Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Glucocorticoids and the regulation of growth hormone secretion

Nature Reviews Endocrinology volume 9, pages 265–276 (2013)Cite this article

Subjects

Abstract

Glucocorticoids modulate the secretion of growth hormone (GH) by various and competing effects on the hypothalamus and pituitary gland. The final effects of this modulation depend on hormone concentrations and the duration of exposure. The traditional hypothesis is that chronically raised levels of glucocorticoids suppress the secretion of GH. However, a functional impairment of the GH reserve might also be observed in patients with low levels of glucocorticoids, such as those with secondary hypoadrenalism, which is consistent with the model of biphasic dose-dependent effects of glucocorticoids on the somatotropic axis. This Review updates our current understanding of the mechanisms underlying the effects of glucocorticoids on the secretion of GH and the clinical implications of the dual action of glucocorticoids on the GH reserve in humans. This Review will also address the potential diagnostic and therapeutic implications of GH for patients with a deficiency or excess of glucocorticoids.

Key Points

  • Glucocorticoids modulate growth hormone (GH) secretion at both the hypothalamic and pituitary level

  • Hypoadrenalism might cause GH deficiency that is reversible during glucocorticoid replacement therapy

  • Testing for GH deficiency in patients with hypopituitarism should always be performed after adequate periods of cortisol replacement

  • Chronic excess of glucocorticoids, either exogenous or endogenous, causes GH deficiency that might be involved in metabolic and cardiovascular complications

  • Treatment with recombinant GH could be considered in children and adults with glucocorticoid-induced GH deficiency

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schematic model of the regulation of GH secretion by central and peripheral neuroendocrine signals.
Figure 2: Triphasic short-term effects of exogenous glucocorticoids on stimulated growth hormone secretion in humans.
Figure 3: The behaviour of bone metabolic markers over time during administration of glucocorticoids and growth hormone.
Figure 4: An integrated model of the effect of circulating glucocorticoids on growth hormone secretion.

Similar content being viewed by others

References

  1. Arnaldi, G. et al. Diagnosis and complications of Cushing's syndrome: a consensus statement. J. Clin. Endocrinol. Metab. 88, 5593–5602 (2003).

    CAS  PubMed  Google Scholar 

  2. Giustina, A. & Wehrenberg, W. B. The role of glucocorticoids in the regulation of growth hormone secretion: mechanisms and clinical significance. Trends Endocrinol. Metab. 8, 306–311 (1992).

    Google Scholar 

  3. Dieguez, C. et al. Role of glucocorticoids in the neuroregulation of growth hormone secretion. J. Pediatr. Endocrinol. Metab. 9 (Suppl. 3), 255–260 (1996).

    PubMed  Google Scholar 

  4. Stratakis, C. A. Cortisol and growth hormone: clinical implications of a complex, dynamic relationship. Pediatr. Endocrinol. Rev. 3 (Suppl. 2), 333–338 (2006).

    PubMed  Google Scholar 

  5. Vakili, H. & Cattini, P. A. The hidden but positive role for glucocorticoids in the regulation of growth hormone-producing cells. Mol. Cell Endocrinol. 363, 1–9 (2012).

    CAS  PubMed  Google Scholar 

  6. Giustina, A. & Veldhuis, J. D. Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr. Rev. 19, 717–797 (1998).

    CAS  PubMed  Google Scholar 

  7. Ghigo, E. et al. Biologic activities of growth hormone secretagogues in humans. Endocrine 14, 87–93 (2001).

    CAS  PubMed  Google Scholar 

  8. Giustina, A. & Wehrenberg, W. B. Influence of thyroid hormones on the regulation of growth hormone secretion. Eur. J. Endocrinol. 133, 646–653 (1995).

    CAS  PubMed  Google Scholar 

  9. Giustina, A. et al. Effects of sex and age on the growth hormone response to galanin in healthy human subjects. J. Clin. Endocrinol. Metab. 76, 1369–1372 (1993).

    CAS  PubMed  Google Scholar 

  10. Beato, M. Gene regulation by steroid hormones. Cell 56, 335–344 (1989).

    CAS  PubMed  Google Scholar 

  11. Nielsen, D. A. & Shapiro, D. J. Insights into hormonal control of RNA stability. Mol. Endocrinol. 4, 953–957 (1990).

    CAS  PubMed  Google Scholar 

  12. Luo, J. & Murphy, L. J. Dexamethasone inhibits growth hormone induction of insulin-like growth factor-1 (IGF-1) messenger ribonucleic acid (mRNA) in hypophysectomized rats and reduces IGF-1 mRNA abundance in the intact rats. Endocrinology 125, 165–171 (1989).

    CAS  PubMed  Google Scholar 

  13. Bennett, P. A., Levy, A., Carmignac, D. F., Robinson, I. C. & Lightman, S. L. Differential regulation of the growth hormone receptor gene: effects of dexamethasone and estradiol. Endocrinology 137, 3891–3896 (1996).

    CAS  PubMed  Google Scholar 

  14. Senaris, R. M., Lago, F., Coya, R., Pineda, J. & Dieguez, C. Regulation of hypothalamic somatostatin, growth hormone-releasing hormone, and growth hormone receptor messenger ribonucleic acid by glucocorticoids. Endocrinology 137, 5236–5241 (1996).

    CAS  PubMed  Google Scholar 

  15. Tomlinson, J. W. et al. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr. Rev. 25, 831–866 (2004).

    CAS  PubMed  Google Scholar 

  16. Bamberger, C. M., Schulte, H. M. & Chrousos, G. P. Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocr. Rev. 17, 245–261 (1996).

    CAS  PubMed  Google Scholar 

  17. Briassoulis, G., Damjanovic, S., Xekouki, P., Lefebvre, H. & Stratakis, C. A. The glucocorticoid receptor and its expression in the anterior pituitary and the adrenal cortex: a source of variation in hypothalamic-pituitary-adrenal axis function; implications for pituitary and adrenal tumors. Endocr. Pract. 17, 941–948 (2011).

    PubMed  PubMed Central  Google Scholar 

  18. Kuo, T. et al. Genome-wide analysis of glucocorticoid receptor-binding sites in myotubes identifies gene networks modulating insulin signaling. Proc. Natl Acad. Sci. USA 109, 11160–11165 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Tantisira, K. G. et al. Genomewide association between GLCCl1 and response to glucocorticoid therapy in asthma. N. Eng. J. Med. 365, 1173–1183 (2011).

    CAS  Google Scholar 

  20. Murani, E., Reyer, H., Ponsuksili, S., Fritschka, S. & Wimmers, K. A substitution in the ligand binding domain of the porcine glucocorticoid receptor affects activity of the adrenal gland. PLoS ONE 7, e45518 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Charmandari, E. et al. Peripheral CLOCK regulates target-tissue glucocorticoid receptor transcriptional activity in a circadian fashion in man. PLoS ONE 6, e25612 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Agha, A. & Monson, J. P. Modulation of glucocorticoid metabolism by the growth hormone-IGF-1 axis. Clin. Endocrinol. 66, 459–465 (2007).

    CAS  Google Scholar 

  23. Neggers, S. J. & van der Lely, A. J. Modulation of glucocorticoid metabolism by the GH-IGF-1 axis. Endocr. Dev. 20, 181–186 (2011).

    CAS  PubMed  Google Scholar 

  24. Kononen, J., Honkaniemi, J., Gustafsson, J. A. & Pelto-Huikko, M. Glucocorticoid receptor colocalization with pituitary hormones in the rat pituitary gland. Mol. Cell. Endocrinol. 93, 97–103 (1993).

    CAS  PubMed  Google Scholar 

  25. Dean, C. E., Morpurgo, B. & Porter, T. E. Induction of somatotroph differentiation in vivo by corticosterone administration during chicken embryonic development. Endocrine 11, 151–156 (1999).

    CAS  PubMed  Google Scholar 

  26. Jenkins, S. A., Muchow, M., Richards, M. P., McMurtry, J. P. & Porter, T. E. Administration of adrenocorticotropic hormone during chicken embryonic development prematurely induces pituitary growth hormone cells. Endocrinology 148, 3914–3921 (2007).

    CAS  PubMed  Google Scholar 

  27. Nogami, H. & Hisano, S. Functional maturation of growth hormone cells in the anterior pituitary gland of the fetus. Growth Horm. IGF Res. 18, 379–388 (2008).

    CAS  PubMed  Google Scholar 

  28. Porter, T. E. & Dean, K. J. Regulation of chicken embryonic growth hormone secretion by corticosterone and triiodothyronine: evidence for a negative synergistic response. Endocrine 14, 363–368 (2001).

    CAS  PubMed  Google Scholar 

  29. Vakili, H., Jin, Y., Nagy, J. I. & Cattini, P. A. Transgenic mice expressing the human growth hormone gene provide a model system to study human growth hormone synthesis and secretion in non-tumor-derived pituitary cells: differential effects of dexamethasone and thyroid hormone. Mol. Cell. Endocrinol. 15, 48–57 (2011).

    Google Scholar 

  30. Evans, R. M., Birnberg, N. C. & Rosenfeld, M. G. Glucocorticoid and thyroid hormones transcriptionally regulate growth hormone gene expression. Proc. Natl Acad. Sci. USA 79, 7659–7663 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Oosterom, R., Verleun, T., Zuiderwijk, J. & Lamberts, S. W. Growth hormone secretion by cultured rat anterior pituitary cells. Effects of culture conditions and dexamethasone. Endocrinology 113, 735–741 (1983).

    CAS  PubMed  Google Scholar 

  32. Tamaki, M., Sato, M., Matsubara, S., Wada, Y. & Takahara, J. Dexamethasone increases growth hormone (GH)-releasing hormone (GHR) receptor mRNA levels in culture rat anterior pituitary cells. J. Neuroendocrinol. 8, 475–480 (1996).

    CAS  PubMed  Google Scholar 

  33. Koyto, A. I. & Cuttler, L. Thyroid hormone and glucocorticoid regulation of pituitary growth hormone-releasing hormone receptor gene expression. J. Endocrinol. 152, R13–R17 (1997).

    Google Scholar 

  34. Tamura, H. et al. Glucocorticoids regulate pituitary growth hormone secretagogue receptor gene expression. J. Neuroendocrinol. 12, 481–485 (2000).

    CAS  PubMed  Google Scholar 

  35. Miller, T. L. & Mayo, K. E. Glucocorticoids regulate pituitary growth hormone-releasing hormone receptor messenger ribonucleic acid expression. Endocrinology 138, 2458–2465 (1997).

    CAS  PubMed  Google Scholar 

  36. Nakagawa, K., Ishizuka, T., Obara, T., Matsubara, M. & Akikawa, K. Dichotomic action of glucocorticoids on growth hormone secretion. Acta Endocrinol. 116, 165–171 (1987).

    CAS  Google Scholar 

  37. Fernandez-Vazquez, G. et al. Corticosterone modulates growth hormone-releasing factor and somatostatin in fetal rat hypothalamic cultures. Neuroendocrinology 61, 31–35 (1995).

    CAS  PubMed  Google Scholar 

  38. Fife, S. K., Brogan, R. S., Giustina, A. & Wehrenberg, W. B. Immunocytochemical and molecular analysis of the effects of glucocorticoid-treatment on the hypothalamic-somatotropic axis in the rat. Neuroendocrinology 64, 131–138 (1996).

    CAS  PubMed  Google Scholar 

  39. Thomas, G. B., Bennett, P. A., Carmignac, D. F. & Robinson, I. I. Glucocorticoid regulation of growth hormone (GH) secretagogue-induced growth response and GH secretagogue receptor expression in the rat. Growth Horm. IGF Res. 10, 45–52 (2000).

    CAS  PubMed  Google Scholar 

  40. Seifert, H., Perrin, M., Rivier, J. & Vale, W. Growth hormone-releasing factor binding sites in rat anterior pituitary membrane homogenates: modulation by glucocorticoids. Endocrinology 117, 424–426 (1985).

    CAS  PubMed  Google Scholar 

  41. Seifert, H., Perrin, M., Rivier, J. & Vale, W. Binding sites for growth hormone releasing factor on rat anterior pituitary cells. Nature 313, 487–489 (1985).

    CAS  PubMed  Google Scholar 

  42. Park, S., Kamegai, J. & Kineman, R. D. Role of glucocorticoids in the regulation of pituitary somatostatin receptor subtype (sst1-sst5) mRNA levels: evidence for direct and somatostatin-mediated effects. Neuroendocrinology 78, 163–175 (2003).

    CAS  PubMed  Google Scholar 

  43. Wehrenberg, W. B., Baird, A. & Ling, N. Potent interaction between glucocorticoids and growth hormone-releasing factor in vivo. Science 221, 556–558 (1983).

    CAS  PubMed  Google Scholar 

  44. Voltz, D. M., Piering, A. W., Magestro, M., Giustina, A. & Wehrenberg, W. B. Effect of GHRP-6 and GHRH on GH secretion in rats following chronic glucocorticoid treatment. Life Sci. 56, 491–497 (1995).

    CAS  PubMed  Google Scholar 

  45. Giustina, A., Misitano, V., Voltz, D., Piering, A. & Wehrenberg, W. B. Adrenergic and cholinergic involvement in basal and growth hormone-releasing hormone-stimulated growth hormone secretion in glucocorticoid-treated rats. Endocr. Res. 21, 719–732 (1995).

    CAS  PubMed  Google Scholar 

  46. Giustina, A., Voltz, D. M., Teik, J. & Wehrenberg, W. B. Galanin counteracts the inhibitory effects of glucocorticoids on growth hormone secretion in the rat. Metabolism 44, 224–227 (1995).

    CAS  PubMed  Google Scholar 

  47. Martin, J. B. Studies on the mechanism of pentobarbital-induced GH release in the rat. Neuroendocrinology 13, 339–350 (1973).

    CAS  Google Scholar 

  48. Wehrenberg, W. B., Bergman, P. J., Stagg, L., Ndon, J. & Giustina, A. Glucocorticoid inhibition of growth in rats: partial reversal with somatostatin antibodies. Endocrinology 127, 2705–2708 (1990).

    CAS  PubMed  Google Scholar 

  49. Tulipano, G. et al. Characterization of new selective somatostatin receptor subtype-2 (sst2) antagonists, BIM-23627 and BIM-23454. Effects of BIM-23627 on GH release in anesthetized male rats after short-term high-dose dexamethasone treatment. Endocrinology 143, 1218–1224 (2002).

    CAS  PubMed  Google Scholar 

  50. Tulipano, G. et al. The somatostatin subtype-2 receptor antagonist, BIM-23627, improves the catabolic effects induced by long-term glucocorticoid treatment in the rat. Regul. Pept. 15, 85–92 (2005).

    Google Scholar 

  51. Tulipano, G. et al. Glucocorticoid inhibition of growth in rats: partial reversal with the full-length ghrelin analog BIM-28125. Pituitary 10, 267–274 (2007).

    CAS  PubMed  Google Scholar 

  52. Aagaard, N. K. et al. Growth hormone and growth hormone secretagogue effects on nitrogen balance and urea synthesis in steroid treated rats. Growth Horm. IGF Res. 19, 426–431 (2009).

    CAS  PubMed  Google Scholar 

  53. Martinelli, C. E. & Moreira, A. C. Relation between growth hormone and cortisol spontaneous secretion in children. Clin. Endocrinol. 41, 117–121 (1994).

    CAS  Google Scholar 

  54. Chalew, S. A., Zadik, Z., McCarter, R. & Kowarski, A. A. Hypocortisolemia in children undergoing evaluation for growth hormone deficiency. J. Clin. Endocrinol. Metab. 71, 952–957 (1990).

    CAS  PubMed  Google Scholar 

  55. Ghizzoni, L. et al. Spontaneous cortisol and growth hormone secretion interactions in patients with nonclassic 21-hydroxylase deficiency (NCCAH) and control children. J. Clin. Endocrinol. Metab. 81, 482–487 (1996).

    CAS  PubMed  Google Scholar 

  56. Charmandari, E. et al. Oral hydrocortisone administration in children with classic 21-hydroxylase deficiency leads to more synchronous joint GH and cortisol secretion. J. Clin. Endocrinol. Metab. 87, 2238–2244 (2002).

    CAS  PubMed  Google Scholar 

  57. Barbarino, A. et al. Corticotropin-releasing hormone inhibition of growth hormone-releasing hormone-induced growth hormone release in man. J. Clin. Endocrinol. Metab. 71, 1368–1374 (1990).

    CAS  PubMed  Google Scholar 

  58. Ghizzoni, L., Vottero, A., Street, M. E. & Bernasconi, S. Dose-dependent inhibition of growth hormone (GH)-releasing hormone-induced GH release by corticotropin-releasing hormone in prepubertal children. J. Clin. Endocrinol. Metab. 81, 1397–1400 (1996).

    CAS  PubMed  Google Scholar 

  59. Pekic, S. et al. The influence of serum cortisol levels on growth hormone responsiveness to GH-releasing hormone plus GH-releasing peptide-6 in patients with hypocortisolism. Hormones 2, 243–249 (2003).

    PubMed  Google Scholar 

  60. Pinto, A. C., Silva, M. R., Martins, M. R., Brunner, E. & Lengyel, A. M. Effects of short-term glucocorticoid deprivation on growth hormone (GH) response to GH-releasing peptide-6: studies in normal men and in patients with adrenal insufficiency. J. Clin. Endocrinol. Metab. 85, 1540–1544 (2000).

    CAS  PubMed  Google Scholar 

  61. Barkan, A. L., DeMott-Friberg, R. & Samuels, M. H. Growth hormone (GH) secretion in primary adrenal insufficiency: effects of cortisol withdrawal and patterned replacement on GH pulsatility and circadian rhythmicity. Pituitary 3, 175–179 (2000).

    CAS  PubMed  Google Scholar 

  62. Giustina, A. et al. Effects of short-term glucocorticoid deprivation on growth hormone (GH) response to GH-releasing hormone in man. Horm. Metab. Res. 21, 693–694 (1989).

    CAS  PubMed  Google Scholar 

  63. Giustina, A. et al. Reciprocal relationship between the level of circulating cortisol and growth hormone secretion in response to growth hormone-releasing hormone in man: studies in patients with adrenal insufficiency. J. Clin. Endocrinol. Metab. 79, 1266–1272 (1994).

    CAS  PubMed  Google Scholar 

  64. Hochberg, Z., Hardoff, D., Atias, D. & Spindel, A. Isolated ACTH deficiency with transitory GH deficiency. J. Endocrinol. Invest. 8, 67–70 (1985).

    CAS  PubMed  Google Scholar 

  65. Giustina, A., Romanelli, G., Candrina, R. & Giustina, G. Growth hormone deficiency in patients with idiopathic adrenocorticotropin deficiency resolves during glucocorticoid replacement. J. Clin. Endocrinol. Metab. 68, 120–124 (1989).

    CAS  PubMed  Google Scholar 

  66. Giustina, A., Candrina, R. & Romanelli, G. Growth hormone deficiency rapidly reversible during glucocorticoid replacement in a case of adrenocorticotrpin deficiency. Neth. J. Med. 33, 219–297 (1988).

    Google Scholar 

  67. Inagaki, M. et al. Improved response of growth hormone to growth hormone-releasing hormone and reversible chronic thyroiditis after hydrocortisone replacement in isolated adrenocorticotropic hormone deficiency. Tokai J. Exp. Clin. Med. 20, 34–38 (2009).

    Google Scholar 

  68. Kamijo, K., Saito, T., Sato, M., Kawasaki, K. & Yachi, A. Reports of two cases of selective adrenocorticotropin (ACTH) and growth hormone (GH) deficiency: differential diagnosis from cases with isolated ACTH deficiency associated with transient GH insufficiency. Endocrinol. Jpn. 36, 781–786 (1989).

    CAS  PubMed  Google Scholar 

  69. Vincenzi, P., Francia, G., Dorizi, R., Predrazzoli, R. & Lazzarin, M. Isolated ACTH deficiency and transient GH deficiency. Presentation of a case. Minerva Endocrinol. 17, 127–131 (1992).

    CAS  PubMed  Google Scholar 

  70. McMahon, S. K. et al. Neonatal complete generalized glucocorticoid resistance and growth hormone deficiency caused by a novel homozygous mutation in Helix 12 of the ligand binding domain of the glucocorticoid receptor gene (NR3C1). J. Clin. Endocrinol. Metab. 95, 297–302 (2010).

    CAS  PubMed  Google Scholar 

  71. McEachern, R. et al. Severe cortisol deficiency associated with reversible growth hormone deficiency in two infants: what is the link? J. Clin. Endocrinol. Metab. 96, 2670–2674 (2011).

    CAS  PubMed  Google Scholar 

  72. Kageyama, K. et al. Deficiency of growth hormone in an adult man case of idiopathic adrenocorticotropin deficiency. Intern. Med. 48, 607–610 (2009).

    PubMed  Google Scholar 

  73. De Marinis, L., Bonadonna, S., Bianchi, A., Maira, G. & Giustina, A. Primary empty sella. J. Clin. Endocrinol. Metab. 90, 5471–5477 (2005).

    CAS  PubMed  Google Scholar 

  74. Doga, M. et al. Current guidelines for adult GH replacement. Rev. Endocr. Metab. Disord. 6, 63–70 (2005).

    PubMed  Google Scholar 

  75. Giustina, A. et al. Guidelines for the treatment of growth hormone excess and growth hormone deficiency in adults. J. Endocrinol. Invest. 31, 820–838 (2008).

    CAS  PubMed  Google Scholar 

  76. Molitch, M. E. et al. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 96, 1587–1609 (2011).

    CAS  PubMed  Google Scholar 

  77. Filipsson, H. & Johannsson, G. GH replacement in adults: interactions with other pituitary hormone deficiencies and replacement therapies. Eur. J. Endocrinol. 161, S85–S95 (2009).

    CAS  PubMed  Google Scholar 

  78. Swords, F. M. et al. The effects of growth hormone deficiency and replacement on glucocorticoid exposure in hypopituitary patients on cortisone acetate and hydrocortisone replacement. Clin. Endocrinol. 59, 613–620 (2003).

    CAS  Google Scholar 

  79. Debono, M., Price, J. N. & Ross, R. J. Novel strategies for hydrocortisone replacement. Best Pract. Res. Clin. Endocrinol. Metab. 23, 221–232 (2009).

    CAS  PubMed  Google Scholar 

  80. Giustina, A. et al. Acute effects of cortisone acetate on growth hormone response to growth hormone-releasing hormone in normal adult subjects. Acta Endocrinol. 122, 206–210 (1990).

    CAS  Google Scholar 

  81. Giustina, A. et al. Pyridostigmine blocks the inhibitory effect of glucocorticoids on growth hormone releasing hormone stimulated growth hormone secretion in normal men. J. Clin. Endocrinol. Metab. 71, 580–584 (1990).

    CAS  PubMed  Google Scholar 

  82. Wehrenberg, W. B., Wiviott, S. D., Voltz, D. M. & Giustina, A. Pyridostigmine-mediated growth hormone release: evidence for somatostatin involvement. Endocrinology 130, 1445–1450 (1992).

    CAS  PubMed  Google Scholar 

  83. Giustina, A. et al. Effect of hydrocortisone on the growth hormone (GH) response to GH-releasing hormone in acromegaly. Horm. Res. 41, 33–37 (1994).

    CAS  PubMed  Google Scholar 

  84. Giustina, A. et al. Arginine blocks the inhibitory effect of hydrocortisone on circulating growth hormone levels in patients with acromegaly. Metab. Clin. Exp. 42, 664–668 (1993).

    CAS  PubMed  Google Scholar 

  85. Casanueva, F. F., Burguera, B., Muruais, C. & Dieguez, C. Acute administration of corticoids: a new and peculiar stimulus of growth hormone secretion in man. J. Clin. Endocrinol. Metab. 70, 234–237 (1990).

    CAS  PubMed  Google Scholar 

  86. Burguera, B., Muruais, C., Penalva, A., Dieguez, C. & Casanueva, F. F. Dual and selective actions of glucocorticoids upon basal and stimulated growth hormone release in man. Neuroendocrinology 51, 51–58 (1990).

    CAS  PubMed  Google Scholar 

  87. Kaufmann, S., Jones, K. L., Wehrenberg, W. B. & Culler, F. L. Inhibition by prednisone of growth hormone (GH) response to GH-releasing hormone in normal men. J. Clin. Endocrinol. Metab. 67, 1258–1261 (1988).

    CAS  PubMed  Google Scholar 

  88. Malerba, M. et al. Growth hormone response to growth hormone-releasing hormone is reduced in adult asthmatic patients receiving long-term inhaled corticosteroid treatment. Chest 127, 515–521 (2005).

    CAS  PubMed  Google Scholar 

  89. Giustina, A. et al. Effects of pyridostigmine on spontaneous and growth hormone-releasing hormone stimulated growth hormone secretion in children on daily glucocorticoid therapy after liver transplantation. Clin. Endocrinol. 35, 91–98 (1991).

    Google Scholar 

  90. Giustina, A. et al. Arginine normalizes the growth hormone (GH) response to GH-releasing hormone in adult patients receiving chronic daily immunosuppressive glucocorticoid therapy. J. Clin. Endocrinol. Metab. 74, 1301–1305 (1992).

    CAS  PubMed  Google Scholar 

  91. Giustina, A., Bossoni, S., Bussi, A. R., Pozzi, A. & Wehrenberg, W. B. Effect of galanin on the growth hormone (GH) response to GH-releasing hormone in patients with Cushing's disease. Endocr. Res. 19, 47–56 (1993).

    CAS  PubMed  Google Scholar 

  92. Terzolo, M. et al. Growth hormone (GH) responses to GH-releasing hormone alone or combined with arginine in patients with adrenal incidentaloma: evidence for enhanced somatostatinergic tone. J. Clin. Endocrinol. Metab. 85, 1310–1315 (2000).

    CAS  PubMed  Google Scholar 

  93. Lima, L., Arce, V., Diaz, M., Treguerres, J. & Devesa, J. Glucocorticoids may inhibit growth hormone release by enhancing β-adrenergic responsiveness in hypothalamic somatostatin neurons. J. Clin. Endocrinol. Metab. 76, 439–444 (1993).

    CAS  PubMed  Google Scholar 

  94. Giustina, A. et al. Pyridostigmine enhances even if it does not normalize the growth hormone responses to growth hormone-releasing hormone in patients with Cushing's disease. Horm. Res. 35, 99–103 (1991).

    CAS  PubMed  Google Scholar 

  95. Leal-Cerro, A. et al. Effect of withdrawal of somatostatin plus growth hormone (GH)-releasing hormone as a stimulus of GH secretion in Cushing's syndrome. Clin Endocrinol. 57, 745–749 (2002).

    CAS  Google Scholar 

  96. Gola, M., Bonadonna, S., Doga, M., Mazziotti, G. & Giustina, A. Cardiovascular risk in aging and obesity: is there a role for GH. J. Endocrinol. Invest. 28, 759–767 (2005).

    CAS  PubMed  Google Scholar 

  97. Chrousos, G. P., Charmandari, E. & Kino, T. Glucocorticoid action networks—an introduction to systems biology. J. Clin. Endocrinol. Metab. 89, 563–564 (2004).

    CAS  PubMed  Google Scholar 

  98. Hochberg, Z. Mechanisms of steroid impairment of growth. Horm. Res. 58, S33–S38 (2002).

    Google Scholar 

  99. Touati, G., Prieur, A. M., Ruiz, J. C., Noel, M. & Czernichow, P. Beneficial effects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition. J. Clin. Endocrinol. Metab. 83, 403–409 (1998).

    CAS  PubMed  Google Scholar 

  100. Bechtold, S. et al. Growth hormone increases final height in patients with juvenile idiopathic arthritis: data from a randomized controlled study. J. Clin. Endocrinol. Metab. 92, 3013–3018 (2007).

    CAS  PubMed  Google Scholar 

  101. Stikkelbroeck, N. M., Van't Hof-Grootenboer, B. A., Hermus, A. R., Otten, B. J. & Van't Hof, M. A. Growth inhibition by glucocorticoid treatment in salt wasting 21-hydroxylase deficiency: in early infancy and (pre)puberty. J. Clin. Endocrinol. Metab. 88, 3525–3530 (2003).

    CAS  PubMed  Google Scholar 

  102. Zeiger, R. S. et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N. Eng. J. Med. 365, 1990–2001 (2011).

    CAS  Google Scholar 

  103. Rachelefsky, G. Inhaled corticosteroids and asthma control in children: assessing impairment and risk. Pediatrics 123, 353–366 (2009).

    PubMed  Google Scholar 

  104. Frois, C., Wu, E. Q., Ray, S. & Colice, G. L. Inhaled corticosteroids or long-acting beta-agonists alone or in fixed-dose combinations in asthma treatment: a systematic review of fluticasone/budesonide and formoterol/salmeterol. Clin. Ther. 31, 2779–2803 (2009).

    CAS  PubMed  Google Scholar 

  105. Main, C. et al. Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting β2 agonists for the treatment of chronic asthma in children under the age of 12 years. Health Technol. Assess. 12, 1–174 (2008).

    CAS  PubMed  Google Scholar 

  106. Savage, M. O., Simon, D. & Czernichow, P. C. Growth hormone treatment in children on chronic glucorticoid therapy. Endocr. Dev. 20, 194–201 (2011).

    CAS  PubMed  Google Scholar 

  107. Svantesson, H. Treatment of growth failure with human growth hormone in patients with juvenile chronic arthritis. A pilot study. Clin. Exp. Rheumatol. 9 (Suppl. 6), 47–50 (1991).

    PubMed  Google Scholar 

  108. Bartosh, S. et al. Effects of growth hormone administration in pediatric renal allograft recipients. Pediatr. Nephrol. 6, 68–73 (1992).

    CAS  PubMed  Google Scholar 

  109. Allen, D. B. & Goldberg, B. D. Stimulation of collagen synthesis and linear growth by growth hormone in glucocorticoid-treated children. Pediatrics 89, 416–421 (1992).

    CAS  PubMed  Google Scholar 

  110. Davies, U. M., Rooney, M., Preece, M. A., Ansell, B. M. & Woo, P. Treatment of growth retardation in juvenile chronic arthritis with recombinant human growth hormone. J. Rheumatol. 21, 153–158 (1994).

    CAS  PubMed  Google Scholar 

  111. Sarna, S., Sipilä, I., Rönnholm, K., Koistinen, R. & Holmberg, C. Recombinant human growth hormone improves growth in children receiving glucocorticoid treatment after liver transplantation. J. Clin. Endocrinol. Metab. 81, 1476–1482 (1996).

    CAS  PubMed  Google Scholar 

  112. Loke, K. Y. et al. Efficacy and safety of one year of growth hormone therapy in steroid-dependent nephrotic syndrome. J. Pediatr. 130, 793–799 (1997).

    CAS  PubMed  Google Scholar 

  113. Davies, U. M. et al. Juvenile chronic arthritis. Effects of disease activity and recombinant human growth hormone on insulin-like growth factor 1, insulin-like growth factor binding proteins 1 and 3, and osteocalcin. Arthritis Rheum. 40, 332–340 (1997).

    CAS  PubMed  Google Scholar 

  114. Allen, D. B., Julius, J. R., Breen, T. J. & Attie, K. M. Treatment of glucocorticoid-induced growth suppression with growth hormone. National Cooperative Growth Study. J. Clin. Endocrinol. Metab. 83, 2824–2829 (1998).

    CAS  PubMed  Google Scholar 

  115. Simon, D., Touati, G., Prieur, A. M., Ruiz, J. C. & Czernichow, P. Growth hormone treatment of short stature and metabolic dysfunction in juvenile chronic arthritis. Acta Paediatr. Suppl. 88, 100–105 (1999).

    CAS  PubMed  Google Scholar 

  116. Simon, D., Prieur, A. & Czernichow, P. Treatment of juvenile rheumatoid arthritis with growth hormone. Horm. Res. 53 (Suppl. 1), 82–86 (2000).

    CAS  PubMed  Google Scholar 

  117. Bechtold, S. et al. GH therapy in juvenile chronic arthritis: results of a two-year controlled study on growth and bone. J. Clin. Endocrinol. Metab. 86, 5737–5744 (2001).

    CAS  PubMed  Google Scholar 

  118. Mauras, N. et al. Growth hormone has anabolic effects in glucocorticosteroid-dependent children with inflammatory bowel disease: a pilot study. Metabolism 51, 127–135 (2002).

    CAS  PubMed  Google Scholar 

  119. Bechtold, S. et al. Growth hormone improves height in patients with juvenile idiopathic arthritis: 4-year data of a controlled study. J. Pediatr. 143, 512–519 (2003).

    CAS  PubMed  Google Scholar 

  120. Simon, D., Lucidarme, N., Prieur, A. M., Ruiz, J. C. & Czernichow, P. Effects on growth and body composition of growth hormone treatment in children with juvenile idiopathic arthritis requiring steroid therapy. J. Rheumatol. 30, 2492–2499 (2003).

    CAS  PubMed  Google Scholar 

  121. Grote, F. K. et al. Growth hormone treatment in children with rheumatic disease, corticosteroid induced growth retardation, and osteopenia. Arch. Dis. Child. 91, 56–60 (2006).

    CAS  PubMed  Google Scholar 

  122. Simon, D., Prieur, A. M., Quartier, P., Charles Ruiz, J. & Czernichow, P. Early recombinant human growth hormone treatment in glucocorticoid-treated children with juvenile idiopathic arthritis: a 3-year randomized study. J. Clin. Endocrinol. Metab. 92, 2567–2573 (2007).

    CAS  PubMed  Google Scholar 

  123. Reiter, E. O., Price, D. A., Wilton, P., Albertsson-Wikland, K. & Ranke, M. B. Effect of growth hormone (GH) treatment on the near-final height of 1258 patients with idiopathic GH deficiency: analysis of a large international database. J. Clin. Endocrinol. Metab. 91, 2047–2054 (2006).

    CAS  PubMed  Google Scholar 

  124. Haffner, D. et al. Effect of growth hormone treatment on adult height of children with chronic renal failure. German study group for growth hormone treatment in chronic renal failure. N. Engl. J. Med. 343, 923–930 (2000).

    CAS  PubMed  Google Scholar 

  125. Bechtold, S. et al. Bone mass development and bone metabolism in juvenile idiopathic arthritis: treatment with growth hormone for 4 years. J. Rheumatol. 31, 1407–1412 (2004).

    PubMed  Google Scholar 

  126. Bechtold, S. et al. Growth hormone changes bone geometry and body composition in patients with juvenile idiopathic arthritis requiring glucocorticoid treatment: a controlled study using peripheral quantitative computed tomography. J. Clin. Endocrinol. Metab. 90, 3168–3173 (2005).

    CAS  PubMed  Google Scholar 

  127. Bechtold, S. et al. Dynamics of body composition and bone in patients with juvenile idiopathic arthritis treated with growth hormone. J. Clin. Endocrinol. Metab. 95, 178–185 (2010).

    CAS  PubMed  Google Scholar 

  128. Mazziotti, G., Canalis, E. & Giustina, A. Drug-induced osteoporosis: mechanisms and clinical implications. Am. J. Med. 123, 877–884 (2010).

    CAS  PubMed  Google Scholar 

  129. Mazziotti, G., Angeli, A., Bilezikian, J. P., Canalis, E. & Giustina, A. Glucocorticoid-induced osteoporosis: an update. Trends Endocrinol. Metab. 17, 144–149 (2006).

    CAS  PubMed  Google Scholar 

  130. Giustina, A., Mazziotti, G. & Canalis, E. Growth hormone, insulin-like growth factors, and the skeleton. Endocr. Rev. 29, 535–559 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Mazziotti, G. et al. Increased prevalence of radiological spinal deformities in adult patients with GH deficiency: influence of GH replacement therapy. J. Bone Miner. Res. 21, 520–528 (2006).

    CAS  PubMed  Google Scholar 

  132. Mazziotti, G., Bilezikian, J., Canalis, E., Cocchi, D. & Giustina, A. New understanding and treatments for osteoporosis. Endocrine 41, 58–69 (2012).

    CAS  PubMed  Google Scholar 

  133. Canalis, E., Giustina, A. & Bilezikian, J. P. Mechanisms of anabolic therapies for osteoporosis. N. Engl. J. Med. 357, 905–916 (2007).

    CAS  PubMed  Google Scholar 

  134. Mazziotti, G. et al. Glucocorticoid replacement therapy and vertebral fractures in hypopituitary adult males with GH deficiency. Eur. J. Endocrinol. 163, 15–20 (2010).

    CAS  PubMed  Google Scholar 

  135. Malerba, M. et al. Bone ultrasonometric features and growth hormone secretion in asthmatic patients during chronic inhaled corticosteroid therapy. Bone 38, 119–124 (2006).

    CAS  PubMed  Google Scholar 

  136. Ortoft, G., Andreassen, T. T. & Oxlund, H. Growth hormone can reverse glucocorticoid-induced low bone turnover on cortical but not on cancellous bone surfaces in adult Wistar rats. Bone 36, 123–133 (2005).

    CAS  PubMed  Google Scholar 

  137. Giustina, A., Bussi, A. R., Jacobello, C. & Wehrenberg, W. B. Effects of recombinant human growth hormone (GH) on bone and intermediary metabolism in patients receiving chronic glucocorticoid treatment with suppressed endogenous GH response to GH-releasing hormone. J. Clin. Endocrinol. Metab. 80, 122–129 (1995).

    CAS  PubMed  Google Scholar 

  138. Berneis, K., Oehri, M., Kraenzlin, M. & Keller, U. Effects of IGF-1 combined with GH on glucocorticoid-induced changes of bone and connective tissue turnover in man. J. Endocrinol. 162, 259–264 (1999).

    CAS  PubMed  Google Scholar 

  139. Horber, F. F., Scheidegger, J. R., Gruenig, B. E. & Frey, F. J. Thigh muscle mass, and function in patients treated with glucocorticoids. Eur. J. Clin. Invest. 15, 302–307 (1985).

    CAS  PubMed  Google Scholar 

  140. Horber, F. F. et al. Altered body fat distribution in patients with glucocorticoid treatment and in patients on long-term dialysis. Am. J. Clin. Nutr. 43, 758–769 (1986).

    CAS  PubMed  Google Scholar 

  141. Darmaun, D., Matthews, D. E. & Bier, D. M. Physiological hypercortisolemia increases proteolysis, glutamine and alanine production. Am. J. Physiol. 255, E366–E373 (1988).

    CAS  PubMed  Google Scholar 

  142. Horber, F. F. & Haymond, M. W. Human growth hormone prevents the protein catabolic side effects of prednisone in humans. J. Clin. Invest. 86, 265–272 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Bennet, W. M. & Haymond, M. W. Growth hormone and lean tissue catabolism during long-term glucocorticoid treatment. Clin. Endocrinol. 36, 161–164 (1992).

    CAS  Google Scholar 

  144. Burt, M. G., Johannsson, G., Umpleby, A. M., Chisholm, D. J. & Ho, K. K. Impact of growth hormone and dehydroepiandrosterone on protein metabolism in glucocorticoid-treated patients. J. Clin. Endocrinol. Metab. 93, 688–695 (2008).

    CAS  PubMed  Google Scholar 

  145. Bowes, S. B. et al. The effect of recombinant human growth hormone on glucose and leucine metabolism in Cushing's syndrome. J. Clin. Endocrinol. Metab. 82, 243–246 (1997).

    CAS  PubMed  Google Scholar 

  146. Markell, M. S. & Friedman, E. A. Hyperlipidemia after organ transplantation. Am. J. Med. 87, 61N–67N (1989).

    CAS  PubMed  Google Scholar 

  147. Danilowicz, K., Bruno, O. D., Manavela, M., Gomez, R. M. & Barkan, A. Correction of cortisol overreplacement ameliorates morbidities in patients with hypopituitarism: a pilot study. Pituitary 11, 279–285 (2008).

    CAS  PubMed  Google Scholar 

  148. Gola, M., Bonadonna, S., Doga, M. & Giustina, A. Growth hormone and cardiovascular risk factors. J. Clin. Endocrinol. Metab. 90, 1864–1870 (2005).

    CAS  PubMed  Google Scholar 

  149. Bismuth, E., Chevenne, D., Czernichow, P. & Simon, D. Moderate deterioration in glucose tolerance during high-dose growth hormone therapy in glucocorticoid-treated patients with juvenile idiopathic arthritis. Horm. Res. Paediatr. 73, 465–472 (2010).

    CAS  PubMed  Google Scholar 

  150. Mazziotti, G., Gazzaruso, C. & Giustina, A. Diabetes in Cushing syndrome: basic and clinical aspects. Trends Endocrinol. Metab. 22, 499–506 (2011).

    CAS  PubMed  Google Scholar 

  151. Giordano, R. et al. Glucose metabolism in patients with subclinical Cushing's syndrome. Endocrine 41, 415–423 (2012).

    CAS  PubMed  Google Scholar 

  152. Horber, F. F., Marsh, H. M. & Haymond, M. W. Differential effects of prednisone and growth hormone on fuel metabolism and insulin antagonism in humans. Diabetes 40, 141–149 (1991).

    CAS  PubMed  Google Scholar 

  153. Arnaldi, G., Mancini, T., Polenta, B. & Boscaro, M. Cardiovascular risk in Cushing's syndrome. Pituitary 7, 253–256 (2004).

    PubMed  Google Scholar 

  154. Franco, C. et al. Growth hormone treatment reduces abdominal visceral fat in postmenopausal women with abdominal obesity: a 12-month placebo-controlled trial. J. Clin. Endocrinol. Metab. 90, 1466–1474 (2005).

    CAS  PubMed  Google Scholar 

  155. Maison, P. et al. Impact of growth hormone (GH) treatment on cardiovascular risk factors in GH-deficient adults: a meta-analysis of blinded, randomized, placebo-controlled trials. J. Clin. Endocrinol. Metab. 89, 2192–2199 (2004).

    CAS  PubMed  Google Scholar 

  156. Mauras, N. & Haymond, M. W. Metabolic effects of recombinant human insulin-like growth factor-I in humans: comparison with recombinant human growth hormone. Pediatr. Nephrol. 10, 318–323 (1996).

    CAS  PubMed  Google Scholar 

  157. Tzanela, M., Karavitaki, N., Stylianidou, C., Tsagarakis, S. & Thalassinos, N. C. Assessment of GH reserve before and after successful treatment of adult patients with Cushing's syndrome. Clin. Endocrinol. 60, 309–314 (2004).

    CAS  Google Scholar 

  158. Carroll, P. V. et al. Successful treatment of childhood-onset Cushing's disease is associated with persistent reduction in growth hormone secretion. Clin. Endocrinol. 60, 169–174 (2004).

    CAS  Google Scholar 

  159. Magiakou, M. A., Mastorakos, G., Gomez, M. T., Rose, S. R. & Chrousos, G. P. Suppressed spontaneous and stimulated growth hormone secretion in patients with Cushing's disease before and after surgical cure. J. Clin. Endocrinol. Metab. 78, 131–137 (1994).

    CAS  PubMed  Google Scholar 

  160. Hughes, N. R., Lissett, C. A. & Shalet S. M. Growth hormone status following treatment for Cushing's syndrome. Clin. Endocrinol. 51, 61–66 (1999).

    CAS  Google Scholar 

  161. Pecori Giraldi, F. et al. Significant GH deficiency after long-term cure by surgery in adult patients with Cushing's disease. Eur. J. Endocrinol. 156, 233–239 (2007).

    PubMed  Google Scholar 

  162. Mancini, T., Porcelli, T. & Giustina, A. Treatment of Cushing disease: overview and recent findings. Ther. Clin. Risk Manag. 6, 505–516 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Devoe, V. J. et al. Long-term outcome in children and adolescents after transsphenoidal surgery for Cushing's disease. J. Clin. Endocrinol. Metab. 82, 3196–3202 (1997).

    CAS  PubMed  Google Scholar 

  164. Ragnarsson, O. et al. Comorbidity and cardiovascular risk factors in adult GH deficiency following treatment for Cushing's disease or non-functioning pituitary adenomas during childhood. Eur. J. Endocrinol. 166, 593–600 (2012).

    CAS  PubMed  Google Scholar 

  165. Höybye, C. et al. Clinical features of GH deficiency and effects of 3 years of GH replacement in adults with controlled Cushing's disease. Eur. J. Endocrinol. 162, 677–684 (2010).

    PubMed  Google Scholar 

  166. Webb, S. M. et al. Metabolic, cardiovascular, and cerebrovascular outcomes in growth hormone-deficient subjects with previous Cushing's disease or non-functioning pituitary adenoma. J. Clin. Endocrinol. Metab. 95, 630–638 (2010).

    CAS  PubMed  Google Scholar 

  167. Lebrethon, M. C. et al. Linear growth and final height after treatment for Cushing's disease in childhood. J. Clin. Endocrinol. Metab. 85, 3262–3265 (2000).

    CAS  PubMed  Google Scholar 

  168. Savage, M. O. Growth in disorders of adrenal hyperfunction. Horm. Res. 58, 39–43 (2002).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Endocrine and Bone Unit, Azienda Ospedaliera Carlo Poma of Mantua, Mantua, 46100, Italy

    Gherardo Mazziotti

  2. Department of Clinical and Experimental Sciences, Chair of Endocrinology, University of Brescia, Brescia, 25018, Italy

    Andrea Giustina

Authors
  1. Gherardo Mazziotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrea Giustina
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G. Mazziotti researched data for the article. G. Mazziotti and A. Giustina contributed to discussion of content, writing and reviewing/editing the manuscript before submission.

Corresponding author

Correspondence to Andrea Giustina.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mazziotti, G., Giustina, A. Glucocorticoids and the regulation of growth hormone secretion. Nat Rev Endocrinol 9, 265–276 (2013). https://doi.org/10.1038/nrendo.2013.5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2013.5

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing