review article thyroid hormone and wound...

Hindawi Publishing CorporationJournal of Thyroid ResearchVolume 2013 Article ID 124538 5 pageshttpdxdoiorg1011552013124538

Review ArticleThyroid Hormone and Wound Healing

Joshua D Safer

Section of Endocrinology Boston University School of Medicine Room M-1016 715 Albany Street Boston MA 02118 USA

Correspondence should be addressed to Joshua D Safer jsaferbuedu

Received 29 January 2013 Accepted 9 February 2013

Academic Editor Constantinos Pantos

Copyright copy 2013 Joshua D Safer This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Although thyroid hormone is one of themost potent stimulators of growth andmetabolic rate the potential to use thyroid hormoneto treat cutaneous pathology has never been subject to rigorous investigation A number of investigators have demonstratedintriguing therapeutic potential for topical thyroid hormone Topical T

3has accelerated wound healing and hair growth in rodents

Topical T4has been used to treat xerosis in humans It is clear that the use of thyroid hormone to treat cutaneous pathology may

be of large consequence and merits further study This is a review of the literature regarding thyroid hormone action on skin alongwith skinmanifestations of thyroid diseaseThe paper is intended to provide a context for recent findings of direct thyroid hormoneaction on cutaneous cells in vitro and in vivo which may portend the use of thyroid hormone to promote wound healing

1 Introduction

Despite early observation of cutaneous pathology associatedwith thyroid disease [1 2] research on the topic remainssparse Direct thyroid hormone action has been demon-strated on cutaneous biology including on the epidermisdermis and hair In addition autoimmune diseases withcutaneous manifestations may be associated with thyroiddysfunction (which may be autoimmune in etiology itself)

The lack of investigation into cutaneous responses to thy-roid hormone might be attributed to the fact that mostcasesof thyroid disease are controlled with existing medicationHowever there is a slowly evolving literature that suggeststhat the thyroid hormone pathway is integral to cutaneousphysiology and that manipulation of the thyroid hormonepathway in skin could be used to treat cutaneous disease

The skin manifestations of hypothyroidism have beendescribed since the 1800s Indeed the observation associatinghypothyroidismwith the skin [1] predates the classic publica-tion associating hypothyroidism with the thyroid [2]

Thyrotoxicosis is also associated with cutaneous manifes-tations [3] Although autoimmune-associated manifestationsmay be specific to Gravesrsquo disease thyrotoxicosis in generalmay result in skin sequelae Starting in the 1950s there wereattempts to use parenteral and topical tri-iodothyronine (T

3)

to treat pretibial myxedema in Gravesrsquo patients [4ndash7] In all

cases lesions improved with topical or intralesional steroidswhich ended further study of thyroid hormone action At thattime it was noted that topical thyroxine (T

4) stimulated hair

growth and pigmentation in cows [8]

2 Direct Thyroid Hormone Action onSkin Tissues

Thyroid hormone action on skin is mediated through thethyroid hormone receptor (TR) The three most recognizedthyroid hormone binding isoforms of TR have been foundin cutaneous tissues [9ndash12] although methods used do notspecifically distinguish which of the three isoforms predomi-nates

The predominant circulating thyroid hormone is the pro-hormone T

4 T4is converted to the active thyroid hormone

T3 by intracellular thyroid hormone deiodinases [13 14] Two

of the enzymes (D1 D2) primarily activate T4to T3 The

third enzyme D3 converts T4to inactive reverse T

3(rT3)

Investigators have showed conversion of T4to either T

3or rT3

in cutaneous cultures demonstrating indirectly the presenceof thyroid hormone deiodinases in skin [15ndash17] D3 is notexpressed significantly in most peripheral tissues Howeverassays of enzyme activity suggest that D3 is active in goatepidermis [18] mouse epidermis [19] and human skin in

2 Journal of Thyroid Research

vivo [20 21] D2 activity has been demonstrated in culturedhuman fibroblasts [22] Neither D1 nor D3 has been foundto be active in the dermal fibroblasts suggesting that D3expression may be limited to epidermis

In addition investigators have identified elements of thehypothalamic-pituitary-thyroid hormone axis in human skin[23ndash25] and have determined that thyroid hormone receptorsmediate skin proliferation and inflammation along with skinresponse to retinoids [26 27]

21 Epidermal Changes Thyroid hormone accelerates barrierformation by increasing the activity of enzymes in thecholesterol sulfate cycle and hypothyroidism may hinderthe epidermal barrier function [28 29] Hypothyroidismalso may affect the development of the lamellar granules(Odland bodies) which are vital in the establishment of anormal stratum corneum [30] In vitro keratinocyte studieshave shown that depletion of T

3results in elevated levels of

transglutaminase (involved in the formation of the cornifiedenvelope) Further in vitro analysis has suggested that T

3

depleted keratinocytes have diminished levels of plasmino-gen activator [31]

In tissue culture studies T3has been shown to directly

stimulate proliferation of both epidermal keratinocytes anddermal fibroblasts [32ndash34] However in vivo skin prolifera-tion directly stimulated by T

3may be offset by inhibiting fac-

tors dependent on the systemic T3[33] Clinical observations

of skin in thyrotoxic patients are complicated by the fact thatmost cases of thyrotoxicosis are the result of Gravesrsquo diseasewhich has an associated finding of autoimmune-mediatedglycosaminoglycan deposition in the dermis [35]

22 Dermal Changes The skin tends to be pale in hypothy-roidism both because of the dermal mucopolysaccharidesand the dermal water content Changes in hypothyroiddermis can be seen in weeks and reversed in weeks [3637] Hyaluronic acid is the major glycosaminoglycan thataccumulates inmyxedema [38] In addition lack of lymphaticdrainage may explain the formation of exudates that areapparent in the myxedematous state [39] Increased dermalcarotene may appear as a yellow hue on the palms solesand nasolabial folds In vitro thyroid hormone actionson cultured skin fibroblasts include inhibiting synthesis ofhyaluronic acid fibronectin and collagen [40ndash42]

The net effect of thyroid hormone on dermal thicknessremains the subject of debate In the past investigatorshave reported skin thinning in rats made thyrotoxic withintraperitoneal (IP) T

4[43]There have been demonstrations

both of decreased collagen production in the thyrotoxicanimals and increased collagen catabolism in thyrotoxicanimals [43 44]More recent investigations suggest increaseddermal thickness inmice treatedwithT

3 whether topically or

intraperitoneally [32 33] There is also a report of increaseddermal thickness in mice treated topically with TRIAC (athyroid hormone analog [45])

23 Hair and Nail Changes Hale and Ebling demonstratedthat intraperitoneal T

4decreased both the resting phase

of the hair growth cycle (telogen) and the growth phaseof the hair growth cycle (anagen) Although there was anenhanced turnover the net hair length at any given timewas not changed from that of untreated animals [46] Thetime to regrowth of hair following epilation was shortenedby approximately 10

In hypothyroidism hair can be dry coarse brittle andslow growing Nails may be thickened brittle and slowgrowing [47] Diffuse or partial alopecia may be observedalongwith loss of the lateral third of the eyebrow (madarosis)The alopecia connected to hypothyroidism may be mediatedby hormone effects on the initiation as well as the duration ofhair growthThere is one report of long terminal hairs on thebacks and extremities of hypothyroid children [48] The hairdisappeared following thyroid hormone replacement but nomechanism was determined

Clinically the hair in thyrotoxicosis may be fine and softNail changes may also occur characterized by a concavecontour and distal onycholysis (Plummerrsquos nails) Diffusenonscarring alopecia may also be observed

Like with epidermal proliferation hair changes withthyrotoxicosis are different thanwhatmight be seenwith top-ically administered thyroid hormone Mice and rats treateddaily for 1-2 weeks with topical T

3had increased hair counts

but mice made thyrotoxic with daily intraperitoneal T3for 1-

2 weeks had decreased hair counts [33 44] Thyrotoxic goatshad increased mohair length but decreased fiber diameter[49] A topical mixture including thyroxine insulin andgrowth hormone increased hair counts over a 6-monthtreatment period in men with androgenic alopecia [50]

The dryness of hypothyroid skin results from decreasedeccrine gland secretionThemechanism for decreased sweat-ing is not clear although the glands are atrophic on histologicexamination [51] Hypothyroidism has been reported to be acause of increased sweat electrolytes requiring differentiationfrom cystic fibrosis [52]

Hypothyroid patients may sometimes suffer Candidafolliculitis It has been theorized that this may result fromdecrease sebum production relative to euthyroid personsThe hair follicles may develop a flora with fewer lipophilicorganisms which are replaced by Candida albicans [53]

3 Potential Use of Thyroid Hormone in theTreatment of Cutaneous Pathology

Knowledge of cutaneous manifestations of thyrotoxicosisdoes not predict the direct effects of T

3on skin in vivo T

3

effects on skin depend on route of delivery Because epidermisexpresses the inactivating type 3 deiodinase [19] thyroidhormone action on epidermis in systemic thyrotoxicosis isless than might be predicted In contrast to the findings withsystemic thyrotoxicosis topical T

3bypasses the inactivating

type 3 deiodinase and stimulates epidermal proliferation der-mal thickening and hair growth [32 33] Topical applicationof TRIAC (tri-iodothyroacetic acid) the thyroid hormoneanalog thickens skin by stimulating production of collagen[45] Further topical TRIAC has been shown to reverse thedermal atrophy associated with corticosteroids

Journal of Thyroid Research 3

The importance of thyroid hormone in wound healinghad been debated historically In 1973 and 1974 Mehreganand Zamick reported that oral T

3accelerated the rate of

wound healing in euthyroid rats and improved the qual-ity of the wounds [54 55] Scars were smoother in T

3-

treated animals Lennox and Johnston reported acceleratedwound healing and increased tensile strength when ratswere given supraphysiologic doses of T

4[56] Pirk et al

reported no change in wound healing with 13 120583g100mgbody weight intraperitoneal T

4in hamsters but increased

rate of fracture repair [57] Ashton and Dekel also reportedincreased fracture repair rate in mice given 20120583g100mgbody weight subcutaneous T

4[58] In small series there are

reports that hypothyroid patients required thyroid hormoneto achieve healing of radiation-induced neck fistulae [59 60]Conversely Cannon [61] reported that hypothyroidism didnot diminish wound strength in pigs and Ladenson et al [62]did not detect wound healing deficits in hypothyroid humans

In contrast most recent data suggest that topical thyroidhormone may accelerate wound healing rate Topical appli-cation of supraphysiological doses of T

3accelerated wound

healing in normal mice and rats [63ndash65] A human woundhealing formulation has been described that requires T

4in

addition to growth hormone and insulin [66]While direct thyroid hormone action has been demon-

strated on cutaneous cell biology much more study remainsto be done There is a slowly evolving literature to suggestan important role for thyroid hormone in cutaneous woundrepair that could be harnessed as a pharmaceutical

Conflict of Interests

The author has no conflict of interests relating to this paper

References

[1] W M Ord ldquoOn myxoedema term proposed to be applied toan essential condition in the ldquocretinoidrdquo affection occasionallyobserved in middle-aged womenrdquoMedico-Chirurgical Transac-tions vol 61 pp 57ndash78 1878

[2] V Horsley ldquoThe thyroid gland its relation to the pathology ofmyxoedema and cretinism to the question of surgical treatmentof goitre an to the general nutrition of the bodyrdquoBritishMedicalJournal vol 1 pp 111ndash115 1885

[3] J Abulkadir A Besrat G Abraham et al ldquoThyrotoxicosisin Ethiopian patients-a prospective studyrdquo Transactions of theRoyal society of Tropical Medicine and Hygiene vol 76 pp 500ndash502 1982

[4] T A Warthin and B B Boshell ldquoPretibial myxedema treatedwith local injection of triiodothyroninerdquo American MedicalAssociationArchives of InternalMedicine vol 100 no 2 pp 319ndash321 1957

[5] J L Gabrilove A S Alavarez and J Churg ldquoGeneralized andlocalized (pretibial) myxedema effect of thyroid analogues andadrenal glucocorticoidsrdquo The Journal of Clinical Endocrinologyand Metabolism vol 20 pp 825ndash832 1960

[6] T M D Gimlette ldquoPretibial myxoedemardquo British MedicalJournal vol 2 no 5195 pp 348ndash351 1960

[7] B D Cohen R S Benua and R W Rawson ldquoLocalizedmyxedema involving the upper extremitiesrdquoArchives of InternalMedicine vol 111 pp 641ndash646 1963

[8] A Berman ldquoPeripheral effects of L-thyroxine on hair growthand coloration in cattlerdquo Journal of Endocrinology vol 20 pp288ndash292 1960

[9] M K Ahsan Y Urano S Kato H Oura and S AraseldquoImmunohistochemical localization of thyroid hormonenuclear receptors in human hair follicles and in vitro effect ofL-triiodothyronine on cultured cells of hair follicles and skinrdquoJournal of Medical Investigation vol 44 no 3-4 pp 179ndash1841998

[10] H Torma O Rollman and A Vahlquist ldquoDetection of mRNAtranscripts for retinoic acid vitamin D3 and thyroid hor-mone (c-erb-A) nuclear receptors in human skin using reversetranscription and polymerase chain reactionrdquo Acta Dermato-Venereologica vol 73 no 2 pp 102ndash107 1993

[11] N Billoni B Buan B Gautier O Gaillard Y F Mahe and BA Bernard ldquoThyroid hormone receptor 1205731 is expressed in thehuman hair folliclerdquo British Journal of Dermatology vol 142 no4 pp 645ndash652 2000

[12] H Torma T Karlsson G Michaelsson O Rollman and AVahlquist ldquoDecreased mRNA levels of retinoic acid receptor120572 retinoid X receptor 120572 and thyroid hormone receptor 120572 inlesional psoriatic skinrdquoActa Dermato-Venereologica vol 80 no1 pp 4ndash9 2000

[13] A C Bianco D Salvatore B Gereben M J Berry and PR Larsen ldquoBiochemistry cellular and molecular biology andphysiological roles of the iodothyronine selenodeiodinasesrdquoEndocrine Reviews vol 23 no 1 pp 38ndash89 2002

[14] A C Bianco and B W Kim ldquoDeiodinases implications of thelocal control of thyroid hormone actionrdquoThe Journal of ClinicalInvestigation vol 116 no 10 pp 2571ndash2579 2006

[15] S Refetoff R Matalon and M Bigazzi ldquoMetabolism of L-thyroxine (T4) and L-triiodothyronine (T3) by human fibrob-lasts in tissue culture evidence for cellular binding proteins andconversion of T4 to T3rdquo Endocrinology vol 91 no 4 pp 934ndash947 1972

[16] T S Huang I J Chopra A Beredo D H Solomon andG N Chua Teco ldquoSkin is an active site for the inner ringmonodeiodination of thyroxine to 33101584051015840-triiodothyroninerdquoEndocrinology vol 117 no 5 pp 2106ndash2113 1985

[17] M M Kaplan C Pan P R Gordon J K Lee and B AGilchrest ldquoHuman epidermal keratinocytes in culture convertthyroxine to 3531015840-triiodothyronine by type II iodothyroninedeiodination a novel endocrine function of the skinrdquo Journal ofClinical Endocrinology and Metabolism vol 66 no 4 pp 815ndash822 1988

[18] D Villar F Nicol J R Arthur et al ldquoType II and typeIII monodeiodinase activities in the skin of untreated andpropylthiouracil-treated cashmere goatsrdquo Research in Veteri-nary Science vol 68 no 2 pp 119ndash123 2000

[19] M P Huang K A Rodgers R OrsquoMara et al ldquoThe thyroidhormone degrading type 3 deiodinase is the primary deiodinaseactive in murine epidermisrdquo Thyroid vol 21 pp 1263ndash12682011

[20] J P Schroder-VanDer Elst DVanDerHeideGMDeEscobarandM J Obregon ldquoIodothyronine deiodinase activities in fetalrat tissues at several levels of iodine deficiency a role for theskin in 3531015840-triiodothyronine economyrdquo Endocrinology vol139 no 5 pp 2229ndash2234 1998


[21] F Santini P Vitti L Chiovato et al ldquoRole for inner ringdeiodination preventing transcutaneous passage of thyroxinerdquoJournal of Clinical Endocrinology andMetabolism vol 88 no 6pp 2825ndash2830 2003

[22] A M Dumitrescu X H Liao M S Y Abdullah et alldquoMutations in SECISBP2 result in abnormal thyroid hormonemetabolismrdquoNatureGenetics vol 37 no 11 pp 1247ndash1252 2005

[23] A Slominski J Wortsman L Kohn et al ldquoExpression ofhypothalamic-pituitary-thyroid axis related genes in the humanskinrdquo Journal of Investigative Dermatology vol 119 no 6 pp1449ndash1455 2002

[24] E Bodo B Kany E Gaspar et al ldquoThyroid-stimulating hor-mone a novel locally producedmodulator of human epidermalfunctions is regulated by thyrotropin-releasing hormone andthyroid hormonesrdquo Endocrinology vol 151 no 4 pp 1633ndash16422010

[25] R Paus ldquoExploring the ldquothyroid-skin connectionrdquo conceptsquestions and clinical relevancerdquo Journal of Investigative Der-matology vol 130 pp 93ndash101 2010

[26] C Contreras-Jurado L Garcıa-Serrano M Gomez-Ferrerıa CCosta J M Paramio and A Aranda ldquoThe thyroid hormonereceptors as modulators of skin proliferation and inflamma-tionrdquo The Journal of Biological Chemistry vol 286 no 27 pp24079ndash24088 2011

[27] L Garcia-Serrano M A Gomez-Ferreria C Contrera-JuradoC Segrelles J M Paramio and A Aranda ldquoThe thyroidhormone receptors modulate the skin response to retinoidsrdquoPLoS ONE vol 6 Article ID e23825 2011

[28] R M Rosenberg R R Isseroff V A Ziboh and A CHuntley ldquoAbnormal lipogenesis in thyroid hormone-deficientepidermisrdquo Journal of Investigative Dermatology vol 86 no 3pp 244ndash248 1986

[29] K Hanley Y Jiang C Katagiri K R Feingold and M LWilliams ldquoEpidermal steroid sulfatase and cholesterol sulfo-transferase are regulated during late gestation in the fetal ratrdquoJournal of Investigative Dermatology vol 108 no 6 pp 871ndash8751997

[30] K Hanley U P Devaskar S J Hicks et al ldquoHypothyroidismdelays fetal stratum corneum development in micerdquo PediatricResearch vol 42 no 5 pp 610ndash614 1997

[31] R R Isseroff K T Chun and R M Rosenberg ldquoTriiodothyro-nine alters the cornification of cultured human keratinocytesrdquoBritish Journal of Dermatology vol 120 no 4 pp 503ndash510 1989

[32] J D Safer L M Fraser S Ray and M F Holick ldquoTopicaltriiodothyronine stimulates epidermal proliferation dermalthickening and hair growth in mice and ratsrdquo Thyroid vol 11no 8 pp 717ndash724 2001

[33] J D Safer TM Crawford LM Fraser et al ldquoThyroid hormoneaction on skin diverging effects of topical versus intraperitonealadministrationrdquoThyroid vol 13 no 2 pp 159ndash165 2003

[34] P J A Holt ldquoIn vitro responses of the epidermis to triiodothy-roninerdquo Journal of Investigative Dermatology vol 71 no 3 pp202ndash204 1978

[35] P J A Holt and R Marks ldquoThe epidermal response to changein thyroid statusrdquo Journal of Investigative Dermatology vol 68no 5 pp 299ndash301 1977

[36] M J Reuter ldquoHistopathology of the skin in myxedemardquoArchives of Dermatology and Syphilology vol 24 pp 55ndash71 1931

[37] J L Gabrilove and A W Ludwig ldquoThe histogenesis ofmyxedemardquo The Journal of Clinical Endocrinology andMetabolism vol 17 no 8 pp 925ndash932 1957

[38] T J Smith R S Bahn and C A Gorman ldquoConnective tissueglycosaminoglycans and diseases of the thyroidrdquo EndocrineReviews vol 10 no 3 pp 366ndash391 1989

[39] H H Parving J M Hansen and S L Nielsen ldquoMechanisms ofedema formation in myxedemamdashincreased protein extravasa-tion and relatively slow lymphatic drainagerdquo The New EnglandJournal of Medicine vol 301 no 9 pp 460ndash465 1979

[40] T J Smith Y Murata A L Horwitz L Philipson and SRefetoff ldquoRegulation of glycosaminoglycan synthesis by thyroidhormone in vitrordquoThe Journal of Clinical Investigation vol 70no 5 pp 1066ndash1073 1982

[41] Y Murata P Ceccarelli S Refetoff A L Horwitz and NMatsui ldquoThyroid hormone inhibits fibronectin synthesis by cul-tured human skin fibroblastsrdquo Journal of Clinical Endocrinologyand Metabolism vol 64 no 2 pp 334ndash339 1987

[42] C De Rycker J L Vandalem and G Hennen ldquoEffects of 3531015840-triiodothyronine on collagen synthesis by cultured human skinfibroblastsrdquo FEBS Letters vol 174 no 1 pp 34ndash37 1984

[43] C W Fink J L Ferguson and J D Smiley ldquoEffect of hyper-thyroidism and hypothyroidism on collagen metabolismrdquo TheJournal of Laboratory and Clinical Medicine vol 69 no 6 pp950ndash959 1967

[44] K I Kivirikko O Laitinen J Aer and J Halme ldquoMetabolism ofcollagen in experimental hyperthyroidism and hypothyroidismin the ratrdquo Endocrinology vol 80 no 6 pp 1051ndash1061 1967

[45] J Faergemann T Sarnhult E Hedner et al ldquoDose-responseeffects of tri-iodothyroacetic acid (Triac) and other thyroidhormone analogues on glucocorticoid-induced skin atrophy inthe haired mouserdquo Acta Dermato-Venereologica vol 82 no 3pp 179ndash183 2002

[46] P A Hale and F J Ebling ldquoThe effect of a single epilation onsuccessive hair eruptions in normal and hormone-treated ratsrdquoJournal of Experimental Zoology vol 207 no 1 pp 49ndash71 1979

[47] G E Mullin and J S Eastern ldquoCutaneous signs of thyroiddiseaserdquo American Family Physician vol 34 no 4 pp 93ndash981986

[48] W H Perloff ldquoHirsutism a manifestation of juvenile hypothy-roidismrdquo Journal of the American Medical Association vol 157no 8 pp 651ndash652 1955

[49] R Puchala I Prieto V Banskalieva A L Goetsch M Lachicaand T Sahlu ldquoEffects of bovine somatotropin and thyroidhormone status on hormone levels body weight gain andmohair fiber growth ofAngora goatsrdquo Journal of Animal Sciencevol 79 no 11 pp 2913ndash2919 2001

[50] E S Lindenbaum A L Feitelberg M Tendler et al ldquoPilotstudy of a novel treatment for androgenetic alopecia usingenriched cell culture medium clinical trialsrdquo DermatologyOnline Journal vol 9 article 4 2003

[51] M A Means and R L Dobson ldquoCytological changes inthe sweat gland in hypothyroidismrdquo Journal of the AmericanMedical Association vol 186 pp 113ndash115 1963

[52] L Squires and T F Dolan ldquoAbnormal sweat chloride in auto-immune hypothyroidismrdquo Clinical Pediatrics vol 28 no 11 pp535ndash536 1989

[53] S Dekio C Imaoka and J Jidoi ldquoCandida folliculitis associatedwith hypothyroidismrdquo British Journal of Dermatology vol 117no 5 pp 663ndash664 1987

[54] P Zamick and A H Mehregan ldquoEffect of 1-tri-iodothyronineon marginal scars of skin grafted burns in ratsrdquo Plastic andReconstructive Surgery vol 51 no 1 pp 71ndash75 1973


[55] A H Mehregan and P Zamick ldquoThe effect of triiodothyroninein healing of deep dermal burns and marginal scars of skingrafts A histologic studyrdquo Journal of Cutaneous Pathology vol1 no 3 pp 113ndash116 1974

[56] J Lennox and I D Johnston ldquoThe effect of thyroid status onnitrogen balance and the rate of wound healing after injury inratsrdquo British Journal of Surgery vol 60 no 4 p 309 1973

[57] FW Pirk TM El-Attar and G D Roth ldquoEffect of analogues ofsteroid and thyroxine hormones onwoundhealing in hamstersrdquoJournal of Periodontal Research vol 9 no 5 pp 290ndash297 1974

[58] I K Ashton and S Dekel ldquoFracture repair in the snell dwarfmouserdquo British Journal of Experimental Pathology vol 64 no5 pp 479ndash486 1983

[59] M M V Alexander J T Zajtchuk and R L HendersonldquoHypothyroidism and wound healing Occurrence after headand neck radiation and surgeryrdquoArchives of Otolaryngology vol108 no 5 pp 289ndash291 1982

[60] Y P Talmi Y Finkelstein and Y Zohar ldquoPharyngeal fistulas inpostoperative hypothyroid patientsrdquo Annals of Otology Rhinol-ogy amp Laryngology vol 98 no 4 pp 267ndash268 1989

[61] C R Cannon ldquoHypothyroidism in head and neck cancerpatients experimental and clinical observationsrdquo Laryngoscopevol 104 no 11 pp 1ndash21 1994

[62] P W Ladenson A A Levin E C Ridgway and G H DanielsldquoComplications of surgery in hypothyroid patientsrdquo AmericanJournal of Medicine vol 77 no 2 pp 261ndash266 1984

[63] J D Safer T M Crawford and M F Holick ldquoTopical thyroidhormone accelerates wound healing in micerdquo Endocrinologyvol 146 no 10 pp 4425ndash4430 2005

[64] M Tarameshloo M Norouzian S Zarein-Dolob M Dadpayand R Gazor ldquoA comparative study of the effects of topicalapplication of Aloe vera thyroid hormone and silver sulfa-diazine on skin wounds in Wistar ratsrdquo Laboratory AnimalResearch vol 28 pp 17ndash21 2012

[65] R Kassem Z Liberty M Babaev H Trau and O CohenldquoHarnessing the skin-thyroid connection for wound healinga prospective controlled trial in guinea pigsrdquo Clinical andExperimental Dermatology vol 37 pp 850ndash856 2012

[66] E S Lindenbaum Y H Shai Y Ullmann et al ldquoStimu-lated healing of recalcitrant wounds by topical application ofenriched cell culture medium a clinical reportrdquo Plastic andReconstructive Surgery vol 108 no 1 pp 104ndash113 2001

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

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Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


vivo [20 21] D2 activity has been demonstrated in culturedhuman fibroblasts [22] Neither D1 nor D3 has been foundto be active in the dermal fibroblasts suggesting that D3expression may be limited to epidermis

In addition investigators have identified elements of thehypothalamic-pituitary-thyroid hormone axis in human skin[23ndash25] and have determined that thyroid hormone receptorsmediate skin proliferation and inflammation along with skinresponse to retinoids [26 27]

21 Epidermal Changes Thyroid hormone accelerates barrierformation by increasing the activity of enzymes in thecholesterol sulfate cycle and hypothyroidism may hinderthe epidermal barrier function [28 29] Hypothyroidismalso may affect the development of the lamellar granules(Odland bodies) which are vital in the establishment of anormal stratum corneum [30] In vitro keratinocyte studieshave shown that depletion of T

3results in elevated levels of

transglutaminase (involved in the formation of the cornifiedenvelope) Further in vitro analysis has suggested that T

3

depleted keratinocytes have diminished levels of plasmino-gen activator [31]

In tissue culture studies T3has been shown to directly

stimulate proliferation of both epidermal keratinocytes anddermal fibroblasts [32ndash34] However in vivo skin prolifera-tion directly stimulated by T

3may be offset by inhibiting fac-

tors dependent on the systemic T3[33] Clinical observations

of skin in thyrotoxic patients are complicated by the fact thatmost cases of thyrotoxicosis are the result of Gravesrsquo diseasewhich has an associated finding of autoimmune-mediatedglycosaminoglycan deposition in the dermis [35]

22 Dermal Changes The skin tends to be pale in hypothy-roidism both because of the dermal mucopolysaccharidesand the dermal water content Changes in hypothyroiddermis can be seen in weeks and reversed in weeks [3637] Hyaluronic acid is the major glycosaminoglycan thataccumulates inmyxedema [38] In addition lack of lymphaticdrainage may explain the formation of exudates that areapparent in the myxedematous state [39] Increased dermalcarotene may appear as a yellow hue on the palms solesand nasolabial folds In vitro thyroid hormone actionson cultured skin fibroblasts include inhibiting synthesis ofhyaluronic acid fibronectin and collagen [40ndash42]

The net effect of thyroid hormone on dermal thicknessremains the subject of debate In the past investigatorshave reported skin thinning in rats made thyrotoxic withintraperitoneal (IP) T

4[43]There have been demonstrations

both of decreased collagen production in the thyrotoxicanimals and increased collagen catabolism in thyrotoxicanimals [43 44]More recent investigations suggest increaseddermal thickness inmice treatedwithT

3 whether topically or

intraperitoneally [32 33] There is also a report of increaseddermal thickness in mice treated topically with TRIAC (athyroid hormone analog [45])

23 Hair and Nail Changes Hale and Ebling demonstratedthat intraperitoneal T

4decreased both the resting phase

of the hair growth cycle (telogen) and the growth phaseof the hair growth cycle (anagen) Although there was anenhanced turnover the net hair length at any given timewas not changed from that of untreated animals [46] Thetime to regrowth of hair following epilation was shortenedby approximately 10

In hypothyroidism hair can be dry coarse brittle andslow growing Nails may be thickened brittle and slowgrowing [47] Diffuse or partial alopecia may be observedalongwith loss of the lateral third of the eyebrow (madarosis)The alopecia connected to hypothyroidism may be mediatedby hormone effects on the initiation as well as the duration ofhair growthThere is one report of long terminal hairs on thebacks and extremities of hypothyroid children [48] The hairdisappeared following thyroid hormone replacement but nomechanism was determined

Clinically the hair in thyrotoxicosis may be fine and softNail changes may also occur characterized by a concavecontour and distal onycholysis (Plummerrsquos nails) Diffusenonscarring alopecia may also be observed

Like with epidermal proliferation hair changes withthyrotoxicosis are different thanwhatmight be seenwith top-ically administered thyroid hormone Mice and rats treateddaily for 1-2 weeks with topical T

3had increased hair counts

but mice made thyrotoxic with daily intraperitoneal T3for 1-

2 weeks had decreased hair counts [33 44] Thyrotoxic goatshad increased mohair length but decreased fiber diameter[49] A topical mixture including thyroxine insulin andgrowth hormone increased hair counts over a 6-monthtreatment period in men with androgenic alopecia [50]

The dryness of hypothyroid skin results from decreasedeccrine gland secretionThemechanism for decreased sweat-ing is not clear although the glands are atrophic on histologicexamination [51] Hypothyroidism has been reported to be acause of increased sweat electrolytes requiring differentiationfrom cystic fibrosis [52]

Hypothyroid patients may sometimes suffer Candidafolliculitis It has been theorized that this may result fromdecrease sebum production relative to euthyroid personsThe hair follicles may develop a flora with fewer lipophilicorganisms which are replaced by Candida albicans [53]

3 Potential Use of Thyroid Hormone in theTreatment of Cutaneous Pathology

Knowledge of cutaneous manifestations of thyrotoxicosisdoes not predict the direct effects of T

3on skin in vivo T

3

effects on skin depend on route of delivery Because epidermisexpresses the inactivating type 3 deiodinase [19] thyroidhormone action on epidermis in systemic thyrotoxicosis isless than might be predicted In contrast to the findings withsystemic thyrotoxicosis topical T

3bypasses the inactivating

type 3 deiodinase and stimulates epidermal proliferation der-mal thickening and hair growth [32 33] Topical applicationof TRIAC (tri-iodothyroacetic acid) the thyroid hormoneanalog thickens skin by stimulating production of collagen[45] Further topical TRIAC has been shown to reverse thedermal atrophy associated with corticosteroids





3-


4[56] Pirk et al







3accelerated wound


4in





References










































































of






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References










































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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