MINI REVIEW
published: 24 Sep embe 2019
doi: 10.3389/ endo.2019.00653
F on ie s in Endoc inology | www. on ie sin.o g 1Sep embe 2019 | Volume 10 | A icle 653
Edi ed by:
John Lui Yo ich,
Pi e Medical Cen e , Aus alia
Re iewed by:
Biagio Cangiano,
Uni e si y o Milan, I aly
Nalini Mahajan,
Independen Resea che , India
*Co espondence:
Signe Al mäe
signeal mae@ug .es
Special y sec ion:
This a icle was submi ed o
Rep oduc ion,
a sec ion o he jou nal
F on ie s in Endoc inology
Recei ed: 09 July 2019
Accep ed: 09 Sep embe 2019
Published: 24 Sep embe 2019
Ci a ion:
Al mäe S and Aghajano a L (2019)
G ow h Ho mone and Endome ial
Recep i i y. F on . Endoc inol. 10:653.
doi: 10.3389/ endo.2019.00653
G ow h Ho mone and Endome ial
Recep i i y
Signe Al mäe1,2,3*and Lusine Aghajano a4
1Depa men o Biochemis y and Molecula Biology, Facul y o Sciences, Uni e si y o G anada, G anada, Spain,
2Compe ence Cen e on Heal h Technologies, Ta u, Es onia, 3Ins i u o de In es igación Biosani a ia ibs.GRANADA,
G anada, Spain, 4Di ision o Rep oduc i e Endoc inology and In e ili y, Depa men o Obs e ics and Gynecology, S an o d
School o Medicine, Sunny ale, CA, Uni ed S a es
Adminis a ion o g ow h ho mone (GH) du ing o a ian s imula ion has shown bene icial
e ec s on in i o e iliza ion (IVF) ou comes. I is gene ally belie ed ha his imp o emen
is due o he s imula ing e ec o GH on oocy e quali y. Howe e , s udies a e eme ging
ha show possible posi i e e ec o GH adminis a ion on endome ial ecep i i y,
hus sugges ing an addi ional po en ial bene i a he le el o he u e us, especially
among women wi h ecu en implan a ion ailu e, hin endome ium, and olde no mal
esponde s. This e iew summa izes ecen da a on GH co- ea men e ec s on
endome ium and endome ial ecep i i y among in e ile women unde going IVF, and
p oposes possible mechanisms o GH ac ions in he endome ium.
Keywo ds: endome ium, endome ial ecep i i y, g ow h ho mone, in e ili y, in i o e iliza ion, ansc ip ome
INTRODUCTION
Recep i e endome ium is an absolu e p e equisi e o a success ul emb yo implan a ion, being
de ined by a limi ed ime- ame when he endome ium is a o able o emb yo adhesion and he
subsequen a achmen and in asion p ocesses (1).
Endome ial ecep i i y is a complex p ocess ha is o ches a ed by he syne gis ic ac ions
o main ep oduc i e ho mones es ogen and p oges e one, as well as plead o o he endoc ine,
pa ac ine and au oc ine ac o s (2,3). Impai ed endome ial ecep i i y is hough o be one o he
majo easons o emb yo implan a ion ailu e (4). In assis ed ep oduc i e echnologies (ART),
whe e he good quali y emb yos a e ans e ed as a s anda d o ca e, implan a ion ailu e emains
an unsol ed obs acle (5,6). Rega dless o he ad ances in assis ed ep oduc ion, pa icula ly
ega ding he mo e e ec i e means o emb yo selec ion and c yop ese a ion, many pa ien s
epea edly ail he ea men p ocedu e. Wha we a e acing oday is ha implan a ion ailu e in
ART is common, and we lack he e idence-based he apeu ic solu ions o ea ing i . As a esul ,
clinicians o en eel obliged o o e ea men s ha a e la gely empi ical, based on some biologic
a ionale bu wi h li le clinical e idence o suppo hei use (7,8). The ea men ailu e is equally
us a ing o bo h pa ien s and hei p o ide s, which e en mo e emphasizes he u gen need o
no el e ec i e ea men o p e en ye ano he ailu e.
The ole o g ow h ho mone (GH) in emale ep oduc ion has gained enewed in e es and
has become a hea ed opic o e he las decade. The local GH p oduc ion in he ep oduc i e
issues hemsel es exe an impo an au oc ine/in ac ine e ec s on hose issues, in addi ion o he
pi ui a y p oduc ion o GH (9). Mo eo e , local insulin g ow h ac o 1 (IGF-1) p oduc ion (known
downs eam media o o GH) has been shown o be con olled by gonado opins and es adiol as
well (10). E idence eme ging om clinical p ac ice sugges s ha GH adminis a ion du ing o a ian
s imula ion may imp o e oocy e quali y [highe numbe o oocy es collec ed, highe e iliza ion
Al mäe and Aghajano a GH and he Endome ium
a e, and highe numbe o emb yos eaching he ans e s age
(11–15)], inc ease p egnancy a e (16–24), implan a ion a e (16,
20–23,25,26), and li e bi h a e (12,16,19,20,23,25,27). The
accumula ing bene icial e ec s o GH on assis ed ep oduc ion
ou comes do no exclude he possibili y ha his e ec is due, a
leas in pa , o an ac ion o GH on endome ial ecep i i y.
GROWTH HORMONE IN THE
ENDOMETRIUM
GH is a pep ide ho mone sec e ed by he an e io pi ui a y
gland, ha ing impo an ole in cell g ow h and me abolism
h oughou he body. GH oge he wi h i s ecep o , GHR,
and ela ed g ow h ac o s including IGF-1, is exp essed in
he endome ium o a s and human (28–31). The s udy by
Sb acia e al. ob ained biopsies om women in p oli e a i e
and sec e o y phases, as well as i s imes e decidua ( om
elec i e p egnancy e mina ions) (28). They showed ha he e
was no GH exp ession in p oli e a i e glandula epi helium,
bu GH immuno eac i i y appea ed in he mid-lu eal sec e o y
phase (no subdi ision wi hin sec e o y phase was done) and
inc eased in he decidua om he i s imes e abo ions,
wi h simila exp ession in he decidual samples om he
e m p egnancies, sugges ing a ole in emb yo implan a ion
p ocess. In e es ingly, no s omal exp ession o GH was obse ed
in any sample (28). Mo eo e , he au ho s analyzed GH
exp ession in he endome ium om women wi h “lu eal
phase de ec ,” de ined by low p oges e one le els <8 ng/mL
and delayed endome ial ma u a ion, and saw signi ican ly
lowe exp ession o GH (28). This da a sugges ed close
ela ionship be ween GH exp ession in endome ium and
p oges e one le el/ unc ion. Fu he , a ecen s udy on human
endome ial cell line indica ed ha GH may ac in a di ec
o IGF-1-media ed manne on human endome ial cells o
p omo e p oli e a ion and ascula iza ion and up- egula ion o
ecep i i y- ela ed genes such as ascula endo helial g ow h
ac o (VEGF) and in eg in be a 3 (ITGB3) (21). VEGF is
an impo an playe in angiogenesis (32), and i has been
shown o ac in an au oc ine manne on endome ial epi helial
cell adhesion as a key egula o in he implan a ion p ocess
(33). ITGB3 is a well-known bioma ke o ecep i i y (34),
and down- egula ion o his bioma ke (phenomenon de ec ed
in women wi h unexplained in e ili y, endome iosis, and
lu eal phase de iciency) has been ela ed o lowe p egnancy
a es (35,36).
Apa om he e ec s o ci cula ing GH and locally p oduced
GH on endome ium, he e is a p oposed indi ec e ec o
o a ian GH on endome ial unc ion, namely i s in ol emen
in he unc ion and main enance o he co pus lu eum (37,
38). While he majo i y o he da a come om a ious animal
models, hey a e ne e heless signi ican . Lu eal unc ion and i s
main enance a e i al o he es ablishmen o p egnancy and i s
iabili y due o he p oduc ion o p oges e one by he co pus
lu eum— he main “keepe ” o he no mal ea ly p egnancy.
Hence, he s imula o y e ec o GH on o a ian s e oidogenic
cell unc ion may play a majo ole in endome ial unc ion and
dys unc ion ia i s e ec on o a y (see Figu e 1 o he p oposed
mechanisms o GH ac ion on endome ium).
CLINICAL USE OF GH AND EFFECT ON
THE ENDOMETRIUM
Ini ial epo s on he use o GH in clinical p ac ice
come om cases o hypogonado opic hypogonadism o
panhypopi ui a ism (46). Subsequen ly, he use o GH has been
expanded on di e en pa ien popula ion, such as women wi h
poo o a ian ese e, poo esponde s, o wi h poo oocy e
quali y due o ad anced ma e nal age (25,47,48). In gene al,
GH adminis a ion in he in e ili y clinic se ing has ocused on
GH e ec s on oocy e, and he e ec on endome ium has been
la gely o e looked.
Subsequen ly, he a en ion has been u ned on o he
endome ium, and in e es ing obse a ions ha e been made
sugges ing posi i e e ec o g ow h ho mone ea men on
endome ial hickness and implan a ion po en ial (see Table 1 o
he s udies). A case epo o a pa ien wi h panhypopi ui a ism
demons a ed imp o ed endome ial hickness and success ul
implan a ion and p egnancy a e adding g ow h ho mone o he
ea men p o ocol ollowing mul iple ailed in i o e iliza ion
(IVF)/emb yo ans e cycles (55). Al e na i ely, a s udy on 20
pa ien s wi h documen ed GH de iciency epo ed imp o ed
emb yo quali y, bu no imp o emen in endome ial hickness,
when supplemen ed wi h GH in IVF cycle (15) (Table 1). Below
we will discuss he a ailable li e a u e on he use o GH in a ious
clinical IVF se ings.
In e ile Pa ien s Wi h Recu en
Implan a ion Failu e
This is a g oup o pa ien s ha ail o achie e p egnancy in esh
o ozen emb yo ans e cycles despi e app op ia e endome ial
de elopmen ( hickness and pa e n) and good quali y emb yo
ans e ed. Pa ien s wi h ecu en implan a ion ailu e (RIF),
ha ing unde gone h ee o mo e emb yo ans e cycles a e
IVF ea men wi hou a clinical p egnancy, a e among he mos
di icul pa ien s o ea , wi h no p o en s anda d ea men .
Impai ed endome ial ma u a ion is sugges ed as a common
cause o RIF (56–58), making i a a ge pa ien g oup who
could po en ially bene i om GH co-adminis a ion du ing IVF
p ocedu e. Chen e al. s udy on 42 RIF pa ien s unde going IVF
ea men ound ha GH ea men h oughou he s imula ion
inc eased he endome ial hickness and consequen p egnancy
and li e bi h a es among young pa ien s <35 yea s old
supplemen ed wi h GH when compa ed o no GH RIF g oup
(19). Pa ien s in bo h g oups had simila peak es adiol le els
and simila numbe o oocy es e ie ed (19). While i is unclea
i he di e ence in endome ial hickness o 11.61 ±2.9 s.
9.7 ±1.46 mm be ween s udy and con ol g oups, espec i ely
was c ucial in achie ing highe p egnancy a es in he s udy
g oup, he obse a ion is ne e heless impo an . This has been
epo ed again in he second s udy, a andomized clinical ial
including 70 RIF pa ien s in oocy e dona ion p og am (as an ideal
model o assessing GH e ec on pa ien ’s endome ium wi hou
F on ie s in Endoc inology | www. on ie sin.o g 2Sep embe 2019 | Volume 10 | A icle 653
Al mäe and Aghajano a GH and he Endome ium
FIGURE 1 | Possible mechanisms o GH e ec s on o a ian and endome ial unc ion (A) and on endome ial cells (B). Numbe s in he igu e indica e s udies whe e
he in o ma ion is p esen ed in de ail: 1 (39); 2 (40,41); 3 (42); 4 (23); 5 (21); 6 (43); 7 (44); 8 (45).
con ounding ac o s o o a ian age and esponse) (20). In ha
s udy pa ien s, who we e ea ed wi h GH h oughou medica ed
ozen emb yo ans e cycle demons a ed signi ican ly hicke
endome ium, 9.3 ±1.5 mm s. 8.6 ±1.0 mm, espec i ely, and
highe p egnancy and li e bi h a es compa ed wi h RIF pa ien s
in he placebo g oup (20) (Table 1).
These a e he i s wo s udies assessing GH e ec s on
endome ium in RIF pa ien s, and, al hough he indings a e
p omising, clea ly mo e s udies on la ge pa ien popula ion,
as well as andomized clinical ials (RCTs), a e needed
o any clinically meaning ul conclusions. I is well-accep ed
ha endome ial hickness does no necessa ily mean ha
he endome ium is ecep i e, ye i is conside ed as a
measu e o endome ial ma u i y, and op imal g ow h o he
endome ium (>7 mm) is equi ed o a success ul emb yo
implan a ion (59–61).
F on ie s in Endoc inology | www. on ie sin.o g 3Sep embe 2019 | Volume 10 | A icle 653
Al mäe and Aghajano a GH and he Endome ium
TABLE 1 | S udies assessing he e ec o g ow h ho mone (GH) co- ea men in in i o e iliza ion ( esh ea men cycles and ozen emb yo ans e cycles) on endome ium.
S udy RCT S udy g oup;
E hnici y
GH/con ol
(mean age)
Inclusion c i e ia Exclusion c i e ia In e en ion P ima y ou come E ec on endome ial hickness (mm)
GH Con ol p- alue
FRESH EMBRYO TRANSFER CYCLE
Rajesh e al.
(15)
No In e ile women
wi h GH
de iciency;
Chinese
20/20*
(32.9 y)
*same women
cycle be o e
wi hou GH
se ed
as con ols
GH de iciency based on
clonidine es ; p e ious
IVF cycle wi hou GH;
became p egnan wi h
GH ea ed cycle
Panhypopi ui a ism; GH
de icien pa ien s wi h
p e ious cycle ea ed a
o he hospi al
12 IU GH e e y 3 d day,
s a ing om GnRH
s imula ion day un il hCG
adminis a ion
Imp o ed emb yo
quali y; highe
e iliza ion a e a
ICSI
11.4 ±1.9 10.3 ±1.5 0.108
E ekha e al.
(49)
Yes Poo esponde s;
I anian
40/42
(36.0 ±4.6
y/36.2 ±3.7 y)
p e ious ailed IVF-ET
cycles wi h ≤3 oocy es,
and ≤3 emb yos
ob ained; and/o E2
le els ≤500 pg/mL on
hCG day
BMI ≥30, FSH >15 IU/L,
endoc ine o me abolic
diso de s, and PCOS,
se e e endome iosis
and azoospe mia
GnRH an agonis
p o ocol; + ea men
g oup 4 IU/d GH om
day 21 om p e ious
cycle un il hCG igge ing
Highe numbe o
e ie ed oocy es and
ob ained emb yos,
while no e ec on
implan a ion and
p egnancy a es
8.5 ±1.0 8.1 ±0.9 0.158a
Bayoumi e al.
(50)
Yes Poo esponde s;
Egyp ian
72/73
(34.9 ±4.9
y/34.8 ±5.6 y)
ESHRE consensus
c i e ia 2011 o poo
esponde s
FSH >20 IU/l; p e ious
o a ian su ge y; in e ili y
o he han poo o a ian
esponse; endoc ine
diso de ; male ac o
in e ili y
GnRH agonis (mic o la e)
p o ocol; + ea men
g oup 7.5 IU/d GH om
day 6 o hMG s imula ion
un il day o hCG
igge ing
Highe numbe o
ma u e oocy es and
emb yos ob ained,
while no e ec on
implan a ion and
p egnancy a es
11.9 ±1.6 11.7 ±1.7 0.590a
Dakhly e al.
(51)
Yes Poo esponde s;
Egyp ian
74/74/68/71*
(36.4 ±5.8
y/38.1 ±5.0
y/36.8 ±6.3
y/36.4 ±5.8 y)
*Compa ison o
4 di e en GH
p o ocols, no
con ol g oup
ESHRE consensus
c i e ia 2011 o poo
esponde s
>45 y; FSH >20 IU/l;
p e ious o a ian su ge y;
o he causes o in e ili y
(o he han poo
esponde ); male ac o
o in e ili y
G 1: GnRH long p o ocol;
G 2: GnRH sho
p o ocol; G 3: GnRH
an agonis p o ocol; G 4:
GnRH mini la e p o ocol.
In all g oups 7.5 IU/d GH
om day 6 o hMG
s imula ion un il day o
hCG igge ing
The long/GH (G 1)
p o ocol was supe io
ega ding he numbe
o oocy es e ie ed
and e ilized. No
signi ican di e ences
in p egnancy a es
11.5 ±1.6 (G 1);
11.4 ±1.6 (G 2)
12.1 ±1.4 (G 3);
11.1 ±1.8 (G 4)
NA 0.003a
(G 3 s. G 4)
Bassiouny
e al. (13)
Yes Poo esponde s;
Egyp ian
68/73
(35.8 ±5.6
y/35.5 ±6.0 y)
ESHRE consensus
c i e ia 2011 o poo
esponde s
FSH >20 IU/l; p e ious
o a ian su ge y; in e ili y
o he han poo o a ian
esponse
GnRH an agonis
p o ocol; + ea men
g oup 7.5 IU/d GH om
day 6 o hMG s imula ion
un il day o hCG
igge ing
Highe numbe o
ma u e oocy es and
emb yos ob ained,
while no e ec on
p egnancy a es
12.1 ±1.3 11.6 ±1.6 0.029a
(Con inued)
F on ie s in Endoc inology | www. on ie sin.o g 4Sep embe 2019 | Volume 10 | A icle 653
Al mäe and Aghajano a GH and he Endome ium
TABLE 1 | Con inued
S udy RCT S udy g oup;
E hnici y
GH/con ol
(mean age)
Inclusion c i e ia Exclusion c i e ia In e en ion P ima y ou come E ec on endome ial hickness (mm)
GH Con ol p- alue
Du e al. (16) No No mal
esponde s;
Chinese
556/558
(32.8 ±4.3
y/31.6 ±4.4 y)
(*olde women
≥35 y: 278/265;
**younge
women <35
y: 278/293)
20-45 y; allopian ube
mal unc ion o male
s e ili y; no mal ho mone
le els; no mal u e ine
ca i y; egula mens ual
cycles, BMI <25
Recu en spon aneous
abo ion; se e e pel ic
adhesions o
hyd osalpinx;
ce eb o ascula , li e o
kidney disease;
endoc ine diseases;
PCOS; endome iosis;
u e ine leiomyoma;
adenomyosis
Long GnRH agonis
p o ocol; + ea men
g oup 4.5 IU/d GH o 5
days s a ing om day o
FSH adminis a ion
Highe implan a ion
and clinical
p egnancy a es
12.2 ±4.7
*12.0 ±2.2
**12.5 ±7.0
11.8 ±4.8
*11.6 ±2.5
**12.0 ±6.8
0.18b
*0.038b
**0.50 b
Choe e al.
(52)
Yes In e ile women
wi h diminished
o a ian ese e;
Ko ean
62/65
(39.8 ±3.6
y/39.4 ±4.1 y)
≥40 y o any o he ac o
o poo o a ian
esponse; ≤3 oocy es
wi h con en ional
s imula ion p o ocol;
an al ollicle coun <5–7
o AMH <0.5–1.1 ng/ml;
no mal u e us; egula
mens ual cycle
Gene ic cause o
in e ili y; BMI >30;
abno mal u e ine
bleeding; o a ian umo ;
b eas cance ;
hyd osalpinx;
con aindica ion o GH
ea men
GnRH an agonis
p o ocol; + ea men
g oup sus ained- elease
GH (20 mg) 3×be o e
and du ing COS
(mid-lu eal, la e lu eal,
cycle day 2)
Highe numbe o
ma u e oocy es
ob ained, while no
e ec on p egnancy
a es
8.8 ±2.2 9.1 ±1.9 0.24a
Dakhly e al.
(53)
Yes Poo esponde s;
Egyp ian
120/120
(36.4 ±4.4
y/36.2 ±4.5 y)
ESHRE consensus
c i e ia 2011 o poo
esponde s
>45 y; FSH >20 IU/l;
p e ious o a ian su ge y;
o he causes o in e ili y
(o he han poo
esponde ); male ac o
o in e ili y
GnRH long p o ocol;
+ ea men g oup 7.5
IU/d GH om day 21 o
p e ious cycle un il day
o hCG igge ing
Highe numbe o
oocy es and emb yos
ob ained, while no
e ec on implan a ion
and p egnancy a es
11.8 ±1.3 11.3 ±1.2 <0.001a
Chen e al.
(19)
No Recu en
implan a ion ailu e
(RIF) pa ien s;
Chinese
22/20
(33.9 ±2.9
y/34.0 ±3.4 y)
No mal ho mone le els;
no use o syn he ic
ho mones >3 mon hs
p io o en y
P io endome ial
esec ion o endome ial
polyps; an iphospholipid
synd ome; in ec ious
disease; hype hy oidism;
hype p olac inemia;
ch omosomal
abno mali ies;
halassemia; male ac o s
GnRH; + ea men g oup
4 IU/d GH h ough
s imula ion un il he day
o hCG adminis a ion
Highe clinical
p egnancy and li e
bi h a es
11.6 ±2.9 9.7 ±1.5 0.009a
Liu e al. (24) No No mal
esponde s;
Chinese
781/781 (31.3 ±
3.6 y/31.3 ±3.3
y)
No mal o a ian esponse;
age 20–40 y; poo quali y
emb yos in p e ious
IVF/ICSI; epe i i e esh
o ozen ET wi hou
p egnancy
Poo o high o a ian
esponse; adju an
he apy as DHEA,
CoQ10; se ious and
uns able diseases
(ca dio ascula ,
ce eb o ascula
diseases); ecu en
spon aneous abo ion;
male ac o in e ili y
GH ea men g oup 2
IU/4 IU GH daily since
day 2 o p e ious cycle (6
weeks GH p e ea men )
o day 2 om o a ian
s imula ion un il hCG
igge (2 weeks GH
p e ea men )
Inc eased p egnancy
a e
12.0 ±2.2 11.6 ±2.8 0.036a
(Con inued)
F on ie s in Endoc inology | www. on ie sin.o g 5Sep embe 2019 | Volume 10 | A icle 653

Al mäe and Aghajano a GH and he Endome ium
TABLE 1 | Con inued
S udy RCT S udy g oup;
E hnici y
GH/con ol
(mean age)
Inclusion c i e ia Exclusion c i e ia In e en ion P ima y ou come E ec on endome ial hickness (mm)
GH Con ol p- alue
FROZEN EMBRYO TRANSFER/OOCYTE DONATION PROTOCOL
Wu e al. (43) NA Pa ien s wi h hin
endome ium;
Chinese
32/30
(NA)
NA NA HRT; + ea men g oup
subcu aneous injec ions
o GH
Imp o ed endome ial
blood low and
inc eased
endome ial hickness
8.8 ±1.3 7.1 ±1.9 <0.05
Yu e al. (54) No Pa ien s wi h
pe sis en hin
endome ium;
Chinese
5/5*
(32.2 ±5.5 y)
*same women
se ed as
con ols be o e
en e ing
GH ea men
Regula mens ual cycle;
use o a i icial cycle;
endome ium ≥7 mm; no
abno mali ies wi h
hys e oscopy; <40 y;
pel ic ubal o male
ac o in e ili y
NA HRT; +GH ea men
wi h 4–5 in au e ine GH
pe usions o 6 IU GH
dilu ed wi h 0.5 ml 0.9%
saline on 9 h o 12 h day
o he cycle (bed es
15 min)
Imp o ed endome ial
hickness and
ecep i i y
8.0 ±0.6 5.8 ±0.7 <0.05b
Xue-Mei e al.
(23)
No In e ile women
unde going FET;
Chinese
77 G 1/ 77 G 2/
76 con ols
(cycles; n=240
women)
(30.3 ±4.1
y/31.3 ±5.0
y/30.7 ±4.3 y)
≤38 y; i i ied emb yos
no olde han 2 y; ≥2
emb yos ozen
Congeni al o acqui ed
u e ine mal o ma ion;
endome ial polyps;
submucosal ib oids;
in au e ine adhesion;
se e e endome iosis o
adenomyosis; diabe es
melli us; abno mal blood
clo ing
HRT wi h o al es adiol
ale a e om cycle day 3.
+ ea men g oup 1
(G 1): 4 IU/d GH
injec ions om cycle day
8 un il p og injec ion;
+ ea men g oup 2
(G 2): 4 IU/d GH
injec ions om cycle day
3 un il p og injec ion
Highe implan a ion,
clinical p egnancy
and li e bi h a es
9.2 ±0.9 (G 1);
9.6 ±1.0 (G 2)
9.2 ±0.8 <0.001b
Al mäe e al.
(20)
Yes RIF pa ien s wi h
esh dona ed
oocy es; Spanish
35/70
(42.2 ±4.5
y/42.4 ±3.7
y/43.8 ±2.5 y)
(35 GH RIF;
Con ol G 1 35
nonGH RIF;
Con ol G 2 35
pos con ols
unde going 1s
oocy e dona ion)
RIF (≥2 implan a ion
ailu es); 30–51 y
NA GnRH agonis +o al
es adiol; + ea men
g oup daily injec ions o
1 mg GH (∼3 IU) o 10
days o p oli e a i e
phase induced by
exogenous o al es adiol.
1–2 days la e aginal P
ea men was s a ed
Highe implan a ion,
p egnancy and li e
bi h a es
9.3 ±1.5 8.6 ±1.0
(G 1 non-GH);
9.4 ±1.7
(G 2
pos con ol)
0.046b
Yang e al.
(22)
No Pa ien s wi h hin
endome ium;
Chinese
184/61 (cycles;
n=225 women)
(33.7 ±3.6
y/33.7 ±3.4 y)
<40 y; ecei ing 2
blas ocys s; endome ial
hickness <8 mm on
p og adminis a ion day.
All pa ien s wi h
hys e oscopy o
adhesions be o e FET
U e ine mal o ma ions;
se e e endome iosis o
adenomyosis; umo ;
diabe es melli us;
immune abno mali ies
GnRH agonis +es adiol
ale a e om day 2–3 o
cycle+ aginal es adiol
a e mens ua ion +
p og o 5 days; +
ea men g oup 4.5 IU
GH e e y al e na e day
subcu aneously injec ed
om day o p og
adminis a ion un il ET
Highe clinical
p egnancy and
implan a ion a es
6.6 ±2.9 6.7 ±0.7 0.24c
(Con inued)
F on ie s in Endoc inology | www. on ie sin.o g 6Sep embe 2019 | Volume 10 | A icle 653
Al mäe and Aghajano a GH and he Endome ium
TABLE 1 | Con inued
S udy RCT S udy g oup;
E hnici y
GH/con ol
(mean age)
Inclusion c i e ia Exclusion c i e ia In e en ion P ima y ou come E ec on endome ial hickness (mm)
GH Con ol p- alue
Cui e al. (21) Yes Pa ien s wi h hin
endome ium;
Chinese
40/53
(29.8 ±3.0
y/29.7 ±3.6 y)
Endome ium ≤7 mm;
<40 y; no mal o a ian
ese e; esh ET
canceled due o hin
endome ium; ≥2 D3
emb yos ozen
U e ine anomaly;
in au e ine adhesion;
endome ial polyp;
adenomyosis;
malignancy
O al es adiol ale a e
om day 3 o cycle un il
day 18 + i ginal
es adiol on days 15–18
o cycle. + ea men
g oup 5 IU/d GH
subcu aneous injec ions
cycle days 15–18
Highe implan a ion
and clinical
p egnancy a es
7.9 ±0.7 6.3 ±0.9 <0.001b
aDay o hCG adminis a ion.
bDay o ET.
cDay o p oges e one adminis a ion.
AMH, an i-Mülle ian ho mone; BMI, body mass index (kg/m2); COS, con olled o a ian s imula ion; ET, emb yo ans e ; FET, ozen emb yo ans e ; GH, g ow h ho mone; HRT, ho mone eplacemen he apy; GnRH, gonado opin-
eleasing ho mone; hCG, human cho ionic gonado opin; hMG, human menopausal gonado opin; ICSI, in acy oplasmic spe m injec ion; IU, in e na ional uni ; NA, no applicable; PCOS, polycys ic o a ian synd ome; Pos, posi i e; P og,
p oges e one; RIF, ecu en implan a ion ailu e; RCT, andomized clinical ial. Bold ex highligh s he GH g oup o signi ican di e ence om con ol g oup.
Thin Endome ium
In e ile women wi h hin endome ium ep esen ano he
po en ial pa ien popula ion ha could bene i om he GH
adminis a ion. All s udies on GH co- ea men du ing ea men
o in e ile women wi h hin endome ium we e conduc ed in
ozen emb yo ans e (FET) cycles, whe e GH was adminis e ed
du ing he endome ial p epa a ion o FET (21,22,43,54)
(Table 1). The la ges s udy by Yang e al. was conduc ed on 225
in e ile women, and did no de ec any signi ican GH e ec
on endome ial hickness, while epo ing signi ican ly highe
clinical p egnancy and implan a ion a es (22). They assessed
GH e ec on endome ial hickness on he day o p oges e one
adminis a ion, which could explain he di e ence in hei esul s
om he es o he s udies. The o he h ee s udies all no ed
signi ican imp o emen in endome ial hickness on he day o
emb yo ans e among pa ien s wi h hin endome ium a e
adminis e ing GH h oughou he FET cycle (21,43,54), and
signi ican ly highe implan a ion and clinical p egnancy a es
(21). Wu e al. s udy also de ec ed imp o ed endome ial blood
low in he GH-adminis e ed pa ien g oup (43), simila o la e
indings by Xue-Mei e al. s udy (23), who showed inc eased
VEGF exp ession and imp o ed pe usion o he u e ine a e ies
in he g oup o in e ile women ea ed wi h GH. In line wi h
abo e, Cui e al. s udy de ec ed VEGF up- egula ion oge he
wi h ITGB3 and IGF-1 in endome ial cells when exposed o GH
(21). The s a e o high blood low esis ance and VEGF down-
egula ion wi h inadequa e epi helial g ow h and ascula iza ion
ha e been desc ibed as pa hophysiologic cha ac e is ics o hin
endome ium (62), and subendome ial blood low on he day
o emb yo ans e is ela ed o he implan a ion and p egnancy
a e in IVF (63). Cui e al. concluded ha up- egula ed VEGF
in hei s udy se ing, in he GH g oup, pa ly esul ed in he
inc ease o subendome ial blood low and he eby imp o ed
endome ial ecep i i y (21). Ne e heless, he exac mechanisms
o GH ac ions on he endome ium and endome ial ecep i i y
in gene al a e o be un a eled in u u e s udies. Also new s udies
wi h la ge s udy g oups and well-designed RCTs a e equi ed in
o de o cla i y whe he in e ile women wi h hin endome ium
bene i om he GH ea men .
Poo Responde s
Women wi h poo o a ian esponse in ART is ano he pa ien
g oup whe e GH co- ea men in s imula ion p o ocols ha e been
s udied. All hese s udies (see Table 1) ha e been RCTs, howe e
wi h limi ed sample sizes, and all ha e epo ed bene icial e ec
o GH adminis a ion on he numbe and quali y o oocy es and
on he numbe o emb yos ob ained. Rema kably, while some
imp o emen o endome ial hickness has been no ed, hose
s udies ailed o show any bene icial e ec on clinical p egnancy
and li e bi h a es (13,49–53). Based on hese indings, one
could conclude ha GH co- ea men in poo esponde s wi h
no mal endome ium does no seem o ha e any signi ican
impac on endome ial ecep i i y and hence p egnancy a es.
Ne e heless, we should be cau ious in d awing p elimina y and
po en ially w ong conclusions in his ype o s udies wi hou
aking in o ca e ul conside a ion all po en ial con ounde s,
including quali y and numbe o emb yos ans e ed, clea age
F on ie s in Endoc inology | www. on ie sin.o g 7Sep embe 2019 | Volume 10 | A icle 653
Al mäe and Aghajano a GH and he Endome ium
s. blas ocys s age emb yos and e en ype o lu eal suppo
p o ided in esh and/o ozen emb yo ans e cycles (64). In
addi ion, he o al p oduc i i y a e om a single oocy e e ie al
is highes when mo e and be e quali y emb yos a e ob ained,
which can be exac ly he case wi h GH-supplemen ed cycles in
poo esponde s, esul ing in highe cumula i e p egnancy a es
a he han pe cycle success in his g oup o pa ien s. Clea ly,
ca e ully designed la ge s udies wi h ans e s o single good
quali y emb yo ( esh and ozen) a e wa an ed, albei qui e
challenging o pe o m, in o de o cla i y whe he endome ial
ecep i i y in in e ile women wi h poo esponse in ART would
bene i om GH adminis a ion.
No mal Responde s
Thus a , he la ges g oup o in e ile pa ien s in ol ed in
s udies on GH adminis a ion du ing IVF has been he no mal
esponde s (Table 1). The i s s udy was pe o med on 240
in e ile women unde going FET, whe e wo di e en GH
supplemen a ion p o ocols we e compa ed—GH adminis a ion
h oughou he FET, and a single GH injec ion on day 8 o
es ogen ea men (23). No ably, signi ican endome ial
hickness imp o emen oge he wi h highe emb yo
implan a ion, clinical p egnancy, and li e bi h a es we e
de ec ed among women wi h longe GH adminis a ion
(23). The au ho s also no ed ha he longe GH addi ion
o he ea men p o ocol inc eased he le els o es adiol,
IGF-1, and VEGF se um le els, and imp o ed pe usion o
he u e ine endome ial a cua e a e y (23). The pulsa ili y
index, esis ance index, and peak sys olic eloci y/end dias olic
eloci y o he u e ine a cua e a e ies ep esen he esis ance
o blood low om he poin o measu emen downs eam;
inc eased impedance o hese a e ies migh co ela e wi h poo
endome ial ecep i i y and clinical ou comes (65).
The nex s udies analyzed 1,114 (16) and 1,562 (24) in e ile
women, espec i ely unde going o a ian s imula ion o IVF
wi h GH co-adminis a ion h oughou he s imula ion, and a
posi i e GH e ec on endome ial hickness in addi ion o he
highe clinical p egnancy a es was de ec ed in s udy compa ed
o con ol g oups. GH e ec on endome ial hickness was
signi ican ly inc eased among olde in e ile women o ≥35 yea s
old compa ed o <35 yea s old, while bo h g oups exhibi ed
highe implan a ion and clinical p egnancy a es, mos likely
a ibu ed o he highe numbe o high quali y emb yos ob ained
in GH- ea ed g oups (16). In humans, changes in GH sec e ion
could be age- ela ed, as pos -adolescence he sec e ion o GH
dec eases wi h age, which is why GH hyposec e ion is obse ed in
olde pa ien s (66). GH insu iciency can dis up o a ian unc ion
and lead o ep oduc i e di icul ies (66). As men ioned abo e,
in Du e al. s udy (16), GH- ea ed olde women (≥35 yea s
old) had implan a ion and clinical p egnancy a es mo e han
wo imes highe han hose obse ed du ing IVF cycles wi hou
GH. This esul sugges ed ha adding GH migh be bene icial o
olde pa ien s.
To conclude, esea ch on he e ec s o GH co- ea men
in ART among no mal esponde s has been pe o med
on su icien ly powe ed s udies in e ms o he sample
size, ne e heless as all hese s udies we e no andomized
con olled ials, u he well-designed esea ch is needed o
objec i ely assess he GH e ec on ART ou comes in (young)
women wi h no mal o a ian ese e and no mal esponse o
o a ian s imula ion.
Fu u e Pe spec i es
Fu he s udies a e wa an ed in o de o de e mine he op imal
dose, ime, and du a ion o GH adminis a ion and o in es iga e
he long- e m sa e y o GH o pa ien s and hei o sp ing. The
dosage and ea men du a ion o GH di e ed among conduc ed
s udies (see Table 1). Because o he limi ed expe ience wi h he
GH co- ea men p o ocols, he e is a lack o e idence o suppo
he supe io i y o one o e he o he . In all he p o ocols used
(see Table 1), GH was adminis e ed ia subcu aneous injec ions,
excep o one s udy whe e GH in au e ine pe usion in 5
pa ien s wi h non- esponsi e hin endome ium was success ully
used (54).
Ano he c ucial pa is o de ine he app op ia e pa ien
popula ion ha would uly bene i om GH ea men o
imp o ing hei u e ine lining quali y in e ms o hickness
and/o ecep i i y. GH seems o p omo e endome ial g ow h,
and i s use could be conside ed in women whose endome ium
does no g ow and/o ma u e su icien ly wi h s anda d ea men
p o ocols. In addi ion, he cu en e iew concludes ha
e en no mal esponde s could po en ially bene i om he
GH adminis a ion in IVF p og ams, howe e , he imp o ed
p egnancy a es in some o he s udies u ilizing esh IVF cycles
could no be sepa a ed om imp o ed emb yo quali y. While
endome ial hickness and pa e n upon GH adminis a ion
has been eco ded and epo ed, e alua ion o endome ial
ecep i i y is no as simple. Fu u e s udies need o ocus
on he molecula le el in o de o e alua e he endome ial
ansc ip ome/p o eome/sec e ome (67), wi h emphasis on
ecep i i y ma ke s o unde s and and cla i y he possible
mechanisms o GH on endome ial ecep i i y. An ideal se ing
would be o design an RCT wi h GH-supplemen ed mock
cycles s. con ol, du ing which endome ial ecep i i y could
be s udied on molecula le el in de ail ( ansc ip omics and/o
use o comme cially a ailable endome ial ecep i i y es s;
epigenomics and/o p o eomics analyses). The mock cycle could
be ollowed by a “ ue” FET cycle o enable e alua ion and
co ela ion o p egnancy a es. To sum up, undoub edly mo e
esea ch on la ge coho s wi h ca e ully designed s udies [as
highligh ed in a ecen commen (64)] is needed o iden i y he
pa ien g oup in whom he addi ion o GH o he ea men
p o ocol in IVF p og ams will be mos aluable.
Sample size and objec i ely designed s udies ( andomized
clinical ials) is a delica e opic in ART as s ic double-
blind, placebo-con olled, RCTs a e di icul o accomplish (68).
I is ex emely ha d o pe o m ully blinded RCTs in IVF
because o he pa ien ec ui men issues, whe e aging women
p e e no o pa icipa e in he placebo g oup ha equi es
commi men o se e al mon hs o hei ep oduc i e li espan
and which ul ima ely may no help hem achie e p egnancy
(68). Unde s andingly, pa ien s end o op o any addi ional
ea men , cos pe mi ing, ha would po en ially help hem o
become p egnan . As a esul , he s udies o GH ea men e ec s
F on ie s in Endoc inology | www. on ie sin.o g 8Sep embe 2019 | Volume 10 | A icle 653
Al mäe and Aghajano a GH and he Endome ium
on IVF ou comes a e a he limi ed on i s sample size and/o
a e e ospec i e o obse a ional in na u e; none heless, hey
p o ide impo an da a conce ning he apeu ic in e en ions in
IVF and open up u u e possibili ies o imp o ing in e ili y
ea men p o ocols.
CONCLUSIONS
The cu en e iew summa izes he ecen da a on GH
co- ea men e ec s on endome ial pa ame e s in assis ed
ep oduc ion and p oposes possible mechanisms o GH ac ions
in he endome ium. S udies a e indica ing ha co- ea men
wi h GH could imp o e he endome ial hickness, and
possibly ecep i i y among in e ile women. This e ec migh
occu h ough inc easing endome ial blood pe usion and
he exp ession o genes and p o eins ela ed o endome ial
ecep i i y such as VEGF and ITGB3 oge he wi h IGF-1,
howe e he exac mechanisms in he endome ium emain o
be cla i ied.
Whe he GH adminis a ion du ing IVF is use ul and which
pa ien g oups could bene i om i needs u he in es iga ion,
bu he p elimina y da a sugges ha women su e ing RIF,
pa ien s wi h hin endome ium and olde no mo- esponde s
could bene i om GH ea men when unde going ART. S ill,
ca e ully designed and su icien ly powe ed coho s udies,
RCTs, a e equi ed in he ield in o de o es ablish he mos
sui able he apeu ic egimen o hese pa ien s and o cla i y
he con usion a isen om a ious s udies ha ha e shown
ei he inconsis en o con lic ing indings, used small pa ien
coho s and/o ha e been poo ly designed wi h no blinding o
placebo con ols.
AUTHOR CONTRIBUTIONS
SA and LA equally con ibu ed o he e iew idea and
manusc ip w i ing.
FUNDING
This s udy was suppo ed by he Uni e si y o G anada
Plan P opio de In es igación 2016–Excellence ac ions: Uni o
Excellence on Exe cise and Heal h (UCEES)–and Plan P opio
de In es igación 2018–P og ama Con a os-Puen e, and he
Jun a de Andalucía, Conseje ía de Conocimien o, In es igación
y Uni e sidades, Eu opean Regional De elopmen Funds ( e .
SOMM17/6107/UGR); and he Spanish Minis y o Economy,
Indus y and Compe i i eness (MINECO), and Eu opean
Regional De elopmen Fund (FEDER): g an s RYC-2016-21199
and ENDORE SAF2017-87526.
ACKNOWLEDGMENTS
We hank D . Albe o Sola-Ley a o his help in he
igu e p epa a ion.
REFERENCES
1. Wilcox AJ, Bai d DD, Weinbe g CR. Time o implan a ion o he
concep us and loss o p egnancy. N Engl J Med. (1999) 340:1796–9.
doi: 10.1056/NEJM199906103402304
2. Ca son DD, Lagow E, Tha hiah A, Al-Shami R, Fa ach-Ca son MC,
Ve non M, e al. Changes in gene exp ession du ing he ea ly o mid-
lu eal ( ecep i e phase) ansi ion in human endome ium de ec ed by
high-densi y mic oa ay sc eening. Mol Hum Rep od. (2002) 8:871–9.
doi: 10.1093/moleh /8.9.871
3. Al mäe S, Reimand JR, Ho a a O, Zhang P, Ke e J, Laisk T, e al. Resea ch
esou ce: in e ac ome o human emb yo implan a ion: iden i ica ion o gene
exp ession pa hways, egula ion, and in eg a ed egula o y ne wo ks. Mol
Endoc inol. (2012) 26:203–17. doi: 10.1210/me.2011-1196
4. No wi z ER, Schus DJ, Fishe SJ. Implan a ion and he su i al o ea ly
p egnancy. N Engl J Med. (2001) 345:1400–8. doi: 10.1056/NEJM a000763
5. Edwa ds RG. Clinical app oaches o inc easing u e ine ecep i i y
du ing human implan a ion. Hum Rep od. (1995) 10(Suppl. 2):60–6.
doi: 10.1093/hum ep/10.suppl_2.60
6. Ma galio h EJ, Ben-Che i A, Gal M, Elda -Ge a T. In es iga ion and
ea men o epea ed implan a ion ailu e ollowing IVF-ET. Hum Rep od.
(2006) 21:3036–43. doi: 10.1093/hum ep/del305
7. H iid MM, Macklon N. Immune modula ion ea men s-
whe e is he e idence? Fe il S e il. (2017) 107:1284–93.
doi: 10.1016/j. e ns e .2017.04.009
8. E e s JLHH. Is RIF i e? Hum Rep od. (2016) 31:2661.
doi: 10.1093/hum ep/dew277
9. Hull KL, Ha ey S. G ow h ho mone and ep oduc ion: a e iew o endoc ine
and au oc ine/pa ac ine in e ac ions. In J Endoc inol. (2014) 2014:234014.
doi: 10.1155/2014/234014
10. Cailleau J, Ve mei e S, Ve hoe en G. Independen con ol o he
p oduc ion o insulin-like g ow h ac o I and i s binding p o ein
by cul u ed es icula cells. Mol Cell Endoc inol. (1990) 69:79–89.
doi: 10.1016/0303-7207(90)90091-L
11. Kolibianakis EM, Vene is CA, Died ich K, Ta la zis BC, G iesinge G.
Addi ion o g ow h ho mone o gonado ophins in o a ian s imula ion
o poo esponde s ea ed by in- i o e iliza ion: a sys ema ic
e iew and me a-analysis. Hum Rep od Upda e. (2009) 15:613–22.
doi: 10.1093/humupd/dmp026
12. Li X-LL, Wang L-PP, L F, Huang X-MM, Wang L-PP, Pan Y, e al.
The in luence o di e en g ow h ho mone addi ion p o ocols o poo
o a ian esponde s on clinical ou comes in con olled o a y s imula ion
cycles: a sys ema ic e iew and me a-analysis. Medicine. (2017) 96:e6443.
doi: 10.1097/MD.0000000000006443
13. Bassiouny YA, Dakhly DMR, Bayoumi YA, Hashish NM. Does he addi ion
o g ow h ho mone o he in i o e iliza ion/in acy oplasmic spe m
injec ion an agonis p o ocol imp o e ou comes in poo esponde s?
A andomized, con olled ial. Fe il S e il. (2016) 105:697–702.
doi: 10.1016/j. e ns e .2015.11.026
14. Kucuk T, Kozinoglu H, Kaba A. G ow h ho mone co- ea men wi hin
a GnRH agonis long p o ocol in pa ien s wi h poo o a ian esponse: a
p ospec i e, andomized, clinical ial. J Assis Rep od Gene . (2008) 25:123–7.
doi: 10.1007/s10815-008-9212-7
15. Rajesh H, Yong YY, Zhu M, Chia D, Yu SL. G ow h ho mone de iciency
and supplemen a ion a in- i o e ilisa ion. Singapo e Med J. (2007)
48:514–518.
16. Du FX, Yang XH, Li J, Hao M, Goa YH. G ow h ho mone co- ea men
wi hin a GnRH agonis long p o ocol imp o es implan a ion and p egnancy
a es in pa ien s unde going IVF-ET. A ch Gynecol Obs e . (2016) 294:877–83.
doi: 10.1007/s00404-016-4163-1
17. Hazou A, Junca Am, Ménézo Y, Demouzon J, Cohen-Bac ie P.
E ec o g ow h ho mone on oocy e compe ence in pa ien s wi h
mul iple IVF ailu es. Rep od Biomed Online. (2009) 18:664–70.
doi: 10.1016/S1472-6483(10)60011-9
F on ie s in Endoc inology | www. on ie sin.o g 9Sep embe 2019 | Volume 10 | A icle 653