Sensitivity of supplementation of thyroid hormone on treatment of idiopathic short-stature children during therapy with recombinant human growth hormone

Abstract

This study aimed to evaluate the effects of thyroid hormone supplementation on growth rate of children with idiopathic short stature (ISS) and low-normal serum free thyroxine FT4 who were receiving growth hormone therapy. We selected 64 prepubertal children with FT4 levels in the lowest third of the normal range as the lower FT4 group, and these children were divided randomly into two subgroups: L-thyroxine (L-T4)-treated subgroup was treated with L-T4 (0.5–3.0 g/(kg·d)) from the beginning of the study, and the non-L-T4-treated subgroup received placebo. We also selected 39 ISS children with FT4 in the upper two-thirds of the normal range as the higher FT4 group. During the first year, the lower FT4 group featured lower FT3, FT4, thyroid stimulating hormone (TSH), and insulin-like growth factor-I standard deviation score (IGF-I SDS) and significantly lower height velocity (HV) compared with the higher FT4 group. However, in the lower FT4 group, the L-T4-treated subgroup presented higher FT4, FT3, TSH, and IGF-I SDS concentrations and significantly higher HV compared with children in the non-L-T4-treated subgroup. In children with ISS, the negative effect of thyroid hormone deficiency on growth rate should be considered when FT4 level lies in the low-normal range prior to recombinant human growth hormone treatment.

Keywords

therapeutic / idiopathic short-stature children / free T4 / the first year / recombinant human growth hormone

Introduction

Recombinant human growth hormone (rhGH) therapy is approved for treating idiopathic short stature (ISS) in children. The main goal of the treatment is to increase height velocity (HV) of patients with idiopathic short stature and to improve their attained final height. Insulin-like growth factor-I (IGF-I) is the most important peripheral mediator of growth hormone (GH) activity. Normal thyroid function is necessary for the ideal effect of GH secretion and rhGH substitution on growth rate. As a result, correct substitution of L-thyroxine is important for obtaining the ideal effect of rhGH substitution on growth rate.

Various studies have thoroughly evaluated long-term effects of rhGH replacement therapy to exclude secondary thyroid failure and have demonstrated that neither adults [¹−³] nor children [⁴−¹¹] with growth hormone deficiency (GHD) develop hypothyroidism during rhGH administration. Other studies have reported that rhGH therapy in ISS children did not induce changes in serum thyroid hormone levels over a 12-month period [¹²]. However, Rose [¹³] reported that administration of L-T4 therapy for 6 months resulted in a significant change in HV in ISS patients with FT4 values in the upper two-thirds of the normal range and in those with FT4 values in the lowest third of the normal range. García et al. [¹⁴] reported that L-T4 supplementation for 120 days in ISS children with FT4 concentrations between the 3rd percentile and 25th percentile led to a shift in serum thyroxine concentrations from the low-normal to the high-normal range and a remarkable increase in HV. Thus, such results cause conflict. The present study aimed to evaluate the effects of thyroid hormone supplementation on growth rate of prepubertal children with ISS and low-normal FT4 receiving GH therapy.

Clinical study process

This analysis included 103 children (58 boys and 45 girls) with ISS (7.5±1.4 years of age) from the Pediatric Endocrinology Clinic of the Third Affiliated Hospital of Zhengzhou University and who qualified for rhGH therapy. Written informed consent was obtained from all participants. This study was approved by the Institutional Review Board at the Third Affiliated Hospital of Zhengzhou University. At the onset of therapy, according to the normal height of children in nine Chinese cities in 2005 as reference, patient height was considered below the third percentile. Inclusion criteria comprised short stature, a condition in which the height of an individual is higher than 2 standard deviations (SD) below the corresponding mean height for a given age, sex, and population group; normal weight and height at birth; prepubertal status; peak GH levels>10 ng/mL on at least two GH stimulation tests; normal thyroid, heart, and kidney functions; and normal blood and urine. Exclusion criteria comprised chronic organic diseases, GHD, small for gestational age at birth, chromosomal abnormalities, skeletal dysplasia, genetic metabolic diseases, thyroid dysfunction, psychosocial deprivation, and the use of medication interfering with GH secretion or action.

Sixty-four prepubertal children with FT4 levels in the lowest third of the normal range (FT4: 11.5–15.2 pmol/L) were selected as the lower FT4 group, and they were divided randomly into two subgroups: the L-T4-treated subgroup included 29 prepubertal children with ISS who were supplemented with L-T4 from the beginning of rhGH therapy in doses (0.5–3.0 g/(kg·d)), causing an increase in serum FT4 to the upper two-thirds (15.2–22.7 pmol/L) of the normal range throughout the 12-month period; the non-L-T4-treated subgroup included 33 children with ISS who received placebo during the same period. Thirty-nine prepubertal children with ISS and with FT4 in the upper two-thirds of the normal range (FT4: 15.2–22.7 pmol/L) were also selected as the higher FT4 group (control group). Only data from children who remained prepubertal throughout the 12-month period were included in analysis. Two patients (0.06%) in the low FT4 group received L-T4 supplementation for 6 months to 12 months due to hyperthyrotropinemia (FT4 concentration below the limit of the normal range) and were excluded from the group; pharmacological euthyroidism was later confirmed.

Description of clinical study object

In all patients, height, weight, and secondary sexual characteristics for girls and testicular volume for boys (measured using a testicle mold) were recorded at 3-month intervals (as determined by two trained doctors) to exclude puberty children (breast Tanner stage≥2 or testicular volume≥4 mL). We used single X-ray of the left wrist to determine bone age (BA) using Greulich and Pyle method. Two stimulating tests were performed (using 0.15 mg/m² oral clonidine and 50 µg/kg insulin, not exceeding 1 mg, i.m.). Diagnosis of ISS was established when GH peak in both stimulating tests reached at least 10 ng/mL. IGF-I generation test was performed, and a satisfactory response to rhGH administration was indicated by at least a twofold increase in IGF-I secretion. This response excluded GH insensitivity and indicated decreased bioactivity of endogenous GH; this finding supports the indication of rhGH administration. rhGH therapy at doses of 0.35 mg/(kg·week) [¹⁵,¹⁶] was administered for at least 1 year. In each patient, thyroid stimulating hormone (TSH), FT3, and FT4 concentrations were assessed thrice: prior to the first rhGH injection and after 6 months and 1 year of treatment. All blood samples were obtained in the morning. Additionally, IGF-I concentrations were measured at the same time points, and IGF-I SD score (SDS) for age and sex and plasma TSH, FT3, FT4, and IGF-I concentrations were measured using immunoradiometric assay (Siemens Healthcare Diagnostics, USA). For TSH, analytical sensitivity range measured 0.004 µIU/mL to 75 µIU/mL, and intra-assay coefficient of variance (CV) reached 5.1% to 12.5%. For FT4, analytical sensitivity range totaled 3.9 pmol/L to 77.2 pmol/L, and intra-assay CV was 3.0% to 7.8%. For FT3, analytical sensitivity ranged within 1.5–61 pmol/L, and intra-assay CV was 4.3% to 8.4%. For GH, analytical sensitivity range reached 0.01 ng/mL to 17 000 ng/mL, and intra-assay CV was 2.9% to 4.2%. For IGF-I, analytical sensitivity measured 20 ng/mL, calibration ranged up to 100 000 ng/mL, and intra-assay CV was 2.3% to 3.9%. For comparisons between children of different ages and sex, IGF-I concentrations were expressed as IGF-I SDS according to IMMULITE reference data. Reference ranges of serum parameters for euthyroid subjects were as follows: FT3, 2.77 pmol/L to 6.47 pmol/L; FT4, 11.5 pmol/L to 22.7 pmol/L; and TSH, 0.35 mIU/L to 6.5 mIU/L.

Data analysis

Data are expressed as mean±SD. Statistical analysis was conducted using SPSS 17.0 software. Differences between the two groups were compared using the least significant difference t-test. Differences between the three different time periods were assessed by one-way analysis of variance for independent samples. Level of statistical significance was set at P<0.05.

Results of the study

A total of 103 children were recruited for this study. However, two patients (0.06%) in the low FT4 group who received L-T4 supplementation for 6–12 months due to hyperthyrotropinemia were excluded. Table 1 shows clinical and hormonal characteristics of children in the two groups.

Additionally, FT3, FT4, and TSH levels prior to rhGH substitution and after 6 months and 1 year of rhGH therapy were much lower in the lower FT4 group compared with the higher FT4 group. Interestingly, changes in IGF-I SDS and HV after 1 year of rhGH therapy were similar in the above-mentioned groups. Simultaneously, in the lower FT4 group, a significant decrease in FT3, FT4, and TSH was observed at the sixth month and the first year during rhGH therapy compared with pre-treatment values. Detailed comparisons of the children are presented in Figs. 1, 2, and 3.

Notably, HV was significantly improved with L-T4 supplementation from the initial phase of rhGH therapy on FT4 levels in the low-normal range group of children. FT3, FT4, TSH, and IGF-I SDS levels significantly increased after L-T4 treatment compared with children whose FT4 remained in the low-normal range. Unexpectedly, BA did not increase in children supplemented with L-T4 throughout the study period compared with unsupplemented ones. Detailed data are presented in Table 2 and Figs. 1, 2, 3, and 4.

Discussion

ISS is a condition in which the height of an individual is higher than 2 SDS below the corresponding mean height for a given age, sex, and population group without evidence of systemic, endocrine, nutritional, or chromosomal abnormalities [¹⁶]. After excluding specific causes of short stature, a large heterogeneous group of short-stature children remains, and conditions surrounding most of these children are uncharacterized [¹⁵]. rhGH therapy was approved for children with ISS in 2003 by the US Food and Drug Administration [¹⁷]. However, responses to rhGH therapy vary. Analyses of clinical data show that responses to the drug are not entirely dependent on age, bone age, or drug dose; therefore, individual variability may be associated with thyroid function [¹⁵]. Increasing evidence indicates that peripheral thyroid function may vary in ISS children, and the effect of rhGH treatment on thyroid function may be involved in growth response.

This analysis on prepubertal children affected by ISS and the effects of rhGH administration on thyroid hormone levels revealed that rhGH therapy in children with ISS induced slight changes in FT4, FT3, and TSH levels. However, for children with FT4 levels in the lowest third of the normal range at the beginning of rhGH therapy, administration of rhGH therapy induced a slightly continuous decrease in FT3, FT4, and TSH levels. Additionally, a few of these patients developed overt hypothyroidism during the first year of treatment. Thus, our study revealed that rhGH therapy in children with ISS affects thyroid hormone secretion in those with FT4 levels in the low-normal range.

No research has clarified the mechanism through which rhGH therapy affects thyroid hormone secretion in children with ISS and with FT4 levels in the low-normal range. In this study, we propose two possible mechanisms of action. One is that children with FT4 levels in the lowest third of the normal range are at risk of mild subclinical primary hypothyroidism. A slightly raised TSH concentration may alert the clinician regarding the presence of mild subclinical primary hypothyroidism. However, loss of normal hypothalamic-pituitary regulation often occurs without altered TSH concentrations, thus making this condition difficult to diagnose. Furthermore, mild subclinical primary hypothyroidism does not result in low GH responses to stimulation tests or in low overnight GH measures; these results create difficulties in diagnostic recognition [¹³]. rhGH therapy may reveal central hypothyroidism and induce thyroid failure [¹⁸]. The other mechanism is the key role of IGF-I. Thyroid function disorders influence GH secretion, the IGF system, and bone acquisition [¹⁹–²²]. Therefore, even in its subclinical form, hypothyroidism may affect IGF-I secretion [²³]. Ramos et al. [²⁵] demonstrated that hepatic IGF expression increases with thyroid supplementation in thyroidectomized rats. Our study revealed IGF-I levels in the low-normal range in ISS children. Furthermore, L-T4 replacement therapy improved previously decreased IGF-I secretion.

The use of L-T4 supplementation at the beginning of rhGH therapy in euthyroid patients has not been recommended before; however, various studies have demonstrated that L-T4 supplementation may increase HV in patients with subclinical hypothyroidism and/or in short children with FT4 levels in the low-normal range [¹³,²⁴,²⁶–²⁸]. Our results indicate the important role of maintaining euthyroid status of patients with FT4 levels in the low-normal range to maximize the effectiveness of rhGH therapy given that FT4 levels in the low-normal range may cause HV to increase less during the first year of rhGH administration. This result confirms either the earlier assessment of TSH and FT4 concentrations after rhGH therapy onset or L-T4 administration at the beginning of rhGH therapy in children with normal but relatively low FT4 secretion.

Our study only recruited 103 prepubertal children in China, a small protocol number, and we only measured the effects of GH on thyroid hormone levels. Thus, further studies are necessary to measure the effects of rhGH on thyroid hormone secretion.

Summary

In conclusion, in children with ISS, the negative effect of thyroid hormone deficiency on growth rate should be considered when FT4 levels fall in the low-normal range prior to rhGH treatment.

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