Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1992 Jul;90(1):113–120. doi: 10.1172/JCI115823

Thyroid hormone modulation of the hypothalamic growth hormone (GH)-releasing factor-pituitary GH axis in the rat.

N Miki 1, M Ono 1, N Hizuka 1, T Aoki 1, H Demura 1
PMCID: PMC443069  PMID: 1634603

Abstract

Both thyroid hormone and hypothalamic growth hormone (GH)-releasing factor (GRF) facilitate pituitary somatotroph function. However, the pathophysiological role of thyroid hormone in GRF secretion is less well understood. Thyrotoxicosis, induced by administration of thyroxine (T4) in rats, inhibited both pituitary GH levels and immunoreactive GRF secretion from incubated hypothalamus. At the highest dose of T4 given for 12 d, GRF secretion and pituitary GH decreased by 50 and 39%, respectively. Hypothyroidism induced by thyroidectomy (Tx) enhanced GRF secretion approximately twofold while depleting pituitary GH by greater than 99%. Both of these hypothalamic and pituitary effects were reversed by replacement of T4 but not human GH for 7 or 14 d. Human GH was as potent as T4 in restoring decreased body weight gains or serum insulin-like growth factor-1 levels in Tx rats. These results indicate that at both physiological and pathological concentrations in serum, thyroid hormone acts as an inhibitory modulator of GRF secretion, probably not involving a feedback mechanism through GH. A biphasic effect of thyroid hormone on pituitary GH levels appears to derive from the difference in primary target tissues of hyper- and hypothyroidism, the hypothalamus and the pituitary, respectively.

Full text

PDF
113

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abelenda M., Puerta M. L. Relationship among food intake, thyroid status and chronic cold-exposure in the rat. Horm Metab Res. 1991 Feb;23(2):90–91. doi: 10.1055/s-2007-1003622. [DOI] [PubMed] [Google Scholar]
  2. Barinaga M., Yamonoto G., Rivier C., Vale W., Evans R., Rosenfeld M. G. Transcriptional regulation of growth hormone gene expression by growth hormone-releasing factor. Nature. 1983 Nov 3;306(5938):84–85. doi: 10.1038/306084a0. [DOI] [PubMed] [Google Scholar]
  3. Berelowitz M., Maeda K., Harris S., Frohman L. A. The effect of alterations in the pituitary-thyroid axis on hypothalamic content and in vitro release of somatostatin-like immunoreactivity. Endocrinology. 1980 Jul;107(1):24–29. doi: 10.1210/endo-107-1-24. [DOI] [PubMed] [Google Scholar]
  4. Bloch B., Brazeau P., Ling N., Bohlen P., Esch F., Wehrenberg W. B., Benoit R., Bloom F., Guillemin R. Immunohistochemical detection of growth hormone-releasing factor in brain. Nature. 1983 Feb 17;301(5901):607–608. doi: 10.1038/301607a0. [DOI] [PubMed] [Google Scholar]
  5. Bloch B., Gaillard R. C., Brazeau P., Lin H. D., Ling N. Topographical and ontogenetic study of the neurons producing growth hormone-releasing factor in human hypothalamus. Regul Pept. 1984 Jan;8(1):21–31. doi: 10.1016/0167-0115(84)90025-9. [DOI] [PubMed] [Google Scholar]
  6. Bowsher R. R., Lee W. H., Apathy J. M., O'Brien P. J., Ferguson A. L., Henry D. P. Measurement of insulin-like growth factor-II in physiological fluids and tissues. I. An improved extraction procedure and radioimmunoassay for human and rat fluids. Endocrinology. 1991 Feb;128(2):805–814. doi: 10.1210/endo-128-2-805. [DOI] [PubMed] [Google Scholar]
  7. Brazeau P., Vale W., Burgus R., Ling N., Butcher M., Rivier J., Guillemin R. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science. 1973 Jan 5;179(4068):77–79. doi: 10.1126/science.179.4068.77. [DOI] [PubMed] [Google Scholar]
  8. Burstein P. J., Draznin B., Johnson C. J., Schalch D. S. The effect of hypothyroidism on growth, serum growth hormone, the growth hormone-dependent somatomedin, insulin-like growth factor, and its carrier protein in rats. Endocrinology. 1979 Apr;104(4):1107–1111. doi: 10.1210/endo-104-4-1107. [DOI] [PubMed] [Google Scholar]
  9. Chernausek S. D., Underwood L. E., Van Wyk J. J. Influence of hypothyroidism on growth hormone binding by rat liver. Endocrinology. 1982 Nov;111(5):1534–1538. doi: 10.1210/endo-111-5-1534. [DOI] [PubMed] [Google Scholar]
  10. Clark R. G., Robinson I. C. Growth induced by pulsatile infusion of an amidated fragment of human growth hormone releasing factor in normal and GHRF-deficient rats. Nature. 1985 Mar 21;314(6008):281–283. doi: 10.1038/314281a0. [DOI] [PubMed] [Google Scholar]
  11. Coulombe P., Ruel J., Dussault J. H. Effects of neonatal hypo- and hyperthyroidism on pituitary growth hormone content in the rat. Endocrinology. 1980 Dec;107(6):2027–2033. doi: 10.1210/endo-107-6-2027. [DOI] [PubMed] [Google Scholar]
  12. Crantz F. R., Larsen P. R. Rapid thyroxine to 3,5,3'-triiodothyronine conversion and nuclear 3,5,3'-triiodothyronine binding in rat cerebral cortex and cerebellum. J Clin Invest. 1980 Apr;65(4):935–938. doi: 10.1172/JCI109749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Daughaday W. H., Rotwein P. Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr Rev. 1989 Feb;10(1):68–91. doi: 10.1210/edrv-10-1-68. [DOI] [PubMed] [Google Scholar]
  14. De Gennaro Colonna V., Bertola G., Coco C. B., Bifano M., Cocchi D., Maggi A., Müller E. E. Hypothalamic-pituitary somatotropic function in prepubertal hypothyroid rats: effect of growth hormone replacement therapy. Proc Soc Exp Biol Med. 1991 Apr;196(4):432–437. doi: 10.3181/00379727-196-43212. [DOI] [PubMed] [Google Scholar]
  15. De Gennaro V., Cella S. G., Bassetti M., Rizzi R., Cocchi D., Muller E. E. Impaired growth hormone secretion in neonatal hypothyroid rats: hypothalamic versus pituitary component. Proc Soc Exp Biol Med. 1988 Jan;187(1):99–106. doi: 10.3181/00379727-187-42643. [DOI] [PubMed] [Google Scholar]
  16. DeFesi C. R., Astier H. S., Surks M. I. Kinetics of thyrotrophs and somatotrophs during development of hypothyroidism and L-triiodothyronine treatment of hypothyroid rats. Endocrinology. 1979 Apr;104(4):1172–1180. doi: 10.1210/endo-104-4-1172. [DOI] [PubMed] [Google Scholar]
  17. Dieguez C., Foord S. M., Peters J. R., Hall R., Scanlon M. F. The effects of thyroid hormone deprivation in vivo and in vitro on growth hormone (GH) responses to human pancreatic (tumor) GH-releasing factor (1-40) by dispersed rat anterior pituitary cells. Endocrinology. 1985 Mar;116(3):1066–1070. doi: 10.1210/endo-116-3-1066. [DOI] [PubMed] [Google Scholar]
  18. Downs T. R., Chomczynski P., Frohman L. A. Effects of thyroid hormone deficiency and replacement on rat hypothalamic growth hormone (GH)-releasing hormone gene expression in vivo are mediated by GH. Mol Endocrinol. 1990 Mar;4(3):402–408. doi: 10.1210/mend-4-3-402. [DOI] [PubMed] [Google Scholar]
  19. Evans R. M., Birnberg N. C., Rosenfeld M. G. Glucocorticoid and thyroid hormones transcriptionally regulate growth hormone gene expression. Proc Natl Acad Sci U S A. 1982 Dec;79(24):7659–7663. doi: 10.1073/pnas.79.24.7659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Finkelstein J. W., Boyar R. M., Hellman L. Growth hormone secretion in hyperthyroidism. J Clin Endocrinol Metab. 1974 Apr;38(4):634–637. doi: 10.1210/jcem-38-4-634. [DOI] [PubMed] [Google Scholar]
  21. Frohman L. A., Downs T. R. Measurement of growth hormone-releasing factor. Methods Enzymol. 1986;124:371–389. doi: 10.1016/0076-6879(86)24029-x. [DOI] [PubMed] [Google Scholar]
  22. Gick G. G., Zeytin F. N., Brazeau P., Ling N. C., Esch F. S., Bancroft C. Growth hormone-releasing factor regulates growth hormone mRNA in primary cultures of rat pituitary cells. Proc Natl Acad Sci U S A. 1984 Mar;81(5):1553–1555. doi: 10.1073/pnas.81.5.1553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Guillemin R., Brazeau P., Böhlen P., Esch F., Ling N., Wehrenberg W. B. Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly. Science. 1982 Nov 5;218(4572):585–587. doi: 10.1126/science.6812220. [DOI] [PubMed] [Google Scholar]
  24. Hervas F., Morreale de Escobar G., Escobar Del Rey F. Rapid effects of single small doses of L-thyroxine and triiodo-L-thyronine on growth hormone, as studied in the rat by radioimmunoassy. Endocrinology. 1975 Jul;97(1):91–101. doi: 10.1210/endo-97-1-91. [DOI] [PubMed] [Google Scholar]
  25. Jones P. M., Burrin J. M., Ghatei M. A., O'Halloran D. J., Legon S., Bloom S. R. The influence of thyroid hormone status on the hypothalamo-hypophyseal growth hormone axis. Endocrinology. 1990 Mar;126(3):1374–1379. doi: 10.1210/endo-126-3-1374. [DOI] [PubMed] [Google Scholar]
  26. Katakami H., Downs T. R., Frohman L. A. Decreased hypothalamic growth hormone-releasing hormone content and pituitary responsiveness in hypothyroidism. J Clin Invest. 1986 May;77(5):1704–1711. doi: 10.1172/JCI112490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lewinson D., Harel Z., Shenzer P., Silbermann M., Hochberg Z. Effect of thyroid hormone and growth hormone on recovery from hypothyroidism of epiphyseal growth plate cartilage and its adjacent bone. Endocrinology. 1989 Feb;124(2):937–945. doi: 10.1210/endo-124-2-937. [DOI] [PubMed] [Google Scholar]
  28. Lumpkin M. D., McDonald J. K. Blockade of growth hormone-releasing factor (GRF) activity in the pituitary and hypothalamus of the conscious rat with a peptidic GRF antagonist. Endocrinology. 1989 Mar;124(3):1522–1531. doi: 10.1210/endo-124-3-1522. [DOI] [PubMed] [Google Scholar]
  29. Lumpkin M. D., Mulroney S. E., Haramati A. Inhibition of pulsatile growth hormone (GH) secretion and somatic growth in immature rats with a synthetic GH-releasing factor antagonist. Endocrinology. 1989 Mar;124(3):1154–1159. doi: 10.1210/endo-124-3-1154. [DOI] [PubMed] [Google Scholar]
  30. Maiter D. M., Gabriel S. M., Koenig J. I., Russell W. E., Martin J. B. Sexual differentiation of growth hormone feedback effects on hypothalamic growth hormone-releasing hormone and somatostatin. Neuroendocrinology. 1990 Feb;51(2):174–180. doi: 10.1159/000125334. [DOI] [PubMed] [Google Scholar]
  31. Martial J. A., Baxter J. D., Goodman H. M., Seeburg P. H. Regulation of growth hormone messenger RNA by thyroid and glucocorticoid hormones. Proc Natl Acad Sci U S A. 1977 May;74(5):1816–1820. doi: 10.1073/pnas.74.5.1816. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Martin D., Epelbaum J., Bluet-Pajot M. T., Prelot M., Kordon C., Durand D. Thyroidectomy abolishes pulsatile growth hormone secretion without affecting hypothalamic somatostatin. Neuroendocrinology. 1985 Dec;41(6):476–481. doi: 10.1159/000124222. [DOI] [PubMed] [Google Scholar]
  33. Miki N., Ono M., Miyoshi H., Tsushima T., Shizume K. Hypothalamic growth hormone-releasing factor (GRF) participates in the negative feedback regulation of growth hormone secretion. Life Sci. 1989;44(7):469–476. doi: 10.1016/0024-3205(89)90462-1. [DOI] [PubMed] [Google Scholar]
  34. Miki N., Ono M., Shizume K. Evidence that opiatergic and alpha-adrenergic mechanisms stimulate rat growth hormone release via growth hormone-releasing factor (GRF). Endocrinology. 1984 May;114(5):1950–1952. doi: 10.1210/endo-114-5-1950. [DOI] [PubMed] [Google Scholar]
  35. Miki N., Ono M., Shizume K. Withdrawal of endogenous somatostatin induces secretion of growth hormone-releasing factor in rats. J Endocrinol. 1988 May;117(2):245–252. doi: 10.1677/joe.0.1170245. [DOI] [PubMed] [Google Scholar]
  36. Minamitani N., Chihara K., Iwasaki J., Matsukura S., Fujita T. Attenuation by hypocalcemia of pulsatile growth hormone secretion in conscious male rats. Neuroendocrinology. 1982 Dec;35(6):405–410. doi: 10.1159/000123416. [DOI] [PubMed] [Google Scholar]
  37. Miyakawa M., Hizuka N., Takano K., Tanaka I., Horikawa R., Honda N., Shizume K. Radioimmunoassay for insulin-like growth factor I (IGF-I) using biosynthetic IGF-I. Endocrinol Jpn. 1986 Dec;33(6):795–801. doi: 10.1507/endocrj1954.33.795. [DOI] [PubMed] [Google Scholar]
  38. Ono M., Miki N., Demura H. Effect of antiserum to rat growth hormone (GH)-releasing factor on physiological GH secretion in the female rat. Endocrinology. 1991 Oct;129(4):1791–1796. doi: 10.1210/endo-129-4-1791. [DOI] [PubMed] [Google Scholar]
  39. Oppenheimer J. H. Thyroid hormone action at the cellular level. Science. 1979 Mar 9;203(4384):971–979. doi: 10.1126/science.218285. [DOI] [PubMed] [Google Scholar]
  40. Pascual-Leone A. M., Garcia M. D., Hervás F., de Escobar G. M. Decreased pituitary growth hormone content in rats treated neonatally with high doses of L-thyroxine. Horm Metab Res. 1976 May;8(3):215–217. doi: 10.1055/s-0028-1093643. [DOI] [PubMed] [Google Scholar]
  41. Peake G. T., Birge C. A., Daughaday W. H. Alterations of radioimmunoassayable growth hormone and prolactin during hypothroidism. Endocrinology. 1973 Feb;92(2):487–493. doi: 10.1210/endo-92-2-487. [DOI] [PubMed] [Google Scholar]
  42. Plotsky P. M., Vale W. Patterns of growth hormone-releasing factor and somatostatin secretion into the hypophysial-portal circulation of the rat. Science. 1985 Oct 25;230(4724):461–463. doi: 10.1126/science.2864742. [DOI] [PubMed] [Google Scholar]
  43. Reichlin S. Somatostatin. N Engl J Med. 1983 Dec 15;309(24):1495–1501. doi: 10.1056/NEJM198312153092406. [DOI] [PubMed] [Google Scholar]
  44. Riskind P. N., Kolodny J. M., Larsen P. R. The regional hypothalamic distribution of type II 5'-monodeiodinase in euthyroid and hypothyroid rats. Brain Res. 1987 Sep 8;420(1):194–198. doi: 10.1016/0006-8993(87)90260-5. [DOI] [PubMed] [Google Scholar]
  45. Rivier J., Spiess J., Thorner M., Vale W. Characterization of a growth hormone-releasing factor from a human pancreatic islet tumour. Nature. 1982 Nov 18;300(5889):276–278. doi: 10.1038/300276a0. [DOI] [PubMed] [Google Scholar]
  46. Root A. W., Shulman D., Root J., Diamond F. The interrelationships of thyroid and growth hormones: effect of growth hormone releasing hormone in hypo- and hyperthyroid male rats. Acta Endocrinol Suppl (Copenh) 1986;279:367–375. doi: 10.1530/acta.0.112s367. [DOI] [PubMed] [Google Scholar]
  47. Root J. L., Duckett G. E., Sweetland M., Strzelecki J. A., Root A. W. Hypothyroidism blunts the growth hormone (GH) releasing effect of human pancreatic GH releasing factor in the adult male rat in vivo and in vitro. Endocrinology. 1985 May;116(5):1703–1706. doi: 10.1210/endo-116-5-1703. [DOI] [PubMed] [Google Scholar]
  48. Seo H., Vassart G., Brocas H., Refetoff S. Triiodothyronine stimulates specifically growth hormone mRNA in rat pituitary tumor cells. Proc Natl Acad Sci U S A. 1977 May;74(5):2054–2058. doi: 10.1073/pnas.74.5.2054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Spiess J., Rivier J., Vale W. Characterization of rat hypothalamic growth hormone-releasing factor. Nature. 1983 Jun 9;303(5917):532–535. doi: 10.1038/303532a0. [DOI] [PubMed] [Google Scholar]
  50. Takeuchi A., Suzuki M., Tsuchiya S. Effect of thyroidectomy on the secretory profiles of growth hormone, thyrotropin and corticosterone in the rat. Endocrinol Jpn. 1978 Aug;25(4):381–390. doi: 10.1507/endocrj1954.25.381. [DOI] [PubMed] [Google Scholar]
  51. Thorngren K. G., Hansson L. I. Effect of thyroxine and growth hormone on longitudinal bone growth in the hypophysectomized rat. Acta Endocrinol (Copenh) 1973 Sep;74(1):24–40. doi: 10.1530/acta.0.0740024. [DOI] [PubMed] [Google Scholar]
  52. Wakabayashi I., Tonegawa Y., Ihara T., Hattori M., Shibasaki T., Ling N. Plasma growth hormone response to human growth hormone releasing factor in rats administered with chlorpromazine and antiserum against somatostatin. Effects of hypo- and hyperthyroidism. Neuroendocrinology. 1985 Oct;41(4):306–311. doi: 10.1159/000124194. [DOI] [PubMed] [Google Scholar]
  53. Wehrenberg W. B., Brazeau P., Luben R., Böhlen P., Guillemin R. Inhibition of the pulsatile secretion of growth hormone by monoclonal antibodies to the hypothalamic growth hormone releasing factor (GRF). Endocrinology. 1982 Dec;111(6):2147–2148. doi: 10.1210/endo-111-6-2147. [DOI] [PubMed] [Google Scholar]
  54. Wehrenberg W. B. The role of growth hormone-releasing factor and somatostatin on somatic growth in rats. Endocrinology. 1986 Feb;118(2):489–494. doi: 10.1210/endo-118-2-489. [DOI] [PubMed] [Google Scholar]
  55. Wilkins J. N., Mayer S. E., Vanderlaan W. P. The effects of hypothyroidism and 2,4-dinitrophenol on growth hormone synthesis. Endocrinology. 1974 Nov;95(5):1259–1267. doi: 10.1210/endo-95-5-1259. [DOI] [PubMed] [Google Scholar]
  56. Williams T., Maxon H., Thorner M. O., Frohman L. A. Blunted growth hormone (GH) response to GH-releasing hormone in hypothyroidism resolves in the euthyroid state. J Clin Endocrinol Metab. 1985 Sep;61(3):454–456. doi: 10.1210/jcem-61-3-454. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES