Low Testosterone Concentrations in Men: Identifying causative factors and non-pharmacological treatment strategies

Stephen J Smith

Background: Low testosterone concentrations in men are associated with several pathophysiological factors that affect the hypothalamic-pituitary-gonadal (HPG) axis functioning. Currently, the primary treatment for low testosterone concentrations in men is testosterone replacement therapy (TRT). However, according to the Endocrine Society of Australia, this treatment may exacerbate pre-existing medical conditions and is only suitable for men with irreversible hypogonadism. Conversely, men who have comorbid conditions that are associated with the pathophysiological factors that affect the HPG axis are therefore encouraged to treat the comorbid conditions and/ or the pathophysiological factors that cause HPG axis dysfunction. Specific Aims: Within this thesis, the pathophysiological factors associated with low testosterone concentrations that affect the HPG axis were identified and examined (Chapter 2). Since chronic alcohol abuse (lifestyle factor) is a consistent contributor to low testosterone concentrations, alcohol consumption and its effects on testosterone synthesis in men was investigated (Chapter 3). Additionally, various comorbidities are also associated with low testosterone concentrations in men. Therefore, a cross-sectional analysis was conducted using two National Health and Nutrition Examination Survey (NHANES) periods to identify factors associated with low testosterone concentrations (Chapter 4). Since lifestyle modification and improvement of comorbid conditions results in improved HPG functioning, a meta-analysis was conducted to examine the effects of calorie restriction (CR), which induced weight loss, on testosterone concentrations in men (Chapter 5). Moreover, natural treatment options for low testosterone concentrations in men, such as herbal-based nutritional supplementation, may provide an alternative to TRT. Therefore, a Systematic Review was conducted to assess the literature in this field (Chapter 6). The outcomes of a randomised controlled trial using ashwagandha (Withania somnifera), one of the effective herbs identified in the Systematic Review, was also conducted to determine its effects on testosterone concentrations (and associated hormones), the pathophysiological factors, and the comorbidities associated with low testosterone concentrations (Chapter 7). Methods: The pathophysiological factors associated with low testosterone concentrations in men were identified and examined. These are inflammation, oxidative stress (OS), insulin resistance (IR), and increased hypothalamic-pituitary-adrenal (HPA) axis activity. The mechanisms through which these factors disrupt HPG axis functioning were elucidated (Chapter 2). Many lifestyle factors are also associated with low testosterone concentrations in men. These lifestyle factors initiate one or more pathophysiological factors and may also contribute to the comorbidities associated with low testosterone concentrations in men. Alcohol is consumed by a significant portion of the male population, with excess alcohol consumption being one of the first identified lifestyle factors associated with low testosterone concentrations. Therefore, a review paper was prepared investigating its effects on the HPG axis via the pathophysiological factors (Chapter 3). Comorbidities are also associated with low testosterone concentrations in men. Therefore, two NHANES survey periods were selected for analysis (2013-2014 and 2015-2016). Adult male participants were identified and categorised according to body mass index (BMI) (normal, 18.5-24.99; overweight, 25-29.99; and obese, >30), with underweight participants excluded. An analysis was conducted examining the associations between BMI, oral glucose tolerance test (OGTT), homeostatic assessment for insulin resistance (HOMA-IR), insulin, glucose, and age with total testosterone and sex hormone-binding globulin (Chapter 4). Two systematic searches were conducted to identify articles from inception until March 2020 investigating the effects of CR and herbal extracts on testosterone concentrations in men (Chapters 5 and 6). Data for both searches were extracted by two authors independently using the Cochrane Collaboration Data Collection Form. Risk of bias of the included studies was also conducted independently by the two authors. A qualitative synthesis was conducted on the included studies with results summarised in tables (Chapters 5 and 6). Meta-analyses were conducted on the CR papers based on random-effects models (Chapter 5). A randomised controlled trial (RCT) was conducted using 400 mg per day of an ashwagandha (Withania somnifera) root extract for 12 weeks. The RCT investigated ashwagandha’s effects on testosterone concentrations (and associated hormones) in men as well as the pathophysiological factors and the comorbidities associated with low testosterone concentrations in men (Chapter 7). Results: Evidence from the research indicated that low-to-moderate alcohol consumption may increase testosterone concentrations in men via its effect on hepatic enzymes. The evidence also indicated that excessive alcohol consumption, alcohol use disorder (AUD), has a significant negative effect on testosterone synthesis in men. AUD affects each level of the HPG axis via several pathophysiological factors including increased HPA axis activity, increased inflammation, and increased oxidative stress (Chapter 3). Data from 2286 men were available for analysis from the two NHANES data sets (Chapter 4). The main findings of this study were (i) overweight and obese conditions were inversely associated with TT and SHBG concentrations, even after adjusting for other variables; (ii) the measurements associated with type 2 diabetes mellitus (T2DM) [OGTT, HOMA-IR, insulin, and glucose] were inversely associated with TT concentrations, and all variables remained significant, except glucose concentrations and HOMA-IR levels, after adjusting for other variables; (iii) insulin was significantly inversely associated with SHBG, even after adjusting for other variables; (iv) HOMA-IR was significantly inversely associated with SHBG; however after adjusting for other variables only the pre-diabetic level remained significant; (v) Glucose concentrations and OGTT were not significantly associated with SHBG concentrations; however, after adjusting for other variables OGTT became significant; (vi) and age was positively associated with SHBG concentrations and this relationship strengthened after adjusting for the other variables. The potential mechanisms of action through which these comorbidities may affect testosterone production in men via the pathophysiological factors was also examined. In the systematic review and meta-analysis investigating the effects of CR on testosterone concentrations in men (Chapter 5), 7 randomised controlled trials (449 participants) that employed either a crossover (n = 1) or parallel (n = 6) study design were identified as eligible following assessment using the selection criteria. The main findings of this systematic review provided some support for the hypothesis that CR increases testosterone concentrations in overweight or obese males and decreases testosterone concentrations in normal-weight, healthy males. The potential mechanisms through which these processes occur were also examined. In the systematic review investigating the effects of herbs/ herbal extracts on testosterone concentrations in men (Chapter 6), 32 randomised controlled trials (2488 participants in total; 2446 males and 42 females) that employed either a parallel (n = 29) or crossover (n = 3) design were identified as eligible following assessment using the selection criteria. Only the outcome measures from men were used in this review. The main findings of this review indicated that some herbs, particularly, fenugreek seed extracts and ashwagandha extracts, have positive effects on testosterone concentrations in males. A single trial on a forskohlii root extract was also associated with increased testosterone as was a single trial on Asian ginseng. In a randomised controlled trial (Chapter 7), with 60 male participants aged between 40 and 75 years and who were experiencing stress and fatigue, an ashwagandha (Withania somnifera) root extract was used to determine its effects on testosterone, associated hormones, and physiological factors associated with low testosterone concentrations in men. The main findings of this trial were that supplementing with 200 mg of an ashwagandha extract twice daily, totalling 400 mg a day, was associated with a significant increase in free testosterone (FT) and luteinising hormone (LH) concentrations, an increase in heart rate variability (HRV), and a reduction in fatigue scores, based on the Chalder Fatigue Scale (CFS), compared to men in the placebo group. However, compared to the placebo, ashwagandha extract supplementation did not significantly improve Perceived Stress Scale (PSS) scores, Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) scores, adiposity measures, fasting glucose or glycated haemoglobin (HbA1c) concentrations, grip strength, malondialdehyde (MDA) concentrations, or concentrations in several sex hormones including total testosterone (TT), oestradiol, and dehydroepiandrosterone sulphate (DHEA-S). Conclusions: The findings presented in this thesis provide evidence for using natural strategies to support endogenous testosterone production in men. These strategies include low-to-moderate consumption of alcohol, weight loss for overweight or obese men, potentially via calorie restriction, and the use of specific herbal extracts that attenuate the causes of low testosterone concentrations. These nutrition-based lifestyle factors may assist with reducing inflammation, oxidative stress, and insulin resistance, as well as modulating the HPA response, allowing the body to optimise testosterone synthesis, ultimately increasing testosterone concentrations in men.

Low Testosterone Concentrations in Men: Identifying causative factors and non-pharmacological treatment strategies

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