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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0941
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 11 4144-4153
Copyright © 2007 by The Endocrine Society

Growth Hormone Replacement Improves Thyroxine Biological Effects: Implications for Management of Central Hypothyroidism

Manoel R. A. Martins, Fabio C. Doin, William R. Komatsu, Turibio L. Barros-Neto, Valdir A. Moises and Julio Abucham

Divisions of Endocrinology (M.R.A.M., W.R.K., J.A.) and Cardiology (F.C.D., V.A.M.) and Centro de Medicina do Esporte (T.L.B.-N.) da Escola Paulista de Medicina-Universidade Federal de São Paulo, São Paulo, Brazil 04039

Address all correspondence and requests for reprints to: Julio Abucham, M.D., Ph.D., Division of Endocrinology, Escola Paulista de Medicina-Universidade Federal de São Paulo, Rua Pedro de Toledo 910, São Paulo, Brazil 04039-002. E-mail: julioabucham{at}uol.com.br.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The biological significance of GH-induced changes in serum TH concentrations is unknown. It has been suggested that serum free T4 (FT4) should be targeted at the high-normal range during GH replacement.

Objective: Our objective was to evaluate the effects of GH replacement on T4 biological effects.

Hypothesis: If GH modulates thyroxine biological effects, serum FT4 should be targeted accordingly.

Design and Setting: We conducted observational (study 1) and interventional (studies 2 and 3)/outpatient studies.

Patients: Thirty-two GH-deficient patients (13 off GH; 22 on L-T4) participated in the study.

Interventions: In study 2, levothyroxine was administered to increase FT4 (>1.0 ng/dl). In study 3, GH was administered or withdrawn.

Main Outcome Measures: We measured FT4, total T3 (TT3), myocardial isovolumic contraction time (ICT), and resting energy expenditure (REE).

Results: In study 1, off-GH and on-GH groups had similar FT4, but off GH showed lower TT3 (P < 0.01) and REE (P = 0.02), higher ICT (P < 0.05) than on-GH and controls. On GH, ICT and REE correlated only with TT3 (r = –0.48; r = 0.58; P < 0.05). Off GH, ICT correlated only with FT4 (P < 0.01). In study 2, off GH, levothyroxine intervention increased FT4 (P = 0.005) and TT3 (P = 0.012), decreased ICT (P = 0.006), and increased REE (P = 0.013); ICT and FT4 changes correlated (r = –0.72; P = 0.06). On GH, levothyroxine increased FT4 (P = 0.0002), TT3 (P = 0.014), and REE (P = 0.10) and decreased ICT (P = 0.049); REE and TT3 changes correlated (r = 0.60; P = 0.05). In study 3, GH decreased FT4, increased TT3, decreased ICT, and increased REE (P < 0.05). REE correlated (P < 0.05) with IGF-I (r = 0.57) and TT3 (r = 0.64). ICT correlated only with TT3 (r = –0.46).

Conclusions: GH replacement improves the biological effects of T4. Serum FT4 should be targeted at the high-normal range in GH-deficient patients only off GH replacement.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CENTRAL HYPOTHYROIDISM (CH) is a common disorder in patients with hypothalamic-pituitary disease. It results from decreased stimulation of an otherwise normal thyroid gland by a decreased and/or biologically less active TSH (1, 2). At diagnosis, serum TSH levels in CH may be decreased, normal, or slightly elevated and consistently decline to low/undetectable levels during physiological levothyroxine replacement (3). Thus, both diagnosis and adequacy of levothyroxine replacement in CH have to rely on serum T4 levels, which show intraindividual variations much narrower than the normal reference range (4). In addition, GH deficiency (GHD) is usually present in patients with CH, and GH replacement is known to change serum concentrations of thyroid hormones (TH), decreasing T4 and increasing T3 through peripheral mechanisms (5, 6, 7, 8, 9).

In practice, a low serum T4 in patients with hypothalamic-pituitary disease is highly specific, but insensitive, to diagnose CH given the high prevalence of CH in that population. Biochemical markers of peripheral TH action like cholesterol, SHBG, angiotensin-converting enzyme, carboxyl-terminal telopeptide of type I collagen, osteocalcin, and bone {gamma}-carboxyglutamic acid protein have all been proved insufficiently sensitive and/or specific in the diagnosis and management of CH (10). Furthermore, optimal T4 levels during levothyroxine replacement in CH have not been established through biological markers of TH action. Notwithstanding, targeting serum T4 levels to the high-normal reference range, both in children receiving GH or in any patient with CH irrespective of GH replacement, has been widely recommended (11).

Resting energy expenditure (REE), on the other hand, is very sensitive to changes in TH concentrations and relatively easy to measure using indirect calorimetry (12), but REE is also influenced by GH (13). More recently, we have shown that the isovolumic contraction time (ICT), a sensitive and specific marker of TH action in the heart (14, 15), was increased in nearly all adult patients with hypothalamic-pituitary disease and low free T4 (FT4) levels and in 38% of those with normal FT4 and that increasing serum FT4 levels within the normal range with levothyroxine normalized ICT in most patients (16, 17).

The aim of the present study was to investigate the biological significance of the changes in serum TH concentrations that occur during GH replacement in GHD children and adolescents using both ICT and REE as biological markers of TH action.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The study protocol was approved by the local ethical committee, and written informed consent was always obtained.

Patients. Thirty-two patients (21 males, age 15.8 ± 5.7 yr, range, 6–23 yr) with hypothalamic-pituitary disease followed at our Neuroendocrine Clinic were consecutively enrolled (Table 1Go).


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  		TABLE 1. Clinical data of 32 patients with hypothalamic-pituitary disease (on GH, patients 1–19; off GH, patients 20–32) at the beginning of the study

 
Thirty patients had GHD (GH < 10.0 µg/liter after clonidine and insulin-induced hypoglycemia), 17 on GH replacement with recombinant human GH (0.035 mg/kg·d sc); 22 had CH, all on levothyroxine (50–125 µg/d by mouth); eight had ACTH deficiency (cortisol <18 µg/dl after insulin-induced hypoglycemia), all on prednisone (2.5–5.0 mg/day by mouth); and 12 had gonadotropic deficiency, all on sexual steroid replacement. Hormone replacements were kept unchanged for at least 3 months before the study.

Controls. Twenty-three age- and sex-comparable healthy subjects (13 males, age 12.6 ± 3.8 yr, range, 5–19 yr) were included in the study as controls.

Study 1: influence of GH replacement on basal serum total T3 (TT3), ICT, and REE

All patients underwent an initial evaluation after a 10- to 12-h overnight fast, starting with indirect calorimetry, followed by blood collection, dual-energy x-ray absorptiometry, and echocardiographic evaluation.

Study 2: influence of GH replacement on the responses of serum TH, ICT, and REE to levothyroxine intervention

Eight GHD patients (three off and five on GH) with low FT4 (<0.7 ng/dl) and 10 GHD patients (four off and six on GH) with FT4 between 0.7 and 1.0 ng/dl were reevaluated after starting and/or increasing levothyroxine (by 12.5–25 µg each 5–6 wk) until FT4 reached 1.0–1.54 ng/dl.

Study 3: influence of GH intervention on serum TH, ICT, and REE

Patients who started (n = 4) or stopped (n = 3) GH replacement after basal evaluation or after levothyroxine intervention were reevaluated using the same protocol after 5–6 wk of changing GH status. Replacement of other hormones was kept unchanged.

Hormone assays

Hormones were measured, in duplicate, in serum.

FT4. An immunofluorometric assay (Delfia Wallac Oy, Turku, Finland) with a sensitivity of 0.16 ng/dl was used. Intraassay and interassay coefficients of variation were 4.4 and 6.1%, respectively. Normal reference values are 0.7–1.54 ng/dl.

TT3. An immunofluorometric assay (Delfia Wallac Oy) with sensitivity of 20 ng/dl was used. Intraassay and interassay coefficients of variation were 3.0%. Normal reference values are 80–210 ng/dl.

IGF-I. An immunoradiometric assay (Diagnostic Systems Laboratories, Webster, TX) was used with a sensitivity of 0.8 ng/ml. Intraassay and interassay coefficients of variation were 1.5–3.4 and 1.5–8.2%, respectively.

Echocardiographic examination

A complete two-dimensional and Doppler echocardiogram was performed using a 2.0- to 2.5-MHz transducer (HDI 5000; Philips, Andover, MA). ICT and other measurements in the same patient were made by the same echocardiographist (F.C.D. or V.A.M.) without knowledge of the patient’s data, as previously described (16).

REE

REE was measured using the Vista Mini-CPX metabolic system (Vacumed, Ventura, CA) linked to a gas analyzer CO2/O2 Vacumed Turbofit connected to a computer and monitored by Vista Turbofit 4.0 software as described elsewhere (12). Estimated REE was calculated by an equation (18) using fat-free mass (dual-energy x-ray absorptiometry, QDR 4500; Hologic Inc., Waltham, MA). REE was expressed as measured/estimated REE x 100.

Data analysis

We used GraphPad Prism 4.03 (www.graphpad.com) for statistical analysis. Comparisons were done by paired or unpaired t test (two groups) or ANOVA (more than two groups) followed by Student-Newman-Keuls test. Correlations were done by Pearson’s test. Significance was set at 0.05. Results are expressed as mean ± SE.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Study 1: influence of GH replacement on basal TT3, ICT, and REE

Twenty-four patients (14 on and 10 off GH) had FT4 within the normal reference range, including 14 patients with CH receiving levothyroxine and similarly distributed between on-GH and off-GH subgroups (seven of 14 vs. seven of 10, P = 0.42). Eight patients had low FT4 (five on and three off GH), all with undertreated CH.

Patients with normal FT4 levels. As shown in Fig. 1Go, no difference in FT4 was observed between off- and on-GH groups (0.99 ± 0.07 vs. 0.98 ± 0.04 ng/dl, respectively, P = 0.89), which reflected a similar target of serum FT4 (midnormal range) in our patients with CH taking levothyroxine irrespective of GH replacement. FT4 levels were 13% lower in both groups compared with controls (1.12 ± 0.03 ng/dl, P < 0.05).


Figure 1
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  		FIG. 1. Serum FT4 levels (A), serum TT3 levels (B), ICT (C), and REE (D) in children with hypothalamic-pituitary disease and normal FT4 according to GH status: on GH (17 GH-replaced GHD and two GH-sufficient) and off GH (13 non-GH-replaced GHD) and in 23 normal controls (CTRL). NS, Not significant.

 
TT3 was lower in off-GH compared with on-GH patients (109.1 ± 7.4 vs. 141.1 ± 9.7 ng/dl, P < 0.01) or controls (156.3 ± 5.2 ng/dl, P < 0.001), but similar between on-GH patients and controls (P > 0.05). TT3/FT4 ratios were significantly lower in off-GH (114.7 ± 10.3, P = 0.02) but not in on-GH patients (148.1 ± 13.8, P = 0.55), compared with controls (140.4 ± 5.2).

ICT was similar in on-GH patients and controls (39 ± 3.6 vs. 38 ± 2.9 msec, P = 0.91) but higher in off-GH patients (49 ± 2.8 msec) compared with on-GH patients (P = 0.049) and controls (P = 0.032).

REE was lower in off-GH patients compared with controls (88 ± 5.8 vs. 104 ± 3.5%, P = 0.02) and lower, but not significantly, when compared with on-GH patients (98 ± 3.5%, P=0.14). On-GH patients and controls showed similar REE (P = 0.26).

Patients with low FT4 levels. FT4 levels were similar in patients with low FT4 on GH and the only three patients off GH (0.54 ± 0.08 vs. 0.53 ± 0.04 ng/dl, respectively, P = 0.84), but both groups had lower FT4 (P < 0.001) compared with controls.

TT3 was not different in off- and on-GH patients with low FT4 (110.7 ± 23.1 vs. 97.6 ± 13.0 ng/dl, P = 0.61) but was lower in both groups compared with controls (156.3 ± 5.2 ng/dl, P < 0.05 and P < 0.001, respectively).

ICT was increased in off- compared with on-GH patients (65.0 ± 1.5 vs. 41.4 ± 6.7 msec, P < 0.05) or controls (P < 0.01), but no significant difference in ICT was observed between on-GH patients and controls (41.4 ± 6.7 vs. 38 ± 2.9 msec, P > 0.05).

REE was decreased in off-GH compared with on-GH patients (69 ± 2.5 vs. 93.4 ± 5.9%, P < 0.05) or controls (104 ± 3.5%, P < 0.01) but not between on-GH patients and controls.

Correlations between ICT, REE, and TH levels. As shown in Fig. 2Go, ICT was inversely correlated with FT4 in off-GH (r = –0.79; P < 0.01) but not in on-GH (r = –0.12; P = 0.64) and with TT3 in on-GH (r = –0.48; P = 0.04) but not in off-GH (r = –0.11; P = 0.73) groups. REE was correlated with TT3 in on-GH (r = 0.58; P = 0.01) but not in off-GH (r = –0.17; P = 0.59) groups. REE showed no significant correlations with FT4 in either on-GH (r = 0.07; P = 0.78) or off-GH groups (r = 0.30; P = 0.32).


Figure 2
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  		FIG. 2. Correlations between ICT, REE, and serum TH levels and in two groups of children with hypothalamic-pituitary disease according to somatotrophic status: off GH (n = 13, left side) and on GH (n = 19, right side).

 
Study 2: response to levothyroxine intervention

Non-GH-replaced patients. As shown in Fig. 3Go, FT4 increased from 0.68 ± 0.06 to 1.33 ± 0.11 ng/dl (P = 0.005), TT3 increased from 110 ± 11.4 to 146 ± 14.9 ng/dl (P = 0.012), ICT decreased from 60 ± 2.3 to 37 ± 2.5 msec (P = 0.0006), and REE increased from 80.0 ± 6.2 to 93.4 ± 4.9% (P = 0.013) after levothyroxine in non-GH-replaced patients. Compared with controls, levothyroxine intervention resulted in a 19% higher FT4 (1.33 ± 0.11 vs. 1.12 ± 0.03 ng/dl, P = 0.0127) but similar TT3 (146 ± 14.9 vs. 156.3 ± 5.2 ng/dl, P = 0.43), ICT (37 ± 2.5 vs. 38 ± 2.9 msec, P = 0.81), and REE (93.4 ± 4.9 vs. 103.8 ± 3.5%, P = 0.15). None of the seven non-GH-replaced patients showed abnormal ICT or REE suggestive of excessive levothyroxine replacement.


Figure 3
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  		FIG. 3. Response of serum FT4 levels (A), serum TT3 levels (B), ICT (C), and REE (D) to levothyroxine intervention in 11 GH-replaced GHD children (left side) and seven non-GH-replaced GHD children with serum FT4 levels less than 1.0 ng/dl (right side). Horizontal bars represent mean values. Dotted lines represent normal reference ranges.

 
In the three patients with low FT4, ICT was high and decreased to the normal reference range, whereas REE was low and increased to the normal reference range in two patients after levothyroxine. In the four patients with FT4 between 0.7 and 1.0 ng/dl, both FT4 and TT3 increased to within the normal reference ranges or slightly above (FT4 in one patient), ICT decreased from high to normal in two and to within the normal range in another two patients, whereas REE increased only slightly to within the normal reference range in three and remained below that range in one patient.

GH-replaced patients. As shown in Fig. 3Go, FT4 increased from 0.72 ± 0.06 to 1.25 ± 0.07 ng/dl (P = 0.0002), TT3 increased from 117.9 ± 12.0 to 149.5 ± 11.0 ng/dl (P=0.014), ICT decreased from 41.4 ± 4.0 to 32.3 ± 3.4 msec (P = 0.049), and REE increased from 99.3 ± 4.3 to 109.4 ± 6.3% (P = 0.10) in GH-replaced patients after levothyroxine. Compared with controls, levothyroxine intervention resulted in a 12% higher FT4 (1.25 ± 0.07 vs. 1.12 ± 0.03 ng/dl, P = 0.06), but similar TT3 (149.5 ± 11.0 vs. 156.3 ± 5.2 ng/dl, P = 0.53), ICT (32.3 ± 3.4 ms vs. 38 ± 2.9 ms, P = 0.21), and REE (109.4 ± 6.3 vs. 103.8 ± 3.5%, P = 0.49). After levothyroxine intervention, four patients showed high REE values, one with a low ICT, suggesting levothyroxine excess. TT3 levels were slightly increased in two of them but in none of the remaining seven patients who did not show REE or ICT values compatible with levothyroxine excess. FT4 was slightly increased in only one of those four patients as well as in another one of the remaining seven patients. As a subgroup, these four patients presented increased TT3 (180.3 ± 20.5 vs. 131.0 ± 8.0 ng/dl, P = 0.03) but similar FT4 (1.18 ± 0.14 vs. 1.29 ± 0.09 ng/dl, P = 0.51) and IGF-I (119.5 ± 19.3 vs. 254.0 ± 143.5 ng/ml, P = 0.51) levels compared with the seven patients without abnormalities in REE and/or ICT suggestive of levothyroxine excess.

In the five patients on GH replacement and low FT4, both TT3 and REE were low in one and ICT was high in another patient (with the lowest FT4). After levothyroxine, these two patients increased FT4, TT3, ICT, and REE values into the normal reference ranges. In the remaining three, levothyroxine intervention resulted in normal FT4 and TT3 levels in two patients, one with a low ICT, and slightly high FT4 and TT3 with a high REE in another one. In the six patients with FT4 levels between 0.7 and 1.0 ng/dl before levothyroxine, one patient had low TT3, high ICT, and REE at the lower limit, and another one had a slightly increased REE with the lowest ICT and the highest TT3 before levothyroxine intervention. In the former, FT4 increased, and both TT3 and ICT, but not REE, were corrected after levothyroxine. In the latter, FT4 increased to the midrange, TT3 and REE increased slightly, and ICT remained unchanged.

Correlations between changes in ICT, REE, and TH after levothyroxine intervention

ICT. Changes in ICT after levothyroxine intervention showed a strong inverse correlation with changes in FT4 levels (r = –0.72; P = 0.06) in non-GH-replaced but not in GH-replaced patients (r = –0.38; P = 0.25) (Fig. 4Go, bottom). Changes in ICT showed no significant correlations with changes in TT3 in GH-replaced (r = 0.08; P = 0.82) and non-GH-replaced patients (r = 0.17; P = 0.61).


Figure 4
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  		FIG. 4. Correlations between changes in ICT and serum FT4 levels (top) and between REE and serum TT3 levels (bottom) after levothyroxine intervention in two groups of GHD children according to GH replacement.

 
REE. Changes in REE after levothyroxine intervention showed a positive correlation with changes in TT3 (r = 0.60; P = 0.05) in GH-replaced but not in non-GH-replaced patients (r = 0.15; P = 0.75) (Fig. 4Go). Changes in REE showed no significant correlation with changes in T4 in GH-replaced (r = 0.12; P = 0.72) and non-GH-replaced patients (r = 0.39; P = 0.39).

Study 3: Influence of GH intervention on TH, ICT, and REE

Seven GHD patients with FT4 within the normal reference range were evaluated both on GH and off GH replacement. As expected, IGF-I levels were higher during GH replacement (558 ± 140 vs. 122 ± 40 ng/ml, P = 0.0082).

As shown in Fig. 5Go, FT4 decreased from 1.36 ± 0.08 to 1.09 ± 0.09 ng/dl (P = 0.031) (–25%), TT3 increased from 111.0 ± 7.0 to 147.9 ± 13.3 ng/dl (P = 0.003) (+33%), the TT3 to FT4 ratio increased from 82.7 ± 5.8 to 143.3 ± 18.9 (P = 0.01) and became similar to controls (140.4 ± 5.2, P = 0.84), whereas ICT decreased from 38.9 ± 3.0 to 29.9 ± 3.1 msec (P = 0.048) and REE increased from 76.0 ± 3.7 to 92.4 ± 6.4% (P = 0.036) after GH replacement. ICT remained within the normal reference range. REE values were low (<80%) in five patients before GH and remained low in two during GH replacement (both with the lowest T3 values).


Figure 5
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  		FIG. 5. Response of serum FT4 levels (A), serum TT3 levels (B), ICT (C), and REE (D) to GH replacement in seven GHD children with normal serum FT4 levels. Horizontal bars represent mean values. Dotted lines represent normal reference ranges.

 
Correlations between biological markers of TH action (ICT and REE) and TH and IGF-I concentrations. When all ICT and REE values were observed along a wide range of IGF-I concentrations (4–1011 ng/ml) obtained by changing somatotropic status in seven GHD patients, ICT showed no significant correlations with IGF-I (r = –0.01; P = 0.98) or FT4 (r = 0.34; P = 0.23) but tended to correlate inversely with TT3 levels (r = –0.46; P = 0.09).

REE showed positive correlations with IGF-I (r = 0.57; P = 0.03) and TT3 (r = 0.64; P = 0.01) but not with FT4 (r = –0.22; P = 0.44) levels (Fig. 6Go).


Figure 6
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  		FIG. 6. Correlations between ICT (left) or REE (right) and serum IGF-I (top) and TT3 (bottom) levels in seven children with GHD on and off GH replacement.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Although the effects of GH replacement on TH concentrations are well established (9), their biological significance remains unclear. Because serum FT4 levels usually decrease during GH replacement therapy, it has been widely recommended that FT4 levels should be targeted to the upper midrange of reference levels with levothyroxine to avoid impairment of linear growth due to hypothyroidism. Undoubtedly, GH replacement can lower FT4 levels to the hypothyroid range and unmask CH in some GHD patients, which should prompt levothyroxine replacement. However, targeting a high-normal FT4 level in patients with normal FT4 levels is completely empirical and ignores the fact that serum concentrations of T3, the bioactive form of TH, usually increases during GH therapy (10, 11, 19).

Changes in FT4 levels within the reference range, as seen in primary subclinical hypothyroidism and hyperthyroidism, are able to change pituitary TSH secretion and affect other target organs (20). These subclinical states represent mild thyroid dysfunctions that, in the long run, have been variably shown to affect quality of life and/or morbidity-mortality indexes (21). Considering that patients with CH usually have GHD and frequently other pituitary hormone deficiencies, both under- and overreplacement of levothyroxine in these patients are likely to have even more deleterious consequences than in patients with primary hypothyroidism.

In study 1, we have shown that GH-replaced GHD children with normal FT4 levels had higher TT3 levels compared with patients without GH replacement with similar FT4 levels. In study 3, using the same group of patients on and off GH, we confirmed that GH replacement decreased FT4 and increased TT3 levels. In both studies, these changes resulted in TT3/FT4 ratios indicating that untreated GHD is a state of decreased T4 to T3 conversion that can be fully corrected by GH replacement. GH-induced changes in serum TH levels result from peripheral mechanisms, because they have been shown in children on fixed doses of levothyroxine and undetectable TSH levels (9). In addition, GH had no effect on thyroid gland secretion because serum thyroglobulin levels were unaffected by GH replacement in study 3 (data not shown). Similar studies in children with unequivocal GHD have also shown decreased T4 (5, 7, 9, 22, 23) and increased T3 levels (5, 7, 9, 22, 24) during GH replacement. In contrast, these changes have been shown to occur only transiently in children with GHD diagnosed by less strict criteria (25), whereas no changes have been found in non-GHD short children receiving GH (26). These differences are likely to reflect the more dramatic change in somatotropic status that take place when severely GHD patients are replaced with GH compared with partially or non-GHD patients.

The effects of GH replacement on serum TH levels seem to be mediated directly by GH and not via IGF-I, because T3 levels remained unchanged after IGF-I administration to patients with GH insensitivity due to mutations in the GH receptor (27). Also, a much higher increase in serum T3 levels has been shown after GH than after IGF-I in GHD patients (28). The sites where GH affects TH metabolism in humans are not known. The peripheral metabolism of TH is under control of three monodeiodinases (D1–3), with different tissue distribution, substrate preference, and kinetics (29). The monodeiodination of T4 to generate T3 (activation pathways) is mediated by either D1 or D2, whereas monodeiodination of T4 to generate rT3 as well as of T3 to generate T2 (inactivation pathways) are mediated by D3 (29). In humans, GH actions on peripheral TH metabolism could take place in one or more sites because GH receptors are expressed in several organs and tissues that express predominantly one or more TH deiodinases: liver and kidney (D1), skeletal and heart muscle and brown adipose tissue (D2), and brain (D1, D2, and D3). The decreased conversion of T4 to T3 observed in untreated GHD, which is accompanied by increased rT3 (9), indicates a physiological role of endogenous GH in peripheral conversion of TH in humans. Additional studies are necessary to define which TH activation pathway is controlled by GH.

Hitherto, the biological consequences of GH-induced changes in serum FT4 and T3 levels had not been studied. In our observational study (study 1), we have shown that non-GH-replaced GHD patients had increased ICT and decreased REE compared with GH-replaced patients with similar FT4 levels. In contrast, GH-replaced GHD patients showed ICT, REE, and T3 levels similar to controls, despite slightly but significantly lower FT4 levels than controls, indicating that targeting a high-normal FT4 is unnecessary to avoid hypothyroidism in most GH-replaced GHD patients. The heart is one of the organs most sensitive to variations in plasma TH levels (30). ICT or other systolic time intervals are increased in patients with primary hypothyroidism and decreased in patients with hyperthyroidism and can be corrected by restoring normal TH/TSH levels by proper treatment (14, 31, 32). In a preliminary report, we found a surprisingly high prevalence of increased ICT in adult patients with hypothalamic-pituitary disease and normal FT4 levels, most of them with non-GH-replaced GHD. Increasing T4 levels within the reference range with levothyroxine corrected ICT in nearly all those patients (16, 17), indicating that measurement of ICT in patients with hypothalamic-pituitary disease and normal FT4 levels may be useful both to detect subclinical hypothyroidism and to determine optimal individual serum FT4 levels during levothyroxine replacement.

In study 3, administration of GH to GHD patients not only decreased FT4 and increased T3 levels, as expected, but also improved peripheral markers of TH action, shortening ICT and increasing REE. In this study, ICT was much more correlated with T3 (r = –0.46; P = 0.09) than with IGF-I (r = –0.01; P = 0.98), indicating that ICT reflected TH and not intrinsic GH action in the heart. This effect of GH on ICT could result from GH-induced local conversion of T4 to T3 in the heart and/or GH-induced increased serum T3 levels. Altogether, these data indicate that somatotrophic status modulates TH action in the heart. On the other hand, REE, which has been shown to reflect both intrinsic and indirect (via T3) actions of GH, correlated with both T3 (r = 0.64; P=0.01) and IGF-I levels (r = 0.57; P = 0.03) in this study. Contrary to the widespread concern of inducing hypothyroidism during GH replacement, this study shows that declining FT4 and increasing T3 levels within the normal reference, as typically observed in GHD children, usually improves TH biological effects.

In study 2, we tested the empirical recommendation of targeting a high-normal serum FT4 level in patients with CH, especially in GHD children receiving GH replacement therapy. In effect, mean FT4 levels reached 1.25 ng/dl, T3 levels and REE increased, and ICT decreased in both GH-replaced and non-GH-replaced patients. These effects were observed in patients starting the study with low FT4 and normal or low T3, increased ICT, and decreased REE as well as in those with FT4 between 0.7 and 1.0 ng/dl and normal or low T3, normal or high ICT, and low or normal REE. However, as expected from the positive influence of GH on peripheral markers of TH action shown in studies 1 and 3, abnormal ICT and/or REE indicating excessive TH replacement were observed only in GH-replaced patients (four of 11 patients). Interestingly, levothyroxine overreplacement could also be identified by increased TT3 levels in two of these four patients, but not by FT4, which is in agreement with our findings that both REE and ICT correlated with TT3 but not with FT4 in GHD patients on GH replacement. On the other hand, only ICT was significantly correlated with FT4 but not with TT3 in non-GH-replaced GHD patients. Altogether, these observations indicate that targeting a high-normal serum FT4 level may compensate for decreased TH conversion in non-GH-replaced GHD children but may be unnecessary or even harmful in GH-replaced children.

In conclusion, our study demonstrated that GH status is a major determinant of T4 biological effects and should be considered in the interpretation and adjustment of serum FT4 levels in GHD children. A statistically appropriate target value for serum FT4 in GH-replaced children has no biological reason to be different from controls; thus, a serum FT4 in the midnormal range should suffice for most patients. Conversely, a higher target serum FT4 into the upper normal range seems biologically more appropriate when GH is not being replaced. Serum TT3 levels should also be monitored to detect excessive levothyroxine replacement during GH therapy. Finally, ICT and REE could be used to better define thyroid status and establish individual targets of serum T4 levels in GHD patients.


   Acknowledgments
 
We are grateful to Teresa Kasamatsu, Felipe Crispim, Walkiria Miranda, and Edgard Freire for technical assistance, and Clóvis Peres and Gianni Yanaguibashi for statistical advice.


   Footnotes
 
Disclosure Statement: The authors have nothing to disclose.

First Published Online September 4, 2007

Abbreviations: CH, Central hypothyroidism; D1, deiodinase 1; FT4, free T4; GHD, GH deficiency; ICT, isovolumic contraction time; REE, resting energy expenditure; TH, thyroid hormone; TT3, total T3.

Received April 26, 2007.

Accepted August 23, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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