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Is telomere length a biomarker of sperm quality? A systematic review and meta-analysis of observational studies.
Fernández de la Puente, M, Salas-Huetos, A, Valle-Hita, C, Babio, N, Murphy, MM, Canudas, S, Salas-Salvadó, J
Andrology. 2024;(2):277-288
Abstract
BACKGROUND Telomeres are essential for the integrity of chromosome ends during cell division and their involvement in different processes linked to aging has been established. These chromosome components are involved in spermatogenesis and seem to play an important role in fertilization and embryo development. Telomere length is shortened with each cell division. Recently, short sperm telomere length has been proposed as a potential biomarker of male infertility. OBJECTIVES To conduct a systematic review and meta-analysis of studies exploring the association between spermatozoa and/or leukocyte telomere length with sperm quality parameters and different infertility conditions. MATERIAL AND METHODS A systematic review and meta-analysis was conducted with studies from Medline-PUBMED and Cochrane Library databases until May 2022. Eligible studies included cohort, cross-sectional and case-control studies, and telomere length in spermatozoa and/or leukocytes cells was defined as the exposure. Semen quality parameters or infertility conditions (e.g., oligozoospermia, asthenozoospermia, teratozoospermia, or other spermatogenic impairment combinations) were defined as the outcomes. RESULTS Twenty-three observational studies were included. In the qualitative analysis, high heterogeneity was observed between studies regarding the associations between telomere length and semen parameters in different normozoospermic/fertile and oligozoospermic/infertile populations. In the meta-analysis, spermatozoa and leukocyte telomere length were shorter in infertile individuals than in fertile individuals (mean difference [95% confidence interval]: -1.43 [-1.66 to -1.21], p-value <0.001 and -1.67 [-2.02 to -1.31], p-value <0.001, respectively). Moreover, in terms of sperm telomere length, these differences were also significant between individuals with a normal seminogram and individuals with a low quantity of spermatozoa in the ejaculate (-0.97 [-1.32, -0.61], p-value <0.001). CONCLUSION The current systematic review and meta-analysis suggests the potential role of spermatozoa or leukocyte telomere length as a reliable biomarker of semen quality, which may help distinguish between infertility conditions beyond the routine semen analysis.
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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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Sperm DNA methylation changes after short-term nut supplementation in healthy men consuming a Western-style diet.
Salas-Huetos, A, James, ER, Salas-Salvadó, J, Bulló, M, Aston, KI, Carrell, DT, Jenkins, TG
Andrology. 2021;(1):260-268
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Abstract
BACKGROUND Many environmental and lifestyle factors have been implicated in the decline of sperm quality, with diet being one of the most plausible factors identified in recent years. Moreover, several studies have reported a close association between the alteration of specific sperm DNA methylation signatures and semen quality. OBJECTIVES To evaluate the effect of tree nut consumption on sperm DNA methylation patterns in healthy individuals reporting eating a Western-style diet. MATERIAL AND METHODS This is a post hoc analysis conducted in a subset of participants (healthy, non-smoking, and young) from the FERTINUTS 14-wk randomized-controlled, parallel trial, recruited between December 2015 and February 2017. The participants included in the current study (n = 72) were randomly selected in a proportion 2:1 from the original FERTINUTS trial between the 98 participants that completed the entire dietary intervention (nut group, n = 48; control group, n = 24). Sperm DNA methylation patterns were examined at baseline and after 14 weeks in 48 individuals consuming 60 g/d of mixed nuts (nut group) and in 24 individuals following the usual Western-style diet avoiding consumption of nuts (control group). RESULTS Over the course of the trial, no significant changes in global methylation were observed between groups. However, in the nut group, we identified 36 genomic regions that were significantly differentially methylated between the baseline and the end of the trial and 97.2% of the regions displayed hypermethylation. We identified no such change in the control group over the same period of time. We also utilized the recently developed germ line age calculator to determine if nut consumption resulted in alterations to the epigenetic age of cells and no significant differences were found. DISCUSSION AND CONCLUSION Adding nuts to a regular Western-style diet subtly impacts sperm DNA methylation in specific regions, demonstrating that there are some sperm epigenome regions that could respond to diet.
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Male adiposity, sperm parameters and reproductive hormones: An updated systematic review and collaborative meta-analysis.
Salas-Huetos, A, Maghsoumi-Norouzabad, L, James, ER, Carrell, DT, Aston, KI, Jenkins, TG, Becerra-Tomás, N, Javid, AZ, Abed, R, Torres, PJ, et al
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2021;(1):e13082
Abstract
The present updated systematic review and meta-analysis aims to summarize the evidence from published studies with low risk for any important bias (based on methodological quality assessment) investigating the potential associations of adiposity with sperm quality and reproductive hormones. We conducted a systematic search of the literature published in MEDLINE-PubMed and EMBASE through June 2019. Based on the criteria in our review, 169 eligible publications were used for data abstraction. Finally, 60 articles were included in the qualitative analysis and 28 in the quantitative analysis. Our systematic review results indicated that overweight and/or obesity were associated with low semen quality parameters (i.e., semen volume, sperm count and concentration, sperm vitality and normal morphology) and some specific reproductive hormones (e.g., inhibin B, total testosterone and sex hormone-binding globulin). Overweight and/or obesity were also positively associated with high estradiol concentrations. Meta-analysis indicated that overweight and/or obesity categories were associated with lower sperm quality (i.e., semen volume, sperm count and concentration, sperm vitality, total motility and normal morphology), and underweight category was likewise associated with low sperm normal morphology. In conclusion, our results suggest that maintaining a healthy body weight is important for increasing sperm quality parameters and potentially male fertility.
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Dietary Antioxidants in the Treatment of Male Infertility: Counteracting Oxidative Stress.
Torres-Arce, E, Vizmanos, B, Babio, N, Márquez-Sandoval, F, Salas-Huetos, A
Biology. 2021;(3)
Abstract
Infertility affects about 15% of the population and male factors only are responsible for ~25-30% of cases of infertility. Currently, the etiology of suboptimal semen quality is poorly understood, and many environmental and genetic factors, including oxidative stress, have been implicated. Oxidative stress is an imbalance between the production of free radicals, or reactive oxygen species (ROS), and the capacity of the body to counteract their harmful effects through neutralization by antioxidants. The purpose of this review, by employing the joint expertise of international researchers specialized in nutrition and male fertility areas, is to update the knowledge about the reproductive consequences of excessive ROS concentrations and oxidative stress on the semen quality and Assisted Reproduction Techniques (ART) clinical outcomes, to discuss the role of antioxidants in fertility outcomes, and finally to discuss why foods and dietary patterns are more innocuous long term solution for ameliorating oxidative stress and therefore semen quality results and ART fertility outcomes. Since this is a narrative review and not a systematic/meta-analysis, the summarized information in the present study should be considered cautiously.
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Effects of Dietary Phytoestrogens on Hormones throughout a Human Lifespan: A Review.
Domínguez-López, I, Yago-Aragón, M, Salas-Huetos, A, Tresserra-Rimbau, A, Hurtado-Barroso, S
Nutrients. 2020;12(8)
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Phytoestrogens are polyphenolic molecules with a structural similarity to endogenous human hormones. The main dietary source of these plant secondary metabolites is legumes (particularly soy), and to a lesser extent fruits, vegetables, and cereals. The aim of this study was to synthesize the results obtained by human studies and assess the potential hormone-related health effects of dietary phytoestrogens throughout the human lifespan. Literature shows that: - the impact of phytoestrogens can vary according to the life stage. - soy isoflavones appear not to have any influence on sex and thyroid hormones, bone remodelling and insulin-like growth factor. - although phytoestrogens transfer from maternal blood to the foetus, no effects have been observed in early life. - in later stages of childhood, an increase of androgens and decrease of oestrogens associated with dietary phytoestrogens have been observed in girls and boys, respectively. - in adulthood, endocrine changes arising from phytoestrogen consumption are unclear, although goitrogenic [compounds that interfere with the normal function of the thyroid gland] activity has been observed in men. - in premenopausal women results regarding sex hormones, breast cancer protection and bone remodelling are uncertain. Authors conclude that intake of phytoestrogens does have some physiological effects in humans related to hormone regulation, but like hormones, the benefits depend on the stage of life.
Abstract
Dietary phytoestrogens are bioactive compounds with estrogenic activity. With the growing popularity of plant-based diets, the intake of phytoestrogen-rich legumes (especially soy) and legume-derived foods has increased. Evidence from preclinical studies suggests these compounds may have an effect on hormones and health, although the results of human trials are unclear. The effects of dietary phytoestrogens depend on the exposure (phytoestrogen type, matrix, concentration, and bioavailability), ethnicity, hormone levels (related to age, sex, and physiological condition), and health status of the consumer. In this review, we have summarized the results of human studies on dietary phytoestrogens with the aim of assessing the possible hormone-dependent outcomes and health effects of their consumption throughout a lifespan, focusing on pregnancy, childhood, adulthood, and the premenopausal and postmenopausal stages. In pregnant women, an improvement of insulin metabolism has been reported in only one study. Sex hormone alterations have been found in the late stages of childhood, and goitrogenic effects in children with hypothyroidism. In premenopausal and postmenopausal women, the reported impacts on hormones are inconsistent, although beneficial goitrogenic effects and improved glycemic control and cardiovascular risk markers have been described in postmenopausal individuals. In adult men, different authors report goitrogenic effects and a reduction of insulin in non-alcoholic fatty liver patients. Further carefully designed studies are warranted to better elucidate the impact of phytoestrogen consumption on the endocrine system at different life stages.
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Lysine pathway metabolites and the risk of type 2 diabetes and cardiovascular disease in the PREDIMED study: results from two case-cohort studies.
Razquin, C, Ruiz-Canela, M, Clish, CB, Li, J, Toledo, E, Dennis, C, Liang, L, Salas-Huetos, A, Pierce, KA, Guasch-Ferré, M, et al
Cardiovascular diabetology. 2019;(1):151
Abstract
BACKGROUND The pandemic of cardiovascular disease (CVD) and type 2 diabetes (T2D) requires the identification of new predictor biomarkers. Biomarkers potentially modifiable with lifestyle changes deserve a special interest. Our aims were to analyze: (a) The associations of lysine, 2-aminoadipic acid (2-AAA) or pipecolic acid with the risk of T2D or CVD in the PREDIMED trial; (b) the effect of the dietary intervention on 1-year changes in these metabolites, and (c) whether the Mediterranean diet (MedDiet) interventions can modify the effects of these metabolites on CVD or T2D risk. METHODS Two unstratified case-cohort studies nested within the PREDIMED trial were used. For CVD analyses, we selected 696 non-cases and 221 incident CVD cases; for T2D, we included 610 non-cases and 243 type 2 diabetes incident cases. Metabolites were quantified using liquid chromatography-tandem mass spectrometry, at baseline and after 1-year of intervention. RESULTS In weighted Cox regression models, we found that baseline lysine (HR+1 SD increase = 1.26; 95% CI 1.06-1.51) and 2-AAA (HR+1 SD increase = 1.28; 95% CI 1.05-1.55) were both associated with a higher risk of T2D, but not with CVD. A significant interaction (p = 0.032) between baseline lysine and T2D on the risk of CVD was observed: subjects with prevalent T2D and high levels of lysine exhibited the highest risk of CVD. The intervention with MedDiet did not have a significant effect on 1-year changes of the metabolites. CONCLUSIONS Our results provide an independent prospective replication of the association of 2-AAA with future risk of T2D. We show an association of lysine with subsequent CVD risk, which is apparently diabetes-dependent. No evidence of effects of MedDiet intervention on lysine, 2-AAA or pipecolic acid changes was found. Trial registration ISRCTN35739639; registration date: 05/10/2005; recruitment start date 01/10/2003.
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Changes in circulating miRNAs in healthy overweight and obese subjects: Effect of diet composition and weight loss.
Giardina, S, Hernández-Alonso, P, Díaz-López, A, Salas-Huetos, A, Salas-Salvadó, J, Bulló, M
Clinical nutrition (Edinburgh, Scotland). 2019;(1):438-443
Abstract
BACKGROUND MicroRNAs (miRNAs) are small non-coding RNA molecules that can play an important role in several chronic metabolic conditions, including obesity. However, to date little is known about how they are regulated. Weight loss induced by surgical procedures has been effective at modulating specific circulating miRNAs, but the effect of energy-restricted diets with different macronutrient compositions on circulating miRNAs is not well understood. The objective of the present analysis was to explore the effect of three energy-restricted diets of different macronutrient composition and carbohydrate quality on plasma miRNA levels. METHODS The GLYNDIET study is a 6-month, parallel, randomized clinical trial conducted on overweight and obese subjects who were randomized to one of three different dietary intervention groups: i) a moderate-carbohydrate and low glycemic index diet (LGI), ii) a moderate-carbohydrate and high glycemic index diet (HGI), and iii) a low-fat and high glycemic index diet (LF). We assessed the genome-wide circulating miRNA profile in a subsample of eight randomly selected participants. A total of 8 miRNAs (miR-411, miR-432, miR-99b, miR-340, miR-423, miR-361, let-7c) were differently quantified according to diet intervention, and were therefore longitudinally validated in 103 participants before and after the energy-restricted diets. RESULTS Circulating miR-361 levels were lower in the LGI group than in the HGI group, even after adjusting for differences in weight loss. The intra-group analyses demonstrated a significant down-regulation of all miRNAs screened in our study subjects after the LGI intervention. Similarly, miR-139 and miR-340 were down-regulated after the HGI intervention, while miR-139, miR-432 and miR-423 were down-regulated after the low-fat diet. Changes in circulating miR-139 and let-7c were significantly associated with changes in lipid profile and insulin resistance. CONCLUSION An energy-restricted low-glycemic index diet down-regulates circulating miRNA-361 more than an energy-restricted high-glycemic index, regardless of the magnitude of the weight loss.
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Effect of Nut Consumption on Erectile and Sexual Function in Healthy Males: A Secondary Outcome Analysis of the FERTINUTS Randomized Controlled Trial.
Salas-Huetos, A, Muralidharan, J, Galiè, S, Salas-Salvadó, J, Bulló, M
Nutrients. 2019;11(6)
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National Institutes of Health define erectile dysfunction as a persistent difficulty achieving and maintaining an erection sufficient for satisfactory sexual intercourse. The main aim of the study was to explore the effects of nuts supplementation on erectile function determined by the International Index of Erectile Function and the endothelial (inner lining of blood vessels) function. The study is a randomised controlled, two-interventions parallel, clinical trial conducted in healthy males who reported a Western-style diet. The 119 participants were randomly assigned to one of the two interventions. Results indicate that adding 60 g/d of mixed raw nuts to a Western-style diet for 14-wk improved the auto-reported orgasmic function and sexual desire parameters in a group of healthy reproductive-aged participants compared with an age-matched control group. Authors conclude that compliance with a healthy diet supplemented with mixed nuts may help to improve erectile and sexual desire.
Abstract
Lifestyle risk factors for erectile and sexual function include smoking, excessive alcohol consumption, lack of physical activity, psychological stress, and adherence to unhealthy diets. In the present study, we evaluated the effects of mixed nuts supplementation on erectile and sexual function. Eighty-three healthy male aged 18-35 with erectile function assessment were included in this FERTINUTS study sub-analysis; a 14-week randomized, controlled, parallel feeding trial. Participants were allocated to (1) the usual Western-style diet enriched with 60 g/day of a mixture of nuts (nut group; n = 43), or (2) the usual Western-style diet avoiding nuts (control group; n = 40). At baseline and the end of the intervention, participants answered 15 questions contained in the validated International Index of Erectile Function (IIEF), and peripheral levels of nitric oxide (NO) and E-selectin were measured, as surrogated markers of erectile endothelial function. Anthropometrical characteristics, and seminogram and blood biochemical parameters did not differ between intervention groups at baseline. Compared to the control group, a significant increase in the orgasmic function (p-value = 0.037) and sexual desire (p-value = 0.040) was observed during the nut intervention. No significant differences in changes between groups were shown in peripheral concentrations of NO and E-selectin. Including nuts in a regular diet significantly improved auto-reported orgasmic function and sexual desire.
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Effect of nut consumption on semen quality and functionality in healthy men consuming a Western-style diet: a randomized controlled trial.
Salas-Huetos, A, Moraleda, R, Giardina, S, Anton, E, Blanco, J, Salas-Salvadó, J, Bulló, M
The American journal of clinical nutrition. 2018;(5):953-962
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BACKGROUND Human semen quality has declined in industrialized countries. Pollution, smoking, and the consumption of a Western-style diet are all hypothesized as potential causes. OBJECTIVE We evaluated the effect of chronic consumption of nuts on changes in conventional semen parameters and the potential mechanisms implicated. DESIGN The FERTINUTS study was a 14-wk randomized, controlled, parallel trial. A total of 119 healthy men, aged 18-35 y, were allocated to 1 of 2 intervention groups: one group was fed the usual Western-style diet enriched with 60 g of a mixture of nuts/d (nut group), and the other was fed the usual Western-style diet avoiding nuts (control group). Semen and blood samples were collected at baseline and at the end of the intervention. Dietary information was recorded throughout the trial. Changes in conventional semen parameters (pH, volume, sperm count and concentration, motility, and morphology) were determined as primary outcomes. The effect of nut consumption on sperm DNA fragmentation (SDF), reactive oxygen species (ROS) production, chromosome anomalies (X, Y, and 18), total DNA methylation, and microRNA expression were measured in sperm samples as potential causes of the changes in the seminogram. RESULTS Compared with the control group, improvements in total sperm count (P = 0.002) and vitality (P = 0.003), total motility (P = 0.006), progressive motility (P = 0.036), and morphology of sperm (P = 0.008) were observed in the nut group. Participants in the nut group showed an increase in the consumption of total fat, monounsaturated fatty acids, polyunsaturated fatty acids, magnesium, vitamin E, α-linolenic acid, total omega-3 (n-3) and ω-3:ω-6 ratio intake during the intervention. Participants in the nut group showed a significant reduction in SDF (P < 0.001) and in the expression of hsa-miR-34b-3p (P = 0.036). No significant changes in ROS, sperm chromosome anomalies, or DNA methylation were observed between groups. CONCLUSIONS The inclusion of nuts in a Western-style diet significantly improves the total sperm count and the vitality, motility, and morphology of the sperm. These findings could be partly explained by a reduction in the sperm DNA fragmentation. This trial was registered at ISRCTN as ISRCTN12857940.