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Associations between circulating obesity-related biomarkers and prognosis in female breast cancer survivors: a systematic review of observational data in women enrolled in lifestyle intervention trials.
Meyer, D, Pastor-Villaescusa, B, Michel, S, Hauner, H, Hauner, D
BMC cancer. 2022;22(1):1187
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Overweight and obesity play a role in the development and potential outcomes in breast cancer. Several factors have been implicated linking cancer and obesity including hormones imbalances and inflammation, however exact links have yet to be elucidated. This systematic review of 4 randomised control trials containing 5234 women aimed to examine obesity related blood factors such as hormones, fats and sugar and their relationship with prognosis in individuals with breast cancer. The results showed that higher levels of testosterone were associated with an increased risk of recurrence of breast cancer. The female sex hormones, oestradiol and sex hormone binding globulin were not associated with breast cancer recurrence. Blood sugar levels and insulin resistance were not associated with breast cancer recurrence. There were certain growth factors, which are molecules responsible for stimulating cellular processes, that were responsible for an increased chance of recurrence of breast cancer and insulin-like growth factor and platelet derived growth factor were shown to increase risk but only when increased in combination with each other. Inconsistent results were seen with C-reactive protein, which is an inflammatory marker. It was concluded that testosterone may be associated with an increased risk of breast cancer recurrence, however the evidence from the other blood factor was unreliable due to poor quality trials. More trials are needed to investigate these factors further. This study could be used by healthcare professionals to understand that weight loss is the key to the prevention of recurrence of breast cancer in those who are overweight and that testosterone levels could be used to identify those who are at an increased risk.
Abstract
Obesity plays an important role in the development and progression of breast cancer via various oncogenic pathways. However, the biological mechanisms underlying this relationship are not fully understood. Moreover, it is unclear whether obesity-related and further associated biomarkers could be suitable targets for lifestyle interventions. This systematic review was conducted to examine relationships between obesity-related blood parameters and prognosis for breast cancer survivors enrolled in lifestyle intervention studies. A systematic, computerized literature search was conducted from inception through August 26th, 2020 in PubMed, EMBASE, and CENTRAL. The focus was on observational data from randomized controlled lifestyle intervention trials investigating associations between selected baseline biomarkers, measured in remission, and breast cancer recurrence, breast cancer mortality and/or all-cause mortality. Four studies with data from 5234 women met the inclusion criteria.Studies herein provide moderate evidence that bioavailable or serum testosterone may be positively linked to breast cancer recurrence and inversely linked to disease-free survival. Limited evidence suggests no associations with circulating estradiol or insulin levels on prognosis outcomes, whereas HDL cholesterol was inversely associated with breast cancer recurrence. For some other biomarkers, such as growth factors, adipokines, and CRP, the evidence for associations with disease prognosis was too weak to draw conclusions.Overall, despite potential candidates, there is insufficient evidence to confirm or refute that obesity-related biomarkers and sex hormones have a prognostic value for breast cancer survival. More longitudinal studies in breast cancer survivors to examine the clinical utility of obesity-related biomarkers are needed.
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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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Evaluating the Clinical Utility of Daily Heart Rate Variability Assessment for Classifying Meaningful Change in Testosterone-to-Cortisol Ratio: A Preliminary Study.
DeBlauw, JA, Crawford, DA, Kurtz, BK, Drake, NB, Heinrich, KM
International journal of exercise science. 2021;14(3):260-273
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Exercise-induced hormonal responses are controlled by the hypothalamic-pituitary adrenal axis, a key regulator of homeostasis, which responds to stress by triggering a series of endocrine changes resulting in the release of testosterone (T) and cortisol (C). The aim of this study was to determine the relationship between daily resting heart rate variability (HRV) and pre-exercise T:C ratio and evaluate the clinical utility (i.e., diagnostic validity and reliability) of daily HRV assessment in classifying atypical T:C ratio changes throughout a nine-week high-intensity functional training (HIFT) intervention. This study is a secondary analysis of a subset of participants from a larger study. Eight recreationally active men and women ages 18-35 were recruited for participation. Following 14 days of baseline HRV assessments, participants were randomized to either the treatment or control condition. Results show a statistically significant negative relationship between HRVdaily and the T:C ratio throughout 9-weeks of HIFT. Additionally, there was no significant relationship found between C and HRVdaily and neither sex nor group were significant factors. Authors conclude that their findings emphasize the potential of HRV for the guidance of training, however, as hormonal responses to training are highly individual, the creation of individual autonomic nervous systems and hormonal profiles would increase the accuracy of training stress modulation.
Abstract
The study purpose was to determine the relationship of resting heart rate variability (HRV) and testosterone to cortisol (T:C) ratio, along with the diagnostic ability of HRV to assess changes in T:C ratio during a 9-week high-intensity functional training intervention. Eight recreationally-active men (n = 4, age 24.25 ± 1.75 yrs, height 181.25 ± 3.86 cm, weight 79.68 ± 11.66 kg) and women (n = 4, age 26 ± 3.6 yrs, height 164.25 ± 3.3, weight 73.4 ± 8.42) completed daily HRV measurements (HRVdaily) using photoplethysmography via a commercially-available smartphone application along with weekly saliva samples. Saliva samples were analyzed for concentrations of testosterone (T) and cortisol (C) via enzyme-linked immunosorbent assays. Upon study completion 72 data points were available, due to participant compliance and inadequate saliva sample, 67 matched pairs of HRV and T:C ratio were analyzed. A statistically significant negative relationship (n = 67, r = -.315, p < 0.05) was found between HRVdaily and saliva T:C ratio concentrations within aggregate data. Individual participant relationships showed considerable variability (r = -0.101 - 0.665, p = 0.103 to 0.829 The model which best explained the data resulted in AIC = 130.247 with factors HRVdaily (β = -0.218, 95%CI = -0.391, -0.044, t = -2.46, p < 0.05), Sex (β = 0.450, 95%CI = -0.214, 1.114, t = 1.113, p = 0.242), and Group (β = -0.394, 95%CI = -1.089, 0.302, t = -1.11, p = 0.311). Diagnostically, HRVdaily demonstrates excellent sensitivity (95%), but poor specificity (5%) for detecting meaningful changes in T:C ratio. Assessment of HRVdaily may be a clinically valid proxy measure for monitoring hormonal changes throughout a training intervention.
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Manipulation of Dietary Intake on Changes in Circulating Testosterone Concentrations.
Zamir, A, Ben-Zeev, T, Hoffman, JR
Nutrients. 2021;13(10)
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Androgens, like testosterone, are steroid hormones commonly associated with reproduction. However, they also govern metabolic functions, body composition and growth. Higher levels of circulating androgens enhance athletic performance by supporting metabolic activities such as protein production, regeneration and growth and by inhibiting breakdown processes. Manipulating testosterone to enhance athletic performance without the use of anabolic steroids hormones has been of much interest. As macro-and micronutrients can influence androgen hormones, this review examined whether specific energy and nutrient intake can ‘naturally’ manipulate testosterone levels. The authors describe the metabolic functions of testosterone before exploring the current evidence on selected plant extracts and nutrients and their impact on aromatase activity. Inhibiting aromatase can prevent androgens from being converted into oestrogen and thus may help to raise circulating androgens. Discussed are a range of plant-derived compounds, flavonoids, macronutrients and micronutrients (Vitamin D, Zinc and Magnesium) and their impact on testosterone levels. The authors conclude that the nutrients discussed have some supportive evidence, yet overall findings are inconclusive due to limited studies. Regarding macronutrients more research is available, and the evidence supports that low energy intake negatively impacts testosterone levels and performance. Whereby supplementation of vitamins crucial to testosterone production seems to provide value in cases of deficiency further research is required. This article yields an overview of plant compounds, macro-and micronutrients and their potential impact on circulating testosterone levels. While low energy intake and nutrient deficiencies appears to be unfavourable, the absence of clear evidence on other compounds would warrant further case-specific investigations.
Abstract
Elevations in the circulating concentration of androgens are thought to have a positive effect on the anabolic processes leading to improved athletic performance. Anabolic-androgenic steroids have often been used by competitive athletes to augment this effect. Although there has been concerted effort on examining how manipulating training variables (e.g., intensity and volume of training) can influence the androgen response to exercise, there has been much less effort directed at understanding how changes in both macronutrient and micronutrient intake can impact the androgen response. Thus, the focus of this review is to examine the effect that manipulating energy and nutrient intake has on circulating concentrations of testosterone and what the potential mechanism is governing these changes.
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Time-restricted eating effects on performance, immune function, and body composition in elite cyclists: a randomized controlled trial.
Moro, T, Tinsley, G, Longo, G, Grigoletto, D, Bianco, A, Ferraris, C, Guglielmetti, M, Veneto, A, Tagliabue, A, Marcolin, G, et al
Journal of the International Society of Sports Nutrition. 2020;17(1):65
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Adequate nutrition is important for elite athletes, as nutrient availability influences energy expenditure, body composition, performance and exercise-induced immune responses. Time-restricted eating (TRE) is a form of intermittent fasting that has received much interest in recent years. Previous research of TRE suggested beneficial effects on performance in untrained individuals, by allowing weight loss whilst maintaining muscle functions. These qualities are of interest for endurance cyclists hence the authors of this study sought to investigate the impact of TRE in elite cyclists. Sixteen under-23 year old, elite cyclists were randomly assigned to eat within a TRE window of 8-hr or 15hr window during a 4-week, high-level endurance training phase. Both groups consumed their full estimated energy needs and markers such as fat and fat-free mass, VO2 max, basal metabolism, blood counts, anabolic hormones and inflammatory markers were measured. As a result, TRE produced weight loss, improved body composition and increased peak power output in relation to body weight without compromising aerobic performance. Furthermore, the TRE pattern proved helpful in mitigating some of the exercise-induced suppressions of the immune system. The authors concluded that TRE could be considered as part of a performance nutrition plan in endurance athletes. Particularly where there is a need to reduce body fat mass or for the management of training-induced depression of the immune system and associated respiratory infection susceptibility. This can be of clinical relevance in the support of endurance athletes.
Abstract
BACKGROUND Although there is substantial interest in intermittent fasting as a dietary approach in active individuals, information regarding its effects in elite endurance athletes is currently unavailable. The present parallel randomized trial investigated the effects of a particular intermittent fasting approach, called time-restricted eating (TRE), during 4 weeks of high-level endurance training. METHODS Sixteen elite under-23 cyclists were randomly assigned either to a TRE group or a control group (ND). The TRE group consumed 100% of its estimated daily energy needs in an 8-h time window (from 10:00 a.m. to 6:00 p.m.) whilst energy intake in the ND group was distributed in 3 meals consumed between 7:00 a.m. and 9:00 p.m. Fat and fat-free mass were estimated by bioelectrical impedance analysis and VO2max and basal metabolism by indirect gas analyzer. In addition, blood counts, anabolic hormones (i.e. free testosterone, IGF-1) and inflammatory markers (i.e. IL-6, TNF-α) were assessed. RESULTS TRE reduced body weight (- 2%; p = 0.04) and fat mass percentage (- 1.1%; p = 0.01) with no change in fat-free mass. Performance tests showed no significant differences between groups, however the peak power output/body weight ratio (PPO/BW) improved in TRE group due to weight loss (p = 0.02). Free testosterone and IGF-1 decreased significantly (p = 0.01 and p = 0.03 respectively) in TRE group. Leucocyte count decreased in ND group (p = 0.02) whilst the neutrophils-to-lymphocytes ratio (NLR) decreased significantly (p = 0.03) in TRE group. CONCLUSIONS Our results suggest that a TRE program with an 8-h feeding window elicits weight loss, improves body composition and increases PPO/BW in elite cyclists. TRE could also be beneficial for reducing inflammation and may have a protective effect on some components of the immune system. Overall, TRE could be considered as a component of a periodized nutrition plan in endurance athletes. TRIAL REGISTRATION This trial was retrospectively registered at clinicaltrials.gov as NCT04320784 on 25 March 2020.
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The effects of d-aspartic acid supplementation in resistance-trained men over a three month training period: A randomised controlled trial.
Melville, GW, Siegler, JC, Marshall, PWM
PloS one. 2017;12(8):e0182630
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D-aspartic acid (DAA) is an amino acid that is currently purported as a testosterone-boosting supplement. Research has shown that DAA supplementation increases testosterone levels in untrained men, however in trained men has been shown to produce no effect. The aim of this study was to evaluate the effects of DAA to alter testosterone levels over three months of resistance training in 22 men. Participants were randomised to receive DAA or placebo and performed 12 weeks of supervised resistance training. Blood analyses and muscle measurements were assessed at baseline, six weeks and 12 weeks. This study found that DAA supplementation is ineffective in trained men at changing testosterone levels or positively affecting training outcomes. According to these findings, the authors suggest future studies further exploring the effects of supplementation in a trained population.
Abstract
CONTEXT Research on d-aspartic acid (DAA) has demonstrated increases in total testosterone levels in untrained men, however research in resistance-trained men demonstrated no changes, and reductions in testosterone levels. The long-term consequences of DAA in a resistance trained population are currently unknown. OBJECTIVE To evaluate the effectiveness of DAA to alter basal testosterone levels over 3 months of resistance training in resistance-trained men. DESIGN Randomised, double-blind, placebo controlled trial in healthy resistance-trained men, aged 18-36, had been performing regular resistance training exercise for at least 3 d.w-1 for the previous 2 years. Randomised participants were 22 men (d-aspartic acid n = 11; placebo n = 11) (age, 23.8±4.9 y, training age, 3.2±1.5 y). INTERVENTION D-aspartic acid (6 g.d-1, DAA) versus equal-weight, visually-matched placebo (PLA). All participants performed 12 weeks of supervised, periodised resistance training (4 d.w-1), with a program focusing on all muscle groups. MEASURES Basal hormones, total testosterone (TT), free testosterone (FT), estradiol (E2), sex-hormone-binding globulin (SHBG) and albumin (ALB); isometric strength; calf muscle cross-sectional area (CSA); calf muscle thickness; quadriceps muscle CSA; quadriceps muscle thickness; evoked V-wave and H-reflexes, were assessed at weeks zero (T1), after six weeks (T2) and after 12 weeks (T3). RESULTS No change in basal TT or FT were observed after the intervention. DAA supplementation (n = 10) led to a 16%, 95% CI [-27%, -5%] reduction in E2 from T1-T3 (p<0.01). The placebo group (n = 9) demonstrated improvements in spinal responsiveness (gastrocnemius) at the level of the alpha motoneuron. Both groups exhibited increases in isometric strength of the plantar flexors by 17%, 95% CI [7%, 28%] (p<0.05) as well as similar increases in hypertrophy in the quadriceps and calf muscles. CONCLUSIONS The results of this paper indicate that DAA supplementation is ineffective at changing testosterone levels, or positively affecting training outcomes. Reductions in estradiol and the blunting of peripheral excitability appear unrelated to improvements from resistance training. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry ACTRN12617000041358.