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Endocrine Care |
Institute of Endocrine Sciences, Inc. (S.P., C.G., C.R., M.A., P.B.-P.), University of Milan, Ospedale Maggiore IRCCS, 20122 Milan; Department of Molecular and Clinical Endocrinology and Oncology (G.L.), University Federico II, 80100 Naples; and Department of Medical and Surgical Sciences (M.Z.), University of Padua, 35100 Padua; and Eli Lilly \|[amp ]\| Co. Italia (D.V.), 50100 Florence, Italy
Address all correspondence and requests for reprints to: Paolo Beck-Peccoz, M.D., Institute of Endocrine Sciences, Ospedale Maggiore IRCCS, Pad. Granelli, Via Francesco Sforza, 35; 20122 Milano, Italy. E-mail: . paolo.beckpeccoz{at}unimi.it
Abstract
The effect on thyroid function of GH administration to 66 adult patients with severe GH deficiency was studied. Seventeen patients were euthyroid, and 49 had central hypothyroidism and were adequately treated with L-T4. Forty patients were assigned to a low recombinant human GH (rhGH) regimen (3 µg/kg body wt·d for 3 months followed by 6 µg/kg body wt·d for another 3 months) and 26 to a higher one (6 µg/kg body wt·d for 3 months followed by 12 µg/kg body wt·d for another 3 months). Serum IGF-I, TSH, free T4 (FT4), free T3 (FT3), reverse T3, T4-binding globulin, and antithyroid autoantibody (TgAb and TPOAb) were measured in basal condition and after 3 and 6 months of therapy.
Normalization of IGF-I levels was obtained after 6-month rhGH treatment in 67% of patients, independently from the dose, whereas a significant reduction in FT4 and reverse T3 levels was recorded (P < 0.01), without variations in all the other parameters studied, including serum TSH, FT3, and T4-binding globulin circulating levels. Antithyroid autoantibodies were detected in 11 of 66 patients (16.6%).
Eight of 17 (47%) euthyroid subjects and 9 of 49 (18.3%) central hypothyroid patients, despite adequate substitution at baseline, showed FT4 levels under the normal range at the end of the study. Altogether, 17 of 66 patients (25.7%) worsened their thyroid function.
This study shows that GH deficiency masks in a consistent number of adult patients a state of central hypothyroidism. Therefore, during rhGH treatment, a careful monitoring of thyroid function is mandatory to start or adjust L-T4 substitutive therapy.
THERE ARE COMPLEX relationships between GH system and hypothalamic-pituitary-thyroid axis, and the effects of GH replacement therapy on thyroid function still remain controversial. Most studies have reported significant changes in thyroid function, including a slight decline in serum T4, reverse T3 (rT3), and TSH levels and an elevation in T3 levels caused by an increase in peripheral conversion of T4 to T3 and a decreased conversion of T4 to rT3, selectively mediated by GH (1, 2, 3, 4, 5). Some studies have also suggested that another possible mechanism responsible for the decline in serum T4 concentration after GH therapy could be an inhibition of TSH release (3, 6) via an increased somatostatinergic tone or by a T3 negative feedback mechanism within the pituitary, attributable to increased T3 production from T4 deiodination (1, 4, 7, 8, 9, 10, 11). However, many contrasting data have been reported in the literature about the clinical impact of these modifications. In healthy subjects, previous data showed no significant effects of GH administration on thyroid function, apart from a small decline in the binding capacity of T4-binding globulin (TBG), accompanied by a decline in serum total proteins and albumin (7). This decline could have been caused by fluid retention, known to accompany GH administration (12). Grunfeld and collaborators (3) studied the acute effects of GH on thyroid function in normal men. In their study, after 4 d of GH administration, there was a parallel decline in serum total T4 and FT4 along with an increase in total T3 and no changes in serum rT3. These modifications were accompanied by a marked decrease in serum TSH. Moreover, several trials, aimed to evaluate the effect of prolonged replacement with recombinant human GH (rhGH) on thyroid function, have been performed in GH-deficient (GHD) children with and without concomitant L-T4-treated central hypothyroidism. Porter and collaborators (8) described the occurrence of central hypothyroidism, with no changes in T4 levels but a decrease in basal and TRH-stimulated TSH in two out of five GHD adolescents during GH treatment. Lippe and collaborators (13) observed a decline in serum T4, accompanied in some patients by a decrease in growth response, which again improved after L-T4 substitution, with no change in serum T3. Sato and collaborators (1) noted a decrease in serum T4 and an increase in serum T3 accompanied by an increased TSH release in eight GHD adolescents (five euthyroid and three central hypothyroid), who were treated with GH for 2 months. Recent observations suggest that most hormonal modifications are transient and do not require L-T4 replacement (14, 15).
The reasons for the above mentioned discrepancies may be related to either the different methods used for the measurement of thyroid hormones, or the small number of subjects evaluated in the various reports, or the different study protocols (diverse GH doses and timing of the studies). Moreover, they have been performed many years ago, when the used pituitary GH preparations were of variable purity and, in some instances, 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 rhGH, have prompted this multicenter study to evaluate the effects of 6-month treatment with low rhGH doses on thyroid function in a large group of adult GHD patients. The aim was to investigate the possibility that the administration of low doses of GH could disclose the presence of a mild central hypothyroid state or even to worsen a preexisting central hypothyroidism, making it necessary to adjust the L-T4 replacement dose.
Subjects and Methods
Subjects
Sixty-six patients (43 males and 23 females; mean age, 39 ± 16 yr; range, 18–71) with adult or childhood onset severe GHD were studied. GHD was isolated in 12 patients; whereas, in the remaining 54, it was associated with other multiple deficiencies. In 31 patients, GHD was congenital; whereas, in 35, it was acquired after surgery (n = 18), after radiotherapy on the pituitary region (n = 3), or both (n = 14). Severe GH deficiency was defined as a peak response of serum GH less than 3 µg/liter to a provocative test (arginine + GH-releasing hormone, or insulin tolerance test). Serum basal concentrations of IGF-1 were under the normal range for age and sex in the majority of patients (mean values, 8.5 ± 5.9 nM).
Conventional hormone replacement therapy with L-T4 (mean dosage, 1.5 ± 0.5 µg/kg body wt·d), cortisol, sex steroids, and desmopressin was given when necessary, at stable doses, for at least 3 months before the start of the study. None of the patients suffered from kidney or liver diseases or diabetes mellitus or had a history of malignancy. None of the subjects received GH replacement in the 6 months before the beginning of the study.
Written informed consent, approved by the ethics committee of each institution, was obtained from each patient.
Study protocol
All the subjects were followed for a period of 6 months, undergoing different low rhGH dosages (Humatrope; supplied by Eli Lilly \|[amp ]\| Co., Indianapolis, IN), without changes of other hormonal substitutions. Seventeen patients were euthyroid and 49 had central hypothyroidism on adequate L-T4 replacement therapy. Forty patients were treated with a lower rhGH regimen (3 µg/kg body wt·d for 3 months, followed by 6 µg/kg body wt·d for other 3 months; low regimen, euthyroid group: n = 10; and low regimen, central hypothyroid on L-T4 replacement therapy group: n = 30) and 26 with a higher rhGH regimen (6 µg/kg body wt·d for 3 months, followed by 12 µg/kg body wt·d for other 3 months; high rhGH regimen, euthyroid group: n = 7; and high rhGH regimen, central hypothyroid on L-T4 therapy: n = 19).
Methods
Serum TSH, FT4, FT3, and TBG levels were measured by an immunofluorometric assay (Wallac, Inc. Oy, Turku, Finland); serum total rT3 was measured by an RIA method (Biodata Diagnostics, Rome, Italy). TPOAb and TgAb were measured by indirect noncompetitive enzyme immunoassays (Pharmacia \|[amp ]\| Upjohn, Inc. Diagnostic GmbH & Co., Berlin, Germany). All samples were processed centrally in the laboratory of our Institution in Milan.
Serum IGF-I was measured by an RIA method, centrally in the Lilly laboratory of Dr. Werner Blum at the University Children’s Hospital in Giessen, Germany; this method succeeds in obtaining separation between IGF binding protein and IGF-I, by acidification in the presence of IGF-II excess. The cross-reactivity with IGF-II is less than 0.05%; the sensitivity is 0.01 nM; and the intra- and interassay coefficients of variation are 3.2% and 7.4%, respectively.
Total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were measured with standard techniques; low-density lipoprotein (LDL) cholesterol was calculated using Friedwald’s formula (16).
Statistics
The data are expressed as mean values ± SD. Differences among group means were assessed by the two-tailed t test for paired observations. A P-value less than 0.05 was accepted as significant.
Results
Serum IGF-I levels were low in basal condition (8.5 ± 4.8 and 8.6 ± 7.4 nM in the low regimen and high regimen groups, respectively) and reached the normal range after 6 months of rhGH therapy in 44 patients (67%; mean values, 20.7 ± 11.5 and 28.0 ± 11.9 nM after the low and the high regimens, respectively). Four patients (6%) showed IGF-I levels above the normal range for age, at the end of the study; and 18 patients (27%) did not normalize IGF-I levels, the majority of them belonging to the group treated with the lowest rhGH doses.
Compared with the basal thyroid values (Table 1
), a significant reduction in serum FT4 and rT3 levels was observed in the euthyroid patients, not accompanied by an increase in FT3 at any time. Neither TSH nor TBG and cholesterol levels significantly changed in this group of patients. In patients with central hypothyroidism, the observed significant reduction in serum FT4 and rT3 levels was accompanied by an increase in FT3 levels that was manifest only after 3 months of GH therapy, and then disappeared. Serum TSH levels were undetectable in these patients, as usually seen in L-T4-treated central hypothyroid patients (17), and, together with TBG and serum lipids, did not show any significant modification during the study period.
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) at the end of the study. In 3 of them, signs and symptoms of hypothyroidism (such as bradycardia, asthenia, and constipation) were recorded. Only 1 of the 8 patients had idiopathic GH deficiency, the others having pituitary tumors treated with surgery and/or radiotherapy. Mean TSH levels did not significantly change during rhGH therapy. Moreover, levels of FT4 compatible with hypothyroidism were seen in 9 of 49 L-T4-treated patients (18.3%), independent of the substitutive L-T4 dose. Only 1 of them was symptomatic, and the L-T4 dose was promptly increased.
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Discussion
To our knowledge, this is the first report focusing on a very large number of adult GHD patients (66 subjects) treated with low rhGH doses (from 3–12 µg/kg body wt·d), as well as investigating both euthyroid and central hypothyroid patients, the latter undergoing an adequate L-T4 therapy. The main result of this multicenter study is the finding of a significant and persistent reduction in rT3 and FT4 levels, the latter being at the end of the study into the hypothyroid range in 25.7% of all patients. Most relevant is the fact that about half of euthyroid GHD patients became biochemically hypothyroid; and, in a few of them, even clinical signs and symptoms of hypothyroidism appeared. Also, the finding of a reduction in serum lipid concentrations that did not reach statistical significance could be related to the appearance of hypothyroidism in a relevant number of rhGH-treated patients. Indeed, it is well known that rhGH therapy improves the lipid profile, with the exception of lipoprotein(a) concentrations, which show a trend to increase (2, 18, 19, 20). Our data suggest that GH deficiency probably masks a state of mild central hypothyroidism that becomes manifest only during rhGH therapy. In addition, the higher incidence of antithyroid autoantibodies in GHD patients may contribute to the worsening of the thyroid function.
The present results are in contrast with those reported by both Amato and co-workers (21) in 9 GHD L-T4-treated adults and by Wyatt and collaborators (14) in 15 euthyroid children. In the former study (21), the authors did not observe any significant modification of thyroid function after 12-months of rhGH administration at 10 µg/kg body wt·d. They concluded that L-T4-treated GHD patients do not require an increased L-T4 replacement dose when treated with low rhGH doses. The other paper (14) did not find, at the end of the 12-month rhGH administration, any significant difference in total T4 or free T4 index, compared with the pretreatment values. They found transient reduction in total T4 and T4 index levels, thus suggesting that only patients with persistent decline of the above parameters need to be treated. The use of indirect measurement of circulating free T4 as well as a possible bias attributable to the selection of GHD patients, the majority having an idiopathic isolated GH deficiency, may explain the discrepancies in our results.
In our study, the alteration of hypothalamic-pituitary-thyroid function was documented only by the decline in serum FT4 levels, TSH and FT3 remaining unchanged along all the study period. This observation stresses the importance of the direct measurement of FT4 in the management of central hypothyroid patients (17).
The lack of a parallel and significant change in FT3 and TSH levels may suggest that the mechanisms regulating the interaction between GH and thyroid axis are more complex than expected. Two mechanisms have been suggested to explain the above discrepancies. The first one points to an inhibition of TSH release mediated by a hypersecretion of somatostatin directly induced by GH. The second underlines an increase of extrathyroidal conversion of T4 to T3. A recent study demonstrates that this latter putative mechanism seems to work also at the level of central nervous system, because FT4 concentrations in the cerebrospinal fluid significantly decreased during rhGH therapy, with possible consequent beneficial effects on mood and behavior (5). Jørgensen and collaborators (22) also suggested that enhancement of T4 to T3 deiodination could probably be mediated by the generation of IGF-1; the main role of IGF-1 is supported by the observation that many catabolic conditions characterized by impaired peripheral conversion of T4 to T3 are accompanied by high GH and low IGF-1 levels. On the contrary, Klinger and collaborators (23) did not observe any increase in serum T3 after short- or long-term IGF-1 administration, and they supposed that rhGH is able to induce its own effect also by accelerating the half-life of T4 and inversely delaying the T3 half-life.
In conclusion, the present study emphasizes the need of a careful monitoring of thyroid function of GHD adults during rhGH administration, particularly by means of the direct measurement of circulating free T4. The high percent of GHD patients who become hypothyroid during such a treatment indicates 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 substitutive L-T4-treatment is mandatory; whereas, in already-L-T4-treated patients, an adjustment of L-T4 therapy is necessary.
Acknowledgments
Footnotes
Abbreviations: Ab, Antibody; GHD, GH-deficient; HDL, high-density lipoprotein; rhGH, recombinant human GH; LDL, low-density lipoprotein; rT3, reverse T3; TBG, T4-binding globulin.
Received September 25, 2001.
Accepted January 31, 2002.
References
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) and after (
) 6-month rhGH therapy in 17 euthyroid patients (10 at low and 7 at high rhGH regimen). Dotted line, Lower limit of the normal FT4 range.