From pituitary cells to prostate gland in health and disease: direct and indirect endocrine connections

Re iews in Endoc ine and Me abolic Diso de s (2025) 26:187–203
h ps://doi.o g/10.1007/s11154-025-09948-7
Abb e ia ions
ACTH Ad enoco ico opic Ho mone
AR And ogen Recep o
AVP A ginine Vasop essin
AVPR1A A ginine Vasop essin Recep o 1A
AVPR1B A ginine Vasop essin Recep o 1B
AVPR2 A ginine Vasop essin Recep o 2
BPH Benign P os a ic Hype plasia
CRPC Cas a ion Resis ance P os a e Cance
DHT Dihyd o es os e one
ER Es ogen Recep o
FSH Follicle-S imula ing Ho mone
FSHR Follicle-S imula ing Ho mone Recep o
GH G ow h Ho mone
GHR G ow h Ho mone Recep o
GHRH G ow h Ho mone (GH)-Releasing Ho mone
GnRH Gonado opin-Releasing Ho mone
GR Glucoco icoids Recep o
IGF1 Insulin-Like G ow h Fac o 1
LH Lu einizing Ho mone
LHR Lu einizing Ho mone Recep o
MCR1 Melanoco in Recep o 1
And é Sa men o-Cab al
[email p o ec ed]g
Raúl M. Luque
[email p o ec ed]
1 Maimonides Biomedical Resea ch Ins i u e o Co doba
(IMIBIC), A da. Menéndez Pidal s/n., Co doba 14004, Spain
2 Depa men o Cell Biology, Physiology, and Immunology,
Uni e si y o Co doba, Co doba 14014, Spain
3 ReinaSo iaUni e si yHospi al(HURS),Co doba
14004, Spain
4 Depa men o Biomedical Sciences, Ceda s-Sinai Medical
Cen e , Los Angeles, CA 90048, USA
5 Boa d o Go e no s Regene a i e Medicine Ins i u e, Ceda s-
Sinai Medical Cen e , Los Angeles, CA 90048, USA
6 Facul y o Heal h Sciences, Al onso X el Sabio Uni e si y,
Villanue a de la Cañada 28691, Spain
7 Depa men o Pha macology, Facul y o Pha macy,
Uni e si y o Se ille, Se ille 41012, Spain
8 CIBER Physiopa hology o Obesi y and Nu i ion
(CIBERobn), Co doba 14004, Spain
Abs ac
The p os a e gland is an endoc ine-sensi i e o gan esponding o mul iple s imuli. I s de elopmen and unc ion a e
egula ed by mul iple ho mones (i.e. s e oids such as and ogens, es ogens and glucoco icoids) bu also by o he key
ho monal sys ems such as hose comp ised by insulin-like g ow h ac o  1 and insulin, which a e sou ced by di e en 
issues [e.g. es icles/ad enal-gland/adipose- issue/li e /panc eas, e c.). Pa icula ly impo an o he endoc ine con ol
o p os a icpa hophysiologyandana omya eho monesp oducedand/o sec e edbydi e en cell ypeso  hepi ui a y
gland [g ow h-ho mone, lu einizing-ho mone, ollicle-s imula ing ho mone, and p olac in, oxy ocin, a ginine- asop essin
andmelanocy e-s imula ingho mone],whicha ec p os a egland unc ionei he di ec lyo indi ec lyunde physiological
and pa hophysiological condi ions [e.g. me abolic dys egula ion (e.g. obesi y), and p os a e ans o ma ions (e.g. p os a e
cance )]. This e iew summa izes he impac o all pi ui a y ho mone ypes on p os a e gland unde hese di e se condi-
ions including in i o and in i o s udies.
Keywo ds P os a e · Pi ui a y · Ho mones · Endoc ine egula ion · P os a e cance · Obesi y
Accep ed: 27 Janua y 2025 / Published online: 6 Feb ua y 2025
© The Au ho (s) 2025
F om pi ui a y cells o p os a e gland in heal h and disease: di ec and
indi ec endoc ine connec ions
And éSa men o-Cab al1,2,3 · An onio C.Fuen es-Fayos1,2,4,5 · Fe nando Ma aO doñez1,2,3,6 ·
An onio J.León-González1,2,3,7 · An onio J.Ma ínez-Fuen es1,2,3,8 · Manuel D.Gahe e1,2,3,8 ·
Raúl M.Luque1,2,3,8
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Re iews in Endoc ine and Me abolic Diso de s (2025) 26:187–203
MCR2 Melanoco in Recep o 2
MCR3 Melanoco in Recep o 3
MCR4 Melanoco in Recep o 4
MCR5 Melanoco in Recep o 5
MSH Melanocy e-S imula ing Ho mone
OXT Oxy ocin
OXTR Oxy ocin Recep o
PCa P os a e Cance
PRL P olac in
PRLR P olac in Recep o
STAT5 Signal T ansduce and Ac i a o o T ansc ip-
ion 5
T3 T iiodo hy onine
T4 Thy oxine
TSH Thy oid S imula ing Ho mone
TSHR Thy oid S imula ing Ho mone Recep o
1 In oduc ion
The endoc ine sys em is comp ised by mul iple glands
and o gans ha p oduce and sec e e a wide a ie y o
egula o y ho mones (Fig. 1), which play a c i ical ole in
egula ing whole-body homeos asis and con olling he
de elopmen and main enance o almos all issues and
o gansin hebody.Speci ically, hemos  ele an endoc ine
o gans a e he hypo halamus [ ha p oduces among o he s,
hy o opin- eleasing ho mone, dopamine, g ow h ho mone
(GH)- eleasing ho mone (GHRH), soma os a in, gonado o-
pin- eleasing ho mone (GnRH), and co ico opin- eleasing
ho mone [1]], he pineal gland [ ha p oduces mela onin
[2]], he hy oid gland [ ha p oduces iiodo hy onine, hy-
oxine, calci onin [3]], he panc eas [ ha p oduces insulin,
glucagon, soma os a in, gh elin, panc ea ic polypep ide,
e c [4]], he ad enal glands [ ha p oduces glucoco icoids,
mine aloco icoids, and ogens, ad enaline, no ad enaline,
dopamine, e c [5]], he li e [insulin-like g ow h ac o 1
(IGF1), Vi amin D and Angio ensinogen, e c [6]], he adi-
pose issue [ ha p oduces es ogens, mul iple adipokines
(e.g. lep in, adiponec in, esis in, e c.), e c [7]], he s omach
[ ha sec e es soma os a in, gh elin, e c [8]] o he gonads
[ ha sec e e and ogens, es ogens, e c [9]].
Howe e , among all endoc ine issues, he pi ui a y gland
is conside ed as he “mas e gland” since i p oduces and
sec e es a se ies o key ho mones ha con ol he homeo-
s asis and ho monal p oduc ion o mos endoc ine o gans
and issues [Fig. 2; i.e. GH, ad enoco ico opic ho mone
(ACTH), lu einizing ho mone (LH), ollicle-s imula ing
ho mone (FSH), p olac in (PRL), hy oid s imula ing ho -
mone (TSH), melanocy e-s imula ing ho mone (MSH),
oxy ocin (OXT), and a ginine asop essin (AVP) [10]].
2 The pi ui a y gland
The pi ui a y gland is a undamen al egula o o a ple ho a
o ele an physiological unc ions such as g ow h, ep o-
duc ion, pube y, lac a ion, me abolism, s ess esponse,
whole-body endoc ine homeos asis, e c. This gland is
loca ed in a dep ession in he sphenoid bone, he sella u -
cica, a he base o he b ain, and is comp ised o he adeno-
hypophysis (also known as an e io pi ui a y, which consis s
o he an e io lobe and in e media e, o pa s in e media)
and he neu ohypophysis (pos e io lobe, o pos e io pi u-
i a y). An e io and pos e io pi ui a y lobes a e wo dis inc
s uc u es om he mo phological and unc ional poin o
iew, bu exhibi a s ong de elopmen al and unc ional
in e play [11] (Fig. 2).
The pos e io pi ui a y gland is esponsible o s o ing
and eleasing ho mones p oduced by he hypo halamus
[i.e. AVP, wi h ac ions on kidneys; and OXT, esponsible
o con ac ions o he u e us du ing labo ] (Fig. 2). On
heo he hand, hean e io pi ui a ycoun swi h i edi -
e en cell ypes esponsible o he syn hesis and elease
o se en undamen al ho mones, in ol ed in he de elop-
men and homeos asis o mul iple issues/o gans as well as
in he egula ion o he ple ho a o ele an physiological
unc ions (Fig. 2).Speci ically:(i)soma o opecellssyn he-
size and sec e GH, essen ial o soma ic g ow h and issue
de elopmen , among o he me abolic unc ions; (ii) gonad-
o ope cells a e esponsible o he syn hesis and elease
o FSH and LH, impo an ho mones o he egula ion o
he ep oduc i e unc ion and he p ope p os a e unc ion;
(iii) lac o oph cells syn hesize and sec e PRL, essen ial o
mamma y gland de elopmen and milk p oduc ion du ing
b eas eeding; (i ) co ico ope cells a e he main espon-
sible o he p oduc ion and elease o ACTH and MSH ( he
las one also sec e ed by he pa s in e media o he pi ui a y
gland), which a e c ucial o he egula ion o ad enal gland
unc ion and skin da kness, espec i ely; and, ( ) inally,
hy o ope cells syn hesize and sec e TSH, esponsible o
he p ope unc ioning o he hy oid [ex ensi ely e iewed
in [12, 13]].
To inely egula e hep oduc ionandsec e iono  hese
ho mones and o app op ia ely exe all hese unc ions, he
pi ui a y gland ecei es, p ocesses and in eg a es bo h cen-
al (mainly hypo halamic) and pe iphe al signals p oduced
and sec e ed by nume ous issues and o gans [10, 14]. These
cen al and pe iphe al egula o s signal h ough speci ic
ecep o s on he pi ui a y gland, which comp ehensi ely
con eys his in o ma ion o app op ia ely con ol he unc-
ion o mul iple key a ge o gans [ex ensi ely e iewed in
[12, 14–18]], including he p os a e gland.
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3 P os a e gland as a componen o he
endoc ine sys em
The p os a e is an o al-shaped gland loca ed be ween he
bladde and he penis and wi h he size o a walnu (app oxi-
ma ely 4 cm wide and 3 cm hick), which is pa o he male
ep oduc i e sys em. This gland is esponsible o he p o-
duc ion and sec e ion in o he u e h a, du ing ejacula ion, o
a luid ha nou ishesandp o ec s hespe m[19, 20].
In he endoc ine con ex , he p os a e has been classi-
cally conside ed an exoc ine gland ha depends on o he
ho mones (i.e. s e oids) o main ain i s size and no mal
sec e o y unc ion. Howe e , i is becoming e iden ha he
p os a e can also ac as an endoc ine, pa ac ine, and au o-
c ine o gan p oducing a a ie y o egula o y ac o s (i.e.
ho monessuchasand ogensandes ogens) ha canin lu-
ence he g ow h and unc ion o he p os a e i sel , bu also
o o he o gans [21, 22].
In ac , p os a e gland de elopmen and unc ion a e eg-
ula ed by mul iple ho mones [i.e. s e oids ho mones such as
and ogens, es ogens and glucoco icoids [19–21, 23, 24]]
p oducedbydi e en  issues[e.g. es icles,ad enalgland,
Fig. 1 Main endoc ine sys em comp ised by glands and o gans, which
p oduce and/o sec e e a wide a ie y o ho mones. ACTH - Ad e-
noco ico opic Ho mone; ADR - Ad enalin; As - And ogens, AVP -
A ginine Vasop essin; CRH - Co ico opin Releasing Ho mone; DA
- Dopamine; FSH - Follicle S imula ing Ho mone; GCs - Glucoco i-
coids; GH -G ow h Ho mone; GHRH - G ow h Ho mone Releasing
Ho mone; GHRL - Gh elin; GLUC - Glucagon; GnRH - Gonado opin
Releasing Ho mone; IGF1 - Insulin-Like G ow h Fac o 1; IGFBPs
- Insulin-Like G ow h Fac o Biding P o eins; INS - Insulin; LH -
Lu einizing Ho mone; MCs - Mine aloco icoids; MSH - Melanocy e
S imula ing Ho mone; NA - No ad enaline; OXT - Oxy ocin; PRL -
P olac in; SST - Soma os a in; T3 - T iiodo hy onine; T4 - Thy ox-
ine; TRH - Thy o opin Releasing Ho mone; TSH - Thy oid S imula -
ingHo mone.This igu ewasc ea edwi hBioRende .comandwi h
Mic oso Powe Poin 365
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Re iews in Endoc ine and Me abolic Diso de s (2025) 26:187–203
es ogens, and glucoco icoids exe hei ac ions a he
p os a e le el ia binding hei cogna e nuclea ecep o s
(AR, ER and GR, espec i ely), hus egula ing p os a e
unc ion [29–32]. Hence, al hough he physiological ole
o glucoco icoids as egula o s o p os a ic biology is s ill
unclea [33], he ac ions o and ogens (mainly p oduced by
he es icles) and es ogens (mainly p oduced in he adipose
issue) a e c ucial o p os a e de elopmen , g ow h, and
unc ion [Fig. 3 [20, 34, 35]].
Howe e , no el in o ma ion om bo h human p os a ic
pa hologies and animal models indica es ha he endo-
c ine con ol o p os a ic pa hophysiology is no as simple
and s aigh o wa d as o iginally en isioned and migh
in ol e a wide a ie y o ac o s p oduced by o he endo-
c ine o gans (e.g. adipose issue, li e , panc eas, e c.) such
asinsulin,IGF1,di e en adipokinesandmic oRNAs,and
adipose issue, e c [25, 26]; Fig. 3]. In his ega d, and o-
gens a e classically conside ed o be he mos impo an
ho mones con olling p os a e gland homeos asis, de elop-
men , and unc ion. The con ol o and ogens p oduc ion is
highly complex since i is he esul o a c oss alk be ween
he hypo halamus, he pi ui a y gland, and he es icles
( esponsible o he p oduc ion o 95% o he es os e -
one) [25, 27], bu also wi h he pa icipa ion o he ad enal
glands, which, besides being he main sou ce o glucoco -
icoids, also p oduce addi ional and ogenic ho mones as
and os enedione and dehyd oepiand os e one [26]. In his
sense, he majo i y o es ogens p esen in men a e de i ed
om he pe iphe al con e sion, mainly in he adipose is-
sue, o and os enedione and es os e one o es one and
es adiol [28], howe e , es ogens ha e been also epo ed
o be p oduced in he es icles [29]. As a esul , and ogens,
Fig. 2 Rep esen a i e model summa izing ana omy o pi ui a y gland
andmain(well-known)whole-bodyac ionso  hedi e en ho mones
syn he ized and/o sec e ed by he an e io and pos e io pi ui a y
gland. ACTH - Ad enoco ico opic Ho mone; AVP - A ginine Vaso-
p essin; FSH - Follicle S imula ing Ho mone; GH -G ow h Ho mone;
LH - Lu einizing Ho mone; MSH - Melanocy e S imula ing Ho -
mone; OXT - Oxy ocin; PRL - P olac in; TSH - Thy oid S imula -
ingHo mone.This igu ewasgene a edusingSe ie MedicalA ,
p o ided by Se ie , licensed unde a C ea i e Commons A ibu ion
3.0 unpo ed license, wi h BioRende .com, and wi h Mic oso Pow-
e Poin 365
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Re iews in Endoc ine and Me abolic Diso de s (2025) 26:187–203
Al hough his ho monal he apy is especially e ec i e
when combined wi h adical he apeu ic app oaches such as
adio he apy, app oxima ely 20% o he pa ien s unde his
he apy will e en ually de elop esis ance, p og essing o
a pheno ype known as cas a ion esis ance p os a e cance
(CRPC) [45–47], wi h limi ed he apeu ic op ions.
The main accep ed isk ac o s con ibu ing o PCa a e
olde age, e hnic o igin, and gene ic p edisposi ion [44, 48,
49]; howe e , ho monal changes and endoc ine dis up o s
[36, 44, 50–54], as well as oxida i e s ess, die and obesi y
[37, 55, 56], ha e also been associa ed wi h PCa isk and
agg essi eness. This ple ho a o isk ac o s and molecula
al e a ions associa ed wi h PCa de elopmen may be ela ed
o he high in a- umo al complexi y and he e ogenei y
obse ed in PCa [57].
None heless, as p e iously men ioned, he iden i ica-
ion o a g owing numbe o cen al and pe iphe al p os a e
gland egula o s suppo s he iew ha he con ol o p os-
a e unc ion is mo e complex han o iginally en isioned. In
his scena io, and as will be desc ibed below, he e is g ow-
ing e idence indica ing ha mos o he pi ui a y ho mones,
sec e edby hedi e en pi ui a ycell ypes,candi ec lyand
indi ec lyin luence hep os a eglandhomeos asis.
pa icula ly om he pi ui a y gland, which also is a sou ce
o impo an di ec o indi ec egula o s o he unc ion o
p os a ic cells unde bo h physiological and pa hological
condi ions [19–21, 23, 24, 36–41].
4 Unde s anding p os a e changes and
condi ions
The p os a e gland is abou he size and shape o a walnu
bu , p os a e enla gemen is a e y common condi ion asso-
cia edwi hagingwhichcanbeaccompaniedbydi e en 
p os a e gland diso de s [42]. In ac , p os a e diso de s a e
common, pa icula ly in men aged o e 50, and include
in lamma ion(p os a i is),enla gedp os a e[benignp os-
a ic hype plasia (BPH)], and p os a e cance (PCa). Despi e
p os a i is and BPH a e non- umo al pa hologies, hese con-
di ions a e associa ed wi h an inc eased isk o de elop PCa
[43], being his umo al pa hology he second mos common
cance among male popula ion wo ldwide [44]. In ac , PCa
is highly dependen on and ogen signaling, being and ogen
dep i a ion he apy he main pha macological app oach
o ea ing PCa, inhibi ing sys emic and ogen p oduc ion.
Fig. 3 Di ec egula ion o p os a e gland cells by ho mones p oduced
a he es icles ( es os e one), adipose issue (es ogens) and he ad e-
nal gland (Glucoco icoids). AR - And ogen Recep o ; ER - Es ogen
Recep o ;GR-Glucoco icoidRecep o s.This igu ewasc ea edwi h
BioRende .com and wi h Mic oso Powe Poin 365
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Re iews in Endoc ine and Me abolic Diso de s (2025) 26:187–203
6 Oxy ocin
OXT is p oduced by he hypo halamus and eleased by he
pos e io pi ui a y gland [12]. Classically associa ed wi h
u e us con ac ion and milk ejec ion, his ho mone has also
impo an ac ions on o he o gans h ough he ac i a ion o
i sspeci ic ecep o (OXTR)[58]. In ac , i has been docu-
men ed ha OXT ac s on se e al male ep oduc i e sys em
issues [58]. A he p os a e le el, a conside able amoun o
OXT mRNA has been de ec ed [59]. In line wi h his, some
epo s ha e indica ed ha OXT could be impo an in he
ejacula ion p ocess helping he con ac ion and one o he
p os a e gland [60, 61].Mo eo e ,di e en  OXTan ago-
nis s ha e ecen ly been shown o educe p os a e con ac il-
i y, which could be impo an o he p ema u e ejacula ion
condi ion and o educe in olun a y con ac ions ha may
causedi icul iesinu ina ing[61–64] (Fig. 4).
No ably, some s udies ha e shown inc eased le els o
OXT in plasma o PCa pa ien s compa ed o con ols wi hou
PCa [65], which migh be in ol ed in a o ing he p oduc-
ion o es os e one and i s con e sion o dihyd o es os e one
5 Pi ui a y con ol o p os a e gland unde
physiological and pa hological condi ions
Asmen ionedabo e, hepi ui a ygland inelycon ols he
physiologyo di e en  issues h ough hesec e iono mul-
iple ho mones, specially OXT and AVP om he pos e io
pi ui a y gland, and GH, FSH, LH, PRL,ACTH, MSH-α
andTSH,p oducedandsec e ed omdi e en cell ypeso 
he an e io pi ui a y gland. These ho mones exe a di ec
ac ionac i a ing hei speci ic ecep o sin he a ge  issues
o mayalsop esen indi ec e ec s h ough hemodula ion
o o he endoc ine sys ems. This is he case o p os a e gland
whe eindi e en pi ui a yho mones(OXT,AVP,LH,FSH,
PRL, GH, ACTH, MSH and TSH) can exe di ec (Fig. 4)
o indi ec (Fig. 5) ac ions as summa ized below.
Fig. 4 Summa y o  he DIRECT ac ions o  di e en  pi ui a y ho -
mones on p os a e gland. ACTH - Ad enoco ico opic Ho mone;
AVP - A ginine Vasop essin; AVPR - A ginine Vasop essin Recep o ;
FSH - Follicle S imula ing Ho mone; FSHR - Follicle S imula ing
Ho mone Recep o ; GH - G ow h Ho mone; GHR - G ow h Ho mone
Recep o ; LH - Lu einizing Ho mone; LHR - Lu einizing Ho mone
Recep o ; MC2R - Melanoco in Recep o 2; MSH - Melanocy e
S imula ing Ho mone; OXT - Oxy ocin; OXTR - Oxy ocin Recep o ;
PRL - P olac in; PRLR - P olac in Recep o ; TSH - Thy oid S imula -
ing Ho mone; TSHR - Thy oid S imula ing Ho mone Recep o . BPH
-BenigneP os a eHype plasia;PCa-P os a ecance .This igu ewas
c ea ed wi h BioRende .com and wi h Mic oso Powe Poin 365. *
Cell line dependen , **Cell line dependen , con adic o y esul s
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7 A ginine asop essin
AVP, also known as an idiu e ic ho mone, is mainly p o-
duced by he hypo halamus and s o ed in he pos e io pi u-
i a y gland. The ac ions o his ho mone a e media ed by
h eespeci ic ecep o s[i.e.AVPR1A,AVPR1BandAVPR2
[73]], which a e exp essed in se e al issues. Besides he
well-known e ec s o  AVP on blood p essu e and wa e 
eabso p ion in he kidneys, i has also been shown o
impac many o he mechanisms, including he modula ion
o painpe cep ion,in lamma ionandcellp oli e a ion,and
also in me abolism and diabe es, [ex ensi ely e iewed in
[73]]. Howe e , wi h he excep ion o he con ac ile unc-
ion [74] (Fig. 4), li le is known abou AVP ac ions on no -
mal p os a e unc ion.
The exp ession o conside able amoun s o AVPR1A
mRNA has been ecen ly epo ed in di e en  PCa cell
lines [75]. Speci ically, exp ession o  AVPR1A has been
de ec ed in 22R 1, CWR-R1, C4-2B, and LNCaP-abl, bu
no in PC-3, DU145, LNCaP, no in no mal p os a e-de i ed
cells RWPE-1. Mo eo e , he knocking-ou o his ecep-
o esul ed in dec eased p oli e a ion in cas a ion esis an
p os a e cance cell lines 22R 1, CWR-R1, C4-2B, and
LNCaP-abl, while o e exp ession o AVPR1A in LNCaP
(DHT) [60]. Thus, OXT could indi ec ly sensi ize p os a e
glandcells oand ogenssinceDHThashighe a ini y o 
AR han es os e one [30], pa icula ly in i o his phenom-
enon was obse ed in LNCaP cells bu no in PC-3 PCa cells
[66]. Mo eo e , i has been shown ha DHT and es ogens
inc eased he OXT le els in p ima y BPH cell cul u es p o-
mo ing a posi i e eedback [67] (Fig. 5). O no e, immuno-
his ochemis y s udies in BPH issues [68] and PCa samples
[65] showed an inc eased exp ession o OXTR compa ed
o no mal p os a e issues. In his con ex , i has been sug-
ges ed ha OXT could ha e an impo an ole in p os a e
gland g ow h and BPH de elopmen [69]. In ac , in i o
s udies ha e shown ha OXT ea men inc eased he p o-
li e a ion a e o non- umo al human p os a e cell lines
(RWPE and WPMY) [68, 70]. Acco dingly, mice ea ed
wi h OXT showed an enla gemen o p os a e gland when
compa ed o non- ea ed con ol mice [70]. Con o e sially,
ano he s udy epo ednoe ec so OXTonno malhuman
p os a e epi helial cells [70]. Rega ding umo al beha io ,
ea men wi h OXT in i o has been shown o inc ease he
p oli e a ion o LNCaP cells and dec eased he apop osis
a es in bo h LNCaP and PC-3 PCa cells [65, 71]. Mo eo e ,
OXT p omo ed PC-3 cell mig a ion, bu did no impac his
pa ame e on DU145 PCa cells [72] (Fig. 4).
Fig. 5 Summa yo  heINDIRECTac ionso di e en pi ui a yho -
mones on p os a e gland. ACTH - Ad enoco ico opic Ho mone; AR -
And ogen Recep o ; BPH - Benign p os a ic hype plasia; DHT - Dihy-
d o es os e one; FSH - Follicle S imula ing Ho mone; GH -G ow h
Ho mone; IGF1 - Insulin-Like G ow h Fac o 1; IGF1R - Insulin-Like
G ow h Fac o 1 Recep o ; LH - Lu einizing Ho mone; OXT - Oxy o-
cin; PRL - P olac in; T - Tes os e one; T3 - T iiodo hy onine; T4 - Thy-
oxine; TRs - Thy oid Ho mone Recep o s; TSH - Thy oid S imula ing
Ho mone; BPH - Benigne P os a e Hype plasia; PCa - P os a e cance .
This igu ewasc ea edwi hBioRende .comandwi hMic oso Pow-
e Poin 365. *cell line dependen
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As ecen ly e iewed, LH and FSH ha e been associa ed
wi h PCa [81]. Speci ically, FSH was shown o s imula e
p oli e a ion in BPH p ima y cell cul u es [80], being FSHR
o e exp essed in PCa compa ed o BPH [81]. In addi ion,
se um FSH le els we e posi i ely associa ed wi h ex a-
p os a ic umo de elopmen [82]. In he same line, a s udy
p oposed ha exogenous FSH adminis a ion could inc ease
xenog a umo s o and ogen-independen human PC-3
PCa cells [in cas a ed mice wi h endogenous FSH supp es-
sion (dega elix- ea ed, a GnRH an agonis ) o in cas a ed
mice], and in and ogen-independen human p os a e can-
ce cells DU-145 (in dega elix ea ed mice) [83]. On he
o he hand, high baseline LH plasma le els we e associa ed
wi h wo se PCa p ognosis [84]. Indeed, LH was capable
o s imula e p oli e a ion and main ain and ogen ecep-
o exp ession in LNCaP and 22RV1 cells [85]. Fu he -
mo e, ea men wi h LH s imula ed and ogen p oduc ion
in LNCaP cells [85], and highe ci cula ing le els o LH
inhumanswe eassocia edwi hinc easedP os a eSpeci ic
An igen (PSA) le els and a wo se p ognosis [84] (Fig. 4).
The e o e,despi e hewell-knownindi ec e ec o LH
and FSH on p os a e gland ia and ogens, limi ed bu solid
e idenceisa ailablesuppo ingadi ec e ec o  hese wo
pi ui a y ho mones on no mal o umo al p os a e gland
cells.
9 PRL
PRL, sec e ed by lac o ope cells, is a well-known key playe
in lac a ion and mamma y gland physiology in emales.
Addi ionally, PRL also pa icipa es in he no mal de elop-
men , g ow h and unc ion o he p os a e gland [86]. In ac ,
he disco e y ha human p os a e exp esses PRL- ecep o
(PRLR; a non-kinase single-pass ansmemb ane ecep o )
demons a es ha his o gan migh be a di ec a ge o PRL
[87]. Fu he mo e, PRL exp ession has also been demon-
s a ed in he p os a e i sel , sugges ing ha his ho mone
migh addi ionally ac as a local g ow h ac o ia an au o-
c ine o pa ac ine mechanism, dis inc om i s classical
endoc ine pa h [87]. Mo eo e , i has been demons a ed
ha PRL ea men di ec ly s imula es cell p oli e a ion in
no mal p os a e explan s o gan cul u es [87], and inhibi s
apop osis o p os a e epi helial cells in a s [88]. In e es -
ingly,micewi ho e exp essiono  a PRL,speci icallyon
p os a e gland (Pb-PRL mice), showed an enla gemen o
his gland, compa able o a BPH s a e [89, 90], suppo ing
he au oc ine impo ance o PRL in p os a e (pa ho)physi-
ology. Complemen a ily, he Pb-PRL ansgenic mice wi h
ubiqui ous exp ession o  PRL (Pb-PRL and Me -Δ1–9-
G129R-hPRL double ansgenic mouse model) p esen ed a
educ ion in STAT5 ac i a ion and cell p oli e a ion when
cells esul ed in inc eased p oli e a ion (in absence o and o-
gen) and inc eased subcu aneous xenog a umo g ow h
in cas a ed mice. Fu he mo e, in i o ea men wi h an
AVPR1Aan agonis (Relco ap an) esul ede ec i ein he
con ol o o ho opic and subcu aneous xenog a umo s
g ow h a e mice cas a ion, sugges ing ha he s imula ion
o his ecep o p omo es umo g ow h in cas a ion esis-
an PCa [75] (Fig. 4).
On he o he side, he AVPR2 ecep o is also exp essed
in PCa cells. Indeed, agonis s o his ecep o ha e been
shown o educe p oli e a ion, doubling ime and mig a ion
o PC-3cells,indica ingapo en ialan i umo ale ec o  he
ac i a ion o his ecep o [76]. Ano he s udy suppo ed
he same esul s showing ha desmop essin ea men ,
a syn he ic analog o AVP ha binds o AVPR2, blocked
p oli e a ion in PC-3 and LNCaP cells, bu only impac ed
he mig a ion and in asion capaci y o PC-3 cells, and p e-
en ed umo g ow h in PC-3 xenog a s [77] (Fig. 4).
The e o e,AVPseems o a o di e en  umo albeha -
io s depending on he ac i a ed ecep o . O e all, hese
da a could sugges an oncogenic ole o he ac i a ion o
AVPR1A,whe easanan i- umo ale ec isobse edwhen
AVPR2 is ac i a ed, and he exp ession a io o hese ecep-
o s may help o p edic he e olu ions o PCa. Con a y, a
ecen s udy p esen ed con adic o y esul s since showed
ha desmop essin could inc ease LNCaP, C4-2B and 22R 1
cell p oli e a ion, and he inhibi ion o AVPR2 (wi h Tol ap-
an) and AVPR1A (wi h Relco ap an), alone o combined,
we e able o educe C4-2B xenog a umo s in mice [78]
(Fig. 4).
8 LH/FSH
I is widely accep ed ha he endoc ine con ol o male
ep oduc i e sys em (i.e. es icles, p os a e, e c.) is p ima -
ily egula ed by he neu oendoc ine ac i i y o he hypo-
halamic-pi ui a y axis [17].Speci ically,LHandFSHa e
sec e ed in a pulsa ile ashion and media e hei ac ions a
he le el o he es icles (i.e. p oduc ion and sec e ion o
es os e one) ia speci ic ansmemb ane ecep o s [LHR
(p edominan ly exp essed in he in e s i ial Leydig cells)
and FSHR (p edominan ly exp essed in he Se oli cells
wi hin he semini e ous co ds/ ubules), espec i ely]. Mo e-
o e , al hough es os e one p oduced om he es icles, in
esponse o LH signaling, is one o he majo egula o s o
p os a e unc ion [79] (Fig. 5), i has also been desc ibed
ha LHR and FSHR a e also exp essed a he p os a e gland
le el [80], sugges ing ha bo h pi ui a y ho mones migh
also ac di ec ly on he p os a e gland, ac ing locally as ho -
mones and g ow h ac o s.
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apop osis, egula ed he exp ession o cance - ela ed genes
in PTEN-P2, PTEN-CaP2, PTEN-P8, and PTEN-CaP8 cells
[106], and inc eased LNCaP cells mig a ion and in asion
capaci y [107] (Fig. 4).
In addi ion, GH was no only shown o be essen ial o
p os a e gland homeos asis, egula ing i s de elopmen [39,
40], bu also o he local exp ession o IGF1 and i s ecep-
o (IGF1R) [94, 104, 108]. In his line, GH/IGF1 axis ac s
as an impo an egula o y sys em in p os a e diso de s and
PCa de elopmen [37, 109–111]. In his sense, sys emic and
locally p oduced IGF1 can play an impo an ole in p os a e
gland unc ion egula ingcellp oli e a ion,di e en ia ion
and also apop osis [37, 41, 106, 112], ac ing as a pa ac ine
and/o  au oc ine ac o . In ac , p os a e gland and di e -
en PCa cell lines exp ess bo h GHR and IGF1R [37]. In
ac , IGF1 ea men was able o inc ease he p oli e a ion
in PC-3 and LNCaP cells and he mig a ion a e in PC-3
cells [37] (Fig. 5). In e es ingly enough, ac omegaly in male
pa ien s, a disease cha ac e ized by hype sec e ion o GH
by he pi ui a y gland and as consequence inc eased plasma
IGF1 le els, was associa ed wi h a 33% inc eased isk o he
diagnosis o PCa [113] oge he wi h heincidenceo di e -
en p os a e condi ions [ e iewed in [103]].
O no e, human GH also has he capaci y o ac i a e
PRLR [114], which signals h ough STAT5, sugges ing ha
bo h GH and PRL could ha e a common pa icipa ion in
PCa de elopmen [88]. In e es ingly, i was ound ha GH
ea men s imula ed AR syn hesis a he p os a e le el, indi-
ca ing ha GH migh ac on his gland by po en ia ing he
e ec so and ogens[94] (Fig. 5). On he o he way a ound,
and ogens ha e been also shown o modula e GH syn he-
sis and sec e ion in soma o oph cells [115], sugges ing he
exis ence o egula o y loop be ween he gonads and he
soma o oph cells.
11 ACTH and MSH
ACTH and MSH, sec e ed by co ico ope cells, a e essen-
ial o he ad enal gland unc ion and skin da kness, espec-
i ely [ e iewed in [12, 13]]. Al hough ACTH and MSH
exe di e en  oles,bo hho monesa egene a ed om he
same mRNA ansc ip  (p oopiomelanoco in), su e ing
pos - ansla ional p ocessing gene a ing ACTH, α-MSH,
β-MSHandγ-MSH(beingα-MSH hemos  ele an among
MSH p oduc s). These ho mones exe hei unc ion ac i-
a ing hemelanoco in ecep o s(MCRs1-5)wi hdi e en 
a ini ies.Speci ically,ACTHbinds oMC1RandMC2R,
whe eas MSH binds o MC-1R, -3R, -4R and −5R [13].
Despi e he well-known oles o hese ho mones, he e a e
limi ed and/o inconclusi e s udies add essing he ole o
ACTH and MSH on p os a e gland unc ion. Indeed, o he
compa ed wi h he p os a e glands om Pb-PRL mice [90].
In ac , a po en ial p ooncogenic ole PRL in 22R 1 and
VCaP PCa cells has been sugges ed in i o [91], indica ing
a pu a i e connec ion be ween p os a e umo igenesis and
excessi e local PRL p oduc ion. In his sense, i has been
shown ha  hean iapop o icandp oli e a i ee ec so PRL
in PCa cells migh be ei he di ec (STAT5-media ed) [91,
92] (Fig. 4) o indi ec [93] (Fig. 5), implying PRL-induced
exp ession o ecep o s o g ow h ac o s such as IGF1R
o AR [94]. Howe e , hese e ec s seem o be cell-line
dependen since PRL induced apop osis in LNCaP cells bu
hadnoe ec sonPC3cells[95].Ne e heless, hee ec s
o PRL a he p os a e gland le el may be a he au oc ine
han pa ac ine since nei he he PRL le els in plasma a e
no inc eased in PCa no he PRLR is o e exp essed in PCa
samples compa ed o non- umo al samples [86]. Despi e
heabsenceo di e enceso PRL(inplasma)o PRLR(in
issue) be ween PCa pa ien s and heal hy subjec s, i was
ecen ly epo ed ha me as a ic CRPC pa ien s wi h low
PRL plasma le els had a be e esponse o abi a e one ea -
men when compa ed o pa ien s wi h high PRL plasma le -
els, sugges ing a p edic i e alue o PRL plasma le els o
he esponse o abi a e one ea men [96].
Cu iously, i has been p oposed ha p os a e gland could
be in ol ed in he egula ion o  se um le els o  di e en 
pi ui a yho mones.Speci ically,subcu aneousadminis a-
ion o p os a e ex ac s was able o es o e PRL and FSH
plasma le els o cas a ed and p os a ec omized a s [97],
which u he sugges s he p esence o a di ec egula o y
eedbackloopbe ween hep os a eanddi e en pi ui a y
cell ypes.
10 GH
GH, sec e ed by he soma o opic cells in a pulsa ile pa -
e n, is a undamen al egula o o a ple ho a o ele an
physiological unc ions such as g ow h, me abolism, whole-
body endoc ine homeos asis, ep oduc ion, e c [98–100].
Mo eo e , GH and IGF1 [mainly sec e ed by he li e in
esponse o GH [101]] sys em ha e been also shown o
exe an impo an egula o y ole in he de elopmen and
homeos asis o p os a e gland unde no mal and pa ho-
physiological condi ions [39, 40, 102, 103] (Figs. 4 and 5).
Pa icula ly, i has been demons a ed ha p os a e glands
and human PCa cell lines (LNCaP, PC-3, MAT-Lu, MAT-
LyLu, and Pi -1) exp ess GH ecep o (GHR) [37, 104].
Mo eo e , he ansc ip ion ac o STAT5, ac i a ed by GH,
has been shown o be up egula ed in PCa p omo ing g ow h
and me as a ic beha io in i o and in i o [ e iewed in
[105]]. Ano he s udy epo ed ha GH could p omo e p o-
li e a ion, while peg isoman (a GH an agonis ) educed
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