ACADEMIA Letters
“Continued Growth Hormone (GH) Treatment after Final
Height Is Necessary to Complete Somatic Development in
Childhood-Onset GH-Deficient Patients?”
Sofia Leka-Emiri
Elpis Athina Vlachopapadopoulou
This letter addresses the importance of growth hormone treatment during transition period
regarding its effect on final height, body composition and peak bone mass in response to the
paper of Attanasio at al from 2004 [1]. In the absence of compelling data to justify widespread
continuation of recombinant human growth hormone (rhGH) into adult life, there are several
questions related to its use that remain unanswered. The publication investigated whether
the maturational deficit in body composition/mass seen in severe growth hormone deficient
(GHD) patients after completion of pediatric GH treatment [1] could be partly or even fully
compensated for by adequate GH treatment during the transition phase into adulthood. They
performed a prospective, multinational (11 countries), randomized, controlled, 2-years study
in patients who completed pediatric rhGH treatment at final height. Patients were randomized
to receive rhGH at 25.0 μg/kg·d (pediatric dose; n = 58) or 12.5 μg/kg·d (adult dose; n = 59) or
no treatment (control; n = 32). The progress to peak bone mass shown previously by the same
study group [2] indicated that patients given additional GH treatment track their individual
bone mass and subsequently bone composition target. During the 2 yr, GH-treated patients
gained a significant amount of lean body mass (LBM) compared with controls (P < 0.001), but
there was no dose effect appreciated. Similarly, the decrease in fat mass (FM) was significantly
(P = 0.029) influenced by treatment, regardless of the dose. When the rhGH treatment effect
was analyzed by gender they found that the divergent pattern of change in LBM and FM in
males and females is consistent with normal developmental sexual dimorphism. However, the
assumption that dose requirements may have to be adjusted by gender, with females requiring
Academia Letters, August 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0
Corresponding Author: Elpis Athina Vlachopapadopoulou, [email protected]
Citation: Leka-Emiri, S., Vlachopapadopoulou, E.A. (2021). “Continued Growth Hormone (GH) Treatment
after Final Height Is Necessary to Complete Somatic Development in Childhood-Onset GH-Deficient Patients?”.
Academia Letters, Article 2820. https://doi.org/10.20935/AL2820.
1
a higher dose than males does not seem obvious considering the study’s design. Other factors
may contribute to the less effect on FM in females such as different habits between males
and females regarding nutrition and exercise that were not assessed in the study. The authors
correctly mention that during normal development from early adolescence until adulthood,
males lose up to 8% FM and females gain up to 6% FM [3]. Therefore, the different changes
seen in the LBM/height ratio and the contrasting changes in FM seen in males and females
suggest that the pattern of response to rhGH replacement in their patients primarily reflects
developmental gender dimorphism.
Underwood at al., had the same design and dose regimen with the one of Attanasio et al.
They randomized 64 patients to a 2-yr treatment with either placebo or rhGH (12.5 or 25.0
μg/kg·d) [4].According to the study criteria, however, patients up to 35 yr of age could be
enrolled, resulting in a mean age of 23.8 yr, i.e. 3–5 yr older than the previous study. In that
cohort, the LBM and FM changes from baseline to the 2-yr end point exhibited a significant
dose dependency [4]. However, the magnitude of the overall LBM increase (�3.5% with the
low dose and �6.5% with the high dose) was significantly less than the 13–14% seen in the
study of Attanasio et al. [1] and that by Vahl et al. [5]. In contrast, the FM changes seen
with the higher dose of 25.0 μg/kg·d, approximately 7%, were comparable with those seen in
the study of Attanasio et al [1,4]. Vahl et al. studied the 1-yr effect of rhGH at a dose of 2.0
IU/m2·d (�6.0 μg/kg·d) in 10 subjects who had discontinued pediatric GH treatment at final
height 1 yr earlier and found quantitative changes in LBM and FM [5]. Thus, there are dis-
crepancies between studies in the age and dose dependency of the body composition response
to GH. It is likely that size and baseline status of the study subjects, account to a large extent
for these discrepancies, but maturational stage seems to be an important factor. In fact, in the
study by Underwood et al. [4], a larger proportion of patients were older than that by Attanasio
et al. and that by Vahl et al. [5] and as such were no longer in transition, but already at adult
age. This difference may explain their overall smaller LBM change, which is quantitatively
comparable to that seen in adult onset (AO) GHD subjects who, over a comparable period,
usually gain not more than 5–6% LBM [6-8].
In contrast, a Phase III multicenter placebo controlled study by Mauras et al concluded
that GH-deficient patients properly treated in childhood have normal bone density and body
composition and QOL when reaching adult height and continuation of GH therapy for 2 yr did
not change these measures as compared to placebo-treated or control subjects. They suggested
that GH-deficient adolescents in good metabolic status at the time of epiphyseal fusion may
safely discontinue GH for at least 2 yr [9].
Furthermore, a prospective non-interventional study by Captosan et al have evaluated the
need for continuation of GH during the transition period of patients with CO-GHD and they
Academia Letters, August 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0
Corresponding Author: Elpis Athina Vlachopapadopoulou, [email protected]
Citation: Leka-Emiri, S., Vlachopapadopoulou, E.A. (2021). “Continued Growth Hormone (GH) Treatment
after Final Height Is Necessary to Complete Somatic Development in Childhood-Onset GH-Deficient Patients?”.
Academia Letters, Article 2820. https://doi.org/10.20935/AL2820.
2
have demonstrated that bone mineral density (BMD) increased after rhGH discontinuation but
they did not find a significant difference among those with permanent and those with transient
GHD. However, the limitation of this study is that the observation time was limited to 6 months
that is not an adequate time interval to permit an effect on BMD [10].
A randomized, controlled, open-label study conducted at 22 sites in 12 countries, with
primary objective to evaluate the effect of 24 months of GH treatment on BMD in young adults
with childhood-onset GHD, revealed that GH treatment was associated with a significantly
greater increase in BMD from baseline to end of treatment compared with controls. Of interest
is that in this trial females received higher dose of rhGH than males [11].
It is noteworthy that among all the studies, there was a considerable variability in definition
of GHD during transition and retesting in terms of stimulated GH peak cut-offs. Additionally
there was population heterogeneity between isolated GHD/multiple pituitary hormone defi-
ciencies (MPHD) and etiologies of GHD as well as duration of discontinuation of rhGH after
final height, rhGH dose during childhood and after final height. Moreover, measurement of
bone density using DXA in children and adolescents with CO-GHD is challenging by con-
founding effects of body size and composition, with no consensus as to what is the optimal
adjustment to express bone densitometry, additional to the lack of reference data that adjusts
for different confounding factors of growth impaired children and adolescents (23) [12]
Recently an official position paper of the American Association of Clinical Endocrinol-
ogists and American College of Endocrinology was published, that recommends that adults
with CO-GHD caused by structural pituitary or brain tumors be followed up closely during
transition as these patients tend to have lower bone mineral density, impaired bone microarchi-
tecture, and more adverse body composition abnormalities [13]. Moreover, resuming rhGH
replacement therapy in patients with confirmed persistent GHD during the transition period
after achievement of final height is recommended, as most studies have reported long-term
improvement in body composition and bone health in adulthood [13]. They have also com-
mented on the impact of the frequency of rhGH injections and reported that dosing in adults on
alternate days or 3 times a week has been shown to be as effective as daily dosing. In addition,
there is no clinically notable difference in the metabolic response to once- versus twice-daily
subcutaneous rhGH. As the frequency of injections is thought to be one of the factors con-
tributing to non-adherence to rhGH therapy in adults with GHD, a lower frequency dosing
schedule would be potentially less burdensome to patients and may improve adherence to
treat [13].
A significant limitation in interpreting the data is the absence of prospective controlled
trials with end point the number of fractures. Realistically, it is unlikely that such trials can
be feasibly conducted, thus caution is needed when interpreting these data. However, based
Academia Letters, August 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0
Corresponding Author: Elpis Athina Vlachopapadopoulou, [email protected]
Citation: Leka-Emiri, S., Vlachopapadopoulou, E.A. (2021). “Continued Growth Hormone (GH) Treatment
after Final Height Is Necessary to Complete Somatic Development in Childhood-Onset GH-Deficient Patients?”.
Academia Letters, Article 2820. https://doi.org/10.20935/AL2820.
3
on available published literature, short- and long-term GH replacement in adults with GHD
is safe [12] Therefore, patients with CO-GHD should be followed after completion of somatic
growth and be screened for permanent growth hormone deficiency and subsequent effects on
body composition, bone density, cardiovascular function, lipid profile and quality of life.
References
[1] Attanasio AF, Shavrikova E, Blum WF, et al (2004). Hypopituitary Developmental Out-
come Study Group. Continued growth hormone (GH) treatment after final height is nec-
essary to complete somatic development in childhood-onset GH-deficient patients. J Clin
Endocrinol Metab Metabolism, 89, 4857–4862
[2] Attanasio AF, Howell S, Bates PC, et al (2002). Body composition, IGF-I and IGFBP-3
concentrations as outcome measures in severely GH-deficient (GHD) patients after child-
hood GH treatment: a comparison with adult onset GHD patients. J Clin Endocrinol
Metab, 87, 3368–3372
[3] Forbes GB 1981 Body composition in adolescence. Prog Clin Biol Res 61:55–72
[4] Underwood LE, Attie KM, Baptista J; the Genentech Collaborative Study Group (2003).
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docrinol Metab, 88, 5273–5280
[5] Vahl N, Juul A, Jørgensen JOL, et al. (2000). Continuation of growth hormone (GH)
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Academia Letters, August 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0
Corresponding Author: Elpis Athina Vlachopapadopoulou, [email protected]
Citation: Leka-Emiri, S., Vlachopapadopoulou, E.A. (2021). “Continued Growth Hormone (GH) Treatment
after Final Height Is Necessary to Complete Somatic Development in Childhood-Onset GH-Deficient Patients?”.
Academia Letters, Article 2820. https://doi.org/10.20935/AL2820.
4
[9] Mauras N, Pescovitz OH, Allada V, et al. (2005) Limited efficacy of growth hormone
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[10]Çamtosun E, Şıklar Z, Berberoğlu M (2018).Prospective Follow-up of Children with Id-
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[11] Conway GS, Szarras-Czapnik M, Racz K, et al; 1369 GHD to GHDA Transition Study
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[12] Bishop N, Arundel P, Clark E, et al (2014). Fracture prediction and the definition of
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[13]Yuen KCJ, Biller BMK, Radovick S,et al (2019)American Association of Clinical En-
docrinologists and American College of Endocrinology Guidelines for Management of
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Care Endocr Pract,25, 1191-1232
Academia Letters, August 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0
Corresponding Author: Elpis Athina Vlachopapadopoulou, [email protected]
Citation: Leka-Emiri, S., Vlachopapadopoulou, E.A. (2021). “Continued Growth Hormone (GH) Treatment
after Final Height Is Necessary to Complete Somatic Development in Childhood-Onset GH-Deficient Patients?”.
Academia Letters, Article 2820. https://doi.org/10.20935/AL2820.
5
