Treating Iodine Deficiency: Long-Term Effects of IodineRepletion on Growth and Pubertal Development

in School-Age Children

Kostas B. Markou,1 Athanasios Tsekouras,1 Eleni Anastasiou,2 Barbara Vlassopoulou,2 Eftychia Koukkou,2

George A. Vagenakis,1 Panagiotis Mylonas,1 Charalampos Vasilopoulos,2 Anastasia Theodoropoulou,1

Loredana Rottstein,1 Evgenia Lampropoulou,1 Dimitris Apostolopoulos,3 Rauf Jabarov,4

Apostolos G. Vagenakis,1 and Neoklis A. Georgopoulos5

Background: Iodine deficiency (ID) is still a major universal health problem. Iodine deficiency disorders (IDDs)affect people of all ages, among whom the most vulnerable are children and adolescents. The aim of the presentstudy was to assess the long-term effects on growth and pubertal development of correcting severe ID in areas ofAzerbaijan between 1999 and 2000.Methods: Iodized oil was administered orally to 293,000 children, aged 6–16 years. Among those, 364 childrenwere randomly selected and were examined 1 year before the administration of iodized oil (Group I-neg, iodinenegative) and 295 children (Group I-Rx, iodine treated) were examined 4 years (Group I-Rx4, iodine treated 4 yearslater; n¼ 173) or 5 years (Group I-Rx5, iodine treated 5 years later; n¼ 122) after the last dose of iodide.Results: In Group I-neg the median urine iodine concentration (UIC) (mcg=L) was 36 (mean: 36.272 ± 11.036) andincreased significantly ( p< 0.001) in Group I-Rx4: 188 (mean: 230.969 ± 155.818) and in Group I-Rx5: 175 (mean:201.176 ± 130.369). The prevalence of goiter was 99% in Group I-neg and 2% in Group I-Rx4. Children in Group I-Rx had a greater standard deviation score (SDS) for height (�0.1364 ± 1.279, n¼ 294) than children in Group I-neg(�0.5019± 1.17, n¼ 363) ( p<0.001, t¼�3.817), which was more significant for boys. SDS for weight was similar inboth groups (Group I-neg: �0.17± 0.78, n¼ 363; Group I-Rx: �0.115± 0.917, n¼ 294). The rate of puberty develop-ment as judged by the development of breast and pubic hair was normalized in both sexes after the correction of ID.Conclusions: Our results demonstrate that long-term correction of severe ID leads to sustained improvement oflinear growth accompanied by a normalization of the time of onset of pubertal development for both sexes.

Introduction

Iodine deficiency (ID) is still a major universal healthproblem. According to the International Council for the

Control of Iodine Deficiency (ICCIDD), 2.2 billion people(about 38% of the world population) live in areas with IDand are at risk for its complications (1). Iodine deficiency dis-orders (IDDs) affect people of all ages, amongwhom the mostvulnerable are pregnant women and their fetuses, neonates,children, and adolescents (2). The most frequent manifesta-tion of ID is endemic goiter, but ID is also associated withabortions, stillbirths, congenital abnormalities, and increased

perinatal and infant mortality. The most important ID dis-order is hypothyroidism, which in its extreme form resultsin cretinism (neurological or myxedematous) (3). ID also im-pairs mental development and somatic growth of childrenand adolescents. The reproductive system may be affectedduring adolescence, although the evidence for this is lim-ited (4). Severe hypothyroidism may cause premature pu-berty, while the consequences of subclinical hypothyroidismare still unknown (5–7). In 1998 school children living inthe mountainous areas of Azerbaijan, specifically in theCaucasus, suffered moderate to severe ID based on WHO=UNICEF=ICCIDD criteria (8,9).

1Division of Endocrinology, Department of Internal Medicine, University of Patras Medical School, University Hospital, Patras, Greece.2Hellenic Endocrine Society, Athens, Greece.3Department of Nuclear Medicine, University of Patras Medical School, University Hospital, Patras, Greece.4Endocrinological Dispensary of Baku, Baku, Azerbaijan.5Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Patras Medical School, University

Hospital, Patras, Greece.

THYROIDVolume 18, Number 4, 2008ª Mary Ann Liebert, Inc.DOI: 10.1089=thy.2007.0277

449

The aim of the present study was to assess the long-termeffects of iodized oil administration on urine iodine concen-tration (UIC) and to estimate its effects on growth and pu-bertal development.

Subjects and Methods

In the fall of 1998 we administered 190mg of iodized oil bythe oral route to 293,000 school children, ranging in age from 6to 17, who lived in seven mountainous regions of the Cau-casus that had moderate to severe ID (10). This treatment wasrepeated twice over the next 6 months. The Ethics Committeeof the University of Patras Medical School gave approval forthe study, and informed oral consent was obtained fromparents and children.

We studied two representative groups of children, living inthose regions (in each region at least 40 schoolchildren wereexamined): Group I-neg (iodine negative) included 364 chil-dren aged 8–14 years (187 males and 177 females), who wereexamined 1 year before the administration of iodide. Group I-Rx (iodine treated) included 295 children aged 6–16 years (154males and 141 females), whowere examined 4 years (Group I-Rx4 [iodine treated 4 years later]: n¼ 173, 97 males and 76females) and 5 years (Group I-Rx5 [iodine treated 5 yearslater]: n¼ 122, 57 males and 65 females) after the last dose ofiodide. In all studied areas the same approach was applied.The children were examined at school, and we randomly se-lected equal number of boys and girls from each class.

The assessment included the following:

1. Registration of demographic data (name, gender, age),height and weight measurements (height was measuredby the same physician and registered as the mean oftwo consecutive measurements). As normative data foreach different ethnic group are not available, height andweight were expressed as standard deviation score(SDS) for the mean height and weight for age, accordingto Tanner et al. (1976), which is developed for thepopulation of normal European children (11). Pubertydevelopment was estimated according to Tanner stages(11), by the same physician.

2. Ultrasound assessment of thyroid volume using a por-table ultrasound apparatus with a 7.5MHz linear trans-ducer (Scanner 100 LC Pie Medical; Phillips MedicalSystems, Maastricht, The Netherlands). A gas generatorand a voltage stabilizer powered the instrument. Thevolume of each lobe was calculated according to theformula for volume of a rotation ellipsoid by multipli-cation of maximal thickness, width, and height of thelobe by the correction factor 0.479 (12). The upper limitsof normal were estimated according to body surfacearea as proposed by Delange et al. (1997) (13). Ultra-sound assessments of the thyroid were all carried out bythe same physician.

3. Morning spot urine specimens were collected at eachexamined region. The measurements of UIC were per-formed by the spectrophotometric method (Sandell–Kolthoff reaction, after digestion with chloric acid at1108C for 1 hour) according to the method of Dunn et al.(1993) (14). The samples were refrigerated at �48C untilassayed at the Endocrine Laboratory of the Universityof Patras Medical School, Greece.

4. Serum measurements of triiodothyronine (T3), thyrox-ine (T4), thyrotropin (TSH), thyroglobulin (Tg), anti-thyroid peroxidase (anti-TPO), and antithyroglobulin(anti-Tg) autoantibodies were conducted in samplesrefrigerated at �48C until assayed at the EndocrineLaboratory of the University Of Patras Medical School,Greece. T3, T4, and TSH were determined with a semi-automatic analyzer (IMX; Abbot Park, Chicago, Illinois).Serum Tg was measured with an immunoradiometricassay (IRMA; DiaSorin, Salugia, Italy). For the measu-rement of anti-TPO and anti-Tg autoantibodies, a radio-immunoassay kit (BRAHMS, Dynotest, DiagnosticaGmbH, Berlin, Germany) was used.

5. Measurement of iodine concentration (n¼ 25) in sam-ples of household salt (Group Rx) collected in eachregion.

Statistics

Data were analyzed using SPSS 14 (SPSS, Chicago, Illinois).Descriptive statistics were generated for all variables. Whenindicated, all values are expressed as means� SD. Student’st-test was used to evaluate differences between groups.Mann–Whitney nonparametric test was used to compare theurine iodine values.

Results

Indicators of iodine intake (Median UIC, serum thyroglo-bulin values, goiter prevalence) and thyroid autoantibodies,TSH, and thyroid hormones are presented in Table 1.

Growth development

Children in Group I-Rx had a significantly greater SDS forheight (�0.1364� 1.279, n¼ 294) than children in Group I-neg(�0.5019� 1.17, n¼ 363) ( p< 0.001, t¼�3.817). When malesand females were considered separately, the difference be-tween Groups I-neg and I-Rx remained significant only formales (Fig. 1). SDS forweight was similar in all groups (GroupI-neg: �0.17� 0.78, n¼ 363; Group I-Rx: �0.115� 0.917,n¼ 294).

Pubertal development

As shown in Table 2A and 2B, the rate of pubertal develop-ment in both sexes, as judged by the mean age at which eachstage of breast and the pubic hair development was achieved,was shifted to an older stage after the correction of ID.

In all examined household salt samples the concentrationof iodide was <20ppm (median, 13.5; max, 17; min, 7), lessthan the WHO=UNICEF=ICCIDD recommendations (15).

Discussion

The results of the present study clearly demonstrate thatthe long-term correction of severe ID leads to a sustainedimprovement of linear growth accompanied by a normaliza-tion of the time of onset of pubertal development. The ad-ministration of 570mg of iodized oil mainly resulted in thecorrection of severe ID 4 and 5 years later, with median UICimproving from 36 to 188mcg=L and 175mcg=L, respectively.Further, a dramatic decrease in the prevalence of goiter wasobserved below the endemic limit (5%) according to WHO.

450 MARKOU ET AL.

These results correspond well with the decrease in Tg values,which is the most reliable indicator of iodine intake. Thesechanges were due mainly to iodine substitution, as iodideconcentrations in the household salt were low.

An increase in the percentage of abnormal values of thyroidautoantibodies (either anti-Tg or anti-TPO) was observedafter the administration of iodide, without gender differences.Clinical studies have shown that the increase of iodine intakein iodine-deficient areas is accompanied by increased auto-immunity (16). These changes have not been associated withan influence on linear growth.

Improvement of growth was observed in the examinedpopulation, while the process of puberty was more delayed ingirls than in boys. Special consideration should be given to theobserved dissociation of the results on linear growth fromthose on body weight. The fact that SDS for weight was notaffected after the iodine repletion suggests an effect of iodinerepletion on linear growth probably through the correction ofthyroid function, as any change in the socioeconomic statusof the population studied would lead to an additional im-provement of body weight.

Growth and physical maturation are dynamic processesinfluenced by a number of genetic and environmental factors.Genetic predisposition to growth can be fully expressed onlyunder favorable environmental conditions (17). The majorregulators of growth are growth hormone (GH), the insulinlike growth factors (IGFs), and thyroid hormones, while go-nadal steroids are responsible for the pubertal growth spurt.

It is well known that untreated congenital hypothyroidismleads to short stature, while untreated subclinical hypothy-roidism leads to a slowing of growth (18–20). This is becausethyroid hormones are important in regulating the normal GHand IGF-1 synthesis (18).

Iodine is the necessary substrate for thyroid hormonesynthesis (21), and severe ID induces both goiter and de-rangement in thyroid hormone production by the thyroidgland (22,23). There are some cross-sectional studies exam-ining the effects of ID on growth. It is expected that children iniodine-deficient areas may show retardation of both lineargrowth and skeletal maturation (24). Therefore, correction ofID should lead to an improvement of the growth in affectedchildren and adolescents. There are limited controversial

FIG. 1. Height standard deviation score (SDS) before (Group I-neg) and after (Group I-Rx) the administration of 570mg ofiodized oil.

Table 1. Indicators of Iodine Intake (Median Urinary Iodine Concentration [UIC], Median Serum Thyroglobulin

[Tg], and Goiter Prevalence as Estimated by Ultrasound), Percentage of Abnormal Values of Thyroid

Autoantibodies (Either Anti-Tg or Anti-TPO), and Mean Serum TSH, T3, and T4 before (Group I-neg) and

4Years (Group I-Rx4) and 5Years (Group I-Rx5) after the Administration of 570mg of Iodized Oil

MedianUIC

(mcg=L)

MedianTg

(ng=mL)Goiter(%)

Abnormalthyroid

autoantibodies (%)Mean TSH(mIU=L)

Mean T3

(ng=mL)Mean T4

(mg=dL)

Group I-neg 36 48.3 99 0 2.18� 0.96 1.39� 0.28 8.33� 1.82Group I-Rx4 188* 89.94 2 8 a a a

Group I-Rx5 175* 4.47 b 9 2.16� 1.23 1.54� 0.03** 7.79� 1.12***

*p< 0.001, **p< 0.01,***p< 0.05.aThyrotropin (TSH), triiodothyronine (T3), and thyroxine (T4) measurements for Group I-Rx4 (mean TSH, 2.74� 1.58; mean T3, 1.73� 0.28;

mean T4, 9.52� 1.69) were performed using a different method of assessment (chemiluminescence-Elecsys; Roche Diagnostics, Laval, Quebec,Canada) and therefore cannot be compared to the findings in the other Groups.

bGoiter in Group I-Rx5 has not been estimated.

IMPROVEMENT OF GROWTH AFTER IODINE DEFICIENCY CORRECTION 451

studies reporting beneficial effects on growth when iodinesubstitution programswere instituted in areas of ID (25–27). Itis unclear whether this improvement was part of a generalchange in the socioeconomic status of the affected populationsdue to the correction of associated malnutrition or to substi-tution of other depleted micronutrients, such as selenium.

Our data are strengthened by the findings of a recentdouble-blind, placebo-controlled study by Zimmermann et al.(28). They reported that short-term correction of ID improvedsomatic growth in three genetically different school-age chil-dren populations, and increases IGF-1 and IGFBP3 serumconcentrations. The results of this study demonstrated for thefirst time that both height and weight improve after short-term (6 months) iodine repletion. This effect was more pro-minent in the most iodine-deficient population and was atleast partly due to an improvement of the IGF-1 synthesis andaction. In the more iodine-deficient populations of the study(Albania and Morocco), iodine repletion increased serumtotal T4 (TT4), IGF-1, and IGF-BP3, as well as both height andweight z-scores for age. In the modest ID population (SouthAfrica) the observed increase in IGF-1 serum concentrationswere not associated with a significant improvement of lineargrowth. Our studywas done in a population after a long-termobservation period through which, according to our personalexperience, nutrition, sanitation, economic development, andaccess to commercial food markets were improved. Our find-ing that weight was not changed after iodide administrationpoints toward a clear effect of iodide repletion on growth.

We found subtle changes in T3 and T4 concentrations afterthe iodine administration. These changes do not reflect a re-markable influence in thyroid function as judged by the ab-sence of changes in TSH concentrations and may represent

random variations. Still, such subtle changes in thyroid hor-mones, although within the normal range, may play an im-portant role in augmenting GH and IGF-1 action. Normalthyroid function is a prerequisite for normal somatic growthbecause thyroid hormones are essential for GH and IGF-1synthesis (29). In children with hypothyroidism treated withthyroid hormone, an increase in serum IGF-1 and IGF-BP3concentrations was observed (30). Thyroid hormone is animportant factor for normal GH cell development. It enhancesGH or growth hormone releasing hormone (GHRH)-receptor gene expression (31) and induces an upregulation ofIGF-I receptors and increased IGF-I binding to cell mem-branes (32).

Severe ID is accompanied by a decrease in serum T3 and T4

concentrations, while severe hypothyroidism may lead toprecocious puberty (5–7). There are few if any clinical studieson the effects of mild hypothyroidism on pubertal develop-ment. It is possible that the observed small changes in serumT3 and T4 values in the iodide-substituted population mightrestore the pubertal set point back to normal and augmenteven more the process of linear growth. This might be moreevident in boys due to their longer duration of puberty, whichallows more effective action of androgens and possibly thy-roid hormones on the skeleton. Nevertheless, height SDS as-sessment in girls shows a more variability than in boys (33),obscuring the beneficial effects of iodine repletion in our fe-male population.

This study has certain limitations. It is a field study, part ofan intervention program in a large population of school-agechildren of a mountainous region. Therefore, there were nooptions for the evaluation of the GH–IGF-1 axis, while aplacebo-controlled double-blind trial was not possible for

Table 2A. Mean Age (in Years) of Pubic Hair Development, According to Tanner Stages, in Male and Female

Subjects before (Group I-neg) and after (Group I-Rx) the Administration of 570mg of Iodized Oil

Tanner II Tanner III Tanner IV–V

Pubic hair

Male

Group I-neg 13.0� 1.11 (n¼ 22) 12.9� 1.07 (n¼ 14) 13.5� 0.6 (n¼ 12)Group I-Rx 13.3� 1.2 (n¼ 29) 13.8� 0.85 (n¼ 21) 14.9� 1.2 (n¼ 59)p n.s. p< 0.05 p< 0.001

Female

Group I-neg 11.5� 1.5 (n¼ 28) 12.1� 1.1 (n¼ 33) 13.5� 0.7 (n¼ 45)Group I-Rx 12.6� 0.7 (n¼ 9) 12.7� 0.7 (n¼ 15) 14.5� 1.5 (n¼ 88)p p< 0.05 p¼ 0.06 p< 0.001

n.s.: not significant.

Table 2B. Mean Age (in Years) of Breast Development, According to Tanner Stages, in Female Subjects

before (Group I-neg) and after (Group I-Rx) the Administration of 570mg of Iodized Oil

Tanner II Tanner III Tanner IV–V

Group I-neg 10.8� 1.2 (n¼ 42) 12.3� 1.1 (n¼ 32) 13.5� 0.8 (n¼ 49)Group I-Rx 12.8� 0.7 (n¼ 12) 12.6� 0.9 (n¼ 14) 14.5� 1.5 (n¼ 89)p p< 0.001 n.s. p< 0.001

n.s.: not significant.

452 MARKOU ET AL.

ethical reasons. Similarly, due to religious ethics of the popu-lation, no data on menarche could be collected.

In conclusion, our results demonstrate that long-term cor-rection of severe ID leads to sustained improvement of lineargrowth accompanied by a normalization of the time of onsetof pubertal development for both sexes, compared to the se-vere iodine-deficient status.

Acknowledgments

We are indebted to the Greek Ministries of Foreign Affairsand Education, the Hellenic Endocrine Society, and the GreekEmbassy in Baku-Azerbaijan, as well as to the Cabinet ofMinisters and the Ministry of Health of Azerbaijan, for theirsupport. Many thanks to all local endocrinologists and healthpersonnel for their invaluable help in carrying out the fieldstudy.

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Address reprint requests to:Apostolos G. Vagenakis, M.D.

Division of EndocrinologyDepartment of Internal Medicine

University of Patras Medical SchoolUniversity Hospital

Rio 26500Greece

E-mail: vagenak@otenet.gr

454 MARKOU ET AL.