IGF-1 and IGFBP in congenital and acquired hypothyroidism after long-term replacement treatment

Thyroid hormones are involved in the regulation of the GH/IGF axis. Hypothyroidism is associated with a reduction in GH pulsatility and in GH-response to stimulatory tests. In hypothyroidism, serum levels of IGF-1 and IGFBP-3 fall and these changes are reversed after short term replacement with L-T4. This study was undertaken to determine the effect of long term replacement therapy with T4 in IGF-1 and IGFBP-3 serum levels.

The study included 12 patients affected with hypothyroidism and in replacement treatment with T4. They were divided into 3 groups according to age at the beginning of treatment. Group A consisted of 4 pre-pubertal subjects with Congenital Hypothyroidism (CH) diagnosed with neonatal screening, where T4 treatment was started within 15 days of life. Group B consisted of 5 young adults where CH was clinically diagnosed at the median age of 6 months and replacement therapy started at this age. Group C consisted of 3 subjects affected with hypothyroidism secondary to thyroiditis where diagnosis and replacement treatment were delayed at age 11, 12 and 14 respectively. All subjects were matched with a control of the same age, sex, weight and pubertal stage.

FT3, FT4 and TSH were in the normal range both in patients and in controls. No correlation was found between FT3 or FT4 and IGF-1 or IGFBP-3 serum levels. IGF-1 serum levels in group A (198 +/- 122 ng/ml) were significantly lower than that in group B (624 +/- 105, p < 0.001) and in group C (649 +/- 98, p = 0.003). IGFBP-3 serum levels in group A (1.98 +/- 0.56 micrograms/ml) were significantly lower than in group B (3.65 +/- 1.10, p = 0.03) and in group C (4.13 +/- 0.49, p = 0.003). The increase in IGF-1 and IGFBP-3 levels was seen also in control groups B and C when compared with control group A. IGF-1 and IGFBP-3 were positively correlated with age both in patients and in controls. A linear correlation was found between IGF-1 and IGFBP-3 which was positive for controls (r = 0.946, p < 0.001) and patient group A and B (r = 0.839, p = 0.005) but tended to be negative for patient group C (r = -0.65, n.s.).

Our data demonstrate that long term replacement therapy in children with hypothyroidism is associated with a physiological increase in IGF-1 and IGFBP-3. The positive correlation between IGF-1 and IGFBP-3 levels in group A and B confirm the efficacy of long term replacement treatment on the IGF-1/BP-3 axis in pre- and post-pubertal patients treated for CH. However, this correlation tended to be negative in patients with hypothyroidism secondary to thyroiditis, suggesting that the cause of thyroid insufficiency and/or the age at the beginning of replacement therapy may have a role in the post-pubertal hormonal status in IGF-1 and IGFBP-3 balance.