The Role of Anabolic Hormones for Wound Healing in Catabolic States

17 Pages·2006·0.28 MB·English

The Role of Anabolic Hormones for Wound Healing
in Catabolic States
RobertH.Demling,MD
Burn Center, Brigham & Women’s Hospital, Boston, MA, and Harvard Medical School,
Boston,MA
Correspondence:[email protected]
Objective: The purpose of this paper is to present an overview of the interrelation-
ship between hormones, nutrition, and wound healing. Methods: The data on various
hormonesandtheireffectsonspecificelementsofnutritionandwoundhealingarere-
viewed.Results:Thekeyanabolichormonesarehumangrowthhormone,insulin-like
growth factor-1, insulin, and testosterone and its analogs. Although each has specific
metabolicactions,thereisalsoaveryimportanthormone-hormoneinteraction.Adefi-
ciencyofthesehormonesoccursinacuteandchroniccatabolicstates,resultinginlean
mass loss and impairing the healing process. Conclusion: There is a well-recognized
interrelationshipbetweenhormones,nutrition,andwoundhealing.Theanabolicprocess
ofproteinsynthesis,withnewtissueformation,requirestheactionofanabolichormones.
Exogenousadministrationoftheseagentshasbeenshowntomaintainorincreaselean
bodymassaswellasdirectlystimulatethehealingprocessthroughtheiranabolicand
anticatabolicactions.
There are a number of key hormones involved with energy production, anabolism
or protein synthesis, and catabolism or protein breakdown. The balance of anabolic and
catabolichormonesaffectswoundhealingbothindirectlybythestatusofoverallnetprotein
synthesis and directly by improving the wound healing process.1–4 A decrease in normal
anabolic hormone activity and an increase in catabolic hormone activity occurs with the
“stressresponse”toinjuryandalsowithagingandchronicillness.
Thealteredhormonalenvironmentcanleadtobothasignificantincreaseincatabolism,
withnettissuebreakdown,andadecreaseintheoverallanabolicactivityrequiredtopreserve
leanmassandmaintainthehealingprocess.Thestressresponsetoinjuryalsoproducesan
alterationinthenormallyprotectiveproteinsparingasseeninthenormalandstarvedstates
aimedatpreservingleanbodymass.
The metabolic pathways, which generate energy to meet daily demands and for new
proteinsynthesis,areverytightlyregulatedinnormalorstarvedhumans.5–8Macronutrients
intheformoffatandcarbohydratesarechanneledintoproductionofenergy,5–11 whilethe
majorityofproteinconsumedisusedforproteinsynthesis,restoringandmaintaininglean
bodymass.Leanmass,themetabolicallyactivebodycompartmentcontainingalltheprotein
plus water, in the body includes muscle, skin, and the immune system, all of which are
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Table 1. Hormonalresponsetostressandstarvation∗
Starvation “Stress”
Catechols ↓ ↑↑
Cortisol ↓ ↑↑
Insulin ↓ ↑
Glucagon ↓ ↑
Growthhormone ↑↑ ↓
Testosterone ↓ ↓
∗Thehormonalresponsetostarvationiscomparedtothatfor“stress.”Withstarvation,anadaptivehormonalresponseis
present,preservingleanmassandenergy,whileamaladaptivecatabolicstateoccurswiththe“stressresponse”activatedby
awound.
composedofprotein.Normally,only5%ofconsumedproteinisusedforenergy.However,
if anabolic activity decreases, as with stress or with aging or chronic illness, there is an
escapeofproteinfromtheproteinsynthesiscompartmenttotheenergycompartment.Up
to 25% of available protein substrate is burned for energy.3–9,12 A protein deficiency can
occur and with the increased energy demands of a wound, a protein energy malnutrition
can quickly evolve, especially in high-risk groups like the elderly with preexisting lean
mass loss.10,11 Morbidity, especially impaired immunity and impaired healing, is directly
proportionaltothedegreeofleanmassloss.13–15Impairedhealingthereforeistheresultof
bothaninadequateintakeofproteinsubstrateandactualshuntingofproteinsubstrateaway
fromthewoundtobeusedinsteadfortherestorationoflostleanmass.
THERATIONALEFORHORMONALMODIFICATION
Itisnowwellrecognizedthatthehormonalenvironment,socriticaltowoundhealing,canbe
beneficiallymodified.1,3,16,17Ingeneral,restorationorimprovementinnetproteinsynthesis,
required in wound healing, is the result of 2 processes. The first is an attenuation of the
catabolichormonalresponsetoinjury.Anyhormonalmanipulationthatdecreasestherateof
catabolismwouldappeartobebeneficialforwoundhealing.Alltheanabolichormoneshave
beenshowntohaveanticortisolactivity.1–4 Thiseffectdecreasesthecatabolicresponseof
cortisolbutdoesnotalteritsprotectiveanti-inflammatoryresponse.Ablockadeofcortisol’s
anti-inflammatory properties could lead to an excessive “autodestructive” inflammatory
process.
Thesecondprocessistheaccentuationofanabolicactivitybothgenerallyandspecific
tothewound.Anumberofclinicalandbasicsciencestudieshavedemonstratedtheability
ofexogenousdeliveryofanabolichormonestoincreasenetnitrogenretentionandoverall
proteinsynthesis.Woundhealinghasalsobeenreportedtobeimproved.However,itremains
difficult to sort out how much of the response is a result of an overall systemic anabolic
effectandhowmuchisduetodirecteffectonwoundhealing.18,19
Thereare4majoranabolichormonesthatindirectlyordirectlyaffectwoundhealing.
They are human growth hormone (HGH), insulin-like growth factor-1 (IGF-1), insulin,
and testosterone (and its analogs) (Table 2). As will be described later, each hormone
has a specific mode of action but there are considerable interrelationships among these
4 hormones. In subsequent sections, the individual anabolic hormones will be discussed.
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Table 2. Effectsofanabolichormones
Increasedanabolism Directwoundeffect
Insulin Yes Unclear
Humangrowthhormone Yes Unclear
Insulin-likegrowthfactor-1 Yes Yes
Testosterone Tes Unclear
Anabolic
Steroids Yes Yes
It is important to emphasize that for any anabolic hormone to stimulate protein synthesis
adequatecaloriesforenergyandproteinforsubstratemustbeprovided.Inthecaseofthe
hypermetabolic state seen in the stress response, a high caloric (30 cal/kg daily) and high
protein(1.5g/kgdaily)intakeisnecessary.20,21
HUMANGROWTHHORMONE
Actions
HGH is a potent endogenous anabolic hormone produced by the pituitary gland in daily
dosesof0.5to0.8mginchildrenandyoungadults.Growthhormoneisalargepolypeptide
that contains 2 receptor-binding sites. There are a number of growth hormone–binding
proteins,andgrowthfactor–bindingsitesarefoundonalargevarietyoftissues,especially
liver.TheproductionofHGHdecreasesrapidlywithincreasingage.Thelevelsareattheir
peak during the growth spurt. Starvation and intense exercise are 2 other potent stimuli
whileacuteorchronicinjuryorillnesssuppressHGHrelease,especiallyintheelderly.22–27
Theaminoacidsglutamineandarginine,whengiveninlargedoses,havealsobeenshown
toincreaseHGHrelease.
HGHhasanumberofmetaboliceffects.Themostprominentisitsanaboliceffect.HGH
increasestheinfluxofaminoacidsintothecellanddecreasestheefflux.Cellproliferation
is accentuated as is overall protein synthesis and new tissue growth. HGH also stimulates
IGF-1productionbytheliver,andsomeoftheanabolismseenwithHGHisthatproduced
by IGF-1, another anabolic agent.26–30 Other effects, listed in Tables 3 and 4, include its
effectsonglucoseandfatmetabolism.
Theeffectonincreasingfatmetabolismisbeneficialinthatfatispreferentiallyused
forenergyproductionandaminoacidsarepreservedforuseinproteinsynthesis.
Table 3. Anaboliceffectsofhumangrowthhormone∗
• Increasescelluptakeofaminoacids
• Acceleratesnucleicacidtranslationandtranscription
• Increasesnitrogenretention
• Increasesproteinsynthesis
• Decreasescortisolreceptoractivity
• Increasesreleaseofinsulin-likegrowthfactor-1
• Increasesinsulinrequirements
∗Levelsdecreasewith“stress”andwithincreasingage.
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Table 4. Metaboliceffectsofhumangrowthhormone∗
• Increaseshydrolysisoffattofattyacids
• Increasesfatoxidationforfuel,decreasingfatstores
• Increasesmetabolicrate(10%–15%)
• Producesinsulinresistance,oftenleadingtohyperglycemia
• Causessomeinitialfluidretention
∗Increased metabolic rate and hyperglycemia are negative effects,
whileincreaseduseoffatforfuelisapositiveeffect.
RecentdataindicatethatinsulinprovidessomeoftheanaboliceffectsofHGHtherapy.
Atpresent,theissueastothespecificanaboliceffectsattributedtoHGHversusIGF-1and
insulinremainsunresolved.
ClinicalresultsofHGHuse
Clinicalstudieshaveinlargepartfocusedonthesystemicanabolicandanticatabolicactions
ofHGH.31–33 PopulationswhereHGHhasbeenshowntobebeneficialincludethosewith
severeburnandtrauma,thosewithHIVinfectionwithwasting,andthefrailelderly(Table5).
In addition, HGH is being used to slow down the aging process. Increases in lean mass,
muscle strength, and immune function have been documented in clinical use. HGH is
approved for use only in short statured children and is an orphan drug when used for
improving protein synthesis. Increased anabolic activity from HGH requires intake of a
high-protein,high-energydiet.
Woundhealingeffect
Astoitsdirectwoundhealingeffects,skinisatargettissueforHGH,bothdirectlythrough
HGHreceptorsonthesurfaceofepidermalcellsandindirectlythroughtheactionofIGF-
1.30,34ExogenouslyadministeredHGHhasbeenshowntoincreaseskinthicknessinnormal
humans.35
Othereffectsonthewoundincludeincreasedrateofre-epithelializationofskingraft
donorsitesinadultsandchildrenwithsevereburnsortrauma(Table6).36–38
In addition, HGH has been shown to increase wound collagen content, granulation
tissueandwoundtensilestrength,andthelocalproductionofIGF-1byfibroblasts.These
dataaremainlyderivedfromanimalstudies.39–41
Table 5. Clinicalusesofhumangrowthhormone∗
• Presenceofseverecatabolismfrominjuryorillness
• Malnourishedpatientswithasuperimposedcatabolicillness
• Acutelossof>15%leanbodymass(muscle)
• Largewounds(burns)orwoundswithpoorhealing
• Immunodeficiencystates(AIDS),especiallywithweightloss
• Anti-agingtreatmentregimens
∗Beneficialeffectsofhumangrowthhormoneonnetanabolismhave
beenreportedforeachofthesepatientpopulations.
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Table 6. Woundhealingeffectsofhumangrowthhormone∗
• Increasesre-epithelializationrateofdonorsites
• Increaseswoundcollagencontent
• Increasesgranulationtissue
• Increaseswoundtensilestrength
∗Thefirst2effectshavebeennotedinhumanswhilethelast2effectshave
beendescribedinanimals.
Complications
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
levelsareknowntobedeleterious.
Increased insulin requirements occur. Complications are listed in Table 7.42,43 It is
important to also point out the findings of a multicenter European study of critically ill
patientsreceivingHGH.Inthisstudyofmainlycriticallyillpostoperativecardiacpatients,
mortality was 2-fold greater in those treated with HGH compared to those treated with
placebo.43
Summary
In summary, HGH used in conjunction with adequate nutrition and protein intake clearly
resultsinincreasedanabolicactivityandwillpositivelyimpactwoundhealingbyincreasing
netproteinsynthesisincatabolicstates.ThereissomedatathatHGHcandirectlyimprove
wound healing. However, the impact of IGF-1 and insulin on the effects of HGH remains
undefined.
INSULIN-LIKEGROWTHFACTOR-1
Actions
IGF-1 is a large polypeptide that has hormone like properties.44–46 IGF-1, also known as
somatomedin-C,hasmetabolicandanabolicpropertiesverysimilartothoseofinsulin.
Although produced by a variety of wound cells, such as fibroblasts and platelets,
the main source of production is liver where its synthesis is initiated by HGH. The
IGF receptor is expressed in many different tissues and the active peptide is bound in
Table 7. Potential problems or issues related to human
growthhormonetreatment
• Insulinresistance(hyperglycemia)
• Increasedinsulindemands
• Fluidretention(usuallyself-limiting)
• Hypercalcemia(uncommonwithshort-termuse)
• Increaseinmetabolicrate
• Mustbegivenparenterally
∗Hyperglycemiaandincreasedinsulinrequirementsarethemostcommon
problems.
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Table 8. Characteristicsofinsulin-likegrowthfactor-1
• Levelsdecreasewithsevereinjury,severetrauma,infection,andincreasingage
• Productiondependentonhumangrowthhormonerelease
• Productionrequiresthepresenceofandrogens
• Actionsmuchlikethoseofinsulin
• Canproducehypoglycemia
• Increasesproteinsynthesisandattenuatesstress-inducedhypermetabolism
plasma by IGF-binding proteins. IGF increases systemic nitrogen retention and protein
synthesis.47–49 However, its anabolic activity is difficult to distinguish from that of HGH
as HGH needs to be present in order for IGF-1 to be produced and to have anabolic
actions. The combination of HGH and IGF-1 delivery results in a synergistic anabolic
effect.49
The effects of HGH on wound healing are also considered to be due in part to
IGF-1.49 IGF-1 production is also dependent on normal levels of circulating androgens.45
Thereisthereforeacloseinterrelationshipbetweenalloftheanabolichormones.IGF-1lev-
elsdecreasewithagingandalsowithamajorinsultsuchastraumaorsepsis.Thedecrease
inIGF-1levelsincreasesthenetnitrogenlossescausedbywounds.
ClinicalresultsofIGF-1use
PropertiesofIGF-1aresummarizedinTable8.Itsmetabolicpropertiesincludeincreased
protein synthesis, decrease in blood glucose, and attenuation of stress-induced hyperme-
tabolism,thelatter2propertiesbeingquitedifferentfromthoseofHGH.50–52 Theattenua-
tionofstress-inducedhypermetabolismisaveryfavorablepropertyofIGF-1.Clinicaltrials,
using an IGF-1 infusion, have focused on demonstrating increased anabolic activity.53,54
Increasedproteinsynthesisandnitrogenretentionhasbeenreportedinburns,headinjury,
andHIV-inducedcatabolicstates.
Woundhealingeffect
ThewoundhealingeffectsofIGF-1aredescribedinTable9.31,32,55,56 IGF-1isconsidered
to be a wound healing stimulant, increasing cell proliferation and collagen synthesis. In
addition, IGF-1 infusion has been shown to reverse diabetes and corticosteroid-induced
impairmentinwoundhealing.Itisimportanttopointoutthatthesepropertieshavelargely
beenreportedinanimalstudies.However,theincreaseinoverallanabolismshouldbenefit
awound.
Table 9. Woundhealingandinsulin-likegrowthfactor-1
• Generalwoundhealingstimulant
Increasescellreplication
Increasesepithelializationrate
Increasesangiogenesisrate
• Reversesbothdiabetesandcorticosteroid-inducedimpairedhealing
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Table 10. Anaboliceffectsofinsulin∗
• Increasescellaminoacidinflux
• Decreasesaminoacidreflux
• Increasesmuscleproteinsynthesisanddecreasesdegradation
• Increasesskinwoundproteincontent
• Increasescarbohydrateutilization
∗Theanaboliceffectdecreaseswithage.
Complications
Hypoglycemiaisthemaincomplication.IGF-1ingeneralappearstohavefewersideeffects
thandoHGH.However,itisusuallygivenasacontinuousinfusionbecauseofitsveryshort
half-life.Thisfactorlimitsitsclinicalusefulness.
Summary
IGF-1usedinconjunctionwithadequatenutritionsignificantlyincreasesnetanabolicac-
tivity. Its direct effect on wound healing is less clear. The attenuation of stress-induced
hypermetabolism is a significant advantage. Clinical use is hampered by the need for a
continuousinfusion.
INSULIN
Actions
Thehormoneinsulinisknowntohaveanabolicactivitiesinadditiontoitseffectonglucose
andfatmetabolism.57Inacatabolicstate,exogenousinsulinadministrationhasbeenshown
todecreaseproteolysisinadditiontoincreasingproteinsynthesis.33,39–41
Theanabolicactivityappearstomainlyaffectthemuscleandskinproteininthelean
body mass compartment (Table 10). An increase in circulating amino acids produced by
wound amino acid intake increases the anabolic and anticatabolic effect in both normal
humansandpopulationsinacatabolicstate.39–41,58
Clinicalresultsofinsulinuse
A number of clinical trials, mainly in burn patients (Table 11), have demonstrated the
stimulationofproteinsynthesisanddecreasedproteindegradationandnetnitrogenuptake,
especiallyinskeletalmuscle.58–63Anincreaseinanabolicactivityisalsoevidentindiabetic
patientswhoareprovidedmoreinsulin.Thepositiveeffectofinsulinonproteinsynthesis
Table 11. Clinicalstudiesoninsulin∗
• Stimulatesmuscleproteinsynthesisincatabolicburnpatients
• Stimulatesmuscleproteinsynthesisinnormalhumans
• Decreasesproteinbreakdownincatabolicpatients
• Increasesthere-epithelializationrateofdonorsitesinburnpatients
∗Thereareclearanaboliceffects.
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decreaseswithaging.64 ThisresponseisdifferentfromthatofHGHandanabolicsteroids
whereagedoesnotappeartoblunttheanabolicresponse.
Woundhealingeffect
There is less data on the actions of insulin on wound healing over and above its systemic
anabolic effect.61,65–67 Increases in skin protein content have been demonstrated with a
chronicinsulininfusion.Increasedre-epithelializationofskingraftdonorsiteswasreported
in one clinical trial in burn patients. Several animal studies have demonstrated increased
collagen production with insulin, and increasing insulin administration to diabetic mice
improvedallphasesofhealing.However,theeffectsofinsulinonwoundhealinghavenot
beenwellstudiedinhumans.
Complications
Themaincomplicationishypoglycemia.Theredoesnotappeartobeanyfluidretentionor
hypermetabolismwithitsuse.
Summary
In summary, hyperinsulinemia in catabolic patients and in normal humans increases net
protein synthesis and decreases protein breakdown. An infusion of glucose is required to
avoidhypoglycemia.Inturn,inadequateinsulinintakeindiabeticpatientsleadstoprogres-
sive lean mass loss and hyperglycemia appears to accentuate the nitrogen loss. Although
somepositivedataarepresentoninsulinimprovinghealing,thedataarelimited.
TESTOSTERONE
Actions
Testosterone,whosebasicstructureisasteroidring,isanaturalendogenousandrogen.68–70
It is synthesized primarily in the Leydig cells of the testes in men and by the ovaries and
adrenal glands in women. Healthy adult men produce 3 to 10 mg of testosterone a day,
yielding plasma concentrations ranging from 300 to 1000 µg/dL.71–73 It acts on the cells’
androgenicreceptorsfoundmainlyinskin,muscle,andmalesexglands.Ithasbothandro-
genic or masculinizing properties and anabolic properties. Androgenic effects are present
to some degree in all anabolic steroids. Androgenic effects include development of male
sex glands, determination of male hair growth pattern, increased libido, and assertiveness
(Table12).Mosttestosteroneanalogsoranabolicsteroidshaveandrogenicpropertiesmuch
lower than those of testosterone itself.57,74,75 The anabolic properties were defined in the
1930s. These include an increase in muscle size, synthesis, and strength. Increased skin
thicknesshasalsobeennotedwithadministrationoftestosteronetohypogonadalmen.The
importance of testosterone is evidenced by the complications seen with low testosterone
levels,whichincludesarcopeniaorlostleanmass,increasedrateofdevelopmentofosteo-
porosis, anemia, thinning of skin and weakness, and impaired wound healing (Tables 13
and14).71,76,77
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Table 12. Testosterone’scharacteristics∗
• Endogenousanabolichormone
• Producedmainlybythetestesinmenandtheadrenalglandinwoman
• Actsonandrogenicreceptorsfoundmainlyinmuscle,skin,andsexglands
• Hasmodestanabolicactivitycomparedtoitsanalogs
• Androgenicactivityincludesmalesexglanddevelopment,malehairgrowthpattern
determination,mood
• Rapidlymetabolizedbytheliver
• Levelsdecreasewithincreasingage
• Levelsdecreasewithinjury/infection
• Decreasedtestosteronecausesleanmasslossinnormalandinjuredman
∗Decreasingtestosteronelevelswithageandillnesswillresultinadecreaseinanabolicactivity.
The native molecule was first used in the 1950s to correct a debilitated state, cor-
rect anemia, and increase calcium deposition in bones as well as to treat hypogonadal
states.68–70,76,77 Thetestosteronemoleculeisrapidlymetabolizedbytheliversuchthatthe
half-life is only about 20 minutes. Adjustments were made to the molecule to increase its
timeofaction,themostpopularbeingtestosteroneenthanate.
Decreased production, leading to a hypogonadal state, occurs with increasing age as
well as with injury or infection, especially severe trauma and chronic illness such as HIV
infectionandchronicwounds.
Ahypogonadalstateisseeninmanypatientpopulations,includingthoseinanacute
severeinjurystate,thosewithinfectionormorechronicstatessuchasaging,andthosewith
chronicobstructivepulmonarydiseaseandotherchronicillnesses.71,72,76
Clinicalresultsoftestosteroneuse
Testosterone administration is used mainly to correct a hypogonadal state, while testos-
teroneanalogs,whichhaveamuchgreateranabolicactivity,areusedtoincreaseanabolism
(Table 14).70–74,76–78Clinical studies have demonstrated a significant increase in net pro-
tein synthesis, especially in muscle and skin, with high doses of testosterone delivered
parenterally.74,75
Woundhealingeffect
Itisclearthattestosteroneisneededforthewoundhealingprocesssincedecreasedlevelsim-
pedehealing.57,79,80AdequatetestosteronelevelsarerequiredforIGF-1production,IGF-1
beingawoundhealingagent.However,thereisnogooddatathatanincreaseintestosterone
levelsabovenormalimproveswoundhealing.Thisisnotthecasewithanumberofanabolic
Table 13. Effectofdecreasedtestosterone(thehypogonadal
state)
• Leanmassloss
• Thinningofskin
• Increasingfatmass
• Impairedwoundhealing
• Decreaseinphysicalandpsychologicalmasculinizingproperties
• Osteoporosis
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Table 14. Clinicaleffectsoftestosteroneadministration∗
• Correctionoftheandrogenic/anabolicdeficiencyofahypogonadalstate
• Increasedanabolismandmusclesynthesisintheelderly
• Increasedleanmasssynthesisinnormalmen
• Decreasedboneloss
• Androgenicsideeffects
∗Androgenicormasculinizingeffectswilldevelopwithexogenoustestosteroneuse.
steroidsthathavebeenshowntoincreasetherateofwoundhealingevenintheabsenceof
hypogonadism.Theseagentswillbediscussednext.
Complications
The major complications are the androgenic side effects. Some fluid retention has been
reported with high doses. A decrease in high-density lipoproteins has also been reported
withtheuseoflargedoses.
Summary
Testosterone is a necessary androgen for maintaining lean mass and wound healing. A
deficiency leads to catabolism and impaired healing. The use of large doses exogenously
increases net protein synthesis, but a direct effect on wound healing has not yet been
demonstrated.
ANABOLICSTEROIDS
Actions
Anabolic steroids refer to the class of drugs produced by modification of
testosterone.68–70,76,77Thesedrugsweredevelopedinordertotakeclinicaladvantageofthe
anabolic effects of testosterone while decreasing androgenic side effects of the naturally
occurringmolecule.Modificationsinthesteroidringweremadebecauseoftheshorthalf-
lifeoftestosteroneanditsmasculinizingproperties.Modificationsincludeda17α methyl
derivative for oral use and a 17β ester configuration for parenteral use. These changes
markedlyincreaseditshalf-lifeanddecreaseditsandrogenicproperties(Table15).
Table 15. Anabolicsteroids(history)
• Allaretestosteronederivatives
• Anabolicpropertiesnotedinthe1940s
• Androgenreceptorsfoundincytosol(1960s)
• Attempttoincreaseanabolism(useofanabolictoandrogenicratiotojudgenewdrugs[1960topresent])
• Derivatives
Oralare17αmethyl
Parenteralare17βesters
• Mostclearedbytheliver(concernforhepatotoxicity)
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