Testosterone Deficiency, Frailty and Muscle Wasting in CKD

A Converging Paradigm?

Giacomo Garibotto; Daniela Picciotto; Daniela Verzola

Disclosures

Nephrol Dial Transplant. 2019;34(5):723-726. 

In the general elderly population, frailty is a condition characterized by loss of biological reserves, failure of homoeostatic mechanisms and susceptibility to adverse outcomes, which increases vulnerability to loss of independence and death.[1] The concept of frailty is comprehensive of a wide spectrum of stages running from a pre-frail state, when individuals are at high risk of becoming overtly frail, through to extreme states in which multiple physiological systems are failing, autonomy is lost, and death is imminent.[1] Several aspects of frailty, including its underlying mechanisms, are still obscure. It is remarkable that some of its components are reversible, particularly in the pre-frail state and after acute illnesses.[2] Also, although frailty is a long-established clinical syndrome, there is no uniformly accepted way of measuring it in the clinical setting.[3] A model that could precisely measure and therefore predict frailty could potentially lead to prevention and treatment of this syndrome at its early stages.

The prevalence of frailty is considerably higher among dialysis patients than among community-resident elders, and frail chronic kidney disease (CKD) patients are also at higher risk of morbidity and mortality.[4] As shown by cross-sectional studies, the prevalence of frailty increases as CKD progresses,[5] supporting the concept of a series of events in which catabolic factors occurring in CKD (such as anorexia, acidosis, insulin resistance and inflammation) progressively lead to wasting, functional impairment and inactivity, with deconditioning leading to further inactivity and disability. However, although CKD and ageing contribute to frailty, there may also be potentially reversible contributors (such as acute illnesses and reduced nutritional intakes) and frailty may not always be a permanent or progressive condition.[6]

Currently, there is no widely accepted treatment for frailty.[1,2] Clearly, the identification of treatable factors could lead to the ability to interrupt the trajectories leading to frailty among patients with CKD. In the general population, there is a sizable body of evidence showing that androgen deficiency is associated with frailty and mortality.[7] In addition, there are readily available androgen replacement therapies that have been shown to be efficacious for the treatment of hypogonadism in men.[8] Thus, androgen deficiency may be an important and potentially treatable mechanism contributing to frailty.

Testosterone regulates lipid, carbohydrate and protein metabolism and modulates the function of different cells and tissues, including endothelial and haematopoietic cells, muscle, fat and bone.[7–9] In addition, testosterone plays a key role in modulating vascular physiology and metabolism.[7–9] In muscle, testosterone increases protein synthesis through stimulation of androgen receptors and activation of the insulin-like growth factor-1 pathway; in addition, it promotes myonuclear accretion and satellite cell recruitment.[7–9] Testosterone circulates in plasma, with 2% unbound free hormone, 40% bound to sex hormone-binding globulin (SHBG) and 58% non-specifically bound to albumin. The biologically active hormone is contained in the unbound and non-specifically bound fractions. Circulating concentrations are ~15–25 times higher in adult men compared with women. With ageing, men have gradual declines in average serum testosterone levels, with a 1% per year decrease in testosterone and a parallel increase in SHBG.[9] The age-related decrease in circulating testosterone associates with decreases in sexual function, bone mass, muscle mass and strength, and increases in body fat, depression and fatigue.[9] In ageing men, free testosterone is a better predictor of arm and leg strength than total testosterone.[10]

In the general elderly population, a cross-sectional association between low testosterone and/or SHBG and frailty has been observed in several studies.[11–13] In middle-aged and older men, low testosterone is also associated with reduced physical activity and several end-organ deficits such as sarcopaenia, reduced bone mass, anaemia, depression and the metabolic syndrome.[13] Therefore, testosterone deficiency may contribute to different components of frailty (Figure 1). Also, prospective studies have shown an association between serum testosterone (or the change in its levels over time) and frailty.[13]

Figure 1.

This graph describes how testosterone deficiency (hypogonadism) may contribute to the different components of frailty. BMD, bone mass density; FM, fat mass; LBM, lean body mass.

Decreased function of the hypothalamic–pituitary–gonadal axis as well as reduced androgen synthesis are common in patients with CKD.[14] African American ethnicity and higher estimated glomerular filtration rate are related to lower odds of having hypogonadism, while diabetes, higher body mass index and visceral adiposity are associated with higher odds.[14,15] Hypogonadism causes sexual disorders, worse quality of life and increased mortality risk. In keeping with the testosterone effects on skeletal muscle, low testosterone levels are associated with reduced muscle strength and fat-free mass both in CKD[16] and in haemodialysis patients.[17,18] It is interesting that key convergent pathological effects of frailty and wasting include loss of muscle mass and strength, with consequent impact on mobility and activities of daily living. A reduced testosterone level may contribute to loss of energy, strength, skeletal and muscle mass, and favour muscle wasting, cachexia and in the end, contribute to frailty and mortality in CKD. Of note, many catabolic factors that are implicated as a cause of frailty, such as inflammation, altered androgen and glucocorticoid secretion, insulin-like growth factor 1 and insulin resistance, are also common to CKD-induced wasting.[1,2,18–20]

In this issue of NDT, Chiang et al.[21] studied the associations between low serum-free testosterone concentrations, frailty and muscle mass in a cohort of 440 men on haemodialysis, recruited from 14 dialysis centers in Atlanta and the San Francisco Bay Area from 2009 to 2011. The authors were able to show that lower levels of serum free testosterone were associated with higher odds of being frail and of becoming frail over 12 months. Further analysis showed that serum-free testosterone was also associated with two major components of the physical function of frailty, i.e. grip strength and gait speed. These associations are especially noteworthy as slow gait speed and low grip strength may be important for maintaining independence and are also predictive of mortality in patients on dialysis.

Muscle mass is an important contributor to physical function, and the associations between free testosterone, serum creatinine and body impedance spectroscopy-derived muscle mass that Chiang et al.[21] observed are consistent with the hypothesis that low testosterone generates frailty because of its effects on skeletal muscle. This observation is seemingly relevant if one considers that early studies have observed associations between plasma-free testosterone and indexes of fat-free mass and strength in elderly subjects[12] and in CKD patients.[16,17] The study of Chiang et al.[21] shows us that 50% lower free testosterone concentration is associated with a 1.72-fold higher odds for developing sarcopaenia and decrease in muscle mass over 12 months. So, the association between testosterone and low muscle mass in the CKD cohort studied by Chiang et al.[21] appears to be stronger than that observed in the elderly, in which blood testosterone accounts for a small proportion (3–11%) of the variance in muscle mass and strength.[22]

The paper by Chiang et al.[21] lends further support to the hypothesis that the measure of free testosterone may be useful for individualized patient care and that androgen replacement may be a feasible therapeutic target towards prevention of frailty in CKD, though studies would be needed to test these possibilities. Administration of supraphysiologic doses of testosterone, especially when combined with strength training, increase fat-free mass and muscle size and strength in patients with burns, chronic obstructive pulmonary disease, cancer and HIV infection.[18,19] Studies involving limited numbers of frail subjects have shown that the administration of testosterone results in improved muscle mass and strength as well as increased bone mass.[22,23] Less clear, however, is testosterone's effect on performance-based measures of physical function, such as walking speed and chair rises; most studies have failed to demonstrate meaningful change in these measures.[22,23] Moreover, none of the studies has been of sufficient size or duration to adequately address potential risks. A recent study on testosterone replacement in older men with testosterone deficiency was terminated early because of an excess of cardiovascular events in the testosterone group.[24] Since then, use and safety of testosterone has been scrutinized by both regulatory authorities and researchers. A recent metanalysis of 39 randomized controlled trials and 10 observational studies[25] concluded that there is no statistically significant increased risk of testosterone treatment on a composite outcome of myocardial infarction, stroke and mortality. However, since none of the available trials is adequately powered to evaluate cardiovascular events, no firm conclusions can be drawn regarding the cardiovascular safety of testosterone treatment.[25]

Several interventional studies in patients on dialysis have explored effects of testosterone or testosterone derivatives on muscle mass and physical function (Table 1). A randomized controlled trial in 29 patients on haemodialysis demonstrated that treatment with nandrolone decanoate for 6 months led to increased lean body mass and a decrease in walk and stair-climbing time, as well as an increase in serum creatinine concentration compared with treatment with placebo.[26] A larger follow-up study that also incorporated exercise showed improvements in body composition with nandrolone over 3 months but no improvement in self-reported physical function or measured strength in the absence of exercise.[27] More recently, Supasyndh et al. observed that oxymeyholone for 24 weeks led to an increase in fat-free mass, hand grip strength and muscle growth factors' mRNA levels,[28] but some patients developed liver toxicity. Pampa Saico et al.[29] tested transdermal testosterone on haemodialysis patients for 3 months and observed an increase in the levels of albumin and decreased use of erythropoietin. An increase in free testosterone levels and an improvement in the total ageing male symptoms scores were observed with the use of testosterone enantholactam acid ester every 2 weeks for 24 weeks.[30] Thus, the few studies available indicate that androgens can increase anabolism, but the extent to which androgen treatment improves physical function is less clear. In addition, follow-up time was limited. Moreover, to date, frailty (as opposed to muscle strength and physical performance) has not been studied as a clinical outcome of interventional trials of testosterone replacement in CKD. Therefore, data from larger and longer interventional studies need to supplement what we have learned from currently available trials.

The study of Chiang et al.[21] has some limitations since it is observational in nature. Therefore, the observed associations between free testosterone, physical function, muscle mass and frailty could be confounded by other unmeasured factors. Also, causality of free testosterone levels in inducing frailty could not be proven. Clearly, we will need large, carefully designed trials of androgen replacement in frail patients with low testosterone levels, including a sufficient number of subjects to allow the assessment of testosterone on key clinical outcomes, such as frailty components, bone-fracture rates, muscle strength and avoidance of falls, as well as the risks for prostate, cardiovascular and other adverse outcomes. Nevertheless, the study of Chiang et al.[21] is in several ways important. On one hand, this study increases nephrologists' awareness of frailty. On the other hand, this study puts the hype on low testosterone as a determinant of frailty and likely, of muscle mass in male patients with CKD. It is important that the associations discussed in this article focus on the potential for improvement and the identification of underlying mechanisms and potential biomarkers of the condition. Analysis of the independent impact of different components of frailty on outcome may also help in understanding the effectiveness of frailty prevention or management strategies in patients with CKD.

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