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Clinical Trial: Probiotics in Metformin Intolerant Patients with Type 2 Diabetes (ProGasMet).
Nabrdalik, K, Drożdż, K, Kwiendacz, H, Skonieczna-Żydecka, K, Łoniewski, I, Kaczmarczyk, M, Wijata, AM, Nalepa, J, Holleman, F, Nieuwdorp, M, et al
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2023;168:115650
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Metformin has been the number one drug of choice for the management of type 2 diabetes, however there is a proportion of individuals who suffer from stomach issues and discontinue therapy. This may be due to the possibility that metformin impacts gut microbiota composition. This randomised control trial of 82 individuals with metformin intolerance aimed to determine the effect of a multi-strain probiotic in conjunction with metformin administration. The results showed that whilst on probiotics, there was a significant improvement in symptoms, with reduced incidence and severity of nausea, reduced frequency and severity of stomach pain and bloating and self-assessed improvement of tolerability of metformin. Nausea was also decreased, but only when the probiotic was allowed time to act. It was concluded that probiotic supplementation improves gastrointestinal side effects associated with metformin intolerance. This study could be used by healthcare professionals to understand that individuals who are on metformin may experience gastrointestinal side effects, which may be relieved with a multi-strain probiotic.
Abstract
BACKGROUND For decades, metformin has been the drug of first choice in the management of type 2 diabetes. However, approximately 2-13% of patients do not tolerate metformin due to gastrointestinal (GI) side effects. Since metformin influences the gut microbiota, we hypothesized that a multi-strain probiotics supplementation would mitigate the gastrointestinal symptoms associated with metformin usage. METHODS AND ANALYSIS This randomized, double-blind, placebo-controlled, single-center, cross-over trial (ProGasMet study) assessed the efficacy of a multi-strain probiotic in 37 patients with metformin intolerance. Patients were randomly allocated (1:1) to receive probiotic (PRO-PLA) or placebo (PLA-PRO) at baseline and, after 12 weeks (period 1), they crossed-over to the other treatment arm (period 2). The primary outcome was the reduction of GI adverse events of metformin. RESULTS 37 out of 82 eligible patients were enrolled in the final analysis of whom 35 completed the 32 weeks study period and 2 patients resigned at visit 5. Regardless of the treatment arm allocation, while on probiotic supplementation, there was a significant reduction of incidence (for the probiotic period in PRO-PLA/PLA-PRO: P = 0.017/P = 0.054), quantity and severity of nausea (P = 0.016/P = 0.024), frequency (P = 0.009/P = 0.015) and severity (P = 0.019/P = 0.005) of abdominal bloating/pain as well as significant improvement in self-assessed tolerability of metformin (P < 0.01/P = 0.005). Moreover, there was significant reduction of incidence of diarrhea while on probiotic supplementation in PRO-PLA treatment arm (P = 0.036). CONCLUSION A multi-strain probiotic diminishes the incidence of gastrointestinal adverse effects in patients with type 2 diabetes and metformin intolerance.
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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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Effects of a Dulaglutide plus Calorie-Restricted Diet versus a Calorie-Restricted Diet on Visceral Fat and Metabolic Profiles in Women with Polycystic Ovary Syndrome: A Randomized Controlled Trial.
Zhang, Y, Qu, Z, Lu, T, Shao, X, Cai, M, Dilimulati, D, Gao, X, Mao, W, Hu, F, Su, L, et al
Nutrients. 2023;15(3)
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Polycystic ovary syndrome (PCOS) is a unification of reproductive endocrine and metabolic disorders. Lifestyle and weight management, particularly dietary intake aimed at weight loss, are initial treatment strategies for PCOS. A calorie-restricted diet (CRD) seems to be the optimal dietary pattern for weight management in the PCOS population. The aim of this study was to evaluate modifications in fat distribution, the androgenic state, and metabolic profiles in the overweight and obese PCOS-affected population, who obtained modest and equivalent weight loss induced by a CRD regimen with or without Dulaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist (RA). This study was a randomised controlled trial which enrolled 68 females diagnosed with PCOS. Participants were randomly assigned to receive to one of the two groups: a GLP-1 RA combined with CRD or CRD alone. Results showed that participants in the GLP-1 RA + CRD group took a shorter time to achieve a 7% weight loss goal than those in the CRD group. Furthermore, both interventions had similar positive effects in improving menstrual frequency and reducing levels of blood pressure, insulin, aminotransferases, lipids, total fat mass, total lean mass, and abdominal subcutaneous adipose tissue mass after equivalent weight loss. Authors conclude that their findings support the importance of dietary intervention as a first-line treatment in women with PCOS, and that GLP-1 RA therapy offers an effective and generally tolerable adjunct therapy to aid in achieving weight targets based on dietary therapy in overweight and obese women with PCOS.
Abstract
The effects of dulaglutide and a calorie-restricted diet (CRD) on visceral adipose tissue (VAT) and metabolic profiles in polycystic ovary syndrome (PCOS) have not been extensively investigated. In this study, we investigated whether dulaglutide combined with CRD could further reduce VAT and promote clinical benefits as compared with a CRD regimen alone in overweight or obese PCOS-affected women. Between May 2021 and May 2022, this single-center, randomized, controlled, open-label clinical trial was conducted. Overall, 243 participants with PCOS were screened, of which 68 overweight or obese individuals were randomly randomized to undergo dulaglutide combined with CRD treatment (n = 35) or CRD treatment alone (n = 33). The duration of intervention was set as the time taken to achieve a 7% weight loss goal from baseline body weight, which was restricted to 6 months. The primary endpoint was the difference in the change in VAT area reduction between the groups. The secondary endpoints contained changes in menstrual frequency, metabolic profiles, hormonal parameters, liver fat, and body composition. As compared with the CRD group, the dulaglutide + CRD group had a considerably shorter median time to achieve 7% weight loss. There was no significant between-group difference in area change of VAT reduction (-0.97 cm2, 95% confidence interval from -14.36 to 12.42, p = 0.884). As compared with CRD alone, dulaglutide + CRD had significant advantages in reducing glycated hemoglobin A1c and postprandial plasma glucose levels. The results of the analyses showed different changes in menstruation frequency, additional metabolic profiles, hormonal markers, liver fat, and body composition between the two groups did not differ significantly. Nausea, vomiting, constipation, and loss of appetite were the main adverse events of dulaglutide. These results emphasize the value of dietary intervention as the first line of treatment for PCOS-affected women, while glucagon-like peptide 1 receptor agonist therapy provides an efficient and typically well tolerated adjuvant therapy to aid in reaching weight targets based on dietary therapy in the population of overweight/obese PCOS-affected women.
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Add-On Effect of Selenium and Vitamin D Combined Supplementation in Early Control of Graves' Disease Hyperthyroidism During Methimazole Treatment.
Gallo, D, Mortara, L, Veronesi, G, Cattaneo, SA, Genoni, A, Gallazzi, M, Peruzzo, C, Lasalvia, P, Moretto, P, Bruno, A, et al
Frontiers in endocrinology. 2022;13:886451
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Graves’ disease (GD) is the most frequent cause of hyperthyroidism in iodine-replete geographical areas. Thionamide anti-thyroid drug therapy is the first-line treatment worldwide under most circumstances, but its major limitation is the high rate of relapses after drug discontinuation. Decreased serum concentrations of selenium (Se) and vitamin D (VitD) have been reported in newly diagnosed GD patients in observational studies. The aim of this study was to determine if concurrent supplementation with Se and VitD in Graves’ patients with suboptimal or low Se and VitD levels may improve early control of hyperthyroidism during methimazole (MMI) [thionamide] treatment. This study is a randomised, single-blinded, controlled, intervention trial. Forty-two patients were randomly assigned to treatment with MMI monotherapy (Group 1, MMI alone group) or MMI combined with Se and VitD (Group 2, intervention group). Results show that supplementation favours a significantly better control of hyperthyroidism, both at short-term (45 days) and long-term (180 and 270 days) assessments. In fact, during MMI treatment, Se and VitD supplementation facilitate restoration of euthyroidism and boost the improvement of quality of life. Authors conclude that Se and VitD status should be assessed at diagnosis of GD, and that Se and VitD supplementation should be offered at adequate and safe dosages even if a slight deficiency of these micronutrients is found.
Abstract
Prompt and stable control of hyperthyroidism is fundamental to avoid the detrimental effects of thyroid hormone excess, and antithyroid drugs, mainly methimazole (MMI), represent the first-line treatment for Graves' disease (GD) hyperthyroidism. Decreased serum concentrations of selenium (Se) and calcifediol (25(OH)D, VitD) have been reported in newly diagnosed GD patients in observational studies. Low Se levels might exacerbate oxidative stress by compromising the antioxidant machinery's response to reactive oxygen species, and low VitD levels might hamper the anti-inflammatory immune response. We performed a randomized controlled clinical trial (EudraCT 2017-00505011) to investigate whether Se and cholecalciferol (VitD) addition to MMI is associated with a prompter control of hyperthyroidism. Forty-two consecutive patients with newly-onset GD and marginal/insufficient Se and VitD levels were randomly assigned to treatment with either MMI monotherapy or MMI combined with Se and VitD. Se treatment was withdrawn after 180 days, while the other treatments were continued. Combination therapy resulted in a significantly greater reduction in serum FT4 concentration at 45 days (-37.9 pg/ml, CI 95%, -43.7 to -32.2 pg/ml) and 180 days (-36.5 pg/ml, CI 95%, -42 to -30.9 pg/ml) compared to MMI monotherapy (respectively: -25.7 pg/ml, CI 95%, -31.6 to -19.7 pg/ml and -22.9 pg/ml, CI 95%, -28 to -17.3 pg/ml, p 0.002). Data at 270 days confirmed this trend (-37.8 pg/ml, CI 95%, -43.6 to -32.1 pg/ml vs -24.4 pg/ml, CI 95%, -30.3 to -18.4 pg/ml). The quality of life (QoL) score was investigated by the validated "Thyroid-related Patient-Reported Outcome" questionnaire (ThyPRO). ThyPRO composite score showed a greater improvement in the intervention group at 45 days (-14.6, CI 95%, -18.8 to -10.4), 180 (-9, CI 95%, -13.9 to -4.2) and 270 days (-14.3, CI 95%, -19.5 to -9.1) compared to MMI group (respectively, -5.2, CI 95%, -9.5 to -1; -5.4, CI 95%, -10.6 to -0.2 and -3.5, CI 95%, -9 to -2.1, p 0-6 months and 6-9 months <0.05). Our results suggest that reaching optimal Se and VitD levels increases the early efficacy of MMI treatment when Se and VitD levels are suboptimal.
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Molecular Regulators of Muscle Mass and Mitochondrial Remodeling Are Not Influenced by Testosterone Administration in Young Women.
Horwath, O, Moberg, M, Hirschberg, AL, Ekblom, B, Apró, W
Frontiers in endocrinology. 2022;13:874748
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Testosterone is a sex hormone normally found in higher amounts in adult males than females. Testosterone plays a number of important roles, including influencing muscle size and strength. Treatment with testosterone has been shown to increase lean mass and muscle strength in women as well as men. However, female-only studies are limited, and the precise mechanisms underlying these changes are not well understood. This randomised control trial examined the effect of testosterone administration on regulators of muscle protein turnover and mitochondrial function in muscle samples collected from young women. 48 healthy, pre-menopausal women were assigned to receive either 10mg of transdermal testosterone gel per day, or a placebo, for 10 weeks. Muscle samples were collected via biopsy before and after the intervention. Testosterone administration did not appear to have a significant effect on androgen receptors, 5-alpha reductase, anabolic signalling, or mitochondrial remodelling in muscle tissue. The researchers concluded that improvements in muscle size and oxidative capacity following testosterone administration cannot be explained by changes in protein expression related to muscle protein turnover or mitochondrial remodelling. The authors went on to suggest that the small sample size in this study may have reduced the ability to detect small but biologically relevant changes in protein levels. Within the research, there is large variability among studies in terms of sex, age, route of administration and length of treatment, which makes putting these findings into context of the wider literature difficult.
Abstract
Testosterone (T) administration has previously been shown to improve muscle size and oxidative capacity. However, the molecular mechanisms underlying these adaptations in human skeletal muscle remain to be determined. Here, we examined the effect of moderate-dose T administration on molecular regulators of muscle protein turnover and mitochondrial remodeling in muscle samples collected from young women. Forty-eight healthy, physically active, young women (28 ± 4 years) were assigned in a random double-blind fashion to receive either T (10 mg/day) or placebo for 10-weeks. Muscle biopsies collected before and after the intervention period were divided into sub-cellular fractions and total protein levels of molecular regulators of muscle protein turnover and mitochondrial remodeling were analyzed using Western blotting. T administration had no effect on androgen receptor or 5α-reductase levels, nor on proteins involved in the mTORC1-signaling pathway (mTOR, S6K1, eEF2 and RPS6). Neither did it affect the abundance of proteins associated with proteasomal protein degradation (MAFbx, MuRF-1 and UBR5) and autophagy-lysosomal degradation (AMPK, ULK1 and p62). T administration also had no effect on proteins in the mitochondria enriched fraction regulating mitophagy (Beclin, BNIP3, LC3B-I, LC3B-II and LC3B-II/I ratio) and morphology (Mitofilin), and it did not alter the expression of mitochondrial fission- (FIS1 and DRP1) or fusion factors (OPA1 and MFN2). In summary, these data indicate that improvements in muscle size and oxidative capacity in young women in response to moderate-dose T administration cannot be explained by alterations in total expression of molecular factors known to regulate muscle protein turnover or mitochondrial remodeling.
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Dynamics of gut microbiota during pregnancy in women with TPOAb-positive subclinical hypothyroidism: a prospective cohort study.
Wu, M, Chi, C, Yang, Y, Guo, S, Li, T, Gu, M, Zhang, T, Gao, H, Liu, R, Yin, C
BMC pregnancy and childbirth. 2022;22(1):592
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Subclinical hypothyroidism (SCH) in pregnancy refers to the elevation of thyroid stimulating hormone level with normal free T4 level. One third of women with SCH have been reported to test positive for anti-thyroid peroxidase antibody (TPOAb+). The aim of this study was to evaluate whether gut microbiota can be potential therapeutic targets for managing TPOAb+ SCH. This study was a nested, prospective observational cohort study. A total of 64 and 68 pregnant women with TPOAb+ and TPOAb negative SCH, respectively, were included in this study. Results showed that women who were diagnosed with TPOAb+ SCH in trimester (T)1 show distinct dynamics of gut microbiota from T2 to T3. Furthermore, changes in the abundances of three types of bacterial species were abnormal in the presence of levothyroxine treatment. Authors conclude that gut microbiota can serve as potential therapeutic targets for TPOAb+ SCH during pregnancy.
Abstract
BACKGROUND Anti-thyroid peroxidase antibody (TPOAb) positivity can contribute to inhibit thyroxine synthesis. Gut microbiota can interact with metabolic or immune diseases. However, dynamics of gut microbiota from the second (T2) to the third trimester (T3) in women with TPOAb-positive/negative subclinical hypothyroidism (TPOAb+/TPOAb- SCH) have not been reported. Therefore, we aimed to evaluate whether gut microbiota can be potential therapeutic targets for managing TPOAb+ SCH. METHODS In this single-center prospective cohort study, we observed gut microbiota dynamics by sequencing 16S rRNA from fecal samples collected in T2 (20-23+ 6 weeks) and T3 (28-33+ 6 weeks). TPOAb+/TPOAb- SCH were stratified depending on whether or not they used levothyroxine (LT4) during the pregnancy (LT4+/LT4-). Microbiome bioinformatics analyses were performed using QIIME2. The linear discriminant analysis effect size (LEfSe) was used for the quantitative analysis of biomarkers. Functional profiling was performed with PICRUSt2. RESULTS Distinct gut microbiota dynamics from T2 to T3 were noted in the TPOAb- (n = 68) and TPOAb+ (n = 64) SCH groups. The TPOAb+ LT4- group was characterized by enriched bacterial amplicon sequence variants (ASVs) of Prevotella in T2 and Bacteria, Lachnospirales, Lachnospiraceae, Blautia, and Agathobacter in T3 and by depleted ASVs of Gammaproteobacteria, Enterobacterales, and Enterobacteriaceae in T2 and Actinobacteriota, Coriobacteriia, Actinobacteria, Coriobacteriales, Bifidobacteriales, Bifidobacteriaceae, Bifidobacterium, Dorea formicigenerans, and Bifidobacterium longum in T3. The TPOAb+ LT4+ group was characterized by enriched bacterial ASVs of Blautia, Streptococcus salivarius, and Bifidobacterium longum in T3 and by depleted ASVs of Bacteroidota, Bacteroidia, Bacteroidales, and Prevotella in T2 and Agathobacter in T3. Moreover, we identified 53 kinds of metabolic functions that were mainly involved in sugar, lipid, and amino acid metabolism. CONCLUSIONS Our results indicated that low dynamics of gut microbiota composition and high dynamics of its metabolic function from T2 to T3 were associated with TPOAb+ SCH. We concluded that gut microbiota could be new targets for treatment of TPOAb+ SCH during pregnancy. TRIAL REGISTRATION This study was retrospectively registered at the Chinese Clinical Trial Registry (registration number ChiCTR2100047175 ) on June 10, 2021.
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Effects of Lactococcus lactis subsp. cremoris YRC3780 daily intake on the HPA axis response to acute psychological stress in healthy Japanese men.
Matsuura, N, Motoshima, H, Uchida, K, Yamanaka, Y
European journal of clinical nutrition. 2022;76(4):574-580
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The hypothalamic-pituitary-adrenal (HPA) axis is involved in the stress response and is linked to the microbiome through a number of possible mechanisms, including immune-related ones. Lactococcus lactis subsp. cremoris YRC3780 (YRC3780), a probiotic isolated from kefir, has been shown to have beneficial immune-modulatory properties. The aim of this double-blind, placebo-controlled trial, which included 27 healthy young men, was to assess sleep quality, mental health, HPA axis activity (salivary cortisol) and response to an acute stress test during/after 8 weeks of supplementation with YRC3780. At 8 weeks, salivary morning cortisol levels were significantly reduced in the probiotic compared to the placebo group. The effect on the stress test depended on whether or not participants were considered “cortisol-responders” or not. Improvements in sleep quality were seen at 6 weeks (but not at any other time points) in 1 out of 2 sleep questionnaires in the YRC3780 group, whilst no significant differences were observed in actigraphy-measured sleep efficiency. There were no differences in mood between groups, but significant improvements in general health in the probiotic group. Interestingly, no changes in the microbiome of the probiotic group were seen, suggesting that the observed effects may be mediated via the immune system.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Research indicates a bidirectional interaction between the gut microbiome and the central nervous system, affecting the functions of the brain and spinal cord.
- This clinical trial suggests that daily intake of Lactococcus lactis subsp. cremoris (YRC3780) may enhance the HPA axis response to acute psychological stress, potentially linked to a reduction in morning cortisol levels.
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:
Introduction
A randomized, placebo-controlled, double-blind clinical trial was conducted to investigate the influence of Lactococcus lactis subsp. cremoris (YRC3780), isolated from kefir, on stress response, sleep quality, and mental health.
Method
Twenty-seven healthy young men, with an average age of 23.5 years, and mean body mass index of 21.5 kg/m2 , were randomly assigned to either the YRC3780 group or the placebo group. Participants were administered YRC3780 or a placebo daily for 8 weeks.
Throughout the study, participants completed assessments, including the Athens Insomnia Scale (AIS), the Pittsburgh Sleep Quality Index (PSQI), the General Health Questionnaire (GHQ-28), and the Profile of Mood States 2nd Edition-Adult Short, Total Mood Disturbance subscale (POMS 2 TMD), every 2 weeks. Additionally, diurnal rhythms of HPA axis activity were assessed every 2 weeks through saliva samples collected at 2-hour intervals during the day. At the end of the 8-week supplementation period, participants underwent the Trier Social Stress Test (TSST) to evaluate the effects of daily YRC3780 intake on the HPA axis stress response. In addition, three fecal samples were collected to analyse the gut microbiome (on the last day of baseline, and at 4 and 8 weeks).
A total of 27 out of 33 subjects (81%) completed the study, with six participants withdrawing without providing explanations.
Results
The primary findings of this study were as follows:
- At week 6 of YRC3780 supplementation, salivary cortisol levels at 2 hours and 6 hours after waking were significantly lower in the YRC3780 group compared to the placebo group (p=0.05).
- Salivary cortisol concentrations at 40 minutes after the TSST were significantly lower in the YRC3780 group (4.2 ± 4.4 nmol/L, mean ± SD) than in the placebo group (7.6 ± 4.7 nmol/L) (p=0.043).
- AIS scores at 6 weeks and GHQ-28 scores at 8 weeks were significantly lower in the YRC3780 group compared to the placebo group (AIS, p=0.031; GHQ-28, p=0.038) indicating better sleep quality and a better mental state.
Conclusion:
Oral supplementation with YRC3780 may have beneficial effects on the HPA axis response to acute psychological stress, potentially associated with a decrease in morning cortisol levels. Additionally, the study suggests that the lower basal activity and stress reactivity of the HPA axis may lead to improvements in subjective sleep quality and mental health.
Clinical practice applications:
- The precise mechanisms underlying the correlation between the gut microbiota and the gut-brain axis remain incompletely understood, emphasising the need for further research.
- This clinical trial demonstrated that daily intake of YRC3780 decreased morning salivary cortisol levels at 6 and 8 weeks and reduced the salivary cortisol response to acute psychological stress.
Considerations for future research:
- Larger, adequately powered clinical trials are required to provide deeper insights into the mechanisms responsible for the stress-reducing and sleep-improving effects of Lactococcus lactis subsp. cremoris.
- Furthermore, investigations into optimal dosage and duration of probiotic supplementation are warranted for a more comprehensive understanding, particularly in diverse demographic groups.
- Comparative research is needed to explore the effects of various probiotic strains on objective stress responses.
Abstract
BACKGROUND Lactococcus lactis subsp. cremoris (YRC3780), which is isolated from kefir, has been associated with anti-allergic effects in humans. However, it remains unknown whether daily intake of YRC3780 attenuates the response to psychological stress in humans in parallel with changes to the gut microbiome. We examined the fundamental role of YRC3780 in the gut microbiome, stress response, sleep, and mental health in humans. METHODS Effects of daily intake of YRC3780 on the hypothalamic-pituitary-adrenal (HPA) axis response to acute psychological stress were investigated in a double-blind, placebo-controlled clinical trial involving 27 healthy young men (mean age and body mass index: 23.5 years and 21.5 kg/m2) who were randomly assigned to placebo (n = 13) or YRC3780 (n = 14) groups. The HPA axis response to acute psychological stress, the diurnal rhythm of HPA axis activity, and gut microbiome were assessed and compared between the two groups. RESULTS The results showed that daily intake of YRC3780 significantly lowered morning salivary cortisol levels compared with placebo. In addition, salivary cortisol levels following a social stress test significantly decreased +40 min after beginning the TSST in the YRC3780-treated group compared to placebo. There were no significant differences between the two groups in terms of actigraphy-based sleep quality, but the subjective sleep quality and mental health were significantly improved in the YRC3780-treated group compared to placebo. CONCLUSIONS Our study suggests that daily intake of YRC3780 improves the HPA axis response to acute psychological stress, which might be associated with a decrease in morning cortisol levels.
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Testosterone does not affect lower urinary tract symptoms while improving markers of prostatitis in men with benign prostatic hyperplasia: a randomized clinical trial.
Rastrelli, G, Cipriani, S, Lotti, F, Cellai, I, Comeglio, P, Filippi, S, Boddi, V, Della Camera, PA, Santi, R, Boni, L, et al
Journal of endocrinological investigation. 2022;45(7):1413-1425
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Benign prostatic hyperplasia (BPH) — also called benign prostate enlargement — is frequent in aging populations, with a 40 – 50% prevalence in men aged 50–60 years and up to 90% in men older than 80 years. The aim of this study was to verify whether testosterone therapy (TTh) in men with BPH, metabolic syndrome (MetS) and low testosterone is able to improve lower urinary tract symptoms (LUTS) and intraprostatic inflammation. This study is a double blind, randomised 24-week clinical trial in men with low testosterone and MetS and a candidate for prostate surgery for BPH. Patients (n=144) were centrally randomised 1:1 to one of the two groups; TTh or placebo. Results show that TTh administered for 24 weeks is a safe option and it improves prostatic inflammatory features thus ameliorating one of the pathogenic components of BPH. However, there were no differences in improvements of the urinary symptoms between both groups (TTh and placebo). Authors conclude that decreased inflammation is not accompanied by a consistent improvement in urinary symptoms, and that their findings show the safety of TTh in subjects with BPH of surgical significance.
Abstract
PURPOSE Benign Prostatic Hyperplasia (BPH) is a result of prostate inflammation, frequently occurring in metabolic syndrome (MetS). Low testosterone is common in MetS. A randomized clinical trial was designed to evaluate if 24 weeks of testosterone therapy (TTh) in BPH men with MetS and low testosterone improve urinary symptoms and prostate inflammation. METHODS One-hundred-twenty men with MetS waitlisted for BPH surgery were enrolled. They were categorized into normal testosterone (TT ≥ 12 nmol/L and cFT ≥ 225 pmol/L; n = 48) and testosterone deficient (TD) (TT < 12 nmol/L and/or cFT < 225 pmol/L; n = 72) then randomized to testosterone gel 2% (5 g/daily) or placebo for 24 weeks. At baseline and follow-up, questionnaires for urinary symptoms and trans-rectal ultrasound were performed. Prostate tissue was collected for molecular and histopathological analyses. RESULTS No differences in the improvement of urinary symptoms were found between TTh and placebo (OR [95% CI] 0.96 [0.39; 2.37]). In TD + TTh, increase in prostate but not adenoma volume was observed (2.64 mL [0.07; 5.20] and 1.82 mL [- 0.46; 0.41], respectively). Ultrasound markers of inflammation were improved. In a subset of 61 men, a hyper-expression of several pro-inflammatory genes was found in TD + placebo when compared with normal testosterone. TTh was able to counteract this effect. For 80 men, the inflammatory infiltrate was higher in TD + placebo than in normal testosterone (0.8 points [0.2; 1.4]) and TD + TTh men (0.9 points [0.2; 1.5]). CONCLUSIONS Twenty-four weeks of TTh in TD men with BPH and MetS improves ultrasound, molecular and histological proxies of prostate inflammation. This does not result in symptom improvement.
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The effect of Melatonin on Improving the benign Prostatic Hyperplasia Urinary Symptoms, a Randomized Clinical Trial.
Fotovat, A, Samadzadeh, B, Ayati, M, Nowroozi, MR, Momeni, SA, Yavari, S, Nasseri, A, Sharifi, L
Urology journal. 2022;19(5):406-411
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Plain language summary
Benign prostatic hyperplasia (BPH) is a common issue in men older than 40. BPH is accompanied by irritating and obstructive symptoms that sometimes lead to surgery due to lack of recovery. Tamsulosin is an alpha-receptor blocker that is considered a standard treatment for patients. The aim of this study was to investigate the effect of melatonin [a hormone secreted by the pineal gland at night that regulates the sleep-wake cycle] along with standard treatment on improving the BPH urinary symptoms as well as patients’ quality of life due to their urinary problems. This study is a single centre, parallel group randomised, double-blind clinical trial with balanced randomisation. Patients (n = 108) were randomly allocated to one of the two groups. Results show the combination of melatonin and tamsulosin was significantly effective in treating the symptoms of frequency and nocturia in patients with BPH. Authors conclude that their findings can be used to pave the way to improving the symptoms of patients with BPH.
Abstract
PURPOSE to investigate the effect of melatonin along with tamsulosin in improving BPH urinary symptoms. MATERIALS AND METHODS A total of 108 men with BPH symptoms, age of ≥ 50 years, and International Prostate Symptom Score (IPSS) ≥ 8 entered into the parallel group randomized, double-blind clinical trial with balanced randomization. The treatment group received of 3mg melatonin plus 0.4mg tamsulosin and the control group received placebo plus 0.4mg tamsulosin. Patients and physicians were concealed by sealed and opaque envelopes. Symptoms were assessed at baseline and 1 month after treatment. Finally all scores at the initial and end of the study were compared and analyzed using SPSS software. RESULTS This study showed that adding melatonin to the classic treatment of BPH patients with tamsulosin could significantly reduce the likelihood of nocturia by 2.39 times (95% CI: 1.07-5.32, OR = 2.39, p = 0.033) and could also reduce the frequency of urination by 2.59 times (95% CI: 1.15-5.84, OR = 2.59, p = 0.021). There was no statistically significant difference between the two groups in IPSS, intermittency, incomplete emptying, straining, urgency, and weak stream. CONCLUSION Melatonin plus tamsulosin treatment is associated with a significant improvement of nocturia and frequency in patients with benign proststic hyperplasia. However, it is necessary to do more studies.