Recei ed: 18 Ma ch 2021
|
Re ised: 20 Sep embe 2021
|
Accep ed: 22 Sep embe 2021
DOI: 10.1111/cen.14626
ORIGINAL ARTICLE
G ow h ho mone ea men does no o lead o insulin
esis ance no excessi e ise in IGF‐1 le els, while
imp o ing heigh in pa ien s small o ges a ional age
A long‐ e m obse a ional s udy
Juan P. López‐Sigue o
1
|Ma ia J. Ma ínez‐Aedo
1
|
Jose An onio Be múdez de la Vega
2
|Jo di Bosch‐Muñoz
3
|
Al onso M. Lechuga‐Sancho
4
|T iana Villalobos
5
|SGA S udy In es iga o
Collabo a i e G oup
1
Paedia ic Endoc inology Uni , Hospi al
Uni e si a io Ma e no‐In an il Ca los Haya,
Málaga, Spain
2
Paedia ic Endoc inology Uni , Hospi al
Uni e si a io Vi gen de la Maca ena, Se ille,
Spain
3
Endoc inology Uni , Hospi al Uni e si a io
A nau de Vilano a, Lleida, Spain
4
Endoc inology Uni , Hospi al Uni e si a io
Pue a del Ma , Cádiz, Spain
5
Medical A ai s, Me ck S.L.U., Mad id, Spain
Co espondence
T iana Villalobos, Medical A ai s, Me ck,
S.L.U., Ma ía de Molina, 40, 28006, Mad id,
Spain.
Email: [email p o ec ed]
Funding in o ma ion
Me ck
Abs ac
Objec i e: In child en bo n small o ges a ional age (SGA), he ela ionship be ween
g ow h ho mone (GH) ea men and insulin esis ance (IR) has only been in es iga ed o
a sho pe iod, necessi a ing a longe obse a ion pe iod. This s udy aimed o e alua e he
long‐ e m (10 yea s) e ec o GH o SGA‐child en on IR and sa e y du ing ea men .
Design: This was a mul icen e obse a ional s udy.
Pa ien s: SGA‐child en who ecei ed GH ea men in Spain (s a i ied by Tanne ‐
s age and age a GH onse [ wo g oups: ≤6 yea s old o >6 yea s old]).
Measu emen s: The analysed a iables (yea ly measu es) included auxologic, me a-
bolic (insulin‐like g ow h ac o ‐1 (IGF‐1), heigh eloci y [HV], weigh and homeo-
s a ic model assessmen ‐IR [HOMA‐IR]) and sa e y da a. Da a we e collec ed
p ospec i ely (since he s udy app o al: 2007) and e ospec i ely (since he ini ia-
ion o GH ea men : 2005–2007).
Resul s: A o al o 389 SGA child en (369 Tanne ‐I) we e ec ui ed om 27 cen es.
The mean age (s anda d de ia ion) o he child en a GH ea men onse was 7.2
(2.8) yea s old. IGF‐1 (s anda d de ia ion sco e [SDS]) and HOMA‐IR alues ended
o inc ease un il he six h yea o GH‐ ea men , wi h signi ican di e ences being
obse ed only du ing he i s yea , while hese emained s able in he la e yea s
(wi hin no mal anges). Heigh (SDS) inc eased signi ican ly (basal: −3.0; en h
yea : −1.13), and he maximum HV (SDS) occu ed du ing he i s yea (2.75 ± 2.39).
Conclusions: HOMA‐IR alues inc eased signi ican ly in SGA‐child en du ing he
i s yea o GH‐ ea men , emained s able and we e wi hin no mal anges in all
cases. Ou 10‐yea da a sugges s ha long‐ e m GH ea men does no p omo e IR
and is well‐ ole a ed, sa e and e ec i e.
Clinical Endoc inology. 2022;96:558–568.558
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© 2021 Me ck Spain S.L.U. Clinical Endoc inology pusblished by John Wiley & Sons L d on behal o Socie y o Endoc inology (SFE) and Clinical Endoc inology
T us (CET).
KEYWORDS
e icacy, g ow h ho mone, homeos a ic model assessmen , insulin esis ance, long‐ e m
ollow‐up, sa e y, small o ges a ional age
1|INTRODUCTION
Small o ges a ional age (SGA), de ined as in an s bo n wi h a weigh
and/o heigh ha is wo s anda d de ia ions (SDs) below he mean
o hei ges a ional age (a e m o p e e m),
1
a ec s app oxima ely
3%–10% o li e bi hs.
2
Mos child en bo n SGA show ca ch‐up
g ow h du ing he i s yea s o li e, bu 10% will con inue wi h a
pa hologically sho s a u e h oughou childhood and adolescence.
3
SGA synd ome a ec s glucose me abolism and insulin sensi i i y
(IS),
4
which en ails he subsequen isk o de eloping ype‐2 diabe es
melli us (DM) and o he in e ela ed me abolic diso de s, such as
dyslipidemia, ca dio ascula diseases and hype ension.
5
SGA chil-
d en wi h sho s a u e show educed le els o insulin‐like g ow h
ac o ‐1 (IGF‐1),
3
a p o ein in ol ed in oe al g ow h, de elopmen
and me abolism egula ion.
5
IGF‐1 le els a e associa ed wi h IS, bu
his associa ion seems o be complex
6
and has no ye been well
cha ac e ized. Se e al s udies on child en ha e shown cu ‐o alues
o insulin esis ance (IR) be ween 2.5 and 3.2, acco ding o he
homeos a ic model assessmen o IR (HOMA‐IR).
7,8
The only s anda d he apy app o ed o SGA synd ome is based
on ecombinan human g ow h ho mone ( hGH), which leads o an
inc ease in he g ow h a e and enables in an s o g ow acco ding o
he no mal limi s and ha e a no mal adul heigh .
9
The hGH he apy
has been shown o induce ansien IR in child en; he e o e, he e is
a conce n ega ding he diabe ogenic po en ial o hGH he apy in
child en bo n wi h SGA.
10
Howe e , a ecen e iew has e ealed
ha , while hGH ea men could pose a isk ac o o he de el-
opmen o DM, amily his o y could ha e mo e impac in i s
de elopmen .
11
Al hough moni o ing glucose homeos asis is ecommended,
he e is no consensus on he app op ia e me hod.
10
A la ge numbe
o pa ien s unde going longe ollow‐up pe iods a e needed o elu-
cida e he ela ionship be ween IS pa ien s and GH‐ ea ed SGA
pa ien s. The e o e, we ca ied ou he i s mul icen e s udy in
Spain o de e mine he long‐ e m e olu ion o IR om he beginning
o GH ea men in a la ge popula ion o SGA‐child en ecei ing
hGH ea men . The seconda y endpoin s o his s udy included he
de e mina ion o he auxological and me abolic hGH ea men e -
ec s o iden i y po en ial p edic i e ac o s and assess he ea -
men 's sa e y p o ile.
2|METHODS
2.1 |S udy design and popula ion
This p ospec i e s udy was pe o med in 27 Spanish cen es.
The pa ien s included in he s udy we e Spanish SGA‐child en
(age ≥4 yea s) bo n a e m and ea ed wi h hGH (Saizen
®
; Me ck‐
Se ono. Eu opean au ho iza ion: Sep embe 2005)
All p ocedu es pe o med du ing he s udy we e in acco dance
wi h he Decla a ion o Helsinki and we e app o ed by he E hics
Commi ee o Hospi al Ma e no In an il Ca los Haya o Málaga. The
pa ien s (≥12 yea s old) o hei pa en s o legal ep esen a i es
p o ided w i en in o med consen .
The child en we e ec ui ed be ween Feb ua y 2007 and No-
embe 2012. Da a om he pa ien s' medical eco ds we e collec ed
bo h p ospec i ely and e ospec i ely, wi h he la e being collec ed
a he s a o he ea men and be o e he s udy au ho isa ion
(2005–2007).
The inclusion c i e ia we e as ollows: child en wi h a cu en
heigh < −2.5 SD; heigh adjus ed o pa en al s a u e < −1 SD; bo n
SGA a e m (a e Week 37 o ges a ion); weigh and/o leng h a
bi h < −2 SD o hei ges a ional age; aged ≥4 yea s old; and e-
cei ing hGH ea men (daily dose: 0.035 mg/kg body weigh ; sub-
cu aneously). The exclusion c i e ia we e as ollows: closed epiphysis,
hGH‐hype sensi i i y, ac i e neoplasia, gene ic o mal o ma ion
synd omes and e idence o p og ession o ecu ence o any un-
de lying in ac anial lesion.
The cessa ion ea men c i e ia we e heigh eloci y (HV) < 2 cm/
yea and bone age (BA) > 14 yea s in emales and ≥15 yea s in males.
Thesamplesize equi ed o assessing he pos ea men sa e y
p o ile (200 pa ien s a e 10 yea so ea men ,basedon heSEPAGE
s udy [NCT01082354] and ou s udy [SER‐GH‐2005‐01]) was de-
e mined based on he Saizen
®
Long Te m Obse a ional s udy
(SALTO).
12
The es ima ed sample size was 450 subjec s, as calcula ed based
on he SEPAGE (poo acc ual and loss o 35% o pa ien s who we e
o pa icipa e in SALTO) and SALTO (po en ial e usal o ou pa ien s
o pa icipa e, and es ima ed loss o he pa icipa ing pa ien s; 12%
du ing ea men and 35% du ing he ollow‐up) s udies.
The sa e y popula ion included all pa ien s who ecei ed ≥1 hGH
dose. The e aluable popula ion was de ined as he sa e y popula ion who
had unde gone ≥1‐yea o ollow‐up om he s a o ea men .
Child en we e s a i ied acco ding o he Tanne s age (S age I
o ≥I [II/III/IV, and adul ]) and he age a ea men onse (6 yea s old
[ea ly s a ], o ≥6 yea s old [la e s a ]). The second s a i ica ion was
due o he di e en ia ion and a oidance o child en en e ing pube y
du ing he i s yea o ea men , aking in o accoun ha some o
hem could ha e had ad anced o p ecocious pube y. The s a i i-
ca ion was es ablished a 6 yea s o age o ensu e a 3‐yea pe iod
be o e eaching pube y as he ime o ca ch‐up g ow h. Pa ien s
wi h Tanne s age >I we e excluded om he analyses acco ding o
he s a ime o ea men o ensu e he ini ial p epube al si ua ion.
LÓPEZ‐SIGUERO ET AL.
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559
2.2 |Measu emen s; analysis/s a is ics
All a iables we e measu ed a leas once a yea , ollowing he s anda d
p ocedu es o each cen e. Only child en wi h Tanne s age‐Iunde wen
analyses, hus ensu ing hei p epube al s a e a he onse o ea men .
S anda dized (s anda d de ia ion sco e [SDS]) alues we e used o a oid
a iabili y in measu emen s among he cen es.
The IR de elopmen /p og ession (p ima y endpoin ) was calcu-
la ed using he HOMA‐IR index (mass uni s): as ing insulin (µu/
ml) × as ing glucose (mmol/L)/22.5.
The auxological e ec s o ea men we e assessed acco ding o he
ollowing pa ame e s: HV (cm/yea ), weigh (kg) and heigh (cm) as SDS
(ch onological age [CA] and sex e e ence alues ob ained om Ca as-
cosa),
13
BA (assessed using he G eulich and Pyle a las)
14
and Tanne ‐
s age ( es icula size o b eas de elopmen ). The po en ial p edic o alue
o body mass index (BMI) (SDS) o IR was calcula ed.
The me abolic e ec s o ea men we e assessed acco ding o he
ollowing pa ame e s: as ing plasma IGF‐I (ng/ml) (SDS) ( e e ence alues
om Elmlinge e al.),
15
plasma iglyce ides (mg/dl), high‐densi y lipo-
p o ein choles e ol (mg/dl), HbA1c (% o o al haemoglobin) and hy oid
ho mones. Assessmen s we e ca ied ou ollowing di e en me hods
and a di e en local labo a o ies, and measu es ( e e ence alues) we e
s anda dized o he compa a i e analyses.
Non esponde s o hGH ea men we e de ined as a g ow h
a e < +1 SDS du ing he i s yea o ea men .
Sa e y a iables included ad e se e en s (AEs; Medical Dic-
iona y o Regula o y Ac i i ies), physical examina ion, i al signs and
blood and u ine es s.
Ca ego ical a iables a e exp essed as absolu e and ela i e
equencies (%), while con inuous a iables a e exp essed as mean,
SD, 95% con idence in e al (95 % CI) and SDS. Con inuous a iables
we e analysed using he ‐ es o Wilcoxon es .
TABLE 1 Cha ac e is ics o he
e aluable popula ion (n= 393)
Pa ien s (N= 393)
Male, n(%) 198 (50.4)
Age, mean (yea s ± SD)
A s udy inclusion 7.8 ± 3.1
A ea men ini ia ion 7.2 ± 2.8
Ges a ional age a bi h, mean (weeks ± SD) 37.6 ± 3.2
Missing (n)=3
Gene ic a ge heigh size, mean (cm ± SD); [SDS] 163.1 ± 7.9
Male ≤6 yea s 169.3 ± 4.8; [1.3]
Female ≤6 yea s 156.9 ± 5.1; [−1.2]
Male > 6 yea s and Tanne I 169.3 ± 4.2; [1.5]
Female > 6 yea s and Tanne I 156.0 ± 4.3; [−1.6]
Missing (n)=29
Bi h heigh , mean (cm ± SD) 43.6 ± 4.0
Missing (n)=21
Bi h weigh , mean (kg ± SD) 2.2 ± 0.6
Missing (n)=2
Rele an medical his o y a baseline, n(%) 50 (12.7)
Pas medical his o y 12 (24.0)
Cu en ongoing
a
38 (76.0)
Mild–mode a e
a
35 (92.1)
Familia clinical his o y, n(%) (b o he /sis e diagnoses SGA)
Missing (n)=13
Yes 34 (9.0)
No 277 (72.9)
NA 56 (14.7)
Abb e ia ions: NA, no applicable; SD, s anda d de ia ion; SDS, s anda d de ia ion sco e; SGA, small
o ges a ional age.
a
Calcula ed on he numbe o pa ien s wi h cu en ele an medical his o y a baseline.
560
|
LÓPEZ‐SIGUERO ET AL.
Reg ession analysis was pe o med on he di ec endpoin s. A
co ela ion analysis was pe o med o de e mine he associa ion
be ween changes in HOMA‐IR and HV (Spea man's co ela ion
coe icien ). S a is ical signi icance was se a p≤.05. I he CI did no
include he ze o‐e ec alue, i could be assumed ha he e was
a s a is ically signi ican esul . All s a is ical p ocedu es we e
pe o med using he SAS 9.2 s a is ical so wa e (SAS Ins i u e).
3|RESULTS
A he ime o he inal analysis in Oc obe 2018, a o al o 410
pa ien s om 27 cen es cons i u ed he sa e y popula ion, o
which 393 we e conside ed o be in he e aluable popula ion
(Table 1).
The sample was sex‐balanced (Table 1), wi h a mean age a
ea men onse o 7.2 ± 2.8 yea s old.
T ea men was comple ed in 150 pa ien s (38.17%). The easons o
discon inua ion among he 200 (50.89%) pa ien s wi h ea ly wi hd awal
included he ollowing: lack o e icacy (a he in es iga o 's disc e ion),
n= 15 (7.5%); inabili y o ollow ea men , n= 10 (5.0%); AEs, n=6
(3.0%); and adminis a i e causes ( ollow‐up da a no epo ed), n= 137
(68.5%). Missing da a occu ed in 43 pa ien s (10.94%). A o al o 8.95%
o he pa ien s had an SGA sibling. A e ial hype ension and ype‐II DM
we e he mos common amilia clinical his o ies (11.32% and 12.1%,
espec i ely). O he ypes o amilia clinical his o y included cance
(10.0%), amilial hype lipidemia (9.47%), obesi y (5.79%), ges a ional dia-
be es (2.37%), ype‐I DM (1.05%) and myoca dial in a c ion o s oke
be o e he age o 40 yea s (0.53% o each case).
3.1 |Insulin esis ance
The mean HOMA‐IR inc eased signi ican ly du ing he i s yea o
ea men : o e all, 0.62 ± 1.47 (Table 2; Figu e 1A); Tanne ‐I≤6 yea s
old, 0.40 ± 0.8 and >6 yea s old, 0.80 ± 1.65 (Table 3); and Tanne ‐II,
0.99 ± 3.16 (Table 3). O e all, no signi ican di e ences we e ob-
se ed he ea e , al hough an inc easing end was obse ed un il
isi 6 (Figu e 1A). The HOMA‐IR alues we e main ained wi hin
no mal anges and we e simila in bo h age g oups (≤6 yea s old and
>6 yea s old; Table 3). The inc ease was highe in child en ≤6 yea s
old because hei alues om baseline o Visi 3 we e signi ican ly
lowe han hose in he >6 yea s old g oup. Ne e heless, he alues
we e simila in bo h g oups a Visi 6 (no mal ange).
The changes in heigh eloci y,heigh and weigh ,BMI, a io o BA
and CA, and IGF‐1can be seen in Tables 2and 3and in Figu e 1B,C.
3.2 |HOMA‐IR ela ions
No ela ionship was ound be ween he HOMA‐IR index and HV,
excep o he second yea (Spea man's co ela ion coe icien =
0.19; p< .05).
3.3 |Mul iple co ela ion analysis
The HOMA‐IR alues inc eased p opo ionally wi h baseline age and
BMI, and in e sely wi h baseline HOMA‐IR and weigh alues. These
ou a iables explained 21% o he change in he HOMA‐IR alues
(Table 4).
3.4 |Me abolic pa ame e s
No signi ican changes in plasma iglyce ides, high‐densi y lipop o-
ein choles e ol, HbA1c and hy oid ho mones we e obse ed du ing
hGH ea men .
3.5 |Sa e y
A o al o 411 pa ien s we e included in he sa e y popula ion, o
which 16 (3.9%) epo ed AEs. In 14 o hem, he e en was due o
he ea men . Fu he mo e, six (2.9%) pa ien s discon inued ea -
men because o AEs. The AEs we e musculoskele al and connec i e
issue diso de s (back pain, os eochond osis, os eonec osis and sco-
liosis), which we e conside ed o be mode a e, excep o one mild AE
(os eochond osis; Table 5).
The e we e ou se ious AEs (SAEs), none was se e e. Two we e
ca ego ized as p obably ela ed o ea men — wo pa ien s de el-
oped signi ican IR and T2DM. When ea men was wi hd awn he
T2DM was esol ed and he IR e u ned o baseline. In bo h cases
no speci ic ea men o IR and T2DM was equi ed. In bo h cases
he e olu ion was a ou able.
One pa ien had a SAE ca ego ized as possibly ela ed o ea -
men , os eochond osis (Phe es), he hGH ea men con inued and
he subjec was de i ed o T auma ology Depa men . One pa ien
had a se ious AE, ch onic enal ailu e, ca ego ized as no ela ed o
ea men and he subjec con inued wi h he hGH ea men . The
e olu ion o hese wo pa ien s in unknown.
4|DISCUSSION
This s udy ha was ca ied ou in a la ge popula ion o SGA in an s
ea ed wi h hGH showed ha , despi e a signi ican inc ease in he
mean HOMA‐IR alues du ing he i s yea o ea men , he alues
emained s able wi hin he no mal ange. Simila esul s we e obse ed
by Jensen e al.
16
in he No h Eu opean Small o Ges a ional Age
S udy (NESGAS), in which he IR, IGF‐I and heigh alues inc eased
du ing he i s yea o hGH ea men in he 110 SGA in an s.
Mo eo e , Ho ikawa e al.
17
showed an inc ease in he mean HOMA‐
IR alues a e 260 weeks o GH ea men , which was simila o ha
obse ed in ou s udy un il Visi 6. This inc ease was ela ed o he
dose adminis e ed, which was also simila o he one we used. A apid
inc ease in IR could lead o a signi ican inc ease in as ing blood glu-
cose, as obse ed Sas e al.
18
in 78 SGA child en (mean age, 7.3 yea s)
LÓPEZ‐SIGUERO ET AL.
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561
TABLE 2 Annual e olu ion by he isi o HOMA‐IR and auxologic and me abolic a iables, up o he 10 h yea o hGH‐ ea men
N
mean ± SD
(95% CI)
HOMA‐IR
(mass uni s) HV (cm/yea ) HV (SDS) Heigh (SDS) Weigh (SDS) BMI (SDS) BA/CA Ra io IGF‐1 (SDS)
Basal 1.19 ± 1.14
(1.05, 1.32)
–– −3.00 ± 0.61
(−3.06, −2.93)
−1.72 ± 0.56
(−1.78, −1.67)
−0.70 ± 0.80
(−0.78, −0.62)
0.71 ± 0.17
(0.70, 0.73)
−0.31 ± 1.06
(−0.41, −0.20)
V1 282
1.91 ± 2.58
(1.60, 2.21)
8.59 ± 2.33
(8.35, 8.83)
2.75 ± 2.39
(2.50, 2.99)
−2.35 ± 0.71
(−2.42, −2.28)
−1.47 ± 0.55
(−1.53, −1.42)
−0.76 ± 0.70
(−0.83, −0.69)
0.79 ± 0.15
(0.78, 0.81)
0.99 ± 1.20
(0.87, 1.12)
V2 235
2.09 ± 1.61
(1.88, 2.30)
6.80 ± 1.48
(6.64, 6.97)
1.09 ± 1.40
(0.94, 1.25)
−2.02 ± 0.73
(−2.10, −1.94)
−1.35 ± 0.60
(−1.42, 1.29)
−0.77 ± 0.74
(‐0.85 ± −0.69)
0.85 ± 0.14
(0.83, 0.87)
1.21 ± 1.21
(1.07, 1.35)
V3 192
2.21 ± 1.40
(2.01, 2.41)
6.51 ± 1.66
(6.30, 6.72)
0.88 ± 1.22
(0.73, 1.04)
−1.60 ± 2.74
(−1.93, −1.26)
−1.06 ± 3.01
(−1.43, −0.69)
−0.75 ± 0.70
(−0.84, −0.67)
0.89 ± 0.13
(0.88, 0.91)
1.37 ± 1.40
(1.20, 1.55)
V4 149
2.40 ± 1.33
(2.19, 2.62)
5.97 ± 2.66
(5.59, 6.35)
0.82 ± 3.08
(0.38, 1.27)
−1.59 ± 0.81
(−1.70, −1.47)
−1.18 ± 0.58
(−1.26, −1.10)
−0.76 ± 0.72
(−0.86, −0.66)
0.92 ± 0.11
(0.91, 0.94)
1.14 ± 1.35
(0.94, 1.35)
V5 97
2.67 ± 2.28
(2.21, 3.13)
5.42 ± 4.26
(4.68, 6.16)
0.30 ± 45.40
(−0.64, 1.24)
−1.66 ± −1.37
(−1.70, −1.47)
−1.17 ± 0.63
(−1.28, −1.06)
−0.77 ± 0.72
(−0.90, −0.65)
0.95 ± 0.10
(0.94,0.97)
1.09 ± 1.40
(0.84, 1.34)
V6 61
2.74 ± 1.57
(2.34, 3.15)
5.42 ± 2.10
(4.95, 5.89)
0.68 ± 3.97
(−0.21, 1.57)
−1.50 ± 0.88
(−1.68, −1.31)
−1.22 ± 0.62
(−1.35, −1.08)
−0.83 ± 0.67
(−0.97, −0.68)
0.95 ± 0.09
(0.93, 0.97)
1.00 ± 1.42
(0.67, 1.33)
V7 38
2.39 ± 1.26
(1.98, 2.81)
5.67 ± 2.23
(5.05, 6.28)
0.33 ± 1.26
(−0.02, 0.68)
−1.39 ± 0.88
(−1.62, −1.17)
−1.14 ± 0.70
(−1.32, −0.97)
−0.76 ± 0.72
(−0.95, −0.58)
0.96 ± 0.09
(0.94, 0.99)
0.86 ± 1.23
(0.51, 1.21)
V8 31
2.37 ± 1.40
(2.21, 3.24)
5.54 ± 2.82
(4.54, 6.39)
0.39 ± 1.67
(−0.16, 0.94)
−1.38 ± 0.79
(−1.62, −1.15)
−1.25 ± 0.55
(−1.42, −1.09)
−0.89 ± 0.60
(−1.07, −0.71)
0.97±0.08
(0.94,1.00)
0.79 ± 1.05
(0.45, 1.12)
V9 14
2.46 ± 0.98
1.89, 3.032
4.38 ± 2.97
(3.18, 5.58)
−0.01 ± 1.24
(−0.51, 0.49)
−1.25 ± 0.73
(−1.55, 0.96)
−1.19 ± 0.62
(−1.44, −0.94)
−0.84 ± 0.72
(−1.13, −0.55
0.97 ± 0.08
(0.94, 1.00)
0.60 ± 0.57
(0.37, 0.84)
V10 9
2.11 ± 0.51
1.72, 2.50
4.44 ± 3.01
(2.29, 6.60)
0.44 ± 1.17
(−0.39, 1.27)
−1.13 ± 0.64
(−1.54, −0.72)
−1.00 ± 0.79
(−1.50, −0.50)
−0.64 ± 0.88
(−1.20, −0.08)
0.97 ± 0.06
(0.92, 1.02)
0.64 ± 0.54
(0.26, 1.03)
No e: E aluable popula ion (n= 393).
a
The bold alues a e in ended o indica e he No pa ien s.
Abb e ia ions: BA, bone age; BMI, body mass index; CA, ch onological age; CI, con idence in e al; HOMA‐IR, homeos a ic model assessmen o insulin esis ance; HV, heigh eloci y; IGF‐I, insulin‐like g ow h
ac o ‐I; hGH, ecombinan human g ow h ho mone; SD, s anda d de ia ion; SDS, s anda d de ia ion sco e.
a
The di e ence be ween he 393 pa ien (e aluable popula ion size) and he numbe o pa ien s wi h da a in each isi a e ‘missing’pa ien s. I includes hose pa ien s ha had comple e/discon inued he ea men .
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LÓPEZ‐SIGUERO ET AL.

(A)
(B)
(C)
FIGURE 1 (A) HOMA‐IR index by isi ( om baseline o Visi 10) and by age a s a o ea men —(Tanne I and Tanne II) (e aluable
popula ion). (B) IGF index by isi ( om baseline o Visi 10) and by age a s a o ea men (e aluable popula ion). (C) h SDS index by isi ( om
baseline o Visi 10) and by age a s a o ea men (e aluable popula ion). HOMA‐IR, homeos a ic model assessmen o insulin esis ance;
IGF, insulin‐like g ow h ac o
LÓPEZ‐SIGUERO ET AL.
|
563
TABLE 3 Change om baseline o HOMA‐IR and heigh measu ed e e y yea e sus p e ious yea by age and Tanne s age a s a o ea men
Change HOMA‐IR Change heigh
N Ea ly s a (≤6 yea s) La e s a (>6 yea s)
Mean ± SD (95% CI) Tanne I Tanne I Tanne II Change in HSDS Gain in HSDS
V1 −basal 0.40 ± 0.84 (0.23, 0.57) 100
0.80 ± 1.65 (0.47, 1.12)
11
0.99 ± 3.16 (−1.13, 3.12)
0.65 (0.48) (0.60, 0.70) 387
3.53 (2.75) (3.26, 3.81)
V2 −V1 76
0.41 ± 1.28 (0.12, 0.70)
98
0.07 ± 2.00 (−0.33, 0.47)
10
−0.02 ± 1.21 (−0.89, 0.84)
0.30 (0.34) (0.27, 0.34) 323
1.77 (2.06) (1.54, 2.00)
V3 −V2 63
0.15 ± 1.30 (−0.18, 0.47)
85
0.03 ± 1.66 (−0.33, 0.38)
8
−0.05 ± 0.76 (−0.69, 0.58)
0.42 (2.67) (0.09, 0.75) 256
1.88 (4.88) (1.28, 2.48)
V4 −V3 41
0.31 ± 1.32 (−0.11, 0.73)
71
0.04 ± 1.45 (−0.31, 0.38)
2
−0.08 ± 1.16 (−10.52, 10.35)
0.18 (0.43) (0.12, 0.24) 195
1.08 (2.62) (0.70, 1.45)
V5 −V4 27
0.02 ± 1.16 (−0.44, 0.48)
54
0.66 ± 2.56 (−0.04, 1.36)
1
0.07 (−)
0.12 (0.51) (0.03, 0.21) 131
0.87 (3.20) (0.32, 1.42)
V6 −V5 15
0.54 ± 1.80 (−0.46, 1.54)
33
0.11 ± 1.35 (−0.37, 0.59
00.09 (0.30) (0.03, 0.16) 86
0.68 (2.09) (0.23, 1.13)
V7 −V6 11
−0.27 ± 2.39 (−1.88, 1.33)
21
−0.03 ± 1.36 (−0.65, 0.59)
00.10 (0.34) (0.02, 0.19) 60
0.75 (2.41) (0.13, 1.37)
V8 −V7 10
0.63 ± 1.25 (−0.27, 1.52)
12
0.05 ± 0.96 (−0.56, 0.66)
00.08 (0.40) (−0.04, 0.20) 44
0.56 (2.95) (−0.34, 1.46)
V9 −V8 6
0.17 ± 1.06 (−.94, 1.28)
4
−0.61 ± 2.49 (−4.57, 3.34)
00.02 (0.28) (−0.09, 0.14) 25
0.22 (2.13) (−0.67, 1.10)
V10 −V9 5
−0.38 ± 0.97 (−1.58, 0.82)
2
−1.62 ± 0.07 (−2.27, −0.98)
00.08 (0.27) (−0.10, 0.26) 11
0.59 (1.99) (−0.74, 1.93)
No e: Desc ip i e s a is ics. E aluable popula ion. The bold alues a e in ended o indica e he No pa ien s.
Abb e ia ions: CI, con idence in e al; HOMA‐IR, homeos a ic model assessmen o insulin esis ance; HSDS, heigh s anda d de ia ion sco e; SD, s anda d de ia ion.
564
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LÓPEZ‐SIGUERO ET AL.
epo ing ela i e IR (inc eased as ing and glucose‐s imula ed in-
sulinemia). Addi ionally, al hough he HOMA‐IR index could be a ib-
u ed o hGH ea men , Ga cía Cua e o e al.
19
in he no mal
popula ion showed a p og essi e inc ease in glucose, insulin, C‐pep ide
and HOMA index alues in ela ion o age, wi h s a is ically signi ican
di e ences be ween p epube al and pube al s ages o bo h sexes.
Al hough Seino e al.
20
ha e e ealed ha pa ien s wi h HOMA‐IR
alues ≥2.5 a e ega ded as being esis an o insulin, A ellano‐Ruiz
e al.
21
has shown ha HOMA‐IR ha e a mode a e diagnos ic accu acy
when measu ing IR in child en and adolescen s, es ablishing alues
be ween 2.30 and 3.59 as he cu ‐o poin s o a oid he isk o me-
abolic synd omes. In ou s udy, he highes HOMA‐IR alue wi hin
ha ange was obse ed a he six h yea (2.74), wi hou signi ican
di e ences ela ed o age being obse ed a he beginning o ea -
men . A simila inc ease in he HOMA‐IR alues wi hin he no mal
ange was obse ed by Güemes Hidalgo e al.
22
in a di e en s udy
ca ied ou in SGA child en ea ed o 3 yea s ( om 0.72 o 1.67) ha
had ini ia ed ea men a he mean age o 5.9 yea s old. Despi e his,
Ho ikawa e al.
17
showed ha including a dose o 0.067 mg/kg/day did
no in luence glucose ole ance and did no a ec glucose me abolism.
Fu he mo e, ou s udy showed a signi ican inc ease in IGF‐1
(SDS) alues du ing he i s yea and a less signi ican inc ease be-
ween Visi s 1 and 2. Simila esul s we e ob ained a 24 mon hs by
Qie and Yang
23
in Chinese SGA child en ea ed wi h hGH. A e wa d,
he inc ease was app oxima ely 1 SDS un il Visi 7. A Visi 7, ollowing
discon inua ion o ea men , he IGF le els p og essi ely dec eased o
no mal le els as desc ibed Sas e al.
18
In SGA child en, Gaddas e al.
24
ha e shown ha IGF‐I is a use ul bioma ke o he sho ‐ e m esponse
o hGH as i inc eases wi h ea men . In he inal analysis o his
s udy, he inc ease in he IGF‐I (SDS) le els du ing he i s yea was
+1.30. This was 2.4 poin s below han he alue obse ed by Jensen
e al.
16
in he NESGAS s udy ha used a dose ha was wice ha
o ou s udy (0.035 mg/kg/day [ou s udy] s. 0.067 mg/kg/day
[NESGAS's s udy]). In addi ion, he basal IGF‐I (SDS) le el (−0.32) was
highe in he 2516 SGA pa ien s (−0.7; B aban 's e e ence alues)
han in any o he s udy o Blankens ein e al.
25
in whom an inc ease in
IGF‐I le els du ing he i s yea was obse ed. The esponse o IGF‐1
o hGH is di ec ly ela ed o he alue o basal IGF‐1
16
and in e sely
ela ed o ha o he basal o al body a as desc ibed Thankamony
e al.
26
Bo h a iables could explain he di e ence in he inc ease in
IGF‐1 le els compa ed o hose obse ed in ou s udy. Addi ionally,
Rus ogi e al.
27
showed a posi i e co ela ion be ween an inc ease in
IGF‐I le els and ca ch‐up g ow h by 18 mon hs in SGA child en. In his
sense, ou s udy showed a highe HV (SDS) du ing he i s yea o
hGH ea men (2.75 ± 2.39). Fu he mo e, he mean HV (SDS) was
g ea e han 2 SDS, which coincides wi h he la ges inc ease in IGF‐I
le els in ou s udy. The HV was cons an ly g ea e han ze o in e e y
e alua ion (5.5 cm/yea ). A e he i s yea , he HV SDS s a ed o
dec ease wi h espec o he i s yea . Acco dingly, Rhie e al.
28
showed simila esul s, wi h he highes inc ease being obse ed du -
ing he i s yea o hGH ea men , and hen i g adually dec eased,
al hough i emained abo e 5 cm. Mo eo e , heigh was ound o be
no mal wi h hGH ea men in sho SGA child en wi h a sa e me a-
bolic p o ile as desc ibed Laba a e al.
29
Rega ding he child en's g ow h, he mean BA–CA a io in-
c eased signi ican ly du ing hGH ea men om baseline o Visi 4
and hen s abilized un il he end o he s udy. BA inc eases o e ime,
as sugges ed by he inc ease in he BA–CA a io (close o 1 a e 6
yea s o ea men ). This esul is consis en wi h he change om 0.8
(basal) o 1 (a e 5 yea s o hGH) obse ed by Ross e al.
30
in 481
SGA child en and in o he condi ions equi ing hGH.
Ou IGF‐I, HV (SDS) and BA esul s inc eased du ing he i s yea
o hGH ea men and hen no malized o e ime. In his espec ,
Zhao e al.
31
showed ha ollowing GH he apy in small child en, he e
was a posi i e associa ion be ween IGF‐1 (SDS) and he BA–CA a io
when he IGF‐1 le el was lowe han 2 SDS, as obse ed in ou s udy,
sugges ing ha a low le el o IGF‐1 could con ibu e o BA delay in
sho child en and adolescen s. Mo eo e , a mode a e bu signi ican
BA accele a ion du ing hGH ea men as he BA–CA a io inc eased
in SGA child en who expe ienced an inc ease in IGF‐1 le els, al hough
i emained wi hin he no mal ange.
29
Taken oge he , he inc ease in
IGF‐I le els due o hGH ea men could po en ia e ca ch‐up g ow h
and no mal BA ma u a ion in SGA child en.
The weigh inc eased du ing he i s 3 yea s and hen s abilized.
The mean weigh change was g ea e han 0 SDS, hough i was close
o 0 SDS in e e y e alua ion. A e he i s yea , he weigh inc ease
began o diminish. Simila esul s we e ob ained by Rod íguez e al.
32
on 152 SGA child en. In line wi h his inding, he BMI was s able
du ing ea men bu dec eased in he la e phase o ollow‐up. This
BMI s abili y has al eady been desc ibed by K ebs e al.
33
a 1 yea o
hGH. In his sense, Reineh e al.
34
in o he diso de s equi ing hGH,
BMI educ ions ha e been obse ed in sizes close o adul alues. Xu
e al.
4
has shown ha glucose me abolism and IS a e a ec ed in SGA
pa ien s, wi h he subsequen isk o de eloping ype‐2 DM and o he
in e ela ed me abolic diso de s.
5
BMI educ ion implies a dec ease in
o e weigh and a educ ion in ca dio ascula isk ac o s. P ä le
e al.
35
u ilized a biosimila hGH in he subg oup o SGA pa ien s,
os eochond osis and ype‐I DM. In a s udy ca ied ou by Rhie e al.
28
in Ko ea using hGH in a subg oup o 208 SGA child en, one case o
glucose in ole ance and one case o scoliosis we e epo ed.
TABLE 4 Fac o s in luencing he change o HOMA‐IR
Pa ame e Es ima e
S anda d
e o P > | |
In e cep −5.1530 1.2605 −4.09 <.0001
Basal insuline esis ance
(HOMA‐IR)
−0.5003 0.1034 −4.84 <.0001
Age a s a o ea men 0.5659 0.1329 4.26 <.0001
Basal weigh −0.2170 0.0646 −3.36 0.0009
Basal BMI 0.4066 0.0987 4.12 <.0001
R
2
0.2138
No e: Mul iple linea eg ession model. E aluable popula ion.
Abb e ia ions: BMI, body mass index; HOMA‐IR, homeos a ic model
assessmen o insulin esis ance.
LÓPEZ‐SIGUERO ET AL.
|
565
The ad e se e ec s ela ed o hyd oca bon me abolism ound in
ou s udy ha e been mild and ansi o y, al hough o de ec hem i is
some imes necessa y o pe o m an o al glucose o e load, since
nei he he HbA1c alue no he HOMA‐R index ha e been use ul.
Os eochond osis and o he al e a ions ela ed o ca ilage ischaemia
a e p esen ed by pain and in lamma o y signs. In all cases, long‐ e m
ollow‐up du ing and a e GH ea men , as pe o med in he SALTO
s udy,
12
is use ul.
One limi a ion o his s udy was i s obse a ional na u e. Age, a
possible con ounding ac o , was e alua ed by s a i ying he sample
acco ding o age a he beginning o ea men in ≤6 o >6 yea s o
age, wi hou inding signi ican di e ences in he HOMA‐IR alues
be ween bo h g oups. Due o his obse a ional na u e, a compa a-
i e no mal age‐and sex‐ma ched popula ion was no included. An-
o he limi a ion was i s mul icen e na u e, which inc eases he
a iabili y in measu emen s, p ocedu es and no mal anges a each
TABLE 5 T ea men eme gence
ad e se e en s acco ding o o gan/sys em
classi ica ion and p e e ed e ms
a
Ad e se e en E en s (n) Se e i y Se ious Rela ed o ea men
Congeni al, amilial and gene ic diso de s
Congeni al hypo hy oidism 1 Mild No No ela ed
Endoc ine diso de s
Au oimmune hy oidi is 1 Mild No No ela ed
Gene al diso de s and adminis a ion si e condi ions
Oedema pe iphe al 1 Mild No Unlikely
Hepa obilia y diso de s
Choleli hiasis 1 Mild No No ela ed
Hype ansaminasaemia 1 Mild No Unlikely
In es iga ions
IGF 1 Mild No P obable
IGF inc ease 4 Mild No P obable
Me abolism and nu i ion diso de s
Hype glycaemia 1 Mode a e Yes Possible
Type 2 diabe es melli us 1 Mode a e Yes P obable
Musculoskele al and connec i e issue diso de s
Back pain 1 Mode a e No P obable
Os eochond osis 2 Mild/mode a e No Unlikely
Os eonec osis 1 Mode a e Yes Possible
Scoliosis 1 Mode a e No Possible
Psychia ic diso de s
Anxie y 1 Mode a e No P obable
Renal and u ina y diso de s
Renal ailu e ch onic 1 Mode a e Yes Unlikely
Rep oduc i e sys em and b eas diso de s
Gynaecomas ia 1 Mild No ela ed
Va icocele 1 Mild No No ela ed
Skin and subcu aneous issue diso de s
De ma i is alle gic 1 Mild No Unlikely
Su gical and medical p ocedu es
Os eo omy 1 Mode a e No Unlikely
To al 23
Abb e ia ion: IGF, insulin‐like g ow h ac o .
a
In en ion o ea popula ion (N= 411).
566
|
LÓPEZ‐SIGUERO ET AL.