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Initialvomeronasalstructuresinstagedhumanembryosareobservedbetweenweeks4and5(Carnegie
stages13to15
10
;Fig.4.1).Themedialepitheliumoftheolfactoryplacodegivesrisetothevomeronasal
neurons,nervusterminalis,cellsexpressinggonadotrophinreleasinghormone(GnRH),andsomefurther
neurons.
11,12
Vomero-nasalandterminalisgangliaappeararoundstages18and19asclustersofprotein
gene product 9.5 (PGP 9.5)–immunoreactive cells migrating out of the epithelium (Fig. 4.2a, c).
Vomeronasalandolfactoryaxonsstarttogrowintotheprimitiveolfactorybulb,andGnRHcellsbeginto
migratetothe hypothalamus,following vomeronasal or nervusterminalis substructures. Theynormally
beginreachingthemedianeminencebyweek8,butsomecellsmayremainalongthemigrationpathway.
13
An intriguing connectionbetween olfactionand sex becomesapparent ifGnRH cells fail to reachthe
hypothalamus,resultinginhypogonadotrophichypogonadism, often associatedwithanosmia (Kallmann
syndrome).
14,15
Aroundweek8,aVNDsimilartothatseeninrodentsbecomesvisible(Fig.4.1a).This
ductislinedbyneuroepithelialcellsreactiveforneurotubulin,neuralcelladhesionmolecule,andPGP
9.5, but not for OMP, a reliable marker for functional olfactory and rodent vomeronasal neurons. In
contrasttorodents,humansdonotformaclearlyseparateAOB.
16,17
Fig.4.1a,bThevomeronasalductinadulthumans.
aLocationofthevomeronasalductinadulthumans.Thedottedlineindicatesthevomeronasalnerveprojection(absentinhumans).Thereis
noaccessoryolfactorybulb.CNV1,cranialnerveV1;CNV2,cranialnerveV2.(ModifiedfromSchünkeetal.ThiemeAtlasofAnatomy.
Head,NeckandNeuroanatomy.Stuttgart,NewYork:Thieme;2007:116.)
bEndoscopyoftheleftnasalcavityshowingtheorificeofthevomeronasalduct(arrow).Se,anteriornasalseptum;iT,inferiorturbinate.
Fig.4.2a–dImmunohistochemicalfeaturesofthehumanvomeronasalduct(VND).
aHumanVNDduringdelevopment,approximatelyweek8.Immunohistochemicalreactionwithanantibodyagainstproteingeneproduct9.5
(black reaction product; PGP 9.5) shows clusters of immunopositive ganglion cells (outwandered epithelial cells; smallarrows) and the
vomeronasalnerve(orterminalnerve?)closetothevomeronasalduct(largearrows)runningintheseptalmucosa.Olf,olfactorycleft,lined
withPGP9.5–immunoreactiveolfactoryepithelium;Se,nasalseptum(cartilage).Scalebar:200µm.
bIncomparison,afrontal sectionofthenasalseptumina newbornratreactedwith anantibodyagainstolfactorymarkerprotein(brownish
reactionproduct;OMP).Thecrescent-shapedvomeronasalductexhibits alateralnonsensoryand a medialsensory epithelium. Thelatter
possesses twolevelsofOMP-positive cells,superficiallyand basallylocated. Theyprojecttodifferentregionsin the accessoryolfactory
bulb.Scalebar:200µm.
c Detail of the developinghuman vomeronasal duct from (a). PGP 9.5–immunoreactive cells with dendritic processes (arrowheads) and
cluster-likeformationofganglioncellsinthelaminapropria(arrows)showsstructuralprerequisitesforprenatalfunction.
dVomeronasalepitheliuminanagedhumanvomero-nasalductafterautopsy.Theimmunoreactivityagainstcaveolin1,anintegralmembrane
proteininvolvedinreceptor-independentendocytosis,showsslender,bipolar,neuron-likecells(arrowheads),butneverreactivitytoclassical
neuron markers. This mirrors the somewhat enigmatic nature of this apparently highly specialized epithelium. Counterstain with
haematoxylin.Scalebar:10µm.
Regression
Usuallytheconnectionoftheneuroepitheliumwithcentralnervoussystemstructuresdegeneratesbefore
week28.ThereareafewreportsofthepersistenceofthevomeronasalnerveandappropriateG
o
-andG
i
-
positive epithelialcells until the latefetalperiod,
18
but, lackingotherimportantcomponents, these are
probably not functional. The vomeronasal nerve has been described as present until the sixth fetal
month,
19
and “vestigial remains” were inconsistently observed until week 18.5.
16
The closure of the
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vomeronasalductwasinterpretedasasignof“degeneration,”
20
but,inmostindividuals,theductremains
opentodifferentextents(seebelow).However,thetimingofdisconnectionofthenervefromepithelial
cellshasnotyetbeendescribed.
MostVomeronasalOrgan–relatedStructureshaveDisappearedinAdultHumans
MostconstituentsoftheVNOarenolongerdetectableatbirthinhumans.Theonlyremainingstructureis
theVND,whichexhibitsconsiderablevariabilityinshape,size,andevenpresenceordetectability.The
VNDissituatedsuperiortotheparaseptalcartilageandrunssmoothlycraniodorsally.Theopeningofthe
VND is less than 2 mm in diameter, sometimes pigmented a brownishyellow (Fig. 4.2). Generally
describedasablind-endingductoramucosalpouchlocatedintheanteriornasalseptum,itslengthvaries
between3and22mm.
17
Thefrequencyofdetectiondependsstrongly onthe techniqueofinvestigation:
histological studiesreveal a higher percentageofVNDsthanrhinoscopic orendoscopicinvestigations
(Table4.1).
29
Unlikeinrodents,thereisnodifferencebetweenthetwosidesoftheductwithregardtoa
possible “sensory” and “nonsensory” epithelium. Histologically, the epithelium of the VND contains
portionsofsensory-likeformations,butneuronalmarkersarenolongerexpressed,andnorarethereany
nerveterminalsleftinthevicinityoftheepithelium.
30
Takentogether,thevomeronasalepitheliumofthe
adulthumanVNDexpresseshighlyspecializedhistochemicalfeatures;however,itdoesnotprovidethe
essential requirements for classical neuroepithelial information transfer into the brain. Owing to its
exposedlocationintheanteriorseptum,theVNDcaneasilybedamagedduringnasoseptalororthognatic
surgery.Despiteoccasionalanecdotalreportsandspeculation(e.g.,FoltánandSedý2009
31
),thereareno
studiesthatprovidemeasurablefunctionalevidencethatVNDdamageleadstobehavioralchangesafter
nasoseptalsurgery.
EvidenceForandAgainstaFunctioningHumanVomeronasalOrgan
AreThereHumanPheromones?
Chemical compounds that convey informationfrom one individual to another of the samespecies are
commonly called pheromones. By original definition (notably in insects which lack a morphological
VNO),theseare,“substanceswhicharesecretedtotheoutsidebyanindividualandreceivedbyasecond
individualofthesamespecies,inwhichtheyreleaseaspecificreaction,e.g.,adefinitebehaviourora
developmentalprocess.”
32
Themediationofchemosensorysignalsinsocialandsexualbehaviorhasbeen
widelydocumentedin animals.
33
A similar function seems likely in humans but has been less widely
documented(reviewedbyGrammeretal2005
34
):
• Meredith
35
proposes restricting the definition for pheromoneby including a requirement for mutual
benefit to sender and receiver, putting pheromone communication in an evolutionary context. The
communicationfunction, ifany,forexample ofhumanodor response,isobscure,sothese wouldnot
necessarilymeetthemorerestrictivedefinitionforpheromonecommunication.However,thisscientific
definitionis not universallyaccepted andthe term pheromoneis usedloosely inboth scientific and
popularpublications.
Table 4.1Frequencyofvomeronasalductinadulthumansvariesaccordingtotheinvestigationtechnique
Reference N Frequency
Potiquet1891
21
200 25%
Johnsonetal1985
22
100
Patients39%(endoscopy)
Postmortemspecimens70%(histology)
Stensaasetal1991
23
410 93%
Moranetal1991
24
200 100%bilateral
Garcia-VelascoandMondragon1991
25
1,000 90%
Trotieretal2000
26
1,842 Patients26%(endoscopy)
Gaafaretal1998
27
200 Patients76%(endoscopy)
Wonetal2000
28
78 36%
Knechtetal2001
29
173 65%(41%bilateral,24%unilateral;endoscopy)
Wittetal2002
30
25 65%(histology)
• The chemical nature of proposed pheromone compounds is heterogeneous, but some pheromone
candidatesin humans andanimalsmaybechemically related.
36
Possibleproduction sitesforhuman
pheromonecandidatesincludeurine,smegma-producingurogenitalglands,lachrymalglands,
37
axillary
apocrineglands,andmammaryglands,
38
mirroringknownpheromonesourcesinanimals.
•Theremayalsobesimilaritiesintherelationshipbetweencomplex“odorprints”andcomponentsofthe
immunesystemthat conferindividualidentity(e.g.,human lymphocyteantigens[HLA],or therodent
majorhistocompatibilitycomplex).
39
Peoplehavebeenshownto be capableofidentifying odors of
closelyrelatedpersons(fromsamplesofaxillaryvolatilescollectedfromT-shirts)betterthanwould
be expected by chance alone.
40
Thus, there could be “signaler pheromones” that help individuals
recognize relatives. There is also some evidence for a physiological response that varies with the
reproductivecycleoffemaleodordonors,includingmodulationofthemenstrualcycleinotherwomen
andanincreaseintestosteroneinmen.
41,42
Theunidentifiedcompoundsinvolvedmaybeclassifiedas
“primerpheromones,”producing an endocrineresponse and(maybe) a delayedchangeinbehavior.
Less convincingly, pheromones representing paternally inherited HLA alleles may influence mate
choice.
43,44
•Inhumans,activationofthehypothalamusbysomeodorsissexuallydimorphic(andsexualorientation–
specific)inbrainimagingstudies,
45
butevidencesuggeststhatthedetectionofsuch odorsis viathe
mainolfactorysystem,notthevomeronasalorganorVND.
PheromonesarenotNecessarilyDetectedbytheVomeronasalOrgan
Innocaseofproposedhumanpheromonecommunicationhasadirectspecificligand–receptorinteraction
involvingvomeronasalorolfactorychemosensorycellsandtheirregulartransductionmechanismsbeen
shown.Casesinwhichthevomeronasalsystemwasthoughttobeinvolvedhavenotbeensupportedby
subsequentsystematicinvestigation(seebelow).Chemosensorydetectionmustinvolvealigand–receptor
interactionofsomekind,butthereisnocompellingevidencethatthisoccursinthedistincthumanVND
ratherthanintheolfactoryepithelium,orelsewhere.
•Althoughthereisnouniversallyaccepteddefinitionof“pheromone,”itisclearthatsomechemosensory
communicationsignalsinanimals,whichwouldbepheromonesbyalmostanydefinition,aredetected
bythemainolfactorysystemandnotthevomeronasalsystem.
46,47
Forexample,innewbornrabbits,a
moleculesecretedbylactatingfemales,the“mammarypheromone,”triggersorofacialresponsesinthe
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pupsthathelpthemlocatethenipples.
48
Interestingly,thesechemosensorycuesarelearnedprenatally
viathemainolfactorysystem,emphasizingthefunctionalityofchemosensoryorgansbeforebirth.Thus,
theideathatafunctionalVNOisnecessaryforpheromonecommunicationiscontradictedbyavailable
data.EquallyerroneousistheideathatasubstancestimulatingtheVNOmustbeapheromone.
EvidenceAgainstHumanVomeronasalOrganFunction
Pheromone-like communication in humans probably exists, but a vomeronasal system is not
necessary.
Allwell-studiedcasesofvomeronasalfunctioninothervertebratesrequirethepresenceofspecifictypes
ofsensoryneuronexpressingcertainstimulus-receptorand-transductionproteins,andpossessingneural
connections capable of transmitting sensory information to the brain. Humans lack many of these
requirements:
• Mostof the genes encoding the vomeronasal receptors belong to theV1R and V2Rfamilies but, in
humans, therearenoV2Rgenes
49
and95%ofall V1Rgenes are pseudogenes(i.e.,cannotproduce
normal functional proteins).
50
(The remaining V1R genes are discussed below.) Evidence from
knockoutanimalssuggeststhattheTRPC2transductionchannelprotein(productofthetrpc2gene) is
critical fornormal VNO function in animals. The human trpc2 gene is also a nonprotein-producing
pseudogene.
51
Formyl-peptide receptors (FPR) are alternative chemosensory receptors in rodent
VNOs
52
butare notexpressedinchemosensoryepitheliaofnonrodentmammals.HumanVNDtissue
has notbeentested for the presence of FPRs, but itlacks the vomeronasal bipolar sensorycells in
whichV1R,V2R,andFPRsarenormallyexpressed.
• In addition to lacking cellular components such as bipolar neurons, humans have no demonstrable
vomeronasal nerve to carry sensory information to the brain, and no AOB, the brain region that
normallyreceivesvomeronasalsensoryinput.
•Electrophysiological experiments
53,54
andpositronemissiontomography(PET)studies
55
showed that
subjectswith or withouta detectable VND, or withtheir VNDcovered, did notdiffer in olfactory
sensitivity or odor threshold for androstenone or androstadienone (previously proposed as human
pheromones)orotherodors.
Chemical communication involving chemosensory transduction via the classical vomeronasal
sensorypathwayorviaotherchemosensorypathwaysinthevicinityofthehumanvomeronasalduct
isunlikely.
EvidenceForPossibleHumanVomeronasalOrgan/VomeronasalDuctFunction
• Although humans lackmost structures required for normal vomeronasal function, they do retainfive
remnantV1Rgeneswithopenreadingframes,
56
andcouldpotentiallyproducehumanV1R-like(hV1R-
L)receptorproteins.Inarecentstudy,allfivecouldfacilitateactivationoftheGα
o
signalpathwayin
culturedHeLa/olfcellsinvitro.
57
•Theabsence ofa functionaltrpc2 gene inhumansdoes notabsolutely rule outsome VNOfunction.
Residual function remains in mice with trpc2 knocked out,
58
so some noncanonical transduction
mechanismcouldallowVR-typereceptorstofunction—butthereisnoevidencefortheirexpressionin
thehumanVND.
•Expression ofonehumanVRgene(hV1R-L1) isreportedinhumanmainolfactory epithelium,
56
but
thereisnoevidencefordisplacedvomeronasal-typesensoryneuronsthere.Ifexpressedinolfactory
sensoryneurons(notdemonstrated),withacompatibletransductionpathway,thenhumanV1Rsmight
behave like olfactory receptors. They could contribute to the regular sense of smell or, with
appropriate central connections, they could contribute to pheromone communication. But this is all
speculation:thereisnoevidencethathV1R-L1hasachemosensoryfunctionofanykind,inolfactory
epitheliumorintheVND.
• Monti Bloch and colleagues
59
reported a sexually dimorphic electrophysiological response to
androstadienone (inwomen) andestratetraenol (in men), recorded from the regionofthe VND and
associatedwithanunconsciousautonomicresponse.Theycalledthesesubstancesandrelatedsteroids
“vomeropherins,”andclaimedtheyweremaleandfemalehumanpheromones,respectively,basedona
mistakenbeliefthatsubstancesstimulatingaVNOmustbepheromones.Thesefindingshavenotbeen
supported by later electrophysiological and PET studies (see above). There has also been no
confirmationofspecificelectrophysiologicalresponsesto“vomeropherins”incellsisolatedfromthe
humanVND.
60
• The recent discovery of a previously unknown vomeronasal receptor family (see above), and the
existenceofsomeVNOchemosensoryfunctionintheabsenceofTRPC2,leavesopenthepossibility
thattheremaybeotherVNOsensorymechanisms.VRreceptorgenesdifferwidelyacrosstaxonomic
groups, perhaps helping to maintain species isolation.
49
Some mammals, including the nonhuman
primatemarmosets,lackfunctionalversionsofallknownvomeronasalreceptorgenes,V1R,V2R,and
FPR,buttheydohaveaclassicalVNO,which,inarelatedspecies,appearstobefunctional.
61
Thus,
there may be vomeronasal receptors yetto be discovered, but they are unlikelytobe the basis for
chemosensoryfunctioninthehumanVND,becauseotheressentialcomponentsaremissing.
Trigeminalreceptorsmaycontributetoodorperception.
•TherearenoclassicalvomeronasalsensoryneuronsinorneartheVNDinadulthumans—buttheremay
beotherchemosensorycells.Thetrigeminalnerveinnervatessolitarychemosensorycellsinthenasal
mucosa,whichexpresssignaltransductioncomponentscommontobotholfactoryandtastesystems
62
andrespondtoodorsathighconcentrations.Trigeminalchemoreceptorsinthenasalcavityprimarily
servetodetectirritantsandtriggerprotectivereflexes(e.g.,sneezing),buttheycanalsocontributeto
odor perception. Solitary chemoreceptor cells cluster in and around the VND in mice,
63
but their
presenceanddistributionaroundthehumanVNDisunknown.
ChemicalCommunicationviaVomeronasalOrgan–orVomeronasalDuct–
independentPathways
ThereisapossibilityofchemosensorycommunicationviaVNO-independentpathways.Themostlikely
pathway,ofcourse,isthemainolfactorysystem.Trigeminalorotherpotentialchemoreceptorsofthenose
(e.g.,Grünebergganglionornervusterminalis)
62
arealsopossible(butunlikely)contributors.Inaddition,
chemical compounds could diffuse into blood vessels in the nose or airways, or after ingestion, for
detection by (undefined) internal chemoreceptors.
64
There are no prominent capillaries close to the
VND,
30
sothisisnotalikelyVND-relatedmechanism.
• There is no reason that the main olfactory system could not mediate all human chemosensory
communicationeventhoughothermammalsdependinpartontheir vomeronasal systems. Unlearned
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communication signals require the identification of particular molecules, which the vomeronasal
system achieves via receptors with highly selective responses. Most main olfactory receptors are
relativelynonspecific,butthemammalianbrainshouldbeabletosolvethecomputationalproblemof
identifying molecules via combinations of input, even if there are no specific olfactory pheromone
receptors.Inthe vomeronasalsystem,informationpassesdirectly totheamygdala,partofthebrain's
limbicsystemimplicatedinunlearnedresponsestopheromones.Themainolfactory systemalso has
projectionstolimbiccircuits,includingtheamygdala,inprimatesandothermammals.
65
• Because vomeronasal input was thought to be essential for pheromone response, and because the
amygdala has relatively indirect pathways to the neocortex, some have proposed
59
that response
without conscious perception would be the hallmark of pheromone communication—but the initial
assumptionisnowknowntobeincorrect.Consciousdetectionofthestimulusisnotincompatiblewith
pheromone communication, although it may be independent and unnecessary for pheromone
communication.
• The most common (canonical) type of olfactory transduction pathway is via olfactory receptor
activation of adenylyl cyclase III to produce cyclic adenosine monophosphate, which opens cyclic
nucleotide–gated channels. However, several other olfactory transduction pathways that use either
conventional or nonconventional (noncanonical) olfactory receptor molecules are now knownto be
expressedinsmallsubsetsofmainolfactorysensoryneurons.Thus,anodorresponseintheabsenceof
the canonical olfactory transduction pathway
66
does not necessarily implicate involvement of
vomeronasal receptors. Ironically,some ofthese specializedolfactory receptorneurons(ORNs)use
thephospholipidtransductioncascadenormallyactivatedbyvomeronasalreceptors,butvomeronasal
receptormoleculesarenotknowntobeexpressedinanyofthem.OneofthesmallsubgroupsofORN
that uses a noncanonical transduction pathway andexpresses the TRPM5 transduction channel does
projectitsaxons to theventral olfactory bulb, whereprojectionstolimbiccircuits mayoriginatein
mice,
67
andthereisevidenceforalimbicprojectionfromtheseparticularneurons.
68
• Recently, an olfactory receptor (OR7D4) has been found to be activated by steroid-derived odors,
including androstenoneandandrostadienone.
69
The associated geneis intact inhumans and may be
responsibleforhumanbehavioralandphysiologicalresponsestovolatilesteroidspreviouslyattributed
toVNOfunction(seeabove).
Summary
Thereisreasonablyconvincingevidenceforchemosensorycommunicationinhumans.Whetheritis
learnedorunlearnedisnotclearinallcases,butitismorelikelytobeaccomplishedbythemain
olfactorysystemthananychemosensorysystemlocatedinorneartheVND.
OutlookandPracticalAdviceforPhysicians
•ThedetectabilityoftheVNDbyendoscopyvariesconsiderablyfromonedaytoanother,asitcanbe
obstructedbymucusorperiodicswelling ofthenasalmucosa.However,evenwhen thepresenceof
VND(s)canbeestablished,thisisunlikelytobehelpfulwithdiagnosisofchemosensoryorbehavioral
disorders.
•Occasionally,aVNDorificecanbemisinterpretedasa(rarely)persistentnasopalatineduct(NPD),a
communication between the oral and nasal cavities that usually closes at birth or at the latest in
childhood.
70
If any NPD is detectable, the opening is located at thenasal floor,whereas theVND
orificeislocatedmoreposteriorly~1to2mmabovethenasalfloor.
•Patientsshouldbereassuredthatthebestscientificevidenceindicatesthatdamageormalfunctionofthe
VNO/VNDisunlikelytobeacontributortoanyadversesymptomstheyareexperiencing.
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