THYROID

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ealth.com%2FSymptom-Checker%3C%2Fspan%3E%3C%2Fa%3E%3Cdiv+class%3D%22AdSep%22+style%3D%22margin-top%3A+0.5em%3B%22%3E%0D%0A%3C%2Fdiv%3E%0D%0A%3Ca+href%3D%22http%3A%2F%2Fgoogleads.g.doubleclick.net%2Faclk%3Fsa%3Dl%26amp%3Bai%3DB1XBnCX8STLjVN83xnAeHz_ixB5aLyhnwp8XiCsCNtwGA8QQQAxgDIOfw9QEoFDgAUIf0oGBgtwSyARZ3d3cudGhlZnJlZWxpYnJhcnkuY29tyAEB2gFWaHR0cDovL3d3dy50aGVmcmVlbGlicmFyeS5jb20vSEdIKy0rdGhlK1RoeXJvaWQrR2xhbmQrYW5kK1RoeXJvaWQrSG9ybW9uZS1hMDEwNzM5ODg4OTGAAgGoAwHoA7gD6AOjA-gD_QHoA4YF9QMAAADE%26amp%3Bnum%3D3%26amp%3Bsig%3DAGiWqtxQac_yfW3BUmx1qyY_wG6ONJQVfg%26amp%3Bclient%3Dca-pub-2694630391511205%26amp%3Badurl%3Dhttp%3A%2F%2Fwww.resonanceschoolofhomeopathy.com%2F%253Fnav%253Donlinelearning%22+style%3D%22color%3A+%23064c82%3B+text-decoration%3A+none%3B%22%3E%3Cspan+class%3D%22OvTitle%22+style%3D%22text-decoration%3A+underline%3B%22%3EHomeopathy+Training%3C%2Fspan%3E%0D%0A%3Cspan+class%3D%22OvDescr%22+style%3D%22color%3A+black%3B%22%3ELearn+w%2F+Live+%26amp%3B+Online+Video+Cases+Start+Your+Distance+Learning+Now+%21%3C%2Fspan%3E%0D%0A%3Cspan+class%3D%22OvURL%22+style%3D%22font-size%3A+0.8em%3B%22%3EResonanceSchoolofHomeopathy.com%3C%2Fspan%3E%3C%2Fa%3E%3C%2Fdiv%3E%0D%0A%0D%0A%3Ca+href%3D%22http%3A%2F%2Fwww.thefreelibrary.com%2FHGH%2B-%2Bthe%2BThyroid%2BGland%2Band%2BThyroid%2BHormone-a01073988891%22+style%3D%22color%3A+%23064c82%3B%22%3ELink+to+this+page%3C%2Fa%3E%0D%0A%3Ci%3EThe+thyroid+gland+is+a+butterfly+shaped+gland+that+is+located+over+the+trachea+%28wind+pipe%29+just+below+the+larynx+%28voice+box%29.+The+thyroid+gland+plays+a+very+important+role+in+most+all+the+metabolic+processes+of+the+body.+The+thyroid+gland+with+its+thyroid+hormone+is+responsible+for+regulating+metabolism.%3C%2Fi%3E%0D%0AThe+thyroid+gland+is+a+butterfly+shaped+gland+that+is+located+over+the+trachea+%28wind+pipe%29+just+below+the+larynx+%28voice+box%29.+The+thyroid+gland+plays+a+very+important+role+in+most+all+the+metabolic+processes+of+the+body.+The+thyroid+gland+with+its+thyroid+hormone+is+responsible+for+regulating+metabolism.%0D%0A%0D%0AHow+Thyroid+Hormone+is+Made%0D%0A%0D%0AThe+hypothalamus%2C+often+referred+to+as+the+body%27s+%22thermostat%22+is+responsible+for+making+sure+the+thyroid+blood+levels+are+normal.+When+the+hypothalamus+notices+the+thyroid+blood+levels+decreasing+it+releases+TRH+%28thyroid+releasing+hormone%29.+The+TRH+then+signals+the+pituitary+gland+to+release+TSH+%28thyroid+stimulating+hormone%29.+TSH+stimulates+the+thyroid+gland+to+begin+producing+thyroid+hormone.%0D%0A%0D%0AWhen+the+body%27s+levels+of+thyroid+hormone+become+normal+and+the+body+is+functioning+normally+the+pituitary+gland+will+cease+its+release+of+TSH+and+the+process+stops+until+the+hypothalamus+notices+the+thyroid+hormone+levels+decreasing+again.%0D%0A%0D%0AHypothyroidism%0D%0A%0D%0AHypothyroidism+is+caused+by+insufficient+production+or+absorption+of+thyroid+hormone+that+causes+abnormally+low+blood+thyroid+hormone+levels.+This+problem+with+the+thyroid+gland+is+usually+brought+about+as+a+result+of+iodine+insufficiency%2C+a+tumor%2C+a+damaged+thyroid+gland%2C+or+vitamin+deficiencies.+This+type+of+hypothyroidism+is+called+%22primary+hypothyroidism%22.%0D%0AHypothyroidism+can+also+be+a+result+of+the+pituitary+gland+and%2For+hypothalamus+failing+to+function+properly.+This+type+of+hypothyroidism+is+called+%22secondary+hypothyroidism%22.%0D%0A%0D%0ALow+thyroid+hormone+levels+may+not+only+make+you+feel+old%2C+they+can+propel+you+into+the+conditions+and+diseases+associated+with+aging.+Low+levels+of+T4+can+be+responsible+for+weight+gain%2C+since+T4+plays+a+role+in+controlling+the+body%27s+metabolism.+The+changes+that+are+brought+about+as+a+result+of+the+aging+process+such+as+changes+in+the+fat+to+muscle+ratio+and+the+shrinkage+of+organs+can+also+be+caused+by+a+lack+of+thyroid+hormone.+A+decrease+in+the+amount+of+lean+body+mass+can+in+turn+interfere+with+the+activity+of+an+enzyme+that+converts+thyroxine+%28T4%29+into+triodothyronine+%28T3%29.+T3+is+about+5+times+more+potent+than+T4.%0D%0A%0D%0AAdequate+levels+of+thyroid+hormone+are+needed+to+regulate+blood+sugar%2C+so+a+deficiency+of+thyroid+hormone+can+lead+to+mature-onset+diabetes.+Low+levels+of+thyroid+hormone+can+also+greatly+increase+the+risk+of+cardiovascular+disease+due+to+an+increase+in+the+levels+of+cholesterol+and+triglycerides+and+may+cause+high+blood+pressure.+Also%2C+iodine+is+essential+to+the+proper+functioning+of+the+thyroid+gland%2C+several+studies+that+have+been+done+have+shown+a+correlation+between+low+iodine+levels+and+an+increased+risk+of+cancer.%0D%0A%0D%0A%0D%0ASymptoms+of+Hypothyroidism%0D%0A%0D%0Aweakness%2C+fatigue%2C+and+lack+of+energy%0D%0Adry%2C+flaky%2C+pale+skin%0D%0Adry%2C+coarse%2C+dull+hair%2C+loss+of+hair%0D%0Alack+of+appetite%0D%0Aweight+gain%0D%0Athinning+of+eye+brows%0D%0Asensitivity+to+cold%0D%0Abrittle+nails%0D%0Acold+hands+and+feet%0D%0Aconstipation%0D%0Alow+body+temperature%0D%0A%0D%0AThe+general+opinion+of+many+in+the+medical+community+has+been+that+the+drop+that+occurs+in+hormone+levels+is+a+normal+part+of+the+aging+process+and+replacement+is+not+necessary.%0D%0AAlthough+some+of+their+aging+patients+are+having+clear+symptoms+of+insufficient+thyroid+hormone+levels%2C+some+physicians+refuse+to+place+these+ailing+patients+on+thyroid+medication+because+they+consider+their+ailing+condition+a+normal+part+of+the+aging+process.+These+physician%27s+poor+patients+are+missing+out+on+thyroid+replacement+therapy+that+should+alleviate+or+improve+most%2C+if+not+all+their+symptoms.+Thankfully+this+negative+opinion+is+slowly+changing.%0D%0A%0D%0AIn+the+older+population+hypothyroidism+is+one+of+the+most+overlooked+conditions.%0D%0A%0D%0ASelf-Detection+of+Hypothyroidism%0D%0A%0D%0AA+test+called+the+Barnes+Basal+Temperature+test+can+show+you+if+your+thyroid+hormone+level+may+be+low.%0D%0A%0D%0APlace+a+thermometer+next+to+your+bed+before+going+to+sleep.+Be+sure+to+shake+the+thermometer+down+if+it+is+a+mercury+thermometer.%0D%0AAs+soon+as+you+awake%2C+place+the+thermometer+under+your+arm%2C+lie+quietly+and+leave+the+thermometer+under+your+arm+for+about+10+minutes.+Be+sure+to+check+your+temperature+before+you+move+around+much+bec2Fh3%3E%0D%0AThe+primary+event+in+the+phylogeny+of+the+thyroid+was+the+development+in+living+forms+of+the+capability+of+collecting+iodide+ion+and+binding+it+to+protein.+These+activities+have+been+observed+widely+among+plants+and+in+the+invertebrate+members+of+the+animal+kingdom.+Brown+algal+kelps+are+the+most+efficient+accumulators+of+iodide+identified+with+enrichment+factors+for+iodine+of+up+to+10%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E6%3C%2Fsup%3E%26nbsp%3B%281%29.+In%26nbsp%3B%3Ci%3ELaminaria+digitata%3C%2Fi%3E%2C+for+example%2C+the+iodine+content+can+reach+up+to+5%25+of+the+dry+weight.+However%2C+only+a+minor+fraction+of+iodine+is+stored+in+the+form+of+iodinated+amino+acid+residues+including+monoiodotyrosine+%28MIT%29+and+diiodotyrosine+%281%29+%282%29+%283%29.+The+biochemical+pathways+involved+in+iodine+uptake%2C+accumulation+and+metabolism+in+these+algae+have+still+not+been+fully+elucidated.+Recent+studies+suggest+that+iodide+is+oxidized+by+a+vanadium-dependent+iodoperoxidase+%284%29+yielding+more+lipophilic+iodine+species+which+diffuse+across+cell+membranes+and+are+subsequently+sequestered+as+labile+iodine+species+in+the+apoplastic+compartment+%281%29.+Thus%2C+the+iodide+uptake+mechanism+utilized+by+these+algae+appears+very+different+from+that+of+vertebrate+thyroid+follicular+cells+and+the+organification+of+iodine+is+still+considered+a+by-product+of+the+reactive+environment.%0D%0AIn+invertebrates%2C+endogenous+synthesis+of+iodothyronines+including+thyroxine+%28T4%29+and+triiodothyronine+%28T3%29+has+been+clearly+demonstrated+for+urochordates+and+cephalochordates+%285%29%2C+whereas+evidence+for+endogenous+iodothyronine+synthesis+outside+the+chordates+is+very+limited+%286%3B7%29+%288%29+%289%29.+Nevertheless%2C+invertebrates+deserve+attention+when+analyzing+the+evolution+of+the+hormonal+signalling+function+of+iodothyronines.+Already+in+1896%2C+Drechsel+%2810%29+recognized+that+sponges+and+corals+contain+large+quantities+of+iodine+as+iodotyrosines.+Iodohistidine+and+bromotyrosine+have+also+been+detected.+Monoiodotyrosine+%28MIT%29+and+diiodotyrosine+%28DIT%29+have+been+found+in+starfish%2C+mollusks%2C+annelids%2C+crustaceae%2C+and+insects+%289%29+%2811%29+%2812%29+In+insects%2C+several+organs+and+tissues+can+concentrate+radioiodide+but+there+is+no+evidence+that+this+results+in+TH+%28TH%29+formation+%2811%29.+One+process+that+is+likely+to+yield+iodinated+compounds+is+cuticle+formation%289%29.+It+has+been+suggested+that+iodinated+substances+may+be+by-products+of+the+process+of+%22quinone+tanning%22.+The+formation+of+benzoquinone+cross-linkages+in+the+molecular+structure+of+scleroproteins+is+probably+responsible+for+hardening+of+the+cuticle%2C+and+it+is+known+that%2C+in+the+presence+of+inorganic+iodide%2C+benzoquinones+can+bring+about+the+iodination+of+proteins+in+vitro%2813%29.+Thus%2C+the+iodination+of+tyrosine+may+be+mediated+quite+accidentally+by+quinones+that+are+involved+in+the+general+tanning+reaction+of+the+exoskeleton.+However%2C+recent+studies+by+Heyland+et+al.+%286%29+%287%29+suggest+that+at+least+some+echinoderms+and+molluscs+might+produce+T4+and+T3+which+was+detected+by+thin+layer+chromatography+and+confirmed+by+ELISA+measurements.+Interestingly%2C+iodothyronine+synthesis+in+these+organisms+was+prevented+by+thiourea+but+not+by+perchlorate+treatment.%0D%0AEven+though+most+invertebrates+might+not+be+able+to+endogenously+synthesize+TH%2C+a+wealth+of+data+indicate+that+organic+iodine+species+are+taken+up+from+the+environment+%28e.g.%2C+via+the+food%29+and+function+as+signalling+molecules+with+pleiotropic+effects+on+various+aspects+of+invertebrate+physiology+%289%29.+In+analogy+to+vitamins%2C+Eales+coined+the+term+%E2%80%9C+vitamones%E2%80%9D+to+describe+this+ancient+function+of+iodinated+compounds+as+external+morphogenic+signals+governing+larval+development+in+some+invertebrates.+This+provocative+model+has+been+supported+by+experimental+studies+%288%3B11%3B12%29.+Recently%2C+putative+orthologs+of+vertebrate+TH+receptors+%28TRs%29+have+been+identified+in+various+invertebrates+%2814%3B15%29+%2816%29.+Functional+characterizations+are+still+sparse+for+these+proteins.+On+the+other+hand%2C+in+the+case+of+the+urochordate+TR%2C+binding+studies+failed+to+demonstrate+T3+binding+to+the+receptor+%2816%29.+However%2C+T4+and+T3+might+not+necessarily+represent+the+biologically+active+iodothyronines+in+invertebrates.+For+example%2C+experimental+data+in+insects+suggest+that+iodothyronines+such+as+T2+may+be+more+potent+signalling+molecules+than+T4+or+T3+to+induce+specific+responses+%288%3B11%29.%0D%0AGorbman%2817%29+has+hypothesized+that+during+evolution%2C+organisms+became+accustomed+to+a+supply+of+iodotyrosines+and+iodothyronines+derived+from+external+sources%2C+and+eventually+developed+a+requirement+for+the+iodinated+amino+acids.+The+first+evidence+of+an+organ+capable+of+providing+iodothyronines+and+thus%2C+related+to+the+vertebrate+thyroid%2C+is+found+in+the+protochordates%2C+comprising+the+subphyla+Urochordata+%28ascidians%29%2C+and+Cephalochordata+%28amphioxus%29+%28Fig.+1-1%29.+In+the+origin+and+evolution+of+the+thyroid+gland%2C+the+protochordates+occupy+key+positions+in+phylogeny%2C+because+ascidians+are+the+most+basal+in+the+phylum+Chordata+and+amphioxus+are+the+closest+living+relatives+of+vertebrates+%285%29.+In+ascidians+and+amphioxus%2C+an+organ+known+as+the+endostyle+lies+on+the+floor+of+the+pharynx+and+connects+with+the+pharynx+by+a+duct.+Notably%2C+an+endostyle+is+still+present+in+the+basalmost+vertebrates%2C+the+lamprey+larvae+%28ammocoete%29.%0D%0AFrom+the+present+point+of+view%2C+the+significant+evolutionary+event+was+the+development+of+iodination+centers+within+the+endostyle.+The+differentiated+endostyles+in+protochordates+and+lamprey+larvae+are+histologically+divided+in+%E2%80%9Czones%E2%80%9D+containing+different+cell+types+%2818%29.+In+the+ascidian%26nbsp%3B%3Ci%3ECiona+intestinalis%3C%2Fi%3E%2C+these+iodination+centers+are+present+in+zones+7%2C+8+and+9+at+the+tip+of+the+endostyle+%2819%29.+The+amphioxus+endostyle+contains+seven+zones+and+iodide+organification+has+been+observed+in+zones+5a%2C+5b%2C+and+6+which+are+also+located+at+the+tip+of+the+endostyle+%2820%29.+In+amphioxus%2C+Barrington+%2821%29+has+shown+that+an+iodinated+glycoprotein+is+formed+in+these+iodination+centers%2C+probably+on+the+surface+of+the+cell.+The+endostyle+secretes+a+mucus+that+passes+down+the+duct+into+the+pharynx+and+thence+is+moved+along+into+the+alimentary+canal%2C+presumably+carrying+iodinated+protein+along+with+it.+Although+early+accounts+were+sometimes+conflicting+%2822%29%2C+accumulation+of+radioiodide%2C+peroxidase+activity+as+well+as+endogenous+synthesis+of+T4+and+T3+has+been+demonstrated+in+the+endostyle+of+several+protochordate+species+%2823-25%29+%2820%3B26%29.%0D%0AIn+the+ascidian%26nbsp%3B%3Ci%3ECiona+intestinales%3C%2Fi%3E%2C+the+proposed+organ+homology+between+the+endostyle+and+the+vertebrate+thyroid+was+strengthened+in+recent+molecular+studies.+For%26nbsp%3B%3Ci%3ECiona%3C%2Fi%3E%26nbsp%3Borthologs+of+vertebrate+thyroid-specific+marker+genes%2C+including+the+transcription+factors+Pax2%2F5%2F8%2C+TTF%26nbsp%3B1+and+TTF%26nbsp%3B2%2C+expression+was+demonstrated+in+several+zones+of+the+endostyle+in+adult%26nbsp%3B%3Ci%3ECiona%3C%2Fi%3E%2818%3B27%29.+In+addition%2C%26nbsp%3B%3Ci%3Ein+situ%3C%2Fi%3E%26nbsp%3Bhybridization+revealed+expression+of%26nbsp%3B%3Ci%3ECiona%3C%2Fi%3Eorthologs+of+TPO+and+Duox+in+the+iodide-concentrating+zone%26nbsp%3B7+of+the+endostyle+%2828%29.+An+interesting+observation+was+that+Pax2%2F5%2F8+and+TTF%26nbsp%3B2+expression+domains+overlapped+with+those+of+TPO+and+Duox+whereas+TTF%26nbsp%3B1+expression+was+not+detectable+in+zone%26nbsp%3B7.+In+amphioxus%2C+however%2C+all+three+transcription+factors%2C+Pax2%2F5%2F8%2C+TTF%26nbsp%3B1+and+TTF%26nbsp%3B2%2C+were+expressed+together+with+TPO+in+the+iodide-concentrating+zones+%2818%29.+The+recently+published+sequence+of+the%26nbsp%3B%3Ci%3ECiona+intestinales%3C%2Fi%3E%26nbsp%3Bgenome+provided+a+first+overview+of+the+repertoire+of+ascidian+genes+encoding+for+components+of+the+thyroid+system+%2829%29.+Orthologous+sequences+were+identified+encoding+for+a+NIS-like+iodide+transporter%2C+a+pair+of+closely+related+iodothyronine+deiodinases+and+a+TR.+The%26nbsp%3B%3Ci%3ECiona%3C%2Fi%3E%26nbsp%3Bgenome+apparently+does+not+contain+a+sequence+homologous+to+thyroglobulin+%28TG%29+suggesting+that+other+protein+substrates+are+used+by+ascidians+for+iodotyrosine+synthesis+%2830%29.+In+amphioxus%2C+a+TG-like+protein+has+been+described+by+Monaco+et+al.+%2831%29%2C+but+a+molecular+characterization+of+this+protein+is+not+yet+available.+Further%2C+no+clear+homologs+of+thyrotropin-releasing+hormone+%28TRH%29+or+the+two+subunits+of+thyroid-stimulating+hormone+%28TSH%29+have+been+detected+in+the%26nbsp%3B%3Ci%3ECiona%3C%2Fi%3E%26nbsp%3Bgenome%2C+which+is+in+accordance+with+the+current+view+that+ascidians+do+not+have+a+pituitary+gland%2832%29.+Based+on+a+comparison+of%26nbsp%3B%3Ci%3ECiona%3C%2Fi%3E%26nbsp%3Band+vertebrate+genomes%2C+Campbell+%2830%29+concluded+that+some+features+of+the+vertebrate+thyroid+system+appear+well+represented+in+urochordates+but+that+critical+genes+involved+in+the+neuroendocrine+control+of+thyroid+function+are+lacking.%0D%0A%3Ctable+align%3D%22center%22+border%3D%221%22%3E%3Ctbody%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cimg+align%3D%22BOTTOM%22+border%3D%221%22+height%3D%22425%22+name%3D%22graphics1%22+src%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Ffigures%2Ffigure1.jpg%22+width%3D%22650%22+%2F%3E%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3Ctr+bgcolor%3D%22%2399ccff%22+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cdiv+style%3D%22background-attachment%3A+initial%3B+background-clip%3A+initial%3B+background-color%3A+%2399ccff%3B+background-image%3A+initial%3B+background-origin%3A+initial%3B+background-position%3A+initial+initial%3B+background-repeat%3A+initial+initial%3B+text-indent%3A+0in%3B%22%3E%0D%0A%3Cstrong%3EFigure%26nbsp%3B1.%26nbsp%3B%3C%2Fstrong%3EPhylogeny+of+the+development+of+the+thyroid+gland.%3C%2Fdiv%3E%0D%0A%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3C%2Ftbody%3E%3C%2Ftable%3E%0D%0A%0D%0AThe+most+primitive+vertebrates+in+which+a+follicular+thyroid+gland+can+be+definitely+demonstrated+are+the+jawless+fishes+%28agnathans%29.+Concerning+the+origin+and+the+evolution+of+the+thyroid+gland%2C+lampreys+are+of+particular+interest+because+they+are+the+only+known+vertebrates+that+possess+a+larval+endostyle+that+directly+transforms+into+a+follicular+thyroid+during+metamorphosis+%2833%29+%2834%29.+Although+the+endostyle+of+the+lamprey+larvae+%28ammocoete%29+has+a+different+structure+and+organization+compared+to+the+endostyle+of+protochordates%2C+physiological+and+molecular+characteristics+are+very+similar.+The+lamprey+endostyle+shows+iodide+uptake+and+organification%2C+the+latter+involving+a+protein+that+is+apparently+related+to+TG+%2834%29+%2835%3B36%29+%2837%29.+The+TG-like+protein+undergoes+proteolytic+digestion+in+the+intestinal+tract+to+liberate+T4+and+T3+which+are+probably+taken+up+directly+from+the+gut+lumen+to+enter+blood+circulation+%2838%3B39%29.+Given+this+pathway+of+TH+synthesis+and+release%2C+it+is+of+particular+interest+that+high+5%E2%80%99-deiodinase+activities+were+determined+in+the+larval+intestine+%2840%29.+Comparative+analyses+of+thyroid-related+genes+confirmed+the+expression+of+Pax2%2F5%2F8+%2841%29+and+TTF%26nbsp%3B1+orthologs+%2833%29+%2827%29+in+the+lamprey+endostyle.+Interestingly%2C+similar+to+ascidians%2C+the+expression+domains+of+TTF%26nbsp%3B1+were+not+clearly+overlapping+with+domains+of+iodide+concentration%2C+Tg+synthesis+or+T4+synthesis+%2818%3B33%29.%0D%0AVery+high+plasma+concentrations+of+TH+have+been+determined+in+lamprey+larvae+%2842%29.+A+unique+feature+of+lamprey+developmental+endocrinology+is+a+dramatic+decrease+of+circulating+TH+levels+concomitantly+with+the+onset+of+metamorphosis.+This+developmental+TH+profile+is+in+sharp+contrast+to+metamorphosis+in+amphibians+and+various+fishes+where+high+TH+titers+are+associated+with+metamorphosis.+Moreover%2C+metamorphosis+in+lamprey+larvae+can+be+induced+by+anti-thyroidal+compounds+such+as+perchlorate+or+methimazole+suggesting+that+the+abrupt+decline+of+plasma+TH+levels+might+trigger+the+onset+of+metamorphosis+%2843%29.%0D%0ADuring+metamorphosis+of+the+ammocoete+into+the+adult+lamprey%2C+the+endostyle+loses+its+connection+with+the+pharynx+and+becomes+a+thyroid+composed+of+scattered+follicles+%2834%29+These+follicles+are+not+encapsulated%2C+but+they+have+the+typical+biosynthetic+functions+associated+with+hormone+formation+in+the+adult+vertebrates.+In+the+lamprey%2C+the+biosynthesis+of+Tg+in+larval+forms+has+the+same+characteristics+as+that+formed+in+thyroid+follicles+of+the+adult+form%2C+with+a+12S+as+the+precursor+of+the+18-19S+protein.+Total+I+in+Tg+is+very+low+%280.002%25%29+and+about+5%25+is+present+in+the+form+of+T3+and+T4+%2844%29.+Curiously%2C+the+thyroid+appears+to+play+no+role+in+the+metamorphosis+of+the+ammocoete%2C+although+the+gland+itself+undergoes+a+remarkable+change.%0D%0AThe+striking+relationship+of+the+thyroid+to+the+gastrointestinal+tract+is+apparent+in+all+phylogenetic+studies.+Dunn+%2845%29+has+actually+found+ciliated+thyroid+cells+in+the+mouse+and+shark%2C+a+reminder+of+the+origin+of+the+gland+from+endoderm.+In+mammals+the+gastric+mucosa+and+the+salivary+glands+retain+a+functional+relationship+to+the+thyroid+in+that+they+too+can+concentrate+iodide+%2846%29%2C+and+the+salivary+gland+contains+a+peroxidase.%0D%0AThus%2C+a+thyroid+capable+of+forming+iodotyrosines+and+iodothyronines+is+present+in+all+vertebrates.+Its+level+of+function+varies+widely+from+species+to+species+and+season+to+season.+With+the+exceptions+noted+below%2C+thyroid+activity+in+the+poikilotherms+is+very+low.+Seasonal+changes+in+thyroid+activity+have+been+found+in+both+warm-+and+cold-blooded+animals.+Certain+morphologic+changes+occur+after+the+biochemical+evolution+of+the+thyroid+has+ceased.+In+the+adult+lamprey+and+in+most+bony+fishes%2C+the+gland+is+not+encapsulated.+The+follicles+may+be+widely+scattered%2C+either+singly+or+in+small+clusters%2C+especially+along+the+course+of+the+ventral+aorta+and+in+the+kidneys+%2847%29.+In+cartilaginous+fish%2C+the+thyroid+is+encapsulated.+In+the+higher+vertebrate+forms%2C+the+thyroid+is+a+one-+or+two-lobed+encapsulated+structure.%0D%0A%0D%0A%3Ca+href%3D%22%22+name%3D%222%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AFunction+of+the+Thyroid+in+Lower+Forms%3C%2Fh3%3E%0D%0AA+functioning+thyroid+is+evident+in+forms+as+primitive+as+lampreys+and+hagfishes.+TH+are+critically+important+for+the+regulation+of+diverse+biological+processes+associated+with+development%2C+growth+and+metabolism+in+non-mammalian+vertebrates+%2848%29+%2849%3B50%29+%2850%29.+In+particular%2C+the+vital+importance+of+TH+for+the+regulation+of+early+developmental+processes+is+not+limited+to+human+or+mammalian+species+%2851%29%2C+but+is+well+conserved+throughout+the+vertebrate+kingdom+%2849%29+%2852%29+%2853%29.+In+avian+species%2C+for+example%2C+TH+are+required+for+nervous+system+and+skeleton+development+%2849%29+and+TH+action+has+also+been+demonstrated+to+regulate+both+direct+larval+and+metamorphic+development+in+fish+%2850%3B54%29.+In+amphibians%2C+TH+are+the+primary+morphogen+regulating+postembryonic+development+%28metamorphosis%29+%2852%29.%0D%0AMost+fish+species+undergo+similar+developmental+phases+as+described+for+amphibians+including+a+larval+stage%2C+juveniles+and+adults+%2853%29+with+a+larvae-to-juvenile+transition+often+associated+with+metamorphic+changes+%2850%29.+Experimental+manipulation+of+the+thyroid+status+as+well+as+the+recent+cloning+of+fish+TRs+and+the+characterization+of+TR+developmental+expression+profiles+clearly+demonstrated+the+important+role+of+THs+for+early+fish+development+%2850%29+At+later+life+stages%2C+TH+have+been+shown+to+assist+in+the+control+of+various+physiological+functions+in+fish+including+osmoregulation%2C+metabolism%2C+somatic+growth%2C+and+behaviour+%2850%29+%2853%29.+In+salmonids%2C+for+example%2C+TH+are+important+for+migration+from+fresh+water+to+salt+water+%28smoltification%29%2C+and+the+high+T4+plasma+levels+during+smoltification+represent+some+of+the+highest+circulating+T4+levels+in+fish+%2855%3B56%29.%0D%0AInitially%2C+it+was+believed+that+TH+had+little+or+no+stimulatory+effect+on+the+oxidative+metabolism+of+cold-blooded+species.+Now+it+is+known+that+the+effect+of+the+thyroid+on+metabolic+activity+in+cold-blooded+species+is+strongly+dependent+on+environmental+temperature.+For+example%2C+T4+causes+stimulation+of+metabolism+in+lizards+at+32%C2%B0C%2C+but+not+when+they+are+acclimated+to+low+temperatures+%2857%29.+The+thyroid+gland+is+also+more+active+at+higher+temperatures+%2823%C2%B0-32%C2%B0C%29+than+at+10%C2%B0-15%C2%B0C+in+snakes%2C+fish%2C+amphibians%2C+turtles%2C+and+lizards+%2858%29.%0D%0ATH+levels+are+also+influenced+by+the+nutritional+status+in+both+endothermic+%28birds%2C+mammals%29+and+ectothermic+%28fish%29+vertebrates+with+a+decreased+T3+and+T4+to+T3+conversion+in+caloric+deficient+states+%2859%29.%0D%0AA+most+striking+effect+of+TH+is+the+induction+of+metamorphosis+in+certain+amphibia%2C+first+reported+by+Gundernatsch+in+1912+%2860%29.+The+physiological+role+of+TH+during+anuran+metamorphosis+is+best+exemplified+by+the+fact+that+surgical+removal+of+the+thyroid+gland+or+chemical+blockage+of+TH+synthesis+leads+to+complete+cessation+of+metamorphic+development+%2861%29+On+the+other+hand%2C+addition+of+minute+amounts+of+T4+%281+nM%29+to+the+rearing+water+of+tadpoles+during+premetamorphosis+leads+to+a+precocious+induction+of+metamorphosis+%2852%29.+Particularly+the+metamorphosis+of+the+South+African+clawed+frog%26nbsp%3B%3Ci%3EXenopus+laevis%3C%2Fi%3E%26nbsp%3Bhas+been+used+for+years+as+a+highly+successful+animal+model+to+understand+TH+function+in+a+developmental+context+%2852%29+%2862%29+%2863%les+%2869%29.+Expression+of+glycoprotein+%CE%B1-subunit+and+TSH+%CE%B2-subunit+%28TSH%CE%B2%29+mRNAs+in+the+pituitary+of+metamorphosing+X.+laevis+tadpoles+increase+from+low+premetamorphic+levels+to+maximum+levels+at+early+climax+stages+and+decrease+towards+the+end+of+metamorphosis+%2870%29+%2871%29.+Thus%2C+there+is+a+concurrent+increase+of+TSH+expression%2C+thyroid+activity+and+circulating+T4+levels+from+premetamorphosis+to+early+climax+stages.+Different+hypotheses+have+been+put+forward+to+explain+this+condition.+Some+authors+stressed+the+importance+of+climax+stage+induction+of+type+II+iodothyronine+deiodinase+%28D2%29+expression+in+pituitary+thyrotrophs+as+a+molecular+switch+to+establish+a+negative+feedback+control+of+TSH+synthesis+%2872%29.+In+contrast%2C+other+studies+could+demonstrate+negative+feedback+control+of+TSH+expression+by+T4+at+much+earlier+stages+suggesting+that+the+developmental+TSH+expression+profile+is+the+net+result+of+negative+feedback+action+of+circulating+TH+and+a+concomitant+increase+in+pituitary+stimulation+by+hypothalamic+factors+%2873%29+%2865%29.+Of+relevance+for+the+increased+hypothalamic+stimulation+of+pituitary+thyrotrophs+might+be+the+TH-dependent+maturation+of+the+median+eminence+%2874%29+as+well+as+increased+synthesis+and+release+of+hypothalamic+peptide+hormones+%2873%29.%0D%0AThe+extent+to+which+different+plasma+proteins+such+as+thyroxine-binding+globulin+%28TBG%29%2C+transthyretin+%28TTR%29+and+albumin+account+for+TH+binding+in+the+blood+varies+among+different+groups+of+vertebrates+%2875%29.+In+humans+and+rodents%2C+TBG+and+TTR+are+the+main+THBP%2C+respectively%2C+showing+a+higher+affinity+for+T4+than+T3+%2876%29.+TTR+is+assumed+to+be+the+main+TH-binding+plasma+protein+in+metamorphosing+tadpoles+and+many+teleost+fish.+One+characteristic+property+of+amphibian+and+teleost+TTRs+is+that+they+display+a+several-fold+higher+affinity+for+T3+than+for+T4%2876%29.%0D%0A%0D%0AIn+their+target+cells%2C+the+biological+action+of+TH+is+mediated+by+activation+of+nuclear+TH+receptors+%28TRs%29.+Two+TR+subtypes+%28TR%CE%B1%2C+TR%CE%B2%29+which+are+encoded+by+separate+genes+have+been+described+in+X.+laevis+%2882%29.+Due+to+pseudo-tetraploidy%2C+there+are+two+TR%CE%B1+%28A+and+B%29+and+two+TR%CE%B2+%28A+and+B%29+in+X.+laevis%2877%29.+Similar+to+mammals%2C+TRs+can+bind+to+TH+response+elements+%28TREs%29+weakly+as+homodimers+whereas+heterodimers+of+TR+and+9+cis+retinoic+acid+receptors+%28RXR%29+strongly+bind+with+TREs+%2863%29.+Extensive+investigations+on+the+gene+expression+profiles+induced+by+T3+made+X.+laevis+one+of+the+leading+resources+for+understanding+TH+action+during+vertebrate+development+%2863%29+%2878%29.+Gene+transcription+in+X.+laevis+tadpoles+can+be+either+up-+or+down-regulated+by+TH%2879%3B80%29.+For+the+category+of+genes+that+are+up-regulated+by+TH%2C+it+has+been+shown+that+unliganded+heterodimeric+TR-RXR+complexes+can+bind+to+TRE+but+repress+transcription+through+recruitment+of+corepressor+%2863%29.%0D%0AIn+X.+laevis%2C+low+mRNA+expression+has+been+demonstrated+for+TR%CE%B1+and+TR%CE%B2+in+oocytes+and+embryos+but+the+putative+functions+are+still+poorly+defined+%2881%29+%2863%29.+During+postembryonic+development%2C+the+expression+profiles+of+TR%CE%B1+and+TR%CE%B2+show+striking+differences+%2852%29+%2863%29%3Cspan+lang%3D%22de-DE%22%3E%26nbsp%3B%2868%3B77%29.+TR%CE%B1+is+expressed+at+high+levels+during+early+premetamorphic+stages+and+expression+is+maintained+at+an+elevated+level+throughout+metamorphic+development%2863%29+%2882%29.+TR%CE%B2+shows+a+more+complex+developmental+expression+profile%2C+characterized+by+low+expression+during+premetamorphosis+and+a+dramatic+up-regulation+in+parallel+with+the+increasing+TH+plasma+levels+during+prometamorphosis+%2863%29.+When+analyzed+in+individual+tissues%2C+TR%CE%B2+was+found+to+be+up-regulated+particularly+during+periods+of+active+tissue+remodelling+%2863%29+%2877%29.+Another+important+aspect+of+TH+action+in+X.+laevis+tadpoles+is+that+exogenous+T3+regulates+the+expression+of+its+cognate+receptors+%2863%29.+Among+the+most+rapid+changes+in+gene+expression+induced+by+T3%2C+a+dramatic+up+regulation+of+TR%CE%B2+gene+expression+has+been+observed+in+all+organs+and+tissues+analyzed+%2863%29+%2877%29.+In+addition%2C+recently+developed+transgenic+models+carrying+dominant+negative+and+constitutively+activated+TR+mutants+could+clearly+demonstrate+the+important+role+of+TR+in+mediating+the+developmental+effects+of+TH+during+X.+laevis+metamorphosis+%2863%29.%3C%2Fspan%3E%0D%0AThree+types+of+iodothyronine+deiodinases+%28D1%2C+D2%2C+D3%29+have+been+identified+in+vertebrates+which+differ+in+tissue+distribution%2C+substrate+specificity+and+sensitivity+to+inhibiting+compounds+%2883%29.+D1+and+D2+catalyze+primarily+the+removal+of+one+iodide+from+the+outer+tyrosine+ring+of+T4+to+produce+T3.+D3+catalyzes+the+cleaving+of+one+iodide+from+the+inner+tyrosine+rings+of+T4+and+T3+generating+inactive+iodothyronine+derivatives+%28e.g.+reverse+T3+and+diiodothyronines%29%2C+respectively.+In+amphibian+tadpoles%2C+the+coordinated+progression+of+metamorphic+development+requires+a+high+degree+of+local+control+of+T3+production+which+apparently+dominates+over+the+general+supply+of+T3%2C+at+least+during+metamorphosis+%2884%29.+Only+recently%2C+a+putative+X.+laevis+homologue+of+mammalian+D1+has+been+identified+%2885%29+but+neither+the+expression+profile+nor+the+putative+regulatory+role+of+D1+during+metamorphic+development+have+been+characterized+so+far.+However%2C+several+studies+have+investigated+the+role+of+D2+and+D3+in+controlling+TH+action+during+metamorphosis+of+anuran+tadpoles+%2884%29.+The+data+derived+from+these+studies+support+the+view+that+both+D2+and+D3+play+a+central+role+in+modulating+the+tissue+responsiveness+to+TH+by+either+increasing+intracellular+concentrations+of+biologically+active+T3+%28e.g.%2C+D2+in+hind+limbs%29+or+by+preventing+TH+action+via+rapid+inactivation+of+T4+and+T3+%28e.g.%2C+D3+in+tadpole+tail%29.%0D%0ACentral+to+the+understanding+of+TH+function+in+lower+vertebrates+are+the+manyfold+interactions+of+TH+with+other+hormones+%28e.g.%2C+corticosterone%2C+prolactin%2C+and+growth+hormone%29+contributing+to+a+fine-tuning+of+developmental+TH+action.+For+example%2C+several+studies+have+shown+that+high+concentrations+of+corticosterone+can+provoke+both+inhibitory+or+accelerating+effects+on+amphibian+metamorphic+development%2C+depending+on+whether+treatment+is+initiated+at+early+%28inhibition%29+or+at+late+developmental+stages+%28acceleration%29+%2886%29.+Concerning+the+accelerating+effects+of+corticosterone+on+the+development+of+tadpoles+at+late+stages%2C+two+molecular+mechanisms+have+been+proposed+including+corticosterone+-induced+increases+in+T3+receptor+binding+capacities+and+corticosterone+-induced+increases+in+peripheral+deiodination+of+T4+to+T3+%2852%29.+Similarly%2C+corticosterone+is+known+to+affect+peripheral+deiodination+of+T4+to+T3+in+avian+species%2C+including+inhibitory+effects+on+D3+and+D1+activities+in+chicken+liver+%2887%29.%0D%0AAnother+hormone+that+has+received+a+great+deal+of+attention+with+regard+to+modulation+of+TH+dependent+metamorphic+development+is+prolactin.+Early+studies+using+mammalian+prolactin+preparations+could+demonstrate+antagonistic+effects+of+prolactin+on+TH+action+in+various+peripheral+tissues+%2888%29.+Inhibitory+effects+on+TR+autoinduction+by+TH+have+been+suggested+as+a+primary+mechanism+of+prolactin+action+to+antagonize+TH+action+in+peripheral+tissues.+It+should+be+noted%2C+however%2C+that+in+a+transgenic+frog+model+of+prolactin+overexpression%2C+no+retardation+of+tadpole+development+was+detectable%2C+with+the+exception+of+blocked+tail+resorption+in+a+limited+number+of+transgene+animals%2889%29.%0D%0AIn+chicken+embryos%2C+GH+appears+to+be+a+potent+inhibitor+of+hepatic+D3+activity+resulting+in+increased+T3+availability+%2887%29.+This+GH+action+on+TH+metabolism+probably+represents+a+physiologically+relevant+hormonal+response+linking+the+nutritional+state+with+the+activity+of+the+thyroid+system.+Given+the+great+diversity+and+heterogeneity+in+fish+physiology+and+ecology%2C+it+is+not+surprising+that+a+multitude+of+hormonal+interferences+have+been+described+in+various+model+species.+The+reader+is+referred+to+several+comprehensive+reviews+about+this+hormonal+interplay+in+fish+%2890-92%29.%0D%0A%0D%0A%3Ca+href%3D%22%22+name%3D%223%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AHypothalamic+and+Pituitary+Control%3C%2Fh3%3E%0D%0AHypothalamic-pituitary+control+of+thyroid+function+in+the+most+primitive+vertebrates+represented+by+hagfishes+and+lampreys+is+still+poorly+understood+%2893%29+%2894%29.+Although+the+pituitary+of+these+primitive+fishes+might+contain+thyrotrophic+factors+%2893%29%2C+their+nature+and+their+hypothalamic-releasing+factors+are+unknown.+TRH+and+TSH+were+largely+ineffective+in+stimulating+thyroid+activity+as+assessed+by+different+experimental+protocols+%2893%29.+Instead%2C+numerous+studies+support+the+concept+that+peripheral+deiodination+of+TH+might+provide+the+major+regulatory+mechanism+for+the+control+of+thyroid+status+%2892%29.+The+intestinal+tract+seems+to+be+a+major+site+of+this+TH+metabolism+in+larval+lamprey+%2840%29.%0D%0ANeuroendocrine+control+of+thyroid+activity+has+been+established+for+teleost+fishes%2C+amphibians%2C+birds+and+reptiles+%2895%29.+TRH+is+regarded+as+the+main+regulator+of+TSH+secretion+in+mammals%2C+and+TSH-releasing+activity+of+this+peptide+hormone+has+also+been+observed+in+various+non-mammalian+vertebrates.+In+avian+species%2C+injection+of+TRH+has+been+shown+to+preferentially+increase+circulating+T3+instead+of+T4%2C+an+effect+that+was+later+related+to+a+GH-dependent+inhibition+of+hepatic+D3+activity+subsequent+to+a+stimulation+of+somatotrophs+by+TRH%2896%29.+In+fact%2C+preferential+binding+of+TRH+was+demonstrated+for+somatotrophs+in+chicken.+In+recent+years%2C+it+became+clear+that+another+hypothalamic+factor%2C+corticotropin-releasing+hormone+%28CRH%29%2C+is+a+more+potent+stimulator+of+TSH+release+in+non-mammalian+vertebrates.+In+chicken%2C+CRH+was+found+to+increase+both+T3+and+T4+plasma+levels+via+stimulation+of+TSH+release+%2897%29.+Studies+by+de+Groef+%2898%29+could+show+a+preferential+expression+of+CRH+receptors+type+1+%28CRH-R1%29+and+type+2+%28CRH-R2%29+in+chicken+corticotrophs+and+thyrotrophs%2C+respectively.+The+role+of+CRH+R2+in+mediating+the+CRH+effect+on+TSH+release+in+chicken+was+corroborated+in+further+studies+using+CRH+R2-specific+agonists+and+antagonists.%0D%0AIn+amphibians%2C+the+regulation+of+TSH+release+by+TRH+and+CRF+appears+to+be+dependent+on+the+life+stage.+While+TRH+was+able+to+increase+TSH+secretion+in+adult+frogs+but+not+in+tadpoles+%2899%3B100%29%2C+the+finding+that+TRH+stimulates+TSH+release+at+least+in+adult+amphibians+argues+against+the+hypothesis+that+the+TSH-stimulating+activity+of+TRH+has+only+recently+been+coopted+in+association+with+the+development+of+endothermy.+Similar+to+the+studies+with+chicken%2C+CRF+proved+to+be+the+most+potent+releasing+factor+for+TSH+in+the+tadpole+pituitary+in+vitro+%28100%3B101%29.+In+vivo%2C+injection+of+CRH+increased+plasma+T4+levels+in+Xenopus+tadpoles+and+accelerated+metamorphic+development+in+ranids.+In+addition%2C+TSH+synthesis+and+release+by+the+amphibian+pituitary+is+under+the+control+of+a+negative+TH+feedback+%2873%3B102%29.+Few+studies+have+addressed+CRH+effects+on+thyrotrophs+in+fish+but+the+available+data+indicate+that+CRH+but+not+TRH+stimulates+TSH+release+in+salmonids+%28103%29.%0D%0A%3Ca+href%3D%22%22+name%3D%224%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AONTOGENY%3C%2Fh3%3E%0D%0AThe+main+anlage+of+the+thyroid+gland+develops+as+a+median+endodermal+downgrowth+from+the+tongue.+It+can+be+seen+in+the+human+embryo+at+the+end+of+the+third+week+%28104%29.+It+is+located+near+the+primordium+of+the+heart%2C+and+as+the+heart+is+pulled+caudally%2C+the+thyroid+anlage+follows.+At+the+5%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3Eth%3C%2Fsup%3Eweek+the+thyroglossal+duct+starts+to+breakdown.+At+about+the+30th+day+it+has+developed+into+a+hollow+bilobed+structure%2C+and+by+the+40th+day%2C+the+original+hollow+stalk+connecting+it+to+the+pharyngeal+floor+atrophies+and+then+breaks.+Shortly+thereafter+the+lateral+extensions+of+the+median+anlage+make+contact+with+the+ultimobranchial+bodies+developing+from+the+4th+pharyngeal+pouches%2C+the+so-called+lateral+anlage+of+the+thyroid.+The+ultimobranchial+cells+or+neural+cells+accompanying+them+are+the+origin+of+calcitonin-secreting+C-cells+in+the+thyroid+gland+and+may+contribute+to+the+formation+of+follicular+cells+as+well+%28105%29.+By+the+8th+week+the+cells+have+a+tubular+arrangement%2C+and+cell+clusters+are+apparent.+Two+weeks+later%2C+when+the+embryo+is+approximately+80+mm+long%2C+follicles+are+present.+Shortly+after+this+time+the+follicles+contain+colloid%2C+and+the+thyroid+accumulates+and+binds+iodide+by+the+11th-12th+week+%28Fig.+2%29.+Secondary+follicles+arise+by+budding+from+the+primary+follicles%3B+they+increase+in+number+until+the+embryo+reaches+a+length+of+about+160+mm.+After+this+time+the+follicles+increase+in+size%2C+but+the+number+remains+the+same.+Under+intense+stimulation%2C+the+adult+thyroid+can+form+new+follicles.%0D%0A%3Ccenter%3E%3Ctable+border%3D%221%22+cellpadding%3D%220%22+cellspacing%3D%220%22+style%3D%22width%3A+448px%3B%22%3E%3Ccol+width%3D%22448%22%3E%3C%2Fcol%3E%3Ctbody%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22+width%3D%22448%22%3E%3Cimg+align%3D%22BOTTOM%22+border%3D%221%22+height%3D%22318%22+name%3D%22graphics2%22+src%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Ffigures%2Ffigure1-2.jpg%22+width%3D%22448%22+%2F%3E%3C%2Ftd%bold%3B%22%3E%0D%0AHypothalamic+and+Pituitary+Control%3C%2Fh3%3E%0D%0AHypothalamic-pituitary+control+of+thyroid+function+in+the+most+primitive+vertebrates+represented+by+hagfishes+and+lampreys+is+still+poorly+understood+%2893%29+%2894%29.+Although+the+pituitary+of+these+primitive+fishes+might+contain+thyrotrophic+factors+%2893%29%2C+their+nature+and+their+hypothalamic-releasing+factors+are+unknown.+TRH+and+TSH+were+largely+ineffective+in+stimulating+thyroid+activity+as+assessed+by+different+experimental+protocols+%2893%29.+Instead%2C+numerous+studies+support+the+concept+that+peripheral+deiodination+of+TH+might+provide+the+major+regulatory+mechanism+for+the+control+of+thyroid+status+%2892%29.+The+intestinal+tract+seems+to+be+a+major+site+of+this+TH+metabolism+in+larval+lamprey+%2840%29.%0D%0ANeuroendocrine+control+of+thyroid+activity+has+been+established+for+teleost+fishes%2C+amphibians%2C+birds+and+reptiles+%2895%29.+TRH+is+regarded+as+the+main+regulator+of+TSH+secretion+in+mammals%2C+and+TSH-releasing+activity+of+this+peptide+hormone+has+also+been+observed+in+various+non-mammalian+vertebrates.+In+avian+species%2C+injection+of+TRH+has+been+shown+to+preferentially+increase+circulating+T3+instead+of+T4%2C+an+effect+that+was+later+related+to+a+GH-dependent+inhibition+of+hepatic+D3+activity+subsequent+to+a+stimulation+of+somatotrophs+by+TRH%2896%29.+In+fact%2C+preferential+binding+of+TRH+was+demonstrated+for+somatotrophs+in+chicken.+In+recent+years%2C+it+became+clear+that+another+hypothalamic+factor%2C+corticotropin-releasing+hormone+%28CRH%29%2C+is+a+more+potent+stimulator+of+TSH+release+in+non-mammalian+vertebrates.+In+chicken%2C+CRH+was+found+to+increase+both+T3+and+T4+plasma+levels+via+stimulation+of+TSH+release+%2897%29.+Studies+by+de+Groef+%2898%29+could+show+a+preferential+expression+of+CRH+receptors+type+1+%28CRH-R1%29+and+type+2+%28CRH-R2%29+in+chicken+corticotrophs+and+thyrotrophs%2C+respectively.+The+role+of+CRH+R2+in+mediating+the+CRH+effect+on+TSH+release+in+chicken+was+corroborated+in+further+studies+using+CRH+R2-specific+agonists+and+antagonists.%0D%0AIn+amphibians%2C+the+regulation+of+TSH+release+by+TRH+and+CRF+appears+to+be+dependent+on+the+life+stage.+While+TRH+was+able+to+increase+TSH+secretion+in+adult+frogs+but+not+in+tadpoles+%2899%3B100%29%2C+the+finding+that+TRH+stimulates+TSH+release+at+least+in+adult+amphibians+argues+against+the+hypothesis+that+the+TSH-stimulating+activity+of+TRH+has+only+recently+been+coopted+in+association+with+the+development+of+endothermy.+Similar+to+the+studies+with+chicken%2C+CRF+proved+to+be+the+most+potent+releasing+factor+for+TSH+in+the+tadpole+pituitary+in+vitro+%28100%3B101%29.+In+vivo%2C+injection+of+CRH+increased+plasma+T4+levels+in+Xenopus+tadpoles+and+accelerated+metamorphic+development+in+ranids.+In+addition%2C+TSH+synthesis+and+release+by+the+amphibian+pituitary+is+under+the+control+of+a+negative+TH+feedback+%2873%3B102%29.+Few+studies+have+addressed+CRH+effects+on+thyrotrophs+in+fish+but+the+available+data+indicate+that+CRH+but+not+TRH+stimulates+TSH+release+in+salmonids+%28103%29.%0D%0A%3Ca+href%3D%22%22+name%3D%224%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AONTOGENY%3C%2Fh3%3E%0D%0AThe+main+anlage+of+the+thyroid+gland+develops+as+a+median+endodermal+downgrowth+from+the+tongue.+It+can+be+seen+in+the+human+embryo+at+the+end+of+the+third+week+%28104%29.+It+is+located+near+the+primordium+of+the+heart%2C+and+as+the+heart+is+pulled+caudally%2C+the+thyroid+anlage+follows.+At+the+5%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3Eth%3C%2Fsup%3Eweek+the+thyroglossal+duct+starts+to+breakdown.+At+about+the+30th+day+it+has+developed+into+a+hollow+bilobed+structure%2C+and+by+the+40th+day%2C+the+original+hollow+stalk+connecting+it+to+the+pharyngeal+floor+atrophies+and+then+breaks.+Shortly+thereafter+the+lateral+extensions+of+the+median+anlage+make+contact+with+the+ultimobranchial+bodies+developing+from+the+4th+pharyngeal+pouches%2C+the+so-called+lateral+anlage+of+the+thyroid.+The+ultimobranchial+cells+or+neural+cells+accompanying+them+are+the+origin+of+calcitonin-secreting+C-cells+in+the+thyroid+gland+and+may+contribute+to+the+formation+of+follicular+cells+as+well+%28105%29.+By+the+8th+week+the+cells+have+a+tubular+arrangement%2C+and+cell+clusters+are+apparent.+Two+weeks+later%2C+when+the+embryo+is+approximately+80+mm+long%2C+follicles+are+present.+Shortly+after+this+time+the+follicles+contain+colloid%2C+and+the+thyroid+accumulates+and+binds+iodide+by+the+11th-12th+week+%28Fig.+2%29.+Secondary+follicles+arise+by+budding+from+the+primary+follicles%3B+they+increase+in+number+until+the+embryo+reaches+a+length+of+about+160+mm.+After+this+time+the+follicles+increase+in+size%2C+but+the+number+remains+the+same.+Under+intense+stimulation%2C+the+adult+thyroid+can+form+new+follicles.%0D%0A%3Ccenter%3E%3Ctable+border%3D%221%22+cellpadding%3D%220%22+cellspacing%3D%220%22+style%3D%22width%3A+448px%3B%22%3E%3Ccol+width%3D%22448%22%3E%3C%2Fcol%3E%3Ctbody%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22+width%3D%22448%22%3E%3Cimg+align%3D%22BOTTOM%22+border%3D%221%22+height%3D%22318%22+name%3D%22graphics2%22+src%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Ffigures%2Ffigure1-2.jpg%22+width%3D%22448%22+%2F%3E%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+bgcolor%3D%22%2399ccff%22+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22+width%3D%22448%22%3E%3Cb%3EFig.+1-2.%3C%2Fb%3E%26nbsp%3BPhotograph+of+thyroid+tissue+from+a+fetus+with+a+50-mm+crown-rump+length%2C+estimated+gestational+age+64+days.+The+arrows+indicate+two+intracellular+canaliculi.+During+incubation+of+the+tissue+in+organ+culture+in+vitro%2C+there+was+no+uptake+or+fixation+of+iodide.+The+figure+shows+the+earliest+stage+of+formation+of+colloid+spaces.+The+tissue+was+fixed+in+ozmium%2C+embedded+in+Epon+epoxy+resin%2C+and+sectioned+at+1-mm+thickness+%28x2%2C400%29.+%28From+T.H.+Shephard%2C+J.+Clin.+Endocrinol.+Metab.%2C+27%3A945%2C1967%2C+with+permission%29.%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3C%2Ftbody%3E%3C%2Ftable%3E%0D%0A%3C%2Fcenter%3EFujita+and+Machino+%28106%29+have+studied+the+origins+of+the+follicular+lumen+in+the+chick+embryo.+They+found+that+colloid+droplets%2C+1-5%C2%B5m+in+diameter+and+enclosed+by+a+limiting+membrane%2C+first+appear+within+the+cytoplasm+of+parenchymal+cells.+As+the+droplets+enlarge%2C+they+approach+the+cell+membrane+and+come+in+contact+with+the+droplets+of+an+adjoining+cell.+The+limiting+cell+membrane+disappears%2C+and+the+droplets+fuse.+By+an+extension+of+this+process+to+cells+close+to+the+original+droplet%2C+an+acinar+structure+containing+colloid+and+enclosed+by+a+ring+of+parenchymal+cells+is+formed.+A+similar+process+can+be+demonstrated+in+aggregates+of+isolated+thyroid+cells+in+vitro+%28107%29.%0D%0A%3Ca+href%3D%22%22+name%3D%225%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AGROSS+ANATOMY%3C%2Fh3%3E%0D%0A%3Ca+href%3D%22%22+name%3D%226%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0A%0D%0APhysical+Appearance+and+Anatomic+Location%3C%2Fh3%3E%0D%0AThe+Germans+call+the+thyroid+the+%22shield+gland%22+%28Schilddr%C3%BCse%29%2C+and+the+English+name%2C+derived+from+the+Greek%2C+means+the+same+thing.+Such+a+term+gives+a+most+erroneous+impression+of+its+shape.+It+is+interesting%2C+however%2C+that+in+the+Minoan+culture%2C+a+shield+was+used+that+had+a+shape+somewhat+like+that+of+the+mammalian+thyroid+gland.+The+gland+as+seen+from+the+front+is+more+nearly+the+shape+of+a+butterfly.+It+wraps+itself+about+and+becomes+firmly+fixed+by+fibrous+tissue+to+the+anterior+and+lateral+parts+of+the+larynx+and+trachea.+Anteriorly%2C+its+surface+is+convex%3B+posteriorly%2C+it+is+concave.+The+isthmus+lies+across+the+trachea+anteriorly+just+below+the+level+of+the+cricoid+cartilage.+The+lateral+lobes+extend+along+either+side+of+the+larynx+as+roughly+conical+projections+reaching+the+level+of+the+middle+of+the+thyroid+cartilage.+Their+upper+extremities+are+known+as+the+upper+poles+of+the+gland.+Similarly%2C+the+lower+extremities+of+the+lateral+lobes+are+spoken+of+as+the+lower+poles%2C+although+they+make+no+such+prominent+projections+as+do+the+upper+%28Fig.+1-3%29.%0D%0A%3Ccenter%3E%3Ctable+border%3D%221%22+cellpadding%3D%220%22+cellspacing%3D%220%22+style%3D%22width%3A+499px%3B%22%3E%3Ccol+width%3D%22499%22%3E%3C%2Fcol%3E%3Ctbody%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22+width%3D%22499%22%3E%3Cimg+align%3D%22BOTTOM%22+border%3D%221%22+height%3D%22468%22+name%3D%22graphics3%22+src%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Ffigures%2Ffigure1-3.jpg%22+width%3D%22499%22+%2F%3E%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+bgcolor%3D%22%2399ccff%22+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22+width%3D%22499%22%3E%3Cb%3EFig.+1-3%3C%2Fb%3E.+Gross+Anatomy+of+the+thyroid+and+surroundings+%28from%3A+Netter+FH%2C+The+Ciba+Collection+of+Medical+Illustrations%2C+vol.+4%2C+Endocrine+system+and+selected+metabolic+diseases%2C+Ciba%2C+1965%2C+with+permission%29.%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3C%2Ftbody%3E%3C%2Ftable%3E%0D%0A%3C%2Fcenter%3EThe+weight+of+the+thyroid+of+the+normal+nongoitrous+adult+is+6-20+g+depending+on+body+size+and+iodine+supply.+The+width+and+length+of+the+isthmus+average+20+mm%2C+and+its+thickness+is+2-6+mm.+The+lateral+lobes+from+superior+to+inferior+poles+usually+measure+4+cm.+Their+breadth+is+15-20+mm%2C+and+their+thickness+is+20-39+mm.%0D%0AThe+thyroid+is+enveloped+by+a+thin%2C+fibrous%2C+nonstripping+capsule+that+sends+septa+into+the+gland+substance+to+produce+an+irregular%2C+incomplete+lobulation.+No+true+lobulation+or+lobation+exists.+In+fact%2C+the+gland+is+throughout+a+uniform+agglomeration+of+follicles+packed+like+berries+into+a+bag.+It+has+no+true+subdivisions.+The+lateral+lobes+lie+in+a+bed+between+the+trachea+and+the+larynx+medially+and+between+the+carotid+sheath+and+the+sternomastoid+muscles+laterally.+The+deep+cervical+fascia%2C+dividing+into+an+anterior+and+a+posterior+plane%2C+lines+this+bed+and+makes+a+loosely+applied+false+or+surgical+capsule+for+the+lateral+portions+of+the+gland.+In+front+are+the+thin%2C+ribbon-like+infrahyoid+muscles.+The+thyroid+is+molded+perfectly+to+fit+the+space+available+between+the+neighboring+structures%2C+and+is+superficially+placed.+It+can+usually+be+outlined+by+careful+palpation+in+normal+humans%2C+but+if+the+neck+is+thick+and+short+or+the+sternomastoid+muscles+heavily+developed%2C+it+may+be+impossible+to+feel+the+gland.%0D%0AThe+shape+and+attachments+of+the+organ+are+important+in+examination+and+diagnosis.+The+relation+of+the+thyroid+gland+to+the+parathyroids%2C+which+are+usually+situated+on+the+posterior+surface+of+the+lateral+lobes+of+the+gland+within+the+surgical+capsule%2C+and+to+the+recurrent+laryngeal+nerves%2C+which+run+in+the+cleft+between+the+trachea+and+esophagus+just+medial+to+the+lateral+lobes%2C+are+most+important+to+the+surgeon.+The+relationship+to+the+trachea+is+important+from+the+point+of+view+of+pressure+symptoms.%0D%0AThe+pyramidal+lobe+is+a+narrow+projection+of+thyroid+tissue+extending+upward+from+the+isthmus+and+lying+on+the+surface+of+the+thyroid+cartilage%2C+to+the+right+or+left+of+the+prominence+of+that+structure.+It+is+a+vestige+of+the+embryonic+thyroglossal+tract.+The+importance+of+the+pyramidal+lobe+is+in+its+relation+to+developmental+anomalies+and+also+in+its+propensity+to+undergo+hypertrophy+when+the+rest+of+the+thyroid+has+been+removed.+Any+pathologic+process+that+is+diffuse+may+involve+the+pyramidal+lobe%2C+for+example%2C+Graves%27+disease+or+Hashimoto%27s+thyroiditis.+It+becomes+thus+an+item+of+some+importance+diagnostically+and+in+thyroid+surgery.+A+pyramidal+lobe+is+found+by+the+surgeon+in+about+80%25+of+patients.%0D%0A%3Ca+href%3D%22%22+name%3D%227%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0A%0D%0ABlood+Supply%3C%2Fh3%3E%0D%0AThe+thyroid+gland+has+an+abundant+blood+supply.+It+has+been+estimated+that+the+normal+flow+rate+is+about+5+ml%2Fg+of+thyroid+tissue+each+minute.+The+blood+volume+of+normal+humans+is+about+5+liters+and+total+blood+flow+5+liters%2Fmin.+This+mass+moves+through+the+lungs+about+once+a+minute%2C+through+the+kidneys+once+in+five+minutes%2C+and+through+the+thyroid+approximately+once+an+hour.+Although+the+thyroid+represents+about+0.4%25+of+body+weight+it+accounts+for+2%25+of+total+blood+flow.+In+disease+the+flow+through+the+gland+may+be+increased+up+to+100-fold.%0D%0AThis+abundant+blood+supply+is+provided+from+the+four+major+thyroid+arteries.+The+superior+pair+arise+from+the+external+carotid+and+descend+several+centimeters+through+the+neck+to+reach+the+upper+poles+of+the+thyroid%2C+where+they+break+into+a+number+of+branches+and+enter+the+substance+of+the+gland.+The+inferior+pair+spring+from+the+thyrocervical+trunk+of+the+subclavian+arteries+and+enter+the+lower+poles+from+behind.+Frequently%2C+a+fifth+artery%2C+the+thyreoidea+ima%2C+from+the+arch+of+the+aorta%2C+enters+the+thyroid+in+the+midline.+There+are+free+anastomoses+between+all+of+these+vessels.+In+addition%2C+a+large+number+of+smaller+arteriolar+vessels+derived+from+collaterals+of+the+esophagus+and+larynx+supply+the+posterior+aspect+of+the+thyroid.+The+branching+of+the+large+arteries+takes+place+on+the+surface+of+the+gland%2C+where+they+form+a+network.+Only+after+much+branching+are+small+arteries+sent+deep+into+the+gland.+These+penetrating+vessels+arborize+among+the+follicles%2C+finally+sending+a+follicular+artery+to+each+follicle.+This%2C+in+turn%2C+breaks+up+into+the+rich+capillary+basket+like+network+surrounding+the+follicle.%0D%0AThe+veins+emerge+from+the+interior+of+the+gland+and+form+a+plexus+of+vessels+under+the+capsule.+These+drain+into+the+internal+jugular%2C+the+brachiocephalic%2C+and+occasionally+the+anterior+jugular+veins.%0D%0AThe+adult+thyroid+is+composed+of+follicles%2C+or+acini.+These+have+lost+all+luminal+connection+with+other+parts+of+the+body+and+may+be+considered%2C+from+both+the+structural+an+functional+points+of+view%2C+as+the+primary%2C+or+secretory%2C+units+of+the+organ.+The+cells+of+the+follicles+are+the+makers+of+hormone%3B+the+lumina+are+the+storage+depots.+In+the+normal+adult+gland+the+follicles+are+roughly+spherical+and+vary+considerably+in+size.+The+average+diameter+is+300+microns.+The+walls+consist+of+a+continuous+epithelium+one+cell+deep%2C+the+parenchyma+of+the+thyroid.+The+epithelium+of+the+normal+gland+is+usually+described+as+cuboidal%2C+the+cell+height+being+of+the+order+of+15+%C2%B5m.+In+the+resting+gland+the+cells+may+become+flatter.+Under+chronic+TSH+stimulation+such+as+occurs+with+iodide+deficiency%2C+the+height%0D%0A%3Ca+href%3D%22%22+name%3D%228%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0ALymphatics%3C%2Fh3%3E%0D%0AA+rich+plexus+of+lymph+vessels+is+in+close+approximation+to+the+individual+follicles%2C+but+no+unique+role+in+thyroid+function+has+been+assigned+to+this+system.+The+major+normal%2C+if+not+only%2C+secretory+pathway+for+thyroid+hormone+is+through+the+venous+drainage+of+the+thyroid+rather+than+through+the+lymphatics+but+thyroglobulin+appears+in+the+lymph.%0D%0A%3Ca+href%3D%22%22+name%3D%229%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AInnervation%3C%2Fh3%3E%0D%0AThe+gland+receives+fibers+from+both+sympathetic+and+parasympathetic+divisions+of+the+autonomic+nervous+system.+The+sympathetic+fibers+are+derived+from+the+cervical+ganglia+and+enter+the+gland+along+the+blood+vessels.+The+parasympathetic+fibers+are+derived+from+the+vagus+and+reach+the+gland+by+branches+of+the+laryngeal+nerves.+Both+myelinated+and+nonmyelinated+fibers+are+found+in+the+thyroid%2C+and+occasionally+in+the+ganglion+cells+as+well.+The+nerve+supply+does+not+appear+to+be+simply+a+secretory+system.+The+major+neurogenic+modifications+of+thyroid+physiology+have+to+do+with+blood+flow+and+are+reviewed+in+Chapter+4.+However+neurotransmitters+have+direct+effects+on+thyroid+follicular+cells%2C+which+vary+from+one+species+to+another.+The+physiological+relevance+of+these+effects+remains+to+be+proved.%0D%0A%3Ca+href%3D%22%22+name%3D%2210%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AThe+Secretory+Unit+-+The+Follicle%3C%2Fh3%3E%0D%0AThe+adult+thyroid+is+composed+of+follicles%2C+or+acini.+These+have+lost+all+luminal+connection+with+other+parts+of+the+body+and+may+be+considered%2C+from+both+the+structural+an+functional+points+of+view%2C+as+the+primary%2C+or+secretory%2C+units+of+the+organ.+The+cells+of+the+follicles+are+the+makers+of+hormone%3B+the+lumina+are+the+storage+depots.+In+the+normal+adult+gland+the+follicles+are+roughly+spherical+and+vary+considerably+in+size.+The+average+diameter+is+300+microns.+The+walls+consist+of+a+continuous+epithelium+one+cell+deep%2C+the+parenchyma+of+the+thyroid.+The+epithelium+of+the+normal+gland+is+usually+described+as+cuboidal%2C+the+cell+height+being+of+the+order+of+15+%C2%B5m.+In+the+resting+gland+the+cells+may+become+flatter.+Under+chronic+TSH+stimulation+such+as+occurs+with+iodide+deficiency%2C+the+height+increases%2C+and+the+term+columnar+is+applied.+Such+stimulation%2C+which+increases+colloid+resorption%2C+also+leads+to+a+reduction+in+size+the+follicular+lumen.+As+a+result%2C+the+height+of+the+epithelium+is+often+inversely+proportional+to+the+diameter+of+the+lumen+of+the+follicle.%0D%0AWithin+the+follicle+and+filling+its+lumen+is+the+homogeneous+colloid.+This+is+a+mixture+of+proteins%2C+principally+thyroglobulin%2C+but+there+are+other+lightweight+iodoproteins+and+serum+proteins+and+albumin%2C+originating+from+the+serum%2C+as+well.%0D%0AIn+addition+to+the+acinar+cells%2C+there+are+individual+cells+or+small+groups+of+cells+that+are+seen+not+to+extend+to+the+follicular+lumen+and+which+may+appear+as+clusters+between+follicles+%28Fig.+1-4a%2Cb%29.+These+light+cells%2C+or+C-cells%2C+are+a+distinct+category+probably+derived+from+the+neural+crest+via+the+ultimobranchial+body%2C+as+shown+by+studies+in+quail+chicks+by+Le+Douarin+and+Le+Li%C3%A8vre+%28108%29.+The+C-cells+secrete+calcitonin+%28or+%22thyrocalcitonin%22%29+in+response+to+an+increase+in+serum+calcium+%28109%29.+This+hormone+is+important+in+the+regulation+of+bone+resorption+and+to+a+lesser+extent+influences+the+concentration+of+serum+calcium.+Calcitonin+acts+primarily+by+suppressing+resorption+of+calcium+from+bone+and+therefore+lowers+plasma+free+Ca%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E%2B%2B%3C%2Fsup%3Elevels.+C-cells+also+contain+somatostatin%2C+calcitonin+gene+related+peptide%2C+gastrin-releasing+peptide%2C+katacalcin+and+helodermin+that+could+have+either+a+stimulatory+or+inhibitory+activity+on+thyroid+hormone+secretion.+Their+physiological+relevance+is+doubtful+%28see+%22Other+Regulatory+Factors%22+in+this+chapter%29.+The+C-cells+are+also+the+origin+of+the+%22medullary%22+thyroid+cancers.+In+adult+human+they+represent+1%25+of+the+cell+population.%0D%0AOutside+the+follicles+two+other+types+of+cells+populate+the+thyroid+the+endothelial+cells+and+fibroblasts.+In+normal+dog+thyroids+the+relative+proportions+of+follicular%2C+endothelial+cells+and+fibroblasts+are+70%25%2C+6%25+and+24%25+%28110%29.%0D%0A%3Ccenter%3E%3Ctable+border%3D%221%22+cellpadding%3D%220%22+cellspacing%3D%220%22+style%3D%22width%3A+612px%3B%22%3E%3Ccol+width%3D%22612%22%3E%3C%2Fcol%3E%3Ctbody%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22+width%3D%22612%22%3E%3Cdiv+lang%3D%22fr-FR%22+style%3D%22text-indent%3A+0in%3B%22%3E%0D%0A%3Cimg+align%3D%22BOTTOM%22+border%3D%221%22+height%3D%22247%22+name%3D%22graphics4%22+src%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Ffigures%2Ffigure1-4.jpg%22+width%3D%22612%22+%2F%3E%3C%2Fdiv%3E%0D%0A%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+bgcolor%3D%22%2399ccff%22+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22+width%3D%22612%22%3E%3Cdiv+lang%3D%22fr-FR%22+style%3D%22text-indent%3A+0in%3B%22%3E%0D%0A%3Cb%3EFig.+1-4.%3C%2Fb%3E%26nbsp%3B%28A%29+Light+microscopy+of+a+parafollicular+cluster+%28arrow%29+in+relationship+to+thyroid+follicle+%28TF%29+%28x900%29.+%28B%29+Parafollicular+cell+in+characteristic+position+between+follicular+cells+and+follicular+basement+membrane%2C+not+abutting+on+colloid+%28TF%29+%28x4%2C200%29.+Tissue+was+obtained+from+normal+thyroid+tissue+of+a+26-year-old+woman+operated+on+because+of+a+solitary+thyroid+adenomatous+nodule.+Specimens+were+fixed+in+glutaraldehyde+and+embedded+in+Araldite-502.+%28From+Teitelbaum+et+al.+Nature%2C+230%2C1971%2C+with+permission%29.%3C%2Fdiv%3E%0D%0A%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3C%2Ftbody%3E%3C%2Ftable%3E%0D%0A%3C%2Fcenter%3E%3Ci%3E%0D%0A%3C%2Fi%3E%0D%0A%0D%0A%3Ca+href%3D%22%22+name%3D%2211%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0ATHE+FINE+STRUCTURE+OF+THE+THYROID+CELLS%3C%2Fh3%3E%0D%0AThe+follicular+organization+and+the+polarity+of+the+thyrocytes+are+essential+to+the+specialized+metabolism+of+the+organ%26nbsp%3B%3A+with+the+vectorial+transport+of+thyroglobulin+and+iodide+at+the+apex%2C+the+synthesis+of+thyroid+hormones+at+the+apical+membrane%2C+the+storage+of+iodine+and+thyroid+hormone+within+thyroglobulin+in+the+lumen+and+endocytosis+of+thyroglobulin+also+at+the+apex.+The+onset+of+thyroid+function+in+embryo+coincides+with+the+appearance+of+this+structure.%0D%0AThe+acinar+surface+of+thyroid+parenchymal+cells+appears+to+be+smooth+in+the+light+microscope%2C+but+the+electron+microscope+shows+that+it+is+covered+with+tiny+villi+and+some+pseudopods.+Each+cell+displays+a+cilium+in+the+follicular+lumen.+The+base+of+the+cell+abuts+on+a+capillary+and+is+separated+from+it+by+a+two-layer+basement+membrane+visible+under+the+electron+microscope.+In+the+usual+hematoxylin+and+eosin+stain%2C+the+cell+cytoplasm+is+neutrophilic%2C+and+colloid+droplets+may+be+present.+The+nucleus+is+at+the+base+of+the+cell.%0D%0AThe+colloid+is+variable+in+tinctorial+response+but+tends+to+be+strongly+eosinophilic+in+resting+follicles+and+pale-staining+or+even+slightly+basophilic+when+the+gland+is+stimulated.+In+hyperactive+follicles+the+margin+of+the+colloid+is+scalloped+by+resorption+vacuoles.+These+vacuoles+may+represent+the+%22negatives%22+of+the+resorption+process.%0D%0AThe+villi+are+extensions+of+cytoplasm+which+increase+cell+secretory+surface.+In+acutely+stimulated+thyroids%2C+pseudopods+extend+out+into+the+colloid+and+surround+and+ingest+it+by+macropinocytosis.+Over+the+course+of+several+hours%2C+the+ingested+droplets+move+toward+the+base+of+the+cell+%28111%29.+These+droplets+of+resorbed+colloid+are+processed+for+secretion+as+hormone+by+the+gland+%28112%29.%0D%0AThe+resolving+power+of+the+electron+microscope+has+been+turned+upon+the+thyroid+acinar+cell+by+several+investigators%2C+among+them+Wissig+%28113%29%2C+Dempsey+and+Peterson+%28114%29%2C+Ekholm+and+Sj%C3%B6strand+%28115%29+and+Herman+%28116%29.+Wissig%27s+and+Ekholm%27s+findings+are+presented+here+in+detail+and+can+be+taken+as+typical+of+the+cytologic+picture+of+most+species.+The+entire+follicular+cell+is+covered+by+an+uninterrupted+plasma+membrane+%28Fig.+1-5+and+Fig.+1-6%29.+The+apical+surface+of+the+cell+is+dome-shaped+and+is+provided+with+numerous+microvilli+that+are+approximately+0.35+mm+tall+and+0.07+mm+broad.+This+membrane+is+composed+of+two+dark+layers+separated+by+a+single+pale+layer+and+is+70+%C3%85+thick.+Terminal+bars+join+opposing+cells+at+the+apical+margin%2C+and+desmosomes+often+occur+on+contacting+cell+surfaces.+Vesicular+structures%2C+approximately+60+mm+broad%2C+appear+in+the+microvilli+and+contain+material+that+has+the+same+density+as+colloid.+Beneath+the+apical+border+there+is+a+band+of+cytoplasm+that+is+approximately+0.5+mm+wide+and+devoid+of+organelles%2C+although+microtubular+and+microfilamentous+structures+are+seen+in+this+area.+Beneath+this+band%2C+a+few+apical+vesicles+of+400-15%2C000+%C3%85+are+seen%2C+and+beneath+this+area+and+extending+to+the+base+of+the+cell+are+the+channels+of+the+endoplasmic+reticulum%2C+also+known+as+ergoplasmic+vesicles.+These+vesicles%2C+or+channels%2C+are+limited+by+a+single+membrane+%28the+a+cytomembrane%29+approximately+60-70+%C3%85+thick%2C+and+their+outer+surface+is+studded+with+ribosomes+approximately+130-150+%C3%85+in+diameter.+In+some+areas+the+membrane+covering+the+cytomembrane+is+devoid+of+ribonucleoprotein+particles%2C+and+in+between+the+vesicles+the+ribonucleoprotein+granules+may+be+seen+to+lie+free.+The+endoplasmic+vesicles+are+very+pleiomorphic.+Small+vesicles+are+seen+near+the+apical+surface%2C+50+nm+to+several+microns+in+diameter%2C+and+closed+by+a+single-layer+membrane+5+nm+in+thickness.+These+droplets+appear+especially+in+the+apex+of+the+cell+and+are+thought+to+be+secretion+droplets.+The+material+within+them+is+frequently+quite+dense.+Large+vesicles+of+up+to+1+micron+appear+especially+in+stimulated+thyroids.+These+are+called+colloid+droplets+because+the+material+within+the+vesicles+is+homogeneous+and+has+the+density+of+colloid+and+results+from+colloid+endocytosis.%0D%0A%3Ccenter%3E%3Ctable+border%3D%221%22+cellpadding%3D%220%22+cellspacing%3D%220%22+style%3D%22width%3A+329px%3B%22%3E%3Ccol+width%3D%22329%22%3E%3C%2Fcol%3E%3Ctbody%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22+width%3D%22329%22%3E%3Cimg+align%3D%22BOTTOM%22+border%3D%221%22+height%3D%22301%22+name%3D%22graphics5%22+src%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Ffigures%2Ffigure1-5.jpg%22+width%3D%22329%22+%2F%3E%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+bgcolor%3D%22%2399ccff%22+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22+width%3D%22329%22%3E%3Cb%3EFig.+1-5%3C%2Fb%3E.+A+thyroid+follicular+cell%2C+including%3A+%28a%29+apical+vessel+of+cell%3B+%28e%29+endoplasmic+reticulum%3B+%28d%29+colloid+droplets%3B+%28v%29+microvilli%3B+%28r%29+ribosomes+on+endoplasmic+reticulum%3B+%28g%29+Golgi+apparatus%3B+%28m%29+mitochondrion%3B+%28p%29+plasma+membrane%3B+%28c%29+capillary+cells%3B+%28n%29+nucleus%3B+%28b%29+basement+membrane%3B+%28o%29+open+%22pore%22+endothelial+cells%26nbsp%3B%3B+%28c%29+cilium.+%28Reproduced+by+permission+of+the+Journal+of+Ultrastructural+Research%29.%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3C%2Ftbody%3E%3C%2Ftable%3E%0D%0A%3C%2Fcenter%3E%3Cdiv+style%3D%22margin-bottom%3A+0.19in%3B+margin-top%3A+0.19in%3B+text-indent%3A+0in%3B%22%3E%0D%0A%0D%0A%3C%2Fdiv%3E%0D%0A%3Ccenter%3E%3Ctable+border%3D%221%22+cellpadding%3D%220%22+cellspacing%3D%220%22+style%3D%22width%3A+445px%3B%22%3E%3Ccol+width%3D%22332%22%3E%3C%2Fcol%3E%3Ccol+width%3D%22114%22%3E%3C%2Fcol%3E%3Ctbody%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22+width%3D%22332%22%3E%3Cimg+align%3D%22BOTTOM%22+border%3D%221%22+height%3D%22482%22+name%3D%22graphics6%22+src%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Ffigures%2Ffigure1-6.jpg%22+width%3D%22306%22+%2F%3E%3C%2Ftd%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22+valign%3D%22TOP%22+width%3D%22114%22%3E%0D%0A%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+bgcolor%3D%22%2399ccff%22+colspan%3D%222%22+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22+width%3D%22445%22%3E%3Cb%3EFig.+1-6.%3C%2Fb%3E%26nbsp%3BElectron+micrographs+of+rat+thyroid.+%28a%29+Appearance+after+inactivation+of+the+gland+by+two+daily+doses+of+T4.+The+micrograph+shows+two+cell+nuclei+%28N%29%2C+well-developed+rough-surfaced+endoplasmic+reticulum+%28RER%29%2C+Golgi+apparatus+%28G%29%2C+mitochondria+%28M%29%2C+lyosomes+%28L%29%2C+and+numerous+dense%2C+apical+%28exocytocic%29+vesicles+%28V%29.+Because+of+the+T4-induced+TSH+suppression%2C+no+colloid+droplets+are+present+%28no+hormone+release%29%3B+TG+synthesis%2C+however%2C+is+still+going+on%2C+as+indicated+by+the+dense+apical+vesicle.+%28b%29+Appearance+20+minutes+after+intravenous+administration+of+TSH+%28100+mU%29+to+a+rat+treated+with+T4+for+two+days.+The+most+characteristic+features+of+these+cells+are+the+large+number+of+colloid+droplets+%28CD%29+and+the+almost+complete+disappearance+of+dense+apical+vesicles%3B+TSH+has+induced+an+emptying+of+these+vesicles+into+the+follicle+lumen.+Other+organelles+are+similar+to+those+in+Fig.+1-2.+Note+the+close+relation+relation+between+colloid+droplets+and+lysosomes+%28L%29.+At+the+base+of+the+follicle+cells+part+of+a+blood+capillary+%28C%29+is+seen.+%28Micrographs+kindly+supplied+by+Professor+Ragnar+Ekholm%2C+Goteborg%2C+Sweden%29.%0D%0AThe+Golgi+apparatus+is+located+near+the+nucleus+and+consists+of+small+vacuoles+and+vesicles+400-800+%C3%85+in+diameter.+No+nucleoprotein+granules+are+found+on+the+surface+of+these+vesicles.+The+content+of+the+Golgi+vesicles+has+a+density+similar+to+that+of+secretion+droplets.%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3C%2Ftbody%3E%3C%2Ftable%3E%0D%0A%3C%2Fcenter%3E%3Cdiv+style%3D%22margin-bottom%3A+0.19in%3B+margin-top%3A+0.19in%3B+text-indent%3A+0in%3B%22%3E%0D%0A%0D%0A%3C%2Fdiv%3E%0D%0ANumerous+rod-shaped+or+irregular+mitochondria+are+present.+Their+average+diameter+is+0.2+mm.+They+are+bordered+by+a+triple-layered+membrane+160+%C3%85+in+width+consisting+of+two+opaque+layers+and+a+less+opaque+interposed+layer.+The+inner+opaque+layer+is+thrown+up+into+folds%2C+or+cristae%2C+which+run+irregularly%2C+either+in+the+long+or+the+short+axis+of+the+mitochondrion.%0D%0AThe+nucleus+is+enclosed+within+a+double-walled+envelope+whose+layers+are+separated+by+a+less+dense+area+approximately+200+%C3%85+thick.+The+outer+nuclear+membrane+is+continuous+with+the+membranes+forming+the+endoplasmic+reticulum.+The+nuclear+envelope+has+characteristic+pores+400+%C3%85+in+diameter.%0D%0AThe+abutting+plasma+membranes+of+adjacent+cells+parallel+one+another+and+are+about+70+%C3%85+thick.+They+are+separated+by+a+space+150+%C3%85+wide%2C+which+contains+a+material+of+the+same+density+as+the+basement+membrane.+The+membrane+at+the+base+of+the+cell+is+covered+on+the+outer+surface+by+a+basement+membrane+that+is+approximately+400+%C3%85+in+width.+A+thin+layer+of+fibers+about+400+%C3%85+in+diameter+may+occur+at+the+outer+surface+of+the+basement+membrane.+The+basement+membrane+of+the+follicular+cell+is+separated+by+a+clear+area+from+the+basement+membrane+of+the+opposing+capillary+endothelium.+At+frequent+intervals%2C+the+wall+of+the+endothelial+cell+is+interrupted+by+a+pore+approximately+450+%C3%85+in+diameter.+Here+the+lumen+of+the+capillary+appears+to+be+in+direct+contact+with+the+basement+membrane+of+the+endothelial+cell.+The+thyroid+follicle+cells+are+separated+by+two+layers+of+basement+membrane+from+the+capillaries%2C+but+the+pores+in+the+endothelial+lining+of+the+capillaries+may+allow%2C+some+plasma+to+come+in+direct+contact+with+basement+membrane.+This+arrangement+should+allow+free+diffusion+of+materials+into+and+out+of+the+acinar+cell.%0D%0ARibosomes+of+the+ergastoplasm+synthesize+thyroglobulin+which+is+processed+in+the+smooth+reticulum+and+Golgi+apparatus.%0D%0AThe+colloid+lumen+is+sealed+by+various+cell-cell+junctions%3A+1%29+the+tight+junctions+of+the+zonula+occludens%2C+close+to+the+apical%26nbsp%3Bborder+and+which+separate+the+basal+from+the+apical+membrane+%28main+protein+constituents%26nbsp%3B%3A+occludins%29%3B+2%29+further+from+the+apex+are+the+tight+junctions+%28main+protein+components%26nbsp%3B%3A+cadherins%29+and+3%29+further+the+desmosome+junctions+%28main+protein+components%26nbsp%3B%3A+desmogleins+and+desmocollins%29.+All+these+junctions+are+linked+to+the+cytoskeleton.+Gap+junctions+%28main+protein+components%26nbsp%3B%3A+connexins%29+provide+joint+channels+allowing+the+passage+of+small+molecules+between+the+cells.%0D%0A%0D%0A%0D%0A%3Ca+href%3D%22%22+name%3D%2212%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AGENERAL+METABOLISM+OF+THE+FOLLICULAR+THYROID+CELL%3C%2Fh3%3E%0D%0AThe+metabolism+of+the+thyroid+as+related+to+hormone+synthesis+and+secretion+is+discussed+in+Chapter+2.+In+this+section%2C+a+review+of+some+general+aspects+of+metabolism+of+the+thyroid+acinar+cell+is+provided.+The+metabolism+of+the+thyroid+has+been+studied+by+all+the+usual+techniques+-+in+vivo+in+men+and+mice%2C+in+situ%2C+in+in+vitro+perfusion%2C+in+slices%2C+cells%2C+homogenates%2C+or+subcellular+fractions.+Several+species%2C+including+humans%2C+have+been+investigated%2C+often+with+obvious+and+consistent+species-related+differences.+Conditions+of+tissue+preparation+and+assays+have+varied+widely.%0D%0A%3Ca+href%3D%22%22+name%3D%2213%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AEnergy+metabolism%3C%2Fh3%3E%0D%0AEnergy+supply+in+the+human+thyroid+cell+is+necessary+for+many+activities+like+synthesis+of+nucleotides%2C+proteins%2C+nuclear+acids%2C+lipids%2C+transport+functions+and+other+activities+like+phagocytosis%2C+lysosome+movement+etc.+It+is+mainly+produced+by+mitochondrial+oxidative+phosphorylation+%28about+85%25%29+and+to+a+minor+extent+by+cytosolic+aerobic+glycolysis+%28117%29.+Energy+metabolism+in+the+human+thyroid+cell+resembles+in+many+aspects+that+in+the+dog+thyroid.+However%2C+the+absolute+values+of+oxygen+uptake%2C+glucose+uptake+and+lactate+formation+are+significantly+less+in+the+human+thyroid+slices.+Adenosine+triphosphate+%28ATP%29+concentration+in+the+thyroid+cell+is+in+the+millimolar+range+and+about+90%25+of+ribonucleotides+are+in+the+form+of+triphosphates+%28118%29.+Free+fatty+acids+are+probably+the+main+source+of+energy+in+thyroid+cells+as+respiration+is+maintained+for+long+periods+in+vitro+in+the+absence+of+exogenous+substrate.+As+there+is+hardly+any+glycogen+present+in+these+conditions%2C+most+probably+free+fatty+acids+are+the+endogenous+substrates.+Compartmentation+may+make+glycolytic+ATP+the+main+energy+source+for+some+membrane+functions+such+as+endocytosis+of+colloid.+Indeed+inhibition+of+glycolysis+inhibits+colloid+endocytosis+much+more+than+total+energy+metabolism+and+addition+of+glucose+counteracts+this+effect+%28118%29.%0D%0AMitochondrial+inhibitors+abolish+the+stimulatory+effect+of+TSH+on+thyroid+cell+respiration+%28119%29.+Cyclic+AMP+does+not+influence+mitochondrial+respiration+in+a+direct+manner.+It+is+therefore+assumed+that+the+stimulatory+effect+of+TSH+on+respiration+is+secondary+to+its+enhancing+effect+on+energy+%28i.e.+ATP%29+consuming+cellular+processes.%0D%0A%3Ca+href%3D%22%22+name%3D%2214%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0ACarbohydrate+metabolism%3C%2Fh3%3E%0D%0AThe+main+source+of+energy+delivery+for+metabolic+processes+in+the+thyroid+cell+are+free+fatty+acids.+However%2C+glucose+metabolism+has+an+important+function+in+the+thyroid+for+several+reasons.+About+70%25+of+the+glucose+taken+up+by+dog+or+human+thyroid+slices+is+transformed+to+lactate%2C+a+further+5%25+is+catabolized+through+the+Embden-Meyerhof+pathway+and+the+Krebs+cycle+%28120%29.+Another+6%25+of+glucose+carbon+is+incorporated+into+protein+and+less+than+1%25+into+lipids+and+glycogen.+The+remaining+part+%28about+10%25%29+is+oxidized+through+the+hexose+monophosphate+pathway+%28HMP%29.+Most+of+the+enzymes+participating+in+the+Embden-Meyerhof+pathway%2C+HMP+and+Krebs+cycle+have+been+demonstrated+in+the+human+thyroid+%28121%29+%28122%29+%28123%29.+As+hexokinase+instead+of+glucokinase+is+present+in+the+thyroid%2C+the+rate+of+phosphorylation+of+glucose+is+probably+independent+of+its+concentration+because+of+the+low+Km+of+hexokinase+for+glucose.%0D%0AGlucose+metabolism+serves+several+purposes.+The+incorporation+of+glucose+carbon+into+proteins+is+related+to+the+function+of+the+thyroid+cell+in+protein+synthesis+i.e.+synthesis+of+thyrogobulin+which+contains+10%25+carbohydrate.+The+metabolism+of+glucose+along+the+HMP+is+related+to+the+generation+of+NADPH+and+pentoses+in+this+pathway.+The+production+of+pentoses+is+obviously+necessary+for+generation+of+nucleotides.+NADPH+production+is+necessary+in+several+respects+%28Fig.+7%29.+It+is+needed+for+generation+of+H2O2+for+oxidation%2C+organification+of+iodide+and+thyroid+hormone+synthesis.+NADPH+is+also+an+important+cofactor+in+iodotyrosines+deiodination.+It+is+also+needed+to+reduce+oxidized+glutathione+after+its+generation+by+GSH+peroxidase+in+the+detoxification+of+the+H2O2+leaking+in+the+cell+%28124%29.%0D%0A%3Ccenter%3E%3Ctable+border%3D%221%22+cellpadding%3D%220%22+cellspacing%3D%220%22+style%3D%22width%3A+497px%3B%22%3E%3Ctbody%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cimg+align%3D%22BOTTOM%22+border%3D%221%22+height%3D%22540%22+name%3D%22graphics7%22+src%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Ffigures%2Ffigure1-7.jpg%22+width%3D%22720%22+%2F%3E%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+bgcolor%3D%22%2399ccff%22+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22+width%3D%22497%22%3E%3Cb%3EFig.+1-7.%3C%2Fb%3E%26nbsp%3BPostulated+NADP+oxidation-reduction+cycle+in+thyroid.+Four+mechanisms+of+NADPH+oxidation+are+outlined%3A+the+reduction+of+any+intermediate+X+by+an+NADPH-linked+dehydrogenase%2C+the+deiodination+of+iodotyrosines+released+by+thyroglobulinolysis%2C+the+generation+of+H2O2+by+THOX+%28thyroid+H2O2+generating+enzyme%29%2C+and+the+reduction+of+H2O2+through+GSH+peroxidase.+TG+and+TGI%3A+uniodinated+and+iodinated+thyroglobulin.+%2B%2C+activation.%26nbsp%3B%3Cspan+lang%3D%22de-DE%22%3E%28From%3A+Dumont+JE+%28124%29.%3C%2Fspan%3E%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3C%2Ftbody%3E%3C%2Ftable%3E%0D%0A%3C%2Fcenter%3E%3Cdiv+lang%3D%22de-DE%22%3E%0D%0A%0D%0A%3C%2Fdiv%3E%0D%0AH2O2+generation+is+stimulated+by+TSH+through+cAMP+in+dog+thyroid+and+by+Ca%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E%2B%2B%3C%2Fsup%3E%26nbsp%3Band+diacylglycerol+in+all+investigated+species%2C+including+humans+and+dogs.%0D%0ATSH+enhances+carbohydrate+metabolism+in+the+dog+thyroid+%28120%29.+During+the+stimulation+there+is+selective+increase+in+the+activity+of+the+HMP+whereas+incorporation+of+glucose+into+proteins+and+lipids+decreases+%28120%29.+The+activity+of+TSH+in+this+metabolism+is+probably+mediated+by+cAMP%2C+since+this+nucleotide+can+reproduce+the+TSH+effects+on+glucose+uptake%2C+catabolism%2C+incorporation+in+protein+and+lipids+and+on+the+HMP+pathway.+TSH+also+causes+an+increase+in+NADPH+and+NADP%2B+concentration+through+increased+NAD%2B+kinase+activity+%28124%29.%0D%0AThe+increased+metabolic+activity+induced+by+TSH+mainly+reflects+increased+consumption+by+NADPH+dependent+processes+stimulated+via+cAMP.+For+instance%2C+the+activity+of+the+HMP+pathway+is+predominantly+dependent+on+the+availability+of+the+substrate+NADP%2B+generated+during+oxidation+of+NADPH+%28124%29.%0D%0A%3Ca+href%3D%22%22+name%3D%2215%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AMitochondrial+Respiration%3C%2Fh3%3E%0D%0AThe+mitochondrion+has+appropriately+been+termed+the+%22powerhouse%22+of+the+cell.+It+provides+about+85%25+of+generated+ATP+in+the+thyroid+cell%2C+only+15%25+coming+from+glycolysis.+The+thyroids+of+different+animal+species+contain+mitochondria+with+their+typical+morphology%2C+having+electron+transport+chain%2C+Krebs+cycle+enzymes%2C+coupled+oxidative+phosphorylation+and+good+respiratory+control+%28119%29.+The+activity+of+mitochondria+is+controlled+by+adenosine+diphosphate+%28ADP%29+levels.+Also+respiration+linked+Ca%2B%2B+accumulation+plays+a+general+and+fundamental+role+in+vertebrate+cell+physiology+%28125%29.+Free+fatty+acids+are+the+preferred+substrate+of+oxidation+in+the+unstimulated+thyroid%2C+presumably+through+mitochondrial+pathways+%28126%29.+In+thyroids+of+patients+operated+for+hyperthyroid+Graves%27+disease+all+enzyme+activities+studied+were+increased+suggesting+an+increase+in+the+mitochondrial+population+in+chronically+stimulated+thyroid+cells+%28118%29.+TSH+increases+oxygen+consumption+in+thyroid+slices+by+20+-+30%25+within+a+few+minutes%2C+independently+of+exogenous+substrates.+The+increased+respiration+is+oligomycin+and+antimycin+sensitive.+Thus%2C+respiration+is+of+largely+mitochondrial+origin+and+probably+represents+the+effect+of+TSH+in+increasing+metabolic+activities+and+consequently+ATP+consumption+%28see+section+on+Energy+Metabolism%29+%28124%29.+TSH+augments+oxidation+of+pyruvate+and+acetate+by+thyroid+slices.+Compounds+such+as+perchlorate%2C+methimazole%2C+iodide%2C+thiocyanate+and+T4+have+no+significant+direct+action+on+thyroid+mitochondria+%28119%29.+In+isolated+thyroid+mitochodria+protein+synthesis+is+dependent+on+intact+electron+transport+and+oxidative+phosphorylation.+It+is+inhibited+by+chloramphenicol+but+not+by+cycloheximide+%28127%29.%0D%0A%3Ca+href%3D%22%22+name%3D%2216%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0ARNA+and+DNA+Metabolism%3C%2Fh3%3E%0D%0AChronic+TSH+stimulation+produces+cell+hypertrophy%2C+and+proliferation+with+a+greater+increase+of+RNA+than+of+DNA.+Since+RNA+and+DNA+synthesis+are+required+for+cell+growth+and+division%2C+it+is+not+surprising+that+TSH+stimulation+causes+rapid+and+continued+increases+in+synthetic+activities.+When+given+in+vivo%2C+TSH+stimulates+uptake+and+incorporation+of+RNA+precursors+within+one+hour+and+net+RNA+increases+in+about+12+hours+%28128%29+%28129%29.+TSH+stimulates+cell+uptake+and+synthesis+of+purine+and+pyrimidine+precursors+%28130%29+%28131%29+and+purine+and+pyrimidine+synthesis.+Synthesis+of+both+messenger+RNA+%28mRNA%29+and+ribosomal+RNA+%28rRNA%29+is+stimulated+by+TSH+%28132%29.+The+population+of+mRNA+preferentially+synthesized+in+response+to+TSH+and+cyclic+AMP+is+important+and+includes+specific+thyroid+gene+expression+such+as+thyroperoxidase+%28TPO%29+Na%2B%2FI-+cotransporters+%28NIS%29+%28133%29%2C+thyroglof+protein+synthesis+by+TSH+can+be+demonstrated+in+vitro+in+dog+thyroid+slices+%28137%29%2C+and+also+in+isolated+thyroid+cells+but+not+in+primary+cultures+of+dog+thyroid+cells.+Within+12-24+hours+of+chronic+TSH+stimulation+in+vivo%2C+net+protein+content+may+be+decreased+by+active+TG+hydrolysis%2C+but+after+this%2C+protein+content+is+increased+%28138%29.+This+response+remains+nearly+linear+over+four+to+five+weeks+as+thyroid+size+in+animals+quintuples.+The+response+is+primarily+due+to+production+of+new+cells%2C+since+DNA+and+protein+change+in+parallel.%0D%0AHuge+polysomes+%2840+to+80+ribosomal+units%29+connected+by+mRNA+have+been+demonstrated+in+the+thyroid+%28139%29+%28140%29+and+were+shown+to+incorporate+precursors+into+TG-related+peptides.+%28Fig.1-8%29.+In+dog+thyroid+slices%2C+TSH+also+shifts+thyroid+monosomes+to+polysomes%2C+and+this+is+stimulated+by+cAMP.+This+action+suggests+a+direct+effect+on+translation+%28141%29.%0D%0A%3Ccenter%3E%3Ctable+border%3D%221%22+cellpadding%3D%220%22+cellspacing%3D%220%22+style%3D%22width%3A+400px%3B%22%3E%3Ccol+width%3D%2281%22%3E%3C%2Fcol%3E%3Ccol+width%3D%22319%22%3E%3C%2Fcol%3E%3Ctbody%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22+width%3D%2281%22%3E%3Cimg+align%3D%22BOTTOM%22+border%3D%221%22+height%3D%22602%22+name%3D%22graphics8%22+src%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Ffigures%2Ffigure1-8.jpg%22+width%3D%2281%22+%2F%3E%3C%2Ftd%3E%3Ctd+bgcolor%3D%22%2399ccff%22+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22+width%3D%22319%22%3E%3Cb%3EFig.+1-8%3C%2Fb%3E.+Electron+microscopic+photograph+of+an+enormous+polysome+containing+60+or+70+monosomes%2C+the+presumed+source+of+TG+synthesis.+The+arrows+point+to+a+thread+possibly+representing+mRNA+holding+the+polysome+together.+%28From+Keyhani+et+al.%2C+J.+Microscop.%2C+10%3A269%2C1971%2C+with+permission%29.%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3C%2Ftbody%3E%3C%2Ftable%3E%0D%0A%3C%2Fcenter%3E%3Ca+href%3D%22%22+name%3D%2218%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0ALipid+metabolism%3C%2Fh3%3E%0D%0AFree+fatty+acids+are+the+main+fuel+of+the+thyroid+cell+and+they+may+be+completely+oxidized.+Sufficient+endogenous+substrate+is+present+to+sustain+respiration+for+several+hours+during+in+vitro+incubation+of+thyroid+slices+%28142%29+%28143%29+%28144%29.+Studies+on+localization+of+lipids+in+human+thyroids+have+shown+that+small+amounts+are+only+present+in+goitres+from+thyrotoxic+patients%2C+but+that+appreciable+amounts+are+present+in+the+normal+human+thyroid+i.e.+phospholipids%2C+cholesterol+and+gangliosides%3A+5.2%2C+4.3+and+0.12+mmol%2Fkg+fresh+tissue.+C-cells+contain+most+abundantly+phospholipids.+The+human+thyroid+contains+phospholipids+in+the+proportion%3A+phosphatidylcholine+%2841.8%25%29%2C+phosphathidylethanolamine+%2826.9%25%29%2C+phosphathidylserine+%2810.4%25%29%2C+phosphathidylinositol+%284.4%25%29%2C+cardiolipin+%283.4%25%29%2C+sphyngomyelin+%2812.4%25%29+%28145%29+%28146%29+%28147%29.+TSH+enhances+the+incorporation+of+precursors+into+most+phospholipids.+The+effect+is+believed+to+reflect+a+direct+stimulation+of+synthesis+of+phospholipids.+However%2C+as+TSH+also+stimulates+phospholipid+degradation%2C+increased+phospholipids+synthesis+under+the+influence+of+TSH+could+correspond+in+part+to+this+accelerated+turnover+rather+than+to+an+accumulation+%7B123%7D.+TSH+also+stimulates+incorporation+of+inositol+into+phosphoinositides+in+a+glucose+free+system.+TSH+specifically+enhances+synthesis+of+phosphatidic+acid+from+glycerophosphate+after+in+vivo+administration+%28148%29+%28149%29.%0D%0A%3Ca+href%3D%22%22+name%3D%2219%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AElectrolyte+Transport+and+men%3B%22%3E%0D%0A%0D%0A%3C%2Fdiv%3E%0D%0A%3Ca+href%3D%22%22+name%3D%2220%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0ATHYROID+REGULATORY+FACTORS%3C%2Fh3%3E%0D%0A%3Ca+href%3D%22%22+name%3D%2221%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AIn+Physiology%3C%2Fh3%3E%0D%0A%0D%0AFour+major+biologic+variables+are+regulated+in+the+thyrocyte+as+in+any+other+cell+type%3A+function%2C+cell+size%2C+cell+number%2C+and+differentiation.+The+first+three+variables+are+quantitative+and+the+latter+is+qualitative.+In+this+chapter+we+consider+the+factors+involved+in+these+controls+in+physiology+and+in+pathology%2C+the+main+regulatory+cascades+through+which+these+factors+exert+their+effects%2C+and+the+regulated+processes%2C+which+are+function%2C+proliferation+and+cell+death%2C+gene+expression%2C+and+differentiation.+Whenever+possible%2C+we+describe+what+is+known+in+humans.%0D%0AThe+two+main+factors+that+control+the+physiology+of+the+thyroid+after+embryogenesis+are+the+requirement+for+thyroid+hormones+and+the+supply+of+its+main+and+specialized+substrate+iodide+%28Table+1-1%29.+Thyroid+hormone+plasma+levels+and+action+are+monitored+by+the+hypothalamic+supraoptic+nuclei+and+by+the+thyrotrophs+of+the+anterior+lobe+of+the+pituitary%2C+where+they+exert+a+negative+feedback.+The+corresponding+homeostatic+control+is+expressed+by+thyroid-stimulating+hormone+%28TSH%2C+thyrotropin%29.+The+hypophysis+adjusts+its+secretion+of+TSH+to+the+sensitivity+of+the+thyroid%2C+increasing+TSH+levels+when+thyrocyte+sensitivity+decreases+%28e.g.+because+of+reduced+TSH+receptor+expression%29+%28150%29+.+The+TSH+receptor+is+also+stimulated+by+a+new+different+natural+hormone+cloned+by+homology%2C+thyrostimuline.+The+physiological+role+of+this+protein+is+unknown+but+its+level+is+not+controlled+by+a+thyroid+hormone+feedback+and+it+does+not+participate+in+the+homeostatic+control+of+the+thyroid+%28151%29.+Iodide+supply+is+monitored+in+part+through+its+effects+on+the+plasma+level+of+thyroid+hormones%2C+but+mainly+in+the+thyroid+itself%2C+where+it+depresses+various+aspects+of+thyroid+function+and+the+response+of+the+thyrocyte+to+TSH.+These+two+major+physiologic+regulators+control+the+function+and+size+of+the+thyroid+-+TSH+positively%2C+iodide+negatively+%28124%3B152-154%29.+These+are+the+specific+controls+exerted+at+the+level+of+the+thyrocyte+itself.+The+follicular+cells+themselves+probably+regulate+the+other+thyroid+cells%2C+fibroblasts+and+endothelial+cells+through+local+extracellular+signals+such+as+NO%2C+prostaglandins%2C+growth+factors+etc.%0D%0A%3Cimg+align%3D%22BOTTOM%22+border%3D%221%22+height%3D%22540%22+name%3D%22graphics9%22+src%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Ffigures%2Ftable1.jpg%22+width%3D%22780%22+%2F%3E%0D%0AIn+mice+embryo%2C+other+unknown+factors+control+differentiation+and+organ+growth+which+takes+place+normally+in+the+absence+of+TSH+receptor+%28155%3B156%29.+However%2C+homozygous+inactivating+mutations+of+the+TSH+receptor+in+familial+congenital+hypothyroidism+were+found+to+be+associated+with+a+very+hypoplastic+thyroid+gland+%28157%29.+Although+the+thyroid+contains+receptors+for+thyroid+hormones+and+a+direct+effect+of+these+hormones+on+thyrocytes+would+make+sense+%28158%29%2C+as+yet+little+evidence+has+indicated+that+such+control+plays+a+role+in+physiology+%28159%29.%26nbsp%3B%3Cb%3E%3C%2Fb%3EHowever+expression+of+dominant+negative+thyroid+hormone+receptors+in+mice+represses+PPAR%CE%B3+expression+and+induces+thyroid+tumors+in+thyroid+%28160%29.+Luteinizing+hormone+%28LH%29+and+human+chorionic+gonadotropin+%28hCG%29+at+high+levels+directly+stimulate+the+thyroid%2C+and+this+effect+accounts+for+the+depression+of+TSH+levels+and+sometimes+elevated+thyroid+activity+at+the+beginning+of+pregnancy+%28161-163%29.%0D%0AThe+thyroid+gland+is+also+influenced+by+various+other+nonspecific+hormones+%28164%29.%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E%26nbsp%3B%3C%2Fsup%3EHydrocortisone+exerts+a+differentiating+action+in+vitro+%28165%29.+Estrogens+affect+the+thyroid+by+unknown+mechanisms%2C+directly+or+indirectly%2C+as+exemplified+clinically+in+the+menstrual+cycle+and+in+pregnancy.+Growth+hormone+induces+thyroid+growth%2C+but+its+effects+are+thought+to+be+mediated+by+locally+produced+somatomedins+%28IGF-I%29.+Nevertheless+the+presence+of+basal+TSH+levels+might+be+a+prerequisite+for+the+growth+promoting+action+of+IGF-I%2C+because+a+GH+replacement+therapy+did+not+increase+thyroid+size+in+patients+deficient+for+both+GH+and+TSH+%28166%29.+The+anomalously+low+endemic+goiter+prevalence+among+pygmies+living+in+iodine+deficient+areas+%28167%29%2C+who+are+genetically+resistant+to+IGF-I%2C+is+also+compatible+with+an+in+vivo+permissive+effect+of+IGF-1+and+IGF-1+receptor+on+TSH+mitogenic+action.+Indeed+thyroids+of+transgenic+mice+overexpressing+IGF1+and+IGF1+receptor+develop+hyperplasia+and+a+degree+of+autonomy+vs+TSH%3A+their+serum+TSH+is+lower+and+thyroid+hormones+level+normal+which+shows+that+they+require+less+TSH+to+maintain+normal+thyroid+hormone+levels+%28168%3B169%29.%3Cb%3E%3C%2Fb%3EIn+dog+and+human+thyroid+primary+cultures%2C+the+presence+of+insulin+receptors+strictly+depends+on+TSH%2C+suggesting+that+thyroid+might+be+a+more+specific+target+of+insulin+than+generally+considered+%28170%3B171%29.+It+is+permissive+for+TSH+mitogenic+action+in+vitro.%0D%0AEffects+of+locally+secreted+neurotransmitters+and+growth+factors+on+thyrocytes+have+been+demonstrated+in+vitro+and+sometimes+in+vivo%2C+and+the+presence+of+some+of+these+agents+in+the+thyroid+has+been+ascertained.+The+set+of+neurotransmitters+acting+on+the+thyrocyte+and+their+effects+vary+from+species+to+species+%28152%3B172%29.+In+human+cells%2C+well-defined+direct%2C+but+short-lived+responses+to+norepinephrine%2C+ATP%2C+adenosine%2C+bradykinin%2C+and+thyrotropin-releasing+hormone+%28TRH%29+have+been+observed+%28152%3B173%3B174%29.+In+rat%2C+as+evidenced+by+superior+cervical+ganglion+decentralization%2C+sympathetic+activity+positively+modulates+function+and+size+of+the+thyroid+%28175%29.%0D%0AGrowth+factor+signaling+cascades+demonstrated+in+vitro+can+exert+similar+effects+in+vivo.+In+nude+mice%2C+the+injection+of+EGF+promotes+DNA+synthesis+in+thyroid+and+inhibits+iodide+uptake+in+xenotransplanted+rat+%28176%29+and+human+thyroid+tissues+%28177%29.+By+contrast%2C+the+injection+of+FGF+induces+a+colloid+goiter+in+mice+with+no+inhibition+of+iodide+metabolism+or+thyroglobulin+and+thyroperoxidase+mRNA+accumulation+%28178%29.+These+effects+are+the+exact+replica+of+initial+observations+from+the+dog+thyroid+primary+culture+system+%28179%29+and+other+thyroid+primary+culture+systems+%28180-183%29.+EGF+and+FGF+have+since+been+reported+to+be+locally+synthesized+in+the+thyroid+gland%2C+as+a+possible+response+to+thyroxine+and+TSH+%28184%29+respectively.+Their+exact+role+as+autocrine+and%2For+paracrine+agents+in+the+development%2C+function+and+pathology+of+the+thyroid+gland+of+different+species+has+yet+to+be+clarified+%28185%3B186%29.+HGF+does+not+activate+mitogenesis+in+normal+human+thyrocyte.+The+Transforming+Growth+Factors+%EF%80%A0%28TGF%29%CE%B2+constitute+another+category+of+cytokines+that+are+produced+locally+by+thyrocytes+and+influence+their+proliferation+and+the+action+of+mitogenic+factors+%28185%3B187%29.+TGF%CE%B2+inhibits+proliferation+and+prevents+most+of+the+effects+of+TSH+and+cAMP+in+human+thyrocytes+in+vitro+%28188%3B189%29.+TGF%CE%B2+is+synthesized+as+an+inactive+precursor+which+can+be+activated+by+different+proteases+produced+by+thyrocytes.+TGF%CE%B2+expression+is+upregulated+during+TSH-induced+thyroid+hyperplasia+in+rats%2C+suggesting+an+autocrine+mechanism+limiting+goiter+size+%28190%29.+Activin+A+and+the+bone+morphogenetic+peptide+%28BMP%29%2C+which+are+related+to+TGF%CE%B2%2C+%EF%80%AC%EF%80%A0are+also+present+in+thyroid+and+inhibit+thyrocyte+proliferation+in+vitro+%28191%29.+Unlike+TGF%CE%B2%2C+they+are+directly+synthesized+as+an+active+form.+Elements+of+a+Wnt%2F%CE%B2+catenin+signaling+pathway+%28Wnt+factors%2C+Frizzled+receptors+and+disheveled+isoforms%29+have+been+identified+in+human+thyroid+and+thyroid+cancer+cell+lines+%28192%29.+The+eventual+role+in+vivo+in+humans+of+most+of+these+factors+remains+to+be+proved+and+clarified.%0D%0AThyroglobulin+has+been+reported+as+a+negative+feedback+inhibitor+repressing+the+expression+of+specific+thyroid+transcription+factors+TTF1%2C+TTF2%2C+Pax8+and+acting+through+a+putative+receptor+at+the+apical+membrane+%28193%29.+However%2C+as+previous+claims+by+the+same+group+%28the+exophtalmic+producing+factor%2C+ganglioside+as+the+TSH+receptor%2C+etc%29+this+one+is+neither+substantiated+nor+supported+by+others.%0D%0AHuman+thyroid+cells+contain+androgen+and+estrogen+receptors+%28194%29.+Estrogens+promote+the+growth+of+these+cells+%28195%29+which+may+explain+the+higher+prevalence+of+thyroid+tumors+and+diseases+in+women%2C+particularly+between+puberty+and+menopause.%0D%0A%3Ca+href%3D%22%22+name%3D%2222%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AIn+Pathology%3C%2Fh3%3E%0D%0AMutated+constitutively+active+TSH+receptors+and+Gs+proteins+cause+thyroid+autonomous+adenomas+%28196%3B197%29.+Mutations+conferring+higher+sensitivity+of+the+TSH+receptor+to+LH%2FHCG+cause+hyperthyroidism+in+pregnancy+%28198%29+%28199%29.+Pathologic+extracellular+signals+play+an+important+role+in+autoimmune+thyroid+disease.+Thyroid-stimulating+antibodies+%28TSAbs%29%2C+which+bind+to+the+TSH+receptor+and+activate+it%2C+reproduce+the+stimulatory+effects+of+TSH+on+the+function+and+growth+of+the+tissue.+Their+abnormal+generation+is+responsible+for+the+hyperthyroidism+and+goiter+of+Graves%27+disease.+The+kinetic+characteristics+of+TSH+and+TSAbs+differ%3A+TSH+effects+on+camp+accumulation+are+rapid+and+disappear+rapidly+in+the+absence+of+the+hormone+%28minutes%29+while+TSAbs+effects+are+slow+and+persistent+%28hours%29+%28200%29.%0D%0AThyroid-blocking+antibodies+%28TBAbs%29+also+bind+to+the+TSH+receptor+but+do+not+activate+it+and+hence+behave+as+competitive+inhibitors+of+the+hormone.+Such+antibodies+are+responsible+for+some+cases+of+hypothyroidism+in+thyroiditis.+Both+stimulating+and+inhibitory+antibodies+induce+transient+hyperthyroidism+or+hypothyroidism+in+newborns+of+mothers+with+positive+sera+%28153%29.+The+existence+of+thyroid+growth+immunoglobulins+has+been+hypothesized+to+explain+the+existence+of+Graves%27+disease+with+weak+hyperthyroidism+and+prominent+goiter+%28201%29.+The+thyroid+specificity+of+such+immunoglobulins+would+imply+that+they+recognize+thyroid-specific+targets.+This+hypothesis+is+now+abandoned+%28202-204%29.+Discrepancies+between+growth+and+functional+stimulation+may+instead+reflect+cell+intrinsic+factors.+Local+cytokines+have+been+shown+to+influence%2C+mostly+negatively%2C+the+function%2C+growth%2C+and+differentiation+of+thyrocytes+in+vitro+and+thyroid+function+in+vivo.+Because+they+are+presumably+secreted+in+loco+in+autoimmune+thyroid+diseases%2C+these+effects+might+play+a+role+in+the+pathology+of+these+diseases%2C+but+this+notion+has+not+yet+been+proved+%28152%29+%28164%29.+Moreover+in+selenium+deficiency+secretion+of+TGF%CE%B2+by+macrophages+has+been+implicated+in+the+generation+of+thyroid+fibrosis+%28205%29+%28206%29+and+the+pathogenesis+of+thyroid+failure+in+endemic+cretinism.%3Cb%3E%26nbsp%3B%3C%2Fb%3EThe+overexpression+of+both+FGF+and+FGF+receptor+1+in+thyrocytes+from+human+multinodular+goiter+might+explain+their+relative+TSH-independence+%28207%29.+On+the+other+hand%2C+the+subversion+of+tyrosine+kinase+pathways+similar+to+those+normally+operated+by+local+growth+factors+%28i.e.+the+activation+of+Ret%2FPTC+%28208%29+and+TRK+%28209%29%2C+the+overexpression+of+Met%2FHGF+receptor+sometimes+in+association+with+HGF+%28210%29%2C+or+erbB%2FEGF+receptor+in+association+with+its+ligand+TGF%CE%B1+%28211%29+can+be+causally+associated+with+TSH-independent+thyroid+papillary+carcinomas.+An+autocrine+loop+involving+IGF-II+and+the+insulin+receptor+isoform-A+is+also+proposed+to+stimulate+growth+of+some+thyroid+cancers+%28212%29.+Thyroid+cancer+cells+often+escape+growth+inhibition+by+TGF%CE%B2+%28213%29.%0D%0A%0D%0A%3Ca+href%3D%22%22+name%3D%2223%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AREGULATORY+CASCADES%3C%2Fh3%3E%0D%0AThe+great+number+of+extracellular+signals+acting+through+specific+receptors+on+cells+in+fact+control+a+very+limited+number+of+regulatory+cascades.+We+first+outline+these+cascades%2C+along+with+the+signals+that+control+them%2C+and+then+describe+in+more+detail+the+specific+thyroid+cell+features%3A+controls+by+iodide+and+the+TSH+receptor.%0D%0A%3Ca+href%3D%22%22+name%3D%2224%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AThe+Cyclic+Adenosine+Monophosphate+Cascade%3C%2Fh3%3E%0D%0AThe+cyclic+adenosine+monophosphate+%28cAMP%29+cascade+in+the+thyroid+corresponds%2C+as+far+as+it+has+been+studied%2C+to+the+canonic+model+of+the+%CE%B2-adrenergic+receptor+cascade+%28153%29+%28Fig.+1-9%29.+It+is+activated+in+the+human+thyrocyte+by+the+TSH+and+the+%CE%B2-adrenergic+and+prostaglandin+E+receptors.+These+receptors+are+classic+seven-transmembrane+receptors+controlling+transducing+guanosine+triphosphate+%28GTP%29-binding+proteins.+Activated+G+proteins+belong+to+the+G%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3Es%3C%2Fsub%3E%26nbsp%3Bclass+and+activate+adenylyl+cyclase%3B+they+are+composed+of+a+distinct+%CE%B1%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3Es%3C%2Fsub%3E%26nbsp%3Bsubunit+and+nonspecific+%CE%B2+and+%CE%B3+monomers.+Activation+of+a+G+protein+corresponds+to+its+release+of+guanosine+diphosphate+%28GDP%29+and+binding+of+GTP+and+to+its+dissociation+into+%CE%B1%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3EGTP%3C%2Fsub%3Eand+%CE%B2%CE%B3+dimers.+%CE%B1%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3EsGTP%3C%2Fsub%3E%26nbsp%3Bdirectly+binds+to+and+activates+adenylyl+cyclase.+Inactivation+of+the+G+protein+follows+the+spontaneous%2C+more+or+less+rapid+hydrolysis+of+GTP+to+GDP+by+%CE%B1%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3Es%3C%2Fsub%3E%26nbsp%3BGTPase+activity+and+the+reassociation+of+%CE%B1%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3EGDP%3C%2Fsub%3E%26nbsp%3Bwith+%CE%B2%CE%B3.+The+effect+of+stimulation+of+the+receptor+by+agonist+binding+is+to+increase+the+rate+of+GDP+release+and+GTP+binding%2C+thus+shifting+the+equilibrium+of+the+cycle+toward+the+%CE%B1%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3EGTP%3C%2Fsub%3E%26nbsp%3Bactive+form.+One+receptor+can+consecutively+activate+several+G+proteins+%28hit-and-run+model%29.+The+thyroid+contains+mainly+three+isoforms+of+adenylyl+cyclase+%3A+III%2C+VI+and+IX+%28214%29.+A+similar+system+negatively+controls+adenylyl+cyclase+through+G%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3Ei%3C%2Fsub%3E.+It+is+stimulated+in+the+human+thyroid+by+norepinephrine+through+%CE%B1%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E-receptors.+Adenosine+at+high+concentrations+directly+inhibits+adenylyl+cyclase.+The+cAMP+generated+by+adenylyl+cyclase+binds+to+the+regulatory+subunit+of+protein+kinase+A+%28PKA%29+that+is+blocking+the+catalytic+subunit+and+releases+this+now-active+unit.+The+activated%2C+released+catalytic+unit+of+protein+kinase+phosphorylates+serines+and+threonines+in+the+set+of+proteins+containing+accessible+specific+peptides+that+it+recognizes.+These+phosphorylations%2C+through+more+or+less+complicated+cascades%2C+lead+to+the+observed+effects+of+the+cascade.+cAMP-dependent+kinases+have+two+isoenzymes+%28I%2C+II%29%2C+the+first+of+which+is+more+sensitive+to+cAMP%2C+but+as+yet+no+clear+specificity+of+action+of+these+kinases+has+been+demonstrated.+In+the+case+of+the+thyroid%2C+this+cascade+is+activated+through+specific+receptors%2C+by+TSH+in+all+species%2C+and+by+norepinephrine+receptors+and+prostaglandin+E+in+humans%2C+with+widely+different+kinetics%3A+prolonged+for+TSH+and+short+lived+%28minutes%29+for+norepinephrine+and+prostaglandins+%28215%29.+Other+neurotransmitters+have+been+reported+to+activate+the+cascade+in+thyroid+tissue%2C+but+not+necessarily+in+the+thyrocytes+of+the+tissue+%28174%29.+Besides+PKA%2C+in+the+thyroid+cAMP+activates+EPAC+%28Exchange+Proteins+directly+Activated+by+cAMP%29+or+Rap+guanosine+nucleotide+exchange+factor-1+%28GEF-1%29+and+the+less+abundant+GEF-2%2C+which+activate+the+small+G+protein+Rap+%28216%29.+However%2C+despite+high+expression+of+EPAC1+in+thyrocytes+and+its+further+increase+in+response+to+TSH%2C+all+the+physiologically+relevant+cAMP-dependent+functions+of+TSH+studied+in+dog+thyroid+cells%2C+including+acute+regulation+of+cell+functions+%28including+thyroid+hormone+secretion%29+and+delayed+stimulation+of+differentiation+expression+and+mitogenesis%2C+are+mediated+only+by+PKA+activation+%28217%29.+The+role+of+the+cAMP%2FEPAC%2FRap+cascade+in+thyroid+thus+remains+largely+unknown.+Activation+of+PKA+inactivates+small+G+proteins+of+the+Rho+family+%28RhoA%2C+Rac1+and+Cdc42%29%2C+which+reorganizes+the+actin+cytoskeleton+and+could+play+an+important+role+in+stimulation+of+thyroid+hormone+secretion+and+induction+of+thyroid+differentiation+genes+%28218%29.+Of+the+other+known+possible+effectors+of+camp%2C+cyclic+guanosine+monophosphate+%28cGMP-dependent+protein+kinases+are+present+in+the+thyroid+but+cyclic+nucleotide-activated+channels+have+not+been+looked+for.+For+several+effects+of+cyclic+AMP+%28eg+NIS+and+thyroglobulin+induction%2C+DNA+synthesis%29+protein+kinase+A+is+required.%0D%0AThe+cAMP+cascade+is+also+controlled+by+several+negative+feedbacks.+The+most+important+is+the+activation+and+induction+by+PKA+of+PDE4+D3+and+other+phosphodiesterases+%28219%29+%28133%29%0D%0AThe+thyrocyte+is+very+sensitive+to+internal+cAMP%3A+a+mere+doubling+of+its+concentration+is+sufficient+to+elicit+near+maximal+thyroglobulin+phagocytosis+%28220%29.%0D%0A%0D%0A%3Ctable+align%3D%22center%22+border%3D%221%22%3E%3Ctbody%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cimg+align%3D%22BOTTOM%22+border%3D%221%22+height%3D%22540%22+name%3D%22graphics10%22+src%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Ffigures%2Ffigure1-9.jpg%22+width%3D%22780%22+%2F%3E%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cdiv+lang%3D%22fr-FR%22+style%3D%22background-attachment%3A+initial%3B+background-clip%3A+initial%3B+background-color%3A+%2399ccff%3B+background-image%3A+initial%3B+background-origin%3A+initial%3B+background-position%3A+initial+initial%3B+background-repeat%3A+initial+initial%3B+text-indent%3A+0in%3B%22%3E%0D%0A%3Cb%3EFig+.1.9.%3C%2Fb%3E%26nbsp%3BRegulatory+cascades+activated+by+thyroid-stimulating+hormone+%28TSH%29+in+human+thyrocytes.+In+the+human+thyrocyte%2C+H%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3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%3A+10px%3B%22%3E2%3C%2Fsub%3E%29+into+diacylglycerol+and+IP%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E3%3C%2Fsub%3E.+IP%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E3%3C%2Fsub%3E%26nbsp%3Benhances+calcium+release+from+its+intracellular+stores%2C+followed+by+an+influx+from+the+extracellular+medium.+The+rise+in+free+ionized+intracellular+Ca%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%2B%3C%2Fsup%3E%26nbsp%3Bleads+to+the+activation+of+several+proteins%2C+including+calmodulin.+The+latter+protein+in+turn+binds+to+target+proteins+and+thus+stimulates+them%3A+cyclic+nucleotide+phosphodiesterase+and%2C+most+importantly%2C+calmodulin-dependent+protein+kinases.+These+kinases+phosphorylate+a+whole+set+of+proteins+exhibiting+serines+and+threonines+on+their+specific+peptides+and+thus+modulate+them+and+cause+many+observable+effects+of+this+arm+of+the+cascade.+Calmodulin+also+activates+constitutive+nitric+oxide+%28NO%29+synthase+in+thyrocytes.+The+generated+NO+itself+enhances+soluble+guanylyl+cyclase+activity+in+thyrocytes+and+perhaps+in+other+thyroid+cells+and+thus+increases+cGMP+accumulation+%28224%29.+Nothing+is+yet+known+about+the+role+of+cGMP+in+the+thyroid+cell+but+NO+causes+vasodilatation.%0D%0ADiacylglycerol+released+from+PIP%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bactivates+protein+kinase+C%2C+or+rather+the+family+of+protein+kinases+C%2C+which+by+phosphorylating+serines+or+threonines+in+specific+accessible+peptides+in+target+proteins+causes+the+effects+of+the+second+arm+of+the+cascade+%28225%29.+It+inhibits+phospholipase+C+or+its+G%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3Eq%3C%2Fsub%3E%2C+thus+creating+a+negative+feedback+loop.+In+the+human+thyroid%2C+the+PIP%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bcascade+is+stimulated+through+specific+receptors+by+ATP%2C+bradykinin%2C+TRH+and+by+TSH+%28174%29+%28226%29+%28227%29.+The+effects+of+bradykinin+and+TRH+are+very+short+lived.+Acetylcholine%2C+which+is+the+main+activator+of+this+cascade+in+the+dog+thyrocyte+%28228%29%2C+is+inactive+on+the+human+cell%2C+although+it+activates+nonfollicular+%28presumably+endothelial%29+cells+in+this+tissue+%28174%29.%0D%0A%3Ca+href%3D%22%22+name%3D%2226%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AOther+Phospholipid-Linked+Cascades%3C%2Fh3%3E%0D%0AIn+dog+thyroid+cells+and+in+a+functional+rat+thyroid+cell+line+%28FRTL5%29%2C+TSH+activates+PIP%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bhydrolysis+weakly+and+at+concentrations+several+orders+of+magnitude+higher+than+those+required+to+enhance+cAMP+accumulation.+Of+course%2C+these+effects+have+little+biologic+significance.+However%2C+in+dog+cells%2C+at+lower+concentrations+TSH+increases+the+incorporation+of+labeled+inositol+and+phosphate+into+phosphatidylinositol.+Similar+effects+may+exist+in+human+cells%2C+but+they+would+be+masked+by+stimulation+of+the+PIP%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bcascade.+They+may+reflect+increased+synthesis%26nbsp%3B%3Cstrike%3E%3Cb%3E%3C%2Fb%3E%3C%2Fstrike%3Eperhaps+coupled+to+and+necessary+for+cell+growth+%28229%29.%0D%0ADiacylglycerol+can+be+generated+by+other+cascades+than+the+classic+Ca%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%2B%3C%2Fsup%3E-IP%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E3%3C%2Fsub%3E%26nbsp%3Bpathway.+Activation+of+phosphatidylcholine+phospholipase+D+takes+place+in+dog+thyroid+cells+stimulated+by+carbamylcholine.+Because+it+is+reproduced+by+phorbol+esters%2C+that+is%2C+by+stable+analogues+of+diacylglycerol%2C+it+has+been+ascribed+to+phosphorylation+of+the+enzyme+by+protein+kinase+C%2C+which+would+represent+a+positive+feedback+loop+%28230%29.+Although+such+mechanisms+operate+in+many+types+of+cells%2C+their+existence+in+human+thyroid+cells+has+not+been+demonstrated+%28231%29.%0D%0ARelease+of+arachidonate+from+phosphatidylinositol+by+phospholipase+A%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Band+the+consequent+generation+of+prostaglandins+by+a+substrate-driven+process+are+enhanced+in+various+cell+types+through+G+protein%E2%80%93coupled+receptors%2C+by+intracellular+calcium%2C+or+by+phosphorylation+by+protein+kinase+C.+In+dog+thyroid+cells+all+agents+enhancing+intracellular+calcium+concentration%2C+including+acetylcholine%2C+also+enhance+the+release+of+arachidonate+and+the+generation+of+prostaglandins.+In+this+species%2C+stimulation+of+the+cAMP+cascade+by+TSH+inhibits+this+pathway.+In+pig+thyrocytes%2C+TSH+has+been+reported+to+enhance+arachidonate+release.+In+human+thyroid%2C+TSH%2C+by+stimulating+PIP%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bhydrolysis+and+intracellular+calcium+accumulation%2C+might+be+expected+to+enhance+arachidonate+release+and+prostaglandin+generation%2C+but+such+effects+have+not+yet+been+proved.%0D%0A%3Ch2+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+16px%3B+font-style%3A+normal%3B+font-weight%3A+bold%3B%22%3E%0D%0A%3C%2Fh2%3E%0D%0A%3Ca+href%3D%22%22+name%3D%2227%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0ARegulatory+Cascades+Controlled+by+Receptor+Tyrosine+Kinases%3C%2Fh3%3E%0D%0AMany+growth+factors+and+hormones+act+on+their+target+cells+by+receptors+that+contain+one+transmembrane+segment.+They+interact+with+the+extracellular+domain+and+activate+the+intracellular+domain%2C+which+phosphorylates+proteins+on+their+tyrosines.+Receptor+activation+involves+in+some+cases+a+dimerization+and+in+others+a+conformational+change.+The+first+step+in+activation+is+interprotein+tyrosine+phosphorylation%2C+followed+by+binding+of+various+protein+substrates+on+tyrosine+phosphates+containing+segments+of+the+receptor.+Such+binding+through+src+homology+domains+%28SH2%29+leads+to+direct+activation+or+to+phosphorylation+of+these+proteins+on+their+tyrosines+and+to+membrane+localization.+In+turn%2C+these+cause+sequential+activation+of+the%26nbsp%3B%3Ci%3Eras%3C%2Fi%3E%26nbsp%3Band%26nbsp%3B%3Ci%3Eraf%3C%2Fi%3E%26nbsp%3Bproto-oncogenes%2C+mitogen-activated+protein+%28MAP%29+kinase+kinase%2C+MAP+kinase%2C+and+so+on%2C+on+the+one+hand%2C+and+phosphatidylinositol-3-kinase+%28PI-3-kinase%29%2C+protein+kinase+B+%28PKB%29%2C+and+TOR+%28target+of+rapamycin%29+on+the+other+hand.+The+set+of+proteins+phosphorylated+by+a+receptor+defines+the+pattern+of+action+of+this+receptor.+In+thyroids+of+various+species%2C+insulin%2C+IGF-I%2C+EGF%2C+FGF%2C+HGF%2C+but+not+platelet-derived+growth+factor+activate+such+cascades+%28232%3B233%29.+In+the+human+thyroid%2C+effects+of+insulin%2C+IGF-I%2C+EGF%2C+FGF%2C+but+not+HGF+have+been+demonstrated+%28152%3B171%3B207%3B234-236%29.%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E%26nbsp%3B%3C%2Fsup%3ETransforming+growth+factor-%CE%B2%2C+acting+through+the+serine+threonine+kinase+activity+of+its+receptors+and+intermediate+proteins+%28Smad%29%2C+inhibits+proliferation+and+specific+gene+expression+in+human+thyroid+cells+%28188%3B189%3B237%29.+TSH+and+cAMP+do+not+activate+either+the+MAPK-ERK+nor+the+JUK+and+p38+phosphorylation+pathways+in+dog+or+human+thyroids+%28233%29.%0D%0A%3Ca+href%3D%22%22+name%3D%2228%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0ACross-Signaling+between+the+Cascades%3C%2Fh3%3E%0D%0ACalcium%2C+the+intracellular+signal+generated+by+the+PIP%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bcascade%2C+activates+calmodulin-dependent+cyclic+nucleotide+phosphodiesterases+and+thus+inhibits+cAMP+accumulation+and+its+cascade+%28238%29.+This+activity+represents+a+negative+cross-control+between+the+PIP%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Band+the+cAMP+cascades.+Activation+of+protein+kinase+C+enhances+the+cAMP+response+to+TSH+and+inhibits+the+prostaglandin+E+response%2C+which+suggests+opposite+effects+on+the+TSH+and+prostaglandin+receptors+%28239%29.+No+important+effect+of+cAMP+on+the+PIP%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bcascade+has+been+detected.+On+the+other+hand%2C+stimulation+of+protein+kinase+C+by+phorbol+esters+inhibits+EGF+action.%0D%0ACross-signaling+between+the+cyclic+AMP+pathway+and+growth+factor+activated+cascades+have+been+observed+in+various+cell+types+%28240%3B241%29.+In+ovarian+granulosa+cells%2C+FSH+through+cAMP+activates+MAP+kinases+and+the+PI3+kinase+pathway+%28242%29.+In+FRTL5%2C+but+not+in+WRT+cell+lines%2C+TSH+through+cAMP+activates+MAP+kinases.+In+WRT+cells+but+not+in+PCCl3+cells%2C+TSH+and+cAMP+activate+PKB+%28243%3B244%29.+Such+cross+signallings+have+not+been+observed+in+human+or+dog+thyroid+cells.+Ras%2C+MAPK%2C+p38%2C+Jun+kinase+and+ERK5%2C+as+well+as+PI3+kinase+and+PKB%2C+are+not+modulated+by+cAMP+%28232%3B233%29+%28245%29+%28246%29.%0D%0AOther+growth+activating+cascades+have+been+little+investigated+in+the+thyroid.+In+dog+and+human+cells+TSH+or+cAMP+have+no+effect+on+STAT+phosphorylations+i.e.+on+the+JAK-STAT+pathways.+The+NF%EF%81%8B%CE%B2+pathway+has+not+yet+been+investigated+in+thyroid+cells.%0D%0A%3Ca+href%3D%22%22+name%3D%2229%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0ASPECIFIC+CONTROL+BY+IODIDE%3C%2Fh3%3E%0D%0AIodide%2C+the+main+substrate+of+the+specific+metabolism+of+the+thyrocyte%2C+is+known+to+control+the+thyroid.+Its+main+effects+in+vivo+and+in+vitro+are+to+decrease+the+response+of+the+thyroid+to+TSH%2C+to+acutely+inhibit+its+own+oxidation+%28Wolff-Chaikoff+effect%29%2C+to+reduce+its+trapping+after+a+delay+%28adaptation+to+the+Wolff-Chaikoff+effect%29%2C+and+at+high+concentrations+to+inhibit+thyroid+hormone+secretion+%28Fig.+1-10%29.+The+first+effect+is+very+sensitive+in+as+much+as+small+changes+in+iodine+intake+are+sufficient+to+reset+the+thyroid+system+at+different+serum+TSH+levels+without+any+other+changes+%28e.g.%2C+thyroid+hormone+levels%29%2C+which+suggests+that+in+physiologic+conditions%2C+modulation+of+the+thyroid+response+to+TSH+by+iodide+plays+a+major+role+in+the+negative+feedback+loop+%28154%3B247%29.+Iodide+in+vitro+has+also+been+reported+to+inhibit+a+number+of+metabolic+steps+in+thyroid+cells+%28248%29+%28249%29.+These+actions+might+be+direct+or+indirect+as+a+result+of+an+effect+on+an+initial+step+of+a+regulatory+cascade.+Certainly%2C+iodide+inhibits+the+cAMP+cascade+at+the+level+of+G%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3Es%3C%2Fsub%3E%26nbsp%3Bor+cyclase+and+the+Ca%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%2B%3C%2Fsup%3E-PIP%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bcascade+at+the+level+of+G%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3Eq%3C%2Fsub%3E%26nbsp%3Bor+phospholipase+C%3B+such+effects+can+account+for+the+inhibition+of+many+metabolic+steps+controlled+by+these+cascades+%28250%29+%28251%29.+In+one+case+in+which+this+process+has+been+studied+in+detail%2C+the+control+of+H%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3EO%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bgeneration%2C+that+is%2C+the+limiting+factor+of+iodide+oxidation+and+thyroid+hormone+formation%2C+iodide+inhibited+both+the+cAMP+and+the+Ca%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%2B%3C%2Fsup%3E-PIP%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bcascades+at+their+first+step+but+also+the+downstream+effects+of+the+generated+intracellular+signals+cAMP%2C+Ca%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%2B%3C%2Fsup%3E%2C+and+diacylglycerol+on+H%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3EO%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bgeneration+%28252%29.+This+effect+account+for+the+inhibition+by+iodide+of+its+oxidation+i.e.+the+Wolff-Chaikoff+effects+%28253%29.%0D%0AThe+mechanism+of+action+of+iodide+on+all+the+metabolic+steps+besides+secretion+fits+the+%22XI%22+paradigm+of+Van+Sande+%28254%29.+These+inhibitions+are+relieved+by+agents+that+block+the+trapping+of+iodide+%28e.g.%2C+perchlorate%29+or+its+oxidation+%28e.g.%2C+methimazole%29%E2%80%94the+Van+Sande+criteria.+The+effects+are+therefore+ascribed+to+one+or+several+postulated+intracellular+iodinated+inhibitors+called+XI.+The+identity+of+such+signals+is+still+unproved.+At+various+times+several+candidates+have+been+proposed+for+this+role%2C+such+as+thyroxine%2C+iodinated+eicosanoids+%28iodolactone%29+%28255%29%2C+and+iodohexadecanal+%28256%29.+The+latter%2C+the+predominant+iodinated+lipid+in+the+thyroid%2C+can+certainly+account+for+the+inhibition+of+adenylyl+cyclase+and+of+H%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3EO%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bgeneration+%28256%29+%28257%29+%28258%29.+It+should+be+emphasized+that+iodination+of+the+various+enzymes%2C+as+well+as+a+catalytic+role+of+iodide+in+the+generation+of+O%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bradicals+%28shown+to+be+involved+in+the+toxic+effects+of+iodide%29%2C+could+account+for+the+Van+Sande+criteria+with+no+need+for+the+XI+paradigm+%28254%29+%28259%29.+Besides%2C+an+inhibition+of+thyroid+secretion+by+iodide+in+antithyroid+drugs+treated+hyperthyroid+patients+suggests+a+direct+Xi+independent+effect.%0D%0ADistinct+from+its+inhibitory+effects%2C+iodide+also+activates+H2O2+generation+and+therefore+protein+iodination+in+the+thyroid+of+some+species+including+humans.+This+effect+is+also+inhibited+by+inhibitors+of+thyroperoxidase+and+NIS.+It+would+link+the+generation+of+H2O2+to+the+availability+of+its+cosubstrate+iodide+%28260%29.%0D%0AIodide+in+vivo%2C+at+moderate+doses+in+dog%2C+decreases+cell+proliferation+and+the+expression+of+TPO+and+NIS+mRNA+but+not+the+synthesis+or+secretion+of+thyroid+hormones.+The+downregulation+of+NIS+explains+the+well+known+delayed+decrease+of+iodide+transport+in+response+to+iodide%2C+i.e.+the+adaptation+to+the+Wolff-Chaikoff+effect+%28261%29.%0D%0A%3Ctable+align%3D%22center%22+border%3D%221%22%3E%3Ctbody%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cimg+align%3D%22BOTTOM%22+border%3D%221%22+height%3D%22540%22+name%3D%22graphics11%22+src%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Ffigures%2Ffigure1-10.jpg%22+width%3D%22780%22+%2F%3E%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cdiv+style%3D%22background-attachment%3A+initial%3B+background-clip%3A+initial%3B+background-color%3A+%2399ccff%3B+background-image%3A+initial%3B+background-origin%3A+initial%3B+background-position%3A+initial+initial%3B+background-repeat%3A+initial+initial%3B%22%3E%0D%0A%3Cb%3EFig+1-10.%3C%2Fb%3E%26nbsp%3BEffects+of+iodide+on+thyroid+metabolism.+All+inhibitory+effects+of+iodide%2C+except+in+part+the+inhibition+of+secretion%2C+are+relieved+by+drugs+that+inhibit+iodide+trapping+%28e.g.%2C+perchlorate%29+or+iodide+oxidation+%28e.g.%2C+methimazole%29.+All+effects+are+direct+inhibitions+except+the+effect+on+iodide+transport+which+bears+on+the+transcription+of+Na%2FI-+symporter+gene.+Three+possible+mechanisms+corrresponding+to+this+paradigm+are+outlined%3A+generation+of+O%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bradicals%2C+iodination+of+target+proteins+and+synthesis+of+an+XI+compound.+Any+of+these+mechanisms+could+account+for+the+various+steps+ascribed+to+XI+inhibition+by+I%26nbsp%3B%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E-%3C%2Fsup%3E%26nbsp%3B%28indicated+by+slashes%29.%3C%2Fdiv%3E%0D%0A%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3C%2Ftbody%3E%3C%2Ftable%3E%0D%0A%3Ch1+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+18px%3B+font-weight%3A+bold%3B%22%3E%0D%0A%3C%2Fh1%3E%0D%0A%3Ca+href%3D%22%22+name%3D%2230%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0ATHE+THYROID-STIMULATING+HORMONE+RECEPTOR%3C%2Fh3%3E%0D%0AAs+the+sensor+for+the+main+regulatory+agent+acting+on+the+thyroid+and+the+target+of+autoimmune+reactions%2C+the+TSH+receptor+had+been+extensively+studied+before+it+was+cloned.+Studies+from+affinity-labeling+experiments+described+the+receptor+quite+accurately+as+an+integral+membrane+protein+inserted+in+the+basolateral+plasma+membrane+and+consisting+of+a+relatively+large+extracellular+domain+responsible+for+TSH+binding+linked+to+a+membrane-spanning+domain+%28262%29.+The+number+of+receptors+was+estimated+to+be+around+1000%2Fcell.+Because+of+its+coupling+to+the+generation+of+cAMP%2C+it+was+classified+as+a+member+of+the+large+family+of+G+protein-coupled+receptors+interacting+with+Gs+%28see+earlier%29.+It+was+its+belonging+to+this+large+receptor+family%2C+and+the+expectation+that+it+would+display+significant+sequence+similarity+with+other+members+of+the+family+%28in+particular+with+the+FSH+and+LH+receptors%29%2C+that+allowed+the+cloning+of+the+TSH+receptor+cDNA+%28263%29+%7B1199%7D+%28264%29+%28265%29+%28266%29+%28267%29%29.%0D%0A%0D%0A%3Ca+href%3D%22%22+name%3D%2231%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AStructure+of+the+Protein.%3C%2Fh3%3E%0D%0AThe+beta+subunits+of+glycoprotein+hormones%2C+to+which+TSH+belongs%2C+are+encoded+by+paralogous+genes+displaying+substantial+sequence+similarity+%28Fig.+1-11%29.+The+corresponding+receptors%2C+FSHr%2C+LH%2FCGr+and+TSHr%2C+are+members+of+the+rhodopsin-like+G+protein-coupled+receptor+family.+As+such%2C+TSHr+contains+a+%E2%80%9Cserpentine%E2%80%9D+portion+containing+seven+transmembrane+helices+with+many+%28but+not+all%29+of+the+sequence+signatures+typical+of+this+receptor+family.+In+addition%2C+and+a+hallmark+of+the+subfamily+of+glycoprotein+hormone+receptors%2C+it+contains+a+large+%28about+400+residues%29+aminoterminal+ectodomain+responsible+for+the+high+affinity+and+selective+binding+of+TSH+%28268%29+%28269%29+%28270%29.+The+higher+sequence+identity+of+the+serpentine+portions+of+glycoprotein+hormone+receptors+%28about+70%25%29+when+compared+with+the+ectodomains+%28about+40%25%2C+see+Fig.+1-11%29+suggested+early+that+the+former+are+interchangeable+modules+capable+of+activating+the+G+proteins+%28mainly+G%CE%B1%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3Es+%3F%3C%2Fsub%3E%29+after+specific+binding+of+the+individual+hormones+to+the+latter+%28153%29.+Contrary+to+other+rhodopsin-like+GPCRs%2C+binding+of+the+hormones+to+their+ectodomains+can+be+observed+with+high+affinity+in+the+absence+of+the+serpentine+%28271%29.+The+intramolecular+transduction+of+the+signal+between+these+two+portions+of+the+receptors+involves+mechanisms+specific+to+the+glycoprotein+hormone+receptor+family+%28see+below%29.+The+relatively+high+sequence+identity+between+the+hormone-binding+domains+of+the+TSH+and+LH%2FCG+receptors+opens+the+possibility+of+spillover+phenomena+during+normal+or%2C+even+more+so%2C+molar+or+twin+pregnancies%2C+when+hCG+concentrations+are+several+orders+of+magnitude+higher+than+TSH.+This+provides+an+explanation+to+cases+of+pregnancy+hyperthyroidism+%28163%29.%0D%0A%3Ctable+align%3D%22center%22+border%3D%221%22%3E%3Ctbody%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cimg+align%3D%22BOTTOM%22+border%3D%221%22+height%3D%22540%22+name%3D%22graphics12%22+src%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Ffigures%2Ffigure1-11.jpg%22+width%3D%22780%22+%2F%3E%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cdiv+lang%3D%22fr-FR%22+style%3D%22background-attachment%3A+initial%3B+background-clip%3A+initial%3B+background-color%3A+%2399ccff%3B+background-image%3A+initial%3B+background-origin%3A+initial%3B+background-position%3A+initial+initial%3B+background-repeat%3A+initial+initial%3B+text-indent%3A+0in%3B%22%3E%0D%0A%3Cb%3EFig.+1-11.%26nbsp%3B%3C%2Fb%3EBoth+the+glycoprotein+hormone+receptors+%28panel+A%29+and+the+beta+subunits+of+glycoprotein+hormones+%28panel+B%29+are+encoded+by+paralogous+genes.+Sequence+identities+are+indicated%2C+separately+for+the+ectodmains+and+serpentine+domains+of+the+three+receptors%2C+and+for+the+beta+subunits+of+the+four+hormones.+The+pattern+of+shared+similarities+suggests+coevolution+of+the+hormones+and+the+ectodomain+of+their+receptors%2C+resulting+in+generation+of+specificity+barriers.+The+high+similarity+displayed+by+the+serpentine+portions+of+the+receptors+is+compatible+with+a+conserved+mechanism+of+intramolecular+signal+transduction+%28272%29.%3C%2Fdiv%3E%0D%0A%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3C%2Ftbody%3E%3C%2Ftable%3E%0D%0A%3Cdiv+style%3D%22text-indent%3A+0in%3B%22%3E%0D%0A%0D%0A%3C%2Fdiv%3E%0D%0A%3Ca+href%3D%22%22+name%3D%2232%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AActivation+by+TSH%3C%2Fh3%3E%0D%0ATSH+is+a+glycoprotein%2C+consisting+of+two+subunits%2C+an+%CE%B1+and+a+%CE%B2+chain+.+TSH+action+requires+binding+to+a+TSH-specific+membrane+receptor+which+activates+adenylate+cyclase+through+a+G-protein+coupled+system.+A+recent+report+suggests+that+the+%CE%B2-unit+of+human+TSH+is+necessary+for+recognizing+the+TSH+receptor+in+FRTL-5+cells+while+the+%CE%B1-subunit+is+required+for+signal+transduction.%0D%0ABinding+to+the+receptor+of+TSH%2C+its+natural+ligand%2C+results+mainly+in+the+activation+of+Gs+causing+the+stimulation+of+adenylyl+cyclase.+The+EC50+for+adenylyl+cyclase+activation+by+bovine+TSH+in+human+thyrocytes+and+in+CHO+cells+transfected+with+the+human+cDNA+is+around+0.3+to+0.4+mU%2Fml+%28226%29.+The+dissociation+constant+for+TSH+binding+%28bovine+TSH%29+expressed+in+biological+units+is+close+to+the+same+value+%281.5+to+1.8+mU%2Fml%29+%28273%29+%28274%29.+In+the+absence+of+a+reliable+knowledge+of+the+bioactivity+of+pure+intact+human+TSH+%28275%29%2C+it+is+difficult+to+translate+this+value+in+molar+terms.+The+consensus+is+that+it+must+be+in+the+nanomolar+range.+The+bioactivity+of+TSH+is+highly+dependent+on+the+glycosylation+state+of+the+hormone.+In+this+respect+it+is+interesting+that+artificially+deglycosylated+TSH+behaves+as+a+potent+antagonist+%28276%29.+The+bioactivity+of+human+TSH+%28and+of+all+glycoprotein+hormones%2C+including+hCG%29+is+lower+than+that+of+bovine+TSH+and+of+other+non+primate+mammals.+This+is+due+to+positive+selection+in+higher+primates+of+alpha+subunits+in+which+several+key+basic+aminoacids+have+been+substituted+%28277%29.+The+observation+that+this+phenomenon+paralels+the+evolution+of+chorionic+gonadotropin+suggests+that+it+may+be+related+to+protection+against+promiscuous+stimulation+of+the+TSH+receptor+by+hCG+during+pregnancy.%0D%0AIn+humans%2C+but+not+in+the+dog%2C+TSH+is+also+able+to+activate+phospholipase+C%2C+resulting+in+the+accumulation+of+IP3+and+diacylglycerol+%28see+earlier%29+%28226%29+%28227%29.+The+EC50+for+the+activation+of+this+pathway+is+about+one+order+of+magnitude+higher+%28about+5+mU%2Fml%29+than+for+the+cAMP+cascade.+The+ability+to+activate+adenylyl+cyclase+and+phospholipase+C+is+an+intrinsic+property+of+the+receptor%2C+since+the+cloned+molecule+expressed+in+Chinese+hamster+ovary+%28CHO%29+cells+displays+both+activities+%28226%29.+Interestingly%2C+the+cloned+canine+TSH+receptor+exhibits+the+same+dual+potential+when+expressed+in+CHO+cells%2C+even+though+it+activates+only+cAMP+accumulation+in+the+dog+thyrocyte.+It+is+likely+that+it+is+the+G+protein+and+receptor+localization+or+a+different+set+of+still+unknown+accessory+proteins+that+determines+whether+the+receptor+couples+to+one+cascade+or+the+other+or+both.+In+dog+and+human+thyroid+membranes+and+cells%2C+TSH+also+activates+Gi+but+no+role+has+yet+been+ascribed+to+this+effect.%0D%0AThe+thyroid+adjusts+rapidly+to+the+current+level+of+TSH+%28278%29+and+cyclic+AMP+generation+and+intracellular+concentration+is+instantaneously+regulated+by+the+level+of+receptor+occupancy+%28200%29.%0D%0AExpression+of+the+TSH+receptor+gene+is+largely+thyroid+specific.+Constructs+made+of+a+chloramphenicol+acetyltransferase+reporter+gene+under+control+of+the+5%E2%80%99+flanking+region+of+the+rat+gene+show+expression+when+transfected+into+FRTL5+cells+and+FRT+cells+but+not+into+nonthyroid+HeLa+or+a+rat+liver+cell+line+%28BRL%29+cells+%28279%29.+However%2C+TSH+receptor+mRNA+has+been+clearly+demonstrated+in+fat+tissue+of+the+guinea+pig+%28280%29%2C+and+following+differentiation+of+preadipocytes+into+adipocytes+%28281%3B282%29.+Functional+significance+in+man+of+reports+showing+its+presence+in+lymphocytes%2C+extraocular+tissue+and%2C+recently%2C+in+cartilage+and+bone%2C+requires+additional+studies.+In+particular+the+reported+effect+of+TSH+on+bone+density+%28283%29+remains+controversial+%28284%29.+Expression+of+the+TSH+receptor+in+thyroid+cells+is+extremely+robust.+It+is+moderately+upregulated+and+downregulated+by+TSH+in+vitro+%28285%29+and+downregulated+by+iodide+in+vivo+%28261%29.%0D%0A%0D%0A%3Cu%3ERecognition+of+the+receptor+by+TSH%3C%2Fu%3E%0D%0AThe+three-dimensional+structures+are+available+for+hCG+and+FSH+%28236-238%29+which+allows+accurate+modelization+of+TSH+on+these+templates.+The+crystal+structure+of+the+human+FSHr-FSH+complex+%28286%29+has+confirmed+that+the+ectodomain+of+glycoprotein+hormone+receptors+belongs+to+the+family+of+proteins+with+leucine-rich+repeats+%28LRRs%29+as+was+previously+suggested+by+sequence+analysis+and+homology+modeling+%28287%29.+The+concave+inner+surface+of+the+receptor+%28Fig.+1A%29+is+an+untwisted%2C+non-inclined+b-sheet+formed+by+ten+LRRs.+Whereas+the+N-terminal+portion+of+the+beta-sheet+%28LRR1%E2%80%937%29+is+nearly+flat%2C+the+C-terminal+portion+%28LRR7%E2%80%9310%29+has+the+horseshoe-like+curvature+of+LRR+proteins.+The+crystal+structure+of+part+of+the+TSHr+ectodomain+in+complex+with+a+thyroid-stimulating+autoantibody+has+recently+been+obtained+%28288%29.+Notably%2C+both+the+structure+of+the+ectodomain+of+TSHr+and+the+receptor+binding+arrangements+of+the+autoantibody+are+very+similar+to+those+reported+for+the+FSHr-FSH+complex.+The+ectodomain+of+glycoprotein+hormone+receptors+also+contains%2C+downstream+of+the+LRR+region%2C+a+cysteine+cluster+domain+of+unknown+structure+%28the+hinge+region%29%2C+involved+in+receptor+inhibition%2Factivation+and+containing+sites+for+tyrosine+sulfation+important+for+hormone+binding+%28see+below%29.%0D%0A%3Ctable+align%3D%22center%22+border%3D%221%22%3E%3Ctbody%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cimg+align%3D%22LEFT%22+height%3D%22387%22+hspace%3D%2212%22+src%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Ffigures%2Ffigure1-12.gif%22+width%3D%22795%22+%2F%3E%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cdiv+lang%3D%22fr-FR%22+style%3D%22background-attachment%3A+initial%3B+background-clip%3A+initial%3B+background-color%3A+%2399ccff%3B+background-image%3A+initial%3B+background-origin%3A+initial%3B+background-position%3A+initial+initial%3B+background-repeat%3A+initial+initial%3B+text-indent%3A+0in%3B%22%3E%0D%0A%3Cb%3EFig.+1-12%3C%2Fb%3E.+%28A%29+General+view+of+the+follicle-stimulating+hormone+receptor+%28FSHr%29-FSH+crystal+structure+as+a+template+to+model+the+interaction+between+TSH+and+the+TSH+receptor+%28288%29.+The+concave+inner+surface+of+the+receptor%2C+formed+by+ten+leucine+rich+repeats+%28LRR2%E2%80%939%2C+shown+in+blue%29%2C+contact+the+middle+section+of+the+hormone+molecule%2C+both+the+C-terminal+segment+of+the+a+subunit+and+the+%E2%80%9Cseat-belt%E2%80%9D+segment+of+the+b-subunit+%28shown+in+red%29.+%28B%29+EachLRR+is+composed+of+theX1-X2-L-X3-L-X4-X5+residues+%28where+X+is+any+amino+acid%2C+and+L+usually+is+Leu%2C+Ile%2C+or+Val%29%2C+forming+the+central+X2-L-X3-L-X4+a+typical+beta-strand%2C+while+X1+and+X5+are+parts+of+the+adjacent+loops.+%28C%29+Molecular+model+of+the+transmembrane+domain+of+the+TSH+receptor%2C+constructed+from+the+crystal+structure+of+bovine+rhodopsin+%28289%29.+The+color+code+of+the+a-carbon+ribbons+is%3A+transmembrane+helix+1+%28crimson%29%2C+2+%28goldenrod%29%2C+3+%28dark+red%29%2C+4+%28gray%29%2C+5+%28red%29%2C+6+%28orange%29%2C+and+7+%28blue%29%2C+and+Helix8+%28blue%29.+Recently+the+crystal+structure+of+the+beta2-adrenergic+receptor+bound+to+the+partial+inverse+agonist+carazolol+has+been+published+%28290%3B291%29.+The+structure+of+both+rhodopsin+and+the+beta2+receptor+are+similar+at+the+transmembrane+domain.+Adapted+from+Caltabiano+et+al+%28292%29.%3C%2Fdiv%3E%0D%0A%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3C%2Ftbody%3E%3C%2Ftable%3E%0D%0AExtensive+amino+acid+substitutions+by+site-directed+mutagenesis+of+the+X%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3Ei%3C%2Fsub%3E%26nbsp%3Bresidues+in+the+LRR+portion+of+the+TSHr+for+their+counterparts+in+the+LH%2FCGr+have+been+preformed+%28293%29.+Exchanging+eight+amino+acids+of+the+TSHr+for+the+corresponding+LH%2FCGr+residues+resulted+in+a+mutant+displaying+a+sensitivity+to+hCG+matching+that+of+the+wild+type+LH%2FCGr.+Surprisingly%2C+while+gaining+sensitivity+to+hCG%2C+the+mutant+kept+a+normal+sensitivity+to+TSH%2C+making+it+a+dual+specificity+receptor.+It+is+necessary+to+exchange+twelve+additional+residues+to+fully+transform+it+into+a+bona+fide+LH%2FCGr+%28293%29.+From+an+evolutionary+point+of+view%2C+these+observations+indicate+that+nature+has+built+recognition+specificity+of+hormone-receptor+couples+on+both+attractive+and+repulsive+residues%2C+and+that+residues+at+different+homologous+positions+have+been+selected+to+this+result+in+the+different+receptors.%0D%0AInspection+of+electrostatic+surface+maps+of+models+of+the+wild+type+TSH+and+LH%2FCG+receptors+and+some+of+the+mutants+is+revealing+in+this+respect+%28292%3B293%29.+The+LH%2FCGr+displays+an+acidic+groove+in+the+middle+of+its+horseshoe%2C+extending+to+the+lower+part+of+it+%28corresponding+to+the+C-terminal+ends+of+the+beta+strands%29.+Generation+of+a+similar+distribution+of+charges+in+the+dual-specificity+and+reverse-specificity+TSHr+mutants+suggests+that+this+is+important+for+hCG+recognition.+A+detailed+modelization+of+the+interactions+between+TSH+and+the+ectodomain+of+its+receptor+has+been+realized+%28292%29.+In+addition+to+the+hormone-specific+interactions+genetically+encoded+in+the+primary+structure+of+glycoprotein+hormones+receptors+and+their+ligands%2C+the+importance+of+non-hormone+specific+ionic+interactions+has+been+demonstrated%2C+involving+sulphated+tyrosine+residues+present+in+the+ectodomains+of+all+three+receptors+%28294%29.+Sulfation+in+the+TSHr+takes+place+on+both+tyrosine+residues+of+a+conserved+Tyr-Asp-Tyr+motif+located+close+to+the+border+between+the+ectodomain+and+the+first+transmembrane+helix+%28Fig.+1-13%29.+However%2C+only+sulfation+of+the+first+tyrosine+of+the+motif+seems+to+be+functionally+important+%28294%29%2C+contributing+crucially+to+the+binding+affinity%2C+without+interfering+with+specificity.+The+functional+role+of+this+postranslational+modification+of+the+TSH+receptor+has+been+confirmed+by+demonstration+of+profound+hypothyroidism+due+to+resistance+to+TSH+in+mice+with+inactivation+of+Tpst2%2C+one+of+the+enzymes+responsible+for+tyrosine+sulfation+%28295%29%28296%29.%0D%0A%0D%0A%3Cu%3EActivation+of+the+serpentine+portion+of+the+TSH+receptor%3C%2Fu%3E%0D%0AAs+it+belongs+to+the+rhodopsin-like+GPCR+family+and+displays+many+of+the+cognate+signatures+in+primary+structure%2C+the+serpentine+portion+of+the+TSH+receptor+is+likely+to+share+with+rhodopsin+common+mechanisms+of+activation+%28289%3B297%29%3Cspan+lang%3D%22fr-FR%22%3E.%3C%2Fspan%3E%0D%0A%3Ctable+align%3D%22center%22+border%3D%221%22%3E%3Ctbody%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cimg+align%3D%22BOTTOM%22+border%3D%221%22+height%3D%22540%22+name%3D%22graphics13%22+src%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Ffigures%2Ffigure1-13.jpg%22+width%3D%22780%22+%2F%3E%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cdiv+style%3D%22background-attachment%3A+initial%3B+background-clip%3A+initial%3B+background-color%3A+%2399ccff%3B+background-image%3A+initial%3B+background-origin%3A+initial%3B+background-position%3A+initial+initial%3B+background-repeat%3A+initial+initial%3B%22%3E%0D%0A%3Cb%3EFig.+1-13.%3C%2Fb%3E%26nbsp%3BLinear+representation+of+the+TSH+receptor.+Sequence+signatures+common+to+all+rhodopsin-like+GPCRs+and+sequence+signatures+specific+to+the+glycoprotein+hormone+receptor+gene+family+are+both+implicated+in+activation+of+GPHRs.+Key+residues+are+indicated+%28red+dots%29+as+well+as+conserved+motifs%3A+SO3%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E--%3C%2Fsup%3E%26nbsp%3Bstands+for+postranslational+sulfation+of+the+indicated+tyrosine+residues.+The+black+boxes+stand+for+transmembrane+helices+and+I1-I3%2C+E1-E3%2C+for+intracellular+and+extracellular+loops%2C+respectively+%28272%29.%3C%2Fdiv%3E%0D%0A%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3C%2Ftbody%3E%3C%2Ftable%3E%0D%0A%0D%0AHowever%2C+sequence+signatures+characteristic+of+the+serpentine+portion+of+the+glycoprotein+hormone+receptors+suggest+the+existence+of+idiosyncrasies+associated+with+a+specific+mechanism+of+activation+%28Fig.+1-13%29.+In+addition%2C+over+the+past+ten+years%2C+the+TSHr+has+been+found+to+be+activated+by+a+wide+spectrum+of+gain+of+function+mutations+%28298-300%29.+Compilation+of+available+data+identifies+more+than+30+residues%2C+the+mutation+of+which+causes+constitutive+activation+%28for+a+complete+list+of+TSHr+mutants%2C+see+%28301%29+and+http%3A%2F%2Fgris.ulb.ac.be.+As+many+somatic+mutations+affecting+a+given+residue+have+been+found+repeatedly%2C+it+is+likely+that+we+are+close+to+a+saturation+map+for+spontaneous+gain+of+function+mutations.+Attempts+to+translate+this+map+into+mechanisms+of+transition+between+inactive+and+active+conformations+of+the+receptor+have+been+made%2C+in+the+light+of+rhodopsin+structural+data.+Three+sequence+patterns+affected+by+gain+of+function+mutations+deserve+special+mention+and+may+help+understanding+how+the+TSH+receptor+is+activated.%0D%0A%3Ci%3E%3Cb%3EThe+first%3C%2Fb%3E%3C%2Fi%3E%2C+is+centered+on+an+aspartate+in+position+6.44+%28Asp633%29%2C+at+the+cytoplasmic+side+of+transmembrane+helix+VI+%28TM-VI%29.+When+mutated+to+a+variety+of+aminoacids+the+result+is+constitutive+activation+%28169%3B298%3B302%29.+This+suggested+that+the+gain+of+function+resulted+from+the+breakage+of+%28a%29+bond%28s%29%2C+rather+than+the+creation+of+novel+interaction%28s%29+by+the+mutated+residue%2C+and+the+main+partner+of+Asp6.44+was+identified+as+Asn7.49%2C+in+transmembrane+helix+VII.+From+a+series+of+site-directed+mutagenesis+studies+%28169%3B303%29%2C+it+was+tentatively+concluded+that+in+the+inactive+conformation+of+the+TSH+receptor%2C+the+side+chain+of+Asp7.49+is+normally+%E2%80%9Csequestered%E2%80%9D+by+both+Thr6.43+and+Asp6.44%2C+and+that+the+active+conformation%28s%29+require%28s%29+establishment+of+novel+interaction%28s%29+of+N7.49+involving+most+probably+Asp+in+position+2.50.%0D%0A%3Ci%3E%3Cb%3EThe+second%3C%2Fb%3E%3C%2Fi%3E%2C+glutamate+3.49+and+arginine+3.50+of+the+highly+conserved+%E2%80%9CD%2FERY%2FW%E2%80%9D+motif+at+the+bottom+of+TM-III+form+an+ionic+lock+with+aspartate+6.30+at+the+cytoplasmic+end+of+TM-VI.+Disruption+of+this+ionic+lock%2C+e.g.+by+mutations+affecting+Asp6.30%2C+leads+to+constitutively+active+mutant+receptors+%28303%29.+Thus%2C+the+movements+of+TM-III+and+TM-VI+at+the+cytoplasmic+side+of+the+membrane%2C+i.e.+presumably+an+opening+of+the+receptor%2C+is+necessary+for+receptor+activation+%28304%29.+The+existence+of+this+ionic+lock+has+however+been+questioned+recently%2C+as+it+is+not+found+in+the+determined+structure+of+the+beta2+adrenergic+receptor+%28291%29.%0D%0A%3Ci%3E%3Cb%3EThe+third%3C%2Fb%3E%3C%2Fi%3E%2C+serine+281+belongs+to+a+GPHR-specific+%E2%80%9CYPSHCCAF%E2%80%9D+sequence+signature+located+at+the+carboxyl+terminal+end+of+the+LRR+portion+in+the+ectodomain+of+the+receptors+%28see+Fig.+96-5%29.+After+mutation+of+this+serine+residue+had+been+shown+to+activate+the+TSH+receptor+constitutively+%28305%29%2C+this+segment%2C+sometimes+referred+to+as+the+%E2%80%9Chinge%E2%80%9D+motif%2C+was+shown+to+play+an+important+role+in+activation+of+all+three+glycoprotein+hormone+receptors+%28151%29.+The+functional+effect+of+substitutions+of+S281+in+the+TSHr+likely+results+of+a+%E2%80%9Closs-of-structure%E2%80%9D%2C+locally%2C+since+the+more+de-structuring+the+substitutions%2C+the+strongest+the+activation+%28151%3B306%29.+This+observation%2C+together+with+results+showing+that+mutation+of+specific+residues+in+the+extracellular+loops+of+the+TSHr+cause+constitutive+activation+%28197%29%2C+led+to+the+hypothesis+that+activation+of+the+receptor+could+involve+the+rupture+of+an+inhibitory+interaction+between+the+ectodomain+and+the+serpentine+domain+%28see+below%29+%28305%29.%0D%0A%0D%0A%3Cu%3EInteraction+between+the+ectodomain+and+the+serpentine+domain%3C%2Fu%3E%0D%0AMutant+TSH+receptor+constructs+devoid+of+the+ectodomain+displayed+a+phenotype+compatible+with+partial+activation%2C+thus+confirming+the+inhibitory+effect+of+the+ectodomain+on+the+serpentine+portion+already+suggested+by+the+partial+activation+of+the+receptor+by+a+trypsin+treatment.+However%2C+activation+of+cAMP+production+in+cells+transfected+with+truncated+constructs+was+much+lower+than+after+full+stimulation+of+the+wild+type+receptor+by+TSH+or+by+mutation+of+Ser281+%28307%29.+These+observations+led+to+the+following+model+for+activation+of+the+TSHr+%28Fig.+1-14%29+%28307%29.%0D%0A%3Ctable+align%3D%22center%22+border%3D%221%22%3E%3Ctbody%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cimg+align%3D%22BOTTOM%22+border%3D%221%22+height%3D%22540%22+name%3D%22graphics14%22+src%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Ffigures%2Ffigure1-14.jpg%22+width%3D%22780%22+%2F%3E%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cdiv+lang%3D%22fr-FR%22+style%3D%22background-attachment%3A+initial%3B+background-clip%3A+initial%3B+background-color%3A+%2399ccff%3B+background-image%3A+initial%3B+background-origin%3A+initial%3B+background-position%3A+initial+initial%3B+background-repeat%3A+initial+initial%3B+text-indent%3A+0in%3B%22%3E%0D%0A%3Cb%3EFig.+1-14%26nbsp%3B%3C%2Fb%3E%3A+Model+for+activation+of+the+thyrotropin+receptor.+Interactions+between+the+ectodomain+and+the+serpentine+domains+are+implicated+in+the+activation+mechanism+and+functional+specificity.+The+TSH+receptor+is+represented+with+its+ectodomain+containing+a+concave%2C+hormone+binding+structure+facing+upwards%2C+and+a+transmembrane+serpentine+portion.+The+basal+state+of+the+receptor+is+characterized+by+an+inhibitory+interaction+between+the+ectodomain+and+the+serpentine+domain+%28indicated+by+the+%E2%8A%83%28-%29blue+sign%29.+The+ectodomain+would+function+as+a+tethered+inverse+agonist+of+the+serpentine+portion.+Mutation+of+Ser281+in+the+ectodomain+into+leucine+switches+the+ectodomain+from+an+inverse+agonist+into+a+full+agonist+of+the+serpentine+domain+%28indicated+by+the+%E2%8A%83%28%3Cb%3E%2B%3C%2Fb%3E%29redsign%29.+Binding+of+TSH+%28indicated+by+%CE%B1%CE%B2+dimeric+structure%29+to+the+ectodomain+is+proposed+to+have+a+similar+effect%2C+converting+it+into+a+full+agonist+of+the+serpentine+portion.+The+serpentine+portion+in+the+basal+state+is+represented+as+a+compact%2C+black+structure.+The+fully+activated+serpentine+portion+is+depicted+as+a+relaxed+red+structures+with+arrows+indicating+activation+of+G%CE%B1s.%3C%2Fdiv%3E%0D%0A%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3C%2Ftbody%3E%3C%2Ftable%3E%0D%0A%3Cdiv+style%3D%22text-indent%3A+0in%3B%22%3E%0D%0A%0D%0A%3C%2Fdiv%3E%0D%0AIn+the+resting+state%2C+the+ectodomain+would+exert+an+inhibitory+effect+on+the+activity+of+an+inherently+noisy+rhodopsin-like+serpentine%2C+qualifying+pharmacologically+as+an+inverse+agonist+of+the+serpentine.+Upon+activation%2C+by+binding+of+the+hormone%2C+or+secondary+to+mutation+of+S281+in+the+hinge+region%2C+the+ectodomain+would+switch+from+inverse+agonist+to+full+agonist+of+the+serpentine+portion.+The+ability+of+the+strongest+S281+mutants+to+fully+activate+the+receptor+in+the+absence+of+hormone%2C+suggests+that+the+ultimate+agonist+of+the+serpentine+domain+would+be+the+%E2%80%9Cactivated%E2%80%9D+ectodomain%2C+with+no+need+for+an+interaction+between+the+hormone+and+the+serpentine+domain.%0D%0AThis+model+in+which+the+%E2%80%9Creal%E2%80%9D+agonist+of+the+serpentine+domain+would+be+the+activated+ectodomain+is+conforted+by+the+identification+of+a+monoclonal+antibody+recognizing+the+ectodomain+and+endowed+with+inverse+agonistic+activity+%28308%29.%0D%0A%3Cdiv+style%3D%22text-indent%3A+0in%3B%22%3E%0D%0A%0D%0A%3C%2Fdiv%3E%0D%0A%3Cu%3EActivation+by+Chorionic+Gonadotropin%3C%2Fu%3E%0D%0AAs+indicated+above%2C+the+sequence+similarity+between+TSH+and+hCG%2C+and+between+their+receptors%2C+allows+for+some+degree+of+promiscuous+stimulation+of+the+TSH+receptor+by+hCG+during+the+first+trimester+of+pregnancy%2C+when+hCG+levels+reach+peak+values.+The+inverse+relation+between+TSH+and+hCG+observed+in+most+pregnant+women+is+clear+indication+that+their+thyroid+is+subjected+to+the+thyrotropic+activity+of+hCG+%28163%29.+Whereas+this+situation+is+usually+associated+with+euthyroidism%2C+thyrotoxicosis+may+develop+in+cases+of+excessive+hCG+production+%28as+it+occurs+in+twin+pregnancies+or+hydatiform+moles%29%2C+or+in+rare+patient+harboring+a+mutant+TSH+receptor+with+increased+sensitivity+to+hCG+%28309%29.%0D%0A%0D%0A%3Cu%3EActivation+by+Autoantibodies%3C%2Fu%3E%0D%0AAutoantibodies+found+in+Graves%27+disease+and+some+types+of+idiopathic+myxedema+can+stimulate+%28TSAb%29+or+block+%28TSBAb%29+TSH+receptor%2C+respectively.+Epitopes+recognized+by+TSAbs+are+being+identified+from+precise+mapping+of+binding+site+of+murine+or+human+monoclonal+antibodies+endowed+with+TSAb+activity+%28288%3B310%29.+However%2C+the+mechanism+implicated+in+activation+of+he+receptor+by+TSAbs+%28and+by+TSH%29+are+still+unknown.+Although+most+TSAbs+do+compete+with+TSH+for+binding+to+the+receptor+%28263%29%2C+and+despite+similarity+in+interaction+surfaces+%28288%29%2C+the+precise+targets+of+the+hormone+and+autoantibodies+are+likely+to+be+different%2C+at+least+in+part.+It+has+indeed+been+shown+that+sulfated+tyrosine+residues%2C+which+are+important+for+TSH+binding%2C+are+not+implicated+in+recognition+of+TSH+receptor+by+TSAbs+%28294%29.+Also%2C+contrary+to+TSH%2C+most+TSAbs+from+Graves%E2%80%99+patients+display+a+delay+in+their+ability+to+stimulate+cAMP+accumulation+in+transfected+cells+%28200%29.+The+recent+availability+of+TSAb+preparations+purified+from+individual+patients+will+hopefully+allow+to+explore+these+issues+in+a+direct+fashion+%28311%29.%0D%0A%0D%0A%3Cu%3EActivation+by+Thyrostimulin%3C%2Fu%3E%0D%0AThyrostimulin+has+been+identified+as+a+novel+agonist+of+the+TSH+receptor.+As+glycoprotein+hormones%2C+it+is+composed+of+two+subunits%2C+coined+a2+and+b5+and+activates+the+receptor+with+a+lower+EC50+than+human+TSH.+It+is+produced+by+the+pituitary+in+corticotrophs+but+its+physiological+significance+remains+mysterious+%28312%3B313%29.%0D%0A%0D%0A%3Cu%3EDownregulation+of+the+TSH+receptor%3C%2Fu%3E%0D%0ADesensitization+of+some+G+protein%E2%80%93coupled+receptors+has+been+shown+to+involve+phosphorylation+of+specific+residues+by+G+protein+receptor+kinases+%28homologous+desensitization%29+or+PKA+%28heterologous+desensitization%29+enzymes+%28219%29.+When+compared+with+other+G+protein%E2%80%93coupled+receptors%2C+the+TSH+receptor+contains+few+phosphorylatable+serine+or+threonine+residues+in+its+intracellular+loops+and+C-terminal+tail%2C+which+probably+accounts+for+the+limited+desensitization+observed+after+stimulation+by+TSH.+Acute+desensitization+of+the+receptor+in+the+presence+of+TSH%2C+presumably+by+phosphorylation%2C+is+weak+and+delayed+%28314%29.+Its+internalization+is+rapidly+followed+by+recycling+to+the+cell+surfaces+while+the+hormone+is+degraded+in+lysosomes+%28315%29.+Similarly+a+weak+downregulation%2C+confounded+by+the+long+life+of+both+TSHR+mRNA+and+protein%2C+takes+place+but+has+little+functional+role+%28285%29.+On+the+other+hand+in+the+presence+of+constant+stimulation+the+cAMP+accumulation+is+downregulated+mostly+as+a+consequence+of+phosphodiesterase+induction+%28316%29.+The+persistence+of+hyperthyroidism+in+patients+submitted+to+constant+TSH+stimulations+in+TSH+secreting+pituitary+adenomas+or+TSAb+stimulation+in+Graves+disease+testifies+to+the+weakness+of+these+negative+regulations.%0D%0A%0D%0AThe+TSHr+contains+six+sites+for+N-glycosylation%2C+of+which+four+have+been+shown+to+be+effectively+glycosylated+%28271%29.+The+functional+role+of+the+individual+carbohydrate+chains+is+still+debated.+It+is+likely+that+they+contribute+to+the+routing+and+stabilization+of+the+receptor+through+the+membrane+system+of+the+cell.%0D%0AAlone+amongst+the+glycoprotein+hormone+receptors%2C+the+TSHr+undergoes+cleavage+of+its+ectodomain%2C+severing+it+from+the+serpentine+domain+%28267%29.+This+phenomenon+has+been+related+to+the+presence+in+the+TSHr+of+a+50+amino+acid+%E2%80%9Cinsertion%E2%80%9D+for+which+there+is+no+counterpart+in+the+FSHr+or+LH%2FCGr.+Current+data+indicate+that+the+initial+cleavage+step%2C+by+a+metalloprotease%2C+takes+place+around+position+314+%28within+the+50+aminoacid+insertion%29%2C+followed+by+nibbling+of+the+aminoterminal+extremity+of+the+serpentine-containing+portion+%28317%3B318%29.+The+aminoterminal+and+serpentine+portions+of+the+resulting+dimer+remain+bound+to+each+other+by+disulphide+bounds.+The+functional+meaning+of+this+TSHr-specific+postranslational+modification+remains+unclear.+Whereas+all+wild+type+TSHr+at+the+surface+of+thyrocytes+seem+to+be+in+cleaved+form%2C+it+has+been+shown+that+non+cleavable+mutant+constructs+are+functionally+undistinguishable+from+cleaved+receptors%2C+when+expressed+in+transfected+cells+%28267%29.+Noteworthy%2C+when+transiently+or+permanently+transfected+in+non-thyroid+cells%2C+the+wild+type+human+TSHr+is+present+at+the+cell+surface+as+a+mixture+of+monomer+and+cleaved+dimer.%0D%0AThe+TSH+receptor+is+specifically+inserted+into+the+baso-lateral+membrane+of+thyrocytes.+This+phenomenon+involves+signals+encoded+in+the+primary+structure+of+the+protein%2C+as+it+is+conserved+when+the+receptor+is+expressed+in+the+MDCK+cell%2C+a+polarized+cell+of+non-thyroid+origin+%28319%29.%0D%0A%0D%0A%3Cu%3EDimerization.%3C%2Fu%3E%0D%0AAS+most+rhodopsin-like+GPCRs%2C+the+glycoprotein+hormone+receptors+have+been+demonstrated+to+dimerize%2Foligomerize+by+a+variety+of+experimental+approchaes+including+FRET%2C+BRET+and+functional+complementation+of+mutants+%28320-324%29.+The+physiological+significance+of+this+phenomenon+remains+unknown%2C+but+it+has+been+shown+to+be+associated+with+allosteric+properties+of+the+dimers%2Foligomers+%28325%29.+TSH+binding+to+the+TSHr+displays+strong+negative+cooperativity%2C+which+is+classically+considered+to+account+for+a+shallow+concentration+action+curve%2C+extending+over+two+orders+of+magnitude.%0D%0AThe+possibility+that+TSHr+are+present+at+the+cell+surface+as+%E2%80%9Cdimers+of+cleaved+dimers%E2%80%9D+has+recently+been+raised+following+demonstration+that+most+rhodopsin-like+GPCRs+do+dimerize+%28326%29.+Functional+complementation+of+mutants+in+the+ecto-+and+the+serpentine+domains+has+been+observed+after+co-transfection+of+FSH+receptor+constructs+in+cells+%28327%29%2C+demonstrating+the+possibility+of+dimerization+for+glycoprotein+hormone+receptors.+Preliminary+data+have+been+provided+for+the+TSHr+%28320%29%2C+but+definitive+demonstration+of+the+functional+significance+of+its+dimerization+is+still+missing.%0D%0ADesensitization+of+some+G+protein-coupled+receptors+has+been+shown+to+involve+phosphorylation+of+specific+residues+by+G+protein+receptor+kinases+%28GRK%29+%28homologous+desensitization%29+or+protein+kinase+A+%28heterologous+desensitization%29+enzymes+%28267%29.+As+compared+with+other+G+protein-coupled+receptors%2C+the+TSH+receptor+contains+few+phosphorylatable+serine+or+threonine+residues+in+its+intracellular+loops+and+carboxyl-terminal+tail%2C+which+probably+accounts+for+the+limited+desensitization+observed+after+stimulation+by+TSH+and+for+the+continuous+TSAb+action+which+accounts+for+Graves+disease.%0D%0A%3Ca+href%3D%22%22+name%3D%2233%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AThe+TSH+Receptor+Gene.%3C%2Fh3%3E%0D%0AThe+gene+coding+for+the+human+TSH+receptor+has+been+localized+on+the+long+arm+of+chromosome+14+%2814q31%29+%28328%3B329%29.+It+spreads+over+more+than+60+kb+and+is+organized+into+10+exons+displaying+an+interesting+correlation+with+the+protein+structure+%28330%29.+The+extracellular+domain+is+encoded+by+a+series+of+9+exons%2C+each+of+which+corresponds+to+one+or+an+integer+number+of+leucine+rich+repeat+motifs+%28see+below%29.+The+C-terminal+half+of+the+receptor+containing+the+C-terminal+part+of+the+ectodomain+and+the+serpentine+domain+is+encoded+by+a+single+large+exon.+This+finding+is+reminiscent+of+the+fact+that+many+G+protein%E2%80%93coupled+receptor+genes+are+intronless.+A+likely+evolutionary+scenario+derives+from+this+gene+organization+%28330%29%3A+the+glycoprotein+hormone+receptor+genes+would+have+evolved+from+the+condensation+of+an+intronless+classic+G+protein%E2%80%93coupled+receptor+with+a+mosaic+gene+encoding+a+progenerally+considered+to+be+passive+and+nonspecific.+At+least+five+types+of+control+have+been+demonstrated+%28248%3B249%3B332%29.%0D%0A1.+Rapid+and+transient+stimulation+of+iodide+efflux+by+TSH+in+vivo%2C+which+might+reflect+a+general+increase+in+membrane+permeability.+The+cascade+involved+is+not+known.%0D%0A2.+Rapid+activation+of+iodide+apical+efflux+from+the+cell+to+the+lumen+by+TSH.+This+effect%2C+which+contributes+to+the+concentration+of+iodide+at+the+site+of+its+oxidation%2C+is+mediated%2C+depending+on+the+species%2C+by+Ca%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%2B%3C%2Fsup%3E%26nbsp%3Band%2For+cAMP+%28228%3B332%29.+In+human+cells+it+is+mainly+controlled+by+Ca%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%2B%3C%2Fsup%3E%26nbsp%3Band+therefore+by+the+TSH+effect+on+phospholipase+C.%0D%0A3.+Delayed+increase+in+the+capacity+%28Vmax%29+of+the+active+iodide+transport+NIS+in+response+to+TSH.+This+effect+is+inhibited+by+inhibitors+of+RNA+and+protein+synthesis+and+is+due+to+activation+of+iodide+transporter+gene+expression.+This+effect+of+TSH+is+reproduced+by+cAMP+analogues+in+vitro+and+is+therefore+mediated+by+the+cAMP+cascade+%28124%29.+mRNA+expression+is+enhanced+by+TSH+and+cAMP+and+decreased+by+iodide+%28261%3B334%29.+TSH+enhancement+of+thyroid+blood+flow%2C+more+or+less+delayed+depending+on+the+species%2C+also+contributes+to+increase+the+uptake+of+iodide+%28124%29.+Iodine+levels+in+the+thyroid+are+also+inversely+related+to+blood+flow+%28335%29.%0D%0A4.+Rapid+inhibition+by+iodide+of+its+own+transport+in+vivo+and+in+vitro.+This+inhibitory+effect+requires+an+intact+transport+and+oxidation+function%2C+that+is%2C+it+fulfills+the+criteria+of+an+XI+effect.+After+several+hours+the+capacity+of+the+active+transport+mechanism+is+greatly+impaired+%28adaptation+to+the+Wolff-Chaikoff+effect%29+%28249%29.+The+mechanism+of+the+first+effect+is+unknown+but+probably+initially+involves+direct+inhibition+of+the+transport+system+itself+%28akin+to+the+desensitization+of+a+receptor%29%2C+followed+later+by+inhibition+of+NIS+gene+expression+and+NIS+synthesis+%28akin+to+the+downregulation+of+a+receptor%29+%28261%29.%0D%0A5.+Inhibition+by+iodide+of+thyroid+blood+flow.+This+effect+may+be+direct+as+it+takes+place+in+patients+treated+with+thyroperoxidase+inhibitors+and+therefore+does+not+fit+the+XI+paradigm.+By+decreasing+the+iodide+input+it+decreases+the+uptake.%0D%0A%3Ca+href%3D%22%22+name%3D%2237%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AIodide+Binding+to+Protein+and+Iodotyrosine+Coupling%3C%2Fh3%3E%0D%0AIodide+oxidation+and+binding+to+thyroglobulin+and+iodotyrosine+coupling+in+iodothyronines+are+catalyzed+by+the+same+enzyme%2C+thyroperoxidase%2C+with+H%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3EO%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bused+as+a+substrate+%28336%29.+The+same+regulations+apply+to+the+two+steps.+H%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3EO%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bis+generated+by+a+NADPH+oxidase+system+of+which+two+proteins+DUOX+or+THOX+have+been+identified+by+cloning+%28337%3B338%29.+The+system+is+very+efficient+in+the+basal+state+inasmuch+as+little+of+the+iodide+trapped+can+be+chased+by+perchlorate+in+vivo.+Also%2C+in+vitro+and+in+vivo+the+amount+of+iodine+bound+to+proteins+mainly+depends+on+the+iodide+supply.+Nevertheless%2C+in+human+thyroid+in+vitro%2C+stimulation+of+the+iodination+process+takes+place+even+at+low+concentrations+of+the+anion%2C+thus+indicating+that+iodination+is+a+secondary+limiting+step.+Such+stimulation+is+caused+in+all+species+by+intracellular+Ca%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%2B%3C%2Fsup%3E%26nbsp%3Band+is+therefore+a+consequence+of+activation+of+the+Ca%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%2B%3C%2Fsup%3E-PIP%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bcascade.+In+many+species%2C+phorbol+esters+and+diacylglycerol%2C+presumably+through+protein+kinase+C%2C+also+enhance+iodination+%28339%29.+It+is+striking+that+in+a+species+such+as+the+human%2C+in+which+TSH+activates+the+PIP%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bcascade%2C+cAMP+inhibits+iodination%2C+whereas+in+a+species+%28dog%29+in+which+TSH+activates+only+the+cAMP+cascade%2C+cAMP+enhances+iodination.+Obviously+in+the+latter+species+a+supplementary+cAMP+control+was+necessary+%28339%3B340%29.%0D%0AThyroperoxidase+does+not+contain+any+obvious+phosphorylation+site+in+its+intracellular+tail.+On+the+other+hand%2C+all+the+agents+that+activate+iodination+also+activate+H%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3EO%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bgeneration%2C+and+inhibition+of+H%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3EO%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bgeneration+decreases+iodination%2C+which+therefore+suggests+that+iodination+is+an+H%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3EO%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3Esubstrate%E2%80%93driven+process+and+that+it+is+mainly+controlled+by+H%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3EO%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bgeneration+and+iodide+supply+%28339%3B341%29.+Congruent+with+the+relatively+high%26nbsp%3B%3Ci%3EK%3C%2Fi%3E%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3Em%3C%2Fsub%3E%26nbsp%3Bof+thyroperoxidase+for+H%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3EO%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%2C+H%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3EO%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bis+generated+in+disproportionate+amounts+with+regard+to+the+quantity+of+iodide+oxidized.+Negative+control+of+iodination+by+iodide+%28the+Wolff-Chaikoff+effect%29+is+accompanied+and+mostly+explained+by+the+inhibition+of+H%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3EO%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bgeneration.+This+effect+of+I%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E%E2%80%93%3C%2Fsup%3E%26nbsp%3Bis+relieved+by+perchlorate+and+methimazole+and+thus+pertains+to+the+XI+paradigm+%28254%3B339%29.%0D%0AIodotyrosine+coupling+to+iodotyrosines+is+catalyzed+by+the+same+system+and+is+therefore+subject+to+the+same+regulations+as+iodination.+However%2C+coupling+requires+that+suitable+tyrosyl+groups+in+thyroglobulin+be+iodinated%2C+that+is%2C+that+the+level+of+iodination+of+the+protein+be+sufficient.+In+the+case+of+severe+iodine+deficiency+or+when+thyroglobulin+exceeds+the+iodine+available%2C+insufficient+iodination+of+each+thyroglobulin+molecule+will+preclude+iodothyronine+formation+whatever+the+activity+of+the+H%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3EO%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bgenerating+system+and+thyroperoxidase.+On+the+other+hand%2C+when+the+iodotyrosines+involved+in+the+coupling+are+present%2C+coupling+is+controlled+by+the+H%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3EO%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bconcentration+but+independent+of+iodide+%28336%29.+In+this+case%2C+H%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3EO%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bcontrol+has+a+significance+even+at+very+low+iodide+concentrations.%0D%0AH%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3EO%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bgeneration+requires+the+reduced+form+of+nicotinamide-adenine+dinucleotide+phosphate+%28NADPH%29+as+a+coenzyme+and+is+thus+accompanied+by+NADPH+oxidation.+Limitation+of+the+activity+of+the+pentose+phosphate+pathway+by+NADP%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E%2B%3C%2Fsup%3E%26nbsp%3Binsures+that+NADPH+oxidation+for+H%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3EO%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bgeneration+causes+stimulation+of+this+pathway.+Also%2C+excess+H%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3EO%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bleaking+back+into+the+thyrocyte+is+reduced+by+glutathione+%28GSH%29+peroxidase%2C+and+the+oxidized+GSH+%28GSSG%29+produced+is+reduced+by+NADPH-linked+GSH+reductase.+Thus+both+the+generation+of+H%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3EO%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Band+the+disposal+of+excess+H%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3EO%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bby+pulling+NADP+oxidation+and+the+pentose+pathway+lead+to+activation+of+this+pathway%E2%80%94historically+one+of+the+earliest+and+unexplained+effects+of+TSH+%28124%3B339%29.%0D%0AOn+the+long-term%2C+in+vivo+or+in+vitro%2C+the+activity+of+the+whole+iodination+system+obviously+also+depends+on+the+level+of+its+constitutive+enzymes.+In+human+thyrocytes+H2O2+generation+but+not+TPO+is+stimulated+by+direct+activation+of+DUOX+by+the+Gq-PLC-Ca%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E%2B%2B%3C%2Fsup%3E%26nbsp%3Bcascade+which+TPO+expression%2C+but+not+DUOX+is+upregulated+by+the+TSH-cAMP+cascade+%28342%29.+It+is+therefore+not+surprising+that+activation+of+thyrocytes+by+the+cAMP+cascade+increases+the+corresponding+gene+expression+whereas+dedifferentiating+treatments+with+EGF+and+phorbol+esters+inhibit+this+expression+and+thus+reduce+the+capacity+and+activity+of+the+system.+Apparent+discrepancies+in+the+literature+about+the+effects+of+phorbol+esters+on+iodination+are+mostly+explained+by+the+kinetics+of+these+effects+%28acute+stimulation+of+the+system%2C+delayed+inhibition+of+expression+of+the+involved+genes%29.%0D%0A%3Ca+href%3D%22%22+name%3D%2238%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AThyroid+Hormone+Secretion%3C%2Fh3%3E%0D%0ASecretion+of+thyroid+hormone+requires+endocytosis+of+human+thyroglobulin%2C+its+hydrolysis%2C+and+the+release+of+thyroid+hormones+from+the+cell.+Thyroglobulin+can+be+ingested+by+the+thyrocyte+by+three+mechanisms+%28124%3B343-345%29.%0D%0AIn%26nbsp%3B%3Ci%3Emacropinocytosis%3C%2Fi%3E%2C+which+is+the+first%2C+pseudopods+engulf+clumps+of+thyroglobulin.+In+all+species+this+process+is+triggered+by+acute+activation+of+the+cAMP%2FPKA+cascade+and+therefore+by+TSH.+Stimulation+of+macropinocytosis+is+preceded+and+accompanied+by+an+enhancement+of+thyroglobulin+exocytosis+and+thus+of+the+membrane+surface+%28341%3B346%3B347%29.+In+dog+thyroid+slices+%28220%29+and+even+%28254%29+primary+cultures%2C+TSH+and+PKA+activation+acutely+induces+phagocytosis+%28348%29%2C+which+appears+as+the%26nbsp%3B%3Ci%3Ein+vitro%3C%2Fi%3E%26nbsp%3Bmanifestation+of+the+macropinocytosis+of+thyroglobulin+involved+in+stimulated+thyroid+hormone+secretion.+This+process+might+be+mediated+by+inactivation+of+the+Rho+family+small+G+proteins+%28Fortemaison+Endocrinology+2005%29%2C+resulting+in+microfilament+depolymerization+and+stress+fiber+disruption+accompanied+by+dephosphorylation+of+cofilin+%28349%29+and+myosin+light+chains+%28350%29.%0D%0ABy%26nbsp%3B%3Ci%3Emicropinocytosis%3C%2Fi%3E%2C+the+second+process%2C+small+amounts+of+colloid+fluid+are+ingested.+This+process+does+not+appear+to+be+greatly+influenced+by+acute+modulation+of+the+regulatory+cascades.+It+is+enhanced+in+chronically+stimulated+thyroids+and+thyroid+cells+early+mobilization+ro+the+membrane+and+later+with+induction+of+vesicle+transport+proteins+Rab+5+and+7+%28351%29+%28352%3B353%29.+It+probably+accounts+for+most+of+basal+secretion.%0D%0AA+third+%28hypothesized%29+process+is%26nbsp%3B%3Ci%3Ereceptor-mediated+endocytosis%3C%2Fi%3E%3B+it+is+enhanced+in+chronically+stimulated+thyroid+cells+%28354-356%29.+The+protein+involved+could+be+megalin+%28357%29+or+and+asyaloglycoprotein.+This+process+probably+accounts+for+the+transcytosis+of+low+hormonehenic+thyroglobulin+%28358%29.%0D%0AContrary+to+the+last+named%2C+the+first+two+processes+are+not+specific+for+the+protein.+They+can+be+distinguished+by+the+fact+that+macropinocytosis+is+inhibited+by+microfilament+and+microtubule+poisons+and+by+lowering+of+the+temperature+%28below+23%C2%B0C%29+%28124%3B314%29.+Whatever+its+mechanism%2C+endocytosis+is+followed+by+lysosomal+digestion+with+complete+hydrolysis+of+thyroglobulin.+The+main+iodothyronine+in+thyroglobulin+is+thyroxine.+However%2C+during+its+secretion+a+small+fraction+is+deiodinated+by+type+I+5+and+in+man+type+II+5+-deiodinase+to+triiodothyronine+%28T%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E3%3C%2Fsub%3E%29%2C+thus+increasing+relative+T%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E3%3C%2Fsub%3E%26nbsp%3B%28the+active+hormone%29+secretion+%28359%29.%0D%0AThe+free+thyroid+hormones+are+released+by+an+unknown+mechanism%2C+which+may+be+diffusion+or+transport.+The+iodotyrosines+are+deiodinated+by+specific+deiodinases+and+their+iodide+recirculated+in+the+thyroid+iodide+compartments.+Under+acute+stimulation%2C+a+release+%28spillover%29+of+amino+acids+and+iodide+from+the+thyroid+is+observed.+A+mechanism+for+lysosome+retention+of+poorly+iodinated+thyroglobulin+on%26nbsp%3B%3Ci%3EN%3C%2Fi%3E-acetylglucosamine+receptors+and+recirculation+to+the+lumen+has+been+proposed.+Under+normal+physiologic+conditions%2C+endocytosis+is+the+limiting+step+of+secretion%2C+but+after+acute+stimulation%2C+hydrolysis+might+become+limiting+with+the+accumulation+of+colloid+droplets.+Secretion+by+macropinocytosis+is+triggered+by+activation+of+the+cAMP+cascade+and+inhibited+by+Ca%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%2B%3C%2Fsup%3E%26nbsp%3Bat+two+levels%3A+cAMP+accumulation+and+cAMP+action.+It+is+also+inhibited+in+some+thyroids+by+protein+kinase+C+downstream+from+cAMP.+Thus+the+PIP%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bcascade+negatively+controls+macropinocytosis+%28239%29.%0D%0AThe+thyroid+also+releases+thyroglobulin.+Inasmuch+as+this+thyroglobulin+was+first+demonstrated+by+its+iodine%2C+at+least+part+of+this+thyroglobulin+is+iodinated%3B+thus+it+must+originate+from+the+colloid+lumen.+Release+is+inhibited+in+vitro+by+various+metabolic+inhibitors+and+therefore+corresponds+to+active+secretion+%28346%3B360%29.+The+most+plausible+mechanism+is+transcytosis+from+the+lumen+to+the+thyrocyte+lateral+membranes+%28347%29.+As+for+thyroid+hormone%2C+this+secretion+is+enhanced+by+activation+of+the+cAMP+cascade+and+TSH+and+inhibited+by+Ca%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%2B%3C%2Fsup%3E%26nbsp%3Band+protein+kinase+C+activation.+Because+thyroglobulin+secretion+does+not+require+its+iodination%2C+it+reflects+the+activation+state+of+the+gland+regardless+of+the+efficiency+of+thyroid+hormone+synthesis.+Thyroglobulin+serum+levels+and+their+increase+after+TSH+stimulation+constitute+a+very+useful+index+of+the+functional+state+of+the+gland+when+this+synthesis+is+impaired%2C+as+in+iodine+deficiency%2C+congenital+defects+in+iodine+metabolism%2C+treatment+with+antithyroid+drugs%2C+and+the+like+%28361%29.+Regulated+thyroglobulin+secretion+should+not+be+confused+with+the+release+of+this+protein+from+thyroid+tumors%2C+which+corresponds+in+large+part+to+exocytosis+of+newly+synthesized+thyroglobulin+in+the+extracellular+space+rather+than+in+the+nonexistent+or+disrupted+follicular+lumen.+In+inflammation+or+after+even+mild+trauma%2C+opening+of+the+follicles+can+cause+unregulated+leakage+of+lumen+thyroglobulin.%0D%0ATranscytosis+or+leakage+from+the+lumen+yields+iodinated+thyroglobulin+while+exocytotic+thyroglobulin+is+not+iodinated.%0D%0A%0D%0A%3Ca+href%3D%22%22+name%3D%2239%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AFunctional+Heterogeneity%3C%2Fh3%3E%0D%0AIt+has+long+been+known+that+at+any+given+time+the+function+of+the+thyroid+follicles+is+not+homogeneous.+For+instance%2C+after+injection+of+radioiodide%2C+some+follicles+will+incorporate+important+amounts+of+radioiodine+while+others+will+not+incorporate+at+all.+Similarly%2C+after+stimulation+with+TSH+in+in+vivo+thyroids+or+in+in+vitro+incubated+slices%2C+some+cells+will+develop+pseudopods+for+macropinocytosis+whithin+15+min+while+others+submitted+to+the+same+stimulus+will+only+respond+after+one+to+two+hours+%28112%3B362%29.%0D%0AIn+a+beautiful+study%2C+G%C3%A9rard+et+al+%28363%29+%28364%29+showed+in+human+thyroids+that+while+some+follicles+exhibit+marked+expression+of+pendrin%2C+TPO+and+THOX%2C+others+did+not.+The+expressing+follicles+were+those+containing+iodinated+thyroglobulin.+They+correspond+to+larger+capillary+networks+and+to+the+expression+in+the+follicular+cells+of+vascular+regulators+nitric+oxide+synthase+and+endothelin.+This+shows+the+existence+of+active+and+inactive+angiofollicular+units.+It+suggests+that+over+time+angiofollicular+units+cycle+from+active+to+inactive+states+and+that+this+is+controlled+by+the+follicular+cells.+It+would+be+interesting+to+know+if+the+inactive+state+corresponds+to+a+lower+sensitivity+to+TSH.%0D%0A%0D%0A%3Ca+href%3D%22%22+name%3D%2240%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0ACONTROL+OF+THYROID-SPECIFIC+GENE+EXPRESSION%3C%2Fh3%3E%0D%0AThe+study+of+specific+gene+expression+and+proliferation+at+the+biochemical+and+mechanistic+level+requires+long+term+in+vitro+incubations%2C+i.e.+cell+culture.+It+is+therefore+easy+and+tempting+to+rely+on+cell+lines+such+as+the+rat+thyroid+FRTL-5%2C+WRT+and+PCCl3+cells.+However+these+cells%2C+sometimes+different+from+one+lab+to+another%2C+are+different+from+each+oth%2C+like+thyroglobulin+and+thyroperoxidase%2C+or+that%2C+although+being+also+found+in+a+few+additional+tissues%2C+are+primarily+involved+in+thyroid+function%2C+like+TSH+receptor+and+sodium%2Fiodide+symporter.+The+transcription+of+these+genes+in+the+thyroid+appears+to+rely+on+the+coordinated+action+of+a+master+set+of+transcription+factors+that+includes+at+least+the+homeodomain+protein+TTF-1+%28also+known+as+Nkx+2.1%29%2C+the+paired-domain+protein+Pax+8%2C+and+perhaps+also+the+forkhead-domain+protein+TTF-2+%28also+known+as+FoxE1%29+%28366%3B367%29.+Loss+of+function+mutant+mice+for+TTF-1%2C+Pax+8+or+TTF-2+have+been+generated+and+allowed+to+identify+a+crucial+role+for+these+transcription+factors+in+the+development+of+the+thyroid+also.+However%2C+as+none+of+these+animals+develop+a+normal+mature+thyroid%2C+they+could+not+be+used+to+investigate+the+exact+role+of+these+key+factors+in+the+control+of+gene+expression+in+the+mature+thyroid.+Most+of+the+work+concerning+this+last+aspect+has+been+conducted+either+in+primary+cultures+of+thyrocytes+%28368%29+or+in+immortalized+thyroid+cell+lines+like+FRTL-5+and+PCCl3+%28369%29.+Although+the+data+gathered+to+date+agree+on+most+basic+aspects%2C+significant+differences+have+sometimes+been+observed+between+primary+versus+immortalized+cell+models+%28370%29.+Part+of+these+discrepancies+may+result+from+the+existence+of+occasional+species-specific+daction.+It+is+also+inhibited+in+some+thyroids+by+protein+kinase+C+downstream+from+cAMP.+Thus+the+PIP%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Bcascade+negatively+controls+macropinocytosis+%28239%29.%0D%0AThe+thyroid+also+releases+thyroglobulin.+Inasmuch+as+this+thyroglobulin+was+first+demonstrated+by+its+iodine%2C+at+least+part+of+this+thyroglobulin+is+iodinated%3B+thus+it+must+originate+from+the+colloid+lumen.+Release+is+inhibited+in+vitro+by+various+metabolic+inhibitors+and+therefore+corresponds+to+active+secretion+%28346%3B360%29.+The+most+plausible+mechanism+is+transcytosis+from+the+lumen+to+the+thyrocyte+lateral+membranes+%28347%29.+As+for+thyroid+hormone%2C+this+secretion+is+enhanced+by+activation+of+the+cAMP+cascade+and+TSH+and+inhibited+by+Ca%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%2B%3C%2Fsup%3E%26nbsp%3Band+protein+kinase+C+activation.+Because+thyroglobulin+secretion+does+not+require+its+iodination%2C+it+reflects+the+activation+state+of+the+gland+regardless+of+the+efficiency+of+thyroid+hormone+synthesis.+Thyroglobulin+serum+levels+and+their+increase+after+TSH+stimulation+constitute+a+very+useful+index+of+the+functional+state+of+the+gland+when+this+synthesis+is+impaired%2C+as+in+iodine+deficiency%2C+congenital+defects+in+iodine+metabolism%2C+treatment+with+antithyroid+drugs%2C+and+the+like+%28361%29.+Regulated+thyroglobulin+secretion+should+not+be+confused+with+the+release+of+this+protein+from+thyroid+tumors%2C+which+corresponds+in+large+part+to+exocytosis+of+newly+synthesized+thyroglobulin+in+the+extracellular+space+rather+than+in+the+nonexistent+or+disrupted+follicular+lumen.+In+inflammation+or+after+even+mild+trauma%2C+opening+of+the+follicles+can+cause+unregulated+leakage+of+lumen+thyroglobulin.%0D%0ATranscytosis+or+leakage+from+the+lumen+yields+iodinated+thyroglobulin+while+exocytotic+thyroglobulin+is+not+iodinated.%0D%0A%0D%0A%3Ca+href%3D%22%22+name%3D%2239%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AFunctional+Heterogeneity%3C%2Fh3%3E%0D%0AIt+has+long+been+known+that+at+any+given+time+the+function+of+the+thyroid+follicles+is+not+homogeneous.+For+instance%2C+after+injection+of+radioiodide%2C+some+follicles+will+incorporate+important+amounts+of+radioiodine+while+others+will+not+incorporate+at+all.+Similarly%2C+after+stimulation+with+TSH+in+in+vivo+thyroids+or+in+in+vitro+incubated+slices%2C+some+cells+will+develop+pseudopods+for+macropinocytosis+whithin+15+min+while+others+submitted+to+the+same+stimulus+will+only+respond+after+one+to+two+hours+%28112%3B362%29.%0D%0AIn+a+beautiful+study%2C+G%C3%A9rard+et+al+%28363%29+%28364%29+showed+in+human+thyroids+that+while+some+follicles+exhibit+marked+expression+of+pendrin%2C+TPO+and+THOX%2C+others+did+not.+The+expressing+follicles+were+those+containing+iodinated+thyroglobulin.+They+correspond+to+larger+capillary+networks+and+to+the+expression+in+the+follicular+cells+of+vascular+regulators+nitric+oxide+synthase+and+endothelin.+This+shows+the+existence+of+active+and+inactive+angiofollicular+units.+It+suggests+that+over+time+angiofollicular+units+cycle+from+active+to+inactive+states+and+that+this+is+controlled+by+the+follicular+cells.+It+would+be+interesting+to+know+if+the+inactive+state+corresponds+to+a+lower+sensitivity+to+TSH.%0D%0A%0D%0A%3Ca+href%3D%22%22+name%3D%2240%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0ACONTROL+OF+THYROID-SPECIFIC+GENE+EXPRESSION%3C%2Fh3%3E%0D%0AThe+study+of+specific+gene+expression+and+proliferation+at+the+biochemical+and+mechanistic+level+requires+long+term+in+vitro+incubations%2C+i.e.+cell+culture.+It+is+therefore+easy+and+tempting+to+rely+on+cell+lines+such+as+the+rat+thyroid+FRTL-5%2C+WRT+and+PCCl3+cells.+However+these+cells%2C+sometimes+different+from+one+lab+to+another%2C+are+different+from+each+other+and+are+very+different+from+the+cells+in+vivo%2C+especially+the+human+cells.+Primary+cultures+are+closer+to+the+in+vivo+situation+but+they+are+difficult+to+obtain+and+not+as+reproducible.+However%2C+in+monolayers%2C+but+not+in+reorganized+follicles%2C+follicular+structure+is+fully+and+cell+polarity+and+structure+are+partially+lost.+As+most+authors+generalize+the+results+of+work+done+on+their+pet+systems+to+%22The+Thyroid%22+the+literature+is+very+confusing+and+full+of+contradictions+%28243%29.+Among+the+various+possibilities+demonstrated+in+such+systems+only+those+validated+in+vivo+in+transgenic+animals+and+in+human+cells+interest+us.%0D%0A%3Cdiv+lang%3D%22fr-FR%22%3E%0D%0AA+positive+in+vivo+effect+of+TSH+on+general+protein+synthesis+has+been+well+documented.+This+effect+is+mimicked+by+cAMP+agonists+and+is+part+of+the+trophic+effect+of+TSH+on+the+thyrocyte.+It+involves+stimulation+of+transcription+and+translation%3B+however%2C+the+detailed+mechanisms+implicated+are+not+known.+In+cells+in+culture+there+is+no+such+effect+and+the+TSH+cyclic+AMP+cascade+has+rather+an+inhibitory+effect.+Stimulation+of+protein+synthesis+and+hypertrophy+of+the+cell+in+culture+results+from+IGF1+action+on+PI3+kinase+%28365%29.+The+in+vivo+effect+of+TSH+might+be+mediated+by+IGF-1.%3C%2Fdiv%3E%0D%0A%3Cdiv+lang%3D%22fr-FR%22%3E%0D%0AThe+so-called+thyroid-specific+genes+encode+proteins+that+are+either+found+in+the+thyroid+exclusively%2C+like+thyroglobulin+and+thyroperoxidase%2C+or+that%2C+although+being+also+found+in+a+few+additional+tissues%2C+are+primarily+involved+in+thyroid+function%2C+like+TSH+receptor+and+sodium%2Fiodide+symporter.+The+transcription+of+these+genes+in+the+thyroid+appears+to+rely+on+the+coordinated+action+of+a+master+set+of+transcription+factors+that+includes+at+least+the+homeodomain+protein+TTF-1+%28also+known+as+Nkx+2.1%29%2C+the+paired-domain+protein+Pax+8%2C+and+perhaps+also+the+forkhead-domain+protein+TTF-2+%28also+known+as+FoxE1%29+%28366%3B367%29.+Loss+of+function+mutant+mice+for+TTF-1%2C+Pax+8+or+TTF-2+have+been+generated+and+allowed+to+identify+a+crucial+role+for+these+transcription+factors+in+the+development+of+the+thyroid+also.+However%2C+as+none+of+these+animals+develop+a+normal+mature+thyroid%2C+they+could+not+be+used+to+investigate+the+exact+role+of+these+key+factors+in+the+control+of+gene+expression+in+the+mature+thyroid.+Most+of+the+work+concerning+this+last+aspect+has+been+conducted+either+in+primary+cultures+of+thyrocytes+%28368%29+or+in+immortalized+thyroid+cell+lines+like+FRTL-5+and+PCCl3+%28369%29.+Although+the+data+gathered+to+date+agree+on+most+basic+aspects%2C+significant+differences+have+sometimes+been+observed+between+primary+versus+immortalized+cell+models+%28370%29.+Part+of+these+discrepancies+may+result+from+the+existence+of+occasional+species-specific+differences+%28371%29.%3C%2Fdiv%3E%0D%0A%3Cdiv+lang%3D%22fr-FR%22%3E%0D%0AThe+main+regulator+of+thyroid+function%2C+the+TSH+signal%2C+which+is+predominantly+conveyed+inside+the+cell+by+cAMP+and+PKA%2C+upregulates+the+expression+of+transcription+factor+Pax+8%2C+both+in+primary+cells+%28372%29+and+established+cell+lines+%28373%29.+However%2C+mice+genetically+deprived+of+TSH+or+of+functional+TSH+receptor+do+not+show+reduced+amounts+of+Pax+8+in+their+thyroids+as+compared+to+wild+type+animals+%28156%29+suggesting+that+compensatory+mechanisms+may+ensure+an+adequate+production+of+this+factor+when+thyroid+development+takes+place+in+the+absence+of+the+normal+physiological+stimulus.+Besides+this+control+on+the+amount+of+Pax+8+protein%2C+there+is+no+firm+evidence+that+TSH%2C+or+cAMP%2C+exerts+any+other+control+at+the+level+of+the+master+thyroid+transcription+factors+identified+presently+%28370%3B374%3B375%29.+The+expression+of+several+other+transcription+factors+was+shown+to+be+upregulated%2C+often+at+least+transiently%2C+in+response+to+TSH%2FcAMP+in+the+thyroid%2C+namely+c-myc+%28376%29%2C+c-fos+%28376%29%2C+fos+B%2C+jun+B%2C+jun+D+%28377%29%2C+CREM+%28378%29%2C+NGFI-B+%28379%29+and+CHOP%28380%29%2C+for+example.+An+hypothetical+role+in+the+control+exerted+by+TSH%2FcAMP+on+the+expression+of+the+thyroid-specific+genes+has+been+proposed+for+some+of+these+factors+%28378%3B380%29%2C+but+no+final+link+has+been+established+yet+%28381%29.+It+is+noteworthy+that+in+addition+to+its+control+on+the+transcription+of+the+individual+thyroid-specific+genes%2C+which+is+detailed+below%2C+TSH+also+regulates+gene+expression+by+acting+at+some+post-transcriptional+steps%2C+as+shown+in+the+case+of+thyroglobulin+%28382%29.+Finally%2C+many+effects+of+TSH+and+cAMP+on+gene+expression+%28including+on+thyroid-specific+genes+such+as+thyroglobulin%29+might+be+rather+indirect+and+depend+in+part+on+the+profound+modifications+of+cell+morphology+and+cytoskeleton+that+result+from+PKA+activation+%28182%29%28218%29.%3C%2Fdiv%3E%0D%0ATGF-%CE%B2+has+been+shown+to+downregulate+the+expression+of+thyroid-specific+genes+%28383%3B384%29.+It+seems+to+involve+a+reduction+in+the+level+of+Pax+8+activity+that+is+mediated+by+Smad+proteins+%28384%3B385%29.+In+human+thyroid+primary+cultures%2C+TGF-%CE%B2+inhibits+most+effects+of+cAMP+on+gene+expression+%28189%29.+As+above%2C+this+might+be+related+in+part+to+an+inhibition+of+morphological+effects+of+TSH%2FcAMP.+In+all+the+species+tested+so+far%2C+EGF+strongly+represses+thyroglobulin+and+thyroperoxidase+gene+expression+as+well+as+iodide+transport+%28165%3B182%3B285%3B386%3B387%29.+FGF+has+a+similar+action+in+some+species+including+bovine+%28165%29.+The+mechanisms+have+not+been+explored.+The+apparent+dedifferentiation+induced+by+EGF+in+dog+thyrocytes+is+associated+with+an+enhanced+vimentin+expression+and+a+progressive+induction+of+a+fusiform+fibroblast-like+morphology%2C+which+is+suggestive+of+an+epithelial-mesenchymal+transition+%28179%29+%28388%29.+This+process+is+reversible+after+elimination+of+EGF+and+re-addition+of+TSH.%0D%0A%3Cdiv+style%3D%22orphans%3A+0%3B+page-break-after%3A+avoid%3B+text-indent%3A+0.5in%3B+widows%3A+0%3B%22%3E%0D%0A%3C%2Fdiv%3E%0D%0A%3Ca+href%3D%22%22+name%3D%2241%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AThyroglobulin%3C%2Fh3%3E%0D%0AThe+regulatory+DNA+elements+of+the+thyroglobulin+gene+have+been+characterized+in+several+species+%28366%3B371%3B389%29.+The+proximal+promoter%2C+as+defined+in+transfection+experiments%2C+extends+over+200+base-pairs+and+contains+binding+sites+for+transcription+factors+TTF-1%2C+TTF-2+and+Pax+8+%28see+Fig.+1-15%29.+An+upstream+enhancer+element+containing+binding+sites+for+TTF-1+has+been+identified+in+beef+and+man+%28390%29.+In+the+latter%2C+the+enhancer+region+is+longer+and+harbors+additional+binding+sites+for+TTF-1+and+cAMP+responsive+element+binding+%28CREB%29+protein+%28391%29.+Both+TTF-1+and+Pax+8+proteins+were+individually+shown+to+exert+a+major+control+on+thyroglobulin+gene+transcription+%28392%3B393%29.+By+contrast%2C+TTF-2+activity+appears+to+be+dispensable+as+the+thyroglobulin+gene+is+expressed+in+cells+devoid+of+TTF-2+protein+%28392%29.+Synergism+in+the+transcriptional+activation+of+the+gene+by+TTF-1+and+Pax+8+appears+to+rely+on+a+direct+interaction+between+these+two+factors+%28394%29%2C+and+on+their+coordinated+action+involving+both+the+enhancer+and+proximal+promoter+sequences+%28395%29.+The+known+thyroglobulin+gene+regulatory+elements+were+shown+to+be+sufficient+to+drive+the+thyroid-restricted+expression+of+a+linked+gene+in+living+mice+%28396%29.+This+thyroid-restricted+expression+likely+results+from+the+requirement+for+the+simultaneous+presence+of+both+TTF-1+and+Pax+8%2C+which+occurs+in+thyroid+only.+It+is+associated+with+the+tissue-specific+demethylation+of+thyroglobulin+gene+sequences+%28397%29.+Demethylation+of+the+DNA+is+supposed+to+relieve+the+constitutive+silencing+of+the+gene+%28398%29.%0D%0A%3Cdiv+lang%3D%22fr-FR%22%3E%0D%0AThyroglobulin+gene+transcription+has+been+shown+to+require+the+presence+of+circulating+TSH+in+the+adult+rat+%28399%29+and+to+be+highly+dependent+on+an+elevated+cAMP+level+in+dog+thyroid+tissue+slices%2C+in+primary+cultured+cells+%28400%29%2C+and%2C+to+a+much+lower+extent%2C+in+immortalized+thyroid+cell+lines+like+FRTL-5+%28401%29.+Although+they+are+devoid+of+classical+cAMP-responsive+element+%28CRE%29%2C+the+proximal+promoter+sequences+are+essentially+involved+in+this+control%2C+as+indicated+by+the+observation+of+TSH%2FcAMP-induced+changes+in+their+chromatin+structure+%28402%29+and+their+TSH%2FcAMP-dependent+activity+in+transfection+experiments+%28403%29.+It+has+however+been+demonstrated+recently+that+the+onset+of+thyroglobulin+gene+expression+during+thyroid+development+takes+place+normally+in+mouse+strains+deprived+of+either+circulating+TSH+or+functional+TSH+receptors+%28155%3B156%29.+This+may+be+consistent+with+the+observation+that+the+thyroglobulin+gene+displays+a+low+level+of+cAMP-independent+transcription+in+primary+cultured+thyrocytes+%28400%29%2C+which+might+depend+on+insulin%2C+as+observed+in+different+culture+models+%28404-406%29.+In+primary+cultures+of+dog+thyrocytes%2C+the+transcriptional+activation+of+the+thyroglobulin+gene+by+cAMP+after+transient+TSH+withdrawal+is+also+delayed+as+compared+to+that+of+the+thyroperoxidase+gene+%28400%29%2C+and%2C+unlike+thyroperoxidase+gene+expression%2C+it%26nbsp%3Brequires+an+active+protein+synthesis+%28400%29.+The+increase+in+Pax+8+concentration+consecutive+to+TSH%2FcAMP+stimulation+of+the+thyrocyte+is+not+sufficient+to+account+for+the+observed+control+on+thyroglobulin+gene+transcription%2C+as+TSH+is+still+required+for+transcriptional+activation+even+in+cells+expressing+high+levels+of+Pax+8+protein+%28373%29.+Thus%2C+besides+TTF-1+and+Pax+8%2C+at+least+one+additional%2C+still+unidentified%2C+factor+is+likely+to+play+a+key+role+in+the+control+of+thyroglobulin+gene+expression%2C+as+also+suggested+by+the+observation+that%2C+in+the+course+of+thyroid+development%2C+both+TTF-1+and+Pax+8+are+present+well+before+thyroglobulin+gene+is+expressed.%3C%2Fdiv%3E%0D%0AIn+addition+to+the+full+length+thyroglobulin+mRNA%2C+a+shorter+transcript+accumulates+in+the+rat+thyroid+in+response+to+TSH+stimulation+%28407%29.+This+transcript+results+from+differential+splicing+and+polyadenylation+of+the+primary+transcript%2C+and+encodes+a+protein+limited+to+the+very+N-terminal+part+of+thyroglobulin.+As+this+truncated+protein+still+contains+a+major+hormonogenic+site%28408%29%2C+it+could+suggest+that%2C+in+conditions+in+which+the+balance+of+thyroid+metabolism+would+favor+hormone+synthesis+over+iodine+storage+%28e.g.%2C+shortage+of+iodine%29%2C+the+rat+thyrocyte+would+manufacture+a+shorter+thyroglobulin+with+a+preserved+hormonogenic+ability+but+lacking+many+of+the+nonhormonogenic+tyrosines.%0D%0A%3Ctable+align%3D%22center%22+border%3D%221%22%3E%3Ctbody%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cimg+align%3D%22BOTTOM%22+border%3D%221%22+height%3D%22540%22+name%3D%22graphics15%22+src%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Ffigures%2Ffigure1-15.jpg%22+width%3D%22780%22+%2F%3E%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cdiv+lang%3D%22fr-FR%22+style%3D%22background-attachment%3A+initial%3B+background-clip%3A+initial%3B+background-color%3A+%2399ccff%3B+background-image%3A+initial%3B+background-origin%3A+initial%3B+background-position%3A+initial+initial%3B+background-repeat%3A+initial+initial%3B+text-indent%3A+0in%3B%22%3E%0D%0A%3Cb%3EFig.+1-15.%3C%2Fb%3E%26nbsp%3BSchematic+of+the+known+regulatory+elements+of+thyroglobulin%2C+thyroperoxidase%2C+sodium%2Fiodide+symporter+and+TSH+receptor+genes.+The+organization+of+the+proximal+promoter+and+upstream+enhancer+elements+of+the+different+genes+is+depicted+as+determined+in+the+studied+so+far.+Coordinates+of+the+proximal+promoters+are+in+base+pairs+and+refer+to+the+transcription+start+site+as+%2B1.+The+positions+of+the+upstream+enhancer+elements+relative+to+the+transcription+start+site+are+not+indicated+as+they+vary+extensively+among+the+different+species.%3C%2Fdiv%3E%0D%0A%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3C%2Ftbody%3E%3C%2Ftable%3E%0D%0A%3Cdiv+style%3D%22orphans%3A+0%3B+text-indent%3A+0.5in%3B+widows%3A+0%3B%22%3E%0D%0A%0D%0A%3C%2Fdiv%3E%0D%0A%3Ca+href%3D%22%22+name%3D%2242%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AThyroperoxidase%3C%2Fh3%3E%0D%0AIn+the+species+studied+so+far%2C+the+architecture+of+the+proximal+promoter+region+of+the+thyroperoxidase+gene+strikingly+resembles+that+of+the+corresponding+region+of+the+thyroglobulin+gene+%28409%3B410%29+%28see+Fig.+1-15%29.+The+upstream+enhancer+element+also+encompasses+a+pair+of+TTF-1+binding+sites+and+contains+an+additional+binding+site+for+Pax+8%2C+as+compared+to+its+counterpart+in+the+thyroglobulin+gene+%28411%3B412%29.+Here+again%2C+the+combination+of+the+upstream+enhancer+and+proximal+promoter+supports+the+synergistic+action+of+TTF-1+and+Pax+8+on+gene+transcription+%28395%29.%0D%0A%3Cdiv+lang%3D%22fr-FR%22%3E%0D%0ADespite+the+existence+of+this+high+similarity%2C+thyroperoxidase+gene+transcription+is+more+tightly+and+more+rapidly+controled+by+TSH+and+cAMP+than+that+of+the+thyroglobulin+gene+in+primary+cultured+thyrocytes%2C+and+does+not+require+a+new+protein+synthesis+%28400%3B413%29.+Contrary+to+the+thyroglobulin+gene+also%2C+the+thyroperoxidase+gene+is+not+expressed+in+the+absence+of+circulating+TSH+or+functional+TSH+receptors+in+intact+animals+%28156%29.+On+the+other+hand%2C+the+constitutive+hyperactivation+of+the+cAMP+cascade+leads+to+an+increased+expression+of+the+gene+as+compared+to+the+normal+situation+%28414%29.+In+spite+of+their+lack+of+a+classical+CRE%2C+the+proximal+promoter+sequences+have+been+shown+to+mediate+this+TSH%2FcAMP+control+on+transcription+in+transfection+experiments+%28409%29.+Low+doses+of+iodide+also+decrease+thyroperoxidase+gene+expression+in+vivo%2C+while+the+expression+of+thyroglobulin+remains+unaffected+%28261%29.+Thus%2C+apart+from+their+basic+dependence+on+the+presence+of+the+transcription+factors+TTF-1+and+Pax+8%2C+which+insures+their+shared+thyroid-restricted+expression%2C+the+thyroperoxidase+and+thyroglobulin+genes+distinguish+themselves+significantly+regarding+the+control+of+their+transcription.+It+has+been+postulated+recently+that+the+hormone-induced+developmental+activation+of+the+thyroperoxidase+gene+involves+the+concerted+action+of+TTF-2+and+NF-1%2C+both+of+which+bind+neighbouring+sequences+in+the+gene+promoter+%28see+figure+1-15%29+resulting+in+the+initial+opening+of+the+chromatin+structure+of+the+promoter+%28354%29.%3C%2Fdiv%3E%0D%0AThe+existence+of+a+major+thyroperoxidase+mRNA+isoform+has+been+detected+in+man+%28415%29.+It+appears+to+encode+a+protein+devoid+of+its+normal+enzymatic+activity.%0D%0AIt+has+been+postulated+recently+that+the+hormone+induced+developmental+activation+of+the+thyroperoxidase+gene+involves+the+concerted+action+of+TTF2+and+NF1%2C+both+of+which+bind+neighbouring+sequences+in+the+gene+promoter+%28see+figure+1-15%29+resulting+in+the+initial+opening+of+the+chromatin+structure+of+the+promoter+%28416%29.+There+are+indications+that%2C+as+in+the+case+of+the+DUOXes%2C+the+expression+of+thyroperoxidase+at+the+membrane+of+the+thyrocyte+is+cell+specific+and+may+require+specific+factors+%28417%29.%0D%0A%0D%0A%3Ca+href%3D%22%22+name%3D%2243%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0ASodium%2Fiodide+Symporter%3C%2Fh3%3E%0D%0AAlthough+the+sodium%2Fiodide+symporter+plays+a+key+role+in+thyroid+hormonogenesis%2C+the+expression+of+the+corresponding+gene+is+not+restricted+to+the+thyroid.+Accordingly%2C+the+proximal+promoter+sequences+identified+so+far+do+not+exhibit+a+thyroid-specific+activity+in+vitro+%28418%3B419%29%2C+even+if+this+activity+may+be+marginally+increased+in+the+presence+of+TTF-1+%28420%29.+The+robust+and+appropriately+controlled+expression+of+this+gene+in+the+thyroid+seems+to+be+mediated+essentially+by+the+upstream+enhancer+element+which+contains+binding+sites+for+both+TTF-1+and+Pax+8%2C+and+a+cAMP+responsive+element+%28CRE%29-like+DNA+motif+which+is+involved+in+the+control+by+TSH%2FcAMP+%28333%3B421%29+%28see+Fig.+1-15%29.+As+for+the+thyroperoxidase+gene%2C+TSH+signaling+is+indispensable+for+sodium%2Fiodide+symporter+gene+transcriptional+activation+in+vivo+%28155%3B156%29%2C+and+iodide+downregulates+the+expression+of+the+gene+%28261%29.+A+very+similar+control+is+thus+exerted+on+the+expression+of+thyroperoxidase+and+sodium%2Fiodide+symporter+genes+in+the+thyroid+in+spite+of+the+fact+that+their+known+regulatory+regions+bear+only+limited+resemblances.%0D%0A%3Cdiv+style%3D%22orphans%3A+0%3B+page-break-after%3A+avoid%3B+text-indent%3A+0.5in%3B+widows%3A+0%3B%22%3E%0D%0A%3C%2Fdiv%3E%0D%0A%3Cdiv+style%3D%22orphans%3A+0%3B+page-break-after%3A+avoid%3B+text-indent%3A+0in%3B+widows%3A+0%3B%22%3E%0D%0A%3C%2Fdiv%3E%0D%0A%3Ca+href%3D%22%22+name%3D%2244%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AThyropin+Receptor%3C%2Fh3%3E%0D%0ALike+the+gene+described+above%2C+the+TSH+receptor+gene+is+also+expressed+in+tissues+other+than+the+thyroid.+Again%2C+the+promoter+elements+identified+presently%2C+which+include+binding+sites+for+thyroid+hormone+receptor+%28TR%29-%CE%B11%2Fretinoid-X+receptor+%28RXR%29+heterodimer+%28422%29%2C+GA-binding+protein+%28GABP%29+%28423%29%2C+cAMP+responsive+element+binding+%28CREB%29+protein%28422%29and+TTF-1+%28424%29+%28see+Fig.+1-15%29%2C+do+not+display+a+clear+thyroid-specific+activity+in+transfection+experiments%2C+as+could+be+expected.+Contrary+to+the+promoters+described+so+far%2C+the+promoter+of+the+TSH+receptor+gene+does+not+contain+a+TATA-box+motif%2C+but+encompasses+a+GC-rich+region+preceding+the+multiple+neighbouring+transcription+start+sites.+Consistent+with+the+presence+of+TTF-1+binding+sites+in+the+promoter+region%2C+the+TSH+receptor+genes+exhibits+a+decreased+activity+in+animals+expressing+reduced+level+of+TTF-1+%28425%29.+No+other+regulatory+DNA+element+specifically+involved+in+the+thyroid-specific+expression+of+this+gene+has+been+identified+as+yet.+On+the+other+hand%2C+DNA+demethylation+events+in+the+promoter+region+have+been+observed+in+thyroid+cells+expressing+the+TSH+receptor+gene%2C+as+compared+to+non-expressing+cells+%28423%29.%0D%0AThe+control+exerted+on+the+expression+of+the+TSH+receptor+gene+in+the+thyroid+seems+to+be+more+complex+than+the+ones+described+previously.+Discordant+effect+of+TSH%2FcAMP+on+the+expression+of+this+gene+have+been+reported+depending+on+the+nature+of+the+experimental+system+used+%28426%29.+The+presence+in+the+promoter+region+of+a+CRE-like+DNA+motif+which+appears+to+be+able+to+bind+the+CREB+protein%28422%29%2C+a+transcriptional+activator+directly+activated+by+cAMP%2C+as+well+as+the+CREM+isoform+ICER%28378%29%2C+a+transcriptional+repressor+induced+by+cAMP%2C+could+explain+both+reported+increase+and+decrease+in+gene+expression+following+TSH+stimulation%2C+depending+on+the+relative+amounts+of+these+factors+%28and+likely+of+other+CRE-binding+proteins+also%29+preexisting+in+the+studied+cells+and+the+kinetics+of+the+individual+observations.+Moreover%2C+the+binding+site+of+the+TR%CE%B11%2FRXR+heterodimer+identified+in+this+promoter+encompasses+the+CRE-like+motif+%28see+figure+1-15%29%2C+which+may+add+a+further+level+of+complexity+depending+on+the+availability+of+thyroid+hormone+in+the+experimental+system.%0D%0A%3Cdiv+style%3D%22orphans%3A+0%3B+text-indent%3A+0.5in%3B+widows%3A+0%3B%22%3E%0D%0A%0D%0A%3C%2Fdiv%3E%0D%0AOn+the+other+hand%2C+the+possible+existence+of+species-specific+differences+could+also+account+for+the+occurrence+of+seemingly+discrepant+reports+%28285%29.+The+accumulation+of+TSH+receptor+mRNA+requires+an+active+protein+synthesis+in+primary+cultured+dog+thyrocytes+%28285%29%2C+which+is+reminiscent+of+what+was+observed+for+the+thyroglobulin+gene+%28see+above%29.+Considering+the+facts+that%2C+after+the+TSH+receptor+gene%2C+the+thyroglobulin+gene+is+the+most+affected+in+its+expression+by+a+reduced+TTF-1+availability+as+compared+to+the+other+known+thyroid-specific+genes%28425%29%2C+and+that%2C+alike+the+TSH+receptor+gene+itself%2C+the+thyroglobulin+gene+is+activated+independently+of+the+TSH%2FTSHR+signaling+during+thyroid+development%28155%3B156%29%2C+it+suggests+that+these+two+genes+may+share+at+least+partially+similar+control+mechanisms.%0D%0AControl+of+TSH+receptor+gene+expression+has+been+studied+in+the+FRTL5+cell+line+%28426-428%29%2C+the+canine+thyrocyte+in+primary+culture+%28285%29%2C+cultured+human+thyrocytes+%28429%3B430%29%2C+and+human+thyroid+cancer+%28365%3B431%29.+The+general+conclusion+emerging+from+these+studies+is+the+extreme+robustness+of+TSH+receptor+gene+expression+as+compared+with+the+other+markers+of+thyroid+cell+differentiation+%28thyroglobulin+and+thyroperoxidase%29.+In+the+dog%2C+levels+of+TSH+receptor+mRNA+remain+virtually+unchanged+in+animals+subjected+for+28+days+to+hyperstimulation+by+TSH+secondary+to+treatment+with+methimazole+or+to+TSH+withdrawal+achieved+by+administration+of+thyroxine+%28285%29.+In+the+same+study%2C+the+effect+of+TSH+or+forskolin+has+been+investigated+in+dog+thyrocytes+in+primary+culture.+This+experimental+system+has+the+advantage+that+the+differentiation+state+of+the+cells+can+be+manipulated+at+will%3A+cAMP+agonists+maintain+expression+of+the+differentiated+phenotype%2C+whereas+agents+such+as+EGF%2C+tetradecanoyl+phorbol+acetate+%28TPA%29%2C+and+serum+lead+to+%22dedifferentiation%22+%28386%29.+The+results+demonstrate+that+the+dedifferentiating+agents+reduce+accumulation+of+the+receptor+mRNA.+However%2C+contrary+to+what+is+observed+with+thyroglobulin+and+thyroperoxidase+mRNA%2C+the+inhibition+is+never+complete.+TSH+or+forskolin+is+capable+of+promoting+reaccumulation+of+the+receptor+mRNA%2C+a+maximum+being+reached+after+20+hours.+As+with+thyroglobulin+but+at+variance+with+the+thyroperoxidase+gene%2C+this+stimulation+requires+ongoing+protein+synthesis+%28285%29.+Chronic+stimulation+of+cultured+dog+thyrocytes+by+TSH+for+several+days+does+not+lead+to+any+important+downregulation+in+mRNA.+Similar+data+have+been+obtained+with+human+thyrocytes+in+primary+culture+%28285%3B430%29.+By+contrast%2C+negative+regulation+of+receptor+mRNA+accumulation+has+been+observed+in+immortal+FRTL5+cells+after+treatment+with+TSH+or+TSAB+%28426%3B428%29.+This+difference+versus+human+and+canine+cells+must+probably+be+interpreted+in+the+general+framework+of+the+other+known+differences+in+phenotype+and+regulatory+behavior+of+this+cell+line+as+compared+with+primary+cultured+thyrocytes+%28see+below%29+%28243%29.+The+presence+in+the+promoter+region+of+a+CRE-like+DNA+motif+which+appears+to+be+able+to+bind+the+CREB+protein+%28422%29%2C+a+transcriptional+activator+directly+activated+by+cAMP%2C+as+well+as+the+CREM+isoform+ICER+%28378%29%2C+a+transcriptional+repressor+induced+by+cAMP%2C+could+explain+both+reported+increase+and+decrease+in+gene+expression+following+TSH+stimulation%2C+depending+on+the+relative+amounts+of+these+factors+%28and+likely+of+other+CRE-binding+proteins+also%29+preexisting+in+the+studied+cells+and+the+kinetics+of+the+individual+observations.+Moreover%2C+the+binding+site+of+the+TR%CE%B11%2FRXR+heterodimer+identified+in+this+promoter+encompasses+the+CRE-like+motif+%28see+Fig.+1-15%29%2C+which+may+add+a+further+level+of+complexity+depending+on+the+availability+of+thyroid+hormone+in+the+experimental+system.%0D%0A%3Cdiv+lang%3D%22fr-FR%22%3E%0D%0AThe+effect+of+malignant+transformation+on+the+amounts+of+TSH+receptor+mRNA+has+been+studied+in+spontaneous+tumors+in+humans+%28365%3B431%29%2C+in+a+murine+transgenic+model+of+thyroid+tumor+promoted+by+expression+of+the+simian+virus-40+large+T+oncogene%28432%29%2C+and+in+FRTL5+cells+transformed+with+v-%3Ci%3Eras%26nbsp%3B%3C%2Fi%3E%28427%29.+In+the+two+last+models%2C+expression+of+the+TSH+receptor+gene+was+suppressed%3A+the+tumor+or+cell+growth+became+TSH+independent.+In+the+transgenic+animal+model%2C+loss+of+TSH+receptor+mRNA+seemed+to+take+place+gradually%2C+with+early+tumors+still+displaying+some+TSH+dependence+for+growth.+In+the+human+tumors+a+spectrum+of+phenotypes+was+observed.+As+expected%2C+anaplastic+tumors+had+completely+lost+the+receptor+mRNA%2C+as+well+as+other+markers+of+thyrocyte+differentiation+%28thyroglobulin+and+thyroperoxidase%29.+In+papillary+carcinoma%2C+variable+amounts+of+TSH+receptor+mRNA+were+invariably+found+%28431%29%2C+even+in+the+tumors+that+had+lost+the+capacity+to+express+the+thyroglobulin+or+thyroperoxidase+genes+%28431%29.+These+data+agree+well+with+the+observations+of+thyrocytes+in+primary+culture%3A+expression+of+the+TSH+receptor+gene+is+robust+and+it+persists+in+the+presence+of+agents+%28or+after+several+steps+in+tumor+progression%29+that+promote+extinction+of+the+other+markers+of+thyroid+cell+differentiation.+This+evidence+leads+to+the+conclusion+that+the+basic+marker+of+the+thyroid+phenotype+is+probably+the+TSH+receptor+itself%2C+which+makes+sense%3A+the+gene+encoding+the+sensor+of+TSH%E2%80%94the+major+regulator+of+thyroid+function%2C+growth%2C+and+differentiated+phenotype%E2%80%94is+virtually+constitutive+in+thyrocytes.+From+a+pragmatic+viewpoint%2C+these+data+provide+a+rationale+for+the+common+therapeutic+practice+of+suppressing+TSH+secretion+in+patients+with+a+differentiated+thyroid+tumor+%28433%29.%3C%2Fdiv%3E%0D%0A%3Cdiv+style%3D%22orphans%3A+0%3B+text-indent%3A+0.5in%3B+widows%3A+0%3B%22%3E%0D%0A%0D%0A%3C%2Fdiv%3E%0D%0A%3Ca+href%3D%22%22+name%3D%2245%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AThyroid+oxidases%3C%2Fh3%3E%0D%0A%3Cdiv+lang%3D%22fr-FR%22%3E%0D%0ATwo+distinct+genes%2C+DUOX-1+and+-2+%28also+known+as+ThOX1+and+ThOX2%29%2C+both+significantly+related+to+the+gene+encoding+the+phagocyte+NADPH+oxidase+gp91%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3EPhox%3C%2Fsup%3E%2C+are+expressed+in+the+thyroid+essentially%2C+but+not+only%2C+at+least+for+ThOX2%28434%3B435%29.+In+the+dog%2C+ThOX+mRNAs+accumulate+in+response+to+TSH%2FcAMP+stimulation+%28434%29.+This+effect+is+much+less+apparent+in+man+%28434%29%2C+and+in+the+rat+conflicting+results+were+obtained+in+vivo+and+in+the+established+FRTL-5+cell+line+respectively+%28435%29.+The+proximal+promoter+sequences+of+both+human+ThOX1+and+ThOX2+genes+have+been+delineated+using+a+functional+assay+%28436%29.+These+promoters+do+not+exhibit+a+thyroid+cell-restricted+activity+in+vitro%2C+and+are+not+controled+positively+by+TSH%2FcAMP%2C+as+could+be+expected.+No+known+regulatory+DNA+motif+could+be+identified+obviously+within+these+promoter+sequences.+Notably%2C+like+the+promoter+of+the+TSH+receptor+gene%2C+both+of+these+promoters+are+devoid+of+a+TATA-box+motif.+Recently%2C+genes+encoding+proteins+required+for+the+functional+maturation+of+the+thyroid+oxidases+were+identified+in+the+close+vicinity+of+both+ThOX+genes%2C+and+named+DUOXA-1+and+-2+respectively+%28416%29.+Within+each+ThOX-DUOXA+pair%2C+the+two+genes+are+arranged+in+a+head+to+head+configuration%2C+the+distance+separating+the+putative+transcription+starts+being+in+the+range+of+one+hundred+of+base+pairs+only.+Each+DUOXA+is+necessary+for+expression+of+the+corresponding+DUOX+%28i.e.+DUOXA1+for+DUOX1%2C+DUOXA2+for+DUOX2%29+at+the+membrane+%28416%29.%3C%2Fdiv%3E%0D%0A%3Cdiv+style%3D%22orphans%3A+0%3B+text-indent%3A+0.5in%3B+widows%3A+0%3B%22%3E%0D%0A%0D%0A%3C%2Fdiv%3E%0D%0A%3Ca+href%3D%22%22+name%3D%2246%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0ACONTROL+OF+GROWTH+AND+DIFFERENTIATION%3C%2Fh3%3E%0D%0A%3Ca+href%3D%22%22+name%3D%2247%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AThyroid+Cell+Turnover%3C%2Fh3%3E%0D%0AThe+thyroid+is+composed+of+thyrocytes+%2870%25%29%2C+endothelial+cells+%2820%25%29%2C+and+fibroblasts+%2810%25%29+%28proportions+measured+in+dog+thyroid%29+%28110%29.+Human+thyroids%3A+80%25+follicular+cells+for+20%25+stromal+endothelial+cells+and+fibroblasts+80%25+%28437%3B437%29.+In+a+normal+adult+the+weight+and+composition+of+the+tissue+remain+relatively+constant.+Because+a+low+but+significant+proliferation+is+demonstrated+in+all+types+of+cells%2C+it+must+be+assumed+that+the+generation+of+new+cells+is+balanced+by+a+corresponding+rate+of+cell+death+%28152%3B437%3B438%29.+The+resulting+turnover+is+on+the+order+of+one+per+5+to+10+years+for+human+thyrocytes%2C+that+is%2C+six+to+eight+renewals+in+adult+life%2C+as+in+other+species.+In+one+child+the+turnover+was+2+per+year+%28438%29.+Normal+cell+population+can+therefore+be+modulated+mainly+at+the+level+of+proliferation+but+also+secondarily+of+cell+death.+In+growth+situations%2C+that+is%2C+either+in+normal+development+or+after+stimulation%2C+the+different+cell+types+grow+more+or+less+in+parallel%2C+which+implies+coordination+between+them+%28164%3B185%3B439%3B440%29.+Because+TSH+receptors+and+iodine+metabolism+and+signaling+coexist+only+in+the+thyrocyte+in+thyroid%2C+this+cell%2C+sole+receiver+of+the+physiologic+information%2C+must+presumably+control+the+other+types+of+cells+by+paracrine+factors+such+as+FGF%2C+IGF-I%2C+NO%2C+and+the+like+%28164%29.+The+successful+isolation+of+human+thyroid+endothelial+cells+will+allow+a+more+detailed+study+of+these+interactions+%28441%29.+TSH+has+been+demonstrated+to+upregulate+the+production+of+vascular+endothelial+cell+growth+factor+%28VEGF%29+by+human+thyrocytes+%28442%29.+It+is+interesting+in+this+regard+that+the+vascular+support+of+the+follicles+reflects+their+activity+suggesting+the+concept+of+angiofollicular+units+%28363%3B364%29.%0D%0A%3Ca+href%3D%22%22+name%3D%2248%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AThe+Mitogenic+Cascades%3C%2Fh3%3E%0D%0AThe+study+of+the+control+of+thyroid+cell+proliferation+has+been+much+confused+by+the+unwarranted+extrapolation+of+data+obtained+in+different+model+systems%2C+including+different+rat+thyroid+cell+lines+at+different+stages+in+their+evolution%2C+to+the+human+thyroid.+Sentences+like+%E2%80%9CAgent+X+stimulates+pathway+Y+in+PCCl3+cells%2C+thus+human+thyroids+could+ne+treated+by+agent+Z+which+inhibits+agent+X+action%E2%80%9D+are+not+acceptable+even+if+only+implied+%28243%29.%0D%0AIn+the+thyroid+at+least+three+families+of+distinct+mitogenic+pathways+have+been+well+defined+%28Fig.+1-16%29%3A+%281%29+the+hormone+receptor%E2%80%93Gs-adenylyl+cyclase%E2%80%93cAMP-dependent+protein+kinase+system%2C+%282%29+the+hormone+receptor%E2%80%93tyrosine+protein+kinase+pathways%2C+and+%283%29+the+hormone+receptor%E2%80%93Gq-phospholipase+C+cascade+%28152%3B443%29.+The+thyroid+also+autoregulates+its+size+by+an+unknown+mechanism.+Thyroxin+treated+dogs%2C+and+humans%2C+compensate+the+loss+of+one+thyroid+lobe+independently+of+TSH+%28261%29.%0D%0AThe+receptor%E2%80%93tyrosine+kinase+pathway+may+be+subdivided+into+two+branches%3B+some+growth+factors%2C+such+as+EGF%2C+induce+proliferation+and+repress+differentiation+expression%2C+whereas+others%2C+such+as+FGF+in+dog+cells+or+IGF-I+and+insulin%2C+are+either+mitogenic+or+are+necessary+for+the+proliferation+effect+of+other+factors+without+being+mitogenic+by+themselves%2C+but+they+do+not+inhibit+differentiation+expression+%28179%3B404%29.+In+human+thyroid+cells%2C+IGF-I+is+required+for+the+mitogenic+action+of+TSH+or+EGF+but+by+itself+it+only+weakly+stimulates+proliferation+%28236%29.+In+dog+and+human+thyrocytes+in+primary+cultures%2C+after+induction+of+insulin+receptors+by+TSH%2C+physiological+concentrations+of+insulin+permit+the+proliferative+action+of+TSH+%28170%3B171%29.+In+PCCl3+and+rat+cells%2C+and+in+mouse+thyroid+in+vivo+%28168%29%2C+IGF-I+is+weakly+mitogenic+per+se+%28444%29%2C+whereas+in+pig+thyroid+cells+it+produces+a+strong+effect+%28445%29.%0D%0A%3Ctable+align%3D%22center%22+border%3D%221%22%3E%3Ctbody%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cimg+align%3D%22BOTTOM%22+border%3D%221%22+height%3D%22540%22+name%3D%22graphics16%22+src%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Ffigures%2Ffigure1-16.jpg%22+width%3D%22780%22+%2F%3E%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cdiv+style%3D%22background-attachment%3A+initial%3B+background-clip%3A+initial%3B+background-color%3A+%2399ccff%3B+background-image%3A+initial%3B+background-origin%3A+initial%3B+background-position%3A+initial+initial%3B+background-repeat%3A+initial+initial%3B%22%3E%0D%0A%3Cb%3EFig+1-16.%3C%2Fb%3E%26nbsp%3BMitogenic+pathways+in+the+thyroid.+Data+from+the+thyroid+cell+systems+are+integrated+into+the+present+general+scheme+of+cell+proliferation+cascades.+In+the+first+line%2C+known+activator+of+various+cascades+in+dog+and+human+thyroid+cells+are+shown.+Various+levels+indicate+a+time+sequence+and+postulated+causal+relationships+from+initial+interaction+of+extracellular+signal+with+its+receptor+to+endpoints%3A+proliferation+and+differentiation+expression.+In+dog+but+not+in+human+thyroid+cells%2C+acetylcholine+through+muscarinic+receptors+activates+the+phospholipase+C+cascade.+PCNA%2C+proliferating+cell+nuclear+antigen%3B+cAPK%2C+cyclic+adenosine+monophosphate-dependent+kinase%3B+CDK%2C+cyclin-dependent+kinase%3B+DAG%2C+diacylglycerol%2C+%E2%88%92%E2%88%92%E2%88%92%E2%88%92%E2%88%92%E2%88%92%E2%86%92%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E%2B%3C%2Fsup%3E%2C+stimulation%3B+%E2%88%92%E2%88%92%E2%88%92%E2%88%92%E2%88%92%E2%88%92%2F%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E%2B%3C%2Fsup%3E%2C+inhibition%3B+%3B+%E2%88%92%E2%88%92%E2%88%92%E2%88%92%E2%88%92%E2%88%92%E2%99%A6%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E%2B%3C%2Fsup%3E%2C+induction%3B+GFR%2C+growth+factor+receptor%3B+ODC%2C+ornithine+decarboxylase%3B+PI3K%2C+phosphatidylinositol+3-kinase%3B+PKB%2C+protein+kinase+B%3B+PLC%2C+phospholipase+C%3B+RSK%2C+ribosomal+S6+kinase.%3C%2Fdiv%3E%0D%0A%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3C%2Ftbody%3E%3C%2Ftable%3E%0D%0A%0D%0AIt+should+be+noted+that+TSH+directly+stimulates+proliferation+while+maintaining+the+expression+of+differentiation.+Differentiation+expression%2C+as+evaluated+by+NIS+or+by+thyroperoxidase+and+thyroglobulin+mRNA+content+or+nuclear+transcription%2C+is+induced+by+TSH%2C+forskolin%2C+cholera+toxin%2C+and+cAMP+analogues+%28152%29.+These+effects+are+obtained+in+all+the+cells+of+a+culture%2C+as+shown+by+in+situ+hybridization+experiments+%28404%29.+They+are+reversible%3B+they+can+be+obtained+either+after+the+arrest+of+proliferation+or+during+the+cell+division+cycle+%28387%3B404%29.+Moreover%2C+the+expression+of+differentiation%2C+as+measured+by+iodide+transport%2C+is+stimulated+by+concentrations+of+TSH+lower+than+those+required+for+proliferation+%28236%29.%0D%0AAll+the+proliferation+effects+of+TSH+are+mimicked+by+nonspecific+modulators+of+the+cAMP+cascade%2C+that+is%2C+cholera+toxin+and+forskolin+%28which+stimulate+adenylate+cyclase%29%2C+cAMP+analogues+%28which+activate+the+cAMP-dependent+protein+kinases%29%2C+and+even+synergistic+pairs+of+cAMP+analogues+acting+on+the+different+sites+of+these+two+kinases+%28222%3B236%3B446%29.+They+are+reproduced+in+vitro+and+in+vivo+by+expression+of+the+adenosine+A%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Breceptor%2C+which+is+constitutively+activated+by+endogenous+adenosine+%28414%29%2C+and+by+constitutively+active+Gs%CE%B1+%28447%29+and+cholera+toxin+%28448%29.+They+are+inhibited+by+antibodies+blocking+G%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3Es%26nbsp%3B%3C%2Fsub%3E%28449%29.+Inhibition+of+cAMP-dependent+protein+kinases+%28PKA%29+inhibits+the+proliferation+and+differentiation+effects+of+cAMP+%28450%3B451%29.+Moreover%2C+stimulation+of+PKA+by+selective+cAMP+analogs+that+do+not+activate+EPAC+proteins+is+sufficient+to+fully+mimic+mitogenic+effects+of+TSH+and+forskolin+in+dog+thyrocytes+%28450%29.+There+is%2C+therefore%2C+no+doubt+that+the+mitogenic+and+differentiating+effects+of+TSH+are+mainly+and+probably+entirely+mediated+by+cAMP-dependent+protein+kinases.+A+complementary+role+of+the+Rap+guanyl+nucleotide+exchange+factor+EPAC+and+of+Rap+has+been+proposed+in+rat+thyroid+cell+lines+%28452%3B453%29+but+not+observed+in+canine+thyroid+primary+cultures+%28450%29.%0D%0AEGF+also+induces+proliferation+of+thyroid+cells+from+various+species+%28152%3B164%3B236%29.+However%2C+the+action+of+EGF+is+accompanied+by+a+general+and+reversible+loss+of+differentiation+expression+assessed+as+described+above+%28386%29.+The+effects+of+EGF+on+differentiation+can+be+dissociated+from+its+proliferative+action.+Indeed%2C+they+are+obtained+in+cells+that+do+not+proliferate+in+the+absence+of+insulin+and+in+human+cells%2C+in+which+the+proliferative+effects+are+weaker%2C+or+in+pig+cells+at+concentrations+lower+than+the+mitogenic+concentrations+%28152%29.%0D%0AFinally%2C+the+tumor-promoting+phorbol+esters%2C+the+pharmacologic+probes+of+the+protein+kinase+C+system%2C+and+analogues+of+diacylglycerol+also+enhance+the+proliferation+and+inhibit+the+differentiation+of+thyroid+cells.+These+effects+are+transient+because+of+desensitization+of+the+system+by+protein+kinase+C+inactivation.%0D%0AActivation+of+the+Gq%2Fphospholipase+C+%28PLC%29%2FPKC+cascade+by+a+more+physiological+agent+such+as+carbamylcholine+in+dog+thyroid+cells+does+not+reproduce+all+the+effects+of+phorbol+esters.+In+particular%2C+prolonged+stimulation+of+this+cascade+by+carbamyl+choline+permits+the+cAMP-dependent+mitogenesis+of+dog+thyrocytes+%28454%29%2C+but+unlike+phorbol+esters+it+does+not+induce+proliferation+in+the+presence+of+insulin+%28455%29.+The+Ras+protooncogene+is+strongly+activated+by+phorbol+esters+but+more+weakly+by+carbachol+%28246%29.+Thus+we+cannot+necessarily+equate+the+effects+of+phorbol+esters+and+prolonged+stimulation+of+the+PLC+cascade.+The+dedifferentiating+effects+of+phorbol+esters+do+not+require+their+mitogenic+action+either.+Thus+the+effects+of+TSH%2C+EGF%2C+and+phorbol+esters+on+differentiation+expression+are+largely+independent+of+their+mitogenic+action+%28152%29.%0D%0AIn+several+thyroid+cell+models%2C+very+high+insulin+concentrations+are+necessary+for+growth+even+in+the+presence+of+EGF.+We+now+know+that+this+prerequisite+mainly+reflects+a+requirement+for+IGF-I+receptor+%28152%3B234%3B444%3B456%29.+It+is+interesting+that+in+FRTL5+cells%2C+as+in+cells+from+thyroid+nodules%2C+this+requirement+may+disappear%2C+probably+because+the+cells+secrete+their+own+somatomedins+and+thus+become+autonomous+with+regard+to+these+growth+factors+%28234%3B457%29.%26nbsp%3B%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E%3C%2Fsup%3EBy+contrast%2C+in+primary+cultures+of+normal+dog+and+human+thyrocytes%2C+very+low+concentrations+of+insulin%2C+acting+on+insulin+receptors%2C+are+sufficient+to+support+the+mitogenic+effects+of+TSH+and+cAMP+when+insulin+receptors+have+been+induced+to+high+levels+by+TSH+%28170%3B171%29.+This+puzzling+regulation%2C+which+is+reminiscent+of+the+induction+of+insulin+receptors+during+the+differentiation+of+adipocytes%2C+suggests+that+thyroid+might+well+be+revealed+as+a+more+specific+target+of+circulating+insulin+than+hitherto+recognized.%0D%0AIn+the+action+of+growth+factors+on+receptor+protein+tyrosine+kinase+pathways%2C+the+effects+on+differentiation+expression+vary+with+the+species+and+the+factor+involved%3A+from+stimulation+%28e.g.%2C+insulin%2C+as+well+as+IGF-II+in+dog+and+FRTL5+cells%29+%28405%29+to+an+absence+of+effect+%28458%29%2C+to+transitory+inhibition+of+differentiation+during+growth+%28FGF+and+HGF+in+dog+cells+%28179%3B459%29+to+full+but+reversible+dedifferentiation+effects+%28EGF+in+dog+and+human+cells%29+%28235%3B386%29.%26nbsp%3B%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E%3C%2Fsup%3ERet%2FPTC+rearrangements%2C+activating+mutations+of+Ras%2C+as+well+as+oncogenic+mutation+of+B-Raf%2C+which+are+responsible+of+most+differentiated+carcinoma%2C+constitutively+activate+the+signaling+cascades+of+growth+factors+%28460-462%29.%0D%0AThe+kinetics+of+the+induction+of+thymidine+incorporation+into+nuclear+DNA+of+dog+thyroid+cells+is+similar+for+TSH%2C+forskolin%2C+EGF%2C+and+TPA.+Whatever+the+stimulant%2C+a+minimal+delay+of+about+16+to+20+hours+takes+place+before+the+beginning+of+labeling%2C+that+is%2C+the+beginning+of+DNA+synthesis+%28463%29.+This+time+is+the+minimal+amount+required+to+prepare+the+necessary+machinery.+For+the+cAMP+and+EGF+pathways%2C+the+stimulatory+agent+has+to+be+present+during+this+whole+prereplicative+period%3B+any+interruption+in+activation+%28e.g.%2C+by+washing+out+the+stimulatory+forskolin%29+greatly+delays+the+start+of+DNA+synthesis+%28464%29.+This+limitation+explains+why+norepinephrine+and+prostaglandin+E%2C+which+also+activate+the+cAMP+cascade%2C+do+not+induce+growth+and+differentiation%3A+the+rapid+desensitization+of+their+receptors+does+not+allow+a+sustained+rise+in+cAMP+levels.%0D%0AThe+three+main+types+of+mitogenic+cascade%2C+specifically%2C+the+growth+factor%E2%80%93protein+tyrosine+kinase%2C+phorbol+ester%E2%80%93protein+kinase+C%2C+and+TSH-cAMP+cascades%2C+are+fully+distinct+at+the+level+of+their+primary+intracellular+signal+and%2For+the+first+signal-activated+protein+kinase+%28152%29.%0D%0AIodide+actually+inhibits+the+cAMP+and+the+Ca%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%2B%3C%2Fsup%3E-phosphatidylinositol+cascades+and+in+a+more+delayed+and+chronic+effect+decreases+the+sensitivity+of+the+thyroid+to+the+TSH+growth+response.+These+effects+are+relieved%2C+according+to+the+general+paradigm+of+Van+Sande%2C+by+perchlorate+and+methimazole+%28254%3B465%29.%0D%0A%3Ca+href%3D%22%22+name%3D%2249%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0ASteps+in+the+Mitogenic+Cascades+%28Fig.+1-17%29%3C%2Fh3%3E%0D%0AThe+phenomenology+of+EGF%2C+TPA%2C+and+TSH+proliferative+action+cells+has+been+partially+elucidated+using+dog+thyroid+primary+cultures+%28152%3B243%3B368%29.+The+mechanisms+of+TSH%2FcAMP+mitogenic+effects+have+also+been+investigated+using+immortal+rat+thyroid+cell+lines+%28FRTL-5%2C+WRT+and+PC+Cl3+cells%29+%28244%29.+Whereas+the+signaling+cascades+involved+in+the+action+of+growth+factors+and+IGF-I+are+likely+to+be+well+conserved+in+the+different+thyroid+systems%2C+as+generally+observed+in+the+other+cell+types%2C+the+mechanistic+logics+of+cell+cycle+regulation+by+cAMP+has+disappointingly+turned+out+to+strongly+diverge+in+the+various+thyroid+in+vitro+models+%28243%29.+These+divergences+do+not+only+reflect+species+differences+%28152%29.+Among+the+apparently+similar+rat+thyroid+cell+lines%2C+or+even+among+different+subclones+of+FRTL-5+cells%2C+major+differences+have+been+observed+%28243%29.+For+instance%2C+the+PI3+kinase%2FPKB+cascade+is+activated+by+cAMP+in+WRT+cells+%28466%29%2C+but+inhibited+by+cAMP+in+PC+Cl3+cells+%28467%29.+The+induction+of+c-jun+by+TSH%2FcAMP+in+FRTL-5+cells+and+its+repression+by+cAMP+in+WRT+cells+%28468%29+as+in+dog+%28469%29+and+human+thyrocytes+likely+reflect+major+differences+in+upstream+signaling+cascades%2C+and+should+result+in+divergent+expression+of+downstream+target+genes%2C+such+as+cyclin+D1.+Cyclin+D1+synthesis%2C+an+accepted+endpoint+of+mitogenic+cascades%2C+is+indeed+induced+by+cAMP+in+FRTL-5+and+PC+Cl3+cells%2C+but+rather+repressed+by+cAMP+in+dog+and+human+thyroid+primary+cultures+%28243%3B470%29.+The+reasons+for+such+discrepancies+are+unclear.+Some+signaling+features%2C+when+they+lead+to+selective+proliferative+advantages%2C+might+have+been+acquired+during+the+establishment+and+continuous+cultures+of+the+cell+lines+and+stabilized+by+subcloning.+Many+mechanisms+demonstrated+in+the+dog+thyroid+primary+culture+system+so+far+apply+to+normal+human+thyrocytes+%28470%29%2C+but+much+remains+to+be+defined+%28243%29.+In+the+following+lines%2C+we+thus+rely+mostly+on+these+systems.%0D%0AThree+biochemical+aspects+of+the+proliferative+response+occurring+at+different+times+of+the+prereplicative+phase+have+been+considered.+The+pattern+of+protein+phosphorylation+induced+within+minutes+by+TSH+is+reproduced+by+forskolin+and+cAMP+analogues.+It+totally+diverges+from+the+phosphorylations+induced+by+EGF+and+phorbol+esters+%28471%29.+EGF%2C+HGF+and+phorbol+ester+actions+rapidly+converge+on+the+activation+of+Ras+%28246%29+and+the+resulting+activation+of+p42%2Fp44+MAP+kinases+and+p90%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3ERSK%3C%2Fsup%3E%26nbsp%3B%28232%3B233%3B245%29.+PI-3-kinase+and+its+effector+enzyme+PKB+are+activated+for+several+hours+only+by+insulin+and+IGF-I%2C+the+effect+of+EGF+being+short+lived+%28232%29.+This+activity+is+therefore+the+one+specific+feature+of+insulin+action+and+presumably+the+mechanism+of+the+facilitating+effect+on+mitogenesis.+In+dog+thyrocytes%2C+only+HGF+can+trigger+cell+proliferation+in+the+absence+of+insulin%2FIGF-I%3B+this+is+explained+by+the+fact+that+only+this+factor+strongly+activates+both+PI3+kinase+and+MAP+kinase+cascades+%28232%29.+Only+insulin%2C+IGF-I+and+HGF+also+markedly+enhance+general+protein+synthesis+and+induce+cell+hypertrophy+%28472%29.+By+contrast%2C+TSH+and+cAMP+are+very+unique+as+mitogens%2C+as+they+do+not+activate+Ras%2C+the+PI3kinase%2FPKB+pathway%2C+or+any+of+different+classes+of+MAP+kinases+in+dog+thyrocytes+%28232%3B233%3B245%3B246%29.+TSH+and+cAMP+also+do+not+activate+MAPkinases+in+human+thyrocytes+%28233%29.+The+phosphorylation+and+activation+of+p70%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3ES6K%3C%2Fsup%3E%26nbsp%3Band+thus+likely+of+mTOR+cascade+constitutes+the+only+early+convergence+point+of+growth+factor+and+cAMP-dependent+mitogenic+cascades+%28232%3B473%29.+A+recent+study+has+demonstrated+the+crucial+role+of+this+cascade+for+TSH-elicited+thyroid+follicular+hyperplasia%26nbsp%3B%3Ci%3Ein+vivo%3C%2Fi%3E%26nbsp%3Bin+mice+%28474%29.+Indeed%2C+as+found+in+dog+thyroid+primary+cultures+%28232%29+and+PCCl3+cells+%28Blancquaert+and+Roger%2C+unpublished%29%2C+TSH+stimulates+in+mice+the+mTOR%2F+p70%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3ES6K%3C%2Fsup%3E%26nbsp%3Baxis+without+activating+PKB%2C+and+a+rapamycin+derivative+abrogates+the+hyperplastic+%28but%2C+interestingly%2C+not+the+hypertrophic%29+responses+to+TSH+%28474%29.+The+cAMP-dependent+mitogenesis+and+gene+expression+also+appears+to+require+the+phosphorylation+by+PKA+and+activity+of+CREB%2FCREM+transcription+factors+%28475%3B476%29.%0D%0AAs+in+other+types+of+cells%2C+EGF+and+TPA+first+enhance+c-fos+and+c-myc+mRNA+and+protein+concentrations+in+dog+thyrocytes.+On+the+other+hand%2C+TSH+and+forskolin+strongly%2C+but+for+a+short+period%2C+enhance+the+c-myc+mRNA+concentration+and+with+the+same+kinetics+as+the+enhancement+of+the+c-fos+mRNA+concentration+by+EGF%2FTPA.+In+fact%2C+cAMP+first+enhances+and+then+decreases+c-myc+expression.+This+second+phenomenon+is+akin+to+what+has+been+observed+in+the+fibroblast%2C+in+which+cAMP+negatively+regulates+growth.+As+in+fibroblasts%2C+EGF+and+TPA+enhance+c-jun%2C+junB%2C+junD%2C+and+egr1+expression.+However%2C+as+in+fibroblasts%2C+activators+of+the+cAMP+cascade+decrease+c-jun+and+egr1+expression.+c-Jun+is+therefore+not%2C+as+has+been+claimed%2C+a+gene+whose+expression+is+universally+necessary+for+growth+%28377%3B469%29.%0D%0AThe+investigation+of+the+pattern+of+proteins+synthesized+in+response+to+the+various+proliferation+stimuli+has+suggested+very+early+that+the+proliferation+of+dog+thyroid+cells+is+controlled+during+G1+phase+by+at+least+two+largely+distinct%2C+cAMP-dependent+or+cAMP-independent%2C+pathways+%28232%3B477%29.+Recent+microarray+analyses+have+confirmed+and+extended+this+concept+in+human+thyrocytes+%28133%3B478%29.+Nevertheless%2C+the+different+mitogenic+cascades+are+expected+to+finally+modulate+the+level+and+activity+of+proteins+that+are+the+primary+regulators+of+the+cell+cycle+machinery.%0D%0AAs+generally+considered%2C+mitogenic+signals+regulate+mammalian+cell+cycle+by+stimulating+the+accumulation+of+D-type+cyclins+and+their+assembly+through+a+ill-defined+mechanism+with+their+partner+the+cyclin-dependent+kinases+%28cdk%29+4+and+6.+These+complexes+operate+in+mid-to-late+G1+phase+to+promote+progression+through+the+restriction+point%2C+and+thus+commit+cells+to+replicate+their+genome+%28479%29.+In+the+current+model%2C+this+key+decision+depends+on+the+initiation+by+cyclin+D-cdk+complexes+of+the+phosphorylation+of+the+growth%2Ftumor+suppressor+protein+pRb%2C+which+triggers+the+activation+of+transcription+factors%2C+including+those+of+the+E2F+family%2C+the+synthesis+of+cyclin+E+and+then+cyclin+A%2C+and+cdk2+activation+by+these+cyclins.+Activated+cdk2+in+turn+further+phosphorylates+pRb+and+other+substrates+and+initiates+and+organizes+the+progression+through+the+DNA+synthesis+phase+%28479%29.+The+down+regulation+of+cdk+inhibitors+of+the+CIP%2FKIP+family%2C+including+p27%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3Ekip1%3C%2Fsup%3E%2C%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E%26nbsp%3B%3C%2Fsup%3Eby+mitogenic+factors+and%2For+their+sequestration+by+cyclin+D-cdk+complexes+participate+to+cdk2+activation%2C+but+their+proposed+role+of+adaptor+and%2For+nuclear+anchor+for+cyclin+D-cdk+complexes+suggests+positive+influences+on+cell+cycle+progression+as+well+%28480%29.+These+mechanisms+have+been+well+studied+in+dog+thyroid+cells+%28Fig.+1-17%29.+As+expected%2C+the+different+mitogenic+stimulations+%28TSH%2C+cAMP%2C+growth+factors%29+require+the+activity+of+cdk4+%28481%29%2C+and+converge+on+the+inactivating+phosphorylation+of+pRb+and+related+proteins+p107+and+p130+%28482%29%2C+on+the+phosphorylation+and+nuclear+translocation+of+cdk2%2C+and+on+the+induction+of+cyclin+A+and+cdc2+%28483%29.+These+effects+are+dependent+on+insulin+action+%28482%3B484%29.+What+is+strikingly+different+between+the+cascades+is+the+mechanism+of+D-type+cyclin-cdk4+activation.+TSH%2C+unlike+all+the+other+known+mitogenic+factors%2C+does+not+induce+the+accumulation+of+cyclins+D+%28485%29%2C+but+it+paradoxically+stimulates+the+expression+of+the+cdk+%E2%80%9Cinhibitor%E2%80%9D+p27%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3Ekip1%26nbsp%3B%3C%2Fsup%3E%28486%29.+However+the+predominant+cyclin+D3+is+required+for+the+proliferation+stimulated+by+TSH%2C+but+not+in+the+proliferation+of+dog+thyrocytes+stimulated+by+EGF+or+HGF+that+induce+cyclins+D1+and+D2+in+addition+to+increasing+cyclin+D3+levels+%28485%29.+The+formation+and+the+nuclear+translocation+of+essential+cyclin+D3-cdk4+complexes+depend+on+the+synergistic+interaction+of+TSH+and+insulin+%28484%3B485%29.+These+complexes+are+absent+from+cells+stimulated+by+TSH+or+insulin+alone.+Paradoxically%2C+in+the+absence+of+insulin+TSH+inhibits+the+basal+accumulation+of+cyclin+D3+%28484%29.+On+the+opposite+insulin+alone+stimulates+the+required+cyclin+D3+accumulation+and+it+overcomes+in+large+part+the+inhibition+by+TSH+%28484%29%2C+but+it+is+unable+to+assemble+cyclin+D3-cdk4+complexes+in+the+absence+of+TSH.+In+the+presence+of+insulin%2C+TSH+%28cAMP%29+unmasks+some+epitopes+of+cyclin+D3+and+induces+the+assembly+of+cyclin+D3-cdk4+complexes+and+their+import+into+nuclei+%28484%3B485%29+where+these+complexes+are+anchored+by+their+association+with+p27%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3Ekip1%3C%2Fsup%3E%26nbsp%3B%28487%3B488%29.+This+also+sequesters+p27+away+of+cdk2+complexes+%28487%29%2C+thus+contributing+to+cdk2+activation.+Moreover%2C+cAMP+exerts+an+additional+crucial+function+in+very+late+G1+phase+to+stimulate+the+enzymatic+activity+of+cyclin+D3-cdk4-p27+complexes%2C+which+involves+the+stimulation+of+the+activating+Thr172-phosphorylation+of+cdk4+%28489%29.+TGF%CE%B2+selectively+inhibits+the+cAMP-dependent+proliferation+of+dog+thyrocytes+by+preventing+the+association+of+the+cyclin+D3-cdk4+complex+with+nuclear+p27%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3Ekip1%3C%2Fsup%3Eand+the+Thr172-phosphorylation+of+cdk4+%28487%3B488%29+%28490%29%0D%0A%3Ctable+align%3D%22center%22+border%3D%221%22%3E%3Ctbody%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cimg+align%3D%22BOTTOM%22+border%3D%221%22+height%3D%22540%22+name%3D%22graphics17%22+src%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Ffigures%2Ffigure1-17.jpg%22+width%3D%22780%22+%2F%3E%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cdiv+style%3D%22background-attachment%3A+initial%3B+background-clip%3A+initial%3B+background-color%3A+%2399ccff%3B+background-image%3A+initial%3B+background-origin%3A+initial%3B+background-position%3A+initial+initial%3B+background-repeat%3A+initial+initial%3B%22%3E%0D%0A%3Cb%3EFig.+1-17%3C%2Fb%3E%26nbsp%3B%3A+Targets+of+cell+cycle+regulatory+effects+of+TSH%2C+insulin%2FIGF-1+and+TGF%CE%B2%2C+as+demonstrated+in+the+dog+thyroid+primary+culture+system.+Diamond%2Frectangle+arrowheads+represent+inductions%2Frepressions%3A+the+other+dashed+arrows+are+activations+%28%2B%29+and+inhibitions+%28-%29.+TSH+%28cAMP%29+does+not+induce+cyclins+D+but+assembles+and+then+activates+the+cyclin+D3-cdk4-p27+holoenzyme.+IGF-1+and+insulin+allow+the+accumulation+of+the+required+cyclin+D3.+TGF%CE%B2+inhibits+the+nuclear+translocation+of+the+cyclin+D3-cdk4+complex%2C+its+association+to+p27+and+its+activation+by+TSH%28cAMP%29.+See+text+for+full+explanation.%3C%2Fdiv%3E%0D%0A%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3C%2Ftbody%3E%3C%2Ftable%3E%0D%0A%3Cdiv+style%3D%22text-indent%3A+0.32in%3B%22%3E%0D%0A%0D%0A%3C%2Fdiv%3E%0D%0AThe+investigation+of+cell+cycle+regulatory+proteins+has+thus+clearly+established+that+both+cdk4+activation+and+pRb+phosphorylation+result+from+distinct+but+complementary+actions+of+TSH+and+insulin%2C+rather+than+from+their+interaction+at+an+earlier+step+of+the+signaling+cascades+%28454%3B484%29+%28Fig.+1-17%29.+Together+with+the+fact+that+the+necessary+increase+of+cell+mass+before+division+depends+on+insulin%2FIGF-I+but+not+TSH+%28472%29%2C+these+observations+provide+a+molecular+basis+for+the+well+established+physiological+concept+that+in+the+regulation+of+normal+thyroid+cell+proliferation%2C+TSH+is+the+%E2%80%9Cdecisional%E2%80%9D+mitotic+trigger%2C+while+locally+produced+IGF-I+and%2For+circulating+insulin+are+supporting+%E2%80%9Cpermissive%E2%80%9D+factors+%28152%29.+Of+note%2C+in+all+these+experiments%2C+the+facilitative+action+of+insulin+can+be+replaced+by+activation+of+the+Gq%2FPLC+cascade+by+carbamylcholine+%28454%29.%0D%0AStudies+of+protein+phosphorylation%2C+proto-oncogene+expression%2C+and+cell+cycle+regulatory+proteins+in+dog+thyrocytes+allow+discrimination+between+two+models+of+cAMP+action+on+proliferation+in+this+system%3A+a+direct+effect+on+the+thyrocyte+or+an+indirect+effect+through+the+secretion+and+autocrine+action+of+another+growth+factor.+If+the+effect+of+TSH+through+cAMP+involved+such+an+autocrine+loop%2C+one+would+expect+to+find+faster+kinetics+of+action+of+the+growth+factor+and+at+least+some+common+parts+in+the+patterns+of+protein+phosphorylation+and+protein+synthesis+induced+by+cAMP+and+the+growth+factor.+The+results+do+not+support+such+an+hypothesis%2C+at+least+for+the+growth+factors+tested+%28152%29+%28Fig.+1-16%29.+Moreover%2C+the+data+on+cAMP+action+in+the+dog+and+human+thyrocyte+systems+do+not+support+a+major+role+for+various+mechanisms+involving+cross-signaling+of+cAMP+with+growth+factor+pathways%2C+as+claimed+in+rat+thyroid+cell+line+studies+%28reviewed+and+discussed+in+%28243%29%29.+Indeed%2C+in+primary+cultures+of+normal+human+thyrocytes%2C+EGF%2Bserum+increases+cyclin+D1+and+p21+accumulation%2C+and+it+stimulates+the+assembly+and+activity+of+cyclin+D1-cdk4-p21.+By+contrast%2C+TSH+%28cAMP%29+represses+cyclin+D1+and+p21%2C+but+it+stimulates+the+activating+phosphorylation+of+cdk4+and+the+pRb-kinase+activity+of+preexisting+cyclin+D3-cdk4+complexes+%28470%29.+Cyclin+D1+or+cyclin+D3+are+thus+differentially+used+in+the+distinct+mitogenic+stimulations+by+growth+factors+and+TSH%2C+and+potentially+in+hyperproliferative+diseases+generated+by+the+overactivation+of+their+respective+signaling+pathways.%0D%0AThe+validity+of+these+concepts+in+vivo+has+been+established+by+using+transgenic+mice+models.+The+expression+in+thyroid+of+oncogene+E7+of+HPV-16%2C+which+sequestrates+pRb+protein%2C+leads+to+thyroid+growth+and+euthyroid+goiter.+Expression+in+the+thyroid+of+the+adenosine+A%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E2%3C%2Fsub%3E%26nbsp%3Breceptor%2C+which+behaves+as+a+constitutive+activator+of+adenylyl+cyclase%2C+induces+thyroid+growth%2C+goitrogenesis%2C+and+hyperthyroidism+%28414%29.+Similar%2C+albeit+weaker+phenotypes+are+obtained+in+mice+expressing+constitutive+Gs+%28the+G+protein+activating+adenylyl+cyclase%29+%28447%29%3Cspan+lang%3D%22fr-FR%22%3E%26nbsp%3Bor+cholera+toxin+%28448%29.+A+contrario%2C+the+expression+in+thyroid+of+a+dominant+negative+CREB+provokes+a+marked+thyroid+hypotrophy%2C+suggesting+the+crucial+role+of+CREB+and+its+activating+phosphorylation+by+PKA+%28476%29.+By+contrast%2C+transgenic+mice+overexpressing+both+human+IGF-I+and+IGF-I+receptor+in+their+thyroid+%28TgIGF-I%E2%80%93TgIGF-IR%29+and+the+downregulation+of+PTEN+the+PIP3+3%E2%80%99+phosphatase+develop+only+a+mild+thyroid+hyperplasia+and+respond+to+some+extent+to+a+goitrogenic+effect+of+antithyroid+drugs+while+maintaining+a+comparatively+low+serum+TSH+level.+This+indicates+some+autonomy+of+these+thyroids%2C+as+in+acromegalic+patients%2C+and+a+much+greater+sensitivity+to+endogenous+TSH+%28168%29.+Very+recently%2C+thyrocyte-specific+deficiency+of+Gq%2FG%3Csub+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E11%3C%2Fsub%3E%26nbsp%3B%28the+G+proteins+activating+PLC%CE%B2%29+in+mice+was+shown+to+impair+not+only+the+TSH-stimulated+iodine-organification+and+thyroid+hormone+synthesis%2C+but+also+TSH-dependent+development+of+goiter+%28491%29.+It+remains+to+be+defined+whether+this+impaired+follicular+cell+hyperplasia+could+result+in+part+from+the+lack+of+induction+of+VEGF+and+angiogenesis+%28491%29+which+normally+accompany+goitrogenesis.+Nevertheless%2C+the+phenotype+of+these+mice+underscores+the+role+in+TSH-dependent+goitrogenesis+of+PLC%2C+which+is+activated+by+TSH+but+even+more+strongly+by+neurotransmitters.+Noteworthy%2C+section+of+inferior+laryngeal+nerve+in+rats+was+similarly+found+to+impair+both+thyroid+function+and+growth+stimulated+by+TSH+%28492%29.+Moreover%2C+activation+of+Gq+%2FPLC+by+carbamycholine+can+facilitate+cAMP-dependent+mitogenesis+in+dog+thyrocytes+cultured+without+insulin+or+IGF-I+%28454%29.+On+the+other+hand%2C+expression+of+Ret%2C+which+is+a+rearranged+constitutive+growth+factor+receptor%2C+in+papillary+thyroid+carcinoma+%28PTC%29%2C+leads+to+growth%2C+cancer%2C+and+hypothyroidism+%28493%3B494%29.%3C%2Fspan%3E%0D%0A%3Ca+href%3D%22%22+name%3D%2250%22+style%3D%22color%3A+%23000066%3B+text-decoration%3A+none%3B%22%3E%3C%2Fa%3E%3Ch3+style%3D%22color%3A+%23000066%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+14px%3B+font-weight%3A+bold%3B%22%3E%0D%0AProliferation+and+Differentiation+%28Fig+1-18%29%3C%2Fh3%3E%0D%0A%3Ctable+align%3D%22center%22+border%3D%221%22%3E%3Ctbody%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cimg+align%3D%22BOTTOM%22+border%3D%221%22+height%3D%22540%22+name%3D%22graphics18%22+src%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Ffigures%2Ffigure1-18.jpg%22+width%3D%22780%22+%2F%3E%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3Ctr+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Ctd+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+13px%3B%22%3E%3Cdiv+style%3D%22background-attachment%3A+initial%3B+background-clip%3A+initial%3B+background-color%3A+%2399ccff%3B+background-image%3A+initial%3B+background-origin%3A+initial%3B+background-position%3A+initial+initial%3B+background-repeat%3A+initial+initial%3B+text-indent%3A+0in%3B%22%3E%0D%0A%3Cb%3EFig+1-18.%3C%2Fb%3E%26nbsp%3BMain+controls+of+the+principal+biologic+variables+of+the+human+thyrocyte.+EGF%2C+epidermal+growth+factor%3B+FGF%2C+fibroblast+growth+factor%3B+GH%2C+growth+hormone%3B+HGF%2C+hepatocyte+growth+factor%3B+I%26nbsp%3B%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E-%3C%2Fsup%3E%2C+iodide%3B+IGF-I%2C+insulin-like+growth+factor%3B+IFN%2C+interferon%3B+IL-1%2C+interleukin-1%3B+TGF%CE%B2%2C+tumor+growth+factor-%CE%B2%3B+TNF%2C+tumor+necrosis+factor%3B+TSAb%2C+thyroid-stimulating+immunoglobulins%3B+positive+control+%28stimulation%29%3B+%E2%86%92%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3E%2B%3C%2Fsup%3E%3A+negative+control+%28inhibition%29+%E2%88%92%E2%88%92%E2%88%92%2F.%3C%2Fdiv%3E%0D%0A%3C%2Ftd%3E%3C%2Ftr%3E%0D%0A%3C%2Ftbody%3E%3C%2Ftable%3E%0D%0A%0D%0AThe+incompatibility+at+the+cell+level+of+a+proliferation+and+differentiation+program+is+commonly+accepted+in+biology.+In+general%2C+cells+with+a+high+proliferative+capacity+are+poorly+differentiated%2C+and+during+development+such+cells+lose+this+capacity+as+they+progressively+differentiate.+Some+cells+even+lose+all+potential+to+divide+when+reaching+their+full+differentiation%2C+a+phenomenon+called+terminal+differentiation.+Conversely%2C+in+tumor+cells%2C+proliferation+and+differentiation+expression+are+inversely+related.+Activation+of+Ras+and+p42%2Fp44+MAPkinases%2C+induction+of+c-jun%2C+sustained+expression+of+c-myc%2C+induction+of+cyclin+D1+and+down+regulation+of+p27%3Csup+style%3D%22color%3A+black%3B+font-family%3A+verdana%2C+helvetica%2C+arial%2C+sans-serif%3B+font-size%3A+10px%3B%22%3Ekip1%3C%2Fsup%3E%2C+all+have+been+shown+to+be+causatively+associated+not+only+with+proliferation%2C+but+also+with+loss+of+differentiation+in+a+large+variety+of+systems%2C+sometimes+independently+of+proliferation+effects.+It+is+therefore+not+surprising+that+in+thyroid+cells+the+general+mitogenic+agents+and+pathways%2C+phorbol+esters+and+the+protein+kinase+C+pathway%2C+EGF%2C+and+in+calf+and+porcine+cells%2C+FGF+and+the+protein+tyrosine+kinase+pathway%2C+induce+both+proliferation+and+the+loss+of+differentiation+expression.+The+effects+of+the+cAMP+cascade+are+in+striking+contrast+with+this+general+concept.+Indeed%2C+TSH+and+cAMP+induce+proliferation+of+dog+thyrocytes+while+maintaining+differentiation+expression%3B+both+proliferation+and+differentiation+programs+can+be+triggered+by+TSH+in+the+same+cells+at+the+same+time+%28404%29.+This+situation+is+by+no+means+unique+because+neuroblasts+in+the+cell+cycle+may+also+simultaneously+differentiate.+It+is+tempting+to+relate+this+apparent+paradox+to+the+unique+characteristics+of+the+cAMP-dependent+mitogenic+pathway%2C+such+as+the+lack+of+activation+%28or+even+the+inhibition%29+of+the+Ras%2FMAPkinase%2Fc-jun%2Fcyclin+D1+cascade%2C+as+demonstrated+in+dog+and+human+thyrocytes.+For+instance%2C+if+one+generalization+could+be+made+about+proto-oncogenes%2C+it+is+the+dedifferentiating+role+of+c-myc.+A+rapid+and+dramatic+decrease+in+c-myc+mRNA+by+antisense+myc+sequences+induces+differentiation+of+a+variety+of+cell+types.+It+is+therefore+striking+that+in+the+case+of+the+thyrocyte%2C+in+which+activation+of+the+cAMP+cascade+leads+to+both+proliferation+and+differentiation%2C+the+kinetics+of+the+c-myc+gene+expression+appears+to+be+tightly+controlled.+After+a+first+phase+of+1+hour+of+higher+level+of+c-myc+mRNA%2C+c-myc+expression+is+decreased+below+control+levels.+In+this+second+phase%2C+cAMP+decreases+c-myc+mRNA+levels%2C+as+it+does+in+proliferation-inhibited+fibroblasts.+It+even+depresses+EGF-induced+expression.+The+first+phase+could+be+necessary+for+proliferation%2C+whereas+the+second+phase+could+reflect+stimulation+of+differentiation+by+TSH+%28376%3B495%29.+The+specific+involvement+of+cyclin+D3+in+the+cAMP-dependent+mitogenic+stimulation+of+dog+and+human+thyrocytes%2C+but+not+for+their+response+to+growth+factors%2C+is+also+interesting+in+this+context+%28470%3B485%29.+Indeed%2C+unlike+cyclins+D1+and+D2%2C+cyclin+D3+is+highly+expressed+in+several+quiescent+tissues+in+vivo%2C+and+its+expression+is+not+only+stimulated+by+mitogenic+factors+but+also+induced+during+several+differentiation+processes+associated+with+a+repression+of+cyclin+D1+%28496%29.+We+have+recently+shown+that+the+differential+utilization+of+cyclin+D1+or+cyclin+D3+affects+the+site+specificity+of+the+pRb-kinase+of+cdk4%2C+including+in+dog+and+human+thyrocytes+%28470%3B470%29.+In+addition+to+inhibiting+E2F-dependent+gene+transcription+related+to+cell+cycle+progression%2C+pRb+plays+positive+roles+in+the+induction+of+tissue-specific+gene+expression+by+directly+interacting+with+a+variety+of+transcription+factors%2C+including+Pax8+in+thyroid+cells+%28497%29.+Whether%2C+the+selective+utilization+of+cyclin+D3+in+the+TSH+cascade%2C+associated+with+a+more+restricted+pRb-kinase+activity%2C+could+allow+the+preservation+of+some+differentiation-related+functions+of+pRb+thus+remains+to+be+examined.%0D%0AWe+now+consider+the+distinct+cAMP-dependent+mitogenic+pathway%2C+which+appears+to+be+adjuncted+to+the+more+general+mechanisms+used+by+growth+factors%2C+as+pertaining+to+the+specialized+differentiation+program+of+thyroid+cells+%28240%29.+In+dog+thyrocytes%2C+the+proliferation+in+response+to+serum+or+growth+factors+specifically+extincts+their+capacity+to+respond+to+TSH%2FcAMP+as+a+mitogenic+stimulus+%28498%29.+Similarly%2C+in+less+differentiated+thyroid+cancers+generated+by+the+subversion+of+growth+factor+mechanisms%2C+the+TSH-dependence+of+growth+is+generally+found+to+be+lost.%0D%0ABecause+the+cell+renewal+rate+is+very+low+in+the+thyroid+%28once+every+8+years+in+adults%29%2C+the+role+of+apoptosis+is+unimportant.+However%2C+under+different+circumstances+the+apoptotic+role+can+greatly+increase%2C+such+as+after+the+arrest+of+an+important+stimulation+in+vitro+%28499%29+and+in+vivo+%28500%29+%28501%3B502%29.%0D%0A%3Cdiv%3E%0D%0A%3Ca+href%3D%22http%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Fchapter01.htm%22%3Ehttp%3A%2F%2Fwww.thyroidmanager.org%2FChapter1%2Fchapter01.htm%3C%2Fa%3E%3C%2Fdiv%3E%0D%0A%3Cdiv%3E%0D%0A%0D%0A%3C%2Fdiv%3E%0D%0A%3Cdiv%3E%0D%0A%0D%0A%3C%2Fdiv%3E%0D%0A%3Cdiv%3E%0D%0A%3Cspan+class%3D%22Apple-style-span%22+style%3D%22font-family%3A+sans-serif%3B+line-height%3A+19px%3B%22%3E%3Ch2+style%3D%22background-attachment%3A+initial%3B+background-clip%3A+initial%3B+background-color%3A+initial%3B+background-image%3A+none%3B+background-origin%3A+initial%3B+background-position%3A+initial+initial%3B+background-repeat%3A+initial+initial%3B+border-bottom-color%3A+rgb%28170%2C+170%2C+170%29%3B+border-bottom-style%3A+solid%3B+border-bottom-width%3A+1px%3B+color%3A+black%3B+font-size%3A+19px%3B+font-weight%3A+normal%3B+margin-bottom%3A+0.6em%3B+margin-left%3A+0px%3B+margin-right%3A+0px%3B+margin-top%3A+0px%3B+padding-bottom%3A+0.17em%3B+padding-top%3A+0.5em%3B%22%3E%0D%0A%3Cspan+class%3D%22mw-headline%22%3EIntroduction%3C%2Fspan%3E%3C%2Fh2%3E%0D%0A%3Cdiv+style%3D%22line-height%3A+1.5em%3B+margin-bottom%3A+0.5em%3B+margin-left%3A+0px%3B+margin-right%3A+0px%3B+margin-top%3A+0.4em%3B%22%3E%0D%0AThe+thyroid+gland+produces%26nbsp%3B%3Ca+href%3D%22http%3A%2F%2Fwww.ganfyd.org%2Findex.php%3Ftitle%3DThyroxine%22+style%3D%22background-attachment%3A+initial%3B+background-clip%3A+initial%3B+background-color%3A+initial%3B+background-image%3A+none%3B+background-origin%3A+initial%3B+background-position%3A+initial+initial%3B+background-repeat%3A+initial+initial%3B+color%3A+%23002bb8%3B+text-decoration%3A+none%3B%22+title%3D%22Thyroxine%22%3Ethyroxine%3C%2Fa%3E%26nbsp%3B%28T%3Csub%3E4%3C%2Fsub%3E%29%2C%26nbsp%3B%3Ca+class%3D%22mw-redirect%22+href%3D%22http%3A%2F%2Fwww.ganfyd.org%2Findex.php%3Ftitle%3DTriiodothyronine%22+style%3D%22background-attachment%3A+initial%3B+background-clip%3A+initial%3B+background-color%3A+initial%3B+background-image%3A+none%3B+background-origin%3A+initial%3B+background-position%3A+initial+initial%3B+background-repeat%3A+initial+initial%3B+color%3A+%23002bb8%3B+text-decoration%3A+none%3B%22+title%3D%22Triiodothyronine%22%3Etriiodothyronine%3C%2Fa%3E%26nbsp%3B%28T%3Csub%3E3%3C%2Fsub%3E%29+and%26nbsp%3B%3Ca+href%3D%22http%3A%2F%2Fwww.ganfyd.org%2Findex.php%3Ftitle%3DCalcitonin%22+style%3D%22background-attachment%3A+initial%3B+background-clip%3A+initial%3B+background-color%3A+initial%3B+background-image%3A+none%3B+background-origin%3A+initial%3B+background-position%3A+initial+initial%3B+background-repeat%3A+initial+initial%3B+color%3A+%23002bb8%3B+text-decoration%3A+none%3B%22+title%3D%22Calcitonin%22%3Ecalcitonin%3C%2Fa%3E.+Thyroid+hormones+are+responsible+for+maintaini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