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Age-Dependent Relationships Between Disease Risk and Testosterone Levels: Relevance to COVID-19 Disease.
Muehlenbein, M, Gassen, J, Nowak, T, Henderson, A, Morris, B, Weaver, S, Baker, E
American journal of men's health. 2023;17(2):15579883221130195
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A growing body of research finds that in men, testosterone levels may be prognostic of clinical outcomes related to coronavirus disease 2019 (COVID-19 disease). The presence of pre-existing chronic conditions in many patients with COVID-19 disease further complicates the relationship among testosterone and severe outcomes. The aim of this study was to examine whether pre-existing conditions for severe COVID-19 disease were related to serum-free testosterone levels in men who had not been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. This study obtained data from men (n = 142) who participated in the longitudinal study Waco COVID Survey. All data included in the study was collected as part of the initial intake survey and first laboratory appointment. Results show that serum-free testosterone levels decreased as a function of age. In fact, greater burden of pre-existing conditions for severe COVID-19 disease was related to lower testosterone levels among men younger than 40 years of age. Furthermore, in men older than 40 years of age the decrease in testosterone that accompanies aging attenuated the effect of the clinical risk score on free testosterone levels. Authors conclude that their findings add important insights into the complex role of androgens in chronic and infectious diseases and contribute to the growing body of literature on the relationship between chronic disease and men’s testosterone levels.
Abstract
Testosterone levels in men appear to be prognostic of a number of disease outcomes, including severe COVID-19 disease. Testosterone levels naturally decline with age and are lower in individuals with a number of comorbidities and chronic conditions. Low testosterone may therefore be both a cause and a consequence of illness, including COVID-19 disease. The present project examines whether preexisting conditions for severe COVID-19 disease were themselves related to serum-free testosterone levels in men who had not been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. A clinical risk score for severe COVID-19 disease was computed based on the results of previously published meta-analyses and cohort studies, and relationships between this score and testosterone levels were tested in 142 men ages 19 to 82 years. Greater burden of preexisting conditions for severe COVID-19 disease was related to lower testosterone levels among men younger than 40 years of age. In older men, the decrease in testosterone that accompanies aging attenuated the effect of the clinical risk score on free testosterone levels. Given that older age itself is a predictor of COVID-19 disease severity, these results together suggest that the presence of preexisting conditions may confound the relationship between testosterone levels and COVID-19 disease outcomes in men. Future research examining relationships among testosterone and outcomes related to infectious and chronic diseases should consider potential confounds, such as the role of preexisting conditions.
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Lack of association between endocrine disrupting chemicals and male fertility: A systematic review and meta-analysis.
Martínez, MÁ, Marquès, M, Salas-Huetos, A, Babio, N, Domingo, JL, Salas-Salvadó, J
Environmental research. 2023;217:114942
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Exposure to natural or synthetic chemicals is directly related to environmental conditions, dietary and other lifestyle factors. Some of these chemicals are named endocrine disrupting chemicals (EDCs) because of their capability to interfere with the endocrine system. The aim of this study was to summarise and explore the association between exposure to EDCs and human male fertility indicators. This study is a systematic review and meta-analysis of seven studies; 4 assessed bisphenol A (BPA) in urine and sperm quality parameters, while 3 articles evaluated PCB153 [polychlorinated biphenyls] in serum and sperm quality parameters. Results show that there weren’t any positive or inverse associations between BPA or PCB153 and the sperm parameters analysed. Authors conclude that the systematic review showed a high disparity between studies, making difficult a consensus on the possible detrimental effect of the 12 groups of EDCs on male fertility. Thus, no conclusive statements can be drawn. Further studies are needed in order to provide more robust data.
Abstract
The incidence of infertility currently affects about 15% of the world's population. Male factors are estimated to be responsible for up to 40-50% of these cases. While the cause of these reproductive disorders is still unclear, the exposure to a family of ubiquitous compounds in our daily life, named endocrine disrupting chemicals (EDCs) could be involved. This paper was aimed at performing a systematic review and meta-analysis of population studies exploring whether human male exposure to EDCs affects male fertility. Clinical and observational studies assessing the exposure to EDCs along with sperm quality, the most common reproductive disorders, sperm DNA damage, sperm oxidative stress, fertilization rate, implantation rate, clinical pregnancy rate, live birth rate, and miscarriage rate were included. The quality assessment tool from the NHLBI-NIH was used to assure that studies met standardized quality criteria. Sensitivity analysis and heterogeneity among studies was assessed. Overall, the 32 selected articles, including 7825 individuals in the systematic review, explored 12 families of EDCs. The results revealed a high heterogeneity among studies in relation to the association between exposure to EDCs and the endpoints analyzed. Meta-analyses were performed with data from 7 articles including 479 individuals, 4 articles assessing the association between BPA in urine and sperm quality, and 3 articles evaluating PCB153 in serum and sperm quality. In the meta-analysis, we identified an unpredicted significant positive association between PCB153 exposure and sperm concentration. However, it would not be clinically relevant. No positive or inverse associations were found neither for BPA, nor for PCB153 and the rest of sperm parameters analyzed. The high disparity between studies made difficult to draw conclusions on the potential harmful effects of EDCs on male fertility. Consequently, to delineate the potential relationship that EDCs can have on male fertility, an important condition stressing the health system, further investigations are required.
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Systematic review and meta-analysis of candidate gene association studies of benign prostate hyperplasia.
Lin, L, Li, P, Liu, X, Xie, X, Liu, L, Singh, AK, Singh, HN
Systematic reviews. 2022;11(1):60
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Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of the prostate which can cause urinary dysfunction and may affect the quality of life of patients. Polymorphism in several genes has been linked to the high susceptibility of BPH. The aim of this study was to analyse genetic variations in important genes towards the susceptibility of BPH. This study is a systematic review and meta-analysis of twenty-three case-control studies (11 for CYP17 [gene], 10 for VDR - vitamin D receptor [a member of the steroid/ thyroid hormone receptor family] and 4 for ACE - angiotensin-converting enzyme [component of the renin–angiotensin system] polymorphisms). The sample size in each study ranged from 20 to 588 participants. Results show that genetic polymorphism in the ACE gene was significantly associated with the risk of BPH when compared with control subjects. Whereas there was a negative association for the polymorphism located in VDR and CYP17 genes with the risk of BPH. Authors conclude that larger studies with prospective data and larger sample sizes are required.
Abstract
BACKGROUND Benign prostate hyperplasia (BPH) is the most common urological problem in elderly males. Recent studies have reported polymorphism in various metabolic genes in BPH. However, their association with the susceptibility of BPH is still inconsistent. Here, we systematically reviewed and performed a meta-analysis of CYP17, VDR, and ACE genes to determine their precise association with the risk of BPH. METHODS A comprehensive literature search for published studies on candidate gene associations involving vitamin D receptor (VDR), angiotensin-converting enzyme (ACE), and CYP17 genes with the risk of BPH was done up to April 2020 in PubMed, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar databases. Fixed/random effects models were used to estimate the odd's ratio (OR) and 95% confidence intervals (CIs). Begg's funnel plot was used to assess the potential for publication bias. RESULTS We found a total of 23 studies containing 3461 cases and 3833 controls for these gene polymorphisms. A significant association of ACE gene polymorphism was observed under the recessive (II vs. ID + DD) model for BPH susceptibility compared to control subjects (overall OR = 1.67, 95% CI = 1.03-2.73). Similar trends were observed for ACE gene polymorphism in Caucasian (OR = 6.18, 95% CI = 1.38-27.68) and Asian (OR = 1.42, 95% CI = 0.99-2.03) populations under study. No significant association was observed in VDR and CYP17 gene polymorphisms in any dominant or recessive models. CONCLUSION Significant OR demonstrated the implication of ACE gene polymorphism in the proliferation of prostate tissue, which in turn is associated with BPH susceptibility. However, prospective studies at large scale and sample size are needed to confirm the current findings.
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The impact of diabetes mellitus type 1 on male fertility: Systematic review and meta-analysis.
Facondo, P, Di Lodovico, E, Delbarba, A, Anelli, V, Pezzaioli, LC, Filippini, E, Cappelli, C, Corona, G, Ferlin, A
Andrology. 2022;10(3):426-440
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The relationship between type 2 diabetes mellitus and male hypogonadism is well known, whereas the impact of type 1 diabetes mellitus (DM1) on male fertility and testis functions has been less studied. The aim of this study was to systematically review and discuss the available evidence evaluating paternity rate, male gonadal axis, and sperm parameters in men with DM1. This study is a systematic review and meta-analysis of fourteen studies. Results show: - reduced fertility potential in patients with DM1, as they have a lower number of children compared with unaffected population. In fact, the rate of children is statistically significantly lower among men who had been diagnosed with DM1 at an earlier age, according to a longer duration of the disease. - that men with DM1, compared with controls, have significantly lower normal sperm morphology, progressive motility and a trend toward a reduced semen volume, without difference in total sperm count and concentration. Authors conclude that DM1 might impair reproductive health at different levels, including functional sperm alterations definitively leading to reduced fertility rate in these patients.
Abstract
BACKGROUND Some evidence suggests that diabetes mellitus type 1 (DM1) could affect male fertility, gonadal axis, semen parameters, and spermatogenesis because of effects of hyperglycemia and insulin deficiency. Anyhow, the exact impact of DM1 on male fertility is unclear. OBJECTIVES To review the studies evaluating paternity rate, male gonadal axis, and semen parameters in men with DM1. MATERIALS AND METHODS A review of relevant literature from January 1980 to December 2020 was performed. Only studies published in English reporting data on fatherhood (rate of children by natural fertility), hormonal and seminal parameters were included. Out of 14 retrieved articles, the eight studies evaluating semen parameters were meta-analyzed. RESULTS The rate of children (four studies) was lower than controls among men affected by DM1, especially in men with a longer duration of disease. The data of gonadal hormonal profile in DM1 men (six studies) are very heterogeneous and a neutral effect of DM1 or a condition of subclinical hypogonadism could not be concluded. Meta-analysis showed that men with DM1 (n = 380), compared with controls (n = 434), have significantly lower normal sperm morphology [-0.36% (-0.66; -0.06), p < 0.05, six studies] and sperm progressive motility [33.62% (-39.13; -28.11), p < 0.001, two studies] and a trend toward a lower seminal volume [-0.51 (-1.03; 0.02), p = 0.06, eight studies], without difference in total sperm count and concentration. Data on scrotal ultrasound and sperm DNA fragmentation are too few. No study evaluated other factors of male infertility, such as transrectal ultrasound, semen infections, sperm auto-antibodies, and retrograde ejaculation. DISCUSSION DM1 might impair male fertility and testis functions (endocrine, spermatogenesis), but definition of its actual impact needs further studies. CONCLUSION Men with DM1 should be evaluated with a complete hormonal, seminal, and ultrasound workup to better define their fertility potential and need for follow up of testis functions.
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Cadmium exposure and risk of diabetes and prediabetes: A systematic review and dose-response meta-analysis.
Filippini, T, Wise, LA, Vinceti, M
Environment international. 2022;158:106920
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Cadmium is a toxic metal released in the environment after both natural and anthropogenic activities, particularly in contaminated and industrial areas devoted to smelting and refining of metals, and the manufacturing of batteries, coatings, or plastics. Exposure to cadmium may occur through occupational activities, smoking, food, and air pollution. The aim of this study was to provide updated literature on cadmium exposure and the risk of both type 2 diabetes and prediabetes, and to model the shape of these associations using a dose response approach. This study is a systematic review and meta-analysis of forty-two studies. Diabetes was investigated as an outcome in thirty-one studies, prediabetes in four studies, and both diabetes and prediabetes in seven studies. Results show that higher cadmium exposure was associated with increased risks of both diabetes and prediabetes. Diabetes risk increased linearly in studies using urinary cadmium concentrations, while disease risk increased only at the highest exposure levels when assessed using blood concentrations. The analysis for prediabetes also showed a linear increase in risk from low exposure, with a flattening effect at higher urinary cadmium concentrations. Authors conclude that their findings add to the available evidence on potential adverse health effects of environmental exposure to cadmium.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Cadmium exposure through diet, occupational exposure and smoking may increase the risk of type 2 diabetes in affected individuals.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Background
Cadmium exposure might occur through occupational activities, food, air pollution, and smoking. Smokers, in particular, have higher blood cadmium concentrations than non-smokers. Food is the main transmission route for non-smokers, particularly cereals, vegetables, mollusks, and offal. Females and older adults are at a greater risk due to an increased risk of iron deficiency in these population groups, leading to increased absorption, as well as greater age-related bioaccumulation.
Furthermore, cadmium exposure has been associated with an increased risk of diabetes in a number of studies, as referenced in the present manuscript. However, the magnitude and shape of the correlation are uncertain.This systematic review and meta-analysis therefore investigates the relationship between exposure to cadmium and type 2 diabetes and prediabetes risk.
Methods
- The systematic review was conducted and reported in line with the PRISMA 2020 statement. Search strings related to the terms “cadmium” and “diabetes”, or “prediabetes state” in PubMed/MEDLINE, Web of Science and EMBASE databases were employed to search for relevant articles. Latest search date: 1 October 2021.
- Eligibility criteria included: studies evaluating cadmium exposure via biomarker levels with outcomes of interest being type 2 diabetes or prediabetes using WHO criteria and the American Diabetes Association; and reporting of relative risk estimates using the hazard ratio (HR), risk ratio (RR), or odds ratio (OR) with the corresponding 95% confidence interval (CIs). For inclusion in dose-response meta-analysis: reported effect estimates for all exposure categories along with dose in each category.
- Studies were assessed for risk of bias using theROBINS-E tool. Overall certainty of the evidence was assessed using the GRADE approach.
- The meta-analysis involved estimating RRs with corresponding 95% CIs from each study. Generalised least-squares regression with a random effects model and restricted maximum likelihood estimation were used. The highest versus lowest exposure categories were compared. The association between exposure and risk of diabetes or prediabetes was investigated using a one-stage dose-response meta-analysis. Sensitivity analyses were performed and heterogeneity between studies was assessed..
Results
- 42 eligible studies (case-control, cross-sectional, and cohort studies), ranging 65-34, 814 male and female adult participants, were identified investigating the association between cadmium exposure and risk of diabetes or prediabetes. Seven of the included studies were at overall high risk of bias; heterogeneity in the resulting meta-analyses was moderate to substantial. Sensitivity analyses indicated comparable results. Assessment with GRADE found no major inconsistency, indirectness or imprecision for either outcome.
- Comparing the highest versus lowest cadmium exposure concentrations associated with type 2 diabetes resulted in a RR of 1.24 (95% CI 0.96–1.59), RR 1.21 (CI 95% 1.00–1.45), and RR 1.47 (CI 95% 1.01–2.13) for blood, urinary, and toenail matrices, respectively. Concurrently, there was an elevated risk of prediabetes for cadmium levels in urine of RR 1.41 (95% CI: 1.15–1.73) and blood RR 1.38 (95% CI: 1.16–1.63), respectively.
- In the dose-response meta-analysis, a linear positive correlation between increasing urinary cadmium levels and diabetes risk was observed, with a RR 1.25 (95% CI 0.90–1.72) at concentration 2.0 µg/g of creatinine compared with no exposure. Conversely, for blood cadmium concentrations, the diabetes risk seemed to rise above 1 µg/L compared with no exposure. Moreover, prediabetes risk increased up to approximately 2 µg/g creatinine beyond which a plateau was reached with RR 1.40 (95% CI 1.12–1.76) at 2 µg/g creatinine.
- The meta-regression showed a negligible correlation between blood cadmium levels and diabetes risk. However, a positive yet imprecise association was found with increasing urinary cadmium concentrations. Similarly, no association was observed between blood cadmium concentrations and risk of prediabetes, whereas a positive relationship with urinary cadmium levels was observed. However, these findings were based on a limited cohort of studies.
Conclusions
- A positive linear correlation between cadmium concentration (measured in multiple matrices) and risk of both type 2 diabetes and prediabetes with a dose-response relationship (moderate-certainty evidence) were observed in this systematic review and meta-analysis. Diabetes risk increased linearly in studies using urinary cadmium concentrations, whereas disease risk increased only at the highest exposure levels when assessed using blood levels. The analysis for prediabetes also demonstrated a linear increase in risk from low exposure, which plateaued at higher urinary cadmium concentrations.
Clinical practice applications:
- To inform practitioners and clients of the risks of cadmium exposure in the diet, through occupational exposure, and through smoking.
- To motivate practitioners to educate themselves and their clients regarding the foods which may pose a higher risk of cadmium exposure (not reviewed in the present article).
- To advise clients on prediabetes and type 2 diabetes risk from cadmium exposure through smoking.
Considerations for future research:
- As cited by the authors, future studies could incorporate stratified analysis in specific subgroups, e.g., non-smokers, or could be restricted to prospective cohort studies with more sufficient data,
- Large-scale observational studies could be conducted investigating cadmium exposure in smokers versus non-smokers.
- Clinical trials could be performed to evaluate the effect of reduction or cessation of tobacco smoking on total body cadmium concentrations .
- Continuous surveillance of dietary cadmium exposure and other heavy metals should be prioritised to inform public health.
- Dietary interventions could assess the possibility to attenuate the risk of cadmium exposure.
Abstract
BACKGROUND Cadmium exposure has been associated with increased diabetes risk in several studies, though there is still considerable debate about the magnitude and shape of the association. OBJECTIVE To perform a systematic review and meta-analysis of observational studies investigating the relation between cadmium exposure and risk of type 2 diabetes and prediabetes, and to summarize data on the magnitude and shape of the association. DATA SOURCE After conducting an online literature search through October 1, 2021, we identified 42 eligible studies investigating the association between cadmium exposure and risk of diabetes and prediabetes. STUDY ELIGIBILITY CRITERIA We included studies that assessed cadmium exposure through biomarker levels; examined type 2 diabetes or prediabetes among outcomes; and reported effect estimates for cadmium exposure for meta-analysis only. STUDY APPRAISAL AND SYNTHESIS METHODS Studies were evaluated using ROBINS-E risk of bias tool. We quantitively assessed the relation between exposure and study outcomes using one-stage dose-response meta-analysis with a random effects meta-analytical model. RESULTS In the meta-analysis, comparing highest-versus-lowest cadmium exposure levels, summary relative risks (RRs) for type 2 diabetes were 1.24 (95% confidence interval 0.96-1.59), 1.21 (1.00-1.45), and 1.47 (1.01-2.13) for blood, urinary, and toenail matrices, respectively. Similarly, there was an increased risk of prediabetes for cadmium concentrations in both urine (RR = 1.41, 95% CI: 1.15-1.73) and blood (RR = 1.38, 95% CI: 1.16-1.63). In the dose-response meta-analysis, we observed a consistent linear positive association between cadmium exposure and diabetes risk, with RRs of 1.25 (0.90-1.72) at 2.0 µg/g of creatinine. Conversely for blood cadmium, diabetes risk appeared to increase only above 1 µg/L. Prediabetes risk increased up to approximately 2 µg/g creatinine above which it reached a plateau with RR of 1.42 (1.12-1.76) at 2 µg/g creatinine. LIMITATIONS AND CONCLUSIONS This analysis provides moderate-certainty evidence for a positive association between cadmium exposure (measured in multiple matrices) and risk of both diabetes and prediabetes.
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The association between environmental exposures to chlordanes, adiposity and diabetes-related features: a systematic review and meta-analysis.
Mendes, V, Ribeiro, C, Delgado, I, Peleteiro, B, Aggerbeck, M, Distel, E, Annesi-Maesano, I, Sarigiannis, D, Ramos, E
Scientific reports. 2021;11(1):14546
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Chlordane is a synthetic organochlorine pesticide used for several decades in agriculture, but also in housing for pest control. Chlordane compounds are endocrine disrupting chemicals (EDCs), which means that they may affect the natural function of hormones by blocking, mimicking, displacing, or acting to subvert their roles. The aim of this study was to investigate whether exposure to chlordane compounds increases the risk of adiposity and diabetes in humans. This study is a systematic review and meta-analysis of 31 publications. Results demonstrate that there is no association between chlordane compounds and adiposity. However, there are higher odds of having diabetes-related features with increasing levels of all the chlordane compounds evaluated. Authors conclude that an international agreement on methods to measure both exposure and outcome variables and to conduct epidemiological studies could increase the knowledge on how adverse effects of exposure to various stressors (exposome) can influence human health.
Abstract
Chlordane compounds (CHLs) are components of technical chlordane listed in the Stockholm convention on persistent organic pollutants identified as endocrine disrupting chemicals (EDCs) and may interfere with hormone biosynthesis, metabolism or action resulting in an unbalanced hormonal function. There is increasing scientific evidence showing EDCs as risk factors in the pathogenesis and development of obesity and obesity-related metabolic syndromes such as type 2 diabetes, but there is no systematized information on the effect of CHLs in humans. Our aim is to identify the epidemiological data on the association between CHLs with adiposity and diabetes using a systematic approach to identify the available data and summarizing the results through meta-analysis. We searched PubMed and Web of Science from inception up to 15 February 2021, to retrieve original data on the association between chlordanes, and adiposity or diabetes. For adiposity, regression coefficients and Pearson or Spearman correlation coefficients were extracted and converted into standardized regression coefficients. Data were combined using fixed effects meta-analyses to compute summary regression coefficients and corresponding 95% confidence intervals (95% CI). For the association between chlordanes and diabetes, Odds ratios (ORs) were extracted and the DerSimonian and Laird method was used to compute summary estimates and respective 95% CI. For both, adjusted estimates were preferred, whenever available. Among 31 eligible studies, mostly using a cross-sectional approach, the meta-analysis for adiposity was possible only for oxychlordane and transchlordane, none of them were significantly associated with adiposity [(β = 0.04, 95% CI 0.00; 0.07, I2 = 89.7%)] and (β = 0.02, 95% CI - 0.01; 0.06), respectively. For diabetes, the estimates were positive for all compounds but statistically significant for oxychlordane [OR = 1.96 (95% CI 1.19; 3.23)]; for trans-nonachlor [OR = 2.43 (95% CI 1.64; 3.62)] and for heptachlor epoxide [OR = 1.88 (95% CI 1.42; 2.49)]. Our results support that among adults, the odds of having diabetes significantly increase with increasing levels of chlordanes. The data did not allow to reach a clear conclusion regarding the association with adiposity.