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first:The Role of Anabolic Hormones for Wound Healing in Catabolic States
Robert H. Demling, MD
Burn Center, Brigham & Women's Hospital, Boston, MA, and Harvard Medical School, Boston, MA
Objective: The purpose of this paper is to present an overview of the interrelationship between hormones, nutrition, and wound healing. Methods: The data on various hormones and their effects on specific elements of nutrition and wound healing are reviewed. Results: The key anabolic hormones are human growth hormone, insulin-like growth factor-1, insulin, and testosterone and its analogs. Although each has specific metabolic actions, there is also a very important hormone-hormone interaction. A deficiency of these hormones occurs in acute and chronic catabolic states, resulting in lean mass loss and impairing the healing process. Conclusion: There is a well-recognized interrelationship between hormones, nutrition, and wound healing. The anabolic process of protein synthesis, with new tissue formation, requires the action of anabolic hormones. Exogenous administration of these agents has been shown to maintain or increase lean body mass as well as directly stimulate the healing process through their anabolic and anticatabolic actions.
Background:
Multisystem injury and major surgical stress result in a hypermetabolic state with accelerated breakdown of protein stores. Loss of lean muscle mass impairs wound healing, increases infection rates, and weakens respiratory musculature. Oxandrolone is an anabolic steroid that attenuates loss of lean body mass and improves wound healing in burn patients. We hypothesized that oxandrolone would improve outcome for ventilator-dependent surgical patients.
Methods:
We conducted a randomized, double-blind, placebo-controlled trial of oxandrolone therapy for surgical/trauma patients requiring >7 days of ventilation. The primary end point was time on the ventilator.
Results:
Forty-one patients were enrolled between January 1, 2001, and June 15, 2003, 18 received oxandrolone (10 mg po BID) and 23 received a placebo. Groups were comparable for age, gender, injury severity score, and APACHE II score. The majority were trauma patients (83%), and 90% received enteral feeding. The oxandrolone group received higher caloric and protein intake before enrollment, but these differences were not significant. Contrary to our hypothesis, patients receiving oxandrolone spent significantly longer time on the ventilator than the placebo group (mean 21.7 days vs. 16.4 days, P = 0.03). There was no difference in infectious complications, acute respiratory distress syndrome, or multiple organ failure scores. Patients receiving oxandrolone had a longer intensive care unit stay but no difference in total hospital stay.
Conclusion:
Ventilator-dependent surgical patients receiving oxandrolone had a more prolonged course of mechanical ventilation, suggesting that oxandrolone may be detrimental in this circumstance. Oxandrolone may enhance collagen deposition and fibrosis in the later stages of acute respiratory distress syndrome and thus prolong recovery.
The Effect of Oxandrolone Treatment on Human Osteoblastic Cells
Lian Xiang Bi, MD,adf Kristine M. Wiren, PhD,gh Xiao-Wei Zhang, MD,gh Gisele V. Oliveira, MD,cef Gordon L. Klein, MD,bf Elgene G. Mainous, DDS,a and David N. Herndon, MD
Objective: Oxandrolone, administered to severely burned children over the first year postburn, produces increased lean body mass by 6 months; however, an increase in total body bone mineral requires 12 months. Consequently, this bone mineral response may be due to increased muscle mass. Alternatively, oxandrolone may act directly on bone. The current study seeks to determine whether oxandrolone can transactivate the androgen receptor in osteoblasts. Methods: Collagen, alkaline phosphatase, osteocalcin, osteoprotegerin, and androgen receptor abundance were determined by qRT-PCR, confocal laser scanning microscopy, or immunoquantitative assay. To determine the effect of oxandrolone on gene expression in differentiated cells, osteocytic cultures were grown to confluence in differentiation medium and then treated 24 hours or 5 days with 15 μg/mL oxandrolone. Results: Increased nuclear fluorescence of the androgen receptor and increased cellular type I collagen were observed with oxandrolone at 15 and 30 μg/mL but not at lower doses. Alkaline phosphatase (7%–20%) and osteocalcin (13%–18%) increases were modest but significant. Short-term treatment produced no significant effects, but at 5 days androgen receptor levels were increased while collagen levels were significantly decreased, with little effect on alkaline phosphatase, osteocalcin, or osteoprotegerin. Conclusions: These data suggest oxandrolone can stimulate production of osteoblast differentiation markers in proliferating osteoblastic cells, most likely through the androgen receptor; however, with longer treatment in mature cells, oxandrolone decreases collagen expression. Thus it is possible that oxandrolone given to burned children acts directly on immature osteoblasts to stimulate collagen production, but also may have positive effects to increase bone mineral through other mechanisms.
Robert H. Demling, MD
Burn Center, Brigham & Women's Hospital, Boston, MA, and Harvard Medical School, Boston, MA
Objective: The purpose of this paper is to present an overview of the interrelationship between hormones, nutrition, and wound healing. Methods: The data on various hormones and their effects on specific elements of nutrition and wound healing are reviewed. Results: The key anabolic hormones are human growth hormone, insulin-like growth factor-1, insulin, and testosterone and its analogs. Although each has specific metabolic actions, there is also a very important hormone-hormone interaction. A deficiency of these hormones occurs in acute and chronic catabolic states, resulting in lean mass loss and impairing the healing process. Conclusion: There is a well-recognized interrelationship between hormones, nutrition, and wound healing. The anabolic process of protein synthesis, with new tissue formation, requires the action of anabolic hormones. Exogenous administration of these agents has been shown to maintain or increase lean body mass as well as directly stimulate the healing process through their anabolic and anticatabolic actions.
Background:
Multisystem injury and major surgical stress result in a hypermetabolic state with accelerated breakdown of protein stores. Loss of lean muscle mass impairs wound healing, increases infection rates, and weakens respiratory musculature. Oxandrolone is an anabolic steroid that attenuates loss of lean body mass and improves wound healing in burn patients. We hypothesized that oxandrolone would improve outcome for ventilator-dependent surgical patients.
Methods:
We conducted a randomized, double-blind, placebo-controlled trial of oxandrolone therapy for surgical/trauma patients requiring >7 days of ventilation. The primary end point was time on the ventilator.
Results:
Forty-one patients were enrolled between January 1, 2001, and June 15, 2003, 18 received oxandrolone (10 mg po BID) and 23 received a placebo. Groups were comparable for age, gender, injury severity score, and APACHE II score. The majority were trauma patients (83%), and 90% received enteral feeding. The oxandrolone group received higher caloric and protein intake before enrollment, but these differences were not significant. Contrary to our hypothesis, patients receiving oxandrolone spent significantly longer time on the ventilator than the placebo group (mean 21.7 days vs. 16.4 days, P = 0.03). There was no difference in infectious complications, acute respiratory distress syndrome, or multiple organ failure scores. Patients receiving oxandrolone had a longer intensive care unit stay but no difference in total hospital stay.
Conclusion:
Ventilator-dependent surgical patients receiving oxandrolone had a more prolonged course of mechanical ventilation, suggesting that oxandrolone may be detrimental in this circumstance. Oxandrolone may enhance collagen deposition and fibrosis in the later stages of acute respiratory distress syndrome and thus prolong recovery.
The Effect of Oxandrolone Treatment on Human Osteoblastic Cells
Lian Xiang Bi, MD,adf Kristine M. Wiren, PhD,gh Xiao-Wei Zhang, MD,gh Gisele V. Oliveira, MD,cef Gordon L. Klein, MD,bf Elgene G. Mainous, DDS,a and David N. Herndon, MD
Objective: Oxandrolone, administered to severely burned children over the first year postburn, produces increased lean body mass by 6 months; however, an increase in total body bone mineral requires 12 months. Consequently, this bone mineral response may be due to increased muscle mass. Alternatively, oxandrolone may act directly on bone. The current study seeks to determine whether oxandrolone can transactivate the androgen receptor in osteoblasts. Methods: Collagen, alkaline phosphatase, osteocalcin, osteoprotegerin, and androgen receptor abundance were determined by qRT-PCR, confocal laser scanning microscopy, or immunoquantitative assay. To determine the effect of oxandrolone on gene expression in differentiated cells, osteocytic cultures were grown to confluence in differentiation medium and then treated 24 hours or 5 days with 15 μg/mL oxandrolone. Results: Increased nuclear fluorescence of the androgen receptor and increased cellular type I collagen were observed with oxandrolone at 15 and 30 μg/mL but not at lower doses. Alkaline phosphatase (7%–20%) and osteocalcin (13%–18%) increases were modest but significant. Short-term treatment produced no significant effects, but at 5 days androgen receptor levels were increased while collagen levels were significantly decreased, with little effect on alkaline phosphatase, osteocalcin, or osteoprotegerin. Conclusions: These data suggest oxandrolone can stimulate production of osteoblast differentiation markers in proliferating osteoblastic cells, most likely through the androgen receptor; however, with longer treatment in mature cells, oxandrolone decreases collagen expression. Thus it is possible that oxandrolone given to burned children acts directly on immature osteoblasts to stimulate collagen production, but also may have positive effects to increase bone mineral through other mechanisms.
