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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-2555
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 3 860-864
Copyright © 2006 by The Endocrine Society

Thyroid Morphology and Function in Adults with Untreated Isolated Growth Hormone Deficiency

Marta Regina Silva Alcântara, Roberto Salvatori, Paula Regina Silva Alcântara, Luciana Michele A. Nóbrega, Vera Simone Campos, Elma Cristina O. Oliveira, Marcelo Henrique S. Oliveira, Anita Hermínia Oliveira Souza and Manuel Hermínio Aguiar-Oliveira

Division of Endocrinology, Federal University of Sergipe (M.R.S.A., P.R.S.A., L.M.A.N., V.S.C., E.C.O.O., M.H.S.O., A.H.O.S., M.H.A.-O.), Aracaju, SE Brazil 49060-100; and Division of Endocrinology, The Johns Hopkins University School of Medicine (R.S.), Baltimore, Maryland 21287

Address all correspondence and requests for reprints to: Dr. Roberto Salvatori, Division of Endocrinology, Johns Hopkins University, 1830 East Monument Street, Suite 333, Baltimore, Maryland 21287. E-mail: salvator{at}jhmi.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Objective: GH influences thyroid function and anatomy. Although goiter is frequent in acromegalic patients, the effects of GH deficiency (GHD) are difficult to assess, because hypopituitaric subjects who lack GH often also have a partial or complete deficit of TSH.

Study Design: We studied thyroid morphology and serum levels of thyroid hormones in adult members of a large Brazilian kindred with untreated isolated GHD due to a homozygous mutation in the GHRH receptor gene (GHRHR; nine men and 15 women; GHD group) and compared them to subjects heterozygous for the same mutation (eight men and 10 women; HET group) and subjects homozygous for the wild-type allele [seven men and 11 women; control (CO) group].

Results: GHD subjects had a smaller thyroid volume (TV) than HET and CO. The TV of the HET group was intermediate between those of the GHD and CO groups. When TV was corrected by body surface area, it remained smaller in the GHD and HET groups than in the CO group, but the difference between GHD and HET groups disappeared. The GHD group had lower serum T3 levels than the CO group and higher free T4 levels than HET and CO groups.

Conclusions: Individuals with severe untreated GHD due to a homozygous GHRHR mutation and heterozygous carriers of the same mutation have smaller TV than normal subjects, suggesting that GH has a permissive role in the growth of the thyroid gland. In addition, GHD subjects have reduced serum total T3 and increased serum free T4, suggesting a reduction in the function of the deiodinase system.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
COMPLEX INTERACTIONS EXIST between the GH-IGF-I axis and the TSH-thyroid axis. Thyroid hormones have a fundamental role in the initiation and maintenance of somatic growth and are important in regulation of the secretion and action of GH (1). In contrast, IGF-I is a proliferative factor for thyrocytes, increasing the stimulatory effect of TSH (2, 3, 4, 5, 6).

An association between GH excess and goiter has been reported. Clinically evident goiter is present in 25–70% of acromegalic patients (7, 8) and in up to 100% patients when they are studied by sonography (9, 10). Excess IGF-I is believed to be implicated in the development of goiter, because sera of acromegalic patients potentiate the proliferative effect of TSH on thyrocytes in vitro (11). Indeed, in acromegaly, serum IGF-I levels correlate positively with thyroid volume (TV) (8, 10). Conversely, a small TV has been reported in pan-hypopituitaric patients. However, because most of these patients lack both GH and TSH, it is impossible to determine the lack of which of the two hormones causes this volume reduction (12).

Besides GH and IGF-I levels, numerous factors are involved in the determination of thyroid volume: anthropometric variables such as weight, height, body surface area (bsa), and body mass index (BMI); body fat mass (FM); fat-free mass (FFM); sex; age; and iodine intake (13, 14, 15, 16, 17). Several of these parameters are influenced by GH status and may indirectly or directly contribute to abnormalities in thyroid volume in GH-deficient (GHD) individuals.

In Itabaianinha, a city in the northeastern Brazilian state of Sergipe, we have identified an extended pedigree (>100 affected individuals) with familial isolated GHD due to a homozygous null mutation (IVS1 + 1G->A) in the GHRH receptor (GHRHR) gene (GHRHR) (18). The adult dwarfs have never received GH therapy and are the largest homogeneous cohort of patients with severe GHD described to date. These subjects are an ideal model to study the consequences of long-term GHD on thyroid function and morphology. We have compared GHD individuals who are homozygous for the GHRHR mutation with subjects heterozygous for the same mutation and with normal controls residing in the same area.


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

Twenty-four GHD-naive adult patients with a genotype-proven homozygous IVS1 + 1G->A GHRHR mutation (nine men and 15 women; GHD group), 18 genotype-proven heterozygous (eight men and 10 women; HET group), and 18 genotype-proven normal homozygous [seven men and 11 women, control (CO) group] were studied. All participants reside in the same rural area in or around the city of Itabaianinha. Patients and families were recruited through the local dwarfs’ association after a detailed explanation of the protocol. All heterozygous and normal control subjects belong to same nuclear families of the GHD subjects. Based on their medical history, all subjects were free of thyroid or other systemic diseases, and none was receiving any medication known to affect thyroid function. This study was approved by ethic committees of the Federal University of Sergipe and Johns Hopkins University, and all subjects gave written informed consent.

Study protocol

All subjects were admitted to the University Hospital of the Federal University of Sergipe at 0800 h after an overnight fast. Blood samples were collected, and anthropometric data (height, weight, bsa, BMI, FFM, FM, and percentage of FM) were measured or calculated. The bsa was calculated using the formula: bsa (meters2) = w0.425 x h0.725 x 71.84 x 10–4, where w is the weight in kilograms, and h is the height in centimeters (19). The SD score height for age (SDS h/a) was calculated using National Center for Health Statistics data (www.cdc.gov/nchs). BMI was calculated by dividing body weight (kilograms) by the square of the height (meters) (20), and FFM, FM, and percent FM were measured using the near-infrared inheritance method to determine body composition (21). This procedure involved placing a fiber optic probe tangentially to the belly of the subject’s biceps brachia and measuring the reflected energy in the near-infrared region at two different frequencies.

TV

TV was estimated using ultrasonic scanning procedure with a high frequency 8.0-MHz linear array transducer (Toshiba ECCOCCE). The examinations were all performed by the same operator with the subject in a supine position and the neck hyperextended. The operator was blinded to the genotype (normal or HET) of the normal stature individuals. The lobes were approximated to ovoid, and their volume, expressed in milliliters, was estimated by the formula: volume of one lobe (ml) = length x width x depth x {pi}/6 (22). The isthmus was not taken into account in volume calculation. The corrected TV was calculated by dividing TV by the bsa.

Hormone assays

Serum TSH, T3, and free T4 (FT4) were assayed by an immunofluorometric assay (Wallac, Inc., Oy, Turku, Finland). Intraassay variabilities were 2.9% (TSH), 3.2% (T3), and 1.5% (FT4). Interassay variabilities were 2.6% (TSH), 1.4% (T3), and 4.3% (FT4). IGF-I was measured by immunoradiometric assay with double extraction and an assay sensitivity of 0.8 ng/ml (Diagnostics Systems Laboratories, Inc., Webster, TX). Intraassay variability was 2.6%, and interassay variability was 4.5%.

Statistical analysis

Statistical analysis was performed using the statistical software SPSS/PC 8.0 (SPSS, Inc., Chicago, IL). Values for continuous variables are expressed as the mean ± SD and frequency to the qualitative variables. ANOVA was used for comparison of the three groups. Spearman correlation was used for the correlation between TV and its determinants. P ≤ 0.05 was considered statistically significant.


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

As shown in Table 1Go, age, sex, and BMI did not differ between groups. As expected, height, weight, SDS h/a, and bsa were significantly lower in the GHD group than in the HET and CO groups. The HET group had lower SDS h/a than the CO group. The GHD group had lower FFM and a higher percentage of FM than the other two groups.


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  		TABLE 1. Anthropometric data (mean ± SD) in the three groups

 
Hormonal data

Serum IGF-I levels were significantly lower in the GHD group than in the other two groups (Table 2Go). IGF-I levels in HET were lower than those in the CO group. The GHD group had lower T3 levels than CO, and higher FT4 levels than HET and CO. TSH levels were not different among groups.


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  		TABLE 2. Hormonal and TV data (mean ± SD) of the three groups

 
TV

The GHD group had smaller absolute TV than the HET and CO groups (Table 2Go). The TV of the HET group was intermediate between those of the GHD and CO groups. When TV was corrected by bsa, it remained higher in the CO group than in the other two groups, and the difference between GHD and HET disappeared.

TV had a positive correlation with serum IGF-I (r = 0.677; P < 0.0001; Fig. 1Go), weight (r = 0.688; P < 0.0001), bsa (r = 0.678; P < 0.0001), FFM (r = 0.717; P < 0.0001), and height (r = 0.748; P < 0.0001) and a negative correlation with percent FM (r = –0.631; P < 0.0001) and FT4 (r = –0.278; P < 0.04) in the total of 60 individuals. When analysis was limited to the GHD group, correlations of TV remained with bsa (r = 0.625; P < 0.002), height (r = 0.489; P < 0.02), and FFM (r = 0.432; P < 0.05; Fig. 2Go).


Figure 1
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  		FIG. 1. Correlation of TV and serum IGF-I (r = 0.677; P < 0.0001).

 

Figure 2
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  		FIG. 2. Correlations between TV (milliliters) and bsa (square meters; r = 0.625; P < 0.002), TV and height (meters; r = 0.489; P < 0.02), and TV and FFM (kilograms; r = 0.432; P < 0.05) in the GHD group.

 
Thyroid nodules

The frequency of thyroid nodules was 4% in the GHD group (only one solid nodule) and 16% in the CO group (three nodules were found in two subjects). All nodules were less than 1.5 cm in diameter. The subjects declined aspiration of the nodules. No thyroid nodule was found in the HET group.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
GH has an important effect on the replication of thyroid epithelial cells; TSH is necessary for its action on thyroid growth (12). Indeed, serum from acromegalic subjects stimulates thyroid cell proliferation, amplifying the mitogenic effect of TSH (11). Although many studies agree that acromegaly is associated with goiter (7, 8, 9, 10), studies of TV and thyroid function in hypopituitaric patients do not allow determination of the individual effects of lack of GH or TSH. The only study carried out in hypopituitaric patients showed that TV was significantly smaller only when it was corrected by BMI or weight (12). The Itabaianinha patients have isolated GHD, with no clinical or biochemical evidence of TSH deficiency. We have found small absolute and corrected TV in individuals who are homozygous and heterozygous for a GHRHR mutation. The absolute TV in GHD subjects was smaller than that in HET, but this difference disappeared after correction for bsa. The GHD subjects present extremely low serum levels of IGF-I. They also have low serum IGF-II, IGF-binding protein-3, and acid-labile subunit (23). The HET subjects have an intermediate serum IGF-I level. It is likely that a reduction in TV reflects the reduction in circulating (and possibly locally produced) IGF-I in GHD and HET. The reduction of TV in HET suggests that even a relatively mild reduction in serum IGF-I may cause a reduction in thyroid growth. This observation is important and calls for a large analysis in the general population to correlate serum IGF-I with TV.

A recent twin study concluded that genetic factors account for 71% of individual differences in TV (17). Because a marked genetic influence has also been described for serum IGF-I levels (24), it is possible that IGF-I is one of the links between genetics and TV.

In other inherited diseases, heterozygous subjects present a phenotype intermediate between normal and homozygous affected individuals. For example, patients homozygous for mutations of the low-density lipoprotein receptor gene have very severe hypercholesterolemia and coronary disease in the first decade of life, whereas heterozygous subjects have less pronounced hypercholesterolemia, with coronary disease appearing at a later age (25). We previously reported reduced serum IGF-I levels in subjects heterozygous for the Itabaianinha mutation (26). We can add reduced TV to their partial phenotype.

GHD subjects have altered anthropometrics parameters (such as low body weight, height, bsa, and FFM), which are believed to influence TV (13, 14, 15, 16, 17, 27). Our study reinforces the importance of these variables in determining TV. The strongest positive correlation of TV was found with FFM and height. Our GHD patients had reduced FFM (28, 29). Positive correlations with height, FFM, and bsa remained statistically significantly when only the GHD group was analyzed, showing that these variables are still important despite the severe short stature of GHD subjects.

One possible limitation of our study is the reported intraobserver variability, which was as high as 14.4% in sonographic measurement of TV (30). We did not assess intraobserver variability. However, the degree of statistical difference in TV among the three groups and the good correlation between TV and serum IGF-I suggest that our TV results are reliable and are not significantly influenced by such variability.

The frequency of thyroid nodular disease was lower in the GHD and HET groups than in the CO group. Because acromegalic patients have more thyroid nodules and goiter (8, 10), it is expected that subjects with low serum IGF-I present a low frequency of thyroid nodules, probably due to the lesser stimulus of IGF-I and other GH-dependent growth factors on thyroid cells. The small number of nodules found in CO, however, does not allow us to draw definitive conclusions on this point.

The content of iodine in the diet is also an important determinant of TV (31, 32). We did not measure urinary iodine in our study subjects. However, salt has been supplemented with iodine in Brazil since 1982. The average urinary iodine excretion in the state of Sergipe is 17 µg/dl (iodine deficiency, <10 µg/dl) (33). Indeed, the prevalence of endemic goiter in children in Sergipe is 0.2%, similar to that in other Brazilian states. These data and the fact that all study subjects reside in the same area (all within a 20-km radius) make any influence of deficiency dietary iodine on our findings unlikely.

The GHD group had lower serum T3 levels and higher serum FT4 levels than normal subjects. We hypothesize that this may be due to the absence of the known effect of GH on the function of 5'-deiodinase, an enzyme that converts T4 into T3 (34, 35, 36, 37). Indeed, it has been previously reported that GHD subjects treated with GH show a reduction of serum FT4 (38, 39). HET subjects did not have a difference in the variables of thyroid function despite the small TV, suggesting that such an effect is limited to subjects with very low serum GH levels. One may expect that serum TSH would be higher in GHD subjects due to lower T3 levels. However, this does not occur in patients who remain euthyroid on long-term treatment with drugs known to decrease 5'-deiodinase, such as amiodarone (40). Indeed, in this study TSH was not different in any of the groups. In the past, we reported a mild increase in TSH in a group of 11 GHD subjects from Itabaianinha (41). However, those GHD subjects were younger (mean age, 22 yr) than those studied here and were compared with normal subjects residing in Aracaju, which is located on the sea approximately 118 km from Itabaininha. We believe that the CO group of this study is more appropriate.

In conclusion, the finding of smaller TV in GHD and HET subjects and its correlation with height and serum IGF-I indicate a critical role of GH in determination of TV. If confirmed in other populations, this observation may suggest that serum IGF-I levels should be considered a determinant of thyroid size.


   Acknowledgments
 
We are grateful to Mrs. Ivanilde Santana de Sousa for her secretarial assistance.


   Footnotes
 
This work was supported by National Institutes of Health Grant 1-R01-DK-065718, Fundação de Amparo à Pesquisa do Estado de Sergipe Grant FAP Edital 2/2002, and a grant from Genentech Center for Clinical Research in Endocrinology.

ClinicalTrials.gov identifier: NCT00149708.

First Published Online January 4, 2006

Abbreviations: BMI, Body mass index; bsa, body surface area; CO, control; FFM, fat-free mass; FM, fat mass; FT4, free T4; GHD, GH deficiency; GHRHR, GHRH receptor; HET, heterozygous; SDS h/a, SD score height for age; TV, thyroid volume.

Received November 28, 2005.

Accepted December 21, 2005.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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