madman
Super Moderator
Testosterone is part of a group of steroid hormones synthesised from the precursor molecule cholesterol. Steroidogenesis occurs in the gonads, adrenal cortex and the placenta. The type of steroid hormone produced depends on tissue-specific enzymes. Testosterone regulates sexual differentiation, producing male sex characteristics, spermatogenesis and fertility. Controlled by the hypothalamic-pituitary-gonadal axis, its effects are mediated through androgen and oestrogen receptors. Given the wide distribution of these receptors, testosterone has a significant biological action on several systems.
Testosterone’s anabolic and androgenic effects have been shown to modulate proinflammatory biomarkers.[1] Critical illness is characterised by a proinflammatory and catabolic state and is accompanied by altered testosterone production, which may persist into the recovery phase.Testosterone may therefore be a potential therapeutic option in critical illness. This paper examined normal testosterone physiology as well as the changes seen during critical illness. We then conducted a semi structured literature review of testosterone therapy during both the acute and chronic phases of critical illness
*Testosterone synthesis and physiology
*Testosterone pathophysiology during acute illness
*Traditional testosterone therapy
*Testosterone and inflammation
Testosterone therapy in the critically ill patient
Acute critical illness
Our search identified fourteen articles (four animal, ten human) related to the use of testosterone in the acute phase of critical illness. The animal studies showed conflicting results as two studies demonstrate that androgen deficiency has a beneficial effect on myocardial function intrauma subjects and improves mortality in septic subjects.[47,48] However,the remaining two studies suggest that testosterone supplementation may improve survival in subjects with sepsis and nitric oxide synthase deficiency; and that testosterone therapy attenuates cerebral vasospasm in cases of subarachnoid haemorrhage.[49,50]
Human studies are sparse, but a clear benefit is seen in patients suffering burn injuries. Oxandrolone therapy among burn patients has been shown to improve mortality,[51,52] improve lean body mass, [53] reduce healing time of donor sites, [54] and reduce the length of hospital stay.[55] Two studies assessing the use of oxandrolone in trauma patients did not show promising results as these patients had a longer duration of mechanical ventilation, and higher reintubation rates and oxandrolone did not improve the length of ICU or hospital stay.[56,57] Table 2 summarises the articles related to the use of testosterone in human patients with acute critical illness.
Recovery after acute critical illness
A systematic review of 70 trials by Tomassini et al.[70] investigated interventions to address sarcopenia in a surgical population. Testosterone exerts its anabolic effect on muscle through the androgen receptor, increasing gene transcription and leading to an increase in protein synthesis and a decrease in catabolism. Testosterone also increases the expression of IGF-1, an important growth factor that regulates skeletal muscle anabolism.[67] Testosterone also has an anti catabolic effect through the inhibition of the nuclear factor-kB-inducing kinase (NIK) pathway which is both proinflammatory and plays a role in skeletal muscle atrophy.[71]
Discussion
Given that the effects of testosterone on acute inflammation are not fully understood and that testosterone is known to cause vasodilation,we would not recommend the use of testosterone in patients who are haemodynamically unstable or going through an acute septic event. Evidence does suggest that once the acute phase of critical illness has subsided, testosterone therapy may be beneficial in reducing the need for mechanical ventilation. The literature also suggests that testosterone may be a valuable tool in treating ICU-acquired weakness and improving the functional activity of patients undergoing physical rehabilitation after surviving critical illness. However, larger studies are needed to confirm these findings. We also recommend that healthcare providers consider routine screening for hypotestosteronaemia in chronic critically ill patients and refer patients who survive critical illness to a multidisciplinary rehabilitation team, which may include testosterone therapy combined with physiotherapy and adequate nutritional intake
An interesting avenue of research would be to determine the effect of using testosterone preoperatively, to improve physical status, on the clinical outcomes of patients undergoing major elective surgery.
Testosterone’s anabolic and androgenic effects have been shown to modulate proinflammatory biomarkers.[1] Critical illness is characterised by a proinflammatory and catabolic state and is accompanied by altered testosterone production, which may persist into the recovery phase.Testosterone may therefore be a potential therapeutic option in critical illness. This paper examined normal testosterone physiology as well as the changes seen during critical illness. We then conducted a semi structured literature review of testosterone therapy during both the acute and chronic phases of critical illness
*Testosterone synthesis and physiology
*Testosterone pathophysiology during acute illness
*Traditional testosterone therapy
*Testosterone and inflammation
Testosterone therapy in the critically ill patient
Acute critical illness
Our search identified fourteen articles (four animal, ten human) related to the use of testosterone in the acute phase of critical illness. The animal studies showed conflicting results as two studies demonstrate that androgen deficiency has a beneficial effect on myocardial function intrauma subjects and improves mortality in septic subjects.[47,48] However,the remaining two studies suggest that testosterone supplementation may improve survival in subjects with sepsis and nitric oxide synthase deficiency; and that testosterone therapy attenuates cerebral vasospasm in cases of subarachnoid haemorrhage.[49,50]
Human studies are sparse, but a clear benefit is seen in patients suffering burn injuries. Oxandrolone therapy among burn patients has been shown to improve mortality,[51,52] improve lean body mass, [53] reduce healing time of donor sites, [54] and reduce the length of hospital stay.[55] Two studies assessing the use of oxandrolone in trauma patients did not show promising results as these patients had a longer duration of mechanical ventilation, and higher reintubation rates and oxandrolone did not improve the length of ICU or hospital stay.[56,57] Table 2 summarises the articles related to the use of testosterone in human patients with acute critical illness.
Recovery after acute critical illness
A systematic review of 70 trials by Tomassini et al.[70] investigated interventions to address sarcopenia in a surgical population. Testosterone exerts its anabolic effect on muscle through the androgen receptor, increasing gene transcription and leading to an increase in protein synthesis and a decrease in catabolism. Testosterone also increases the expression of IGF-1, an important growth factor that regulates skeletal muscle anabolism.[67] Testosterone also has an anti catabolic effect through the inhibition of the nuclear factor-kB-inducing kinase (NIK) pathway which is both proinflammatory and plays a role in skeletal muscle atrophy.[71]
Discussion
Given that the effects of testosterone on acute inflammation are not fully understood and that testosterone is known to cause vasodilation,we would not recommend the use of testosterone in patients who are haemodynamically unstable or going through an acute septic event. Evidence does suggest that once the acute phase of critical illness has subsided, testosterone therapy may be beneficial in reducing the need for mechanical ventilation. The literature also suggests that testosterone may be a valuable tool in treating ICU-acquired weakness and improving the functional activity of patients undergoing physical rehabilitation after surviving critical illness. However, larger studies are needed to confirm these findings. We also recommend that healthcare providers consider routine screening for hypotestosteronaemia in chronic critically ill patients and refer patients who survive critical illness to a multidisciplinary rehabilitation team, which may include testosterone therapy combined with physiotherapy and adequate nutritional intake
An interesting avenue of research would be to determine the effect of using testosterone preoperatively, to improve physical status, on the clinical outcomes of patients undergoing major elective surgery.