In e na ional Jou nal o
Molecula Sciences
Re iew
G ow h Ho mone and he Audi o y Pa hway: Neu omodula ion
and Neu o egene a ion
Joaquín Gue a Gómez 1,* and Jesús De esa 2,*
Ci a ion: Gómez, J.G.; De esa, J.
G ow h Ho mone and he Audi o y
Pa hway: Neu omodula ion and
Neu o egene a ion. In . J. Mol. Sci.
2021,22, 2829. h ps://doi.o g/
10.3390/ijms22062829
Academic Edi o :
Gab iela Pa linko a
Recei ed: 3 Feb ua y 2021
Accep ed: 5 Ma ch 2021
Published: 11 Ma ch 2021
Publishe ’s No e: MDPI s ays neu al
wi h ega d o ju isdic ional claims in
published maps and ins i u ional a il-
ia ions.
Copy igh : © 2021 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
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dis ibu ed unde he e ms and
condi ions o he C ea i e Commons
A ibu ion (CC BY) license (h ps://
c ea i ecommons.o g/licenses/by/
4.0/).
1O ola yngology, Medical Cen e Fol a, 15886 Teo, Spain
2Scien i ic Di ec ion, Medical Cen e Fol a, 15886 Teo, Spain
*Co espondence: [email p o ec ed] (J.G.G.); [email p o ec ed] (J.D.);
Tel.: +34-981-802-928 (J.G.G. & J.D.)
Abs ac :
G ow h ho mone (GH) plays an impo an ole in audi o y de elopmen du ing he
emb yonic s age. Exogenous agen s such as sound, noise, d ugs o auma, can induce he elease o
his ho mone o pe o m a p o ec i e unc ion and s imula e o he media o s ha p o ec he audi o y
pa hway. In addi ion, GH de iciency condi ions hea ing loss o cen al audi o y p ocessing diso de s.
The e a e p omising animal s udies ha e lec a possible egene a i e ole when exogenous GH
is used in hea ing impai men s, demons a ed in
in i o
and
in i o
s udies, and also, e en a ew
s udies show bene icial e ec s in humans p esen ed and subs an ia ed in he main ex , al hough
hey should no exagge a e he main conclusions.
Keywo ds:
g ow h ho mone; IGF-I; cen al audi o y p ocessing; hea ing impai men ; he edi a y
hea ing loss; GH de iciency
1. In oduc ion
Hea ing begins when he hai cells (HC) loca ed in he cochlea pe cei e he sound
s imulus. This senso y o gan ansduces he mechanical ene gy ecei ed o i s ans o ma-
ion in o elec ical ene gy. The audi o y pa hway is esponsible o he ansmission o hese
acous ic signals o he b ain, whe e he in o ma ion ecei ed is p ocessed o conscious
pe cep ion. This pa h (a e en ) has an opposi e pa h (e e en ) om which he ecei ed
signal is egula ed o inhibi ed. Bo h ou es expe ience mul iple in e hemisphe ic c oss-
ings du ing hei ajec o y [1]. The physiological p ocess o sound ansmission in ol es
he pa icipa ion o neu o ansmi e s, in pa icula glu ama e, bu also ace ylcholine o
enkephalins [
2
] The same occu s wi h he de elopmen and p o ec ion o he audi o y
pa hway, p ocesses in which mul iple neu o ansmi e s, ho mones, and pep ides a e also
in ol ed, some o which a e exp essed in he ea i sel , as appea s o be he case wi h
g ow h ho mone (GH) and i s ecep o (GHR), a leas in chick emb yos [
3
]. This is no
su p ising, since GH is a pleio opic ho mone exp essed a he pi ui a y le el and in a
numbe o cells and issues whe e i pe o ms many di e en unc ions, a beyond hose
classically desc ibed [
4
]. Indeed, GH and GHR a e widely exp essed in he b ain, whe e he
ho mone and i s main media o Insulin-like G ow h Fac o -I (IGF-I) play di e en key oles
in e al and pos na al b ain de elopmen , ma u a ion, and unc ion [
5
–
7
]. Fu he mo e,
GH exp ession has been de ec ed in neu al s em cells [
8
,
9
], in which he ho mone induces
he exp ession o IGF-I [9].
In addi ion o he e ec s o GH/IGF-I on no mal b ain de elopmen and unc ioning,
his sys em is also in ol ed in he epai p ocesses o he b ain a e inju y, as many s udies
ha e al eady shown good esul s a e GH adminis a ion o expe imen al animals [
10
–
17
]
and humans [18–27], e en when he e is no GH de iciency.
Gi en he signi ican e ec s o GH on he b ain, i seems logical ha his ho mone
also plays a signi ican ole in he audi o y pa hway. E en and gi en ha GH sec e ion
In . J. Mol. Sci. 2021,22, 2829. h ps://doi.o g/10.3390/ijms22062829 h ps://www.mdpi.com/jou nal/ijms
In . J. Mol. Sci. 2021,22, 2829 2 o 12
expe iences a con inuous dec ease om app oxima ely 20 yea s o being p ac ically unde-
ec able a ound 60 yea s o age [
4
], i is easible o assume ha many o he degene a i e
p ocesses associa ed wi h aging may be ela ed o he de iciency o his ho mone; among
hem could be he hea ing loss ha is o en seen in old age [28,29].
Physiologically, he loss o hai cells (HC) begins in he ea ly s ages o li e, and hey
can be clinically obse ed om he i h decade o li e [
28
,
29
]. The e a e also exogenous
ac o s such as noise, d ug oxici y, ischemia o di ec auma ha can damage hese HC
in a e e sible o i e e sible way, accele a ing he p ocess o audi o y degene a ion. The
abili y o hai cells o egene a e spon aneously seems no o be possible o eally poo in
mammals. Howe e , his egene a ion has been seen in o he animal species, such as bi ds,
ep iles, amphibians and ish [30], a e exposu e o noise o ano he o o oxic agen .
In his s udy we will analyze he ole o GH in hea ing and he physiological pa hways
ha i egula es, as well as some synd omes ela ed o GH ha di ec ly o indi ec ly
condi ion hea ing loss. Finally, we will assess he he apeu ic po en ial o GH in he
ea men o audi o y pa hology.
2. Physiological Role o GH in he Cochlea and he Audi o y Pa hway
Al hough i had been pos ula ed ha GH could be a neu oho mone gi en i s ce eb al
exp ession [
3
], mos o he GH ha exe s i s ac ions a he b ain le el comes om ha
sec e ed by he pi ui a y gland. Plasma GH easily c osses he blood-b ain ba ie (BBB)
o ca y ou i s ac ions on neu ogenesis, synap ogenesis and myelina ion, as well as o
y o epai b ain damage. In he case o IGF-I, al hough i is also exp essed in he b ain,
i s exp ession depends mainly on GH [
4
]. As wi h GH, plasma IGF-I is able o c oss
he BBB, bu only he ee ac ion o he ci cula ing ho mone can do so, he e o e i s
b ain concen a ions depend on he mola a io IGF-I/IGFBP3 (i s main ca ie in plasma).
Fu he mo e, GH induces he exp ession o se e al neu o ophic ac o s ha a e in ol ed
in a ious egula o y unc ions o he audi o y pa hway [31].
S udies in animal models ha e shown he ele ance o GH in he de elopmen o he
o gans o he inne ea . Du ing he emb yonic pe iod, he chicks exp ess high GH immune
eac i i y in he esicles ha will de elop he inne ea [
3
]. Du ing pos na al de elopmen
in mice, ansc ip omic analysis shows an inc eased le el o GH (89) in he cochlea senso y
epi helium [
32
]. Fu he mo e, du ing g ow h and aging, cochlea up egula ion o GH (44)
occu s along wi h up egula ion o p olac in (108) [
33
]. GH is a ho mone ha egula es
calcium mine aliza ion and i is also in ol ed in he g ow h o he empo al bone and
he ossicula chain o he middle ea [
34
]. I is also esponsible o he mine aliza ion
o o oconia, a calcium ca bona e s uc u e loca ed in he es ibula sys em ha in o ms
he cephalic posi ions, h ough ma ix- ela ed sequences [
35
]. Wi h espec o he cen al
audi o y e ec s o GH, pe iphe al adminis a ion o i s sec e agogue GHRH has shown a
educ ion in la e audi o y e oked po en ial la encies in young heal hy men, concomi an
wi h an inc eased ci cula ing GH le els [36].
3. GH and Hea ing Impai men
In e es ingly, hea ing is di ec ly ela ed o he g ow h a e in child en and adolescen s.
In ac , he hea ing h eshold in in ancy can p edic g ow h a e [
37
]. The e a e se e al
synd omes wi h hea ing dys unc ion in which he e is GH de iciency, howe e his is
no a cons an o synd omes in which hea ing loss exis s [
38
]. Tha is, depending on
he synd ome, he e could be an absence o insu icien GH, o a esis ance o dec eased
sensi i i y o he ho mone. In hese cases, he e is a de ici o IGF-I, and hea ing impai men
is mainly ela ed o he dec ease in he le els o his GH media o [37–39].
Adul s wi h un ea ed, congeni al li e ime isola ed GH de iciency usually show p e-
dominance o mild high- ones senso ineu al hea ing loss [
40
]. Neu ophysiologic es s
show signs o cochlea inju y, such as he absence o he s apedial e lex and o oacous ic
emissions, also seen in La on synd ome [
41
]. The absence o he s apedial e lex implies
In . J. Mol. Sci. 2021,22, 2829 3 o 12
hype sensi i i y o noise (hype acusis) [
40
–
42
]. Some synd omic child en wi h impai ed
GH sec e ion may ha e a empo a y conduc i e hea ing loss [43].
Bo h GH de iciency and excess in ol e an al e a ion in cen al audi o y p ocessing,
leading o cogni i e de ici s. GH-de icien subjec s show an inc ease o he acous ic P300
la ency, whe eas in hose wi h ac omegaly he e is a educ ion in he ampli ude o his
wa e, which also condi ions cogni i e impai men [
44
]. B ain auma can also cause a
de ici in GH syn hesis and sec e ion. A e su e ing a head inju y, some boxe s and
kickboxe s become GH de icien . In hem, he P300 wa e ampli udes a e lowe han in
hose wi hou GH de iciency [45].
All o he e idence desc ibed abo e demons a es ha GH plays a majo ole in he
en i e audi o y pa hway, co obo a ing he indings abou un ea ed GH de icien child en
and hea ing loss [42].
4. The Sound as a Modula o o GH Sec e ion
The ac ha noise damages he audi o y pa hway is undoub ed, bu he mechanisms
by which his occu s a e no ye well known. The e ec s o noise on he audi o y pa hway
usually appea apidly, damaging synapses, inducing he appea ance o eac i e oxygen
species (ROS), calcium accumula ion, and ec ui ing in lamma o y media o s (such as IL-6
o TNF) and inc easing glu ama e exci o oxici y. Noise ac i a es se e al pa hways includ-
ing caspase o JNK/MAPK dependen and independen pa hways [
46
–
48
]. Noise also
induces cogni i e dys unc ion ha esul s in he la e onse o hippocampal neu ogenesis,
which de elops long a e oxida i e s ess disappea ed [
49
]. This egion is mo e suscep ible
o noise han he audi o y co ex, wi h g ea e damage om oxida i e s ess and oligome -
iza ion and hype phospho yla ion o Tau, a mic o ubule-associa ed p o ein [
50
], which
can lead o p og essi e synap ic loss and neu onal cell dea h [
51
,
52
]. This pa hological
accumula ion o Tau may be co ela ed wi h neu odegene a ion in he pe iphe al audi o y
sys em [53].
A se ies o s udies showed ha p olonged exposu e o high in ensi y noise ini ially up-
egula es GH exp ession [
54
], inc easing i s ci cula ing le els, as well as o he s ess- ela ed
ho mones, bo h in humans and in animal models [
55
,
56
]. In e es ingly, a sho bu in e -
mi en exposu e o a low equency, mode a e in ensi y sound s imulus inc eases ne e
mo ili y and cellula esponse, implica ing highe ci cula ing GH le els [57]. Howe e , in
he long e m, hese le els a e signi ican ly educed [
58
]. The dec ease in ci cula ing GH is
c i ical in indi iduals who a e g owing and ma u ing, po en ially al e ing hei neu onal
plas ici y and, he e o e, a ec ing hei lea ning and memo y [59].
Based on hese esul s, i seems ha a e exposu e o noise, GH can play an impo an
ole in neu op o ec ion and neu o egene a ion, a leas in animal models, so he nex s ep
is o conside whe he exogenous GH could exe iable clinical e ec s o egene a e he
audi o y pa hway.
5. The E ec s o GH: F om In Vi o/In Vi o S udies o Clinical Repo s
In i o
and
in i o
s udies ha e ied o analyze whe he GH could p o ec , eco e
o e en egene a e cells in ol ed in hea ing. The i s s udies ocused on obse ing he
abili y o GH o success ully s imula e he p oli e a ion o cul u ed ou e ea ca ilaginous
s uc u es (chond ocy es) o abbi s, showing posi i e esul s sugges ing ha GH di ec ly
ini ia es p oli e a ion in abbi ea chond ocy es and, consequen ly, in mammals [60].
Howe e , ew epo s ha e demons a ed he e icacy o exogenous GH in hea ing. In
ac , one migh e en wonde i ea men wi h his ho mone may pose a isk o hea ing
impai men since, heo e ically, he inc ease in GH induces g ea e ossi ica ion o he ea
ca i ies ha could wo sen audi o y ansmission, as appa en ly seen in ac omegaly [
61
].
Howe e , GH ea men does no inc ease he isk o hea ing loss, ei he in in an s o
child en o in adul s, as has been seen in pa ien s wi h Tu ne synd ome and o he condi-
ions [
62
,
63
] (Table 1). In ac , he incidence o middle ea pa hology o en dec eases wi h
accele a ed bone mine aliza ion o he ea ca i ies in hese gi ls wi h Tu ne synd ome [
34
].
In . J. Mol. Sci. 2021,22, 2829 4 o 12
Table 1.
Selec ion o he edi a y hea ing loss synd omes and he in ol emen o GH on hei pa hogenesis, associa ed
condi ions, o ea men .
Condi ion Findings Hea ing Loss GH Le els Bene i wi h hGH
CHARGE synd ome
Coloboma ous mic oph halmia
Congeni al hea de ec s, usually cono uncal
Choanal a esia
Re a ded g ow h and de elopmen
Geni al hypoplasia, possibly o hypo halamic o igin
SNHL
MHL ( a e) No mal
Low ( a e) Yes
Als öm synd ome
A ypical e inal degene a ion wi h loss o cen al
ision in in ancy
Diabe es melli us in childhood
T ansien obesi y
Pos e io co ical ca a ac
Neph opa hy
Acan hosis nig icans
SNHL Low Yes
Ac odysos osis
Sho ening o he in e phalangeal join s o he
hands and ee In ellec ual disabili y
Peculia acies (sho head, small b oad up u ned
nose wi h la nasal b idge and p o uding jaw)
Inc eased bone age
In au e ine g ow h e a da ion
Ju enile a h i is
Sho s a u e
SNHL ( a e)
MHL ( a e) No mal Yes
Combined g ow h ho mone
de iciency wi h hea ing loss
and limi ed neck mo emen
Pi ui a y ho mone de iciencyLimi ed neck
mo emen SNHL Low Yes
La on synd ome
Insensi i i y o GH, usually caused by a mu an
g ow h ho mone ecep o
Sho s a u e
Inc eased sensi i i y o insulin
SNHL
MHL ( a e) No mal No
In au e ine and pos na al
g ow h ailu e wi h
mic ocephaly and in ellec ual
disabili y
P ena al G ow h Failu e
Ele a ed G ow h Ho mone Le els
Men al Re a da ion SNHL Ele a ed No
Hajduk-Cheney synd ome
Dissolu ion o e minal phalanges
Dolichocephaly wi h occipi al p ominence
Sho s a u e
P ema u e loss o ee h
CHL
SNHL
No mal
Low
(spo adic) Yes
Richa ds-Rundle synd ome
A axia
Dis al amyo ophy
In ellec ual disabili y
Diabe es melli us
Absen de elopmen o seconda y sex
cha ac e is ics
SNHL No mal No
EEC synd ome
Va iable ec odac yly o hands and ee
Absence o lac imal punc a
Cle lip-pala e
Occasional es ibula abno mali ies
CHL No mal
Low
(spo adic) Yes
C andall synd ome Gene alized alopecia wi h pili o i
G ow h e a da ion
Hypogonadism SNHL Low Yes
Hypodon ia and PEG-shaped
ee h, oli opon oce ebella
dysplasia, hypogonadism and
hea ing loss
Oli opon oce ebella degene a ion
Hypogonado opic hypogonadism
Hypodon ia
Resis ance o GH
SNHL
(unila e al) No mal No
Tu ne synd ome Sho s a u e
Thick o webbed neck
Gonadal dys unc ion
CHL
MHL
SNHL No mal Yes
Kabuki synd ome
Peculia acial (elonga ed palpeb al issu es and
p ominen ea s)
Pos na al g ow h e a da ion
In ellec ual disabili y
Ca diac anomalies
CHL
MHL
SNHL No mal Yes
SNHL: senso ineu al hea ing loss; CHL: conduc i e hea ing loss; MHC: mixed hea ing loss. Table adap ed om To iello, H e al. He edi a y
hea ing loss and i s synd omes [38].
In . J. Mol. Sci. 2021,22, 2829 5 o 12
A b ain inju y, such as auma ic b ain inju y o ce eb al palsy, can lead o a de ici
o GH, which implies a eplacemen ea men wi h his ho mone ha , as p e iously
men ioned, is sa e and e ec i e in b ain epai . In ac , as ou g oup demons a ed, GH
ea men is able o es o e hea ing in pa ien s wi h ce eb al palsy and hea ing loss [
64
].
I s mechanism o ac ion is unknown, bu i p obably occu s h ough he egene a ion o
senso y cochlea cells and he audi o y ne e o by accele a ing hea ing ma u i y [
64
].
Fu he mo e, GH induces he exp ession o IGF-I, and o he neu o ophic ac o s, which
play a ele an ole in hea ing; ci cula ing le els o IGF-I a e di ec ly p opo ional o he
deg ee o hea ing loss in olde humans [
65
]. Mo eo e , opical adminis a ion o IGF-I had
been seen o ha e posi i e e ec s on hea ing eco e y in pa ien s wi h sudden senso ineu al
hea ing loss [66].
The he apeu ic po en ial o GH o use in o he condi ions such as ischemia, noise-
induced hea ing damage, o d ug oxici y needs o be e alua ed bu appea s p omising.
Ea ly ea men is undoub edly a ac o o ensu e i s success [64].
5.1. Hai Cells
GH adminis a ion can s imula e he p oli e a ion o HC a e cochlea damage. Ze-
b a ish has been he mos s udied species o all animal models due o he inhe en abili y
o his ish o induce neu o egene a ion. In zeb a ish, he use o GH an agonis s leads
o a signi ican dec ease in cell p oli e a ion in he inne ea . Faced wi h a s imulus ha
gene a es cochlea damage, and damage o hai cells, endogenous GH can inc ease i s
exp ession, o s imula e he egene a ion o hose audi o y hai cells. GH mRNA exp ession
in his case is loca ed pe inuclea ly a ound e y h ocy es in he blood essels o he inne
ea epi helium. A e o e exposu e o noise, he densi ies o he saccula hai cells in he
GH- ea ed ea ed ish we e simila o hose o he con ols, and highe han hose o he
ish ha ecei ed bu e . Wi h he use o exogenous GH, cell p oli e a ion was s imula ed
and apop osis was educed in he saccules, lagenae and u icles o he ish ea ed om he
day a e acous ic auma [54,67].
5.2. Audi o y Ne e
Ano he s udy has ocused on e alua ing he e ec s on ne e egene a ion o neu ons
o he spi al ganglion, a g oup o bipola cell bodies ha inne a e he cilia ed cells o he
o gan o Co i and p ojec axons o he cochlea ne e. This
in i o
s udy showed ha
exposu e o di e en concen a ions o GH induces b anching and cell g ow h. Rega ding
an e ec o GH on neu onal su i al, while i inc eased a e he combined adminis a ion
o GH and BDNF (B ain De i ed Ne e Fac o ), he adminis a ion o only GH ailed o
ep oduce his e ec [68].
5.3. Deep B ain
The hippocampus is an a ea o special in e es in he audi o y pa hway since neu al
ci cui s connec o his b ain s uc u e. Neu ons in he hippocampus espond o o ac ion
po en ials gene a ed in he inne ea ollowing sound s imuli and a e no ono opically
o ganized [
69
]. Du ing audi o y wo king memo y (including coding, main enance, and
e ie al p ocesses), he audi o y co ex connec s wi h he hippocampus and he in e io
on al gy us [
70
]. This audi o y in o ma ion a els om he audi o y co ex o neu ons in
he median sep um and is hen p ojec ed di ec ly o he hippocampus [
69
]. In e es ingly,
s udies in a s show ha GH is capable o e e sing hippocampal dys unc ion due o
a ious s ess- ela ed condi ions, including long- e m audi o y ea memo y [
71
]. This
obse a ion abou he e ec o GH on excessi e ea memo y o ma ion has also been
epo ed in he b ain amygdala [72].
In . J. Mol. Sci. 2021,22, 2829 6 o 12
5.4. Audi o y Co ex
The e is a p omising p ospec o he eco e y o audi o y p ocessing in GH-de icien
pa ien s h ough he use o GH eplacemen he apy. Such is he case in pa ien s wi h
Sheehan synd ome. These pa ien s ha e panhypopi ui a ism esul ing om an in a c ion o
he pi ui a y gland due o hypo olemic shock o se e e hemo hage. Neu ophysiological
s udies show ha he adminis a ion o GH dec eases he p olonga ion o P300 la encies
a e six mon hs o ea men [
73
]. GH ea men may also imp o e he equency o speech
in Tu ne synd ome [74].
6. Molecula Mechanisms o GH-Dependen Neu op o ec ion, Synap ogenesis and
Neu ogenesis
As men ioned in he In oduc ion, i is well es ablished ha GH gene exp ession occu s
in many issues and o gans, including he cen al and pe iphe al ne ous sys em, and his
exp ession is independen o ha which occu s in he pi ui a y gland. GH adminis a ion
is capable o inc easing axonal egene a ion, p omo ing einne a ion, main aining o
inducing Schwann cells p oli e a ion, and educing muscle a ophy; all his ansla es in o
g ea po en ial o he ea men o pe iphe al ne e inju ies [
75
–
78
]. Since he basis o
audi o y egene a ion seeks molecula a ge s ha allow he de elopmen o d ugs o
es o e los hea ing, GH could be one o hem.
The neu op o ec i e and neu o egene a i e e ec s o GH a e ca ied ou : 1) by he
di ec ac ion o his ho mone, o 2) by inducing he exp ession o neu o ophic ac o s. The
di ec ac ion o his ho mone begins a e he binding o GH o i s ecep o , which leads o
he ac i a ion o he JAK/STAT signaling pa hway, conside ed as he main in acellula
ansduc ion sys em o he e ec s o GH, al hough also he signaling pa hways PI3K/Ak ,
MAPK and No ch a e ac i a ed by he ho mone and play an impo an ole in he e ec s o
his ho mone [
79
–
81
]. Phospho yla ed STATs o m dime s ha en e he nucleus, whe e
hey bind o speci ic DNA sequences and ac i a e hei a ge genes and o he signaling
pa hways [
80
]. This ac i a ion mechanism has been demons a ed in zeb a ish, p omo ing
egene a ion o hai cells [
82
]. In addi ion, GH has shown o exe an i-in lamma o y
ac ions, o example by modi ying he immuno eac i i y o TNF ecep o s [
83
], as well
as modi ying neu onal exci a ion and neu oplas ici y h ough up- egula ion o he NR2B
subuni o he NMDA ecep o [
71
], and i also inc eases he numbe o neu ons ha
inc ease he exp ession o c-Fos in BLA (basola e al complex amygdala) [72].
As indica ed, GH, ia STAT5, ac i a es he No ch signaling pa hway, which has been
shown o be use ul in e inal neu op o ec ion [
83
]. This e ec is clea ly demons a ed
by he ac ha , co ea men o GH wi h he No ch signal inhibi o , DAPT, inhibi s he
neu op o ec i e e ec o he ho mone [
83
]. In he same s udy, he au ho s ound ano he
neu op o ec i e e ec o GH, exe ed ia No ch, by he phospho yla ion o he PI3K/Ak
signaling pa hway ha educes he egula ion o PTEN, hus dec easing he in lamma o y
esponse o kainic acid adminis a ion. This s udy has been ca ied ou in he e ina o
chicken in which GH also p omo es e inal egene a ion a e damage induced by kainic
acid [
83
]. The e o e, i does no seem ha his could be ex apola ed o wha happens in
he human inne ea , al hough he e ina and inne ea a e e y speci ic senso y s uc u es.
In ac , in mice, No ch inhibi s A oh1, a ele an ac o ha plays a majo ole in he
de elopmen and egene a ion o hai cells [
84
], howe e he same s udy indica es ha
addi ional ac o s a e needed o A oh1 o exe i s egene a i e e ec s a he le el o ce ain
genes p esen in HC. Mos likely, he ype o ela ionships be ween No ch and A oh1 has
led o in es iga e on how o inhibi he a ge gene Hes5 o
γ
-sec e ase o signi ican ly
inc ease he exp ession o A oh1 in he cochlea [85,86].
As indica ed abo e, GH can induce he elease o o he neu o ophic ac o s, namely
IGF-I and neu opep ides, ho mones, neu o ophins, g ow h ac o s, and some cy okine
signaling supp esso s [
80
]. IGF-I is one o he main egula o y media o s o hea ing
unc ion. This ac o , along wi h i s ecep o (IGF-IR), a e exp essed du ing cochlea
de elopmen . IGF-I signaling ensu es g ow h and di e en ia ion o cochlea s uc u es.
In . J. Mol. Sci. 2021,22, 2829 7 o 12
Al hough he lack o signi ican amoun s o IGF-I al e s gene exp ession in hai cells,
pa ial signaling is su icien o hei no mal de elopmen [
87
]. Bu IGF-I also plays a
ele an ole in he myelina ion o he audi o y ne e, ac i a ing he PI3K/Ak pa hway.
This p omo es di e en ia ion h ough he exp ession o myelin co e p o ein and myelin-
associa ed glycop o ein [
88
]. The e o e, i is likely ha some o mos o he e ec s o GH in
he inne ea a e dependen on GH-induced exp ession o IGF-I.
I is in e es ing o no e ha he neu o ophic e ec s o GH a e also media ed by
he induc ion o classical neu o ophins such as BDNF and NT3 [
12
,
89
], suppo ing he
pa icipa ion o GH in he eco e y o unc ional synap ic ansmission a e damage.
BDNF and NT-3 a e exp essed, oge he wi h hei ecep o s y osine kinase B (T kB) and
y osine kinase C (T kC), espec i ely, du ing he emb yonic de elopmen o he inne
ea , and pa icipa e in he senso y ophic suppo o his s uc u e, p o iding inne a ion,
de elopmen and main enance [
90
,
91
]. E y h opoie in (EPO), a ho mone also induced by
GH, is also exp essed in he inne ea , whe e
in i o
s udies in cul u es o he o gan o
Co i o a s ha e shown ha i p o ec s hai cells om ischemia [
92
] o o o oxici y [
93
],
al hough i lacked posi i e e ec s, and e en wo sened hea ing loss, in
in i o
s udies in
hese animals a e noise-induced damage [
94
]. The e o e, he e ec s o EPO a he le el o
he inne ea s ill need o be s udied in mo e de ail.
Al hough no di ec ly ela ed o GH, He egulin (HRG), a membe o he epide mal
g ow h ac o (EGF) amily, has been epo ed o ac as a mi ogen. I s imula es he
p oli e a ion o u icula macules in mouse cul u es, a leas du ing he de elopmen o he
neona al inne ea . I s ecep o s a e exp essed in he inne ea o newbo ns and adul s in
es ibula end o gans and O gan o Co i. Howe e , he addi ion o HRG does no enhace
cell p oli e a ion in adul s. [95].
7. Conclusions
Th oughou his e iew, we see ha lis ening is a complex p ocess ha in ol es
mul iple ac o s ha ac di ec ly o indi ec ly. I is clea ha GH pa icipa es in audi o y
emb yonic de elopmen and his ho mone is eleased by a sound s imulus o a ha m ul
e en . I also plays a ole in cen al audi o y p ocessing. Along he same lines, he absence
o endogenous GH can lead o hea ing loss, while i s eplacemen can help o eco e
hea ing loss, as i has been seen in un ea ed GH-de icien child en. Many child en in
he wo ld, including Spain, do no ecei e GH eplacemen he apy despi e ha hey a e
GH-de icien . The easons o i a e di e se: Heal h agencies o GH Commi ees equi e
wo nega i e GH p o oca i e es s ( hese a e ew eliable), a pi ui a y MRI, and a speci ic
age. Hence, many child en su e GH-de iciency and hey a e no ea ed because hey do
no mee he speci ied equi emen s. This is no logical bu i is he eal hing. We know a
numbe o cases.
We know ha mul iple e iopa hogenic ac o s cause hea ing loss, including gene ic and
en i onmen al diso de s, which a e no ully unde s ood. Agen s ha p omo e p o ec ion
om a auma ic e en o degene a i e p ocess, o ideally egene a e he damage caused,
ha e been in es iga ed o se e al decades. The appa en i e e sibili y o hea ing loss
once he lesion is es ablished o ces us o sea ch o molecules ha slow down o eco e
he senso y cells and audi o y neu ons. Al hough s udies in animal models a e ecen , hei
esul s and hose in some GH-de icien child en p omise o be easible o ea men wi h
GH, alone o in combina ion wi h o he ac o s. In ac , al hough GH migh no ha e a
di ec e ec , he ho mone induces he exp ession o se e al ac o s, mainly IGF-I, which
ha e posi i e ac ions on he eco e y om hea ing loss. In any case, mo e s udies a e
needed o analyze in de ail he e ec s ha GH can ha e on a damaged cochlea.
Au ho Con ibu ions:
J.G.G. and J.D. con ibu ed equally o w i ing his manusc ip . Bo h au ho s
ha e ead and ag eed o he published e sion o he manusc ip .
Funding: This esea ch ecei ed no ex e nal unding.
Ins i u ional Re iew Boa d S a emen : No applicable.
In . J. Mol. Sci. 2021,22, 2829 8 o 12
In o med Consen S a emen : No applicable.
Da a A ailabili y S a emen :
The da a p esen ed in his s udy a e a ailable on eques om he
co esponding au ho .
Acknowledgmen s: To Founda ion Fol a (Teo, Spain) o he help gi en o w i ing his e iew.
Con lic s o In e es : The au ho s decla e no con lic o in e es .
Abb e ia ions
Ak P o ein kinase B
BBB Blood b ain ba ie
BDNF B ain-de i ed neu o ophic ac o
BLA Basola e al complex amygdala
EGF Epide mal g ow h ac o
EPO E y h opoie in
GH G ow h ho mone
GHR G ow h ho mone ecep o
HC Hai cell
HRG He egulin
IGF-I Insulin-like g ow h ac o -I
IGFBP3 Insulin-like g ow h ac o binding p o ein 3
IL-6 In e leukin.6
JAK Janus kinase
JNK c-Jun N- e minal kinase
MAPK Mi ogen-ac i a ed p o ein kinase
NMDA N-Me hyl-d-aspa a e
NR2B Glu ama e [NMDA] ecep o subuni epsilon-2
NT-3 Neu o ophin-3
PI3K Phosphoinosi ide 3-kinase
PTEN Phospha ase and ensin homolog
Ros Reac i e oxygen species
STAT Signal ansduce and ac i a o o ansc ip ion
TNF Tumo nec osis ac o
T kc T opomyosin ecep o kinase C
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