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Testosterone, sex hormone-binding globulin, insulin-like growth factor-1 and endometrial cancer risk: observational and Mendelian randomization analyses.
Mullee, A, Dimou, N, Allen, N, O'Mara, T, Gunter, MJ, Murphy, N
British journal of cancer. 2021;(9):1308-1317
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BACKGROUND Dysregulation of endocrine pathways related to steroid and growth hormones may modify endometrial cancer risk; however, prospective data on testosterone, sex hormone-binding globulin (SHBG) and insulin-like growth factor (IGF)-1 are limited. To elucidate the role of these hormones in endometrial cancer risk we conducted complementary observational and Mendelian randomization (MR) analyses. METHODS The observational analyses included 159,702 women (80% postmenopausal) enrolled in the UK Biobank. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. For MR analyses, genetic variants associated with hormone levels were identified and their association with endometrial cancer (12,906 cases/108,979 controls) was examined using two-sample MR. RESULTS In the observational analysis, higher circulating concentrations of total (HR per unit inverse normal scale = 1.38, 95% CI = 1.22-1.57) and free testosterone (HR per unit log scale = 2.07, 95% CI = 1.66-2.58) were associated with higher endometrial cancer risk. An inverse association was found for SHBG (HR per unit inverse normal scale = 0.76, 95% CI = 0.67-0.86). Results for testosterone and SHBG were supported by the MR analyses. No association was found between genetically predicted IGF-1 concentration and endometrial cancer risk. CONCLUSIONS Our results support probable causal associations between circulating concentrations of testosterone and SHBG with endometrial cancer risk.
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Quality of life in Klinefelter patients on testosterone replacement therapy compared to healthy controls: an observational study on the impact of psychological distress, personality traits, and coping strategies.
Fabrazzo, M, Accardo, G, Abbondandolo, I, Goglia, G, Esposito, D, Sampogna, G, Catapano, F, Giugliano, D, Pasquali, D
Journal of endocrinological investigation. 2021;(5):1053-1063
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PURPOSE We aimed to verify if 1 year-testosterone-replacement therapy could produce a psychopathological recovery and a satisfactory quality of life in Klinefelter syndrome (KS) patients compared to matched healthy controls. Further, we analyzed personality traits and coping strategies, an issue not yet examined in androgen-treated KS patients. We also enquired whether any of the sociodemographic and psychological variables might predict a patient's general and sexual life satisfaction. METHODS The Quality of Life Enjoyment and Satisfaction Questionnaire and the Temperament and Character Inventory-Revised were administered to both 23 KS patients and matched healthy subjects. Psychopathology was investigated by the Symptom Checklist-90-Revised (SCL-90-R) and the Mini-mental State Examination. The COPE Inventory was used to identify cognitive and behavioral strategies to manage disease-related distress. RESULTS In testosterone-treated KS patients, when compared with controls, SCL-90-R subscales analysis evidenced high psychological distress, mainly presented as obsessive thoughts, hanger-hostility, phobias, and psychoticism. Self-directedness and self-transcendence, along with the prevalent use of emotion-focused coping strategies, outlined the personality of our KS patients. Depression and somatization proved to be predictors of general life dissatisfaction. Depression, anger-hostility, and paranoid ideation, instead, emerged as predictors of sexual life dissatisfaction. CONCLUSION Endocrinologists should cooperate with mental health providers to foster a better outcome of the disease in KS patients.
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Neutral effect of exenatide on serum testosterone in men with type 2 diabetes mellitus: A prospective cohort.
Graybill, S, Hatfield, J, Kravchenko, M, Beckman, D, Tate, J, Beauvais, A, Clerc, P, Davila, D, Forbes, W, Wardian, J, et al
Andrology. 2021;(3):792-800
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BACKGROUND Endogenous testosterone increases with weight loss from diet, exercise, and bariatric surgery. However, little is known about testosterone levels after weight loss from medication. OBJECTIVES Uncover the effects of Glucagon-Like Peptide-1 receptor agonist (GLP-1 RA) therapy on serum testosterone. MATERIAL AND METHODS Prospective cohort study of men starting GLP-1 RA therapy for type 2 diabetes mellitus. RESULTS 51 men lost 2.27 kg (p = 0.00162) and their HbA1c values improved by 0.7% (p = 0.000503) after 6 months of GLP-1 RA therapy. There was no significant change in testosterone for the group as a whole. However, in subgroup analyses, there was a significant difference in total testosterone change between men starting with baseline total testosterone <320 ng/dL (238.5 ± 56.5 ng/dL to 272.2 ± 82.3 ng/dL) compared to higher values (438 ± 98.2 ng/dL to 412 ± 141.2 ng/dL) (p = 0.0172);free testosterone increased if the baseline total testosterone was <320 ng/dL (55.2 ± 12.8 pg/mL to 57.2 ± 17.6 pg/mL) and decreased if >320 ng/dL (74.7 ± 16.3 pg/mL to 64.2 ± 17.7 pg/mL) (p = 0.00807). Additionally, there were significant differences in testosterone change between men with HbA1c improvements ≥1% (351.6 ± 123.9 ng/dL to 394.4 ± 136.5 ng/dL) compared to men with HbA1c changes <1% (331.8 ± 128.6 ng/dL to 316.1 ± 126.2 ng/dL) (p = 0.0413). CONCLUSION GLP-1 RA therapy improves weight and HbA1c without adverse effects on testosterone. Those starting with lower testosterone values or attaining greater improvement in HbA1c may see additional benefits.
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Growth and adrenarche: findings from the CATS observational study.
Goddings, AL, Viner, RM, Mundy, L, Romaniuk, H, Molesworth, C, Carlin, JB, Allen, NB, Patton, GC
Archives of disease in childhood. 2021;(10):967-974
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BACKGROUND There is increasing evidence that patterns of pubertal maturation are associated with different patterns of health risk. This study aimed to explore the associations between anthropometric measures and salivary androgen concentrations in pre-adolescent children. METHODS We analysed a stratified random sample (N=1151) of pupils aged 8-9 years old from 43 primary schools in Melbourne, Australia from the Childhood to Adolescence Transition Study. Saliva samples were assayed for dehydroepiandrosterone (DHEA), DHEA-sulfate and testosterone. Anthropometric measures included height, weight, body mass index (BMI) and waist circumference. Associations between (1) anthropometric measures and each androgen, and (2) hormone status with obesity and parental report of pubertal development were investigated using linear regression modelling with general estimating equations. RESULTS Greater height, weight, BMI and waist circumference were positively associated with higher androgen concentrations, after adjusting for sex and socioeconomic status. Being overweight or obese was associated with higher testosterone and DHEA concentrations compared with the normal BMI category. Those who were obese were more likely (OR=2.7, 95% CI 1.61 to 4.43, p<0.001) to be in the top tertile of age-adjusted androgen status in both sexes. CONCLUSION This study provides clear evidence for an association between obesity and higher androgen levels in mid-childhood. The adrenal transition may be a critical time period for weight management intervention strategies in order to manage the risk for metabolic problems in later life for high-risk individuals.
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Circulating Levels of Testosterone, Sex Hormone Binding Globulin and Colorectal Cancer Risk: Observational and Mendelian Randomization Analyses.
Dimou, N, Mori, N, Harlid, S, Harbs, J, Martin, RM, Smith-Byrne, K, Papadimitriou, N, Bishop, DT, Casey, G, Colorado-Yohar, SM, et al
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2021;(7):1336-1348
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BACKGROUND Epidemiologic studies evaluating associations between sex steroid hormones and colorectal cancer risk have yielded inconsistent results. To elucidate the role of circulating levels of testosterone, and sex hormone-binding globulin (SHBG) in colorectal cancer risk, we conducted observational and Mendelian randomization (MR) analyses. METHODS The observational analyses included 333,530 participants enrolled in the UK Biobank with testosterone and SHBG measured. HRs and 95% confidence intervals (CI) were estimated using multivariable Cox proportional hazards models. For MR analyses, genetic variants robustly associated with hormone levels were identified and their association with colorectal cancer (42,866 cases/42,752 controls) was examined using two-sample MR. RESULTS In the observational analysis, there was little evidence that circulating levels of total testosterone were associated with colorectal cancer risk; the MR analyses showed a greater risk for women (OR per 1-SD = 1.09; 95% CI, 1.01-1.17), although pleiotropy may have biased this result. Higher SHBG concentrations were associated with greater colorectal cancer risk for women (HR per 1-SD = 1.16; 95% CI, 1.05-1.29), but was unsupported by the MR analysis. There was little evidence of associations between free testosterone and colorectal cancer in observational and MR analyses. CONCLUSIONS Circulating concentrations of sex hormones are unlikely to be causally associated with colorectal cancer. Additional experimental studies are required to better understand the possible role of androgens in colorectal cancer development. IMPACT Our results from large-scale analyses provide little evidence for sex hormone pathways playing a causal role in colorectal cancer development.See related commentary by Hang and Shen, p. 1302.
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Associations of SRD5A1 gene variants and testosterone with dysglycemia: Henan Rural Cohort study.
Liu, X, Wei, D, Jiang, J, Liu, X, Tu, R, Luo, Z, Wang, Y, Dong, X, Qiao, D, Shen, F, et al
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2020;(4):599-607
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BACKGROUND AND AIM Multiple studies support a complex relationship between testosterone and type 2 diabetes mellitus (T2DM) and the transformation of testosterone is affected by several reductases. Thus, we aimed to explore the associations of steroid-5α-reductase type 1 (SRD5A1) gene polymorphism with impaired fasting glucose (IFG) and T2DM and the interactive effects of testosterone and genotypes on glycometabolism. METHODS AND RESULTS A case-control study including 2365 participants was performed. Genomic DNA was extracted from the whole blood and genotyped for the SRD5A1 single nucleotide polymorphisms (SNP) rs1691053. Multivariable logistic regression and linear regression were performed to estimate the associations of SRD5A1 rs1691053 alleles and genotypes with glycometabolism. Generalized linear models were used to investigate the modulatory effects of serum testosterone on glycometabolism indexes in males. After multivariable adjustment, the odds ratio (OR) of homozygous CC genotypes in male carriers was 2.62 (95%CI: 1.11-6.18) for IFG. Furthermore, significant associations of SRD5A1 rs1691053 polymorphisms with adverse indices of glycometabolism were observed in males. Interestingly, the opposite associations in females were observed. The interactive associations of SNP and testosterone were found and mutations were more likely to lead unfavorable metabolic phenotypes. CONCLUSION These results showed that SRD5A1 rs1691053 gene polymorphism was independently associated with glycometabolism. The interaction between a genetic polymorphism from SRD5A1 and testosterone involved glycometabolism was identified in males. Although this preliminary data should be replicated with other rigorous researches, it highlighted the importance of the SNP-testosterone interaction over the present of glycometabolism.
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The effects of age and obesity on postprandial dynamics of serum testosterone levels in men.
Van de Velde, F, Reyns, T, Toye, K, Fiers, T, Kaufman, JM, T'Sjoen, G, Lapauw, B
Clinical endocrinology. 2020;(3):214-221
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OBJECTIVE Guidelines recommend using fasting samples to evaluate testosterone (T) levels in men, as free and total T levels decrease postprandially. However, it is not clear whether these dynamics are affected by age or obesity. This could be relevant given the obesity epidemic, ageing population and the barrier for screening which fasting could impose. DESIGN/PARTICIPANTS A total of 43 men underwent a solid mixed meal tolerance test. Serum samples were taken fasting, and at 30, 60 and 120 minutes postprandially. A commercial immunoassay was used to determine sex hormone-binding globulin (SHBG) levels, liquid chromatography coupled to tandem mass spectroscopy for total T concentrations and free T levels were calculated. RESULTS Postprandially, both total and free T were lower at all-time points compared with fasting (all, P < .005). At 60 minutes, maximum mean decreases of 15 ± 15% and 17 ± 16% were seen for total and free T levels, respectively. Younger men had greater decreases in both total and free T levels compared with men older than 40 years (all, P < .05). A greater decrease at 30 and 60 minutes postprandially was observed for both total and free T levels in nonobese vs obese men (all, P < .05). CONCLUSIONS After a mixed meal, total and free T serum levels decreased whereas SHBG levels did not change. Interestingly, postprandial decreases were less pronounced in men older than 40 years and/or with obesity. Although this study indicates less pronounced decreases in certain men, fasting samples remain a prerequisite for establishing correct diagnosis of male hypogonadism.
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Clinical association of metabolic syndrome, C-reactive protein and testosterone levels with clinically significant prostate cancer.
Gómez-Gómez, E, Carrasco-Valiente, J, Campos-Hernández, JP, Blanca-Pedregosa, AM, Jiménez-Vacas, JM, Ruiz-García, J, Valero-Rosa, J, Luque, RM, Requena-Tapia, MJ
Journal of cellular and molecular medicine. 2019;(2):934-942
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Recently, the influence that metabolic syndrome (MetS), hormonal alterations and inflammation might have on prostate cancer (PCa) risk has been a subject of controversial debate. Herein, we aimed to investigate the association between MetS-components, C-reactive protein (CRP) and testosterone levels, and the risk of clinically significant PCa (Sig-PCa) at the time of prostate biopsy. For that, men scheduled for transrectal ultrasound guided biopsy of the prostate were studied. Clinical, laboratory parameters and criteria for MetS characterization just before the biopsy were collected. A total of 524 patients were analysed, being 195 (37.2%) subsequently diagnosed with PCa and 240 (45.8%) meet the diagnostic criteria for MetS. Among patients with PCa, MetS-diagnosis was present in 94 (48.2%). Remarkably, a higher risk of Sig-PCa was associated to MetS, greater number of MetS-components and higher CRP levels (odds-ratio: 1.83, 1.30 and 2.00, respectively; P < 0.05). Moreover, higher circulating CRP levels were also associated with a more aggressive Gleason score in PCa patients. Altogether, our data reveal a clear association between the presence of MetS, a greater number of MetS-components or CRP levels >2.5 mg/L with an increased Sig-PCa diagnosis and/or with aggressive features, suggesting that MetS and/or CRP levels might influence PCa pathophysiology.
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Monitoring Blood Biomarkers and Training Load Throughout a Collegiate Soccer Season.
Huggins, RA, Fortunati, AR, Curtis, RM, Looney, DP, West, CA, Lee, EC, Fragala, MS, Hall, ML, Casa, DJ
Journal of strength and conditioning research. 2019;(11):3065-3077
Abstract
Huggins, RA, Fortunati, AR, Curtis, RM, Looney, DP, West, CA, Lee, EC, Fragala, MS, Hall, ML, and Casa, DJ. Monitoring blood biomarkers and training load throughout a collegiate soccer season. J Strength Cond Res 33(11): 3065-3077, 2019-This observational study aimed to characterize the responses of a comprehensive panel of biomarkers, observed ranges, training load (TL) metrics, and performance throughout the collegiate soccer season (August-November). Biomarkers (n = 92) were collected before the start of pre-season (PS), in-season weeks (W)1, W4, W8, and W12 in NCAA Division I male soccer players (n = 20, mean ± SD; age = 21 ± 1 years, height = 180 ± 6 cm, body mass = 78.19 ± 6.3 kg, body fat = 12.0 ± 2.6%, VO2max 51.5 ± 5.1 ml·kg·min). Fitness tests were measured at PS, and W12 and TL was monitored daily. Changes in biomarkers and performance were calculated via separate repeated-measures analysis of variance. Despite similar fitness (p > 0.05), endocrine, muscle, inflammatory, and immune markers changed over time (p < 0.05). Total and free testosterone was lower in W1 vs. PS, whereas free cortisol remained unchanged at PS, W1, and W4 (>0.94 mg·dL). Oxygen transport and iron metabolism markers remained unchanged except for HCT (W1 vs. PS) and total iron binding capacity (W8-W12 vs. W1). Hepatic markers albumin, globulin, albumin:globulin, and total protein levels were elevated (p < 0.05) at W12 vs. W1, whereas aspartate aminotransferase and alanine aminotransferase levels were elevated at W1-W12 and W8-W12 vs. PS, respectively. Vitamin E, zinc, selenium, and calcium levels were elevated (p < 0.05) at W12 vs. W1, whereas Vitamin D was decreased (p < 0.05). Fatty acids and cardiovascular markers (omega-3 index, cholesterol:high-density lipoprotein [HDL], docosahexenoic acid, low-density lipoprotein [LDL], direct LDL, non-HDL, ApoB) were reduced at W1 vs. PS (p ≤ 0.05). Immune, lipid, and muscle damage biomarkers were frequently outside clinical reference ranges. Routine biomarker monitoring revealed subclinical and clinical changes, suggesting soccer-specific reference ranges. Biomarker monitoring may augment positive adaptation and reduce injuries from stressors incurred during soccer.
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Elevated luteinizing hormone despite normal testosterone levels in older men-natural history, risk factors and clinical features.
Eendebak, RJAH, Ahern, T, Swiecicka, A, Pye, SR, O'Neill, TW, Bartfai, G, Casanueva, FF, Maggi, M, Forti, G, Giwercman, A, et al
Clinical endocrinology. 2018;(3):479-490
Abstract
OBJECTIVE Elevated luteinizing hormone (LH) with normal testosterone (T) suggests compensated dysregulation of the gonadal axis. We describe the natural history, risk factors and clinical parameters associated with the development of high LH (HLH, LH >9.4 U/L) in ageing men with normal T (T ≥ 10.5 nmol/L). DESIGN, PATIENTS AND MEASUREMENTS We conducted a 4.3-year prospective observational study of 3369 community-dwelling European men aged 40-79 years. Participants were classified as follows: incident (i) HLH (n = 101, 5.2%); persistent (p) HLH (n = 128, 6.6%); reverted (r) HLH (n = 46, 2.4%); or persistent normal LH (pNLH, n = 1667, 85.8%). Potential predictors and changes in clinical features associated with iHLH and rHLH were analysed using regression models. RESULTS Age >70 years (OR = 4.12 [2.07-8.20]), diabetes (OR = 2.86 [1.42-5.77]), chronic pain (OR = 2.53 [1.34-4.77]), predegree education (OR = 1.79 [1.01-3.20]) and low physical activity (PASE ≤ 78, OR = 2.37 [1.24-4.50]) predicted development of HLH. Younger age (40-49 years, OR = 8.14 [1.35-49.13]) and nonsmoking (OR = 5.39 [1.48-19.65]) predicted recovery from HLH. Men with iHLH developed erectile dysfunction, poor health, cardiovascular disease (CVD) and cancer more frequently than pNLH men. In pHLH men, comorbidities, including CVD, developed more frequently, and cognitive and physical function deteriorated more, than in pNLH men. Men with HLH developed primary hypogonadism more frequently (OR = 15.97 [5.85-43.60]) than NLH men. Men with rHLH experienced a small rise in BMI. CONCLUSIONS Elevation of LH with normal T is predicted by multiple factors, reverts frequently and is not associated with unequivocal evidence of androgen deficiency. High LH is a biomarker for deteriorating health in aged men who tend to develop primary hypogonadism.