THYROIDVolume 11, Number 11, 2001Mary Ann Liebert, Inc.

Serum Insulin-Like Growth Factor Type 1, Insulin-LikeGrowth Factor–Binding Protein-1, and Insulin-Like Growth

Factor–Binding Protein-3 Concentrations in Patients with Thyroid Dysfunction

P. Iglesias,1 C. Bayón,2 J. Méndez,3 P. González Gancedo,3 C. Grande,3 and J.J. Díez4

Thyroid hormones play a role in the regulation of insulin-like growth factor type 1 (IGF-1) and insulin-likegrowth factor–binding protein-3 (IGFBP-3) expression, and both IGF-1 and IGFBPs have been shown to be re-lated to the function and growth of the thyroid. Our aim was to evaluate serum concentrations of IGF-1, IGFBP-1, and IGFBP-3 in patients with thyroid dysfunction before and after normalization of thyroid function. Thestudy was performed in 86 patients with thyroid dysfunction (43 hyperthyroid and 43 hypothyroid patients)and 17 euthyroid subjects. Serum growth hormone (GH), insulin, IGF-1, IGFBP-1, and IGFBP-3 were measuredin all patients before and after normalizing serum thyroid hormone concentrations. Hyperthyroid patientsshowed IGF-1 (198.8 6 17.0 mg/L) and IGFBP-3 levels (4.2 6 0.2 mg/L) similar to those found in the controlgroup (217.9 6 20.3 mg/L and 4.2 6 0.3 mg/L, respectively). After therapy these levels significantly decreasedto 156.6 6 11.1 mg/L (p , 0.01) and 3.3 6 0.1 mg/L (p , 0.001), respectively. IGFBP-1 concentrations wereclearly higher than those found in controls (22.7 6 2.6 vs. 5.7 6 1.5 mg/L, p , 0.001) and exhibited a significantreduction after therapy for thyroid hyperfunction (11.0 6 1.7 mg/L, p , 0.001). Patients with hypothyroidismshowed serum concentrations of IGF-1 (161.5 6 13.1 mg/L, p , 0.05) and IGFBP-3 (3.2 6 0.3 mg/L, p , 0.05) sig-nificantly lower than those found in healthy volunteers. However, replacement therapy with levothyroxine didnot induce any significant modification of these concentrations (152.6 6 10.6 mg/L and 3.2 6 0.2 mg/L, re-spectively). Similarly, patients with thyroid hypofunction exhibited raised levels of IGFBP-1 (15.5 6 0.9 mg/L,p , 0.05 vs. control group) that were significantly decreased after therapy (8.8 6 1.4 mg/L, p , 0.01). The re-sults of the present study show that thyroid status affects GH/IGF axis. Hypothyroidism is associated with sig-nificant reductions of IGF-1 and IGFBP-3, and IGFBP-1 is elevated in both hypothyroidism and hyperthyroidism.

1043

Introduction

INCREASING EVIDENCE for a relationship between thyroidhormone and growth hormone/insulin-like growth factor

(GH/IGF) axis has recently been found (1–6). GH/IGF axisaffects growth and function of the thyroid, as well as thy-roid hormone metabolism (7–9). Long-term elevation ofserum GH levels in acromegaly is associated with goiter de-velopment probably caused by the mitogenic effects of IGF-1 (10). GH, as well as IGF-1 receptor and insulin-like growthfactor–binding proteins (IGFBPs) are expressed in thyroidtissue, and it has been postulated that IGFBPs may play arole as autocrine/paracrine factors regulating the local ac-tions of IGF-1 at the thyroid level (7). Nevertheless, IGF-1

and IGFBP-3 are mainly produced in the liver under the con-trol of GH (11,12) and it is therefore unlikely that the localthyroidal production of these growth factors contributes ina significant way to the circulating pool of these substances.IGFBP-1 is also mainly synthesized in the liver, but unlikeIGFBP-3, its production does not depend on the secretion ofGH (13).

On the contrary, it is known that thyroid hormones are es-sential for normal growth and development (14). Thyrotox-icosis is associated with an increase of mean 24-hour GH con-centrations and GH secretion rates, whereas the oppositeoccurs in hypothyroidism (15,16). These effects explain ac-celerated and delayed linear growth rates observed in hy-perthyroid and hypothyroid children, respectively (17,18).

Departments of 1Endocrinology and 2Biochemistry, Hospital General de Segovia, Madrid, Spain.Departments of 3Biochemistry and 4Endocrinology, Hospital La Paz, Madrid, Spain.

There have been a number of studies examining the ef-fects of thyroid status on serum concentrations of IGF-1 andits binding proteins in patients with thyroid dysfunction(1–4,6,19–22). Main results of these in vivo investigations sug-gest that there is an increase in serum levels of IGF-1 in pa-tients with hyperthyroidism (1,5,19,21,23), and a decrease ofthese values in patients with hypothyroidism (1,2,3,6).IGFBP-3 concentrations have been found to be increased inhyperthyroidism (1,6,19,21) and decreased (6) or unmodified(1) in hypothyroidism. IGFBP-1 concentration in patientswith hypothyroidism has been found to be decreased (2–4)or unmodified (1), and a few studies have dealt with IGFBP-1concentrations in hyperthyroid patients (1). Most of the studies reported so far have been performed in a limitednumber of patients and with no comparison with a controlgroup of euthyroid subjects. Moreover, some of them did notstudy patients after correction of thyroid dysfunction withtherapy.

In view of the lack of comprehensive data and definitiveconclusions relating the effects of hyperthyroidism and hy-pothyroidism and the recovery of normal thyroid status withtherapy on the serum concentration of IGF binding proteins,we decided to perform this study in which we examined alarge group of patients with thyroid dysfunction. Our in-tention was (1) to examine serum levels of IGF-1, IGFBP-1,and IGFBP-3 in a sufficiently large number of patients toreach reliable conclusions, (2) to compare these results withthose obtained in a control group of healthy subjects, and (3)to evaluate patients after normalization of thyroid dysfunc-tion with appropriate therapy.

Patients and Methods

Patients

The study included 86 patients (73 women and 13 men,mean [6 standard error of the mean (SEM)] age 49.9 6 1.9years, range, 14–85 years) with thyroid dysfunction. The hy-perthyroid group consisted of 43 patients (Table 1). The eti-ology of the hyperthyroidism was Graves’ disease (n 5 36),toxic multinodular goiter (n 5 3), toxic adenoma (n 5 2),painless thyroiditis (n 5 1), and subacute thyroiditis (n 5 1).One patient had diabetes. These patients were treated withthionamide antithyroid drugs (methimazole, MMI [n 5 39],and propyltiouracil, PTU [n 5 3]). In one patient, thionamidetherapy was not needed because of spontaneous remissionof the hyperthyroidism. Eight (18.6%) patients were treatedwith radioactive iodine (131I) and 3 (6.9%) were treated bysubtotal thyroidectomy. The hypothyroid group consisted of43 patients (Table 1). The etiology of the hypothyroidism waschronic autoimmune thyroiditis Hashimoto’s thyroiditis(n 5 13) and chronic atrophic thyroiditis (n 5 9), previous131I therapy (n 5 12), postoperative hypothyroidism (n 5 3),excess thionamide therapy (n 5 2), lithium carbonate (n 52), and painless thyroiditis (n 5 2). Five patients had dia-betes. The dosage of levothyroxine (LT4) was adjusted in at-tempt to keep the serum free thyroxine (FT4) and thyrotropin(TSH) concentrations within the normal range. No signifi-cant differences in age, gender, and the presence or absenceof diabetes mellitus between hyperthyroid and hypothyroidpatients were found. We could not find any significant dif-ferences concerning the response to therapy (FT4 and TSH

IGLESIAS ET AL.1044

TABLE 1. CLINICAL AND ANALYTICAL CHARACTERISTICS OF THE STUDIED PATIENTS BEFORE AND AFTER THERAPY

Controlsubjects(n 5 17)

Clinical dataage (years) 48.1 6 3.7gender (M/F) 2/15weight (kg) 67.5 6 3.2BMI (kg/m2) 26.8 6 1.2diabetes (yes/no) 1/16heart rate (bpm) 71.5 6 1.5

Basal Posttherapy Basal Posttherapy

Hormonal dataTSH (mU/L) (0.4–5.0) 2.2 6 0.3 51.3 6 5.7f 2.2 6 0.3h ,0.02c,f 1.8 6 0.3hFT4 (pmol/L) (9–23) 15.4 6 0.5 6.5 6 0.3f 15.7 6 0.5h 48.1 6 2.3f,h 14.6 6 0.5hT3 (nmol/L) (1.2–3.4) 3.3 6 0.2 1.6 6 0.2d 1.6 6 1.8 7.3 6 0.8c,f 2.1 6 0.1hGH (mg/L) (,5) 1.2 6 0.4 1.7 6 0.5 1.3 6 0.2 2.0 6 0.9 1.5 6 0.4insulin (mU/mL) (5–25) 17.0 6 1.9 13.2 6 0.9 13.9 6 0.9 14.9 6 0.9 11.7 6 0.9gIGF1 (mg/L) (54–450) 217.9 6 20.3 161.5 6 13.1d 152.6 6 10.6 198.8 6 17.0 156.6 6 11.1gIGFBP-1 (mg/L) (0.5–28) 5.7 6 1.5 15.5 6 0.9d 8.8 6 1.4g 22.7 6 2.6a,f 11.0 6 1.7hIGFBP-3 (mg/L) (0.9–5.4) 4.2 6 0.3 3.2 6 0.3d 3.2 6 0.2 4.2 6 0.2a 3.3 6 0.1h

Data are the number of patients or the mean 6 SEM.ap, 0.05; bp, 0.01; cp, 0.001 hypothyroid vs. hyperthyroiddp, 0.05; ep, 0.01; fp , 0.001 vs. control groupgp, 0.01; hp, 0.001 vs. basal

Patients withhypothyroidism

(n 5 43)

52.9 6 2.76/37

71.1 6 1.928.8 6 0.7

5/3865.4 6 1.5

Patients withhyperthyroidism

(n 5 43)

46.9 6 2.67/36

63.3 6 2.1a24.9 6 0.6b

1/4299.0 6 2.5b,e

levels, time to reach euthyroid status) in hyperthyroid pa-tients treated with thionamide antithyroid drugs (MMI orPTU), 131I, or surgery nor could we find any significant dif-ferences in the response to thyroxine replacement therapy inhypothyroid patients with or without diabetes mellitus. Agroup of 17 euthyroid subjects was studied as controls. Themain clinical and biochemical characteristics of patients andcontrols are summarised in Table 1.

Methods

Serum concentrations of TSH, FT4, triiodothyronine (T3),GH, insulin, IGF-1, IGFBP-1, and IGFBP-3 were measured inall patients before starting therapy and after normalizationof thyroid function. Fasting samples of venous blood wereobtained from an antecubital vein between 8:00 AM and 9:00AM hours.

Serum GH concentrations were determined using an au-tomated immunoenzymatic assay (AIA 1200, Tosoh Corpo-ration, Tokyo, Japan). Maximal intra-assay and interassay co-efficients of variation were 5.4% and 3.3%, respectively. Thesensitivity of the assay was 0.1 mg/L. Serum insulin levelswere analyzed with a commercial radioimmunoassay (SorinBiomedica, Saluggia, Italy). The intra-assay and interassaycoefficients of variation were 6.6% and 6.2%, respectively.The sensitivity of the assay was 4 mU/mL. Serum IGF-1 con-centrations were determined using commercially availableradioimmunoassay kits (Nichols Institute, San Juan Capis-trano, CA) after extraction by acid-ethanol precipitation.Maximal intra-assay and interassay coefficients of variationwere 3.0% and 8.4%, respectively, and the sensitivity of theassay was 13.5 mg/L. IGFBP-1 was determined by using animmunoenzymometric assay (Medix Biochemica Oy Ab,Kauniainen, Finland). Intra-assay and interassay variationswere 3.4% and 7.4%, respectively. The sensitivity of the as-say was 0.4 mg/L. Serum IGFBP-3 concentrations were ana-lyzed with a commercial radioimmunoassay kit (Nichols In-stitute). Maximal intra-assay and interassay coefficients ofvariation were 8.0% and 6.3%, respectively. The sensitivityof the assay was 0.03 mg/L.

Serum thyrotropin and serum FT4 were measured by animmunoenzymatic assay (MEIA, Abbot Diagnostics,Chicago, IL). Maximal intra-assay and interassay coefficientsof variation was 5% and 6.6% for TSH and 4.3% and 5.8%for FT4. The sensitivity of the assay was 0.05 mU/mL and 5pmol/L, respectively. A commercially available electro-chemiluminescence immunoassay (ECLIA, BoehringerMannheim, Germany) was used to determine total T3 con-centrations. Sensitivity of this assay was 0.3 nmol/L. Maxi-mal intra-assay and interassay coefficients of variation of T3

assay were 5.3% and 5.4%, respectively.

Statistical analysis

Results are given as the mean 6 SEM. Comparisons be-tween groups were made using analysis of variance andFisher’s least significant difference test. For paired data be-fore and after therapy the statistical analysis were carried outwith the paired Student’s t test. (x2) Test was used to studythe relationship between qualitative variables. Correlationsbetween variables were assessed using Pearson’s correlationanalysis. A value of p , 0.05 was accepted as statistically sig-nificant.

Results

Clinical data and thyroid hormones

High or low levels of thyroid hormones associated withinhibited or increased TSH concentrations, respectively, con-firmed the presence of hyperthyroidism and hypothy-roidism. Second hormonal evaluation was performed oncethyroid function was normalized (Table 1). Control of thethyroid function was achieved within 7.8 6 1.2 months in thehyperthyroid group, and within 6.9 6 0.8 months in patientswith hypothyroidism.

IGF-1 and IGFBP-3

Fasting serum IGF-1 concentrations were significantlylower (161.5 6 13.1 vs. 217.9 6 20.3 mg/L, p , 0.05) in the hy-pothyroid group compared with the control group. In pa-tients with hyperthyroidism, pretreatment values of IGF-1(198.8 6 17.0 mg/L) did not differ from those found in con-trols. Hypothyroid group exhibited significantly lower meanserum IGFBP-3 levels (3.2 6 0.3 mg/L, p , 0.05) as com-pared to control (4.2 6 0.3 mg/dL) and hyperthyroid (4.2 60.2 mg/L) groups. In the hypothyroid group, serum IGF-1and IGFBP-3 were unaltered by treatment; however, in hy-perthyroid group, IGF-1 and IGFBP-3 levels fell to 156.6 611.1 mg/L (p , 0.01) and 3.3 6 0.1 mg/L (p , 0.001) duringtreatment, respectively (Table 1, Fig. 1). Baseline GH levelswere, however, similar in patients with thyroid dysfunctionin relation to euthyroid subjects, and the normalization ofthyroid function did not change these values (Table 1).

IGFBP-1

Mean IGFBP-1 levels in the hypothyroid (15.1 6 0.9 mg/L,p , 0.05) and hyperthyroid (22.7 6 2.6 mg/L, p , 0.001)groups were significantly higher than values obtained in thecontrol group (5.7 6 1.5 mg/L). A significant reduction inIGFBP-1 levels was observed after normalization of thyroidfunction in patients with hypothyroidism (8.8 6 1.4 mg/L,p , 0.01) and in patients with hyperthyroidism (11.0 6 1.7mg/L, p , 0.001). Moreover, these values remained high incomparison with those observed in euthyroid subjects.

However, insulin concentrations were similar in the threestudied groups. Restoration of thyroid function in patientswith hypothyroidism was not accompanied by any changein insulin concentration. However, in the hyperthyroidgroup, a significant reduction (p , 0.01) was observed aftertherapy (Table 1, Fig. 1).

Regression analysis

In the hyperthyroid group, serum levels of IGF-1 andIGFBP-3 showed a significant positive correlation both be-fore (r 5 0.47, p , 0.05) and after (r 5 0.48, p , 0.01) nor-malization of thyroid function. In the hypothyroid group,serum GH levels were directly correlated with IGF-1 (r 50.38, p , 0.05) and IGFBP-3 (r 5 0.31, p , 0.05) both beforeand after treatment. IGF-1 was directly correlated withIGFBP-3 (r 5 0.59, p , 0.001) only after normalization of thy-roid hormone. There was no significant correlation betweenserum levels of GH, IGF-1, and IGFBP-3 and the serum lev-els of TSH, FT4, and T3 in the studied groups either beforeor after treatment.

IGF-1, IGFBP-2, AND IGFBP-3 IN THYROID DYSFUNCTION 1045

Baseline serum IGFBP-1 levels showed a significant posi-tive correlation with T3 (r 5 0.55, p , 0.05) in the hyperthy-roid group and with TSH (r 5 0.36, p , 0.05) in the hy-pothyroid group. Moreover, pretreatment values of IGFBP-1were inversely correlated with IGFBP-3 in the hyperthyroid(r 5 20.37, p , 0.05) and the hypothyroid (r 5 20.40, p ,0.05) groups. After normalization of thyroid function thesecorrelations were not observed, as occurred in the controlgroup. Serum insulin concentrations did not correlate withIGFBP-1, TSH, FT4, and T3 in the studied groups.

Discussion

The results of the present study confirm that thyroid sta-tus affects the GH/IGF axis, as well as their binding proteins(IGFBP-1 and IGFBP-3). Untreated hypothyroid patientsshow significant reduction of the serum concentrations ofIGF-1 and IGFBP-3, with significant elevation of IGFBP-1 lev-els. Normalization of circulating thyroid hormone with ex-ogenous thyroxine administration does not modify IGF-1and IGFBP-3 levels, but significantly reduces IGFBP-1 serumconcentrations. On the other hand, untreated hyperthyroidpatients present with normal levels of IGF-1 and IGFBP-3,and significantly higher levels of IGFBP-1 than those ob-served in euthyroid subjects. Normalization of thyroid func-tion with therapy reduces both IGF-1, IGFBP-1, and IGFBP-3 levels. In our patients thyroid dysfunction did not affectbaseline serum GH concentrations suggesting that thesechanges are not directly mediated by GH. Finally, althoughserum insulin concentration was within the normal range inboth groups of patients at the beginning and at the end of

the study, the significant reduction of insulin in treated hy-perthyroid patients suggests that insulin resistance might be,at least in part, responsible for alterations in serum levels ofsome IGFBPs, such as IGFBP-1.

Previous studies have reported several alterations of theGH/IGF axis and their binding proteins in hypothyroidism.They have been described in hypothyroid animal models(24,25), as well as in infants with congenital hypothyroidism(20) and adult hypothyroid patients (1,19). The main alter-ations reported in untreated adult hypothyroid patients havebeen low serum concentrations of IGF-1 and IGFBP-3 thatincrease significantly with the restoration of euthyroidism(1,26). Our results confirm that circulating IGF-1 and IGFBP-3 levels are decreased in untreated adult hypothyroid pa-tients; however, we did not find any significant modificationin these values after normalization of serum thyroid hor-mone concentrations. Our results concerning IGF-1 levels arelimited by the fact that we have not measured free IGF-1 con-centrations. The assay used here measures serum total IGF-1 concentrations, therefore, hypothetical changes in the bio-logically active free form of the IGF-1 after therapy ofhypothyroidism could not be detected.

A significant reduction of IGFBP-1 levels has been re-ported in patients with total thyroidectomy after withdrawalof thyroid hormone replacement with restoration to basalvalues of IGFBP-1 after normalizing circulating thyroid hor-mones with thyroxine therapy (2,3). Significant incrementsof IGFBP-1 have also been reported after thyroxine therapyin adult patients with hypothalamic hypothyroidism (4);however, thyroxine therapy did not change serum levels ofIGFBP-1 in patients with primary hypothyroidism caused by

IGLESIAS ET AL.1046

IGF

-l

FIG. 1. Mean (6 standard error of the mean [SEM]) levels of insulin-like growth factor-1 (IGF-1) (upper left), insulin-likegrowth factor binding protein (IGFBP)-3 (upper right), IGFBP-1 (lower left), and insulin (lower right) in control subjectsand in the two groups of patients before and after normalization circulating thyroid hormones. *p , 0.05; **p , 0.01; ***p ,0.001.

autoimmune disease (1). Our data clearly show that meanserum IGFBP-1 levels in patients with hypothyroidism weresignificantly higher than those observed in the euthyroidgroup. The restoration of circulating thyroid hormone wasaccompanied by a significant reduction of IGFBP-1 levels.Discrepancies with the findings in other studies are unclear.The diverse etiology, severity, and evolution time of the thy-roid hypofunction, as well as the duration of euthyroidismmight account for the different reported results.

Similarly, several alterations in the GH/IGF axis have beendescribed in thyrotoxic patients, although the results of thedifferent studies have not always agreed. Serum concentra-tions of IGF-1 have been reported to be normal (22) or high(1,19,21,23) and serum IGFBP-3 levels have been found to beincreased (1,6,19,21) in thyrotoxicosis. Moreover, control of thethyroid function decreases (1,21) or does not modify (22)serum IGF-1 levels, while IGFBP-3 levels decrease (21) or re-main unaltered (1). In our patients, serum concentrations ofIGF-1 and IGFBP-3 were similar to values found in age-matched euthyroid subjects and the normalization of the thy-roid function significantly reduced both parameters.

Serum IGFBP-1 levels have been found to be elevated inadult hyperthyroid patients with a significant reduction aftercontrol of thyroid function (1,22). It has been reported thatthyroid hormone administration increases IGFBP-1 secretionby human hepatoma cells in vitro. A dose-dependent increasein IGFBP-1 secretion was followed after 24–48 hours of T3 ex-posure in serum-free HepG2 cell cultures. This increment cor-related with accumulation of intracellular IGFBP-1 mRNA,which could be prevented by a protein synthesis inhibitor.These findings suggest that T3 stimulates IGFBP-1 secretionslowly by enhancing IGFBP-1 expression by a protein medi-ator (5). However, IGFBP-1 is primarily regulated by insulin(27), and it has been recently proposed that the mechanism bywhich IGFBP-1 is increased in hyperthyroid patients may bethrough the impaired glucose tolerance commonly observedin these patients, despite normal baseline insulin concentra-tions (22). Our results confirm that hyperthyroid patientsshow significant high levels of IGFBP-1 with normal seruminsulin concentration and the restoration of thyroid functionsignificantly reduces IGFBP-1 levels.

We have found that IGFBP-1 concentrations are elevated inpatients with hypothyroidism and hyperthyroidism. The ex-planation for this is not clear. It might be in relation to theknown derangements in glucose and insulin homeostasis inpatients with thyroid dysfunction (22,28). In this way, two dif-ferent therapies used to increase or decrease thyroid hormonelevels, respectively, may induce similar effects on correctionof glucose metabolism and, as a result, in IGFBP-1 levels.

In conclusion, these results confirm that thyroid status af-fects GH/IGF axis, modifying circulating levels of IGF-1 andsome IGFBPs. While hypothyroidism is associated with sig-nificant reductions of IGF-1 and IGFBP-3 levels, hyperthy-roidism does not modify these parameters. Both hypothy-roidism and hyperthyroidism are associated with reversiblehigh serum concentrations of IGFBP-1.

Acknowledgments

The authors thank Ms. Elvira Alcaria, Ms. Ma Jesús Gar-cía, and Ms. Concepción Moreno for their cooperation in thestudy.

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Address reprint requests to:Dr. Pedro Iglesias

C/Maria Sevilla Diago, 9, 3°28022 Madrid

Spain

E-mail: piglesias@mi.madritel.es

IGLESIAS ET AL.1048