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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

7

Focus on GH deficiency 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 deficient adults effects of GH on thyroid function, firstly 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 deficiency (GHD) in adults is a complex syndrome, in which specific signs and
symptoms are often accompanied by sign and symptoms of other pituitary hormones deficiency in a
picture known as multiple pituitary hormone deficiencies (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.

How- ever. II and III) have been characterized. A second mechanism acting at central level. in children it is frequently congenital and isolated. and it was concluded that GH stimulates the 50 -monodeiodination of T4 to T3. the availability of direct methods for the measurement of circulating free T4 and T3. in untreated GHD. a much higher T3 increase has been described after GH than after IGF-I administration in GHD subjects [17]. different mechanisms have been suggested to explain the interaction between GH and thyroid function. In mammals different types of iodothyronine deiodinating enzymes (type I. However. cattle [9]. while monodeiodination of T4 to rT3 (inactivation pathway) is mediated by type 3 deiodi- nase (D3).72 C. The reported effects of recom- binant human GH (rhGH) administration on thyroid status of GHD patients have been remarkably divergent. Similarly. a finding common to different catabolic conditions characterized by high GH and low IGF-I levels [13]. also supported by the findings of reduced reverse-T3 (rT3) and/or increased T3/T4 ratio after the beginning of rhGH therapy [2e7]. Indeed. Moreover. different dosage schedules. transient in some cases and persistent in others. though one of the most investigated. due to increased T3 production from T4 deiodination [2e4. along with an increased rT3 [11] suggests a physiological role of endogenous GH in the peripheral metabolism of thyroid hormones.14. points to an inhibition of TSH release [12. chicken [10]. also in children lesions of the hypothalamicepituitary region may be associated with GHD. The relationship between the GH system and hypothalamicepituitaryethyroid axis. but also in a variety of vertebrate. is indeed complex and not yet fully understood. For instance. or through IGF-I. The involvement of IGF-I is supported by the demonstration of low T3 levels that reflect reduced deiodination of T4 to T3.15]. On the contrary. it has also been suggested that GH could act directly by accelerating T4 half-life and inversely delaying the half-life of T3 [18]. 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]. such as lambs [8].13] via an increased somatostatinergic tone or by a T3 negative feedback mechanism within the thyrotropes. some Authors reported a sig- nificant blunting of TSH nocturnal surge in GH deficient adults on rhGH replacement [12. while adult GHD is mostly due to organic lesions involving the hypothalamicepituitary region. Giavoli et al. Nonetheless. Thus. it is also crucial to assess the possible interactions between GH treatment and the secretion of other pi- tuitary hormones. 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. as well as by affecting thyroxine clearance rate or reducing levothyroxine (L-T4) uptake from the gastrointestinal tract [19]. though it still remains to be demonstrated in humans which activation pathway is under GH control. GH-IGF-I axis and hypothalamicepituitaryethyroid axis: mechanism of interactions In physiological conditions. Furthermore. The introduction of ultrasensitive TSH immunometric assays. The monodeiodination of T4 to T3 (activation pathway) is catalyzed both by type 1 (D1) and type 2 (D2) deiodinase. several studies reported that the main effect of GH is a reduction of thyroxine (T4) levels. many studies have been performed many years ago. The sites where GH affects thyroid hormone metabolism are not known in humans. in some studies IGF-I administration has not been found to have any effect on serum T3. In humans GH receptors are expressed in many organs and tissues that predominantly express one or more deiodinases: D 1 in liver and kidney. have prompted several studies not only in children but also in adults. mostly because of different methods for hormone measurements. D2 and D3 in brain. duration of treatment and study design. . of a decreased conversion of T4 to T3. as will be later discussed. / Best Practice & Research Clinical Endocrinology & Metabolism 31 (2017) 71e78 Indeed. suggests an increase in extra-thyroidal conversion of T4 to triiodothyronine (T3) chiefly mediated by GH. it is of importance to carefully evaluate the functional state of other hypothalmicepituitary axes before replacing GHD.7. The first one. 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. at peripheral level. as well as the clinical use of recombinant human GH (rhGH).13]. when the used pituitary GH preparations were of variable purity and in some instances they were contaminated with TSH. D1. The stimulatory effect of GH on circulating T3 levels has been demonstrated not only in man. Finally. D2 in skeletal and muscle. diagnostic criteria. It also remains unclear if the effect on the hypothalamicepituitary-thyroid (HPT) axis is directly mediated by GH. patient selection. The finding.

Moreover. GHD is mainly congenital and isolated. It is important that other eventual deficits are adequately replaced before even starting the work-up to diagnose GHD. 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). diagnosis is made by the absence of GH- response to specific stimulation tests (arginine. In a cohort of rhGH-treated children affected with either idiopathic isolated GHD or MPHD due to surgically treated pituitary/hypothalamic tumors. its main feature being short stature and decreased growth velocity. reported TSH levels undetectable in 35% of patients. in a picture known as multiple pituitary hormone deficiencies (MPHD). / Best Practice & Research Clinical Endocrinology & Metabolism 31 (2017) 71e78 73 Central hypothyroidism: diagnosis and pitfalls When considering the effect of GH on HPT axis.21]. caused by hypothalamicepituitary diseases or their therapy (surgery and/or radiotherapy). but devoid of full biological activity [20]. This finding potentially may lead to misdiagnosis of subclinical primary hypothyroidism [20. in 89 patients with CH due to various pituitary diseases. 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. The diagnosis of CH cannot be reached by the sole TSH determination [21e23].27]. In adults. Indeed. Giavoli et al. GHD is frequently associated with other pituitary deficits. as it is based on the finding of a low serum FT4 associated with inappropriately low/ normal/slightly elevated serum TSH levels. Lippe and colleagues [26] observed a decline in serum total T4. In the context of hypothalamicepituitary diseases. with no changes in total T4 levels but a decrease in basal and TRH-stimulated TSH in 2 out of 5 GH deficient (GHD) ad- olescents during GH treatment. Growth hormone replacement and thyroid function The first trials aimed to evaluate the effect of GH replacement on thyroid function have been per- formed in GH-deficient children with and without concomitant L-T4-treated central hypothyroidism. diagnosis of GHD is made by the lack of GH response to specific stimuli. Along with this clinical context. which again improved after L-T4 substitution.23]. However. associated with low/normal TSH levels. the combined evaluation of TSH and thyroid hormone is required for CH diagnosis of whatever origin and is usually suggested by the finding of low FT4 con- centrations. with a GH cut-off of 8 mg/l or GHRH þ arginine with a cut-off of 20 mg/l) [24]. Conversely. In this case. with no change in serum total T3. even in the presence of serum FT4 levels still into the normal range [22]. within the normal range in 41% and above the normal range in 24% [20]. who were treated with GH for 2 months. it is important to take into account the complexity surrounding the diagnosis of CH. in most of adults. Indeed. accompanied in some patients by a decrease in growth response. or any significant effect in the case of an otherwise normal pituitary function [19]. glucagon or insulin. Growth hormone deficiency The growth hormone deficiency (GHD) has different etiopathogenesis and different clinical implications. we showed that in the former . along with an appropriate clinical background. Porter and collaborators [2] described the occurrence of central hypothyroidism. GH replacement should follow specific rules.e. 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. Moreover. as in a small number of children. when GHD is often part of a more complex picture of MPHD. a large study performed in 1979. clonidine. In childhood. C. more recent observations suggest that most hormonal modifications are transient and do not require L- T4 replacement [6. i. in order to allow an early diagnosis and treatment. The diagnostic procedure is extremely challenging and largely biochemical. GHD is organic. Nevertheless. As for replacement therapy. some CH patients with a prevalent hypothalamic defect have high serum immunoreactive TSH levels. GH replacement therapy may exert specific effects on other pituitary axes in the case of MPHD. the most used being or insulin (cut off less than 3 mg/l) or GHRH þ arginine with cut-off varying according to body mass index [25].

. contradictory results have been reported. in a multicenter study. During GH therapy TBG levels remained unaltered. with increased total T3 and FT3 either associated with changes in TSH concentration [29] or combined with decreased rT3 [30]. / Best Practice & Research Clinical Endocrinology & Metabolism 31 (2017) 71e78 the decrease in serum FT4 levels was not of clinical relevance. 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). Amato and collaborators studied 9 GHD adults (7 congenital and 2 acquired GH deficiency). describing a parallel decline in serum total T4 and FT4. 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]. different study protocol. placebo-controlled cross-over study on the effect of 4 months of rhGH therapy (2 IU/m2/day) on thyroid function in GH-deficient adults (13 euthyroid and 9 hypothyroid on L-T4 treatment). in 47% of euthyroid subjects. Other studies in healthy subjects reported similar results. FT3 e TBG levels in the whole group of patients was found. total T4. The above-mentioned discrepancies could be ascribed to different factors as small sample size. serum FT4 clearly fell into the Fig. independently form rhGH dose. different criteria for GHD diagnosis and in the older studies the use of cadaveric GH in some cases possibly contaminated with TSH. suggesting a direct action of IGF-I at central level and/or a negative feedback throughout T4 to T3 conversion enhancement [31]. 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]. different biochemical ana- lytic methods. A significant reduction in FT4 and rT3 levels without variation in TSH. Giavoli et al. apart from a small decline in the binding capacity of thyroxine-binding globulin (TBG). Concerning adults with GHD treated with rhGH. In particular. accompanied by a decline in serum total proteins and albumin possibly caused by fluid retention. known to accompany high-dose and supra-physiological GH administration [14. Jørgensen and colleagues conducted a double blind. Grunfeld and collaborators studied the acute effects of GH on thyroid function in normal men after 4 days of administration of 0. The major studies so far available are reported in Table 1. Later on. Supra-physiological administration of rhGH in 14 healthy athletes caused a prompt and significant decrease in TSH circulating levels. no changes in serum reverse T3 and a marked decrease in serum TSH [5].28]. 1). without FT3 modification and with FT4 reduction delayed in time. 1. an increase in total T3. TSH levels decreased. Initial data in healthy subjects showed no significant impact of GH administration on thyroid function. FT4 serum levels in children with idiopathic isolated GHD (IGHD) and multiple pituitary hormone deficiencies (MPHD) before and during rhGH therapy. 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.74 C.125 mg of rhGH. while in the latter a clear state of central hypothyroidism was seen in more than a half of children [19] (Fig.

In the report by Porretti and colleagues. in adults as well as in children with organic GHD. ↔. (1992) 14 No 0 ↔/↔ ↔ [/[ YNS 0 Amato et al. (2002) 66 Yes 49 NA/Y ↔ NA/[transient Y 47 Agha et al. hidden by the condition of GHD itself.. a significant 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. the alteration of hypothalamicepituitaryethyroid function was documented by the decline in serum FT4 levels. CH. 37 patients were hypothyroid on L-T4 treatment while the remaining 12 patients had normal thyroid function.. NS. (1968) 4 No 0 Y/Y Y [/NA ↔ 0 Ho et al.. (2010) Sgro 14 No 0 NA/Y Y NA/↔ NA 0 GHD. Y. (1989) 21 Yes 9 Y/Y YNS [/[ Y 0 Moller et al.. among both euthyroid and hypothyroid patients. (2008) 49 Yes 37 NA/Y ↔ NA/↔ NA 17  et al. In this study the main predictor for the development of central hypothyroidism was the presence of MPHD. stressing the importance of the direct measure- ment of FT4 in the management of central hypothyroid patients. NA. not available.. (2007) 243 Yes 159 YNS/Y ↔ [NS/NA NA 36 Losa et al. rhGH therapy unmasks a state of central hypothyroidism. Study N GHD CH TT4/FT4 TSH TT3/FT3 rT3 % newCH Grunfeld et al. At baseline. These results have been confirmed by a following study performed by Agha and colleagues in a group of 243 patients with severe GHD due to various hypothalamusepituitary disorders. central hypothyroidism pre-treatment with rhGH.. Recently.. (1996) 9 Yes 9 ↔/↔ ↔ ↔/↔ ↔ 0 Porretti et al. even though the clinical relevance of this decrease was less pronounced than previously reported (only 6% of pa- tients). increased. Authors observed a decrease in FT4 levels in a dose dependent way. The discrepancy with earlier results was explained with the low rhGH doses used in the study . No sig- nificant changes in T3 or TSH were reported [34].month rhGH therapy at low doses (LD: 6 mg/kg bw/day) and high doses (HD 12 mg/kg bw/day). growth hormone deficiency. 2). hypothyroid range and some of these patients reported symptoms of hypothyroidism [33] (Fig. [. Giavoli et al. 2. decreased. unchanged. as previously underlined [23]. 43 with acquired and 6 with congenital GHD. Fig. during 5 years of rhGH treatment. (1989) 6 No 0 ↔/NA Y [/NA NA 0 Jorgensen et al. C. Losa and colleagues studied a cohort of 49 GHD adults. Such results underline that. Before treatment. while 84 patients were euthyroid. During rhGH therapy. / Best Practice & Research Clinical Endocrinology & Metabolism 31 (2017) 71e78 75 Table 1 Alteration of hypothalamicepituitaryethyroid axis during GH therapy in adults... 159 patients had treated central hypothyroidism. not significant. FT4 serum levels in adults with organic multiple pituitary hormone deficiencies before and after 6.

Similarly. Cheung and coworkers evaluated a group of 14 subjects with both TSH and GH deficiency. / Best Practice & Research Clinical Endocrinology & Metabolism 31 (2017) 71e78 [35]. it can induce proliferation of thyrocytes due to its well known proliferative and mitogenic effects. GH does not alter the balance of a functioning hypothalamicepituitaryethyroid axis. a careful monitoring of thyroid function . Growth hormone replacement and thyroid volume Conflicting data exist over the effects of GH therapy on thyroid morphology and thyroid volume (TV). TV significantly increased only in patients without concomitant central hypothyroidism. in which alteration of HPT axis (central hypothyroidism). suggesting once again a leading role of TSH in the stimulation of normal thyroid growth. together with TSH. Conclusion In conclusion. Furthermore. It is known that TSH is the major regulator of thyroid hormone biosynthesis and thyroid growth. Indeed. either through an increased conversion of T4 to T3 or via a decrease in TSH pulse and secretion. As many studies have shown. a real hypothyroid state during rhGH therapy has been observed in patients with organic GH deficiency. but promotes thyroid cell proliferation by potentiating the mitogenic action of TSH [44]. 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]. Authors concluded that IGF-I does not stimulate per se in vivo thyroid growth. 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- firming an essential role for IGF-I receptor signaling in the regulation of thyroid function and TSH- stimulated goitrogenesis [40]. In fact. was already present before rhGH therapy and masked by the condition of GHD. During GH therapy. reduced TV has been described in hypopituitaric patient. On the other had. during rhGH treatment. Moreover. unmasking clinical and biochemical central hypothyroidism in a considerable number of them. the striking fall in serum FT4 levels was present even in patients treated with low rhGH doses [33]. 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. After 6 month of rhGH therapy TV did not change significantly. 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. 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. finely regulated by the feedback system. Pretreatment TV was smaller in GHD patients than in healthy subjects. as observed in the study by Porretti and colleagues. suggesting a permissive role of GH in thyroid growth [45]. In fact. Authors concluded that although GH supplementation cannot restore normal TV in the absence of TSH. Concordantly. 25e70% of acromegalic patients has goiter and elevated IGF-I levels correlate positively with TV [42. IGF-I is able to exert a proliferative role through its own receptors. Curto and collaborators [47] studied 96 subjects with childhood and adult onset GHD before and after 5 years of rhGH therapy. rhGH therapy in hypopituitaric patients is associated with significant reduction in serum FT4 levels. However. Recently. elevated levels of IGF-I have been associated with an increased occurrence of thyroid goiter [41]. in patients with idiopathic isolated GHD (with intact HPT axis).43]. Giavoli et al. as also suggested by “The Endocrine Society Clinical Practice Guideline on Evaluation and Treatment of Adult Growth Hormone Deficiency” [36]. It is not clear if the presence of TSH is fundamental for the growth promoting actions of IGF-I on the thyroid cells. 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. only transient and not significant changes in thyroid hormones have been reported. Thus. since the high percent of subjects becoming hypothyroid during such treatment indicates that GHD frequently masks a state of central hypothyroidism. Conversely.76 C.

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