Neuroendocrine and Pituitary
Tumor Clinical Center (NEPTCC) Bulletin
Winter 2017/2018 | Volume 24, Issue 1
Effects of Growth Hormone on Thyroid Function in Patients with Growth Hormone Deficiency – A Potential Effect of GH on Type 2 Iodothyronine Deiodinase-Janet Lo, M.D.
The growth hormone (GH)-insulin-like growth factor-1 (IGF-I) axis has notable effects on thyroid function and thyroid hormone metabolism. In the literature, concern had been raised that GH replacement may unmask undiagnosed central hypothyroidism1, 2. GH treatment was shown in several studies to lower levels of thyroxine (T4) and free thyroxine (free T4) in adults and children with growth hormone deficiency (GHD)1-6. Some studies have shown that GH and IGF-I can increase levels of triiodothyronine (T3)7, 8, while others have shown no change in free T3 levels with GH replacement3. In healthy men, Grunfeld et al. demonstrated that recombinant human GH (rhGH) at a dose of 0.125mg/day subcutaneously for four days acutely reduced serum total T4 and free T4, increased total T3 and markedly decreased serum TSH, considered likely to be compensatory9.
These prior observations have led endocrinologists to hypothesize that GH likely stimulates the peripheral conversion of T4 to T3. Conversely, effects of an acute decline in GH levels on thyroid function have also been assessed in patients with acromegaly, demonstrating that T3 levels transiently decreased after trans-sphenoidal surgery (TSS)10. Jorgensen et al. demonstrated that GH increased total and free T3 and reduced rT3 in a dose-dependent manner, and therefore, likely induced peripheral T4 to T3 conversion8. The exact mechanism whereby GH increases the conversion of T4 to T3 was previously uncertain although a GH-induced alteration in deiodinase activity was hypothesized. In light of these prior observations, recently Dr. Yamauchi and colleagues performed new mechanistic studies to further elucidate the physiologic mechanisms mediating the effects of growth hormone on thyroid function11.
Yamauchi et al. first performed two retrospective observational studies in 1) adults with severe GHD before and after receiving GH therapy and 2) in adults with acromegaly before and after trans-sphenoidal surgery (TSS)11. In both studies, serum levels of free T3, free thyroxine (free T4) and free T3 and free T4 ratio were assessed before and after intervention. In the first study, consecutive adult patients with GHD (confirmed by peak serum GH <9ng/mL after GH-releasing peptide-2 test according to Japan Endocrine Society guidelines) identified using medical records in Kyoto University Hospital, Japan, who started GH replacement therapy between August 2008 and July 2015 were selected. After exclusion of patients with missing data on thyroid function, 20 patients were included in the analysis. Serum free T3, free T4 and TSH levels were obtained before and 3 months after initiation of GH replacement. The median dose of GH was 0.2mg/day at 3 months and median IGF-I level rose from 95ng/mL to 179 ng/mL. Median free T3 significantly rose (Figure 1). Free T4 tended to decrease, but did not meet statistical significance (Figure 1). The ratio of free T3/free T4 increased and TSH decreased (Figure 1). Changes in IGF-I positively correlated with changes in free T3 and free T4 ratio (Figure 1).
Figure 1. a Box-plot of thyroid function at baseline and 3 months after recombinant human growth hormone (rhGH) replacement therapy in 20 patients with adult GH deficiency. Each box represents the interquartile range. The horizontal line in each box represents the median. The ends of the vertical lines represent the minimum and maximum values. b Linear regression of insulin-like growth factor 1 (IGF-1) and free triiodothyronine /free thyroxine (fT3/fT4) ratio at baseline, and that of changes in IGF-1 (ΔIGF-1) and fT3/fT4 ratio (ΔfT3/fT4) between baseline and 3 months after rhGH therapy. ρ, Spearman’s rank correlation coefficient. Reprinted by permission from: Endocrine/Springer Nature, Yamauchi I, Sakane Y, Yamashita T, Hirota K, Ueda Y, Kanai Y, Yamashita Y, Kondo E, Fujii T, Taura D, Sone M, Yasoda A, Inagaki N. Effects of growth hormone on thyroid function are mediated by type 2 iodothyronine deiodinase in humans. (2018)
In the second study, the authors analyzed medical records of 27 consecutive patients with acromegaly, but had to exclude one patient because of missing data on thyroid function and one patient due to hyperthyroidism, so data from 25 patients were analyzed. Thyroid function tests were measured at post-operative day 16. Median serum free T3 level decreased and free T4 increased sixteen days after TSS. Free T3/free T4 ratio decreased. Changes in IGF-I also correlated positively with changes in free T3/free T4 ratio.
The authors then performed in vitro studies to assess the effects of GH administration on the expression of iodothyronine deiodinases types I, II, and III (D1, D2 and D3) in human cell lines HepG2m (derived from human hepatoblastoma), TSA201 (derived from human embryonic kidney cells), MCF7 (derived from human breast carcinoma), and HTC/C3 (derived from human thyroid undifferentiated carcinoma). Changes in mRNA levels of D1, D2 and D3 iodothyronine deiodinases (DIOs) in these cells were assessed in response to rhGH. The main finding was that mRNA levels of DIO2 increased significantly in HTC/C3 cells in response to GH. Western blot experiments confirmed that protein levels of D2 were significantly increased by GH. DIO1 mRNA expression in HTC/C3 and HepG2 cells was unchanged by GH. D3 protein levels were unchanged and DIO3 mRNA expression showed no change in TSA201, MCF7 and HTC/C3 cells in response to GH. These new studies by Dr. Yamauchi and colleagues shed additional light on the potential mechanism of GH’s impact on thyroid function, suggesting an important effect of GH on DIO2 mRNA expression and increased protein levels of D2.
Serum T3 levels are normally maintained at constant levels in the body, and D1, D2 and D3 in peripheral tissues are the key determinants of serum T3 level12. D2 activity is thought to be an important source of extrathyroidal T3 production in humans. What are the clinical consequences of increased peripheral T4 to T3 conversion for patients with GHD as they initiate GH replacement therapy? It appears that in patients with idiopathic isolated GHD, the effects of GH on the thyroid function is likely to be transient as the normal hypothalamic-pituitary-thyroid (HPT) axis will regulate thyroid function via an intact HPT feedback system. However, in patients with hypopituitarism and those who are at risk for developing central hypothyroidism, close monitoring of thyroid function is warranted before and after initiating GH replacement therapy, as it may unmask abnormal thyrotroph function. Another unanswered question is why teleologically does this effect of GH on thyroid function occur? The stimulatory effects of GH on peripheral conversion of T4 to T3 have been conserved and have been observed in other species including rainbow trout13, chickens14, and lambs15 although possibly via different deiodinases and mechanisms than in humans. The teleological rationale is still unknown.
In summary, the published data support that GH stimulates peripheral T4 to T3 conversion and now Yamauchi et al. have demonstrated that this effect may be mediated by GH-stimulated increase in D2. The long-term clinical implications are still unclear. The Endocrine Society Clinical Practice Guidelines for the Evaluation and Treatment of Adult Growth Hormone Deficiency recommend that “freeT4 levels should be monitored during GH treatment, and doses of T4 should be adjusted as necessary” 16. In conclusion, data and guidelines suggest that it would be prudent for endocrinologists to routinely monitor thyroid function tests in all patients before and after initiating GH, especially in individuals with other pituitary hormonal deficits or pathology that may predispose them to central hypothyroidism.
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