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Background: Both lower and higher estradiol (E2) levels have been associated with increased mortality among women with kidney failure. However, robust data are still lacking. Objective: We investigated the interaction of diabetes and age on linear and nonlinear associations between E2 levels, adverse outcomes, and health-related quality of life (HRQOL) in Canadian women undergoing hemodialysis (HD). Design: Population-based cohort study; data from Canadian Kidney Disease Cohort Study (CKDCS). Setting & patients: A total of 427 women undergoing HD enrolled in the CKDCS. Measurements: Baseline E2 (in pmol/L) and E2 tertiles (<38 pmol/L, 38-95 pmol/L, >95 pmol/L). Methods: Cox-proportional hazards used for all-cause and cardiovascular disease (CVD) mortality. Fine-Gray models used for incident CVD. Mixed models used for Health Utilities Index Mark 3 (HUI3), Kidney Disease Quality of Life Physical Component Scores (KDQOL12-PCS), and Mental Component Scores (KDQOL12-MCS). Results: Over a median follow-up of 3.6 (interquartile range [IQR]: 1.6-7.5) years, 250 (58.6%) participants died; 74 deaths (29.6%) were CV-related. Among 234 participants without prior CV events, 80 (34.2%) had an incident CVD event. There were no significant linear associations between E2 and all-cause mortality, CVD mortality, and incident CVD. However, E2 showed a significant concave association with all-cause mortality, but not with CVD mortality and incident CVD. Among patients aged ≥63 years, higher E2 levels were associated with lower HUI3 scores, mean difference (MD) = -0.062 per 1 - SD pmol/L, 95% confidence interval (CI) = -0.112 to -0.012, but the opposite was observed in younger patients (<63 years) in whom higher E2 levels were associated with higher HUI3 scores (MD = 0.032 per 1 - SD pmol/L, 95% CI = 0.008-0.055), Pinteraction = .045. No associations were observed among E2, KDQOL12-PCS (MD = -0.15 per 1 - SD pmol/L, 95% CI = -1.15 to 0.86), and KDQOL12-MCS (MD = -0.63 per 1 - SD pmol/L, 95% CI = -1.82 to 0.57). Limitations: Unmeasured confounding and small sample size. Conclusions: The association between E2 and all-cause mortality may be nonlinear, while no association was observed for CVD mortality, incident CVD, KDQOL12-PCS, and KDQOL12-MCS. Furthermore, the association between serum E2 and HUI3 was modified by age: Higher levels were associated with higher utility among women aged <63 years and the converse observed among older women.
Contexte: Les taux faibles comme les taux élevés d'estradiol (E2) ont été associés à une mortalité accrue chez les femmes souffrant d'insuffisance rénale. Les données fiables à ce sujet font cependant encore défaut. Objectif: Nous avons étudié l'incidence du diabète et de l'âge sur les associations linéaires et non linéaires entre les niveaux d'E2, les issues défavorables et la qualité de vie liée à la santé (QVLS) chez les Canadiennes suivant des traitements d'hémodialyse (HD). Conception: Étude de cohorte en population réalisée à partir des données de la Canadian Kidney Disease Cohort Study (CKDCS). Sujets et cadre de l'étude: 427 femmes sous HD inscrites à la CKDCS. Mesures: Le taux d'E2 initial (pmol/L) et les taux d'E2 tertiles (<38 pmol/L; 38-95 pmol/L; >95 pmol/L). Méthodologie: Des modèles à risques proportionnels de Cox ont été utilisés pour mesurer la mortalité toutes causes confondues et la mortalité liée aux maladies cardiovasculaires (MCV). Des modèles Fine-Gray ont été utilisés pour mesurer les MCV incidentes; et des modèles mixtes ont été utilisés pour calculer l'indice Health Utilities Index Mark 3 (HUI3) et les scores des composantes physique (KDQOL12-PCS [Physical Component Score]) et mentale (KDQOL12-MCS [Mental Component Score])) du questionnaire sur la qualité de vie (KDQOL). Résultats: Au cours d'un suivi médian de 3,6 ans (intervalle interquartile [IIQ]: 1,6 à 7,5 ans), 250 participantes (58,6 %) sont décédées; 74 décès (29,6 %) étaient liés à un événement CV. Parmi les 234 participantes sans événements cardiovasculaires antérieurs, 80 (34,2 %) ont vécu un événement incident de MCV. Aucune association linéaire significative n'a été observée entre le taux d'E2 et la mortalité toutes causes confondues, la mortalité par MCV ou les MCV incidentes. Le taux d'E2 a cependant montré une association concave significative avec la mortalité toutes causes confondues, mais pas avec la mortalité par MCV ni avec les MCV incidentes. Chez les patientes âgées de 63 ans et plus, des taux élevés d'E2 ont été associés à des scores HUI3 plus faibles (différence moyenne [DM] = -0,062 par 1-SD pmol/L; intervalle de confiance à 95 % [IC95]: -0,112 à 0,012); alors qu'on a observé le contraire chez les patientes plus jeunes (< 63 ans), où des taux élevés d'E2 étaient plutôt associés à des scores plus élevés d'HUI3 (DM = 0,032 par 1-SD pmol/L; IC95: 0,008 à 0,055; p=0,045). Aucune association n'a été observée entre le taux d'E2, le KDQOL12-PCS (DM = -0,15 par 1-SD pmol/L; IC 95: -1,15 à 0,86) et le KDQOL12-MCS (DM = -0,63 par 1-SD pmol/L; IC95: -1,82 à 0,57). Limites: Facteurs de confusion non mesurés; échantillon de petite taille. Conclusion: Il pourrait exister une association non linéaire entre le taux d'E2 et la mortalité toutes causes confondues. Aucune association n'a toutefois été observée entre le taux d'E2 et la mortalité par MCV, les MCV incidentes, le KDQOL12-PCS et le KDQOL12-MCS. En outre, l'association entre le taux sérique d'E2 et l'HUI3 a été modifiée par l'âge: des taux plus élevés d'E2 ont été associés à un indice de santé plus élevé (HUI) chez les femmes âgées de moins de 63 ans, alors que l'inverse a été observé chez les femmes plus âgées.
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Introduction: The role of endogenous androgens in kidney function and disease has not been extensively explored in men and women. Research design and methods: We analyzed data from the observational KORA F4 study and its follow-up examination KORA FF4 (median follow-up time 6.5 years) including 1293 men and 650 peri- and postmenopausal women, not using exogenous sex hormones. We examined the associations between endogenous androgens (testosterone [T], dihydrotestosterone [DHT], free T [fT], free DHT [fDHT], and T/DHT), with estimated glomerular filtration rate (eGFR) at baseline and follow-up, prevalent, and incident chronic kidney disease (CKD) adjusting for common CKD risk factors. Results: At baseline, 73 men (5.7%) and 54 women (8.4%) had prevalent CKD. Cross-sectionally, no significant associations between androgens and kidney function were observed among men. In women, elevated T (ß=-1.305, [95% CI -2.290; -0.320]) and fT (ß=-1.423, [95% CI -2.449; -0.397]) were associated with lower eGFR. Prospectively, 81 men (8.8%) and 60 women (15.2%) developed incident CKD. In women, a reverse J-shaped associations was observed between DHT and incident CKD (Pnon-linear=0.029), while higher fDHT was associated with lower incident CKD risk (odds ratio per 1 standard deviation=0.613, [95% CI 0.369; 0.971]. Among men, T/DHT (ß=-0.819, [95% CI -1.413; -0.226]) and SHBG (Pnon-linear=0.011) were associated with eGFR at follow-up but not with incident CKD. Some associations appeared to be modified by type 2 diabetes (T2D). Conclusion: Suggestive associations are observed of androgens and SHBG with kidney impairment among men and women. However, larger well-phenotyped prospective studies are required to further elucidate the potential of androgens, SHBG, and T2D as modifiable risk factors for kidney function and CKD.
Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Renal Crônica , Masculino , Humanos , Feminino , Androgênios , Globulina de Ligação a Hormônio Sexual , Di-Hidrotestosterona , Insuficiência Renal Crônica/epidemiologia , RimRESUMO
INTRODUCTION: Relationships between endogenous female sex hormones and glycemic traits remain understudied, especially in men. We examined whether endogenous 17α-hydroxyprogesterone (17-OHP), progesterone, estradiol (E2), and free estradiol (fE2) were associated with glycemic traits and glycemic deterioration. RESEARCH DESIGN AND METHODS: 921 mainly middle-aged and elderly men and 390 perimenopausal/postmenopausal women from the German population-based Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort study were followed up for a median of 6.4 years. Sex hormones were measured at baseline using mass spectrometry. We calculated regression coefficients (ß) and ORs with 95% CIs using multivariable-adjusted linear and logistic regression models for Z-standardized hormones and glycemic traits or glycemic deterioration (ie, worsening of categorized glucose tolerance status), respectively. RESULTS: In the cross-sectional analysis (n=1222 men and n=594 women), in men, 17-OHP was inversely associated with 2h-glucose (2hG) (ß=-0.067, 95% CI -0.120 to -0.013) and fasting insulin (ß=-0.074, 95% CI -0.118 to -0.030), and positively associated with Quantitative Insulin Sensitivity Check Index (QUICKI) (ß=0.061, 95% CI 0.018 to 0.105). Progesterone was inversely associated with fasting insulin (ß=-0.047, 95% CI -0.088 to -0.006) and positively associated with QUICKI (ß=0.041, 95% CI 0.001 to 0.082). E2 was inversely associated with fasting insulin (ß=-0.068, 95% CI -0.116 to -0.020) and positively associated with QUICKI (ß=0.059, 95% CI 0.012 to 0.107). fE2 was positively associated with glycated hemoglobin (HbA1c) (ß=0.079, 95% CI 0.027 to 0.132). In women, 17-OHP was positively associated with fasting glucose (FG) (ß=0.068, 95% CI 0.014 to 0.123). fE2 was positively associated with FG (ß=0.080, 95% CI 0.020 to 0.141) and HbA1c (ß=0.121, 95% CI 0.062 to 0.180). In the sensitivity analyses restricted to postmenopausal women, we observed a positive association between 17-OHP and glycemic deterioration (OR=1.518, 95% CI 1.033 to 2.264). CONCLUSIONS: Inter-relations exist between female sex hormones and glucose-related traits among perimenopausal/postmenopausal women and insulin-related traits among men. Endogenous progestogens and estrogens appear to be involved in glucose homeostasis not only in women but in men as well. Further well-powered studies assessing causal associations between endogenous female sex hormones and glycemic traits are warranted.
