The University of Chicago Press

The Thyroid Gland and Its Functions in Cold-Blooded Vertebrates
Author(s): W. Gardner Lynn and Henry E. Wachowski

Source: The Quarterly Review of Biology, Vol. 26, No. 2 (Jun., 1951), pp. 123-168
Published by: The University of Chicago Press
Stable URL: http://www.jstor.org/stable/2809211 .
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VOL. 2.6,NO. 1 June,I951
THE QUARTERLY REVIEW

of BIOLOGY
THE THYROID GLAND AND ITS FUNCTIONS IN

COLD-BLOODED VERTEBRATES
BY W. GARDNERLYNN AND HENRY E. WACHOWSKI
ofAmerica
TheCatholicUniversity
T I. INTRODUCTION
glandwasknown
HE thyroid
ber of earlyGreek and Roman writers amphibianmetamorphosis
active
taken.This studyhas becomeincreasingly
to a num- throughtheyears,and althoughthe phenomenaof
stilloccupythecenterof
who also recognizedgoiteras a patho- interest,
we nowhave availablea considerablebody
logical enlargement of the organ. The of informationon the thyroidgland and its func-
name "glandula thyreoidea"was first tionsin developmentalstages and in the adult in
used by Thomas Wharton,in 1656, in the first fishes,amphibians,and reptiles.
thoroughaccountof its anatomy.It was not until
II. GENERAL MORPHOLOGY
thelatterhalfof the nineteenth century,however,
thatthesignificance of the thyroidas an endocrine The thyroidin cold-bloodedvertebrates,as in
organregulating metabolicactivitywas recognized. higherforms,is a follicular,
highlyvascularorgan
Followingthisdiscoverymuchinterestwas aroused located in the cervical region.It is unpairedin
in studiesof thyroidmorphologyand physiology cyclostomes,fishes,and reptiles,but is usually
in the human being,and in mammalsin general, representedby at least two discrete bodies in
and these studies rapidly yielded resultswhich amphibians.Goldsmith(1949) has givenan excel-
provedofgreattherapeuticimportance.Investiga- lent reviewof the phylogenyof the thyroid,and
tionsdealingwiththeembryology and morphology one considerablymoreextensivethan the present
of the thyroidin lower vertebrateswere less nu- accountcan be. That theglandmaybe represented
merous,but the existenceof the gland in all ver- in protochordateswas firstsuggestedby MUller
tebrategroupsand possiblyeven in some proto- (1871), who regardedthe endostyleof Amphioxus
chordateswas soon demonstrated. Early attempts and the tunicatesas a possiblethyroidhomologue.
to elucidatethe functionof the thyroidby means This hypothesishas been much discussedbut re-
of thyroidectomy in lower vertebrates,such as mainscontroversial. A recentstudentofthesubject
salamandersand reptiles,only resulted in the (Leach, 1939) has stated that the evidence for
death of the operatedanimals,however,and led homologyof the thyroidwith the protochordate
to the erroneousconclusionthat the presenceof a endostyleis still inadequate. On the otherhand,
functionalthyroidis necessaryforlife.It was not he has supportedthe earlierfindingsof Marine
until Gudernatsch's(1912) discoveryof the role (1913) that the thyroidof the adult lampreyis
of the thyroidin controlof amphibianmetamor- formedby differentiation of certaincells derived
phosisthatextensiveexperimental studyofthyroid fromtheendostyleof theammocoeteslarva. In all
functionin cold-bloodedvertebrateswas under- adult cydostomesthethyroidconsistsofa number
123

124 T4E QUARTERLY REVIEW OF BIOLOGY
of diffuselyscatteredfollicleslying in the gill considerablefrequency. The thyroidgland ofNec-

regionbelowthepharynx(Leach, 1939). turus (Charipper,1929; Webster,1934) is com-
The thyroidof an elasmobranch,Squalus, was posed of threedistinctmasses,a mediananterior,
firstdescribedby Muller (1871), who reported a rightlateral,and a leftlaterallobe. The median
that this fishpossesses a persistentthyroglossal massfrequently showslinkageto thelateralmasses
duct. Goodey (1910) founda similarconditionin by chainsof follicles.
Chlamydoselachus, but Norris(1918) failedto con- The majorpoint of difference in the grossmor-
firmthata thyroglossal duct is presentin Squalus. phologyof the thyroidin amphibiansseemsto be
Hill (1935) has describedthe thyroidof the holo- in its blood supply. Maurer (1888) describedfor
stean, Amia, whichconsistsof groupsof follicles Tritona "rete mirabile"arisingfroma branching
scatteredabout the ventralaorta. of the large jugulartrunk.Baldwin (1918) found
The firstaccount of the teleost thyroidwas that in Ambystoma punctatum, althoughthe blood
given by Simon (1844), who, however,reported supply is variable, there is no evidencefor the
that the gland is absent in salmonoidfish.Other originof the "rete" fromthe jugular. He main-
importantearly contributionsto knowledgeof tained that the interfollicular networkis formed
thyroidmorphology in bony fishesweremade by fromsmall venous twigscomingfromvessels in
Maurer (1886), and Gudernatsch(1911). The the sternohyoid or geniohyoidmuscles,and never
latter,in a comparativestudyof thyroidtissuein fromthe main jugular trunk.A connectionwith
29 species of teleosts representing20 different the externalcarotidarterywas shownin a single
families,reportedextremesof arrangement of the case amonghis specimens.Charipper(1929) how-
tissuefromcompactlyunitedto diffusely scattered ever, demonstratedfor Necturusa blood supply
follicles,witha predominanttendencytowardthe that is primarilyarterial.He foundthe capillary
diffuse,scatteredcondition.This is supportedby networkof the thyroidto be in communication
the laterworkof Burne (1926) on the anglerfish, with the jugular sinus,but he could discoverno
Lophius, and of Hoar (1939) on the Atlantic largevein directlyconnectedwiththe gland.
salmon.Severalnotableexceptionsto thisprevail- The grossmorphologyof the thyroidgland in
ing patternof dispersionof thyroidfolliclesin the reptilesclosely approachesthat found in higher
teleostshave been reported,however.The sword- vertebrates.Baldwin (1918), in his reviewof the
fish,Xiphias gladiusL., has a thyroidthat forms thyroid,has referred to the reptilianorgansimply
a large, well-circumscribed mass situated at the as a single,lobulate, follicularstructure,which
cephalic end of the ventralaorta and composed containscolloid,and lies close to the trachea.In
offourwell-defined portions(Addisonand Richter, the turtle,Chrysemys, the thyroidhas been de-
1932). Matthews (1948), upon examiningthree scribed(Shaner,1921) as a flattenedmass ventral
genera of parrot fish (Pseudoscarus,Sparisoma, to the truncus arteriosusat the origin of the
and Scarus), foundthat in each case the thyroid greatvesselsleavingthe heart.It exhibitsa cord-
was a broad, elongate,compact mass separated like arrangement, with large luminafilledwith a
into anteriorand posteriorportionsby the first reddishsecretion.Adams (1939) found that the
afferentbranchialartery. thyroidof Lacerta derivesits blood supply from
Amongearly accountsof the thyroidgland in both the systemicand pulmonarycirculations.
amphibiansare thoseof Leydig (1853) on Triton,
Mtiller(1871) on Rana, Wiedersheim(1884) on a IM. EMBRYONIC ORIGIN
number of anurans and urodeles, and Maurer Descriptionsof the originof the thyroidgland
(1888) on urodeles. In these formsthe gland in cyclostomes and fishespresent,withone notable
typicallyconsistsof two lobes, each envelopedin exception,a fairlyconsistentpicture.The chief
a membranapropria. The latter surroundsnot differences found in different species are in the
onlythefolliclesand theintervening lymphspaces, natureof the thyroidanlage,whichmay be either
but also the inferiorjugularvein in the regionof hollowor solid,and in its mode of originfromthe
the gland. The lobes are coveredmediallyby the pharynx,a mode whichvariesfromthe formation
geniohyoidmuscle,laterallyby the internalhyoid of a long trough-like diverticulumto a localized
of the firstbranchialarch, and dorsallyby the outpushingof a sphericalmass of cells. Stockard
s.ternohyoid muscles.In additionto the mainpor- (1906) found that the thyroidof the lamprey,
tions of the gland, accessorythyroidsoccur with Bdellostoma, originatesas a groovein the pharyn-

THE THYROID IN COLD-BLOODED VERTEBRATES 125
geal floorand extendsthroughthe lengthof the primordiumappears beforethe union of the gill
wholegill area. He pointedout that no otherver- poucheswiththeectoderm.Shortlyafterhatching,
tebrateis knownto have a thyroidanlage of such theanlageseparatesfromthepharyngealfloorand
length,but he attributedthe conditionto the ex- becomesan ovoid mass of cells.This body of cells
tensivegill area of Bdellostomaand did not con- then splits lengthwiseinto two parts, with an
siderit evidenceof any close phyleticrelationto isthmusunitingthe two. Some days later the two
the endostyleof Amphioxusand the ascidians.As lobes become separatedby the sternohyoid mus-
has beennoted,however,laterstudiesoftheorigin cles,althougha fewelementsof the forming gland
ofthecyclostome thyroidhave shownquite clearly may remainin the medianline anteriorto the two
that its cells are derivedfromcertainelementsof halves. Accordingto Maurer, this representsthe
the endostylarregion of the ammocoeteslarva originalisthmus.The twolobesnow arrangethem-
(Leach, 1939). selves into solid cordsand thesedifferentiate into
Norris(1918) describedthe thyroidof Squalus folliclesholding the characteristiccolloid. The
as arisingin theformofa solidepithelialbud ven- principalpoint of disagreement in early accounts
tral and posteriorto the firsttwo gill pouches. of developmentof the gland concernsthe nature
Maurer (1886) foundthe anlage to be a hollow of the thyroidprimordiumitself.Maurer (1888)
evaginationof the pharyngealfloorin the trout, and Baldwin (1918) maintainthat in urodelesthe
and Gudernatsch(1911) regardedthisas applicable primordium is a solidmass ofcells;and muchmore
to teleostsgenerally.Hoar's (1939) study of the recentlyDent (1942) has describeda solidprimor-
salmon indicates,however,that in this formthe dium for the thyroidof the urodele Plethodon.
gland arisesfroma solid knob of cells at the level Platt (1896), however,found that in Necturus
of the hyomandibular pouch. thethyroidprimordium is vesicular.This viewwas
Recently,Thomopoulos(1948) in a preliminary supportedby Webster(1934), buthas beencontro-
paper has reportedforthe salmonfindingswhich vertedby Sanders (1935). Maurer (1888) stated
are quiteat variancewithall precedingdescriptions that in anuransthe primordium beginsas a ve-
of the originof the gland. He maintainsthat the sicular structurewhichlater becomes solid, but
salmon thyroidis mesodermalin origin,arises as Mtiller(1871) foundthat the thyroidrudimentis
an unpairedthickening in thepericardialwall,and solid fromthe beginningin Rana temporaria and
has no relationto thepharynx.Acceptanceof this R. platyrrhinus. It is interesting that similardis-
view must wait upon presentationof more com- agreementshave already been noted concerning
plete evidence. the thyroidprimordiumin fish.The point may
Surprisingly, the literatureon the originof the possiblyhave bearingon phyleticconsiderations
thyroidglandin amphibiansis nonetoo extensive. involvingthe two groups.
Most work has concernedthe later growthand Heidenhain(1921) describedformammalstwo
differentiation of the gland in relationto meta- types of follicularstructure;an associationtype,
morphosis.Webster(1934) has attributedthe first in which folliclesdevelopingfromprimarycell
accountof the developmentof the gland in Rana columns remain in epithelial continuity,and a
to MUller(1871). The generalpatternof develop- dissociationtype in which the folliclesbecome
mentof the thyroidin amphibianswas mostcom- separated. Uhlenhuthand Karns (1928) found
prehensivelyworkedout by Maurer (1888), who that follicularformationin Ambystoma opacumis
studiedthe originof the thyroidin a numberof of the associationtype, and resultsin a thyroid
anurans and urodeles,includingthe axolotl. Ac- composedof a coiled tube whichappears sac-like
cordingto his findings,the primordiumof the at intervals,whereasin A. maculatumthe gland
gland is an outpocketingthat extendsfromthe consistsof complexdiscretefollicles.
floorofthepharynxbetweenthesecondpharyngeal It has been previouslypointedout that a split-
pouchandthe pericardialchamber.It nowappears tingof the anlage of the gland resultsin its even-
that Maurerwas in errorconcerning the position tual paired condition in amphibians. James
occupiedby theprimordium, formorerecentwork- (1946) has demonstratedthat the thyroidanlage
ers agree that it arises fromthe pharyngealfloor will divide into two only when it can come in
betweenthe paired second visceralarches,or, in contact with a cartilaginoushyoid keel. If the
some forms,fromthe floorof the hyomandibular adjacent cartilagemass is rod-like,the gland does
pouch. Maurer found that, chronologically, this not divide but encirclesthe cartilage.

126 THE QUARTERLY REVIEW OF BIOLOGY
In earlystudiesof the originof pharyngealde- less amount of colloid in its lumen.The follicles
rivativesin reptilesspecificconsiderationof the are surroundedby a connectivetissueframework
thyroidwas notextensive.More completeaccounts whichis highlyvascular.Detailed descriptions of
were given by Maurer (1899) and more recently the histologyof the gland in amphibianscenter
by Shaner (1921), who studied the pharyngeal about five of its features:a) the epithelialcells
derivativesof the turtleChrysemys by wax-plate formingthe walls of the follicles,b) the stainable
reconstructionmethods. He has described the colloidwithinthe follicles,c) non-stainableintra-
thyroidrudimentas a mid-ventraloutgrowthof follicular"vacuoles," d) intracellularstructures
the pharynx,between the firstand second gill associatedwithsecretoryactivity,and e) possible
pouches.It remainsattachedto thepharynxfora structuresassociated with release of the thyroid
timeby a slendercordbut eventuallybreaksfree secretion.
and becomesthe singleunpairedbody character- Charipper(1929) describedtwo principalkinds
isticof the group.Shaner'sfindings forChrysemys of cells in the thyroidof Necturus.One type
are confirmedby Naccarati's (1922) study of a corresponds to theso-calledchiefcell and variesin
relatedgenus,Emys,and Hammar (1937) reported size and shapefromlow cuboidalto highcolumnar,
essentiallysimilarobservationsfor the originof witha nucleusthat is rounded.The cytoplasmis
the thyroidin the Crocodilia. clear, light-stainingwith eosin, and contains
numerousgranulesand vacuoles. A second cell
IV. HISTOLOGY AND CYTOLOGY
type,the colloid cell, firstdescribedby Langen-
Investigationsof the finer structureof the dorffin 1889, characteristically contains one or
thyroidare so much more extensiveforthe am- morelarge colloiddropletsin the cytoplasm,and
phibiansthanforothercold-bloodedformsthat it has a nucleusthat is basal in position,spherical,
seemsadvisableto considerthisgroupfirst.It must and granular.Both thesecell typescontainmito-
be notedat the outsetthat one of the outstanding chondria, granular or filamentous,distributed
featuresof the histologyof the thyroidin am- throughout the cytoplasm.Filamentousand gran-
phibiansis its great variabilityin different indi- ular mitochondriahave also been reportedfor
viduals,evenunderseemingly identicalconditions. R. esculentaby Hirschlerowa(1928) and forAmby-
This variabilityfar exceeds that foundin warm- stomaby Uhlenhuth(1928). The formerauthor
bloodedvertebrates and mustconstantlybe borne also pointedout that an increasein mitochondrial
in mind when changesin histologicalappearance size occursat metamorphosis. Charipperdescribed
are utilized as criteria of the effectiveness of the Golgiapparatusas a networksituatedon the
experimentaltreatments.Uhlenhuth,Schenthal, follicular side ofthenucleus,althoughtheamount,
Thompson,Mech, and Algire(1945) as a resultof extent,and positionof the networkis apparently
a criticalstatisticalstudy found,for example,a extremelyvariable. Typically it extends to the
variabilityof 21.0 per cent in colloidlevel in the follicularmarginof the cell, whereit ends in a
normal thyroidof Triturus,compared with a condensationoffinegranules.The Golgiapparatus
variabilityof 5.1 per cent forthe guineapig, and is not as extensivein the colloid cells as it is in
a variabilityof 18.0 per cent in cell heightin the the chief cells. D'Angelo and Charipper(1939)
salamandercomparedwith 1.8 per cent for the foundthat in the early stages of developmentin
guineapig. They pointedout that such differences R. pipiens the apparatus has a small, compact
do not seem explicableon the basis of the known configuration, changinglaterto a highlyelaborate
physiologicalrolesof the salamanderthyroidand networkthat may be eitherfilamentousor ring-
must be attributedto what might be called a like.
generalinstabilityof amphibianendocrines.De- Featurescharacteristicallypresentin thethyroid
spite this variabilityit is, of course,possible to gland are vacuoles, which may appear in the
presenta generalizedpictureof thyroidhistology peripheryof the follicularcolloidas well as in the
for a given species,and this has been done in a follicular cellsthemselvesin materialpreparedwith
numberof outstandingcontributions whichhave the usual fixativesand stains.These vacuoleswere
been fullyreviewedby Eggert(1938). firstdescribedby Anderson(1894). He pointed
As in vertebratesgenerally,the amphibianthy- out that the intracellularvacuoles under certain
roid consistsof follicleseach made up of a single conditionsseemedto communicatewithvacuoles
layerofepithelialcellsand containinga greateror in thefollicularcolloidand he therefore considered

THE THYROID IN COLD-BLOODEDVERTEBRATES 127
themas antecedentsof thevacuolesin the colloid. stainsbasophilically, theintracellularcolloiddrop-

Because theynormallyfailto stain,he calledthem lets take an acid stain. Basophilic intracellular
a "chromophobesecretion."Since then many in- vacuoles have been reported,however,by Grant
vestigatorshave studiedthesevacuoles and have (1930c) and Uhlenhuth(1927, 1937) as occurring
attemptedto ascertainwhatroletheymayplay in regularlyin bothactiveand inactiveglandsof the
the activityof the thyroid(see Ponse's review, Amphibia.D'Angelo (1941) foundin the thyroid
1938). Bensley (1916) and Uhlenhuth (1925b, ofRana at metamorphic climaxintracellulardrop-
1927, 1928) were able to stain the vacuoles and lets ofbothacidophilicand basophilictypes,while
agreedin part withAnderson'sobservations. Aron in early glands only acidophilic droplets were
(1930) and Severinghaus(1933) on the otherhand detectedwith any frequency.He suggestedthat
consideredthemresorption phenomena,and postu- the differential stainingof thesedropletsmay be a
lated that theirpresenceindicateda high rate of means of distinguishing"storing" colloid (aci-
absorptionof colloidfromthe follicle.Uhlenhuth dophilic)from"releasing"colloid (basophilic).It
(1925a) succeededin observingthese vacuoles in must be mentionedthat with the freezing-drying
livingthyroidtissue,and thus demonstrated that technique,as applied to the glandby De Robertis
theywerenotfixation phenomena,as someauthors (1949), all follicularcolloid stains blue, with no
had maintained,but wereintegralfunctionalfea- evidence of red or orange stainingsuch as is
tures of the gland. Williams (1937) observed obtained with the usual fixationand Mallory-
vacuoles in livingthyroidfolliclesin the rabbit, Azan stain.This seemsto indicatethatan artifact
but stated that they are unlike the vacuoles is responsiblefor the color differencesso far
normallyseen in fixedand stainedpreparations. reported.It shouldbe pointedout, however,that
Grant (1930c, 1931a), in a studyof the Necturus the diagnosticvalue of the colordifferences, even
thyroid,presenteda picturein substantialagree- if they are artifacts,does not seem to be over-
ment with that proposed by Aron (1930). She thrown.
found that in thyroidsstimulatedto secretion The problemof colloid release is an especially
thereis a liquefactionof the storedcolloid,witha difficult
one to resolveon thebasis oftheavailable
change in its stainingproperties,as a response evidence. Ulhlenhuth(1927) postulated the re-
possiblyto a digestiveactivityof the epithelial lease of colloidfromthefollicleby an intercellular
cells, and furtheran absorptionof this material route,and describedthepresenceofcolloiddroplets
in the formof dropletsor vacuoles in the cells. between cells. This view was supported by
Uhlenhuth(1937) came to essentiallythe same Hirschlerowa's(1928) reportof the existenceof
conclusionsand also postulatedthe presenceof a intercellularcanals betweenthe follicularlumen
proteolyticenzyme,thyreodase,excretedinto the and theperipheralblood supply.Brink(1939) also
lumen of the folliclesfor transformation of the claimedto have foundintercellular canals in the
colloidintoa substancecapable ofpassagethrough thyroidof the anuran Arthroleptella. Williamson
the apical membranesof the cells (Uhlenhuth, (1923) describedmicro-capillaries in the secreting
1939). De Robertis(1949) has shown that when epitheliumof the gland,but this reporthas been
the freezing-drying techniqueis used, no vacuoles seriouslyquestionedby Wilson (1929), who seems
whatsoeverappear in the colloid withinthe fol- to have establishedquite conclusivelythat the
licles,althoughcolloidalvacuolesand dropletsare so-calledcapillariesare in realityterminalbars.
presentwithinthe cells themselves.He therefore A verydifferent conceptof the mode of colloid
consideredthese marginalvacuoles as artifacts, release was presentedby Grant (1930c), whose
althoughagreeingin substancewiththe resorptive workon the activatedthyroidof Necturusled to
conceptin so far as the dropletsin the cells are the conclusionthat the colloidleaves thefollicular
concerned. lumen by passing throughthe cells themselves.
The stainingreactionexhibitedby the colloid Later studies of a similarnature on Ambystoma
storedin the luminaof the thyroidfolliclesvaries (Grant 1931a, b) gave furtherevidencefor this
fromacidophilicto basophilic.Hewer (1927) has hypothesis,for it was noted that there was a
stated that the colloid of inactive follicles is directratio betweenthe amount of intracellular
acidophilic, while that of active follicles is colloidand the extentof storedcolloidrelease,as
basophilic.Uhlenhuth(1939) foundthat,whilethe shownby the collapse of the follicles.This' ratio
follicularcolloid of the actively secretinggland seemedexplainableonly in termsof transcellular

transport.The same patternof follicularcollapse The histologyofthecyclostome thyroidhas been

was reportedforthe toad by Magdalena (1932) most fullydescribedby Leach (1939), who found
but Uhlenhuth, Schenthal, Thompson, and that afterdefinitefollicleshave been formedfrom
Zwilling(1945)pointedout thatthisis byno means certaincells of the larval endostyle,theyremain
a universalphenomenonaccompanyingthyroid in an inactiveconditionforsometimeand showno
activity. stainablecolloiduntilapproximately fourmonths
De Robertis (1949) stated that in the guinea after the onset of metamorphosis. In the adult
pig and rat aftertreatmentwith thyroidstimu- lamprey,however,the structureof the follicleis
latorsthereis an initialperiodof active secretion quite similarto that describedfor amphibians.
toward the lumen of the follicleand that this Study of the histologyof the fishthyroidreveals
periodis followedby secretiontowardthe base of thatheretoo,despitethe usuallydiffuse natureof
the cell, with simultaneousreabsorptionof the the gland, the fundamentalunits resemblethose
colloidstoredin the lumen.De Robertisand Del of highervertebrates,and changes in epithelial
Conte (1942), however,reportedthat the first heightand stainingreactionofthefollicularcolloid
phase was not observedin the amphibianthyroid. accompany alterationsin the rate of secretory
Uhlenhuth,Schenthal,Thompson, and Zwilling activity(Murr and Sklower,1928; Lieber, 1936;
(1945), followingexhaustiveexperimentson the von Hagen, 1936; Hoar, 1939; Buchmann,1940;
thyroidof Triturustorosusstimulatedwiththyro- Collamandand Fontaine,1942; Robertson,1948,
trophichormone,presentedwhat is possiblythe 1949). A moststrikingfeatureof the fishthyroid,
most convincingpicture of colloid storage and and one which has not been reportedfor other
release as it occurs in amphibians.Their experi- cold-bloodedforms,is the factthat it not uncom-
mentsshowthat thyroidactivityfollowing stimu- monlyexhibitsmarkedpathologicalenlargement,
lation is divisible into two stages. There is a whichhas been variouslydescribedas a goiterous
period of initial release,duringwhich all stored or tumerouscondition.Histologicallythese vary
colloidthatcan be releasedby thedoseofactivator fromsimplehyperplasticgrowthsto noduleslike
administeredand the individualspecimenis re- those seen in thyroidadenoma in the human.
leased.This is thenfollowedby a stageofmaximal However, in certain cases they present an ap-
activation,duringwhichnewlyelaboratedcolloid pearance characteristicof malignancyand may
is dischargedinto the lumen of the follicle.This extensivelyinvade surroundingtissues. Certain
workalso seemsto showthatthe thyroidfunction salmonoidfishseem to be mostsusceptibleto this
is cyclic,so thatemptying ofthefollicleis followed condition,but it has also been reportedin several
by secretionintothe follicle,no matterhow much otherteleosts.(See therecentreviewby Lucke and
the thyroidis stimulated.There is no evidenceof Schlumberger, 1949.)
secretiondirectlyfrom the basal pole of the Histological studies of the reptilian thyroid
epithelialcellintothebloodstream.Both secretion incidentalto various experimentalstudies reveal
and absorptionseem,therefore, to be functionsof nounusualfeatures(Eggert,1933,1936;Hellbaum,
the apical pole of thyroidcells. The apparent 1936; Ratzersdorfer,Gordon, and Charipper,
necessityof repassage of the colloid from the 1949). However, it may be noted that Mason
lumenthroughthecellssuggeststhatstoredcolloid (1938) has describedthe snake thyroidas ex-
is different fromthe colloidfinallyexcreted;that hibitinga remarkably constanthistological picture,
some necessaryfinal change occurs beforeit is showingeven less variabilitythan that of the
deliveredto the blood stream.The authorshave guineapig, and therefore suggestsits use as a test
also correlatedthepatternof secretionand release object forthe assay of thyrotrophic hormone.
with the cell heightof the follicularepithelium,
and have foundthat cell heightincreasesduring V. THE ROLE OF THE THYROID IN
initialrelease,and remainshigh duringmaximal AMPHIBIAN METAMORPHOSIS
activation. The role of the thyroidgland in amphibian

Much of the work on the histologyof the metamorphosis has beenmoreextensivelyinvesti-
amphibianthyroidhas been done in connection gatedthan has any otheraspectofthyroidfunction
withinvestigations oftherelationbetweenthyroid in cold-bloodedvertebrates.This matterhas also
activityand metamorphosis and studiesofseasonal been the subject of several importantreviews
variationsin metabolicactivity.These subjects which have covered the literatureup to about
willbe consideredin later sectionsof thispaper. 1938 (Fulton, 1921; Remy, 1923, 1924; Guder-

natsch,1929;Allen, 1929,1938; Bounhiol, 1942). own thyroid.Proof of this hypothesiswas soon

The presentaccount will therefore be largelyre- forthcoming.Allen (1916) and Hoskins and
strictedto studieswhichhave beenpublishedsince Hoskins (1917) independentlydevised methods
thattime.In orderproperlyto evaluate thesignifi- forsurgicalremovalof the anlage of the thyroid
canceofthesestudies,however,it willbe necessary, gland in early larval stages and showed that
in connectionwithseveralaspects of the subject, animalslackingthe thyroidfail to metamorphose
to give resumesof the main resultsof early in- althoughthey are able to grow normally.Such
vestigations.The transformation of the aquatic larvae, since they continue to grow long after
tadpole into the terrestrialfrog,a process that unoperatedcontrolshave transformed into adults,
involvesprofoundbodily changes,both morpho- may become quite giganticin size. Allen (1917a)
logicaland physiological,has interestednaturalists and Schulze (1922) furthershowed that these
fromveryearlytimes.By theend ofthenineteenth giant tadpoles may at any time be induced to
century much informationwas available con- metamorphose by feedingwiththyroidsubstance.
cerning the sequence in which the events of Meanwhilean independentline of investigation
metamorphosis take place in differentamphibians, was leading to an understanding of the chemical
the detailsof the changesoccurringin the various natureoftheactiveprincipleofthethyroid.It had
organ systems,and the histologicalalterations long been knownthroughthe workof Baumann,
exhibitedby certainof the tissues.There was at Oswald,and othersthat an importantconstituent
thattime,however,no clue as to theagencywhich of the gland is iodineand that thiselementexists
calls forththesechanges. in the follicularcolloidof the livingthyroidin the
formof a globulin,iodothyroglobulin. Two other
A. Inductionof metamorphosis by treatment with iodine-containing compounds,diiodotyrosine and
thyroid substance,iodine,or iodinecompounds thyroxin, werealso isolatedfromthyroidtissueby
The discoveryof the importanceof the thyroid appropriate extractionmethods. Thyroxin was
glandas a controlling factorin metamorphosis is to obtainedin crystallineformby Kendall in 1915,
be creditedto Gudernatsch(1912, 1914), who, in and its synthesiswas accomplishedby Harington
the courseof experiments dealingwiththe effects and Barger in 1927. Various other iodine com-
of feedingcertainspecificmammalianorgans to poundshavingsomewhatsimilarstructural formu-
amphibianlarvae,foundthat thoseanimalswhich las, as well as analogous compoundscontaining
werefedhorsethyroidgland,unlikethosefedwith otherhalogens,have been prepared,and many of
any othertissue,showeda suppressionof further them have been tested both for theireffectson
growthand underwentan extremelyprecocious the metabolismof mammalsand for theirmeta-
metamorphosis.This strikingresult of thyroid morphosis-inducingabilities. Morse (1914)
feedingwas obtainedboth with anuran tadpoles showedthat iodothyroglobulin is veryeffective in
(Rana temporaria, R. esculenta,Bufovulgaris)and the inductionof metamorphosisin the tadpole,
withurodelelarvae (Tritonalpestris).It was soon and Kendall (1919) demonstrated the stillgreater
shownthat the feedingof thyroidsubstancefrom potency of thyroxin.The latter substance has
othermammalsthan the horseis equally effective since been most extensivelyused in experiments
and indeedthatthemetamorphosis-inducing agent where accuratelycontrolleddosages of a strong
is also present in the thyroidglands of fishes, metamorphosis-inducing agentare desired.Various
amphibians,reptiles,and birds.The literatureon related compounds such as iodothyrinand di-
this subject has been reviewed by Uhlenhuth iodotyrosinewere also foundto cause precocious
(1921) and by Schneider(1939) and indicates metamorphosis ofamphibianlarvae,althoughthey
clearlythatthethyroids ofall vertebrates normally wereless effective thanthyroxin.
containa substancewhichcauses a hasteningof Since high iodine content is so peculiarlya
metamorphicprocesses when fed to amphibian characteristicof thyroidsubstance and of the
larvae. Administration of the thyroidsubstance active compoundsextractedfromit, the idea was
by grafting,implantationunder the skin, or in- advancedthatiodinecompoundsotherthan those
jectionof extractsalso provedeffective. occurringin the thyroidgland mightalso affect
This beingthecase it was naturalto supposethat metamorphosis to some degree.This provedto be
in the normaldevelopmentof the frogor newtthe the case, for it was shownthat various complex
transformation from larva to adult is brought iodine-containing substances,such as iodoserum-
about throughsecretoryactivityof the animal's albumin, iodoserumglobulin, and iodocasein are

able tq hasten metamorphosis althoughthe con- administration ofinorganiciodineor simpleiodine

centrationsrequired are much higherthan are compoundsthey do so because the iodine taken
needed in the case of thyroxinor of iodothyro- into the body is readily fixed by the tyrosine
globulin. available in the tissues,and active organiccom-
Romeis (1916), however,in testingvariousthy- pounds such as diiodotyrosine and thyroxinare
roidfractions,foundthateffects couldbe obtained formed.In untreatedthyroidectomized tadpoles
fromprotein-free extractsand thisled to successful the same reactiondoubtlessoccurswiththe small
experimentswith still simpleriodine compounds quantitiesof iodine whichare taken in with the
such as iodoform,potassiumiodide, and sodium foodand water,but theamountofthyroxin formed
iodide. In fact, elemental iodine itself proved in the tissuesin this case is insufficient
to induce
effectivein causing metamorphosis in thyroidec- metamorphicchanges.The workof Gudernatsch
tomizedanimalseitherwhenfed,implantedunder and Hoffmanalso tendstowardthisconclusion, for
the skin,injectedin solution,or simplydissolved they found that tadpoles given various amino
in the water in which the larvae are kept. On acids along with low concentrationsof iodine
the otherhand, experiments with otherhalogens showedincreasedrates of development,and that
such as bromine,and withorganiccompoundsof the degreeof effectiveness differed
dependingon
bromine,like dibromtyrosine, showed that these theaminoacid used,tyrosineand iodinebeingthe
substancesdo not affectmetamorphosis. (See the mosteffective combination(Hoffmanand Guder-
reviewof Allen 1929.) natsch,1933). We may concludethat in all likeli-
In view of thesefindings, Swingle(1918a) sug- hood the metamorphic changeswhichoccurin the
gestedthat iodineis reallythe active principleof larval tissuesalways take place undera stimulus
the thyroidgland and that the thyroid,rather froma complexthyroid-hormone, probablythy-
thanelaboratinga truehormone,chieflyfunctions roxin,even in animalswhichlack a thyroidgland
in extractingiodinefromthe blood and storingit, and regardlessof theformin whichiodineis made
this storediodine then being made available to available to the animal. The iodineis important
the organismwhen needed. Such an hypothesis of course,since it is an indispensableconstituent
seemedto be supportedby experiments in which of the thyroidhormone,and it has been shown
pathologicalthyroidtissue of various types was that even tadpoles with intact thyroidsare not
fed to amphibianlarvae (Graham, 1916; Abder- able to metamorphoseif they are raised in an
halden, 1919; Abelin, 1927; Welti and Roth, environment and fedon a diet whichfurnilshes an
1946), for the generalresult of such work indi- insufficientamountof iodine (Lynn and Brambel,
cated that while thereis no parallelismbetween 1935; Metcalfand Creaser,1937).
the amountof colloidpresentin a goiterousgland It shouldbe notedthatcertainiodinecompounds
and its effecton metamorphosis, thereis oftena have been found ineffective in the inductionof
good correlationbetweenthe iodine contentand metamorphosis. Thus Swingle(1919) obtainedno
the metamorphosis-inducing ability.A similarcor- effectswithpotassiumiodate, and Brandt (1937)
relationwas reportedfor certainovarial struma was unableto get any responsewitha commercial
containinglarge amountsof iodine (Plaut, 1931). proteinpreparationcontainingboth iodine and
Differencesin iodinecontentprobablyalso account bromine.Possiblyinthesecasesthechemicalstruc-
for the differentresultsobtainedby Dessy (1930) tureis suchthattheiodineis notreadilyliberated.
fromfeedingthyroidglandsof olderand younger
animals to tadpoles. It appears, however,in the B. Relation betweenthyroidactivity
lightof recentbiochemicalstudies,that the effec- and metamorphosis
tivenessofiodineand variousiodinecompoundsin With the discoverythat thyroidadministration
inducingmetamorphosis in thyroidectomized am- can cause precociousmetamorphosis a numberof
phibian larvae does not mean, as was earlier workersundertookdetailedstudiesofthestructure
believed,that the complexorganicmoleculethy- of the thyroidgland before,during,and after
roxinis not necessaryto bringabout the tissue metamorphosis in attemptsto correlatephases of
responses.It has now been demonstratedthat activity of the gland with the metamorphic
thyroxinis formedin vitro by the iodinationof changes. Allen (1919), making gross measure-
proteins(Reineke, 1949), and it seems clear that mentsof thyroidglands of toad larvae dissected
when thyroidectomized tadpoles respond to the out at various stages of development,reporteda

gradualincreasein size of the thyroidsduringthe telescopingof the larval stages whichis charac-
earlyphases of metamorphosis, but a cessationof teristic of the embryonicdevelopmentof this
growthand an actual diminutionin size of the animal (Lynn, 1942). A similarsituationobtains
glands when metamorphosis is most active. This in the thyroidof Arthroleptella, a South African
observationhe consideredas an indicationthat anuranwitha somewhatsimilarlifehistory(Brink,
the colloidstoredin theglandis dischargedat this 1936,1939).
time. Shortlyafter this, Mayerowna (1922) de- In thegymnophionan Ichthyophisglutinosus,the
scribedthe histologicalpicturepresentedby the larva goes throughtwo metamorphoses. The first
thyroidin tadpoles of Rana esculenta.In early occurs at the time of hatchingand involvesre-
stages the follicularepitheliumwas fiat and the sorptionof the gills,whereasthe secondis charac-
follicleswere filled with an acidophilic colloid; terizedby cornification of the skin,closureof the
with the onset of metamorphosis the epithelium gill slits,and loss of the dorsalcrest.Klumpp and
increasedin height,and the colloidbecame more Eggert(1934) have shownthat the thyroidshows
fluidand exhibitedchromophobedroplets.Later signsof increasedsecretoryactivityin connection
work by Sklower (1925), Hirschlerowa(1928), withthe secondmetamorphic processonly.
Etkin (1936a, b), Clements (1932), Aleschin In an effortto establisha quantitativebasis for
(1936), Gasche (1939), D'Angelo and Charipper judgingthe activityof the thyroid,Etkin (1930)
(1939), and D'Angelo (1941) has provideda quite studiedthe changesin cell numberand in colloid
completepicture of the changes in the thyroid volume in serially sectionedglands throughout
whichaccompanynormalmetamorphosis in ordi- metamorphosisin Rana pipiens. Both of these
nary anurans, such as Rana, Bufo, and Hyla. featureswere found to show marked increases,
Although the details differsomewhat in these particularlyduringthe periodwhenthe hindlegs
different forms,there is generalagreementthat are growingrapidly.Moreover,the ratio of cell
the gland shows increasedactivityeitherbefore number to colloid volume is greatly increased
the onset of metamorphosis or just as the first duringthis time,but remainsconstantafterthe
metamorphicchangesappear. As metamorphosis periodof tail resorption.In a later,moredetailed
proceeds,the thyroidactivity,as evidencedby study (Etkin, 1936a), the relativevolumesof the
increasedheightofthefollicularepitheliumand by epitheliumand colloidand the relationof theseto
the appearanceof intracellular and intrafollicular total body weight were investigatedin several
vacuoles,increasesgreatlyand reachesa maximum speciesofRana and in Pseudacristriseriata. It was
near the time when the tail is undergoingrapid shown that the thyroidfirstexhibitsincreased
resorption.Afterthis thereis a gradual decrease growthand activityat thebeginning ofrapidhind
in the heightof the epithelium,and intracellular limbgrowthand thatit reachesa peak of activity
vacuoles become scarce. Some workershave re- at thetimewhentheforelimbsemerge.Thereis no
ported that at the climax of metamorphosis the evidenceofa quick simultaneousreleaseof colloid
amountof colloidin thefolliclesdecreasesrapidly, from the follicles,but a gradual regressionin
so that the folliclesbecome collapsed (Sklower, thyroidactivity occurs late in metamorphosis.
1925; Hirschlerowa, 1928; Clements, 1932; Etkinconcludedthatthereis a risingconcentration
D'Angelo and Charipper,1939). Others,however, of thyroidhormonein the blood duringmeta-
have found no such distinctstage of follicular morphosisand that the patternof metamorphic
evacuation(Etkin, 1936a). eventsis determined by the patternof increasing
Certain atypical anurans which have no true thyroidactivity. Morita (1932) carried out a
metamorphosis eggsand similar study of thyroidsize and epithelium-
but insteadlay terrestrial
develop directlyinto small frogsare of special colloidratioat variousstagesin a Japanesespecies
interestin this connection.Study of the develop- of Bufo,and obtainedessentiallythe same results
ment of the thyroidin one such form,the West Woitkewitsch(1937a) has reporteda rise in epi-
Indian tree-toadEleutherodactylus (Lynn, 1936), thelium-colloidratio during metamorphosisin
revealsthattheglandshowsevidenceofprecocious Rana temporaria but he maintainedthat his data
activity but no marked stage of either colloid give evidenceof rapid colloid evacuationduring
storageor colloidrelease.Presumablythehormone theperiodof tail resorption.
secreted is released from the gland almost as The most detailed histologicalstudies of the
quicklyas it is formed,and plays a part in the normal urodele thyroidare those of Uhlenhuth

and his coworkers(Uhlenhuth,1925a, b, 1927, well-developed limbs,and withcarnivorous habits.

1928, 1929, 1934; Uhlenhuthand Karns, 1928; During the transformation fromone to the other,
Uhlenhuth,Schenthal et al, 1945; Algire and therefore, manylarvalorganssuchas gills,tail,and
Uhlenhuth,1944). These investigationsinclude hornyteethdisappear,whileadult structures such
histological,cytological,and biometricstudies of as limbs,lungs,and eyelidsrapidlydevelop.More-
the thyroidin Ambystoma and Triturusat various over,certainstructuresof the larva whichpersist
stages in the life history,and many of these intotheadultundergoratherextensivealterations.
detailshave been consideredin an earliersection The skin thickens,becomesmore glandular,and
of this paper. With respectto metamorphosis, it attains an outer cornifiedlayer, the intestine
was found that the thyroidactivity increases decreasesin length,thevisceralarchesare modified
during this time just as in the Anura, but it to formthe hyoid apparatus,and the brain be-
appears that a much more marked release of comesmorehighlydifferentiated. Detailed analy-
colloid from the thyroidfolliclesoccurs in the ses of many of these changes during normal
urodeles.The studiesof Hirsch (1928) on Triton metamorphosis and of the ways in whichtheyare
and of Grant (1931b) on Ambystoma also support influencedby throidectomy and by thyroidad-
thisconclusion. ministrationhave occupied the attentionof a
It is noteworthythat the thyroidglands of numberof investigators.
animalsundergoingthyroidtreatmentshow clear Growthof the hindlimbsin the Anura,sinceit
histologicalevidences of decreased activity. It is one of the most obvious early signs of meta-
appears that whenthe hormoneis suppliedto the morphosis,was noted as a criterionof thyroid
tissues fromexternalsources the animal's own activityin most of the earlyworkon the subject.
thyroidceases to function,probablybecause of a Allen (1925) studiedthe effectsof thyroidectomy
decreasedoutputofthyrotrophic hormonefromthe upon hind limb growthin Bufo and Rana and
pituitary(Mayerowna,1922; Etkin,1935a; Brink, called attentionto the importantfact that in
1936). different amphibiansthereare differences in the
The questionofwhenthethyroidfirstbeginsthe degreeto whichthelimbswillgrowin the absence
accumulationof iodinehas been attackedby ad- of thyroidstimulation.In Bufo the hind limbsof
ministration ofradioactiveiodineby Gorbmanand thyroidectomized larvae may reach a length of
Evans (1941). They have found that, in Hyla 8 mm., while in Rana they remainsmall buds.
regilla,storageof iodineoccursveryshortlyafter The growthin lengthof the hind limbs during
the folliclesare formed,while theircells are still normalmetamorphosis has been studiedin detail
laden with yolk. There is also evidencethat the by Etkin (1932) for several species of Rana and
storediodineis alreadyin organiclinkage,probably provesto fita sigmoidcurve,the periodof rapid
as thyroglobulin. growthoccurringduringthe earlystagesof meta-
morphosis,and a considerablyslowerrate being
C. Detailedanalysesof thyroidcontrolof characteristic of the laterphases when the tail is
metamorphicevents beingresorbed.Bower (1938) foundthe same type
It has been mentionedearlier that a rather of growthcurve for the limbs of Rana sylvatica
detailed knowledge of the morphologicaland duringboth normaland inducedmetamorphosis.
physiologicalchanges which occur at metamor- Irichimowitsch(1936) advanced the idea that
phosis was already available long before the these differences in "growthenergy"at different
discoveryof the role of the thyroidin inducing timesare relatedto differences in the processesof
thesechanges.The transformation is morestriking histogenesiswhichare occurringin the limb,the
in the Anura than it is in urodeles,but in both earlyperiodof rapidgrowthbeingassociatedwith
groupsmanyimportantalterationsoccurin nearly differentiationand chondrification ofskeletalparts
everyorgansystemof the body.The frogtadpole and the periodof decreasedgrowthbeingcharac-
beforethe onset of metamorphosis is an aquatic terizedby increasein muscletissue,beginningof
animal withwell-developedgills,a long flattened and differentiation
ossification, of skin structure.
tafl,lidlesseyesand,in adaptationto itsvegetarian He called attention,however,to the fact that in
habits, horny rasping teeth and a long coiled induced metamorphosisthe sequence of these
intestine.The adult frog,on the otherhand, is a changesis disarranged.
terrestriallung-breathinganimalwithno tail,with Tail resorption, anotherobviousexternalfeature

of anuran metamorphosis,has been very ex- tweenRana and the salamanderHynobius.At the
tensivelyinvestigated.Barfurth(1887) proposed time of metamorphosisthe anuran tails trans-
the hypothesisthat tail resorptionresultsfrom plantedtosalamandersunderwent resorption,
while
the fact that the rapid growthof the urostyle urodele tails transplantedto frogsexhibitedno
duringmetamorphosis causespressureon theblood atrophicchanges. Concerningthe nature of the
vessels at the base of the tail and gradually histolyticagents which induce tail resorption,
reducesthe vascularsupplyuntilatrophyoccurs. Helffsuggestedthat a generalloweringof the pH
This viewwas supportedby Bataillon (1891), who ofthebloodmaybe thechieffactorwhichactivates
suggestedthat the reduced blood supply would autolyticenzymesin the tail tissues,and he later
cause an accumulationofmetabolitesin thetissues demonstrated(Helff,1932) that such a drop in
and that autolysis would follow the resulting blood pH does occurduringmetamorphosis. Ales-
acidosis. That Barfurth'shypothesisis untenable chin (1935a, b), analyzingthe histologicalchanges
was shownby Helif (1926c, 1930), forligationof duringtail resorption in Rana, Bufo,and Pelobates,
the caudal arteryresultsin no accelerationof tail stated that the phenomenaobservedpresentthe
atrophy,and extirpationof the anlage of the characteristics of an inflammatory reaction,and
urostyledoes not preventtall resorption.It has maintainedthat local acidosis in the tail tissues
also been demonstrated that tails transplantedto causes dissolutionof the connectivetissuestroma
unusual positionswhere they are not in normal and thusplaysan important partin theinvolution.
relationswiththe urostylestilldegenerateconcur- Beginningwiththe workof Ratner(1891), con-
rentlywith the host's tail (Fukai, 1934). More- siderableattentionhas beengivento thegrossand
over,Reis (1930) foundthat tail skintransplanted histologicalchangeswhichoccur in the digestive
to the back undergoeshistolysisduringmetamor- tractduringmetamorphosis. These includeshort-
phosis,whileskinof the back transplantedto the eningofthe tractas a whole,histolysisand subse-
tail does not. Helffand Clausen (1929) carried quent regenerationof much of the intestinal
out reciprocaltransplantsoftail and back muscle mucosa, and great increase in thicknessof the
withsimilarresults.Schwind(1933) transplanted muscularlayerofthestomach.The earlierworkers
optic vesiclesto the tail at the tail-budstage and consideredthe typeof foodeaten as the causative
foundthat thesegraftedeyeswerenot resorbedat factorin intestinalatrophy,but Swingle(1918a)
the time of metamorphosis but slowlymoved in showed that precocious intestinalinvolutionis
and came to lie in the sacral region.It is thusap- one ofthefeaturesproducedby thyroidtreatment,
parentthattheatrophyoftail tissuesis notdue to and Sembrat(1924) demonstrated thattransplants
histolyticinfluencespeculiar to the tail but to of intestinaltissueundergometamorphic changes
more generalizedfactors,and that the tissuesof concurrently with the host intestineregardlessof
the tail have a differential susceptibilityto these the age ofthe transplant.Detailed accountsofthe
influences.In fact, Clausen (1930) has adduced histologicalchangesin the intestineduringnormal
some evidence which indicates that there is a metamorphosis have been givenby Kuntz (1924),
gradientof susceptibility withinthe tail itself;for Liu and Li (1930), Janes (1935), and Iwane
skinand musclegraftstakenfromanteriorregions (1935); and Lim (1920) and Kaywin (1936) have
of the tail and transplantedto the back undergo describedthe histologyand cytologyof the diges-
more rapid histolysisat metamorphosis than do tivetractin tadpolesundergoing acceleratedmeta-
thosetakenfrommoreposteriorlevels.The differ- morphosis.The latter author found clear-cut
ence in behavior of trunk and tail muscle at changesin the Golgi apparatus in the epithelial
metamorphosisis determinedat a quite early cells and proposedthe use of the Golgi as a crite-
stage,inasmuchas Geigy (1937, 1941) has shown rion for followingmicroscopicallythe course of
that myotomesof the tail transplantedto the metamorphosis in thyroidtreatedlarvae. Changes
trunkat the neurulastage are resorbedat meta- in theliverand gall-bladderresulting fromthyroid
morphosissimultaneously withthehost'stail while administrationhave recentlybeen studied by
trunkmyotomestransplantedto the tail region Doetsch (1943), while Janes (1937) has investi-
are not resorbed.That there is a fundamental gated the effectsof thyroidtreatmentupon the
differencebetween the response of anuran and pancreas.
urodeletissueswas shown by Nakamura (1937), Another metamorphicfeature which has at-
who made reciprocaltransplantsof tail-budsbe- tractedspecial interestis the perforationwhich

appears in the operculumto permitemergenceof tookan extensiveseriesof experiments withRana

thefore-limb. Sincethe fore-limbs originateinside temporariaand Bufo bufo.His resultsindicated
the opercularcavityas smallbuds and latergrow thatdifferent speciesofanuransdiffer considerably
rapidly,it was suggestedthatpressureofthegrow- in the mechanismby whichopercularperforation
ing limb upon the overlyingoperculumacts as a occurs,and that no one explanationcan be given
"formativestimulus" which induces perforation whichwillapplyto all. In somespeciesa particular
at the point of contact.However,Braus (1906) area of the operculumdoes seem to possess self-
showedthat whenthe forelimbanlage is removed degenerativepotentialities.Histolytic influences
so that a limbneverforms,a perforation stillap- emanatingfromthe degenerating gillsalso play a
pears at the usual stage in metamorphosis. He part, and the cutaneousglands of the fore-limb
therefore concludedthat the openingof the oper- may be an additionalinfluence.Pressureexerted
cular skin occursas a self-differentiating process, by the growingfore-limb constitutesstilla fourth
and the appearance of the openingat just the stimulusto perforation. In different anuransone
propertimeand place to permitthepassage ofthe or anotherof thesemay be the chieffactor,but
fore-limb was widelycitedas a particularly striking Helffconcludedthat in some speciestwo or three^
exampleof "harmonyof independentprocesses." different influences are effective,
so thattheopercu-
By means of transplantation and extirpationop- lar perforation is doublyor triply"assured." The
erations on several Americanspecies of Rana, recentworkofHama (1942) on theJapanesetoad
Helff (1926a) was able to elucidate the matter Bufovulgarisgivesevidenceof"doubleassurance"
much morecompletely.He foundthat the direct foropercularperforation in thisspecies.
stimuluswhichbringsabout opercularperforation The developmentof the tympanicmembrane
in these frogsis the presenceof atrophyinggill at the time of metamorphosis is anotherfeature
tissuewithintheopercularchamber.Sinceatrophy whichhas been subjectedto detailedanalysisby
of the gillsand growthof the fore-limbs are both Helff(1928, 1937, 1940). The transformation of
processeswhichare dependentupon thyroidfunc- the integumentcoveringthe presumptiveear re-
tion, the opercularperforation does occur at the gion into the characteristic structureof the tym-
time of fore-limb growth.Accordingto this con- panic membranewas foundto be dependentupon
cept,however,theperforation itselfis not directly inductiveinfluencesfromthe underlyingannular
causedby thyroidhormonebut is simplyone reac- tympaniccartilage.Early extirpationof this car-
tionin a chainwhichis set in motionby the thy- tilage preventsmembraneformation,and trans-
roid.This relationship was confirmed by the work plantationof the developingcartilagebeneaththe
of Van der Jagt (1929) and Fukai (1935). Weber skinof theside or back resultsin the development
(1931), however,carriedout experimentson re- of a typicaltympanicmembranein theseregions.
moval of fore-limbanlagen by electrocautery in That this inductive capacity is a remarkably
Bombinatorand in Rana temporariaand found strongone is evidencedby the factthat fullydif-
thatin somecases no perforation oftheoperculum ferentiated integumentary structures(dermalpli-
occurred.He has maintainedthat whetheror not cae) willtransform intotympanicmembranewhen
the perforationappears depends upon whether transplanted above the annularcartilage.Hyaline
cutaneousglandsof the skinof the limbare com- cartilagesother than the annular cartilagehave
pletely eliminated.If any cutaneous glands are the abilityto inducemembraneformation to some
presentin the opercularcavitythena perforation degree,and dead annularcartilagealso has a cer-
is formed. Blacher, Liosner, and Woronzowa tain degreeof effectiveness. Since it is necessary
(1934), workingwith reciprocalskin transplants that the cartilagebe in actual contactwith the
betweentheopercularregionand thebodyin Ranw skinin orderthattheinductiveeffect be evidenced,
temporariaand R. ridibunda,interpretedtheir Helff concluded that the influenceis probably
findingsas demonstrating a self-degenerative po- chemicalin nature.
tentialityspecificin the skin of the opercularre- Characteristic pigmentary changesoccurin the
gion. Alphonseand Baumann (1935a) maintained skinofbothanuransand urodelesat metamorpho-
that the necrosisof operculartissue is initiated sis. Weigl (1913) and Uhlenhuth(1917) early
because the blood vesselswhichsupplythisregion showed that these changes are dependentupon
degenerateat the timeof metamorphosis. In view thyroidfunction,since skin graftsalways show
oftheseconflicting conclusions,Helff(1939) under- the transformation at the time when the host

undergoesmetamorphosis, regardlessof the age poles fail to attain the characteristic differentia-
of the graft.In this way, in some of Uhlenhuth's tions seen in metamorphosedspecimens,and
experiments, differentpiecesofskinfromthesame Cooksey(1922) foundthat thyroid-fed larvae ex-
animalweremade to metamorphose at verydiffer- hibitprecociousdifferentiation of the brain.Koll-
enttimes,rangingfromsevendays to fivemonths. ros (1942, 1943a, b), in a seriesof studieson the
Changesin the pigmentpatternin the irisof the cornealreflexin Rana, has shownthat this reflex
eye werealso shownto occurin relationto meta- is controlledby a centerin the brainwhichis self-
morphosisin the same way. The histological differentiating but whichrequiresthe supplemen-
changes which occur in the epidermalcells at taryaction of thyroidhormonebeforeit becomes
metamorphosiswere investigated by Speidel fullyfunctional. In urodeles,moltingis a metamor-
(1926) and Woronzowaand Liosner (1936) and phic featurefor which thyroidcontrolhas been
were shownto occur followingadministration of clearlydemonstrated(Adams, Kuder and Rich-
thyroidextract.These metamorphicchanges in ards, 1932). It is of special interestthat the
the skin have been inducedin small localizedre- differentiation of the gonads does not seem to be
gions in salamanderlarvae by subcutaneousim- underthyroidcontrol.The testesand ovaries of
plantation of pieces of agar impregnatedwith thyroidectomized tadpoles formmature gametes
thyroxin (Hartwig,1940) and in Rana by implants despitethefactthat the animalas a wholeretains
of thyroidglands containingradioactiveiodine the immaturebodyform(Allen, 1917b; Hoskins
(Kaltenbach, 1950). Alphonse and Baumann and Hoskins,1919; Krichel,1931); and conversely
(1934) have maintained,however,that the skin thegonadsofanimalsprecociously metamorphosed
of Bufolarvae does not respondif the concentra- by thyroidtreatmentshow no accelerationof de-
tion of thyroxinis beyond a certainoptimum. velopment(Swingle,1918b). This is significant in
Observationson metamorphicchanges in skin relation to the occurrenceof sexually mature
transplants wereused by Reis as a meansofeluci- "larvae" (neoteny)in nature.
dating some problemsrelatingto neotenywhich
will be discussedlater.Barden (1943) has studied D. The sequenceand spacingofmetamorphic events
the changes in the pigmentationof the iris at Althoughall the processesdiscussedabove are
metamorphosisby heteroplastictransplantation characteristic featuresof metamorphosis and have
of optic vesiclesin severalspecies of Ambystoma been shownto be eitherdirectlyor indirectly in-
and Triturus. duced by thyroidactivity,it is clearthat theydo
Various other metamorphicfeaturesto which not all go on simultaneously; some metamorphic
special attentionhas been directedcan be men- changesoccurearlywhileothersappearonlymuch
tionedonlybriefly. The differentiation of the anu- later. Thus the events of metamorphosistake
ran tongueduringmetamorphosis has been fully place in a definitechronologicalorder,and it is
describedby Helffand Mellicker(1941), and the possibleto dividetheprocessintovariousstepsor
transplantation experiments of Helff(1929) indi- stagesand to designatecriteriaby whichone can
cate that the changesin the tongueare directly judge how far metamorphosis has proceededin
dependentupon thyroidstimulus.A similarcon- any given specimen.Surprisingly, a really thor-
clusionwas reachedin workon the differentiationough analysis of the metamorphicprocess from
ofthedermalplicae (Helffand Stark,1941).Terry thispointofviewwas notmadeuntilEtkin's(1932,
(1918) showed that ossificationof the vertebrae 1935a) carefulstudiesofthenormal"metamorphic
does not occurin thyroidectomized tadpoles,and pattern"in Rana palustris,R. clanitans,and R.
Schreiber(1932) has presentedevidencethat the catesbiana.Usingfeatureswhichare easilyobserv-
thyroidhormonecontrolsthe courseof endochon- able externally,Etkin described the events of
dralossificationbut doesnotinfluence perichondral normalmetamorphosis as occurringin the follow-
bone formation. The courseof ossification in neot- ing order: 1) beginningof reductionof the anal
enous and metamorphosed axolotlshas been very canal piece; 2) completionof resorptionof the
fullyworked out by Keller (1946). Histological anal canal piece; 3) appearanceof the opercular
changesin muscletissue,skin,connectivetissues, perforation foremergenceof the forelimb;4) fore-
and nervoussystemafterthyroxin administration limbemergence;5) reductionin size ofthetadpole
have been describedby Bredt (1933). Allen(1924) lips and loss ofhornyteeth;6) loss ofhornybeaks;
showed that the brains of thyroidectomized tad- 7) beginningofrapidresorption oftail fin;8) com-

pletionof tail finresorption;9) reductionof tail out of early experimentsupon the effectsof
to a knob; 10) completionof wideningof the different concentrations of metamorphosis-induc-
mouth.The periodof resorption of the anal canal ing agents. At firstthe interestin such studies
piece was designatedthe "prometamorphic" pe- centeredin attemptsto ascertainthe minimum
riod,whilethesucceedingeventswerespokenofas dose of thyroxin,iodine, or other agent which
constitutingthe "metamorphicclimax." Etkin would elicita response.Later, however,attention
demonstrated clearlythatin normalmetamorpho- was given to the comparativeeffectsof different
sis the changes"not onlyfollowin a set order,but doses administeredat varioustimesduringlarval
. . . are so spaced as to allowadequate timeforthe development.Romeis (1923), workingwith tad-
expressionofeach." The sequenceand the spacing poles raised in graded thyroxinconcentrations,
thusmakeup a normal"pattern"ofmetamorpho- was apparentlythefirstto stateclearlythatdiffer-
sis, a patternwhichis a constantfeatureof the ent organs may behave differently toward the
transformation of all the membersof any given same dose of the metamorphosing agent, for he
species. Schreiber(1937) has definedthe meta- noted that with very low concentrationssome
morphicpatternforBufo;and in urodelesa similar metamorphic changesoccurredwhileothersfailed
chronology has been workedout forEurycea,Tri- to make an appearance,a fact which was con-
turus,and Ambystoma by Wilder (1925) and by firmedby Alphonseand Baumann (1935b). Bla-
Grant(1930a, b). cher(1928) extendedthisby thefinding that after
It is necessaryto note,however,thatthisnormal a briefexposureofRana tadpolesto thyroidtreat-
metamorphic patternis not producedwhenlarvae mentcertainstructures are moredefinitely
affected
are inducedto metamorphose Indeed, thanothers.He therefore
precociously. proposedthe hypothesis
in some of the earlieststudies of experimentally that different parts have differentthresholdsof
induced metamorphosisattentionwas called to sensitivity,those having the lowest thresholds
the factthat the transformation whichis brought beingthe oneswhichappear earlyin normalmeta-
about by administration of thyroidsubstanceor morphosis,and those with higherthresholdsap-
iodinecompoundsoftendiffers markedlyfromthe pearing later. Allen (1932) also reporteddiffer-
normalprocess.This is particularlystrikingwhen encesin responseofdifferent tissueswhentadpoles
relativelylargedosesofthemetamorphosing agent of Bufo halophiluswere immersedin variousthy-
are used,forundersuchcircumstances thechanges roxineconcentrations and furtherpointedout that
whichshouldcomelate in metamorphosis occurso the responsevaries in relationto the durationof
precociouslythat they may be completedbefore treatment.
some of the firststages are well begun.Thus the As has been noted,Etkin's (1930, 1932) studies
tail may be completelyresorbedwhen the hind of the growthof the thyroidgland and the corre-
limbs are still small buds. Such disharmonious lated body changesduringnormalmetamorphosis
metamorphicchangesresult in the formationof had indicatedthat the glandbecomesincreasingly
very abnormalanimalswhichare unable to sur- active duringearlymetamorphosis, and had sug-
vive. With extremelylow concentrations of the gested that the normalspacing of metamorphic
metamorphosing agent,on the otherhand, some events could be related to a gradual increasein
changesmay be accelerated,but laterfeaturesare concentrationof thyroidhormonein the blood.
so littleaffectedthat the usual timerelationsbe- Experimentsundertakento test this idea (Etkin,
tween successive events are greatly distorted. 1935a) by analyzingin detail the metamorphosis
Even if one confinesattentionto a singleorgan, of tadpoles raised in various concentrationsof
disharmoniesresultingfrom induced metamor- thyroxinservedto confirmthe hypothesis.For it
phosismaybe found.For example,Romano (1936) was shownthat, whileno singleconcentration is
reportedthat in thyroxin-treated tadpoles the capable of inducinga normalmetamorphic pat-
cornea undergoesmetamorphosis so rapidlythat tern,such a patterncan be obtainedif one begins
it attainsthe adult conditionat a timewhenthe by treatingyoung tadpoles with low concentra-
lens is still larval, an inversionof the normal tions of thyroxinand later changesgraduallyto
chronology, whileSchreiber(1934b),and Schreiber higherdosage levels. The exact concentrations to
and Koch (1941) founddisharmoniesamong the be used and the timeswhenincreasesin level are
parts of the retinain thyroid-accelerated animals. to be made must be determinedempirically, but
Hypotheses to explain this disharmonygrew careful observationof the individual specimen

and propermanipulationof the treatmentcan re- Schreiber'sinterpretation, all eventsare initiated

sultin a normalmetamorphic patternin a thyroid- simultaneouslyand strikingdisharmoniesnatu-
ectomizedanimal. On the basis of his experi- rallyresult.Thus in normalmetamorphosis certain
mentsEtkinconcludedthatthesequenceofevents changes, e.g., rapid hind limb growth,should
is not controlledby the metamorphosis-inducing begin early under the influenceof low thyroid
agent but is inherentin the tissues. The time concentrations and shouldthenproceedforsome
intervalsbetweenevents,on the otherhand, are timebeforethe thyroidactivitybuildsup to such
dependentupon the activatingsubstance,normal a level as to inauguratelaterchanges,such as tail
spacing dependingupon a gradually increasing resorption.In inducedmetamorphosis, since both
concentration of this substance.The evidencein- beginat the same time,it is theeventswhichhave
dicatesthatbeforemetamorphosis a verylow level lowthresholds thatseemretarded,fromnothaving
of thyroidhormoneis probablynecessaryto pre- sufficient time to attain completionbeforethe
parethehindlimbsfortheirperiodofrapidgrowth. otherchangeshave occurred.Schreiberfelt that
This growthis theninitiatedin responseto a rise all of the reportedcases of disharmonies produced
in thyroidactivity,a rise which,however,must by thyroidadministration are explainableon this
extendonlyso far as to allow a maximalrate of basis. A similarconcepthas been advanced more
hindlimbgrowthwithoutprecipitating thechanges recentlyby Gasche (1940).
ofmetamorphic climax.Later,afterthehindlimbs It mustbe pointedout that Etkin's interpreta-
have attained some degree of development,the tion,while it is somewhatsimilarto Schreiber's,
climax phenomena appear and proceed rapidly differs in theimportantrespectthatit is not based
because of a stillgreaterincreasein thyroidactiv- upon an idea of differing thresholdsof response.
ity and a resultingrelativelyhigh concentration Indeed,Etkin's experiments withvariousthyroxin
of thyroidhormonein the tissues.As Etkin has concentrations indicatedthat all of the events of
pointedout, "the significant featureof the inter- metamorphosis do respondeven to extremely low
pretation offeredis that it explains a specific concentrations.Moreover,with high concentra-
developmentaltime patternby a purely quanti- tions, althoughall of the events occur rapidly,
tative mechanism,a variationin hormonecon- theyare still initiatedin the normalsequence.A
centration." point whichis of fundamentalsignificance, how-
A somewhatsimilarexplanationof the chronol- ever,is that the rate of responseis a functionof
ogy of metamorphicevents was proposed by the concentration of the metamorphosing agentso
Schreiber(1934a) in a theoreticalpaper whichis thatin low concentrations all changesoccurslowly
largelyconcernedwithexplainingthe disharmon- whilein high concentrations all occur rapidly.In
ies that are observedin inducedmetamorphosis. the normaltadpole duringprometamorphosis the
Schreiber'stheory is based upon the concept thyroidconcentration is low and althoughall the
earlierproposedby Blacherand othersthatdiffer- tissuesare activated,onlythosewhichrespondby
ent features of metamorphosishave different fairlyrapidratesofgrowthshowreadilydetectable
thresholdsof responseto the thyroidhormone. changes.Since the increasein thyroidconcentra-
SchreibercitedEtkin's (1930) studyofthegrowth tionis gradual,theseearlychangesgo on forsome
of the thyroidgland as indicatingthat a gradual timebeforetheresponsesin othertissuesare rapid
increasein thyroidactivityoccurs duringmeta- enough to attract notice. When, however,the
morphosis,and he concluded that the normal thyroidconcentration has becomehighenoughto
sequenceofeventsis determined by the fact that raise the metamorphic rate sufficiently,theselater
the changeswhichhave low thresholds ofresponse changes become very striking,since they now
occur firstand are followedsuccessivelyby the occur with great rapidity.It is of interestthat
changeswith higherthresholds,as the hormone Etkin also foundevidenceof a rathersuddendrop
concentrationreaches higher levels. Schreiber's in the activityof the thyroidat the end of meta-
theorythusaccountsforboththenormalsequence morphosis,and he suggestedthat the cessation
and the normalspacingof eventson the basis of of metamorphic changein the tissueswhentrans-
differingthresholdand a gradual increase in formationhas been completedmay be relatedto
thyroidactivity.Whenprecociousmetamorphosis the suddenloweringof the hormoneconcentration
is inducedby administration of a moderatelyhigh at thistime.
dosage of thyroidmaterial, then, accordingto It is clearthatEtkin'shypothesisoffers a logical

explanationbothforthenormalmetamorphic pat- to live at a low rate of metabolism,while adult

tern and for the disharmoniesobserved in the tissues are adapted to a higherrate. When the
pattern of precociouslyinduced metamorphosis. metaboliclevelis raisedbeyonda certainthreshold,
Since the theoryis also supportedby a consider- the larval tissues can no longermaintainthem-
able body of experimentalevidence,it has now selves in a functionalstate and they begin to
gainedgeneralacceptence(Allen,1938; Bounhiol, breakdown.On the otherhand the tissuescharac-
1942). teristicof the adult, findingthe new conditions
Thyroxinadministration to very young larvae more favorableto theirfunctionshow an accele-
with externalgills does not affectthe timeofap- ratedgrowthrate.Differences in the metamorphic
pearanceor rate of growthof the hindlimbs(Al- responsesof different tissueswithinthe organism,
phonse and Baumann, 1933). It now appears as well as differences in responsesof the same
that tadpole tissuesfirstacquire their sensitiv- tissue in different species, are explainedon the
ity to thyroxinat the time when the opercular basis ofinherentdifferences in the exactmetabolic
membranebeginsto form(Etkin, 1950). Animals levelto whichthe tissuesare adapted. Some doubt
exposedtotreatment beforethistimeshowno meta- was cast upon the idea of metaboliceffectsas an
morphicchangesuntil they reach the stage of explanationfor metamorphosis,however,when
opercularformation. This is, of course,not to say Kendall (1919) reportedexperiments withan acetyl
that thyroxin administration at very early stages derivativeof thyroxinwhichhad no effectupon
may not produce effectsupon featureswhichare basal metabolismin mammalsand yet induced
notofa metamorphic nature.Forexample,Baumann rapid metamorphosis of tadpoles,a resultwhich
(1936) reportedthat cleavage rate is increasedin was laterconfirmed by Swingle,Helff,and Zwemer
amphibianeggs exposedto thyroxinimmediately (1924). Moreover, Cutting and Tainter (1933)
afterfertilization,and such eggsoftengive riseto foundthatadministration ofdinitrophenol to toad
exogastrulaeor larvae showingspina bifida. larvae does not bring about any accelerationof
metamorphosis, althoughit does cause a definite
E. Theoriesofthemodeofactionofthethyroid increasein the metabolicrate. In this connection
secretionin metamorphosis it shouldbe notedthat a numberof authorshave
With the firstrecognition of the importanceof reportedthat thereis an increasedmetabolicrate,
the thyroidin metamorphosis, it was natural to as measuredby oxygenintake or carbon dioxide
attemptto relate this effectto the alreadywell- output,in amphibianlarvae duringnormalmeta-
recognizedrole of the thyroidin the controlof morphosisor in larvae treatedwith thyroidsub-
metabolism.It was pointedout that manyof the stance (Gayda, 1921a, b; Groebbels,1922; Helff,
featuresof metamorphosis involvea rapid loss of 1926b; Belehradekand Huxley, 1927). Most of
tissue,and that this is also characteristic of the theseworkers,however,have expressedthe belief
clinicalpicturepresentedby hyperthyroid cases. thatsucha risein metabolismis an accompaniment
Some workerswentso faras to suppose that the ratherthan a cause of metamorphosis. Moreover,
thyroidcontrolof metamorphosis is exertedsolely some investigators have failedto findany indica-
throughits influenceon metabolismand that tion of an increase in total metabolismduring
there is no necessityfor postulatingany direct metamorphosis(Abelin and Scheinfinckel, 1923;
effectupon development. Etkin, 1934); and thereis reason to doubt that
Huxley (1922) presenteda ratherdetailedthe- thyroid administrationcauses any increase in
orybased on thisidea. His hypothesisrestsupon metabolicrate in adult amphibians(Drexlerand
the view that the typicalamphibianlife history von Issekutz, 1935). As a matter of fact, with
may be regardedas a consecutivedimorphism increasedknowledgeofthevarietyand complexity
somewhat comparable to the consecutive sex- of the changeswhichoccur at metamorphosis an
dimorphismseen in protandricand protogynous explanationof the phenomenonas a consequence
hermaphrodites and that metamorphosis, like sex- of a generalincreasein metabolicactivityseems
reversal,is associatedwithchangesin the balance hardlypossible.
betweencertaininternalfactors.The mostimpor- Anotherearlygeneralexplanationforthe meta-
tant of thesefactorsis the level of metabolicac- morphiceffectsof thyroidhormonewas based
tivity,whichis underdirectcontrolby thethyroid. upon the hypothesisthat the secretioncauses an
Huxley proposedthat larval tissuesare adapted increasedrate of cell divisionin certainorgans,

while causingretrogressive changesin others.It the originalactivityof the thyroidgland. Ales-

is true that several studies have indicatedthat chin's bases forthis hypothesisrest mainlyupon
thyroidadministration affectsthe mitoticrate in his own observationson the histologyand tissue
various tissues.Lim (1920) observedlarge num- acidity of the tail duringinvolution(Aleschin,
bers of mitoticfiguresin all of the layersof the 1935a) and upon Helff's(1932) findings thatblood
digestivetractin thyroid-treated larvae,and Spei- acidityincreasesin metamorphosing tadpoles.He
del (1929) foundthat the rate of cell divisionin also recalledthat Hoskins (1922) foundevidence
the regenerating tail of the tadpoleis increasedby that metamorphosis, once begun, can be carried
thyroid administrationduring the proliferative throughin the absence of thyroidstimulus.Hos-
phase of regeneration. Champy(1922) maintained kins' experimentsconsistedin transplantingthe
thatthe thyroidhormonecauses a generalincrease thyroidanlage to the tail, allowingthe animal to
in mitoticratein thoseorganswhichare character- developand go part way throughmetamorphosis,
isticof terrestrial life,i.e., lungs,limbs,and intes- and then removingthe tail with the contained
tine,but that it bringsabout regressiveeffectsin graft.He reportedthat when this was done in
parts characteristicof aquatic existence(horny animalswhichhad well-developed hind-legs,most
beaks,tail,gills).He believedthatwhenhighdoses of them continued throughmetamorphosisal-
of thyroidsubstanceare given, the degenerative thoughthey now lacked a thyroid.However,in
effectsare strongerthan thoseinvolvingcell mul- view of Etkin's (1935a) findings that thyroidecto-
tiplication;while with low doses the reverseob- mized tadpoles raised in thyroxinsolutionsvery
tains. promptlycease to show metamorphicchanges
A morerecentattemptat a generalexplanation when removedfromthe solutions,some further
of the thyroidaction in metamorphosis is that of studyofthismatteris desirable.The idea thatthe
Aleschin(1935b), who has maintainedthatduring autolysis of the tail provides the materialsfor
the development of the tadpolethe thyroidgradu- growthof the limbs,a notionwhichis impliedin
ally enlargesand attains a maximumsecretory Aleschin'stheory,has been controverted by Iri-
activityin earlymetamorphosis, but thatit ceases chimowitsch(1936), and Woitkewitsch(1937a),
its activityand goes intoa restingphase beforethe who have pointedout that,since the mostactive
beginningof tail resorption. During the secretory growthof the limbsbeginsbeforethe onsetof tail
periodthe tissuesbecome impregnatedwith thy- resorption,it is not possible to regard the two
roid hormone.When the concentrationin the processesas beinginterdependent. It is clear that
tissuesattainsa certainlevel,intracellular enzymes any real experimentalsupportfor Aleschin'shy-
in the intestineand gills,whichare mostsensitive pothesisis stilllackingand that the necessityfor
to the hormone,begin autolysisof these tissues. involingthe growthhormoneof the pituitaryto
This in turncreatesa stateofacidosisin theentire explainthedifferentiative phasesofmetamorphosis
organism.Moreover,since feedingceases during constitutesa seriousweaknessin the theory.
transformation of the intestine,the organismbe- As a matteroffact,none of the aforementioned
gins to nourishitselfat the expense of the tail hypotheseshas ever gained wide acceptance,for
tissue,the latterbeingalso particularlysensitive it is difficult to imaginethat the diversechanges
to thehistolyzing influence ofthethyroidhormone which occur at metamorphosis can be explained
and thegeneralacidosiswhichnowprevails.After on the basis of any generalphysiologicaleffectof
this,the autolysisof tissuesgoes on automatically the thyroidhormone.It seemspreferableto sup-
because of the accumulationof the acid products pose thatthe characteristic responseswhichdiffer-
resultingfromthese processesthemselves.Thus, ent tissuesgive to thehormoneresultfromfactors
once the degenerativechangesof metamorphosis inherentin the tissues themselves.The question
have begun,theycontinue,despitethe fact that of the originof these different modes of response
the thyroidis by thistimein a restingcondition. then becomes simplyone aspect of the general
To accountforthe differentiative aspectsofmeta- problemof differentiation. This, the centralprob-
morphosisAleschinhad recourseto an entirely lem of embryology, has been subjected to most
different mechanismand ascribedthemto the in- intensive experimentalinvestigationsince the
fluenceof the growthhormoneof the pituitary, pioneeringstudies of Roux and Driesch,and al-
whichhe assumedis increasedconcomitantly with thoughit is by no meanssolved,a greatdeal is now
the increasein tlhyrotrophic hormonethat caused knownabout the factorsinvolvedin the develop-

mentof embryonicdiversity.It is clear that the However,the experiments of Belkin (1933), Tche-
developmentof parts and tissueswhichdifferin povetsky (1934), and Fosi (1935) have demon-
theirconstitutions and in theirlater fates is an stratedthat,whilethe metamorphosis of thyroid-
epigeneticprocess.It occursunderthe influence of treated axolotls or frogs can be hastened by
inductors,"organizers,"and fieldeffects ofvarious increased temperature,a temperatureincrease
types,and in many cases it can be demonstrated alone will not sufficeto induce metamorphosis.
that the futurefates of parts are more or less Huxley (1929) reportedthat at temperatures be-
definitely fixedat quite early stages (gastrulaor low 50 C. R. temporaria tadpolesfailto metamor-
earlier).Althoughmostof the studiesof the "de- phose even whengivenmoderatedoses of thyroid
termination" ofparts and the effects of inductors, substance.The animals undergoa partial trans-
etc., deal withmorphological features,everyem- formation but thencease to change,remainingin
bryologist realizesthat the changeswhichoccurin thisintermediate conditionforseveralweekseven
the tissues involve physiologicalfactorsas well. when returnedto room temperature.Huxley's
It is therefore reasonableto considerthat in the explanationof thiseffectis that the thyroidtreat-
amphibians,duringthe embryonicdifferentiationment causes a compensatoryreductionin the
of diverse morphologicaltypes of tissues, the animal's own thyroidgland and that at low tem-
tissuesalso becomedifferentiated as to theirchar- peraturessome of the administeredthyroidsub-
acteristicphysiologicalresponse to a metamor- stanceis utilizedin counteracting thelow tempera-
phosingagent. The diverse changes initiatedat ture effects.Under these conditionsthe amount
metamorphosis would thenbe determinedjust as ofthyroidmaterialavailable to producemetamor-
muchby the reactingtissuesas by the substance phosis is insufficient to bring about completion
inducingthe changes.The differences in the char- of theprocessand, sincethe animal'sownglandis
acteristicresponsesof the tissuesin diverseam- is now too reducedto effectthe change,metamor-
phibian groups (anura, urodeles,perennibranchi- phosisis haltedwhenonlypartlycomplete.Huxley
ates) could,on suchan hypothesis, be based either concluded from this experimentthat in cold-
upon genetic differences in tissue reactivityor bloodedvertebrates thethyroidacts as a primitive
upon geneticdifferences in the functioning of the temperature-buffer.
endocrinecomplex.Such a viewhas beenpresented Anotherenvironmental factorwhichaffectsthe
by Geigy (1941) in a theoreticalpaper based on action of the thyroidin inducingmetamorphosis
his earlier transplantationexperiments.Hadorn is the acidityofthe mediumin whichthe tadpoles
(1941) has analyzed insect metamorphosison live. Scheer and Berchtold(1926) reportedthat
somewhatthe same basis, and Needham's (1942, thyroidtreatmenthas an increasedtoxicitywhen
pp. 447-456) discussionof amphibianmetamor- the acidity of the medium is increased.Rosen
phosisis also approachedfromthispoint of view. (1938) foundthat acidityor alkalinity,between
pH 4.8 and 11.0, has no effecton the growthor
F. Environmental factorsaffecting metamorphosismetamorphosisof untreated tadpoles but that
Various environmental factorswhich influence acidityacceleratesand alkalinityretardsthemeta-
metamorphicprocesses deserve some comment. morphosingaction of thyroxin.Marzulli's (1941)
The fact that increasedtemperaturehastensthe experiments confirmed thoseof Rosen but further
effectof thyroidtreatmentwas earlyattestedby demonstrated that whenthe thyroxinis adminis-
the workof Terni (1919), and the histologicalob- tered by injectionits effectsare not dependent
servationsofAdler(1916) on the thyroidsofRana upon thepH of the culturemedium.Marzullialso
temporarialarvae from localities having widely showed that the rate of respiratorymetabolism
differing climatic conditionsled him to suggest is greaterin tadpoleskeptin an acid mediumthan
thatprevailingtemperatures may be importantin in thosekept in an alkalinemedium.He therefore
determining whetherthetadpoletransforms during concludedthat the greatereffectiveness of thy-
its firstsummeror over-winters in thelarval state. roxindissolvedin an acid culturemediumis due
He also pointedout the possibilitythat neoteny to a morerapid intakeof the materialundersuch
in amphibiansmay be associated with low tem- conditions.
perature.Eggert (1934) drew similarconclusions Zondekand Reiter(1923) reportedthatelectro-
froma histologicalstudyof the thyroidsof larvae lytes such as CaCl2 and KCl have accelerating
of Molge alpestriskept at different temperatures. effectsupon the metamorphosing action of thy-

roxin,but Kosminand Resnitschenko (1927) were are certainfood substances,however,which do

unable to confirm theseresults.Abelin(1923) pre- appear to have specificeffectsupon the courseof
sented some evidencefor an inhibitingeffectof metamorphosis. McCarrison(1921) presentedevi-
phosphate ion upon thyroxinactivity.It seems dence that tadpoles fed with a high fat diet are
probable that both the results of Zondek and delayed in metamorphosis,and Kniebe (1920)
Reiterand thoseofAbelinweredue to changesin showedthat administration of oleic acid has the
the pH of the mediumratherthan to any specific same effect.This may explain the results of
effectsof the ionsin question. Woitkewitsch(1935b), who found that thyroid
The amountof space available to the larvae,or graftsfailedto inducemetamorphosis whentissue
thedegreeofcrowding, are factorswhichstrikingly fromthe uropygialgland of theyoungpigeonwas
affectthe rate of growth(Bilski, 1921; Adolph, implanted with the thyroid.Gudernatschand
1931a; Rugh, 1934); and the work of Adolph Hoffman(1936) found that certainamino acids
(1931b) and of Lynn and Edelman (1936) has are of importancein promotingdifferentiative
indicated that the time of metamorphosisalso changes in tadpoles. Doetsch (1938) has given
varies in relation to the space factor. Adolph evidence that a vitaminpoor diet causes a de-
(1931b) suggestedthatthedelayofmetamorphosis creasedgrowthrate and a delayedmetamorphosis
whichis seen undercrowdedconditionsis mainly if fed duringearlylarval life.He reported,how-
due to the decreasedgrowthrate and concluded ever,that the feedingof such a diet duringearly
that body size is a tangiblequantitativefactorin metamorphosis causes an accelerationof theproc-
the complex of conditionswhich regulatesthe ess due to an increasedtissuesensitivity. Tanigu-
onset of metamorphosis.In Etkin's (1935a) ex- chi (1930) has shown that certain vitamin B
periments,however,therewas no indicationof a preparationscause some accelerationof metamor-
differencein sensitivityto thyroxintreatment phic processesin severalJapaneseanurans.Vita-
betweenlargeand smalltadpolesof the same age. minA has been reportedto antagonizethe action
The delayed metamorphosis under crowdedcon- of thyroidhormonein both anuransand urodeles
ditionsis probablydue therefore to delayedfunc- (Fleischmannand Kann, 1937), but this has not
tioningof the thyroidratherthan to any lack of been confirmed in the recentexperiments of Klen-
tissuesensitivity in smallanimals. nerand Gennaro(1950).
Several authors have shown that x-radiation Starvationof tadpolesmay resultin eitherre-
alterstadpoleresponseto metamorphosing agents. tardationor accelerationof metamorphosisde-
Puckett (1937) foundthat larvae givensublethal pendingupon the timeduringdevelopmentwhen
doses of x-raysand subsequentlyfedwiththyroid feedingstops.Earlyinanitionretardsdevelopment,
materialgo throughthe retrogressive changesof but starvationinitiatedat late stagescausespreco-
metamorphosismore quickly than do controls, cious metamorphosis.D'Angelo, Gordon, and
butthedifferentiative changesfailto occur.Radia- Charipper(1938) showedthat the criticalperiod
tion of portionsof the body,followedby thyroid of this effectis in the period of early hind limb
feeding,resultsin effectsconfinedto thoseparts growth(5-8 mm.hind-limb lengthin R. sylvatica).
receivingthe x-rays.It appears that the effectof These authors later demonstrated(1941) that
radiationis purelylocal and consistschieflyin an inanitionat earlystagesresultsin
extremeatrophy
inhibitionof cellulardifferentiation.
ofthe thyroidglandand failureof thepituitaryto
G. Effects ofdieton metamorphosis differentiate fully.The evidenceindicatesthat it
is the pituitaryderangement whichis fundamen-
The effects of the typeand amountoffoodcon-
tally responsible forthe metamorphic failure.The
sumedupon the growthof amphibianlarvae have
thyroids of animals subjected to inanition after
been extensivelystudied.The resultsof such in-
vestigationsare notpertinentto thepresentreview the critical stage continue to show histological
exceptin so faras theyrelateto the thyroidfunc- evidenceof secretoryactivityforsome time,and
tionand metamorphosis. Adolph (1931b) has sug- it is suggestedthat earlymetamorphosis in these
gestedthat manyof the earlyexperiments which specimens may result from a precocious and sud-
showedeffects of diet upon the timeof metamor- den burst of thyroid activity,possibly because of
phosis really influenced the processonly because an increased sensitivityto the thyrotrophic hor-
theyaffectedthe body size of the animals.There moneof thepituitary.

H. Relationsofotherendocrine
glands Schliefer(1935) were unable to findany changes
tometamorphosis in the structureor proportionsof the variouscell
typesduringnormalmetamorphosis or undercon-
1. Hypophysis
ditionsof acceleratedmetamorphosis. Spaul and
Adler (1914) was the firstto demonstratethe Howes (1930) concludedthatthe oxyphilcells are
close relationshipbetween thyroidfunctionand associated with thyrotrophic functionin the ox,
the hypophysisin amphibians.He showed that and Kerr (1939), findingan increasein thesecells
destruction of the hypophysisin the larva results duringmetamorphosis in R. temporaria
and B. bufo,
in failureto metamorphose and that hypophysec- maintainedthat thisholds forthe Amphibiaalso.
tomizedlarvae have thyroidglands which lack Most otherinvestigators of the amphibianpitui-
colloid. These findingshave been confirmed and tary,however,have feltthat the evidencetends
extendedby the workof manyinvestigators, and stronglyto the conclusionthat the basophilcells
it is now well establishedthat the hypophysis has are concernedwiththeproductionof thyrotrophic
a controlling influenceupon thyroidactivity.In hormone. Allen, Torreblanca, and Benjamin
the absence of the pituitary,the thyroidfails to (1930), D'Angelo (1940), and Irichimowitsch
attain its normalsize and remainsinactive,and (1941) foundsignificant increasesin the number
metamorphosis is consequentlyinhibited.Adminis- ofbasophilsin theanteriorlobe in associationwith
trationof pituitarysubstanceby injectionto such increased thyroid activity and metamorphic
inhibitedlarvae is rapidlyfollowedby initiation changes during normal developmentin various
of metamorphicchanges.The pituitaryeffectis amphibians,and Grobstein(1938) observedvacuo-
not a directone, forpituitaryadministration to lation of the basophils followingthyroidectomy
thyroidectomized larvae is entirely ineffectual in Triturus.
(Schwartzbachand Uhlenhuth,1928,1933; Figge The developmentof the thyrotrophic function
and Uhlenhuth,1933); and it is clear that the in the pituitaryis independentof specificnervous
pituitarysubstanceacts throughthe inductionof stimulation, forheterotopicpituitarygraftsmade
secretoryactivityand colloidrelease by the thy- intohypophysectomized tadpolesat variousstages
roid. The cytologicalchanges produced in the readily induce metamorphic changes (Etkin,
thyroidby hypophysectomy have been fullyde- 1935b).
scribedby Aleschin(1939). The potencyofthe thyrotrophic hormoneshows
By graftingvariousparts of the pituitaryinto seasonal variations (Keaty, 1942), and there is
hypophysectomized tadpoles,Allen (1921) showed clear evidencethat the thyrotrophins of different
that it is the anteriorlobe of the gland which vertebrate groupsare qualitativelydifferent(Gorb-
affectsthe thyroidactivity;and later work has man, 1946). Studies concerningthe specificity of
demonstratedthat the thyroid-activating sub- the thyrotrophic hormonehave recentlybeen re-
stance is confinedto thisportionof the pituitary. viewed by Adams (1946a). It is of interestthat
Subsequent developmentof various extraction stasis (starved, non-metamorphosing) tadpoles
methodshas resultedin the preparationof quite show a markedsensitivityto this hormoneand
potent thyroid-activating fractionsfromthe an- have therefore been suggestedas test objects for
teriorlobe (Uhlenhuth,1937). It appears that the thyrotrophic hormoneassay (D'Angelo, Gordon,
responseof the thyroidto the thyrotrophic hor- and Charipper,1942; D'Angelo and Gordon,1949,
mone is a quantitativeone, directlyproportional 1950).
to the amount of hormoneinjected (Uhlenhuth, Blountand Blount(1947) haveadducedevidence
Schenthal,Thompson,and Zwilling,1945). Inves- fortwo distincttypesof thyrotrophic activityin
tigationsdealingwiththe chemicalnatureof the amphibians,one concernedwithstorageof colloid
thyrotrophic hormonehave beencarriedoutalmost in the thyroid,the otherconcernedwith colloid
exclusivelyupon mammals. For an account of discharge.Such a dual mechanismmay have im-
thesestudiesthereaderis referred to thereviewof portant bearingsupon the problemof neoteny,
Albert(1949). whichis to be discussedbelow.
Attemptsto ascertainwhetherthe secretionof Duringtheveryearlystagesofthedevelopment
the thyroid-activating hormonecan be ascribedto of the pituitaryin Rana a thyrotrophic effectis
any specificcellularelementsof the anteriorlobe exertedwhichis apparentlynot hormonalbut is
in amphibianshave givensomewhatcontradictory of the nature of a field effect.Thyroid glands
results. Larson (1918), Clements (1932), and transplantedto a positionveryclose to the pitui-

tary at this time show markedstimulation,and when administeredin combinationwith thyroxin

precocious metamorphosisis induced (Etkin, (Gutman, 1926). Neitherthyroxinalone nor ad-
1936c; Etkin and Lasky, 1938; Etkin and Huth, renalinalone producedthese effects.Uhlenhuth,
1939). The stimulusis short-lived and it is ques- van Slyke, and Mech (1934) demonstratedthat
tionablewhetherit is at all relatedto thethyrotro- adrenalinalso increasesthe effectiveness of the
phic effectsof the differentiated pituitary.It is, thyrotrophic hormoneof the pituitary.Simulta-
seemingly, an effectwhichwouldnevercome into neousadministration ofadrenalinand thethyrotro-
play in normal development,since the normal phichormoneto Ambystoma tigrinum larvaecauses
locationsofthyroidand pituitaryare too farapart a muchgreateraccelerationofmetamorphosis than
forany such stimulusto be exerted. is producedby the thyrotrophic hormonealone.
Geiringer(1938) founda similarsynergism in the
2. Thymus effectofadrenalinand thyroxin upon colorchange
In connectionwith Gudernatsch's(1912, 1914) in Hyla.
earlyexperiments on thyroidfeeding,it was also 4. Gonads
reportedthat the feedingof thymustissueto tad-
Althoughearlystudieson the feedingof gonad
poles causes acceleratedgrowthand delayedmeta-
substance,administration of gonad extracts,and
morphosis.Uhlenhuth(1919) obtainedsimilaref-
gonadectomyseemedto show no effectson meta-
fectswithurodelesand concludedthat the inhibi-
morphosis,several recent investigationsindicate
tionofmetamorphosis was due to theabsencefrom
that such effectsmay exist. Kl6se (1941), in a
the thymusdiet of some material requiredfor
detailed study of the results of castratiop in
properdevelopment ofthethyroid.Sklower(1927)
Triton,found an increasedstorage of colloid in
maintainedthat, while thymusfeedingdoes in-
thethyroid, particularly in males.Partialregenera-
hibit thyroidfunctionin young tadpoles, it is
tion of the gonads reducedor nullifiedthiseffect.
withouteffectin olderanimals,a conclusionwhich
Roth (1947b) has maintainedthat testosterone is
has recentlybeen supportedby Mazzeschi (1940).
antagonisticto thyroxin actionwhilethe estrogens
On the other hand, Colosi (1932) reportedthat
show no effect.
simultaneousfeedingof thymusand thyroidis
moreeffective in inducingmetamorphosis than is 5. Pancreas
thyroidfeedingalone. It mustbe noted,however, Aron (1928) demonstratedthat the endocrine
that thymectomy has not been demonstratedto activity of the pancreas is influencedby the
have any effect upon metamorphosis(Allen, thyroid.The Islands of Langerhansincrease in
1920b), and thymusgraftshave also proved in- size and show decreasedpigmentation duringthe
effective(Woitkewitsch, 1935a). early phases of metamorphosis,and the same
Bounhiol(1942) has suggestedthat the contra- changes are exhibited by the islet tissue of
dictoryreportsconcerningthe effectsof thymus thyroxin-treated tadpoles. Glycogenicactivityin
feedingmay be due to the frequent,thoughnot theliveralso beginswiththeonsetofmetamorpho-
invariable,presenceof largeamountsof fat in the sis, and it is clear that the pancreasplays a con-
gland,inasmuchas fat,accordingto thepreviously trollingrole in establishingthis function(Aron,
cited findingsof McCarrison (1921) and others, 1931). Thyroidadministration thus indirectlyaf-
wouldtendto inhibitmetamorphosis. fectsliverfunction, the effectbeingintermediated
by the pancreas.The importanceof this relation
3. Adrenal
has been emphasizedby the work of Bilewicz
Little is known of the relationsbetween the (1938), forthe glycogenreservesin the liverseem
secretionoftheadrenalcortexand metamorphosis. to be significant in the nourishment of the larva
Woitkewitsch(1937b) foundthat implantationof duringthe later phases of metamorphosis, when
mammalianadrenal cortexin tadpoles causes in- thechangesoccurring in thedigestivetractprevent
creased growthbut no accelerationof metamor- feeding.Hepatic glycogenreservesfall to 5 per
phosis.Bock (1938), on the otherhand, reported centof theirformervalue duringthistime.
a definiteincreasein metamorphic rateofthyroxin-
treatedtadpoleswhencortinis administered. 6. Parathyroids
The secretionof the adrenalmedulla,adrenalin, Allen (1920a) reportedthat the parathyroid
was reportedto be effectivein inducingmeta- glands of thyroidectomizedBusfolarvae exhibit
morphicchangesin the gillsand skinof Necturus marked hypertrophybut show no histological

peculiarities.Schulze (1921), however,was not wayto theinfluence ofmetamorphosing substances

able to demonstrateany effectof parathyroid can also be demonstrated by themethodofhetero-
feedingupon the metamorphic process. plastic transplantation.Axolotl tail-buds trans-
planted to the flankof Triturusmetamorphose
I. The thyroid and neoteny concomitantly withthe hosttissues(Geigy,1938).
Althoughmostamphibianshave a larval period Since it was now clear that axolotIsrespondto
of fairlydefiniteduration and then undergoa thyroidsubstanceand iodinein thesamewayas do
characteristicmetamorphosis, it is wellknownthat ordinaryamphibians,experimentswere under-
in certainurodelespeciessome specimensmay be taken to ascertainthe basis for theirfailureto
foundto retainthe larval body formthroughout metamorphose in nature.Adler (1916), in an ex-
life. Such animals reach sexual maturityand are tensivestudyof both experimentally treatedani-
able to reproduce,so that manygenerationsmay mals and neotenicspecimenscollectedin nature,
pass withouta typicaladult ever appearing.This demonstrated that extremesof temperature cause
phenomenonwas firstdescribedby Dumeril for characteristic changesin the histologicalappear-
the Americanaxolotl,Ambystoma tigrinum,and ance of the thyroidgland. He concluded that
Koilman (1884) coined the term neoteny (pro- climaticconditionsacting upon the thyroidare
longedyouth) to designatethe condition.It was probablythe most importantfactorsin the pro-
notedthat neotenyis commonlyfoundin animals longationof the larval periodin Rana temporaria.
which inhabit lakes in high mountain regions, It has been demonstrated(Fosi, 1935), however,
specimensof the same specieslivingat loweral- thatsimplyincreasing thetemperature is not suffi-
titudesexhibiting a normalmetamorphosis. Early cientto cause metamorphosis in tadpolesof Rana
observersadvanced the hypothesisthat in such esculenta having neotenic tendencies. Jensen
lakes the shoresweresteep and difficult to climb, (1921) describedthe thyroidpicturein axolotls
so that the salamanders,beingunable to emerge as indicatingexcessivecolloidstorage,and a simi-
fromthe water,were forcedto remainaquatic. lar situationwas reportedforneotenicspecimens
It was supposedthatif the animalsweregivenan oftheJapanesesalamander,Hynobius(Sasaki and
opportunity to leave the wateror wereforcedout Nakamura, 1937). Duchosal and Junet (1926)
of the water by dryingof the lake they would maintained, however,thatthethyroidsofneotenic
then transform. Dumerilfailedin an attemptto Tritonalpestrisdo not differ significantlyin histo-
demonstratethis experimentally, but Chauvin logicalappearancefromthoseof normalexamples
(1876) reportedsuccessin inducingyoungaxolotls of the species. That the colloid in the glands of
to metamorphose by gradual dryingof the water neotenoussalamandershas an effective hormone
in which they were kept. Boulenger(1913) and content was demonstratedby Swingle (1922),
Huxley (1925) were unable to confirmChauvin's who showed that fragmentsof axolotl thyroids
results,however,and it seems likely that the graftedinto Rana tadpoles induce rapid meta-
larvae she studiedbelongedto one of the races of morphosis.In view of thesefactsit was suggested
axolotls which readilymetamorphoseunder lab- thatthe axolotlfailsto metamorphose notbecause
oratory conditions without treatment. Various of any deficiency in the thyroid secretion, but
otherexternalfactors,suchas temperature, oxygen because of some failurein the releaseof the hor-
tension,and foodsupply,weresuggestedas possible moneinto the blood stream.Swingle(1924), how-
factorsin inducingneotenyin mountainousregions ever,foundthat removalof the thyroidsfroman
but littledirectevidencewas advancedto support axolotland injectionof thesesame glandsintothe
theseideas. Afterthe discoveryof the role of the peritonealcavity did not producemetamorphosis
thyroidin metamorphosis a numberof investiga- and, in fact,injectionof thyroidsfromtwo speci-
tors showed that administration of thyroidsub- menswas also withouteffect. In a fewcases injec-
stance,thyroxin, or various iodine compounds to tion ofthe contents ofthree setsofaxolotlthyroids
young axolotls causes rapid metamorphosis. Ad- was sufficientto inducemetamorphosis. He there-
ministrationof inorganiciodine gave conflicting foreconcludedthat the axolotl'sfailureto meta-
results,but it was finallyshownthatthistreatment morphoseis due to an exceptionalinsensitivity of
is also effective,providingthe iodineis implanted the tissuesto thyroidaction, an insensitivity so
underthe skinor in the peritonealcavityso that greatthat the animal'sown thyroidproductionis
rapid absorptionis assured. The fact that the insufficient to bringabout metamorphicchange.
axolotltissuesare capable of reactingin a typical Anotherhypothesisto account for the meta-

morphicfailure,however,is that the thyrotrophic throughoutlife. There are two well-defined fam-
functionof the pituitaryis somehowimpaired.It ilies of urodeles,the Proteidaeand the Sirenidae,
has been demonstratedthat the thyroidof the all the membersof whichshow this "permanent
youngaxolotl respondsnormallyto the injection larval" condition.The ProteidaeincludetheEuro-
of anteriorpituitarysubstancederivedfromother pean "Olm," Proteus,and the Americanmud-
animals,althoughin older specimensthe thyroid puppy, Necturus.The Sirenidaeare represented
becomesinactiveand no longerseems capable of by the twogeneraSirenand Pseudobranchus, both
response.However, Ingram (1929) has adduced of whichinhabitthe southernUnited States. In
evidencethatin certainpartiallyneotenicanurans addition, the blind cave salamander of Texas,
thereis some failurein the normalformationor Typhlomolge, is a permanentlarvausuallyregarded
release of the thyrotrophic hormoneand this has as a memberof the Plethodontidae.It is natural
been shownquite clearlyin Blount's (1950) recip- to supposethat theseforms,like the axolotl,may
rocal transplantsof the hypophysisbetweenAm- owe their conditionto some peculiarityin the
bystoma tigrinum, a readilymetamorphosing form, endocrinecomplex.Indeed, therewas evidenceto
and A. mexicanum, the Mexican axolotl.Mexican indicate this even beforethe importanceof the
axolotlsreceivingpituitarygraftsfromthe meta- thyroidin metamorphosis was realized,forEmer-
morphosingspecies underwentmetamorphosis, son (1905), in describingthe generalanatomyof
whileA. tigrinum larvaereceiving axolotlpituitaries Typhlomolge,had reportedthat she had failedto
retainedthe larval form.Earlier experimentsof findany thyroidgland in thisanimal. Uhlenhuth
thiskindapparentlyfailedbecauseofdegeneration (1923), in a moreextensivestudy,foundthatthe
of the transplantand, in some cases, regeneration thyroidis actually absent in only a small per-
of the host pituitary.It has already been noted centage of specimensbut is rudimentary in the
that Blount and Blount (1947) have found others.This seemsa sufficient explanationforthe
evidencethat thereare two typesof thyrotrophic failureof Typhlomolge to metamorphose, but it is
hormone,one controllingstorage and one dis- not a general explanationfor all perennibran-
chargeof the thyroidsecretion.They have sug- chiates. Indeed, all of the others have well-
gestedthatthepituitariesofneotenousamphibians developedthyroidglands.The thyroidofNecturus
elaboratethe storagesubstancebut lack the dis- showstypicalsignsof activity(Charipper,1929),
chargehormone.Hartwigand Rotman(1940) car- Proteushas a well-developedthyroidwitha flat-
ried on a comprehensive studyof a populationof tened epitheliumand a predominantlychromo-
neotenicTritontaeniatusfromnearCologne.These phobe colloid (Klose, 1931; Schreiber,1931), and
animalsall had thyroidswhichpresenteda histo- the thyroidof Siren is describedas of normalap-
logicalpictureof low activity.The authorscould pearance (Wilder, 1891). Swingle(1922) demon-
findnothingpeculiarin theenvironmental features strated that the Necturusthyroidcontains the
of the pond wherethe animals were found,and typicalhormone,forit readilyinducesmetamor-
breedingexperiments failedto give any indication phosis when administeredto tadpoles. Grant
thattheneotenicconditionwas hereditary. Experi- (1930c) showedthat the implantationof anterior
ments indicated no loss of tissue sensitivityto pituitarysubstanceis followedby characteristic
thyroxin,and these authorsalso concludedthat colloid evacuationfromthe thyroidin Necturus,
the neotenicconditionmust be ascribedto some and Charipperand Corey (1930) foundthat the
impairmentof the secretionof thyrotrophic hor- Necturusanteriorpituitarycausesprecociousmeta-
mone by the pituitary,even thoughno morpho- morphosiswhenadministered to froglarvae.These
logical modification of the pituitarycould be de- same facts have been demonstratedfor Proteus
tected. Extensive reviewsof the early work on by the work of Vialli (1931). Finally Grant,
theaxolotlare availablein thepapersof Schreiber Clapp, and Ruby (1932) showedthat the thyroid
(1932) and Marx (1935). of Necturusis responsiveto Necturuspituitary;
Followingthesuccessfulexperiments on induced graftsof anteriorlobe substancefromadults into
metamorphosisin neotenoussalamanders,great larvae caused hyperactivity of the larval thyroid
interestwas aroused in attemptsto induce some and dischargeof colloid.
metamorphic changein the so-calledperennibran- Therethusseemsto be a clearindicationthatin
chiateamphibians.These are formswhichare not most of the perennibranchiates whichhave been
knownto undergoany metamorphosis but retain studied the endocrinecomplexis functionalin a
their gills, tail fins,and general larval habitus normalfashion.Nevertheless, attemptsto produce

metamorphicchangesby treatmentwith thyroid VI. THE THYROID AND METAMORPHOSIS IN

materialor iodine compoundshave been almost CYCLOSTOMES AND FISHES
completelyunsuccessful.Early experimentson Cyclostomes have a larva,theammocoetesstage,
this subjectshowedno effectswhatsoever.As has which undergoesa well-definedmetamorphosis.
been noted, however, Gutman (1926) reported There have been a numberof attemptsto demon-
that Necturuskept in a solutionof thyroxinand strate thyroidcontrolof this process,but these
adrenalinshowed gill atrophy,protrusionof the have been largelyunsuccessful.Feeding or injec-
eyes, and sheddingof the skin. Noble (1924) ob- tion of thyroidsubstance or iodine compounds
tained gill reductionin Siren and Pseudobranchus does not induceprecociousmetamorphosis (R6my,
as a resultof treatmentwith iodothyrin,Noble 1922;Horton,1934;Stokes,1939),and administra-
and Richards (1931) reportedgill resorptionand tionofextractsoftheanteriorlobe ofthepituitary
ecdysis in Proteus followingthyroxininjection, is likewiseineffective (Young and Bellerby,1935;
and Noble and Farris (1929) noted some meta- Knowles, 1941). It has also been demonstrated
morphicchanges in the skin of young Crypto- that the larval endostyle,some cells of whichgive
rancsus raised in water containingdesiccated rise to the adult thyroid,does not induceacceler-
thyroidsubstance.Reis (1930, 1932) has made a ated metamorphosis when graftedinto frogtad-
detailed study of the behavior of heteroplastic poles, althoughthe gland of the adult lampreyis
skingraftsin amphibiansduringthemetamorpho- quite effective
(Horton, 1934). Moreover,chemi-
sis of the host. He found that graftsof axolotl cal analysisof the ammocoeteendostylehas failed
skinto adultsalamandersundergoa metamorphosis to revealany evidenceof a concentration ofiodine
to skinwhichis of the adult typein itsglandular in thisregion(RWmy, 1922; Horton,1934). All of
structureand pigmentation. Extendingthisto the this worktends to the conclusionthat, although
perennibranchiates, he showed that Proteusskin the adult cyclostomepossessesan active thyroid,
transplantedto Triton,Salamandra,or Ambystoma the larval endostyledoes not produce a thyroid
also undergoestypicaltransformation, eventhough hormone,and the larval tissuesare not induced
Proteus skin nevershows thesechangesin nature to metamorphosethroughthe agency of such a
and cannotbe inducedto transform even whenthe hormone. Recently, however, Gorbman and
animalissubjectedto thyroxin treatment.Schreiber Creaser(1942) have found
that,afterexposureof
(1938) has modifiedthe experimentby grafting ammocoetesto radioactiveiodine,a specificlocal-
Proteusskinto theaxolotland then inducingmet- izationof iodinein certainof the endostylarcells
amorphosisof the host by thyroxininjections.He can be demonstrated. The localizationoccurs in
has also shown that if axolotl skin is implanted younglarvae,less thanone year old, as well as in
on Proteusand iftheProteusis thengiventhyroxin fiveyearold larvaereadyto beginmetamorphosis.
injections,theaxolotl graftwillundergometamor- In view of these findings,renewedstudy of the
phosis,althoughthe Proteus itselfis not affected. effectsof thyroidadministration on larval growth
Similarresultswereearlierreportedby Noble and and differentiation in cyclostomes seemsdesirable.
Richards(1931) fortransplantsof the skinof vari- Several bony fisheswhichundergochangesof
ous salamanderlarvae to Necturus.
a metamorphicnature duringtheirlife histories
It mustbe concludedthattheperennibranchiate
have also attractedthe attentionof studentsof
amphibiansretainthe larval formchieflybecause
thyroidphysiology.Perhaps the most familiarof
the tissues are extremelyunresponsiveto the
of these is the eel, Anguilla vulgaris.Murr and
thyroidhormoneand not, except in the case of
thebasis ofa histologicalstudy
Typhlomolge, because of any abnormalityin the Sklower(1928), on
of the eel thyroid, reported thatthechangeswhich
endocrinecomplexwhichcontrolsmetamorphosis.
Whether the perennibranchiates representneo- occur in the gland in relationto metamorphosis
tenic forms of which the adult stages no longer precisely parallel those seen in the tadpole and
ever occur, or whetherthey representformsar- therefore concludedthatthethyroidis thecontrol-
rested in their phylogeneticdevelopmentis a ling factorin causing the metamorphicchanges.
questionwhichhas been interestingly discussedby A muchmoredetailedstudyby von Hagen (1936)
Versluys (1925) and by Noble (1931), but this revealed, however, that marked colloid release
subjectdoes notfallwithinthescopeofthepresent firstoccursat the end of metamorphosis, at the
review. timewhenthe youngeel passes fromsalt to fresh

water. CoUlamandand Fontaine (1942) reported VII. THE ROLE OF THE THYROID IN GROWTH AND
that there are two periods of marked thyroid DIFFERENTIATION
activityin thelifeof the eel, but thesecorrespond Despite the lack of evidence for any direct
to the two changesof milieuwhichare character- thyroidcontrolof metamorphic changesin fishes,
istic of the life cycle and are not related to the thereare clear indicationsthat the thyroiddoes
metamorphicprocess. An attempt to ascertain play an importantpart in growthand differentia-
whetheralterationsin thyroidhistologycan be tion in these forms.The growthrate of young
experimentally producedin marinefishesby grad- brooktroutis adverselyaffectedby thyroxinad-
ual reductionofthesalinityofthewaterwas made ministration (Herzfeld, Mayer-Umhofer,and
by Olivereau(1948). He reportedthat thistreat- Scholz, 1931), and such an effectis also obtained
mentresultsin increasedepithelialheight,appear- fromfeedingthyroidpowder to young guppies
ance of manychromophobe vacuoles,and intense (Krockert,1936) or immaturePlatypoecilus (Grob-
vascularizationof the gland.Afterfiveor six days stein and Bellamy, 1939). Smith and Everett
in water of low salinitythe thyroidreturnsto a (1943) reportedno effectson growthrate when
restingstate,indicatingthatit is therapidchange ne-w-born guppies are raised in water containing
in salinityratherthanthe absolutesalt concentra- thyroxinor are fed with thyroidpowder, but
tion that inducesthe response. pointed out that theirexperimentswere carried
In the Atlanticsalmonthe transformation from on forshorterperiodsthan thosecitedabove and
theparr to the smoltstage is accompaniedby ac- thatthismightaccountfortheresult.Impairment
tive hyperplasiaof the thyroid(Hoar, 1939), but of thyroidfunctionby administration of thyroid-
since this transformation also coincideswith the inhibitingdrugs also interfereswith growthin
migrationof the youngsalmonto the sea the sig- fishes (Goldsmith,Nigrelli, Gordon, Charipper,
nificanceof the thyroidchangeremainsin doubt. and Gordon,1944; Frieders,1949; Hopper, 1950).
Robertson(1948), however,had founda similar Grobsteinand Bellamy(1939) foundthat thyroid
increase in thyroidactivity in relation to the feedingcauses precocioussexual developmentin
metamorphosis of the parr of the rainbowtrout, Platypoecilus,as judged by early differentiation
a formwhichdoes not migrateto salt water,and of the gonopodiumin the male, whileGoldsmith,
has also demonstratedthat the smolt stage can Nigrelli,et al. (1944) demonstratedthat thyroid
be induced by injectionof mammalianthyroid inhibitionresultsin a failureof developmentof
extract or thyrotrophichormone (Robertson, the secondarysex characters.
1949). The available information concerning the func-
Buchmann(1940) reportedsome evidenceof a tions of the thyroid hormone in growth and dif-
relationbetweenthyroidactivityand metamorphic ferentiationin amphibians has been consideredin
the sectionon amphibianmetamorphosis.
changesin the herring,and Harms (1935) found
Experimentalstudies on thyroidfunctionin
that elitheradministration of thyroxinor gradual
young reptiles are as yet entirelylacking. In
evaporationof the water can induce accelerated
adults thereis conflicting
evidenceconcerning the
metamorphosis of certaingobiiform fishes.
role of the thyroidin ecdysis.Eggert (1933) has
It is clearthat the evidenceforthyroidcontrol reportedthat
thyroidectomy causes completein-
of metamorphosisin fishes is unconvincing. hibitionofmoltingin thelizardLacertaagilis,but
Thyroidectomy has not yet been successfully per- Noble and Bradley (1933) found that neither
formedin any ofthesemetamorphosing forms,and thyroidectomy norhypophysectomy preventmolt-
conclusionsdrawnfromhistologicalstudy of the ing in Ilemidactylus brookii,althoughthe interval
gland are controversial,particularlyin view of betweenmoltsis lengthened.Ratzersdorfer, Gor-
Olivereau'sdemonstration of the effectsof chang- don, and Charipper(1949), workingwith Anolis
ing salinity.Administrationof thyroidmaterial treatedwith a thyroid-inhibiting drug, obtained
to larval fishesdid prove effective in Robertson's still anotherresult.In theiranimals the interval
experiments, and such studiesshouldbe extended. betweenmoltswas not affectedbut the duration
However,the recentlydevelopedthyroid-inhibit-of the moltingprocesswas greaterin the experi-
ingsubstancesundoubtedlyofferthe mostpromis- mentallizards than in controls.Finally,Schaefer
ingopportunity forfurther researchon thissubject. (1933) has maintainedthat thyroidectomy has a

stimulatingrather than an inhibitinginfluence morphosisin amphibians,and some have attrib-

upon moltingin snakes. uted thisto the increasein thyroidhormonelevel
In adult femalehornedlizards (Phrynosoma), at thistime.The mostrecentworkon the subject,
thyroxininjectionis reportedto cause atrophyof however,that of Etkin (1934), revealsno increase
the ovaries(Mellishand Meyer,1937). In turtles, in oxygenconsumptionduringnormalmetamor-
administrationof thyroxinaffectsthe polymor- phosis in the frog.In the adult frog,thyroidad-
phonuclearleucocyte count in much the same ministrationhas been reportedto have no effect
way as inamphibiansand inwarm-blooded animals on oxygenconsumption (Drexlerand von Issekutz,
(Gordonand Charipper,1947). 1935), but Warren (1940) found that prolonged
treatmentdoes ultimatelycause a rise in oxygen
VIII. THE THYROID AND METABOLISM
consumptionaccompaniedby a reductionin liver
The part played by the thyroidhormonein glycogenand a loss of body weight.Mansfeldand
controlling the rate of metabolicactivityin mam- Linczos (1936) and Lanczos (1939) have also main-
mals is well known.The many attemptsto dem- tainedthatadministration ofthyroxin or thyrotro-
onstratesucha functionin cold blood vertebrates, phichormoneto adult frogsresultsin an increased
however,have largelymet with failure(see the metabolicrate,as evidencedby a risein nitrogen
reviewof Fleischmann,1947). excretion.Henschel and Steuber (1931), on the
Krockert (1936) has stated that guppies fed otherhand,wereunableto demonstrate any effect
with dried beef thyroidshow an increasedneed of thyroxininjectionor thyroidectomy upon heat
foroxygen.This was simplypostulated,however, productionin the frog.Taylor (1936, 1939) found
on the basis of the factthat the experimental ani- that thyroidectomized salamanders(Triturustoro-
mals came to thesurfaceoftenerthanthecontrols. sus) showed a dedine in oxygenconsumptionto
In experimentsin which actual measurements 72.5 per cent of the normalin two to threeweeks
have been made, administrationof mammalian afteroperation.Salamanderswith two extra sets
thyroidextracts,thyroxin,or iodine compounds of thyroidsimplantedunderwentan initialperiod
have been found to cause no change in oxygen of low oxygenconsumption,59 per cent of the
consumption in thelarvallamprey(Horton,1934), normalrate, forabout threeweeks,but the rate
or in adults of the guppy,Lebistes(Drexlerand thenrose to 187 per cent of normal.The athyroid
von Issekutz,1935; Smithand Everett,1943),the salamanders(Taylor, 1936) showed disturbances
toadfish (Root and Etkin, 1937), the goldfish in thestructure oftheglandsoftheskinand diges-
(Etkin, Root, and Mofshin, 1940; Hasler and tive tract,and latermanyof the tissuesexhibited
Meyer,1942),and Fundulus(Matthewsand Smith, signs of nutritionaldeficiencyand emaciation.
1947). Inhibitionof thyroidfunctionin Fundulus Taylor thereforesuggested that the metabolic
by administration of thioureaalso fails to affect changesobservedmay be in part mediatedby dis-
oxygenconsumption (Matthewsand Smith,1947). turbancesto nutrition.
In view of theseresults,most workershave con- Little information is available concerningthe
cluded that,in fishes,the thyroidhormoneplays relationbetweenmetabolicrate and thyroidac-
no part in the controlof oxygenmetabolism.Re- tivityin reptiles.Drexlerand von Issekutz (1935)
cently,however,(Smith and Matthews,1948) it have statedthatneitherthyroxin northyrotrophic
has been reportedthat extractsof the parrotfish hormonecauses increasedmetabolismin turtles,
thyroidare effective in inducinga significantrise even with long-continuedtreatment.Hopping
in oxygenconsumption wheninjectedintoanother (1931), however,has recordeda rise of 150 per
teleost,Bathystoma. There was considerableindi- cent in the tissuemetabolismof the alligatorfol-
vidual variationin responsiveness, but these re- lowingadministration of 4.4 mg. of thyroxin.
sults suggestthat theremay be some specificity Poikilothermousvertebratesnaturally exhibit
in the thyroidhormoneand that earlierexperi- markedresponsesto changesin temperature, both
ments failed because of the use of mammalian in theirgeneralactivityand in theirmetabolism.
extracts.In any case, the necessityfor further It has been pointedout earlierin thisreviewthat
studyofthe matteris indicated. Huxley (1929), fromindirectevidence,concluded
It has been noted in an earliersectionof this that the thyroidhormoneplays a part in combat-
paper that a numberof workershave reportedan ing the effectsof low temperaturein the tadpole,
increase in metabolic rate accompanyingmeta- and the experiments of Joel,D'Angelo, and Char-

ipper (1949) demonstratethat the thyroidof the hormonehas no influenceupon regenerationin

winterfrogdoes carryon secretory activity.Never- the axolotl,and Guyenot(1927), approachingthe
theless,the thyroidsof most cold-bloodedforms problemby a different method,found evidence
show evidencesof a markeddecrease in activity thattheloss ofregenerative poweris due primarily
duringthe winter,and the seasonalchangesin the to changes withinthe tissues ratherthan to a
thyroid have sometimesbeenregardedas thecausal systemicchange. He transplantedlimb and tail
factorsin the seasonal cyclesof activityin these rudimentsfromlarval anuransto salamandersin
animals.Seasonal changesin the histologyof the order to ascertain whetherthe anuran organs,
fishthyroidhave been describedby Lieber (1936), which usually lose their regenerativecapacity
von Hagen (1936), Hoar (1939), and Buchmann completelyat metamorphosis, could be made to
(194)). Similarstudies have been made on am- retainthisabilityto some degreethroughout life,
phibians by Meisenheimer (1936), Holzapfel as salamandersdo. Such transplantedparts lost
(1937), Pisano (1942), and Morgan and Fales theirregenerative capacityat theusual time,how-
(1942). There is evidence (Stein and Carpenter, ever,even thoughthe host appendageswerestill
1943) that differencesin illuminationin summer able to regeneratereadily.Liosner (1931) carried
and wintermay also be a factorin the annual out somewhatsimilarexperiments, transplanting
thyroidcycle in Triturus.Reptileslivingin tem- limbs fromtadpoles in late metamorphicstages
perate regions show a seasonal change in the which had lost regenerativeability to younger
thyroid(Eggert,1936; Evans and Hegre, 1940), specimenswhich were still able to regenerate.
but thereis an indication,forat least one form, The transplantedlimbs showed no recoveryof
that the thyroidundergoesno period of marked regenerativepower despite the changedenviron-
inactivityin animals inhabitingwarmerregions ment.Liosnerreportedthat in the reciprocaltype
(Evans and Hegre, 1938). of transplant,graftinglimbs fromreadilyregen-
eratinglarvae to non-regenerating specimens,no
IX. THE THYROID AND REGENERATION loss of regenerativecapacity occurred.However,
The strikingregenerativeability exhibitedby this aspect of the matterhas been furtherinves-
lower vertebrates,particularlythe amphibians, tigatedby Borssuk (1935) and by Polezaiev and
has made themfavoredobjects for the study of Ginsburg(1939), and it is now clear that limbs
regenerative processes.Amongthemanyimportant transplanted fromearlyto late larvae do gradually
relationsbroughtout by early workin this field lose theirabilityto regenerate.Onlyifamputation
is thefactthatin theAnura,and in a lesserdegree is carriedout withinone or two days aftertrans-
in urodeles,regenerative capacitydecreasesduring plantationis regeneration possible.It appearsthat
late larval and metamorphic stages and the adult thereis somesubstancein the olderanimalwhich,
has a muchlowerpowerof regeneration than does givensufficient timeto act, bringsabout changes
the early larva. This could be consideredas a in the youngerlimb that reduceits regenerative
natural accompanimentof the greaterdegree of capacity(Polezaiev, 1946).
differentiationfoundin thetissuesofolderanimals. It shouldbe noted that thereare some experi-
It seemslogicalto supposethatthetissuesofyoung ments (Naville, 1927) whichseem, at firstsight,
larvae wouldbe able to dedifferentiate and forma to cast some doubt upon this conclusion.Naville
regeneration blastema more easily than those of foundthatpiecesofanurantail can be transplanted
older specimens,and this idea is supportedby to the dorsal lymphsacs of adult frogsand can
histologicalevidence(Goodwin,1946). carryon regenerative processestherefor as long
However, the relationof regenerativeability as severalweeks.It seemspossible,however,that
to metamorphosis also suggestsa possibleinfluence thiscouldbe explainedon thebasisofa lowermain-
ofthethyroidhormoneuponregeneration, and one tenancelevel of thyroxinin the adult than that
mightinferthat a highthyroxin level in the blood whichprevailsin tadpolesat metamorphic climax.
has a directinhibiting effectupon theregeneration Studies of regenerationin metamorphosing and
process.Such an inferencewas supportedby the adult anurans under conditionsof experimental
work of Pawlowsky(1923), whichindicatedthat hypothyroidism would be of interestin this con-
regeneration oflimbsis decreasedbothin rate and nection.
amount in thyroid-fedsalamanders. Belkin The conclusionsderivedfromthe transplanta-
(1934a), however,has maintainedthatthethyroid tion experiments are supportedby the findingsof

Spei4el (1929) concerningthe effectsof thyroid stillbe initiatedthroughcertainspecialtreatments.

administration upon limb and tail regeneration in Thus Polezaiev (1936, 1939a) succeededin induc-
the tadpole. Thyroid treatmentproved effective ing regeneration of limbsin tadpolesafterloss of
in inhibitingregeneration, providingthe hormone regenerative capacityby meansof traumatization,
is givenpriorto, or simultaneously with,amputa- and Rose (1944, 1945) obtained regeneration in
tion.Thyroidadministration aftertheregenerative such animalsby treatingthe wound surfacewith
processhas begun actually causes an increasein salt solution.These latterresultsmay mean that
growthrate of the regenerateand a more rapid one of the reasonsforloss of regenerative ability
maturingofitstissues.Similareffects werereported in the froglimb at the time of metamorphos,is is
by Warrenand Bower(1939) usingdi-iodotyrosine. the changein thicknessof the skin whicho'ccurs
The resultsof administration ofpituitaryextracts as one featureof thisprocess.It is clear,howkver,
beforeor at the timeof tail amputation(Herrell, that the lower regenerativepower cannot be as-
1934; Puckett,1938) agree closelywiththoseob- cribedto skinchangesalone,forPolelaiev (1939b)
tained with thyroidtreatment,althoughin these has shown that mesodermaltissuesalso undergo
experiments the "growthhormone"of the pitui- changesby whichtheirregenerative capacitiesare
tary may be a complicatingfactor(Richardson, reducedin oldertadpoles.
1940,1945). In any case, the indicationis thatthe It seemsclear that thereis a complexoffactors
inhibitinginfluence of thyroidhormoneis not one involvedin the loss of regenerative abilityin the
whichdirectlyaffectsthe regenerating tissues,but tadpole limb.The immediatecause of the failure
is ratheran effectwhichis exertedupon the limb of regeneration in olderanimalsmay be the high
or tail beforeamputation.Exposure to a high degreeof tissuedifferentiation, the greaterthick-
thyroxinlevel seemsto inducechangesin the tis- ness of the skin, or some other morphological
sues whichrenderthemless capable ofregenerative feature,but it appears that directhormonalin-
activity. fluences mayalso be involved.Both thehigherlevel
Early studiesof the effectsof hypothyroidism of differentiation and the altered skin structure
upon regeneration gave conflicting results.Walter are, of course,featureswhichthemselvesdepend
(1911) reportedretardationof regeneration after upon the morphogeneticeffectsof the thyroid
thyroidremovalin Triton,but Allen (1918) was hormone.Grobstein(1947) has described theeffects
unable to detectany such effects in Rana. Schotte of testicularhormoneupon the developmentand
(1926) found that hypophysectomy inhibitsre- differentiation of the gonopodiumof a poeciliid
generationin adult salamandersbut does not af- fishand has foundthat the morphogenesis of this
fecttheprocessin larval Triton.Furtherinvestiga- organis also accompaniedby a loss ofregenerative
tion of this phase of the problem is needed. capacity.In his discussionof thisphenomenon, he
However, it has recentlybeen shown (Ghidoni, has pointedout the close parallelismbetweenthis
1948) that tadpolesin whicha hypothyroid state case and that of the anuran limb, emphasizing
has been producedby administration of thyroid-
particularlythe fact that the loss of regenerative
inhibitingdrugs prior to tail amputation,still
capacity in both cases is the result of morpho-
regenerate normally. If thetreatment withthyroid-
geneticchangesproducedin the organsby a hor-
inhibitorsis deferreduntil aftertail regeneration
moneactingpriorto the onsetofregeneration. He
has begun,the regenerative rate is retarded.Both
concludedthat the hormonaleffects on the organs
of theseresultsare in accord withthe effectsob-
and tissues which bring about theirmore com-
tained by Speidel (1929) withthyroidtreatment.
Liosner (1931), Borssuk (1935), Polezaiev plete differentiation also involve local changes
(1936), and Forsyth(1946) have shownthat dif- in tissuesand cells,changes whichresultin reduc-
ferentspecies of anurans differas to the age at tion of their regenerative capacity. There is no
whichthe loss of regenerative power occurs,and doubt that this is the case. As has been seen,
Schott6and Harland (1943) foundthat regenera- however,thereis someevidencein theamphibians
tive abilityis lost at differenttimes at different that the hormonalenvironment may also have a
levelsin thelimb,proximallevelslosingthepower direct effectupon the regenerativeprocess(cf. the
earlierthan distal levels. Moreover,it has been experimentsof Borssuk, 1935, and of Polezaiev
foundthatevenaftertheperiodwhenregeneration and Ginsburg,1939). This phase of the problem
no longeroccursundernormalconditions,it may deservesfurther study.

X. THYROID ANTAGONIZERS AND INBIBITORS testosteronepropionateeither fail to metamor-

A numberof substanceshave been found to phose or show a markedretardationof the proc-
antagonizetheactionofthe thyroidhormoneor to ess. The effectdiminisheswithincreasingstrength
inhibit to some degree the functioningof the of the thyroxinsolutionsand, in the case of the
thyroidgland. All of these,because of theirpos- axolotl, also varies with the age and sex of the
sible use in treatmentof hyperactivethyroidcon- individual. Various estrogenichormoneswhich
ditionsin human beings,have been ratherthor- were testedprovedineffective. Brandt (1936) has
oughlytestedon thecommonlaboratorymammals. noted an inhibition of thyroxin-induced meta-
Studiesof thiskindon cold-bloodedvertebrates are morphosis by feeding placenta or administering
relativelyfew, however,and those which have placental arterialblood, and Brandt and Thomas
been made have dealt almost exclusivelywith (1941) found that this inhibitingfactorin the
effectsupon amphibianmetamorphosis. placenta is not alcohol-soluble. One mightsuspect
Substancesreportedto antagonizeor neutralize that this effect is due to the chorionic gonadotro-
the metamorphosis-inducing effectsof thyroxin phins of the placenta,but no testsseem to have
include:secretionsofsomeotherendocrineglands, been made withpurifiedextracts.
certain chemicalions, certain amino acids, and Severalauthorshave attributedantagonisticef-
of
some derivatives tyrosine. fects to certainionswhenadministered to thyroxin-
In earlystudieson endocrinefactorsin amphib- treated amphibians.Abelin (1923) reportedsuch
ian metamorphosis it was foundthat tadpolesfed effects withNa2PO4and concludedthatphosphate
on a diet of mammalianthymusgland had a de- ion was responsible.Zondek and Reiter (1923)
layed or completelyinhibitedmetamorphosis, al- maintainedthat calcium tends to neutralizethe
though their growthwas apparentlyunaffected action of thyroxin,but Hellwig (1936), who re-
(Gudernatsch,1912, 1914; Uhlenhuth,1919). A peated theirexperiments, failed to confirmtheir
considerablecontroversy arose concerningthe in- results. Sutter (1941) has found that various
terpretationof these results,some investigators coppersaltsantagonizecertainofthemetamorphic
concludingthat the thymusproducesan internal effectsof thyroxin,such as limb-growth, while
secretionwithan effectantagonisticto the influ- seemingly augmenting the effectson tail resorption
ence of the thyroidhormone,whereasotherhave and loss ofbody weight.
maintainedthat thymus-fed animalsfail to meta- Gudernatschand Hoffman(1931, 1934) and
morphosebecause of a dietarydeficiency.This Hoffman (1935a, b), in connectionwith theirex-
matterhas been discussedin a previoussectionof periments on the effectsof amino acids upon
thisreview,and it willsuffice to say herethat the amphibiangrowthand differentiation, foundthat
basis for the inhibitionof metamorphosisby arginineand some other amino acids show an
thymustissueis stillnot clear. It is probablynot antagonismfor the differentiation effectsof thy-
to be regardedas a hormoneeffect.Gudernatsch roxin. Certain sugars and the hormone insulinwere
now feels that some chemical component also foundto retardthethyroxin effect,and methyl
(1949)
of the thymus,such as glutathione,may have an cyanide(acetonitrile)was reportedto protectthe
effectwhichantagonizesthethyrotrophic hormone amphibian larva against thyroxincompletely.
of the pituitary.Hoffman(1935a) foundthat in- These resultsare regardedas supportingthe view
sulinretardstheresponseofthetadpoleto thyroxin that thyroxinis to be consideredas an oxidative
while suprareninaccelerates it. However, these catalyst.
hormonespresumablyact throughtheireffectson Woolley(1946) has reporteduponseveralethers
carbohydrate metabolism,ratherthan by a direct of n-acetyliodotyrosine which oppose the meta-
influence uponthyroxin activity.In thisconnection morphosing effectof thyroxin.The most effective
it may be noted that monohalogenatedacetic of these were the p-nitrophenylethyl ether and
acids, which have an antiglycolyticaction, are the p-nitrobenzylether.Roth (1948) foundthat
reportedto antagonizethedifferentiative effectsof 3-5, D-L iiodotyrosineprevents thyroxin-induced
thyroxinin Bufo (Scarinci,1946). Roth (1947b) metamorphosis ifit is injectedsimultaneously with
has foundthattestosterone propionateantagonizes the beginningof thyroxintreatmentor any time
the effectof thyroxin upon metamorphosis in both up to two weeksafterthe beginningof treatment.
anuransand urodeles.Larvae placed in thyroxin Injection some days before thyroxinis admin-
solutions and given simultaneousinjections of isteredis not effective. Anothermaterialforwhich

thyroid-antagonizing effectshave been claimedis moneby thepituitary.The highlevel ofthyrotro-

anti-thyroidin (Belkin, 1934b), a preparationde- phic hormonethenbringsabout a hypertrophy of
rived fromthe blood serumof thyroidectomized the thyroidgland,accompaniedby hyperemiaand
sheep; but the evidencefor the effectiveness of collapse of the thyroid follides. This thyroid
thissubstanceis stillinadequate. hypertrophy, althoughit is reallya secondaryef-
Within recent years attention has centered fect,is one of the most strikingresultsof the ad-
chieflyupon antithyroidagents which produce ministration ofantithyroid drugs,and thesedrugs
theireffect by inhibitingtheactivityofthethyroid are therefore commonlyreferred to as goitrogens.
gland ratherthan by antagonizingor neutralizing The work on mammals indicates that in most
the effectsof the thyroidhormone.One type of cases the effectsof the goitrogensare readilyre-
treatment whichinhibitsthyroidactivityhas been versible,discontinuance oftreatment beingquickly
referredto in a previoussectionof this review. followedby reductionof the gland to its normal
Administration of thyroxinor iodineto an animal size and resumptionof its normalfunction.
has the effectof depressingthe animal'sown thy- The earliestreportoftheuse ofthesesubstances
roid.This has been well establishedformammals, in cold-bloodedformsis that of Gordon,Gold-
and iodineadministration has provedusefulas a smith,and Charipper(1943). It was foundthat
preoperativetreatmentin hyperactivethyroid Rana pipiens larvae placed in a .033 per cent
cases. In cold-bloodedformsthesamephenomenon solutionof thioureaat the hind-limbbud stage
has been evidencedin the work of Mayerowna showed a retardationof metamorphosis. The ef-
(1922), Etkin (1935a), Brink(1936), and Aleschin fect was reversibleupon cessationof treatment
(1936). Whetherthis effectof thyroidhormone and could be counteractedby simultaneoustreat-
and iodineupon the activityof the thyroidgland mentwiththyroxin(1 part in 5 million).Hughes
is to be explainedsolelyon the basis of a lowering and Astwood(1944) demonstratedthe inhibiting
of the output of thyrotrophic hormoneby the effectof thiouracilupon the metamorphosisof
pituitaryor whethersome directeffectof these Rana clamitansand showed that simultaneous
substancesupon the thyroidgland itselfis also injectionofthyrotrophic hormonedid not neutral-
involvedis stillopen to question.The matterhas ize theeffect. This resultindicatesthat in amphib-
been studiedin highervertebrates by variousbio- ians, as in mammals,the directeffectof the drug
chemicaltechniques,and the resultshave been is upon the thyroidratherthanthroughthe inter-
criticallyreviewedby Astwood(1949). mediationofthepituitary.Thioureaand thiouracil
There is, however,a large group of substances have also been shownto inhibitmetamorphosis in
which apparentlydo have a direct effectupon Rana sylvatica(Lynn and DeMarie, 1946), Rana
thyroidfunction.The most active of these are temporaria(Koch, 1948), Xenopuslaevis (Gasche,
compoundshaving a thiocarbonamide grouping, 1946; Gascheand Druey, 1946; Harms,1949),and
such as thiourea;but similareffectsare also ob- Discoglossuspictus(Bruce and Parkes, 1947; Del-
tained with various amino-benzenecompounds sol, 1948). Thioureaand phenylthiourea also cause
likethesulfonamides. Extensiveworkon mammals the retentionof larval featuresin the non-aquatic
has not yet fullyelucidatedthe precise mode of embryosof the urodelePlethodoncinereus(Lynn,
actionof theseantithyroid agents,but all of them 1947) and the anuran Eleutherodactylus ricordii
apparentlyinterfere in someway withtheproduc- (Lynn,1948).
tion or release of normalthyroidsecretion.It is Various otherthioureaderivativesand sulfon-
probablethatsomeofthecompoundsact primarily amideswhichhave been foundeffective in inhibit-
by inhibiting the uptake of iodineby the thyroid, ing amphibianmetamorphosis are: thioacetamide,
whereasothersinterfere with some phase of the n-allylthiourea,n-benzylthiourea(Gasche and
enzymaticsynthesisofthyroidhormone.Evidence Druey,1946),aminothiazol(Roth,1947a),methyl-
on thesepointswillbe foundin the recentreviews thiouracil (Blakstad, 1949), and sulfanilamide
of Charipperand Gordon(1947), Trotter(1949), (Thomas, 1947). The effectsof these drugsupon
Astwood(1949), and McGinty (1949). Whatever the histologyof the thyroidin amphibianlarvae
theexactmechanisminvolved,thereducedoutput are quite similarto thoseproducedin mammals.
ofthyroidhormonecausedbyadministration ofthe Gordon,Goldsmith, and Charipper(1945) recorded
antithyroid agentssoon acts as a stimuluswhich hypertrophy, hyperemia,heightenedepithelium,
causes increasedproductionof thyrotrophic hor- and decreasedcolloid volume in the thyroidsof

THE THYROID IN COLD-BLOODED VERTEBRA TES 153
tadpolestreatedfor2 to 6 weeks.Treatmentover Adultnewts(Triturusviridescens) keptin rather

a periodof4 monthsresulted,however,in a regres- strongsolutionsof thioureaforup to 86 days are
sion in thyroidsize and activity.Gasche (1946) reportedto show only slighthyperplasia(Adams,
reportedthat the follicularepitheliumof the 1946b). Furtherstudymightrevealmorestriking
thyroidshows changeswithin24 hoursafterthe resultsat earlierstagesin the treatment, however,
beginningof thioureaadministration in Xenopus for it seems possible that animals treatedfor so
larvae and that chromophobecolloid is entirely longa periodmay be undergoing a thyroidregres-
lost fromthe folliclesin 8 to 10 days. He also sion like that foundin the frog.
notedchangesin thebasophilcellsofthepituitary Still anothertreatmentwhichhas been shown
similarto thosewhichfollowthyroidectomy. Ad- to inhibitthyroidactivityis the administration of
ministration of thioureaand thiouracilto hypo- thiocyanateion. The evidenceat presentavailable
physectomizedanimals did not result in hyper- indicates that in mammals thiocyanate,unlike
plasia of the thyroid,a furtherevidencethat the the otherantithyroid agentswhichhave been dis-
goitrogenic effect to increasedthyro- cussed,acts mainlyby preventingthe uptake of
is attributable
trophicoutput by the pituitary.The effectsof iodineby thethyroid.Littleis knownoftheeffects
methylthiouracil upon the thyroidsof Rana tern- of thiocyanatetreatmentin cold-bloodedverte-
poraria larvae (Blakstad, 1949) and of phenyl- brates.Gascheand Druey (1946) foundthatmeta-
thioureaupon the glandsof Eleutherodactylus em- morphosisof Xenopuslarvae can be inhibitedby
bryos(Lynn, 1948) agree withthosecited above. raising the animals in solutions of ammonium
RecentlyJoel,D'Angelo, and Charipper(1949) thiocyanateor potassiumthiocyanate.Bradley's
have made a detailedstudyof the effectsof thio- (1950) experiments showthatthethyroidsofadult
urea administration upon thyroidhistologyin the frogsgiven a singleinjectionof 1 ml. of a .2 per
adultfrogduringthewinter.The glandis normally cent solutionof potassiumthiocyanateexhibitan
in a state of low secretoryactivityat this time, almost immediateimpairmentof theirabilityto
with colloid storagepredominantand with little take up radioactiveiodine. This effectis quite
evidenceof hormonerelease.Thiourea treatment short-lived, however,and the thyroidreturnsto
was found,however,to produce markedhyper- complete functionalefficiencywithin 24 hours
trophicand hyperplastic changes.One mustthere- unless thiocyanatetreatmentis continuedat fre-
fore conclude that some hormonerelease does quentintervals.
occurin the winterthyroidand that interference Although,as previouslynoted,mostofthework
with this activityresultsin increasedproduction dealing with thyroid-inhibitors in cold-blooded
of thyrotrophic hormoneby the pituitary.These formshas concernedamphibians,thereis sufficient
authorshavepointedout,however,thatamphibian informationavailable for fishesand reptiles to
thyroidsrespondless markedlyto goitrogens than givepromisethatgoitrogens willalso serveas use-
do thoseof highervertebrates, the changesin the ful tools in elucidatingproblemsof thyroidfunc-
glands being less markedboth qualitativelyand tionin theseforms.Amongreptilesseveralspecies
quantitatively thanthosewhichoccurin the chick ofpond turtlesand one speciesoflizardhave been
or mammal,followingapproximatelyequivalent subjectedto thioureatreatment. The turtlethyroid
treatment. In the adult frog,as in the larva,long- (Adams and Craig,1950) respondswiththe usual
continuedtreatmenteventuallyresultsin regres- histologicalsignsof hyperactivity, but appears to
sion of the thyroid.The gland may be reactivated be much less reactivethan that of the mammal.
by administration of thyrotrophic hormone,and In the lizard,Anolis carolinensis, thyroidhyper-
it is thereforesuggestedthat the regression results plasia and follicularcollapseare readilyproduced
fromexhaustionor impairment ofthethyrotrophic by thioureaor thiouraciladministration (Adams
mechanism. and Craig, 1949) and Ratzersdorfer, Gordon,and
By use ofradioactiveiodine,Bradley(1950) has Charipper(1949) have shownthatthehyperplastic
been able to showthat a singleinjectionof .5 ml. reactioncan be inhibitedby simultaneous adminis-
of a 10 per cent solutionof thioureain the adult trationof thyroxin. The latterauthorsalso found
frog results in an impairmentof the thyroid's that thioureatreatmentresultsin an increasein
ability to concentrateiodine, which persistsfor the durationofmoltingin the lizard,althoughthe
about 72 hours. Sulfanilamidetreatmentgives intervalbetweenmoltswas not affected.
similarthoughless strikingresults. Goldsmith,Nigrelli, Gordon, Charipper,and

Gordon (1944) foundthat thioureacaused inhibi- follicle,whichconsistsof a single-layered epithe-

tion of growthand a failureof developmentof lium surrounding a centrallumen that contains
secondarysex charactersin a hybridstrain of the thyroidsecretion.The heightof the follicular
fishesinvolvingPlatypoecilusmaculatusand Xi- epithelium,the staining reaction of the intra-
phophorushellerii. The thyroid gland showed follicularand intracellularcolloid,and the degree
changessimilarto those recordedfor other ver- of "vacuolization"of the cells and colloid mass
tebrates.Similarresultswere obtainedwith two furnishcriteriaforjudgingthe intensityof secre-
other aquarium fishes,Aegindenslatifronsand toryactivityin thegland.Despite extensivestudy
Trichogaster trichopterus, by Frieders(1949); and on amphibians,the precisemechanismof release
Sullivan (1950) found that immersionof adult of the thyroidsecretionfromthe follicleinto the
swordtailsfor a period of 47 days in either.05 blood streamis not yet completelyunderstood.It
per cent or .005 per cent solutionsof phenylthio- seemsclear,however,thatthestoredcolloidpasses
urea or allylthiourearesultedin very extensive throughthe epithelialcells ratherthan between
thyroidhyperplasia,the glandulartissueinvading them, and that the release is controlledby a
the wholelowerjaw regionand even the bases of thyroid-activating principlesecretedby the an-
the gills. This invasion of surroundingtissue is teriorlobe of the pituitarygland.
probablydue to the fact that the thyroidin this The best-known functionofthethyroidhormone
form,as in mostbonyfishes,lacks a definitecap- in cold-bloodedvertebratesis in the controlof
sule. Thiouracil treatmentresults in decreased amphibianmetamorphosis. This functionis dra-
growthrate in youngLebistesand also delays the maticallydemonstrated by theresultsofthyroidec-
maturationof the gonopodium(Hopper, 1950). tomyin tadpoles,forsuchanimalscompletelyfail
The effectsof thioureatreatmentin fish,as in to transform into adult frogsunless thyroidhor-
otherforms,can be neutralizedby simultaneous moneis administered to them.Iodine and various
administration of thyroidmaterial(Nigrelli,Gold- iodine compoundscan replace the thyroidsecre-
smith,and Charipper,1946). tion in promotingamphibianmetamorphosis, but
It is clear that antithyroid agentsare effective this is probablydue to the fact that the typical
in cold-bloodedvertebratesand offera, tool by thyroidhormonecan be producedby combination
which "chemicalthyroidectomy" may be readily of iodinewiththe tyrosineavailable in the body,
carriedout. Much more remainsto be done in even in tissuesotherthan the thyroiditself.
ascertaining themosteffective compoundsand the The thyroidgland showsa definitesequenceof
optimaldosages to be used, as well as the precise histologicalchangescorrelatedwiththe stages of
mechanismof action of the various substances normalmetamorphosis, and thesehave been quite
beforethis tool can be fully exploited.It has, fullydescribedfora numberof amphibians.De-
however,alreadyproved usefulin studies of the tailedanalysisofthevariousbodilychangeswhich
roleofthethyroidin theembryology ofamphibians occur duringmetamorphosis and of the ways in
havingdirectdevelopment(Lynn, 1947, 1948), in which these are influencedby thyroidectomy or
investigationsof the relationof the thyroidto thyroidadministrationreveals that, while most
regeneration(Ghidoni, 1948) and metabolism of these featuresare directlydependent upon
(Matthewsand Smith,1947), and in an attempt thyroidstimulus,others,like the perforationof
to elucidate the possible homologyof the endo- the operculum,are indirectlyinfluencedby the
style of the ammocoeteslarva with the thyroid thyroid,sometimesthrougha quite complexchain
gland (Jones,1947). of interrelationships.
The sequenceand spacingof
the metamorphic changeshave been satisfactorily
XI. SUMMARY
elucidatedby the admirablestudiesof Etkin. He
The thyroidgland originatesfromcertaincells has demonstratedthat the normal sequence of
of the larval endostylein cyclostomesand from eventsis inherentin the tissues,whilethe spacing
the embryonic pharyngealfloorin all otherverte- is broughtabout by a graduallyincreasing level of
brates.It is commonlymade up of diffusely scat- thyroidhormonein theblood,therateofresponse
teredfolliclesin teleostfishes,but in most verte- in thetissuesdependingdirectlyuponthehormone
bratesit is encapsulatedand may take theformof concentration.
a singlebody (reptiles)or two more or less com- Many of the events of metamorphosis involve
pletely separated lobes (amphibians). Histologi- rapid growthand differentiation, but others,such
cally, the unit of structureof the gland is the as atrophyof tail and gills,are of a degenerative

nature.Attemptsto explain these diverseeffects or thyroidadministration uponoxygenmetabolism

of the thyroidhormoneon the basis of any single in cold-bloodedvertebrates have, in general,given
physiologicalactionhave been notablyunsuccess- negative results.However, the investigationsof
ful,and it seems quite clear that the explanation Smithand Matthewson fishesand of Taylor on
lies simplyin the fact that different tissueshave amphibiansindicatethat heretoo a species-speci-
differentand characteristic ways of respondingto ficityof the thyroidmay be important.Experi-
the thyroidstimulus.In somecases thesediffering mentstestingthe effects ofadministration to cold-
modesof responsehave been shownto be "deter- bloodedformsofthyroidmaterialfromthesameor
mined"in the tissuesat quite earlystages. closelyrelatedspeciesmust be carriedout before
The secretoryactivityofthethyroidis controlled any definiteconclusionsconcerning the roleof the
bya thyrotrophic hormonesecretedby theanterior thyroidin metabolismin these animals can be
lobe of the pituitary.In cold-bloodedvertebrates justified.
this has been most clearlydemonstratedin rela- The possible influenceof the thyroidsecretion
tionto amphibianmetamorphosis. It appearsthat, upon regenerative abilityis anotherproblemwhich
in theseforms, it is thebasophilcellsoftheanterior requires clarification.The present indicationis
lobe whichare responsiblefor thyrotrophic hor- that theloss ofregenerative capacitywhichoccurs
moneproduction. at metamorphosis in amphibiansis to be regarded
Neotenousamphibianslike the axolotl offera as an accompanimentof the morphogenetic
special problemin relationto the thyroid'srole changesproducedin thetissuesundertheinfluence
in metamorphosis. Their failureto metamorphose of the thyroidhormone,rather than a direct
in naturehas been variouslyascribedto deficiency effectof the hormoneupon regenerative processes.
in the animal's thyroidsecretion,exceptionaltis- There are certain experiments,however,which
sue insensitivity to the thyroidinfluence,or im- seem to showthat some directinfluence may play
pairment of the thyrotrophicfunctionof the a partand further studyofthismatter,particularly
pituitary.Recent experiments, particularlythose underconditionsof thyroidinhibition,should be
of Blount,indicatethat the latterexplanationis carriedout.
probablythe correctone. In the study of thyroidfunction,as in other
Early attempts to induce metamorphosisin fieldsof physiology,the reptilesremainthe most
perennibranchiate amphibianswere unsuccessful, neglectedgroup.This is a particularlysignificant
but the workof Reis and otherson the metamor- gap in our knowledgein view of the intermediate
phosis of skin graftsfromtheseformssuggestsa positionof the reptilesin the vertebratescale as
numberofotherprocedureswhichshouldbe under- beingthe onlypoikilothermous amniotesand the
taken.Heteroplastictransplantation of gills,eyes, groupfromwhichboth birdsand mammalsstem.
and otherorgansbetweenyoungperennibranchi- One of the chieffactorshamperingthe study of
ates and the larvae of othersalamanderswould thyroidfunctionin both reptilesand fisheshas
be ofinterest.It is possible,also, thattransplanta- been the difficulty in performing thyroidectomy
tionat earlyembryonic stagesmightthrowfurther in theseanimals.In fishesthisis due to theusually
lighton the originof tissueinsensitivity in these diffusenature of the gland. In reptilesthe rela-
animals. tivelylow survivalrate afteroperationhas dis-
Whether the thyroidplays any part in the couraged experimentation. The recent develop-
metamorphosis of cyclostomesor of those fishes mentofthyroid-inhibiting drugsbymeansofwhich
in whicha metamorphic processoccurs,is doubtful. effective"chemical thyroidectomy" can be car-
More experiments likethoseofRobertson,in which ried out opens new opportunities for researchin
thyroidextractwas administered to larval fishes, thisfield.A good beginning has alreadybeenmade
are needed. Moreover,in view of the possibility on such studies,and the rapid expansionof our
of some specificity in the thyroidhormone,such knowledgeof thyroidfunctionin cold-blooded
experiments would be moredecisiveif extractsof formsmay be expectedfromthe further extension
fishthyroidratherthanmammalianthyroidcould oftheseinvestigations. Anotherrecentlydeveloped
be used. technique,theuse ofradioactiveiodine,has yielded
The mostfamiliareffectof thyroidadministra- importantinformationconcerningthe synthesis
tion in mammalsis an increasedmetabolicrate, and release of the thyroidhormonein mammals,
as evidencedby a risein oxygenconsumption, but and it promisesto be equallyproductivein similar
studiesdealingwiththe effectsof thyroidectomy studiesin lowervertebrates.

156 THE QUARTERLY REVIEW OF BIOLGY
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The Thyroid Gland and Its Functions in Cold-Blooded Vertebrates

Author(s): W. Gardner Lynn and Henry E. Wachowski

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THE QUARTERLY REVIEW

THE THYROID GLAND AND ITS FUNCTIONS IN

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of diffuselyscatteredfollicleslying in the gill considerablefrequency. The thyroidgland ofNec-

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This content downloaded from 185.2.32.49 on Wed, 18 Jun 2014 01:14:38 AM

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themas antecedentsof thevacuolesin the colloid. stainsbasophilically, theintracellularcolloiddrop-

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transport.The same patternof follicularcollapse The histologyofthecyclostome thyroidhas been

initialrelease,and remainshigh duringmaximal AMPHIBIAN METAMORPHOSIS

activation. The role of the thyroidgland in amphibian

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natsch,1929;Allen, 1929,1938; Bounhiol, 1942). own thyroid.Proof of this hypothesiswas soon

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able tq hasten metamorphosis althoughthe con- administration ofinorganiciodineor simpleiodine

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and his coworkers(Uhlenhuth,1925a, b, 1927, well-developed limbs,and withcarnivorous habits.

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appears in the operculumto permitemergenceof tookan extensiveseriesof experiments withRana

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and propermanipulationof the treatmentcan re- Schreiber'sinterpretation, all eventsare initiated

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explanationbothforthenormalmetamorphic pat- to live at a low rate of metabolism,while adult

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while causingretrogressive changesin others.It the originalactivityof the thyroidgland. Ales-

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roxin,but Kosminand Resnitschenko (1927) were are certainfood substances,however,which do

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tary at this time show markedstimulation,and when administeredin combinationwith thyroxin

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peculiarities.Schulze (1921), however,was not wayto theinfluence ofmetamorphosing substances

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metamorphicchangesby treatmentwith thyroid VI. THE THYROID AND METAMORPHOSIS IN

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stimulatingrather than an inhibitinginfluence morphosisin amphibians,and some have attrib-

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ipper (1949) demonstratethat the thyroidof the hormonehas no influenceupon regenerationin

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Spei4el (1929) concerningthe effectsof thyroid stillbe initiatedthroughcertainspecialtreatments.

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X. THYROID ANTAGONIZERS AND INBIBITORS testosteronepropionateeither fail to metamor-

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thyroid-antagonizing effectshave been claimedis moneby thepituitary.The highlevel ofthyrotro-

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tadpolestreatedfor2 to 6 weeks.Treatmentover Adultnewts(Triturusviridescens) keptin rather

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Gordon (1944) foundthat thioureacaused inhibi- follicle,whichconsistsof a single-layered epithe-

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nature.Attemptsto explain these diverseeffects or thyroidadministration uponoxygenmetabolism

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