal women were systematically analyzed by ultra-performance liquid chromatography/mass spectrometry in conjunction with univariate and multivariate statistical analysis. Metabolic signatures revealed considerable differences between pre- and post-menopausal women, and clear separations were observed between the groups in partial least-squares discriminant analysis score plots. In total, 28 metabolites were identified as potential metabolite markers for menopause, including up-regulated acylcarnitines, fatty acids, lysophosphatidylcholines, lysophosphatidylethanolamines, and down-regulated pregnanediol-3-glucuronide, dehydroepiandrosterone sulfate, p-hydroxyphenylacetic acid and dihydrolipoic acid. These differences highlight that significant alterations occur in fatty acid β-oxidation, phospholipid metabolism, hormone metabolism and amino acid metabolism in post-menopausal women. In conclusion, our plasma metabolomics study provides novel understanding of the metabolic profiles related to menopause, and will be useful for investigating menopause-related diseases and assessing metabolomic confounding factors.

Metabolite patterns predicting sex and age in participants of the Karlsruhe Metabolomics and Nutrition (KarMeN) study

“…It has been reported before [ 1 , 19 ] and is in line with our own data that concentrations of some metabolites in women do not change continuously with age, but show a sudden increase or decrease in concentration around the age of 50 that is associated with menopause. For men, metabolite concentration changes with age occur continuously starting at 30 or 40 years of age ( S4 Fig ).…”

“…Generally, as reported by others [ 1 , 7 , 18 , 19 , 42 , 50 , 60 ], we found that several amino acids, lipids, and organic acids in plasma are important for the prediction of age in women, with ornithine, choline, hippuric acid, cholesterol, glucuronic acid, and glucose occurring in metabolite patterns for chronological age and menopause ( S3 Table ). Interestingly, all these metabolites have higher concentrations in older and post-menopausal women, respectively.…”

“…Based on our results and observations in other studies [ 5 – 7 ], we argue that age has to be considered as a potentially confounding factor for metabolomics analyses. In addition we and others [ 1 , 19 ] found that age-trajectories of many metabolites are sex-dependent. This means that also age-sex-interactions have to be included in statistical modeling, which can have important implications for the statistical methodology in the field of metabolomics.…”

“…For example, creatinine, tryptophan, histidine or serine have repeatedly been shown to be higher in concentration in urine and/or blood in younger persons, whereas citrate, creatine, glycine, glutamate were described to be higher in older persons [ 2 , 5 , 7 , 13 , 15 – 18 ]. In women, menopausal status causes a clear shift in plasma metabolite concentrations [ 1 , 19 ] and thus may be the underlying cause for apparent age differences. Differences between men and women were suggested to be mainly based on higher plasma and/or urine concentrations of branched-chain amino acids (BCAA) and creatinine in men, whereas several phospholipids, citrate, glycine, hippurate and others were higher in women [ 2 – 5 , 13 , 16 , 18 , 20 – 23 ].…”

Alterations in postmenopausal plasmatic lipidome

“…In our study, we also identified metabolites of these classes; however, the species of LPC and LPE differed from those that we identified as changed in post-menopausal women, possibly due to the lipid extraction methods (acetonitrile x MeOH / CHCl3) [2], the technology used in the detection (UPLC-QTOF/MS x FIA-ESI-MS/MS), as well as the biological sources of the population studied.…”