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Best Practice & Research Clinical Endocrinology & Metabolism 31 (2017) 71e78

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Best Practice & Research Clinical


Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem

Focus on GH deciency and thyroid function


Claudia Giavoli, MD, Specialist in Endocrinology a, b, *,
Eriselda Profka, MD, Resident doctor in Endocrinology a, b,
Giulia Rodari, MD, Resident doctor in Endocrinology a, b,
Andrea Lania, MD, Associate Professor and Head of
Endocrinology Unit c, Paolo Beck-Peccoz, MD d
a
Endocrinology and Diabetology Unit, Fondazione IRCCS Ca  Granda Ospedale Maggiore Policlinico, Milan,
Italy
b
Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
c
Endocrine Unit, IRCCS Humanitas Research Hospital, Department of Biomedical Sciences, Humanitas
University, Rozzano, Italy
d
Professor Emeritus of the University of Milan, Milan, Italy

a r t i c l e i n f o
The relationships between GH system and hypothalamicepituitary
Article history: ethyroid axis are complex and not yet fully understood. The re-
Available online 24 February 2017 ported effects of GH administration on thyroid status of GHD pa-
tients have been remarkably divergent.
Keywords: This review will focus on the main studies aimed to clarify the
growth hormone decient adults effects of GH on thyroid function, rstly going through the diag-
central hypothyroidism nosis of central hypothyroidism and its possible pitfalls, then
recombinant hGH elucidating the possible contexts in which GHD may develop and
thyroid function examining the proposed mechanisms at the basis of interactions
L-T4 replacement therapy
between the GH-IGF-I system and the hypothalamicepituitary
ethyroid axis.
2017 Elsevier Ltd. All rights reserved.

Introduction

Growth hormone deciency (GHD) in adults is a complex syndrome, in which specic signs and
symptoms are often accompanied by sign and symptoms of other pituitary hormones deciency in a
picture known as multiple pituitary hormone deciencies (MPHD) [1].

* Corresponding author. Endocrinology and Diabetology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico,
Via Francesco Sforza 35, 20123, Milan, Italy.
E-mail address: claudia.giavoli@gmail.com (C. Giavoli).

http://dx.doi.org/10.1016/j.beem.2017.02.003
1521-690X/ 2017 Elsevier Ltd. All rights reserved.
72 C. Giavoli et al. / Best Practice & Research Clinical Endocrinology & Metabolism 31 (2017) 71e78

Indeed, while adult GHD is mostly due to organic lesions involving the hypothalamicepituitary
region, in children it is frequently congenital and isolated. Nonetheless, also in children lesions of the
hypothalamicepituitary region may be associated with GHD. Thus, it is of importance to carefully
evaluate the functional state of other hypothalmicepituitary axes before replacing GHD. Moreover, it is
also crucial to assess the possible interactions between GH treatment and the secretion of other pi-
tuitary hormones.
The relationship between the GH system and hypothalamicepituitaryethyroid axis, though one of
the most investigated, is indeed complex and not yet fully understood. The reported effects of recom-
binant human GH (rhGH) administration on thyroid status of GHD patients have been remarkably
divergent, mostly because of different methods for hormone measurements, different dosage schedules,
diagnostic criteria, patient selection, duration of treatment and study design. Furthermore, many studies
have been performed many years ago, when the used pituitary GH preparations were of variable purity
and in some instances they were contaminated with TSH. The introduction of ultrasensitive TSH
immunometric assays, the availability of direct methods for the measurement of circulating free T4 and
T3, as well as the clinical use of recombinant human GH (rhGH), have prompted several studies not only
in children but also in adults, aimed to evaluate the effects of rhGH replacement on thyroid function and
clarify the mechanisms at the basis of the interaction between these two complex endocrine axes.

GH-IGF-I axis and hypothalamicepituitaryethyroid axis: mechanism of interactions

In physiological conditions, several studies reported that the main effect of GH is a reduction of
thyroxine (T4) levels, transient in some cases and persistent in others, as will be later discussed. How-
ever, different mechanisms have been suggested to explain the interaction between GH and thyroid
function. The rst one, at peripheral level, suggests an increase in extra-thyroidal conversion of T4 to
triiodothyronine (T3) chiey mediated by GH, also supported by the ndings of reduced reverse-T3 (rT3)
and/or increased T3/T4 ratio after the beginning of rhGH therapy [2e7]. The stimulatory effect of GH on
circulating T3 levels has been demonstrated not only in man, but also in a variety of vertebrate, such as
lambs [8], cattle [9], chicken [10], and it was concluded that GH stimulates the 50 -monodeiodination of
T4 to T3. In mammals different types of iodothyronine deiodinating enzymes (type I, II and III) have been
characterized. The sites where GH affects thyroid hormone metabolism are not known in humans. The
monodeiodination of T4 to T3 (activation pathway) is catalyzed both by type 1 (D1) and type 2 (D2)
deiodinase, while monodeiodination of T4 to rT3 (inactivation pathway) is mediated by type 3 deiodi-
nase (D3). In humans GH receptors are expressed in many organs and tissues that predominantly express
one or more deiodinases: D 1 in liver and kidney, D2 in skeletal and muscle, D1, D2 and D3 in brain. The
nding, in untreated GHD, of a decreased conversion of T4 to T3, along with an increased rT3 [11]
suggests a physiological role of endogenous GH in the peripheral metabolism of thyroid hormones,
though it still remains to be demonstrated in humans which activation pathway is under GH control.
A second mechanism acting at central level, points to an inhibition of TSH release [12,13] via an
increased somatostatinergic tone or by a T3 negative feedback mechanism within the thyrotropes, due
to increased T3 production from T4 deiodination [2e4,7,14,15]. Indeed, some Authors reported a sig-
nicant blunting of TSH nocturnal surge in GH decient adults on rhGH replacement [12,13]. However,
the fact that many studies have not found TSH variation during rhGH therapy suggests that the
decrease of T4 levels should be independent from TSH secretion [11].
It also remains unclear if the effect on the hypothalamicepituitary-thyroid (HPT) axis is directly
mediated by GH, or through IGF-I. The involvement of IGF-I is supported by the demonstration of low T3
levels that reect reduced deiodination of T4 to T3, a nding common to different catabolic conditions
characterized by high GH and low IGF-I levels [13]. On the contrary, in some studies IGF-I administration
has not been found to have any effect on serum T3. For instance, Klinger and collaborators [16] did not
observe any increase in serum T3 after short or long-term IGF-1 administration in patients with GH
insensitivity due to mutation of GH receptor. Similarly, a much higher T3 increase has been described after
GH than after IGF-I administration in GHD subjects [17]. Finally, it has also been suggested that GH could
act directly by accelerating T4 half-life and inversely delaying the half-life of T3 [18], as well as by affecting
thyroxine clearance rate or reducing levothyroxine (L-T4) uptake from the gastrointestinal tract [19].
C. Giavoli et al. / Best Practice & Research Clinical Endocrinology & Metabolism 31 (2017) 71e78 73

Central hypothyroidism: diagnosis and pitfalls

When considering the effect of GH on HPT axis, it is important to take into account the complexity
surrounding the diagnosis of CH. The diagnostic procedure is extremely challenging and largely
biochemical, as it is based on the nding of a low serum FT4 associated with inappropriately low/
normal/slightly elevated serum TSH levels. Indeed, a large study performed in 1979, in 89 patients with
CH due to various pituitary diseases, reported TSH levels undetectable in 35% of patients, within the
normal range in 41% and above the normal range in 24% [20]. The diagnosis of CH cannot be reached by
the sole TSH determination [21e23]. Indeed, the combined evaluation of TSH and thyroid hormone is
required for CH diagnosis of whatever origin and is usually suggested by the nding of low FT4 con-
centrations, associated with low/normal TSH levels. Nevertheless, some CH patients with a prevalent
hypothalamic defect have high serum immunoreactive TSH levels, but devoid of full biological activity
[20]. This nding potentially may lead to misdiagnosis of subclinical primary hypothyroidism [20,21].
Moreover, in order to allow an early diagnosis and treatment, Alexopoulou and colleagues sug-
gested as diagnostic value the decrease in circulating FT4 levels of 20% from the initial determination in
patients with different pituitary diseases, even in the presence of serum FT4 levels still into the normal
range [22].
As for replacement therapy, optimal L-T4 doses are similar to those actually used in primary hy-
pothyroidism and younger CH patients require higher FT4 administration than older patients [22,23].

Growth hormone deciency

The growth hormone deciency (GHD) has different etiopathogenesis and different clinical
implications.
In childhood, GHD is mainly congenital and isolated, its main feature being short stature and
decreased growth velocity. Along with this clinical context, diagnosis is made by the absence of GH-
response to specic stimulation tests (arginine, clonidine, glucagon or insulin, with a GH cut-off of
8 mg/l or GHRH arginine with a cut-off of 20 mg/l) [24].
Conversely, in most of adults, as in a small number of children, GHD is organic, i.e. caused by
hypothalamicepituitary diseases or their therapy (surgery and/or radiotherapy). In this case, GHD is
frequently associated with other pituitary decits, in a picture known as multiple pituitary hormone
deciencies (MPHD). In adults, along with an appropriate clinical background, diagnosis of GHD is
made by the lack of GH response to specic stimuli, the most used being or insulin (cut off less than
3 mg/l) or GHRH arginine with cut-off varying according to body mass index [25].
In the context of hypothalamicepituitary diseases, when GHD is often part of a more complex
picture of MPHD, GH replacement should follow specic rules. It is important that other eventual
decits are adequately replaced before even starting the work-up to diagnose GHD. Moreover, GH
replacement therapy may exert specic effects on other pituitary axes in the case of MPHD, or any
signicant effect in the case of an otherwise normal pituitary function [19].

Growth hormone replacement and thyroid function

The rst trials aimed to evaluate the effect of GH replacement on thyroid function have been per-
formed in GH-decient children with and without concomitant L-T4-treated central hypothyroidism.
Porter and collaborators [2] described the occurrence of central hypothyroidism, with no changes in
total T4 levels but a decrease in basal and TRH-stimulated TSH in 2 out of 5 GH decient (GHD) ad-
olescents during GH treatment. Lippe and colleagues [26] observed a decline in serum total T4,
accompanied in some patients by a decrease in growth response, which again improved after L-T4
substitution, with no change in serum total T3. Sato and collaborators [3] noted a decrease in serum
total T4 and an increase in serum total T3 accompanied by an increased TSH release in 8 GHD ado-
lescents (5 euthyroid and 3 central hypothyroid), who were treated with GH for 2 months. However,
more recent observations suggest that most hormonal modications are transient and do not require L-
T4 replacement [6,27]. In a cohort of rhGH-treated children affected with either idiopathic isolated
GHD or MPHD due to surgically treated pituitary/hypothalamic tumors, we showed that in the former
74 C. Giavoli et al. / Best Practice & Research Clinical Endocrinology & Metabolism 31 (2017) 71e78

the decrease in serum FT4 levels was not of clinical relevance, while in the latter a clear state of central
hypothyroidism was seen in more than a half of children [19] (Fig. 1).
Recently, the widespread use of rhGH in adults prompted several studies aimed to understand the
possible interaction between GH-IGF-I axis and HPT axis. Initial data in healthy subjects showed no
signicant impact of GH administration on thyroid function, apart from a small decline in the binding
capacity of thyroxine-binding globulin (TBG), accompanied by a decline in serum total proteins and
albumin possibly caused by uid retention, known to accompany high-dose and supra-physiological
GH administration [14,28]. Grunfeld and collaborators studied the acute effects of GH on thyroid
function in normal men after 4 days of administration of 0.125 mg of rhGH, describing a parallel decline
in serum total T4 and FT4, an increase in total T3, no changes in serum reverse T3 and a marked
decrease in serum TSH [5]. Other studies in healthy subjects reported similar results, with increased
total T3 and FT3 either associated with changes in TSH concentration [29] or combined with decreased
rT3 [30]. Supra-physiological administration of rhGH in 14 healthy athletes caused a prompt and
signicant decrease in TSH circulating levels, without FT3 modication and with FT4 reduction delayed
in time, suggesting a direct action of IGF-I at central level and/or a negative feedback throughout T4 to
T3 conversion enhancement [31].
Concerning adults with GHD treated with rhGH, contradictory results have been reported. The
major studies so far available are reported in Table 1. The above-mentioned discrepancies could be
ascribed to different factors as small sample size, different study protocol, different biochemical ana-
lytic methods, different criteria for GHD diagnosis and in the older studies the use of cadaveric GH in
some cases possibly contaminated with TSH.
Jrgensen and colleagues conducted a double blind, placebo-controlled cross-over study on the
effect of 4 months of rhGH therapy (2 IU/m2/day) on thyroid function in GH-decient adults (13
euthyroid and 9 hypothyroid on L-T4 treatment). During GH therapy TBG levels remained unaltered,
TSH levels decreased, total T4, FT4 and rT3 decreased in both groups, while total T3 and FT3 increased
in all patients suggesting a GH-induced enhancement of peripheral deiodination of T4 to T3 [7]. Amato
and collaborators studied 9 GHD adults (7 congenital and 2 acquired GH deciency), before and after a
12-month period of rhGH treatment at the dose of 10 mg/kg/day and no alteration in thyroid function
was observed [32].
Later on, in a multicenter study, we evaluated thyroid function in a quite large cohort of patients
with adult or childhood onset of severe GHD (17 euthyroid patients and 49 with central hypothy-
roidism) treated with different rhGH doses (3e12 mg/kg/day). A signicant reduction in FT4 and rT3
levels without variation in TSH, FT3 e TBG levels in the whole group of patients was found. In particular,
in 47% of euthyroid subjects, independently form rhGH dose, serum FT4 clearly fell into the

Fig. 1. FT4 serum levels in children with idiopathic isolated GHD (IGHD) and multiple pituitary hormone deciencies (MPHD) before
and during rhGH therapy.
C. Giavoli et al. / Best Practice & Research Clinical Endocrinology & Metabolism 31 (2017) 71e78 75

Table 1
Alteration of hypothalamicepituitaryethyroid axis during GH therapy in adults.

Study N GHD CH TT4/FT4 TSH TT3/FT3 rT3 % newCH

Grunfeld et al., (1968) 4 No 0 Y/Y Y [/NA 0


Ho et al., (1989) 6 No 0 /NA Y [/NA NA 0
Jorgensen et al., (1989) 21 Yes 9 Y/Y YNS [/[ Y 0
Moller et al., (1992) 14 No 0 / [/[ YNS 0
Amato et al., (1996) 9 Yes 9 / / 0
Porretti et al., (2002) 66 Yes 49 NA/Y NA/[transient Y 47
Agha et al., (2007) 243 Yes 159 YNS/Y [NS/NA NA 36
Losa et al., (2008) 49 Yes 37 NA/Y NA/ NA 17
 et al., (2010)
Sgro 14 No 0 NA/Y Y NA/ NA 0

GHD, growth hormone deciency; CH, central hypothyroidism pre-treatment with rhGH; , unchanged; Y, decreased; [,
increased; NA, not available; NS, not signicant.

Fig. 2. FT4 serum levels in adults with organic multiple pituitary hormone deciencies before and after 6- month rhGH therapy at
low doses (LD: 6 mg/kg bw/day) and high doses (HD 12 mg/kg bw/day).

hypothyroid range and some of these patients reported symptoms of hypothyroidism [33] (Fig. 2). Such
results underline that, in adults as well as in children with organic GHD, rhGH therapy unmasks a state
of central hypothyroidism, hidden by the condition of GHD itself.
In the report by Porretti and colleagues, the alteration of hypothalamicepituitaryethyroid function
was documented by the decline in serum FT4 levels, stressing the importance of the direct measure-
ment of FT4 in the management of central hypothyroid patients, as previously underlined [23]. These
results have been conrmed by a following study performed by Agha and colleagues in a group of 243
patients with severe GHD due to various hypothalamusepituitary disorders. Before treatment, 159
patients had treated central hypothyroidism, while 84 patients were euthyroid. During rhGH therapy, a
signicant reduction in T4 serum concentration requiring initiation of L-T4 therapy was observed in
36% of euthyroid patients and 16% of hypothyroid patients needed an increase of L-T4 dose. No sig-
nicant changes in T3 or TSH were reported [34]. In this study the main predictor for the development
of central hypothyroidism was the presence of MPHD.
Recently, Losa and colleagues studied a cohort of 49 GHD adults, 43 with acquired and 6 with
congenital GHD, during 5 years of rhGH treatment. At baseline, 37 patients were hypothyroid on L-T4
treatment while the remaining 12 patients had normal thyroid function. Authors observed a decrease
in FT4 levels in a dose dependent way, among both euthyroid and hypothyroid patients, even though
the clinical relevance of this decrease was less pronounced than previously reported (only 6% of pa-
tients). The discrepancy with earlier results was explained with the low rhGH doses used in the study
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[35]. However, as observed in the study by Porretti and colleagues, the striking fall in serum FT4 levels
was present even in patients treated with low rhGH doses [33].
Indeed, the main message of the studies on this topic emphasizes the need of a careful monitoring
of thyroid function in patients with organic GHD during rhGH administration, since the high percent of
subjects becoming hypothyroid during such treatment indicates that GHD frequently masks a state of
central hypothyroidism, as also suggested by The Endocrine Society Clinical Practice Guideline on
Evaluation and Treatment of Adult Growth Hormone Deciency [36].

Growth hormone replacement and thyroid volume

Conicting data exist over the effects of GH therapy on thyroid morphology and thyroid volume
(TV). It is known that TSH is the major regulator of thyroid hormone biosynthesis and thyroid growth.
On the other had, together with TSH, IGF-I is able to exert a proliferative role through its own receptors,
largely expressed in thyroid cells [37e39]. In vitro studies have shown that goiter development in
knock-out mice with thyrocyte-selective ablation of IGF-I receptor was completely abolished con-
rming an essential role for IGF-I receptor signaling in the regulation of thyroid function and TSH-
stimulated goitrogenesis [40]. Concordantly, elevated levels of IGF-I have been associated with an
increased occurrence of thyroid goiter [41]. In fact, 25e70% of acromegalic patients has goiter and
elevated IGF-I levels correlate positively with TV [42,43].
Furthermore, reduced TV has been described in hypopituitaric patient. It is not clear if the presence
of TSH is fundamental for the growth promoting actions of IGF-I on the thyroid cells. Cheung and
coworkers evaluated a group of 14 subjects with both TSH and GH deciency. After 6 month of rhGH
therapy TV did not change signicantly. Authors concluded that IGF-I does not stimulate per se in vivo
thyroid growth, but promotes thyroid cell proliferation by potentiating the mitogenic action of TSH
[44].
Alcantara and collaborators studied adult Brazilians with isolated GHD due to homozygous muta-
tion in the GHRH receptor gene compared with patients heterozygous for the same mutation and with
a normal group. Severe untreated GHD patients due to homozygous GHRH mutation had smaller TV
than normal subjects and GHD patients with heterozygous mutation and TV correlated both with IGF-I
levels and height, suggesting a permissive role of GH in thyroid growth [45].
Similarly, Leite and collaborators described an increase of TV and T3 levels in 20 patients with
congenital isolated GHD after 6 month of rhGH therapy [46].
Recently, Curto and collaborators [47] studied 96 subjects with childhood and adult onset GHD
before and after 5 years of rhGH therapy. Pretreatment TV was smaller in GHD patients than in healthy
subjects. During GH therapy, TV signicantly increased only in patients without concomitant central
hypothyroidism, suggesting once again a leading role of TSH in the stimulation of normal thyroid
growth. Moreover, in this study GH therapy was associated with an increased risk of developing thyroid
nodules depending on pre treatment IGF-levels and treatment duration even in patients with
concomitant central hypothyroidism. Authors concluded that although GH supplementation cannot
restore normal TV in the absence of TSH, it can induce proliferation of thyrocytes due to its well known
proliferative and mitogenic effects.

Conclusion

In conclusion, either through an increased conversion of T4 to T3 or via a decrease in TSH pulse and
secretion, GH does not alter the balance of a functioning hypothalamicepituitaryethyroid axis, nely
regulated by the feedback system. In fact, in patients with idiopathic isolated GHD (with intact HPT
axis), only transient and not signicant changes in thyroid hormones have been reported. Conversely, a
real hypothyroid state during rhGH therapy has been observed in patients with organic GH deciency,
in which alteration of HPT axis (central hypothyroidism), was already present before rhGH therapy and
masked by the condition of GHD.
As many studies have shown, rhGH therapy in hypopituitaric patients is associated with signicant
reduction in serum FT4 levels, unmasking clinical and biochemical central hypothyroidism in a
considerable number of them. Thus, during rhGH treatment, a careful monitoring of thyroid function
C. Giavoli et al. / Best Practice & Research Clinical Endocrinology & Metabolism 31 (2017) 71e78 77

through the direct measurement of FT4 serum levels is mandatory in order to start or adjust L-T4
therapy as necessary.

Practice points

 Recombinant hGH replacement therapy does not induce central hypothyroidism in patients
with idiopathic isolated GHD and a strict monitoring of thyroid function during rhGH treat-
ment is not so necessary in these patients, at the variance of what is mandatory in treated
subjects, either children or adults, with multiple pituitary hormone deficiency due to organic
disease.
 The fall in serum FT4 levels recorded in patients with MPHD is due to the manifestation of a
pre-existing hypothyroid state, hidden by GHD, and unmasked by rhGH substitution.
 The best way to diagnose central hypothyroidism is the direct measurement of serum FT4
and TSH levels, after exclusion of assay interference.
 The high percent of GHD patients who become hypothyroid during such a treatment in-
dicates that GH deficiency, and the consequent low synthesis and secretion of IGF-I,
frequently masks a state of central hypothyroidism. In these patients, an additional substi-
tutive L-T4-treatment is mandatory, whereas in already LT4-treated patients an adjustment of
L-T4 therapy is necessary.

Research agenda

 Better understand the mechanisms through which GH influences thyroid hormones.


 Identify a possible role of GH receptor polymorphism in the interaction between GH and
thyroid during rhGH therapy.
 Investigate the role of rhGH therapy on the expression and function of the various iodo-
thyronine deiodinases.

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