Thomas, Melinda

Abstract Background: Frailty is characterized by an increased vulnerability and a decline in physiological reserve. Frailty has been previously linked to cortisol concentrations and blunted diurnal cortisol secretion. Our objective was to determine the association of urine steroid metabolome and its diurnal variation with frailty and prefrailty in older adults. Methods: Cross-sectional study of community-dwelling adults ≥ 50 years. Participants with adrenal disorders, end-stage renal or liver disease, on exogenous steroids or drugs affecting steroid metabolism were excluded. All participants completed day and night separate urine collection. Frailty was assessed using a phenotype model (weight loss, exhaustion, grip strength, low physical activity, and slow walking pace). Participants were characterized as frail if they met at least three criteria, pre-frail if they fulfilled one or two criteria, and robust if no criteria were met. Urine samples were analyzed with the liquid-chromatography, high-resolution, accurate-mass mass spectrometry for 25 urine steroid metabolites. Results: Of 119 participants, 60 (50.4%) were women, without sex differences in age or education status. On frailty assessment, 5 (4.2%) participants were frail and 33 (27.7%) were prefrail, with equal sex distribution. Urine steroid metabolome analysis demonstrated 21/25 steroids were higher in men vs women. In an age adjusted model, presence of prefrailty or frailty was associated with a higher ratio of total cortisol metabolites/total androgen metabolites (TCM/TAM) in men (estimate 0.64, P-value= 0.0004), but not in women. In men, after adjusting for age, among cortisol metabolites, lower day to night ratio of 5α-Tetrahydrocortisol (estimate -0.36, P-value= 0.0419) and β-Cortol (estimate -0.35, P-value= 0.0238) were associated with frail or prefrail phenotype. After adjusting for age, higher ratio of TCM/TAM was associated lower gait speed in men (estimate -1.2, P-value= 0.046) and women (estimate -3.9, P-value= 0.012); and lower hand grip strength in men (estimate -0.04, P-value= 0.046) but not in women. Conclusion: We showed that a higher glucocorticoid to androgen ratio and a flattened circadian steroid variation were associated with presence of frail or prefrail phenotype in men. Further studies should examine the role of steroid metabolism and HPA axis impairment, and the associated sex differences, in the functional decline in aging population.

Abstract Background: Elevated urine cortisol (<1% of urinary steroid metabolome) was reported to predict future development of dementia. Our objective was to determine the association of urine steroid metabolome and its diurnal variation with cognitive function in men and women. Methods: Cross-sectional study of community-dwelling adults ≥ 50 years. Participants with adrenal disorders, end-stage renal or liver disease, on exogenous steroids or drugs affecting steroid metabolism were excluded. All participants completed day and night separate urine collection. A series of seven IPad-based tests using the National Institute of Health Toolbox Cognition Battery were administered to evaluate five key domains; performance was reported using fully corrected T-scores for age, sex, education, and race with a national normative mean of 50. T-scores were generated for the two summary measures: 1) fluid cognition (includes executive function, episodic memory, working memory, and processing speed), and 2) total composite (composite of fluid and language score). Urine samples were analyzed with the liquid-chromatography, high-resolution, accurate-mass mass spectrometry for 25 urine steroid metabolites. Results: Of 109 participants, 56 (51%) were women, and age and educational status were similar in men and women. On cognitive assessment, men and women had similar median composite cognition (T-score of 53 vs 54, p=0.74) and fluid cognition (T-score of 53 vs 51, p-value 0.96). Urine steroid metabolome analysis demonstrated 21/25 steroids were higher in men vs women. In both women and men, the ratio of total cortisol metabolites/total androgen metabolites (TCM/TAM) was associated with lower fluid cognition (women: ρ= -0.34, p=0.01, men: ρ= -0.43, p=0.001) and composite cognition (women: ρ= -0.27, p=0.04, men: ρ= -0.39, p=0.004). Higher ratio of day to night TCM were associated with a better fluid cognition in men (ρ= 0.35, p=0.01), but not in women (ρ= -0.11, p=0.41). Steroid ratios suggesting a relative enzymatic deficiency of 5α-Reductase type 2 was associated with lower fluid cognition in women (ρ= -0.29, p=0.03). In men, the fluid composite score was associated with a relative deficiency in 21-Hydroxylase (ρ= 0.42, p=0.002), 3β-Hydroxysteroid dehydrogenase (ρ= 0.43, p=0.001), and P450oxidoreductase (ρ= -0.35, p=0.01). Conclusion: We showed that a higher glucocorticoid to androgen ratio and a flattened circadian steroid variation were associated with lower global and fluid cognition score. Steroid ratios reflecting steroidogenesis enzymatic activity demonstrated sex differences in relation to cognition. Additional studies should examine whether the steroid fingerprint associated with lower cognition is predictive of a future dementia onset.