Clinical Neuroendocrinology PDF
Preview Clinical Neuroendocrinology
HANDBOOK OF CLINICAL NEUROLOGY Series Editors MICHAEL J. AMINOFF, FRANC¸OIS BOLLER, AND DICK F. SWAAB VOLUME 124 EDINBURGH LONDON NEW YORK OXFORD PHILADELPHIA ST LOUIS SYDNEY TORONTO 2014 ELSEVIERB.V. Radarweg29,POBox211,1000AEAmsterdam,Netherlands TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UK 225WymanStreet,Waltham,MA02451,USA ©2014,ElsevierB.V.Allrightsreserved. Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans,electronicormechanical, includingphotocopying,recording,oranyinformationstorageandretrievalsystem,withoutpermissioninwriting fromthepublisher.Detailsonhowtoseekpermission,furtherinformationaboutthePublisher’spermissions policiesandourarrangementswithorganizationssuchastheCopyrightClearanceCenterandtheCopyright LicensingAgency,canbefoundatourwebsite:www.elsevier.com/permissions. ThisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightbythePublisher(otherthan asmaybenotedherein). 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ThePublisher PrintedinChina The Publisher's CommissioningEditor:MicaHaley policy is to use DevelopmentEditor:MichaelParkinson paper manufactured from sustainable forests ProjectManager:SujathaThirugnanaSambandam Designer/DesignDirection:AlanStudholme HandbookofClinicalNeurology3rdSeries Availabletitles Vol.79,Thehumanhypothalamus:basicandclinicalaspects,PartI,D.F.SwaabISBN9780444513571 Vol.80,Thehumanhypothalamus:basicandclinicalaspects,PartII,D.F.SwaabISBN9780444514905 Vol.81,Pain,F.CerveroandT.S.Jensen,eds.ISBN9780444519016 Vol.82,Motorneuronedisordersandrelateddiseases,A.A.EisenandP.J.Shaw,eds.ISBN9780444518941 Vol.83,Parkinson’sdiseaseandrelateddisorders,PartI,W.C.KollerandE.Melamed,eds.ISBN9780444519009 Vol.84,Parkinson’sdiseaseandrelateddisorders,PartII,W.C.KollerandE.Melamed,eds.ISBN9780444528933 Vol.85,HIV/AIDSandthenervoussystem,P.PortegiesandJ.Berger,eds.ISBN9780444520104 Vol.86,Myopathies,F.L.MastagliaandD.HiltonJones,eds.ISBN9780444518996 Vol.87,Malformationsofthenervoussystem,H.B.SarnatandP.Curatolo,eds.ISBN9780444518965 Vol.88,Neuropsychologyandbehaviouralneurology,G.GoldenbergandB.C.Miller,eds.ISBN9780444518972 Vol.89,Dementias,C.DuyckaertsandI.Litvan,eds.ISBN9780444518989 Vol.90,Disordersofconsciousness,G.B.YoungandE.F.M.Wijdicks,eds.ISBN9780444518958 Vol.91,Neuromuscularjunctiondisorders,A.G.Engel,ed.ISBN9780444520081 Vol.92,Stroke–PartI:Basicandepidemiologicalaspects,M.Fisher,ed.ISBN9780444520036 Vol.93,Stroke–PartII:Clinicalmanifestationsandpathogenesis,M.Fisher,ed.ISBN9780444520043 Vol.94,Stroke–PartIII:Investigationsandmanagement,M.Fisher,ed.ISBN9780444520050 Vol.95,Historyofneurology,S.Finger,F.BollerandK.L.Tyler,eds.ISBN9780444520081 Vol.96,Bacterialinfectionsofthecentralnervoussystem,K.L.RoosandA.R.Tunkel,eds.ISBN9780444520159 Vol.97,Headache,G.NappiandM.A.Moskowitz,eds.ISBN9780444521392 Vol.98,SleepdisordersPartI,P.MontagnaandS.Chokroverty,eds.ISBN9780444520067 Vol.99,SleepdisordersPartII,P.MontagnaandS.Chokroverty,eds.ISBN9780444520074 Vol.100,Hyperkineticmovementdisorders,W.J.WeinerandE.Tolosa,eds.ISBN9780444520142 Vol.101,Musculardystrophies,A.AmatoandR.C.Griggs,eds.ISBN9780080450315 Vol.102,Neuro-ophthalmology,C.KennardandR.J.Leigh,eds.ISBN9780444529039 Vol.103,Ataxicdisorders,S.H.SubramonyandA.Durr,eds.ISBN9780444518927 Vol.104,Neuro-oncologyPartI,W.GrisoldandR.Sofietti,eds.ISBN9780444521385 Vol.105,Neuro-oncologyPartII,W.GrisoldandR.Sofietti,eds.ISBN9780444535023 Vol.106,Neurobiologyofpsychiatricdisorders,T.SchlaepferandC.B.Nemeroff,eds.ISBN9780444520029 Vol.107,EpilepsyPartI,H.StefanandW.H.Theodore,eds.ISBN9780444528988 Vol.108,EpilepsyPartII,H.StefanandW.H.Theodore,eds.ISBN9780444528995 Vol.109,Spinalcordinjury,J.VerhaagenandJ.W.McDonaldIII,eds.ISBN9780444521378 Vol.110,Neurologicalrehabilitation,M.BarnesandD.C.Good,eds.ISBN9780444529015 Vol.111,PediatricneurologyPartI,O.Dulac,M.LassondeandH.B.Sarnat,eds.ISBN9780444528919 Vol.112,PediatricneurologyPartII,O.Dulac,M.LassondeandH.B.Sarnat,eds.ISBN9780444529107 Vol.113,PediatricneurologyPartIII,O.Dulac,M.LassondeandH.B.Sarnat,eds.ISBN9780444595652 Vol.114,Neuroparasitologyandtropicalneurology,H.H.Garcia,H.B.TanowitzandO.H.DelBrutto,eds. ISBN9780444534903 Vol.115,Peripheralnervedisorders,G.SaidandC.Krarup,eds.ISBN9780444529022 Vol.116,Brainstimulation,A.M.LozanoandM.Hallett,eds.ISBN9780444534972 Vol.117,Autonomicnervoussystem,R.M.BuijsandD.F.Swaab,eds.ISBN9780444534910 Vol.118,Ethicalandlegalissuesinneurology,J.L.BernatandH.R.Beresford,eds.ISBN9780444535016 Vol.119,NeurologicaspectsofsystemicdiseasePartI,J.BillerandJ.M.Ferro,eds.ISBN9780702040863 Vol.120,NeurologicaspectsofsystemicdiseasePartII,J.BillerandJ.M.Ferro,eds.ISBN9780702040870 Vol.121,NeurologicaspectsofsystemicdiseasePartIII,J.BillerandJ.M.Ferro,eds.ISBN9780702040887 Vol.122,Multiplesclerosisandrelateddisorders,D.S.Goodin,ed.ISBN9780444520012 Vol.123,Neurovirology,A.C.TselisandJ.Booss,eds.ISBN9780444534880 Foreword TheHandbookofClinicalNeurology(HCN),foundedbyPierreVinkenandGeorgeBruynin1968,isaprestigious, multivolumereferenceworkondisordersofthenervoussystem.Suchanendeavorrequiresregularupdates.Rapid advancesinneurologyanditscloserrelationshipwithanincreasingnumberofothermedicaldisciplineshaveledus alsotoaddnewtopicsasseparatevolumessincewetookoverin2003aseditorsofthecurrentthirdseries.Thepresent title,ClinicalNeuroendocrinology,isanoveltitlefortheseries.ItincludesanewrangeoftopicsfortheHCNseriesas well as an update and expansion oftopics discussed previously. It focuseson the pathophysiology, diagnosis, and treatment of diseases of the hypothalamus and pituitary gland. Some topics, such as pituitary and hypothalamic tumors,weredealtwithinearliervolumes,buttheinformationongeneticcausesandtreatmenthaschangedtremen- douslyandhasbeenincorporatedintothepresentvolume.Variousothertopics,suchasneuroendocrinemechanisms inathletesandlong-termeffectsoftreatmentofpituitaryadenomas,haveneverbeenincludedintheHCNseries. Clinicalneuroendocrinologyofnecessityinvolvestheintegrationofalargenumberofmedicaldisciplineswithneu- rology,suchasinternalmedicine,pediatrics,neurosurgery,neuroradiology,clinicalgenetics,andradiotherapy,asis evidentfromthepresentvolume.Thebehavioralconsequencesofdisordersandtherapies,uncertaintiesintherapy, controversiesandrecentnovelinsightsfromresearchalsoreceiveattentionhere. Wewereextremelypleasedtohaveasvolumeeditorsthreeinternationallyrenownedexpertsinclinicalneuroen- docrinology.EricFliersisProfessorofEndocrinologyattheAcademicMedicalCenteroftheUniversityofAmster- dam,whereheservesasHeadoftheDepartmentofEndocrinologyandMetabolism.Heisthecurrentchairofthe DutchEndocrineSociety.Hehashisrootsinresearchontheneuroendocrinenucleiinthepostmortemhumanhypo- thalamus,andwasinvolvedinthefoundationoftheNetherlandsBrainBank.Hiscurrentresearchisfocusedonneu- roendocrineaspectsofthehypothalamus–pituitary–thyroidaxis.Ma´rtaKorbonitsisProfessorofEndocrinologyand MetabolismatBartsandtheLondonSchoolofMedicineandDentistry,QueenMaryUniversityofLondon,whereshe headstheCentreforEndocrinology.WiththehelpoftheFamilialIsolatedPituitaryAdenomas(FIPA)consortium,she iscurrentlydefiningtheclinicalcharacteristicsofpatientswithfamilialpituitaryadenomasyndromesanduncovering novelgeneticvariantscausingtheseconditions.JohannesA.RomijnisProfessorofMedicineattheAcademicMedical CenteroftheUniversityofAmsterdamandservesaschairoftheDepartmentofMedicine.HeistheEditor-in-Chiefof theEuropeanJournalofEndocrinology.Hisresearchhasamainfocusonneuroendocrineregulationofmetabolism. Thethreevolumeeditorshaveassembledatrulyinternationalgroupofauthorswithacknowledgedexpertiseto contribute to this volume and have produced with them an authoritative, comprehensive, and up-to-date account ofclinicalneuroendocrinology.ItsavailabilityelectronicallyonElsevier’sScienceDirectsiteaswellasinprintformat shouldensureitsreadyaccessibilityandfacilitatesearchesforspecificinformation.Wearegratefultothevolume editorsandtoallthecontributorsfortheireffortsincreatingsuchaninvaluableresource.Asserieseditorswereadand commentedoneachofthechapterswithgreatinterest.Wearethereforeconfidentthatbothcliniciansandresearchers inmanydifferentmedicaldisciplineswillfindmuchinthisvolumetoappealtothem. AsalwaysitisapleasuretothankElsevier,ourpublishers–andinparticularMichaelParkinsoninLochcarron,and MicaHaleyandKristiAndersoninSanDiego–fortheirunfailingandexpertassistanceinthedevelopmentandpro- ductionofthisvolume. MichaelJ.Aminoff Franc¸oisBoller DickF.Swaab Preface Clinicalneuroendocrinologyfocusesonthepathophysiology,diagnosis,andtreatmentofdiseasesofthehypothal- amusandpituitarygland.Overthepastyears,muchprogresshasbeenmadeinthisfield,sparkedbyseveralmajor breakthroughsincludingthediscoveryofleptinandtheunravelingofitsroleinbodyweightregulationand meta- bolism; the identification of novel genetic causes of pituitary tumors, central hypothyroidism and hypogonadism; the recognition of oxytocin and vasopressin’s roles in social behaviors; and the discovery of medicines effectively reducingtheexcessiveendocrineactivityofselectedpituitarytumors. Thepresentvolumeaimstoinformabroadreadershipofmedicalspecialistsinvolvedinclinicalneuroendocrino- logyaboutrecentdevelopmentsandstate-of-theartknowledgeinthefield. Thefirstsectionofthevolumefocusesonmajoraspectsofhypothalamicfunctionandpathophysiology.Thehypo- thalamusparticipatesincomplexanddivergentpathophysiologicconditionssuchasdisordersofwaterbalance,psy- chiatricconditions,sleepdisturbances,obesity,andcriticalillness.Sometimes,disturbanceswithinthehypothalamus aretheinitiatorofdisease, asinrareformsofobesity,butmorefrequentlydiseases elsewhere inthebodyinduce secondarypathophysiologicconditionsinthehypothalamus,asinthesyndromeofinappropriateantidiuretichormone secretion(SIADH),sleepdeprivationandcriticalillness.Hypothalamicneuropeptidessuchasvasopressin,oxytocin, and corticotropin-releasing hormone (CRH) are discussed in the context of neuroendocrine regulation, stress and watermetabolism,andalsoasmediatorsofemotionalandsocialbehaviors.Usually,thesedifferentfieldsofhypo- thalamicfunctionarenotdescribedinparallel. Thesecondsectionofthevolumefocusesonnewdevelopmentsindisordersofthepituitarygland.Thissection includesdetaileddescriptionsofthepathophysiology,diagnosis,andtreatmentofdifferentpituitarydiseases,includ- ingactiveandinactiveadenomas,Rathke’scleftcysts,craniopharyngioma,andunusualformsofhypopituitarism. Medical,surgical,andradiotherapeuticregimensarediscussedindetail. Thethirdsectionofthevolumeisdevotedtocontroversialissuesandhottopicsinclinicalneuroendocrinology, includingNelsonsyndrome,familialpituitarytumors,andautoimmunehypophysitis.Therearemanyuncertainties inendocrinesubstitutiontherapyforpituitaryinsufficiency.Inthissectiontheseuncertaintiesregardingcentraladre- nalinsufficiency,hypothyroidism,andGHdeficiencyarediscussedindifferentchapters.Inaddition,theirreversible consequences of pituitary tumors and/or their treatment on quality of life and neuropsychologic function are reviewed.Thepituitarydiseasemaybecuredorcontrolledbutitseemsthatpatientsmaystillsufferfromadebilitating chronicsyndrome.Finally,thispartofthebookincludesachapterontheneuroendocrinemechanismsinvolvedwith adaptationtophysicalexercise. Weareconfidentthatthepresentvolumecoversmostaspectsofneuroendocrinologythatarerelevantforclinicians involvedinthecareofpatientswithneuroendocrinedisease,andweexpectthatitwillbeofinterestforinternists, pediatricians, neurologists, neurosurgeons, neuroradiologists, clinical geneticists, and radiotherapists active in thisfield. EricFliers Ma´rtaKorbonits JohannesA.Romijn Contributors N.Alband M.Buchfelder DepartmentofEndocrinology,BartsandtheLondon DepartmentofNeurosurgery,Universityof SchoolofMedicine,QueenMaryUniversityofLondon, Erlangen-Nürnberg,Erlangen,Germany London,UK P.Cappabianca O.Ansorge DepartmentofNeurologicalSciences,Divisionof DepartmentofNeuropathology,NuffieldDepartment Neurosurgery,Universita` degliStudidiNapoliFederico ofClinicalNeurosciences,UniversityofOxford,John II,Naples,Italy RadcliffeHospital,Oxford,UK L.M.Cavallo E.Adams DepartmentofNeurologicalSciences,Divisionof DepartmentofEndocrinology,OxfordCentrefor Neurosurgery,Universita` degliStudidiNapoliFederico Diabetes,EndocrinologyandMetabolism,Churchill II,Naples,Italy Hospital,Oxford,UK P.Chanson R.Bachner-Melman DepartmentofEndocrinologyandDisordersof SchoolofSocialandCommunitySciences,Ruppin Reproduction,HoˆpitalBiceˆtre;ReferenceCenterforRare AcademicCenter,EmekHeferandDepartmentof EndocrineDisordersofGrowth;FacultyofMedicine, Psychology,HebrewUniversityofJerusalem,Jerusalem, Universite´ Paris-Sud11andINSERMU693, Israel LeKremlin-Biceˆtre,Paris,France T.M.Barber K.Cheer DivisionofMetabolicandVascularHealth,Warwick DepartmentofEndocrinology,ChristieHospitalNHS MedicalSchool,UniversityofWarwick,Coventry,UK FoundationTrust,Manchester,UK B.M.K.Biller NeuroendocrineUnit,MassachusettsGeneral A.P.Coll HospitalandHarvardMedicalSchool,Boston,MA, UniversityofCambridgeMetabolicResearch USA Laboratories,MRCMetabolicDiseasesUnit,Wellcome Trust–MRCInstituteofMetabolicScience, A.Boelen Addenbrooke’sHospital,Cambridge,UK DepartmentofEndocrinologyandMetabolism, AcademicMedicalCenter,UniversityofAmsterdam, M.T.Dattani Amsterdam,TheNetherlands DevelopmentalEndocrinologyResearchGroup,Clinical andMolecularGeneticsUnit,UniversityCollege M.Bonomi London–InstituteofChildHealth,London,UK DepartmentofClinicalSciencesandCommunity Health,UniversityofMilan,andDivisionofEndocrine T.G.Dinan andMetabolicDiseases,SanLucaHospital,Istituto DepartmentofPsychiatry,UniversityCollegeCork, AuxologicoItaliano,Milan,Italy Cork,Ireland xii CONTRIBUTORS E.Donga J.S.Loeffler DepartmentofEndocrinology,LeidenUniversity DepartmentofRadiationOncology,Massachusetts MedicalCenter,Leiden,TheNetherlands GeneralHospital,Boston,MA,USA R.P.Ebstein M.J.McCabe DepartmentofPsychology,NationalUniversityof DevelopmentalEndocrinologyResearchGroup,Clinical Singapore,Singapore andMolecularGeneticsUnit,UniversityCollege London–InstituteofChildHealth,London,UK E.-M.Erfurth DepartmentofEndocrinology,LundUniversity,Lund, M.Misra Sweden PediatricEndocrineandNeuroendocrineUnits, MassachusettsGeneralHospitalandHarvardMedical E.Fliers School,Boston,MA,USA DepartmentofEndocrinologyandMetabolism, AcademicMedicalCenter,UniversityofAmsterdam, M.E.Molitch Amsterdam,TheNetherlands DivisionofEndocrinology,MetabolismandMolecular Medicine,NorthwesternUniversityFeinbergSchoolof P.Kamenicky Medicine,Chicago,IL,USA DepartmentofEndocrinologyandDisordersof Reproduction,HoˆpitalBiceˆtre;ReferenceCenterfor H.L.Müller RareEndocrineDisordersofGrowth;Facultyof DepartmentofPediatrics,KlinikumOldenburg, Medicine,Universite´ Paris-Sud11andINSERMU693, MedicalCampusUniversityOldenburg,Oldenburg, LeKremlin-Biceˆtre,Paris,France Germany N.Karavitaki OxfordCentreforDiabetes,Endocrinologyand M.Naughton Metabolism,ChurchillHospital,Oxford,UK DepartmentofPsychiatry,UniversityCollegeCork, Cork,Ireland M.Korbonits DepartmentofEndocrinology,BartsandtheLondon S.J.C.M.M.Neggers SchoolofMedicine,QueenMaryUniversityofLondon, SectionofEndocrinology,DepartmentofMedicine, London,UK ErasmusUniversityMedicalCenter,Rotterdam, TheNetherlands L.Langouche LaboratoryandDepartmentofIntensiveCareMedicine, K.S.Oh UniversityofLeuven,Leuven,Belgium DepartmentofRadiationOncology,Massachusetts GeneralHospital,Boston,MA,USA R.Larder UniversityofCambridgeMetabolicResearch I.Pashtan Laboratories,MRCMetabolicDiseasesUnit,Wellcome HarvardRadiationOncologyProgram,Boston, Trust–MRCInstituteofMetabolicScience, MA,USA Addenbrooke’sHospital,Cambridge,UK S.Larkin S.Pekic DepartmentofNeuropathology,NuffieldDepartment FacultyofMedicine,UniversityofBelgrade,and ofClinicalNeurosciences,UniversityofOxford, ClinicofEndocrinology,DiabetesandMetabolic JohnRadcliffeHospital,Oxford,UK Diseases,UniversityClinicalCenterBelgrade, Belgrade,Serbia C.T.Lim UniversityofCambridgeMetabolicResearch A.M.Pereira Laboratories,MRCMetabolicDiseasesUnit,Wellcome DepartmentofEndocrinologyandCenterforEndocrine Trust–MRCInstituteofMetabolicScience, Tumors,LeidenUniversityMedicalCenter,Leiden, Addenbrooke’sHospital,Cambridge,UK TheNetherlands CONTRIBUTORS xiii L.Persani Y.Takahashi DepartmentofClinicalSciencesandCommunityHealth, DivisionofDiabetesandEndocrinology,Departmentof UniversityofMilan,andDivisionofEndocrineand InternalMedicine,KobeUniversityGraduateSchoolof MetabolicDiseases,SanLucaHospital,Istituto Medicine,Kobe,Japan AuxologicoItaliano,Milan,Italy P.J.Trainer F.Petraglia DepartmentofEndocrinology,ChristieHospitalNHS DepartmentofMolecularandDevelopmentalMedicine, FoundationTrust,Manchester,UK UniversityofSiena,Siena,Italy N.A.Tritos V.Popovic NeuroendocrineUnit,MassachusettsGeneral FacultyofMedicine,UniversityofBelgrade,andClinic HospitalandHarvardMedicalSchool,Boston, ofEndocrinology,DiabetesandMetabolicDiseases, MA,USA UniversityClinicalCenterBelgrade,Belgrade,Serbia J.A.Romijn A.S.P.vanTrotsenburg DepartmentofMedicine,AcademicMedicalCenter, DepartmentofPaediatricEndocrinology,Academic UniversityofAmsterdam,Amsterdam,TheNetherlands MedicalCenter,UniversityofAmsterdam,Amsterdam, TheNetherlands S.Salenave DepartmentofEndocrinologyandDisordersof G.VandenBerghe Reproduction,HoˆpitalBiceˆtreandReferenceCenterfor LaboratoryandDepartmentofIntensiveCareMedicine, RareEndocrineDisordersofGrowth, UniversityofLeuven,Leuven,Belgium LeKremlin-Biceˆtre,Paris,France S.Schlaffer A.J.vanderLely DepartmentofNeurosurgery,UniversityofErlangen- SectionofEndocrinology,DepartmentofMedicine, Nürnberg,Erlangen,Germany ErasmusUniversityMedicalCenter,Rotterdam, TheNetherlands L.V.Scott DepartmentofPsychiatry,UniversityCollegeCork, J.G.Verbalis Cork,Ireland GeorgetownUniversity,Washington,DC,USA D.Solari C.Voltolini DepartmentofNeurologicalSciences,Divisionof DepartmentofMolecularandDevelopmentalMedicine, Neurosurgery,Universita` degliStudidiNapoliFederico UniversityofSiena,Siena,Italy II,Naples,Italy F.M.Swords J.A.H.Wass NorwichMedicalSchoolandDirectorateof DepartmentofEndocrinology,OxfordCentrefor Endocrinology,NorfolkandNorwichUniversity Diabetes,EndocrinologyandMetabolism,Churchill HospitalNHSFoundationTrust,Norwich,UK Hospital,Oxford,UK HandbookofClinicalNeurology,Vol.124(3rdseries) ClinicalNeuroendocrinology E.Fliers,M.Korbonits,andJ.A.Romijn,Editors ©2014ElsevierB.V.Allrightsreserved Chapter1 Genetic aspects of hypothalamic and pituitary gland development MARKJ.MCCABEANDMEHULT.DATTANI* DevelopmentalEndocrinologyResearchGroup,ClinicalandMolecularGeneticsUnit, UniversityCollegeLondon—InstituteofChildHealth,London,UK INTRODUCTION neuralplateasthehypothalamus,opticnerves,andfore- brainasdescribedabove,hypopituitarismisoftenasso- Theprimordialcentralnervoussystemdevelopsduring ciated with craniofacial/midline disorders affecting thethirdweekofhumangestationduringneurulation,a these structures also. Such disorders are characteristi- processwhichgivesrisetotheneural platewith subse- callyheterogeneousbutrangefromincompatibilitywith quent derivations into the spinal cord and brain. Fate life, to holoprosencephaly (HPE) and cleft palate and map studies, which aim to follow the development of septo-optic dysplasia (SOD), which will be described cellsortissuesfromearlystagesofembryogenesis,have later(McCabeetal.,2011a). shown that the pituitary, hypothalamus, optic nerves, Thischapterwillreviewthemolecularbasisunderly- and forebrain each develop from the anterior neural ing the development of the hypothalamo-pituitary axis plate(Schlosser,2006).Complexinteractionsofspatio- andwilldetailhowknowndefectsinmanyoftherequired temporallyregulatedsignalingmoleculesandtranscrip- genescanleadtoHPEandSODaswellasisolatedCPHD/ tionfactorsarecriticallyimportantfortheirsuccessful MPHD. Furthermore, this chapter will discuss the development. increasing evidence of overlapping genotypes between The pituitary gland is a midline structure located in congenital hypopituitarism and Kallmann syndrome thesellaturcicarecessofthesphenoidboneatthebase (KS), defined asthe combination of hypogonadotropic of the brain. It is composed of three lobes which have hypogonadism(HH)andanosmia. dual embryonic ectodermal origins, the oral ectoderm givingrisetothehormone-secretinganteriorandinter- DEVELOPMENTOFTHE mediatelobesandtheoverlyingneuralectodermgiving HYPOTHALAMO-PITUITARYAXIS rise to the posterior lobe (Cohen, 2012). The posterior lobeistheonlyneuralcomponentofthepituitarygland Morphology andprovidesadirectlinktothehypothalamus,whichis also derived from the neural ectoderm. Maintained Asmentionedbrieflyintheintroduction,thethreelobes apposition and interactions betweenthese two ectoder- ofthepituitaryarederivedfromtwoadjacentectoder- mal layers is crucial for normal pituitary development. mal layers. The primordium of the anterior lobe is Insults to this developmental process can result in the termed Rathke’s pouch (RP), and this structure loss or reduction of pituitary hormone-secreting cells develops through the dorsal invagination of the oral resultingincongenitalhypopituitarism,withphenotypes ectodermtowardtheoverlyingneuroectodermcontain- ranging from multiple pituitary hormone deficiencies ing the primordium of the hypothalamus, the ventral (combined/multiple pituitary hormone deficiency diencephalon (VD). The invagination of RP involves (CPHD/MPHD))todeficienciesinsinglehormonesonly, tightregulationofcellularproliferationandsubsequent the most common isolated hormone deficiency being differentiation events to give rise to five highly differ- attributed to growth hormone (Alatzoglou and entiatedcelltypessecretingatotalofsixdifferenthor- Dattani, 2009). Given its midline location, and that the mones: (1) corticotrophs produce adrenocorticotropic pituitary gland is derived from the same region of the hormone (ACTH), (2) thyrotrophs produce thyrotropin *Correspondenceto:ProfessorMehulT.Dattani,UCL-InstituteofChildHealth,30GuilfordStreet,London,WC1N1EH,UK. Tel:þ44-207-905-2657,Fax:þ44-207-404-619,E-mail:[email protected] 4 M.J.MCCABEANDM.T.DATTANI orthyroid-stimulatinghormone(TSH),(3)somatotrophs 2010). The organ is also subdivided into three medial produce growth hormone, (4) lactotrophs (which are to lateral regions: periventricular, medial, and lateral derived from the same precursor cells as the somato- (Szarek et al., 2010). The periventricular region was trophs;termedsomatomammotrophs)produceprolactin, described above, but contained within the medial and (5) gonadotrophs produce follicle-stimulating hor- regionisthemedialpreopticnucleus,theanteriorhypo- mone (FSH) and luteinizing hormone (LH) (Cohen, thalamus, the dorsomedial nucleus, the ventromedial 2012).Thisinvaginationeventalsoleadstotheformation nucleus, and the mammillary nuclei (Szarek et al., of the intermediate lobe, and this contains the melano- 2010). The lateral zone consists of the preoptic area trophs which secrete pro-opiomelanocortin (POMC). andhypothalamicarea. POMC is a major precursor protein to endorphins, Interestingly, however, deciphering hypothalamic melanocyte-stimulating hormone (MSH), and ACTH development during embryogenesis has proved prob- (Alatzoglou and Dattani, 2009). Humans contain only lematic, perhaps due to its anatomic complexity and a vestigial intermediate lobe and as such do not secrete highlydiversecollectionofcellgroupsandneuronalsub- large amounts of POMC-derived hormones. Once typesforwhichthereisadearthofliteraturedefiningthe secreted, each of the hormones targets distant tissues geneticsandsignalingandmarkermoleculesinvolvedin and organsthroughout the body. their delineation and identification (Blackshaw et al., As RP invaginates, part of the VD evaginates ven- 2010). Furthermore, genetic expression studies within trally to form the infundibulum and later the posterior the hypothalamus have knock-on effects on multiple pituitary lobe and pituitary stalk. Throughout develop- neuronal subtypes and downstream physiologic pro- mentthereisacloseassociationbetweentheinfundibu- cesses.However,studiesareslowlyelucidatinghypotha- lumandRPandtheinteractionsandappositionbetween lamic development. Structural organization of the these structures must be maintained for successful developing human hypothalamus was nicely assessed organogenesis.Thepituitarystalkactsasaphysicalcon- by immunohistochemistry in more than 30 brains over nection between the pituitary gland and brain and con- the entire course of gestation, and provided evidence tains the hypophyseal (hypothalamo-pituitary) portal for architectural homologies between species, particu- system, as well as the neuronal connections traversing larly that of the better characterized rat (Koutcherov across the hypothalamic median eminence. These neu- etal.,2002,2003).Inaddition,onerecentstudysuccess- rons originate from the supraoptic, suprachiasmatic, fullylabeledeachmajorhypothalamicnucleusoverthe andparaventricularnucleiwhicharelargehypothalamic entirecourseofneurogenesis(Shimogorietal.,2010). magnocellularbodieslocated withintheperiventricular region of the hypothalamus (Szarek et al., 2010). Timeline of hypothalamo-pituitary Thesupraopticandsuprachiasmaticnucleireleaseargi- organogenesis ninevasopressinwhiletheparaventricularnucleirelease oxytocin (Kelberman et al., 2009). Within the median Asdescribedearlier,thehypothalamusandthepituitary eminence itself at the base of the hypothalamus is the arederivedfromtheanteriorneuralplate.Theirdevel- capillary bed, into which thewidely dispersed hypotha- opmentishighlyconservedacrossvertebratesincluding lamic parvocellular neurons secrete hypophysiotropic humans, and as such, this chapter will outline their hormones.Thesestimulatethereleaseofthesevenante- development in the mouse, a model which is well rior/intermediate pituitary lobe hormones described characterized. above via the hypophyseal portal system. Interestingly, The growth and expansion of the brain during theparvocellularneuronsalsosecreteoxytocinandargi- embryogenesiscausestheembryonicheadtobendante- ninevasopressin,althoughatmuchlowerconcentrations riorly,resultingintheventraldisplacementoftheheart thanthemagnocellularneurons,withtheparvocellular- withthesubsequentformationofadepressionbetween derived argininevasopressin beingimplicatedin acting theheartandbrain,termedthestomodeum,ororalecto- synergistically with corticotropin-releasing hormone in derm. Atembryonic (E) day 8.5, theupper edge ofthe regulating ACTH release. It is therefore evident thatit stomodeumthickens,whichsignalstheonsetofpituitary is the hypothalamus that is the central mediator of organogenesis(Fig.1.1).ByE9.5,1daylater,thisthick- growth, reproduction, and homeostasis, actingthrough enedsectionofthestomodeuminvaginatestoformRP thepituitarygland(Kelbermanetal.,2009). (Takuma et al., 1998; Rizzoti and Lovell-Badge, 2005), Theanatomyofthedevelopedhypothalamusiswell justpriortothecommencementofhypothalamicneuro- understood.Itextendsfromtheanteriorlylocatedoptic genesis at E10 (Shimogori et al., 2010). At E10.5, the chiasmtotheposteriorlylocatedmammillarybodyand infundibulum evaginates from theVD, whichbecomes isorganizedintodistinctrostraltocaudalregions:pre- morphologicallyevidentintheneuralectodermatE9.5 optic, anterior, tuberal, and mammillary (Szarek et al., (Szareketal.,2010),tocomeintocontactwithRP.This
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