Sex-associated differences in baseline urinary metabolites of healthy adults

Abstract

The biological basis for gender variability among disease states is not well established. There have been many prior efforts attempting to identify the unique urine metabolomic profiles associated with specific diseases. However, there has been little advancement in investigating the metabolomic differences associated with gender, which underlies the misconception that risk factors and treatment regimens should be the same for both male and female patients. This present study aimed to identify biologically-meaningful baseline sex-related differences using urine samples provided by healthy female and male participants. To elucidate whether urinary metabolic signatures are globally distinct between healthy males and females, we applied metabolomics profiling of primary metabolism with comprehensive bioinformatics analyses on urine samples from 60 healthy males and females. We found that levels of α-ketoglutarate and 4-hydroxybutyric acid increased 2.3-fold and 4.41-fold in males compared to females, respectively. Furthermore, chemical similarity enrichment analysis revealed that differentially expressed metabolites, such as saturated fatty acids, TCA, and butyrates, were significantly related to the gender effect. These findings indicate that there are baseline sex-related differences in urinary metabolism, which should be considered in biomarker discovery, diagnosis, and treatment of bladder diseases, such as interstitial cystitis.

Influence of Sex on Urinary Organic Acids: A Cross-Sectional Study in Children

“…Knowledge of the reference values for urinary organic acids in a healthy pediatric population is important, applying reference values specific for a single sex to another sex being inappropriate. Then, the role of sex should be taken in account for a personalized diagnosis, and to give more rigorous scientific background with better standardized entry criteria in studies on biomarkers as already suggested [9,10,14,28,[70][71][72].…”

“…Urine adult metabolome seems to be influenced also by sex [14,[19][20][21]. In the urine of adult women, fumarate, succinate, 2-hydroxy-glutarate, malate, Hippurate, and citrate are higher [14,[22][23][24], whereas alpha-ketoglutarate, stearate, and 4-hydroxy-butyrate are higher in healthy men [14].…”

“…For example, creatinine increases with age, while creatine, glycine, citrate, succinate, and acetone show a negative correlation with age in 12 year old children [18], while lactate, citrate succinate, N-acetylglutamic acid, dimethylamine, glutamine, 1-methylnicotinamide decrease with age in children from 6 months to 4 years of age [17]. Urine adult metabolome seems to be influenced also by sex [14,[19][20][21]. In the urine of adult women, fumarate, succinate, 2-hydroxy-glutarate, malate, Hippurate, and citrate are higher [14,[22][23][24], whereas alpha-ketoglutarate, stearate, and 4-hydroxy-butyrate are higher in healthy men [14].…”

“…For example, changes in fumarate and malate urinary concentrations are associated with mitochondrial diseases [6]. Among endogenous factors, age and sex seem to have the strongest impact [7][8][9][10][11][12][13][14][15].…”

Circulating Pro- and Anti-Inflammatory Metabolites and Its Potential Role in Rheumatoid Arthritis Pathogenesis

“…In addition, Fan et al found that 2-hydroxyglutaric acid, α-ketoglutarate, and 2-oxyglutaric acid were higher in women. However, UDP-glucoronic acid was higher in men, suggesting that this could be linked to sex hormones [84]. Another study showed differences between sex and metabolic profile in serum, suggesting that glycine, serine, and sphingomyelines are upregulated in women, and ornithine, arginine, acyl carnitines, and amino acids derived from glutamine pathway are elevated in males [85].…”