We are living in a time of worsening global health through a surge in modifiable illness. With reduced levels of daily physical activity and diets high in refined carbohydrate, we are seeing a rise in the rate of metabolic syndrome (MetS) among men globally. The role of testosterone remains crucial for men’s health, and we are continuing to learn more about the links between testosterone and MetS.
Testosterone, the primary male sex hormone, is a naturally occurring androgen, produced in both the testes and adrenal glands, with anabolic and virilising effects, stimulating and controlling the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. Women also produce testosterone, however to a much lesser extent.
Symptoms of reduced testosterone include decreased libido and sexual function, fatigue, muscle weakness and memory impairment. With such symptoms, clinicians can often overlook testosterone and focus on more common causes such as diabetes, depression or medication side-effects.
Many studies have shown age-related cross-sectional declines in total and/or Free Testosterone (FT) levels in men (Harman et al, 2001). Correlation studies have shown that visceral fat increases with age, with an inverse correlation between the amount of visceral fat and plasma insulin with levels of testosterone and sexhormone binding globulin (SHBG) (Kupelian et al, 2006). Approximately 50% of men in their 80s will have testosterone levels in the hypogonadal range. Correlation studies cannot distinguish between cause and effect relationships between whether low testosterone induces visceral fat deposition or whether a large visceral fat deposit leads to low testosterone levels. Prospective studies have confirmed that lower endogenous androgens predict central adiposity in men (Rosmond et al, 2003) and that these low testosterone levels are significantly inversely associated with levels of blood pressure, fasting plasma glucose, triglycerides, and body mass index and positively correlated with HDL-cholesterol (Zmuda et al, 1997). A five-year follow- up study of Swedish men indicated that elevated plasma cortisol and low testosterone were prospectively associated with increased incidence of cardiovascular-related events and Type 2 Diabetes Mellitus (T2DM) (Rosmond et al, 2003).
The extent to which the decline of FT is the result of the ageing process as opposed to chronic illness, medication use and other age-related factors remains controversial. There are several reasons to believe that adiposity is a significant factor in lowering levels of testosterone, which can be seen in men as young as 40 (Goncharov et al, 2009). Increased adiposity, with its associated hyperinsulinism, suppresses SHBG synthesis, and reduces levels of circulating FT (Eckel et al, 2005). Testosterone has been found to inhibit triglyceride uptake and lipoprotein lipase activity and cause a rapid turnover of triglycerides in abdominal adipose tissue (Martin et al, 1996). Furthermore, insulin (Pitteloug et al, 2005) and leptin (Isidori et al,1999) have a suppressive impact on testicular steroidogenesis (Stamler et al, 1976). The role of testosterone on insulin sensitivity was further investigated, where acute androgen deprivation resulted in reduced insulin sensitivity among young men (Yiamalas et al, 2007) and strongly impaired the glycaemic control of men with T2DM (Haidar et al, 2007).
The metabolic syndrome
The metabolic syndrome (MetS) is a constellation of metabolic risk factors (including hypertension, dyslipidaemia, abdominal obesity and impaired glucose metabolism), which is associated with a twofold increased risk of cardiovascular disease (CVD) (Ford, 2005), and an even higher risk of T2DM (Grundy, 2008). The prevalence of MetS increases with age and is higher in men (RegitzZagrosek, 2006), with MetS-associated risks varying according to sex (Boden-Albala et al, 2008), where women have a stronger risk factor for developing CVD (Takahashi et al, 2007).
Since the first formalised definition of MetS by the World Health Organization in 1998 (Alberti, 1998), there has been considerable disagreement over the terminology and diagnostic criteria used, with differing views from several scientific bodies. These include the International Diabetes Federation, the World Health Organization, the American Heart Association/National Heart, Lung and Blood Institute and the European Cardiovascular Society (Alberti, 2009). Furthermore, there is further controversy over whether MetS is a true syndrome or a mixture of unrelated phenotypes (Alberti, 2009). This has understandably led to confusion among practitioners. However in 2009, a consensus agreement was reached to unify the approach in defining MetS worldwide (see Figure 1).
The obesity epidemic
More than half of Europeans are now either overweight or obese (Tuomilehto and Schwartz, 2010), with alarming trends also seen in children (Health and Social Care Information Centre, 2013). Physical inactivity (6%) and obesity (5%) are now recognised as some of the leading causes of global mortality (WHO, 2011). In the United States, 63% of men and 55% of women are classified as being overweight, with 22% having a BMI of more than 30kg/m2 (Ogden et al, 2006). Approximately 80% of obese adults suffer from at least one, and 40% from two or more, of the diseases associated with obesity, such as T2DM, hypertension, cardiovascular disease, gallbladder disease, cancers, and arthritis (Janssen and Mark, 2007).
A large number of cross-sectional studies have established a relationship between abdominal obesity and MetS (Carr and Brunzell, 2004). Testosterone has also been identified as being inversely related to abnormal waist circumference, raised C-reactive protein (CRP) levels, and dyslipidemia (Crysohoou et al, 2013). Often people who have features of MetS also manifest a prothrombotic and proinflammatory state (Alberti, 2009). The mechanisms underlying the contribution of abdominal obesity and insulin resistance to metabolic risk factors is not fully understood (Alberti, 2009), however lipid levels, raised BMI, and raised inflammatory and insulin marker levels seem to explain the relationship, suggesting a potential mediating effect. This finding may support a research hypothesis relating serum testosterone with cardiovascular disease (Crysohoou et al, 2013).
Relationship between testosterone and METs
Previous studies have suggested a role for sex hormones in the development of MetS, with androgen-deprivation therapy in prostate cancer patients (Shahani et al, 2008), and total testosterone levels in hypogonadal men (Chubb et al, 2008) being associated with the development of the condition. MetS and its individual components are also common in hyperandrogenic conditions in women, including polycystic ovary syndrome (PCOS) (Ehrmann et al, 2006). Low sex hormone binding globulin levels have been observed in both men and women with MetS (Maggio et al, 2007). However, little is known about possible sex differences in this association. The Ikaria Study, which researched the diet and lifestyle of Greek people over the age of 80 on the island of Ikaria, suggested a mediating effect of testosterone on the prediction of having MetS (Crysohoou et al, 2013). Inhabitants of this island were four times as likely to reach 90 than their American counterparts.
A systematic review and meta-analysis of crosssectional studies indicated that testosterone levels were significantly lower in men with type 2 diabetes, and men with higher testosterone levels (range 449.6 –605.2 ng/dL) had a 42% lower risk of developing T2DM (Ding et al, 2006). Numerous studies have also found inverse associations between the severity of features of the MetS and plasma testosterone (Kaplan et al, 2006), which can be consistent across race and ethic groups (Kupelian et al, 2008). Furthermore, an inverse relationship has been found in men between testosterone and diabetes (Saad and Gooren, 2009), where those with diabetes have lower testosterone levels (Stanwort and Jones, 2009).
Longitudinal studies have revealed epidemiological evidence that low testosterone levels are independent risk factors for the development of both MetS and T2DM (Triash et al, 2009) and also cerebrovascular events (Yeap et al, 2009). Furthermore, to further clarify the causal nature of the observed associations, more large-scale longitudinal studies are required, particularly in women. Therefore, additional tools, such as Mendelian randomisation studies and intervention studies, are needed to establish true causation. (Brand et al, 2011)
The traditional view among physicians was that the administration of testosterone can lead to an increased risk of malignancy and voidal symptoms among elderly men. Several follow-up studies of men receiving testosterone treatment (Calof et al, 2005) have failed to demonstrate an exacerbation of voiding symptoms due to benign prostatic hyperplasia, with complications such as urinary retention in therapy groups similar to those receiving placebo. There is also no convincing evidence that testosterone is a main factor in the development of prostate cancer in elderly men (Morgentaler, 2009). Guidelines for monitoring have been developed which, if rigorously applied, render testosterone administration to elderly men an acceptably safe therapy in men without a history of prostate carcinoma or without evidence of harboring a prostate carcinoma (Wang et al, 2008). A meta-analysis found that testosterone treatment in older men compared to placebo was not associated with a significantly higher risk of detection of prostate cancer, although the frequency of prostate biopsies was much higher in the testosterone- treated group than in the placebo group (Calof et al, 2005). While there may be a role for administering testosterone for some patients, a more holistic approach is to address both nutrition and physical activity levels in order to improve testosterone production and sensitivity.
The role of exercise for MetS
In 2011, the UK Chief Medical Officer released the Start Active, Stay Active campaign to promote physical activity among the general population. Current exercise guidelines recommend either 75 minutes of vigorous intensity or 150 minutes of moderate intensity per week, or a combination of both. Several physical activity programmes have been produced throughout the UK, including Sport and exercise medicine – a fresh approach, which are designed for physicians and patients to further understand the importance of physical activity for health.
Exercise has been proven to significantly improve blood glucose control, reduce cardiovascular risk factors, contribute to a reduction in waist circumference and prevent the progression to T2DM (Knowler et al, 2002). This is due in part to heightened control of satiety hormones (insulin, leptin, adiponectin, glucagon-like peptie and cholecystokinin) which is linked to healthy testosterone levels. Structured exercise interventions have been shown to improve HbA1c in patients with T2DM, independent of body weight with a linear relationship of higher intensity levels being associated with larger reductions (Boule et al 2003). This was also identified in patients with hypertension (Colbery et al, 2010). There is also compelling evidence that regular exercise is effective in the primary prevention of several other chronic diseases, including ischaemic heart disease (RR 40%), stroke (RR 27%), colon cancer (RR 25%), and breast cancer (24%).
Exercise promotion can include simple light aerobic programmes to more intense resistant and high intensity interval exercising (HIIE). Physicians should consider patient age and previous activity levels when recommending an exercise regimen (Bax et al, 2007). Provided there are no contra-indications, patients with diabetes would benefit from a programme which consists of several exercise modalities (Colberg et al, 2010). While the evidence base lacks large trial results, there is no evidence of harm including cardiovascular events during exercise, and/or a worsening of diabetes and/or blood pressure levels by dynamic resistance exercise regiments. There is a strong argument for the promotion of limiting daily physical inactivity, irrespective of level of intensity.
Most exercise protocols designed to promote weight loss have previously focused on regular light aerobic training (three times a week) which have resulted in negligible weight loss (Wu et al, 2009). However, aerobic training is known to improve glycaemic control in the diabetic population (Snowling and Hopkins, 2006). A meta-analysis of endurance training included 72 trials which identified a median training time of 40 minutes, 3 times a week over 16 weeks of a moderate intensity (60% of heart rate reserve). Significant reductions were seen in resting blood pressure (-3.0/-2.4 mmHg), with more significant reductions seen in the hypertensive participants (-6.9/-4.9 mmHg). These trials did not observe the effects of specific training frequency, intensity or mode on blood pressure however (Fagard and Cornelissen, 2007).
Dynamic resistance training
Resistance training includes activities where physical effort is applied against opposing forces with the use of large muscle movements. Progressive resistance exercise programmes have been found to significantly improve insulin sensitivity in individuals with T2DM at a similar or greater impact as observed with aerobic activities (Cauza et al, 2005). One meta-analysis included 25 trials of differing resistance intervention programmes and revealed net mean reductions in blood pressure of -2.7/-2.9 mmHg (Cornelissen et al, 2011)
The precise mechanisms by which resistance training can improve blood pressure are unclear, although several physiological changes are proposed in the literature:
- improvements and chanes in endothelial function (Casey et al, 2007)
- changes in arterial compliance (Rakobowchuk et al, 2005)
- changes in sympathetic activity (Carter et al, 2003)
- changes in cardiac heart rate variability (Collier et al, 2009)
- changes in arterial elasticity and aortic wave reflections (Cortez-Cooper et al, 2009).
High intensity interval exercise (HIIE)
Early research on HIIE has produced preliminary evidence that it can lead to modest reductions in subcutaneous and abdominal fat, with greater reductions in those with T2DM. Regular HIIE (three sessions a week) has also been shown to significantly increase both aerobic and anaerobic fitness while also significantly lowering insulin resistance, resulting in an increase in skeletal muscle capacity for fatty acid oxidation and glycolytic enzyme content (Boutcher, 2011). There is growing evidence for the positive impact of high-intensity interval exercise (HIIE) on weight reduction for overweight individuals (Boucher, 2011). HIIE protocols can vary, but they typically involve an all-out intensity exercise followed by a period of either very low intensity or rest. Most commonly, cycle-sprints are performed on static cycle ergometers at an intensity in excess of 90% of maximal oxygen uptake (V 02 max). Subjects have included adolescents, young men and women, older adults and a selection of patient groups (Boucher, 2011).
The most used protocol is the Wingate test, which consists of 30 seconds of all-out cycle-sprints followed by several minutes of very low intensity cycling (Gibalaand and Mcgee, 2008). This protocol amounts to just three to four minutes of exercise a session, with sessions being performed three times a week. Most of our insight into the skeletal muscle adaptation to HIIE has been achieved through this protocol (Gibalaand and McGee, 2008). Hormonal response has been shown to be significantly elevated after the WIngate sprints, which include catacholamines, cortisol and growth hormones (Vincent et al, 2004). Chronic responses include increased aerobic and anaerobic fitness, skeletal muscle adaptations and decreased fasting insulin and insulin resistance. As this protocol is particularly challenging, participants need to be highly motivated to tolerate the accompanying discomfort, thus this is unlikely to be suitable for most sedantary and overweight individuals. Less intensive protocols have been established, which include an 8 second sprint followed by a 12 second recovery for a 20 minute period (Trapp et al, 2008). It is hoped that these less intense protocols may be more readily adopted by those with a lower fitness baseline.
When measured (Boucher et al, 2010), HIIE has had positive impact on insulin sensitivity, subcutaneous fat, abdominal trunk fat, BMI, waist circumference and VO2 max. Studies included had an average intervention length of 10 weeks. As yet, the mechanisms underlying the positive impact of HIIE remain unclear, but may include HIIE-induced fat oxidation during and after oxygen and appetite suppression.
Lifestyle behaviour change is considered the most difficult part of diabetes management, with GPs often providing generic advice for exercise (Avery et al, 2016). In general, primary care physicians are knowledgeable about the underlying physiological mechanisms of T2DM, but often experience difficulty when communicating this information to patients (Avery et al, 2016). The most common barrier which I am faced with is what I refer to as the diet and exercise paradigm. ‘I don’t have the time’ and ‘I eat a healthy diet’. By exploring what patients feel a healthy diet is, I often find that there is a very high intake of refined carbohydrate along with alcohol…a recipe for poor mental, cardiovascular, digestive and metabolic health (Lustig, 2016).
Simple suggestions can give patients realistic physical activity measures without the dreaded lycra or gym membership.
As a young GP with a passion for holistic care, I enjoy supporting patients in making positive impacts on their health through a variety of lifestyle interventions. Through several motivational interview techniques, I try to sensitively explore patient concerns regarding health and weight. From my experience, I find that patients are often very willing to share their concerns regarding weight and lifestyle when done in a sensitive way. By using SMART goals (specific, measurable, achievable, realistic, timebound) and a SWOT analyses (strengths, weaknesses, opportunities, threats), I aim to develop positive and proactive lifestyle plans for patients to explore. Ultimately, this is a patient-driven intervention, so by targeting patient-centred issues, we can improve adherence and engagement.
By exploring exercise solutions, often simple suggestions such as limiting daily inactivity can give patients realistic and non-threatening physical activity measures to strive for, without the dreaded lycra or gym membership. Pre-exercise counselling can often be a helpful way to encourage an increase in physical activity. By identifying patients’ previous level of sporting involvement, we can identify suitable programmes to follow. This can range from a simple ‘couch to 5km’ for the more novice exercisers to sports fans using sports commentary to accompany their exercise training; where they would previously sit and watch a game, they could simply exercise for the first half of a game for example.
The current globally accepted dietary guidelines support a low saturated fat and high carbohydrate diet, with some national guidelines suggesting a 60% intake of carbohydrates (Noakes and Windt, 2016). The flawed science behind this message has resulted in an increase in consumption of junk food, low in fat, high in refined carbohydrates and polyunsaturated vegetable oils (Credit Suisse, 2015). Most current diets are calorie-based, with the UK Clinical Practice Research Datalink from 2004–2014 revealing that the probability of gaining a normal weight through the current dietary guidelines being 1:167, equating a failure rate of more than 99% (Fildes et al, 2015).
Dietary fat has been targeted for many years, which is reflected in current nutritional guidelines (Credit Suisse, 2015). This is in the absence of supporting evidence from randomised control trials (Harcombe et al, 2015). This also led to an increase in consumption of omega-6 vegetable oils, which has previously been found to increase mortality rates when compared with saturated fat ingestion in a double-blinded study (The Minnesota Coronary Experiment) involving 9,432 participants 45 years ago (Ramsden et al, 2016). Diets low in fat have also been linked with lower levels of testosterone in men (Sharp and Pearson, 2010).
In my clinical practice I tend to favour a low carbohydrate and high fat (LCHF) approach, with an emphasis on eating cruciferous vegetables while avoiding baked and refined carbohydrates. I support patients with an ad lib LCHF nutritional plan. LCHF diets have been found to be as good as low fat diets in several meta-analyses (Phelan et al, 2009; Johnson et al, 2014). I have found that patients report increased satiety and lower levels of perceived hunger as alluded to in the literature (Noakes and Windt, 2016). With a clear message supporting the consumption of nutrient-dense food, patients can have increased satiety levels with an overall decrease in energy intake, resulting in a negative energy balance, leading to weight loss without perceived hunger (Noakes and Windt, 2016).
The approach is very consistent – unprocessed cruciferous vegetables, raw nuts and seeds, eggs, fish, unprocessed animal meat and natural plant oils (Noakes and Windt, 2016). LCHF diets have been found to have several metabolic advantages over low fat diets, including improved T2DM, obesity and MetS (Feinman et al, 2015). This has been challenged in several inpatient studies measuring low carb v high carb diets (Hall et al, 2016) and energy-restricting low carb, low fat diets (Hall et al, 2015). Both patient groups were found to have equal weight loss which appears to dismiss the specific metabolic advantages of an LCHF approach, however this was not performed in free-living subjects, which failed to allow for patient choice or flexibility. My current experience is that I have had more success with LCHF patients than those who have continued with the low-fat approach.
LCHF diets are now being considered as first-line treatments for T2DM (Schofield et al, 2016), however there needs to be a shift away from unhelpful and inaccurate guidelines which target certain food groups to an emphasis on food quality and source rather than targeting macronutrients.
With a growing global obesity epidemic, there needs to be a change in how we approach this crisis in primary care. Through the promotion of more holistic care, I feel that we can promote patient empowerment and encourage more healthy lifestyle choices. By using a variety of motivational interviewing techniques, I find that patient adherence and compliance is improved and my best outcomes to date are from those patients who are adopting simple daily improvements over a sustained period of time. Through limiting both physical inactivity and limiting the intake of refined carbohydrates, my male patients continue to improve their health, evident through both clinic and laboratory measurements and also through improved mood, concentration and masculinity!
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