Nutrition, Anabolism, and the Wound Healing Process: An Overview

Robert H. Demling, MD

Disclosures

ePlasty. 2009;9:65-94. 

In This Article

Human Growth Hormone

HGH is a potent endogenous anabolic hormone produced by the pituitary gland. HGH levels are at there highest during the growth spurt, decreasing with increasing age. Starvation and intense exercise are 2 potent stimuli, while acute or chronic injury or illness suppresses HGH release, especially in the elderly. The amino acids glutamine and arginine, when given in large doses, have been shown to increase HGH release.

HGH has a number of metabolic effects (Table 19). The most prominent is its anabolic effect. HGH increases the influx and decreases the efflux of amino acids into the cell. Cell proliferation is accentuated, as are overall protein synthesis and new tissue growth. HGH also stimulates IGF-1 production by the liver, and some of the anabolism seen with HGH is that produced by IGF-1, another anabolic agent.[134–138,142]

The effect on increasing fat metabolism is beneficial in that fat is preferentially used for energy production, and amino acids are preserved for use in protein synthesis. Recent data indicate that insulin provides some of the anabolic effect of HGH therapy. At present, the issue as to the specific anabolic effects attributed to HGH versus that of IGF-1 and insulin remains unresolved.

Clinical studies have in large part focused on the systemic anabolic and anticatabolic actions of HGH. Populations in which HGH has been shown to be beneficial include severe burn and trauma. Increases in LBM, muscle strength, and immune function have been documented in its clinical use. Increase of anabolic activity requires implementation of a high-protein, high-energy diet.[136–138,142–144]

Significant complications can occur with the use of HGH. The anti-insulin effects are problematic in that glucose is less efficiently used for fuel and increased plasma glucose levels are known to be deleterious.

In summary, use of HGH in conjunction with adequate nutrition and protein intake clearly results in increased anabolic activity and will positively impact wound healing by increasing protein synthesis in catabolic populations.

Insulin-like Growth Factor-1

IGF-1 is a large polypeptide that has hormone-like properties. The IGF-1, also known as somatomedin-C, has metabolic and anabolic properties similar to insulin. Practically speaking, this agent is not as much used for its clinical wound healing effect or anabolic activity as HGH or IGF. The main source is the liver, where IGF synthesis is initiated by HGH. Decreased levels are noted with a major body insult.[144,146]

Metabolic properties include increased protein synthesis, a decrease in blood glucose, and an attenuation of stress-induced hypermetabolism, the latter 2 properties being quite different from HGH. The attenuation of stress-induced hypermetabolism is a favorable property of IGF-1. The major complication is hypoglycemia.

Insulin

The hormone insulin is known to have anabolic activities in addition to its effect on glucose and fat metabolism. In a catabolic state, exogenous insulin administration has been shown to decrease proteolysis in addition to increasing protein synthesis.[137,138,142–144] The anabolic activity appears to mainly affect the muscle and skin protein in the LBM compartment. An increase in circulating amino acids produced by wound amino acid intake increases the anabolic and anticatabolic effect in both normal adults and populations in a catabolic state.

A number of clinical trials,[137,138,142–144] mainly in burn patients, have demonstrated the stimulation of protein synthesis, decreased protein degradation, and a net nitrogen uptake, especially in skeletal muscle. The positive insulin effect on protein synthesis decreases with aging. There are much less data on the actions of insulin on wound healing over and above its systemic anabolic effect. The main complication is hypoglycemia.

Testosterone Analogues

Testosterone is a necessary androgen for maintaining LBM and wound healing. A deficiency leads to catabolism and impaired healing. The use of large doses exogenously has increased net protein synthesis, but a direct effect on wound healing has not yet been demonstrated. In general, it has relatively weak anabolic and wound healing properties.

Anabolic steroids refer to the class of drugs produced by modification of testosterone.[143–154] These drugs were developed to take clinical advantage of the anabolic effects of testosterone while decreasing androgenic side effects of the naturally occurring molecule. The mechanisms of action of testosterone analogues are through activation of the androgenic receptors found in highest concentration in myocytes and skin fibroblasts. Some populations of epithelial cells also contain these receptors. Stimulation leads to a decrease in efflux of amino acids and an increase in influx into the cell. A decrease in fat mass is also seen because of the preferential use of fat for fuel. There are no metabolic effects on glucose production.

All anabolic steroids increase overall protein synthesis and new-tissue formation, as evidenced by an increase in skin thickness and muscle formation. All these agents also have anticatabolic activity decreasing the protein degradation caused by cortisol and other catabolic stimuli. In addition, all anabolic steroids have some androgenic or masculinizing effects.

The anabolic steroid oxandrolone happens to have the greatest anabolic and least androgenic side effects in the class of anabolic steroids.[147–149] Most of the recent studies on anabolic steroids and LBM have used the anabolic steroid oxandrolone. Oxandrolone has potent anabolic activity, up to 13 times that of methyltestosterone. In addition, its androgenic effect is considerably less than testosterone, minimizing this complication common to other testosterone derivatives. The increased anabolic activity and decreased androgenic (masculinizing) activity markedly increase its clinical value. Oxandrolone is given orally, with 99% bioavailability. It is protein bound on plasma with a biologic life of 9 hours[149] (Table 20).

The anabolic steroids, especially oxandrolone, have been successfully used in the trauma and burn patient population to both decrease LBM loss in the acute phase of injury as well as more rapidly restore the lost LBM in the recovery phase. Demonstrated in several studies is an increase in the healing of chronic wounds. However, significant LBM gains were also present.[153,154]

It is important to point out that in all of the clinical trials where LBM gains were reported, a high-protein diet was used. In most studies, a protein intake of 1.2 to 1.5 g/kg/day was used. The effects of anabolic steroids on wound healing appear to be, in a large part, due to a general stimulation of overall anabolic activity. However, there is increasing evidence of a direct stimulation of all phases of wound healing by these agents.[153,154]

The mechanism of improved wound healing with the use of anabolic steroids is not yet defined. Stimulation of androgenic receptors on wound fibroblasts may well lead to a local release of growth factors.

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