Sex and gender disparities in the epidemiology and outcomes of chronic kidney disease. After reading the full texts, ten additional reports were excluded, leaving ten reports that met the eligibility criteria and were included in the systematic review. Low testosterone was associated with an increased risk of all-cause mortality and CV events (pooled HR: 1.98, 95% CI: 1.36;2.89; pooled HR of 2.40, 95% CI: 1.22;4.71, respectively). An official website of the United States government. J Transl Med. Furthermore, in male rats that were exposed to renal ischemia, testosterone infusion attenuated the rise in plasma creatinine, urinary kidney injury molecule-1, and kidney inflammation, and prevented a reduction in outer medullary blood flow (13). Testosterone 1% gel 2.5 - 10 g/day; Testosterone patch 2.5 - 7.5 mg/day i.m., intramuscular. doi: 10.1161/CIRCEP.122.011466. As the association between serum testosterone and kidney function in the general population was investigated in only one study (26), results should be interpreted with caution and further studies are needed to replicate the results. Estrogen, progesterone and testosterone are the most commonly used bioidentical hormones. Cystatin C versus creatinine in determining risk based on kidney function. Kyriazis J, Tzanakis I, Stylianou K, Katsipi I, Moisiadis D, Papadaki A, Mavroeidi V, Kagia S, Karkavitsas N, Daphnis E. Low serum testosterone, arterial stiffness and mortality in male haemodialysis patients. Genetically predicted bioavailable testosterone in men and women, as well as genetically predicted total testosterone in women, showed the associations expected from meta-analysis of RCTs [19], i.e., a positive association with hemoglobin and inverse association with HDL-cholesterol (Table3), whist total testosterone in men was related to higher HDL-cholesterol in univariable MR but was as expected, related to lower HDL-cholesterol, in multivariable MR controlling for SHBG (Additionalfile1: Table S5). Metcalfe PD, Leslie JA, Campbell MT, Meldrum DR, Hile KL, Meldrum KK. 2018;25:22430. doi: 10.1016/S0140-6736(13)60687-X. Our finding may be relevant to the sex disparity in CKD and kidney function, consistent with the sex-specific role of testosterone in CVD [40], and with expectations from evolutionary biology [4,5,6]. A socio-biological explanation for social disparities in non-communicable chronic diseases: the product of history? First, the association with CKD needs to be replicated in a larger sample with more power. The current evidence on the association of serum testosterone with kidney function in the general population and with clinical outcomes in patients with CKD was compiled in this systematic review and meta-analysis. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. The authors of a 2021 study noted that males with high levels of dihydrotestosterone (DHT) a substance that works with testosterone may have a higher chance of acne and hair loss. As such, the effect on CKD and kidney function might not be comparable to the acute renal effect of testosterone supplementation, although the use of testosterone gel lowers eGFR in RCT [14]. Horm Behav. -, Couser WG, Remuzzi G, Mendis S, Tonelli M. The contribution of chronic kidney disease to the global burden of major noncommunicable diseases. Schooling CM, Leung GM. In the UK Biobank, genotyping was assessed using two very similar arrays, i.e., the UK BiLEVE array and UK Biobank Axiom array. At an approximate R2 of 0.056 in men and of 0.085 in women, the UK Biobank has 0.8 power to detect an odds ratio (OR) of about 1.17 for CKD and 1.14 for albuminuria per one standard deviation increase in testosterone in men and an OR of about 1.14 for CKD and 1.12 for albuminuria in women [37], as well as an effect size of about 0.03 standard deviations for eGFR in men and of 0.02 in women [35]. Quality assessment of the identified studies was performed by two reviewers independently using the NewcastleOttawa Scale (NOS) (24) for cohort and casecontrol studies, with a score ranging between 0 and 9, or the Cochrane risk of bias tool (25) for RCTs, where the overall risk of bias was scored as low, moderate, or high risk of bias. The tour begins on Aug. 3 in Sterling . Accessibility Lanktree MB, Theriault S, Walsh M, Pare G. HDL cholesterol, LDL cholesterol, and triglycerides as risk factors for CKD: a Mendelian randomization study. Moreover, this study only included eGFR based on serum creatinine as an assessment of kidney function, which might not be the most optimal assessment of kidney function to investigate the association of interest because of the potential mediating role of muscle mass. Accessibility We dropped palindromic SNPs if the minor allele frequency was close to 0.50, such as 0.48 to 0.52, which are difficult to align unequivocally. JVZ designed the study. Correspondence should be addressed to L Chaker: Received 2022 Apr 29; Accepted 2022 May 12. Please enable it to take advantage of the complete set of features! 2018;362:k601. Un programa que dej de tener gracia cuando se. Kurita N, Horie S, Yamazaki S, Otani K, Sekiguchi M, Onishi Y, Takegami M, Ono R, Konno S, Kikuchi S, et al. If you take sildenafil for pulmonary arterial hypertension, do not take Viagra or other PDE5 inhibitors, including tadalafil (Cialis) or vardenafil (Levitra). Of these SNPs, 6 SNPs in men and 2 SNPs in women were not available in the summary statistics from Neale Lab (http://www.nealelab.is/uk-biobank/), nor were their proxies, so 119 SNPs in men and 252 SNPs in women were used for hemoglobin and HDL-cholesterol, whereas all SNPs were used for CKD and kidney function. However,. To satisfy the assumption of independence, we checked for their association with potential confounders, including Townsend index, smoking, alcohol drinking, and physical activity in the UK Biobank summary statistics. 2018;210:70. In multivariable MR, we used MR Egger to detect whether the genetic predictors were acting other than via testosterone or SHBG (directional pleiotropy) indicated by a non-zero intercept [39], in which case we used multivariable MR Egger estimates in the main analysis. Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. From the perspective of evolutionary biology, growth and reproduction trade off against longevity, with men and women having different investments in these trade-offs and as a result have different vulnerabilities to disease [4,5,6]. Stat Med. 3). Evolution, human-microbe interactions, and life history plasticity. J Am Med Dir Assoc. 2019;17:62. 2020. https://www.biorxiv.org/content/10.1101/716621v3.full.pdf. In addition, these studies have never been systematically analyzed, which could result in increased power to investigate the associations of interest. eCollection 2022. This limited our possibilities to perform meta-analyses on all associations of interest and to perform stratification analyses. Low testosterone was reported to be associated with an increased risk of incident CKD when compared to normal testosterone (HR: 1.38, 95% CI: 1.05;1.80, Table 2). Your testosterone levels may be higher or lower based on your age, sex, medications you take, and other . Curr Opin Endocrinol Diabetes Obes. 2008;27:113363. 2010;95:256075. An official website of the United States government. Similarly, no signs of publication bias for the association between categorized serum testosterone and CV events were shown (Supplementary Fig. Nat Genet. Hak AE, Witteman JC, de Jong FH, Geerlings MI, Hofman A, Pols HA. Am J Epidemiol. The main strength of our study is that we performed an extensive literature search in multiple electronic databases with a limited amount of restrictions in order to provide an up-to-date and complete overview of the available literature on the association between serum testosterone and kidney function and on the association between serum testosterone and clinical outcomes in patients with CKD. The genetic instruments were obtained from the largest, sex-specific genome-wide association study (GWAS) conducted in the UK Biobank (178,782 white British men and 230,454 white British women) and replicated in three independent studies (CHARGE Consortium, Twins UK, and EPIC-Norfolk) [21]. -, Schooling CM. Neugarten J, Golestaneh L. Influence of sex on the progression of chronic kidney disease. Statistical heterogeneity was assessed by using the I2 statistic where I2 values of 25% indicate low, 2550% moderate, and 50% high heterogeneity. 2014;64:36774. Key takeaways: A high creatinine level on a blood test can be a sign of decreased kidney function or kidney disease. Two studies showed an increased risk of all-cause mortality with decreased dehydroepiandrosterone sulfate (DHEAS) in men with CKD; results regarding CV events were conflicting. Kidney Int. 1. To control for the bias arising from competing risk, we adjusted for common causes of CKD and CVD [29], specifically BMI, smoking, and blood pressure. Chronic kidney disease and hypothalamic-pituitary axis dysfunction: the chicken or the egg? Two studies showed an increased risk of all-cause mortality with decreased dehydroepiandrosterone sulfate (DHEAS) in men with CKD; results regarding CV events were conflicting. The other nine studies investigated the association of testosterone status with clinical outcomes in men with moderate or severe CKD (stage G3G5), although one of them included men with mild CKD as well (stage G1G2) (27). PubMedGoogle Scholar. Whether you need to or should, depends. Correspondingly, castration in males increases renal clearance [11], lowers proteinuria, and protects against glomerular injury assessed from renal morphology [11, 12]. Carrero JJ, Barany P, Yilmaz MI, Qureshi AR, Sonmez A, Heimburger O, Ozgurtas T, Yenicesu M, Lindholm B, Stenvinkel P. Testosterone deficiency is a cause of anaemia and reduced responsiveness to erythropoiesis-stimulating agents in men with chronic kidney disease. or uncontrolled high blood pressure (hypertension) Have severe liver disease; Have kidney disease that requires dialysis; Side effects. Acta Clin Belg. Int J Epidemiol. 2012;77:75563. It would be valuable to assess the role of testosterone in CKD progression, specifically the relevance to decline in kidney function, when sufficient follow-up data in the UK Biobank and suitable analytic techniques are available [52]. Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects. MC_PC_17228/MRC_/Medical Research Council/United Kingdom, MC_QA137853/MRC_/Medical Research Council/United Kingdom, NCI CPTC Antibody Characterization Program, Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, et al. Meuwese CL, Carrero JJ. The sex-specific associations of each SNP with hemoglobin and HDL-cholesterol were obtained from the UK Biobank summary statistics provided by Neale Lab (http://www.nealelab.is/uk-biobank/), using linear regression adjusted for age, age2, and 20 principal components in the UK Biobank. 2013;57:2478. doi: 10.1002/14651858.CD007784.pub2. If MR-PRESSO identified outlier(s), we used the corrected estimates from MR-PRESSO instead of IVW in the main analysis. Given it is a two-sample MR, we also checked for palindromic SNPs (i.e., SNPs with alleles (A/T and C/G) that pair with each other) and aligned on effect allele frequency. Careers. 2019 Dec;105(6):582-588. doi: 10.1007/s00223-019-00606-0. Specifically, the variance explained by each SNP was calculated using beta22minor allele frequency (MAF)(1MAF), where beta is the standardized beta coefficient for the effect allele and MAF is the minor allele frequency [36]. Whether the well-established sex-specific evolutionary biology trade-off between reproduction and longevity might inform CKD has not previously been considered. 1). ED may also cause emotional problems, such as low self-esteem, anxiety, or depression. Our results suggest that low serum testosterone is detrimental for kidney function. J Epidemiol Community Health. The .gov means its official. Curr Opin Endocrinol Diabetes Obes. All studies adjusted for a different set of covariates are displayed in Table 2. National Library of Medicine We also used multivariable MR to control for sex hormone binding globulin (SHBG). Publication bias was assessed visually by using funnel plots and statistically by using an Egger test. Increased levels of log-transformed serum testosterone were associated with a statistically non-significant decreased risk of incident CKD (HR: 0.82, 95% CI: 0.61;1.10, Table 2). Npoje s vysokm obsahom antioxidantov, ako s vitamny C a E, preukzatene zlepuj erektiln funkciu tm, e brnia pokodeniu buniek, produkujcich oxid dusnat," hovor Pearlmanov. Yuki A, Otsuka R, Kozakai R, Kitamura I, Okura T, Ando F, Shimokata H. Relationship between low free testosterone levels and loss of muscle mass. 1998;36:85966. Kidney stones Anyone can get a kidney stone, but men are more likely to get kidney stones than women. The weighted median estimate is robust to invalid instruments and able to provide consistent estimation even when up to 50% of the weight is from invalid SNPs [33]. An official website of the United States government. We used the previously published 125 genome-wide significant SNPs for bioavailable testosterone in men and 254 SNPs for total testosterone in women. 2021 Mar;32(3):686-694. doi: 10.1681/ASN.2020050659. The .gov means its official. A clinical case report showed testosterone therapy induced renal impairment [13]. Federal government websites often end in .gov or .mil. Additionally, we investigated the association of testosterone, its precursors, its active metabolites, and its supplementation with clinical outcomes in patients with CKD. BMC Med. No original data were collected for the MR study. *Unless specified otherwise; **Pattern of results of tertiles similar to categorized testosterone; #Low T had impact on mortality risk, although weak. Chronic kidney disease compendium. Article Genome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium. Hazard ratios with 95% CIs are delineated by squares with horizontal lines; pooled hazard ratios are delineated by diamonds. Neither the visual assessment of the funnel plots (Supplementary Fig. Clin Sci (Lond). Epub 2023 Jan 3. The corresponding author was contacted to request an investigation of the association using non-transformed serum testosterone, but responded that this was not possible due to the non-normal distribution of serum testosterone. PubMed Chronic kidney disease (CKD) has an apparent sex disparity, with a more rapid progress in men than in women. Ferrucci L, Maggio M, Bandinelli S, Basaria S, Lauretani F, Ble A, Valenti G, Ershler WB, Guralnik JM, Longo DL. Conclusions: Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. Serum testosterone could exert positive effects on the kidney by causing vasodilatation in the renal vascular bed (12). In contrast, some observational studies have found higher testosterone associated with lower mortality in CKD patients [15] and higher eGFR [16]. Kawano H, Yasue H, Kitagawa A, Hirai N, Yoshida T, Soejima H, Miyamoto S, Nakano M, Ogawa H. Dehydroepiandrosterone supplementation improves endothelial function and insulin sensitivity in men. Your US state privacy rights, Altman R, Motton DD, Kota RS, Rutledge JC. 2C1). An explanation for this discrepancy in findings might be found within the use of serum total testosterone vs serum bioavailable testosterone. Revision of sex hormone replacement therapy for CKD Pediatric cases. Canela-Xandri O, Rawlik K, Tenesa A. J Epidemiol Community Health. We obtained the Wald estimate for each SNP and then meta-analyzed them using inverse variance weighting (IVW) with multiplicative random effects. Epub 2020 Dec 14. As such, multivariable MR controlling for SHBG may have the greatest validity for these instruments, but for comprehensiveness, we also presented results of univariable MR for comparison. The associations were robust to different methods (Additionalfile1: Table S2) and to excluding SNPs related to alcohol drinking (Additionalfile1: Table S3). In the other two studies, serum testosterone was categorized into low and normal serum testosterone, with cut-offs of 8.1 (30) and 8.0 nmol/L (33). Li L, Tang W, Yi F. Role of inflammasome in chronic kidney disease. The study aimed to compare the kinetics of two novel combination drug products for Female Sexual Interest/Arousal Disorder (FSIAD). Furthermore, similar results were reported in this study on the association between serum free testosterone and CV events (HR: 0.65, 95% CI: 0.530.80). Google Scholar. We selected independent SNPs (r2<0.01) predicting eGFR using the clumping function of MR-Base. Relevant evidence from randomized controlled trials (RCTs) is not available. Ask Dr Testosterone E 144 Genetically predicted eGFR was not related to serum testosterone in men or in women. Article PMC Keywords: Two studies categorized serum testosterone into three categories, i.e., low, borderline, and normal, although different cut-offs were used. PubMed Central doi: 10.1002/14651858.CD011998.pub2. Genetically predicted testosterone and cardiovascular risk factors in men: a Mendelian randomization analysis in the Guangzhou Biobank Cohort Study. Google Scholar. 2014;43:9229. PubMed Laaksonen DE, Niskanen L, Punnonen K, Nyyssonen K, Tuomainen TP, Valkonen VP, Salonen R, Salonen JT. Given the unclear causal role of alcohol in CKD, we kept these SNPs in the main analysis but excluded them in the sensitivity analysis. All three studies individually reported that low serum testosterone was associated with an increased risk of all-cause mortality when compared to the reference, and an overall pooled HR of 1.98 (95% CI: 1.362.89, Fig. In one (28) of the three studies that investigated the association between continuous serum testosterone and all-cause mortality, serum testosterone was log-transformed and increased levels of this log-transformed serum testosterone were associated with a decreased risk of all-cause mortality (HR: 0.58, 95% CI: 0.37;0.90, per 10 ng/dL, Table 2). PLoS Med. A catalog of genetic loci associated with kidney function from analyses of a million individuals. Careers, Unable to load your collection due to an error. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men, Journal of Clinical Endocrinology and Metabolism. Therefore, we performed a systematic review and meta-analysis. Nat Genet. 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