Skip to main content
SpringerLink
Log in

The acute effect of fludrocortisone on basal and hCRH-stimulated hypothalamic–pituitary–adrenal (HPA) axis in humans

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

Mineralocorticoid receptors (MR) in the hippocampus display an important role in the control of hypothalamic–pituitary–adrenal (HPA)-axis, mediating the “proactive”-feedback of glucocorticoids. Fludrocortisone (FC), a potent MR agonist, has been shown to decrease HPA activity through a mechanism placed at hippocampal level. In order to clarify the effects of MR agonism on HPA function in humans, we studied the effects of FC, in a dose-related manner, on both basal and CRH-stimulated HPA axis during the quiescent phase. 8 young women were studied. ACTH, cortisol and aldosterone levels were evaluated every 15′, from 1600 to 2000 hours, in randomized sessions: (1) placebo p.o. + placebo i.v., (2) 0.3 mg FC p.o. + placebo, (3) 0.1 mg FC. + placebo, (4) 0.075 mg FC + placebo, (5) 0.05 mg FC + placebo, (6) placebo + hCRH (2.0 μg/kg iv-bolus), (7) 0.3 mg FC + hCRH, (8) 0.1 mg FC + hCRH, (9) 0.075 mg FC + hCRH, (10) 0.05 mg FC + hCRH. FC induced a dose-related trend toward a further decrease of the ACTH and cortisol levels, while it showed a significant and dose-dependent inhibition of the hormonal response to hCRH (p < 0.05 for the doses of 0.3, 0.1 and 0.075 mg). Conversely, 0.05 mg FC did not modify the CRH-stimulatory effect on both ACTH and cortisol secretion. Aldosterone levels were not modified by FC administration. Fludrocortisone inhibits corticotrope and adrenal response to hCRH in humans, in a dose-dependent manner. The 0.075 mg FC seems the lowest active while 0.05 mg the first neutral dose on HPA activity. These data suggest a possible hypophysial MR-mediated inhibiting effect of FC, although its pituitary glucocorticoid-mediated effect cannot be excluded. The interplay between fludrocortisone and hypophysial glucocorticoid receptors needs to be clarified in order to define better the clinical consequences of the hormonal replacement therapy of patients with primary adrenal insufficiency.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Gaillard RC, Al-Damluji S (1987) Stress and the pituitary-adrenal axis. Baillieres Clin Endocrinol Metab 1(2):319–354

    Article  CAS  PubMed  Google Scholar 

  2. Orth DN (1992) Corticotropin-releasing hormone in humans. Endocr Rev 13:164–191

    CAS  PubMed  Google Scholar 

  3. Jacobson L, Sapolsky R (1991) The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endocr Rev 12:118–134

    Article  CAS  PubMed  Google Scholar 

  4. De Kloet ER, Vreugdehil E, Oitzl MS, Joels M (1998) Brain corticosteroid receptor balance in health and disease. Endocr Rev 19(3):269–301

    Article  PubMed  Google Scholar 

  5. Arvat E, Maccagno B, Giordano R, Pellegrino M, Broglio F, Gianotti L, Maccario M, Camanni F, Ghigo E (2001) Mineralocorticoid receptor blockade by canrenoate increases both spontaneous and stimulated adrenal function in humans. J Clin Endocrinol Metab 86(7):3176–3181

    Article  CAS  PubMed  Google Scholar 

  6. Grottoli S, Giordano R, Maccagno B, Pellegrino M, Ghigo E, Arvat E (2002) The stimulatory effect of canrenoate, a mineralocorticoid antagonist, on the activity of the hypothalamus-pituitary-adrenal axis is abolished by alprazolam, a benzodiazepine, in humans. J Clin Endocrinol Metab 87(10):4616–4620

    Article  CAS  PubMed  Google Scholar 

  7. Funder JW (1997) Glucocorticoid and mineralcorticoid receptors: biology and clinical relevance. Annu Rev Med 48:231–240

    Article  CAS  PubMed  Google Scholar 

  8. Ribeiro RC, Kushner PJ, Baxter JD (1995) The nuclear hormone receptor gene superfamily. Annu Rev Med 46:443–453

    Article  CAS  PubMed  Google Scholar 

  9. Grossmann C, Scholz T, Rochel M, Bumke-Vogt C, Oelkers W, Pfeiffer AF, Diederich S, Bahr V (2004) Transactivation via the human glucocorticoid and mineralocorticoid receptor by therapeutically used steroids in CV-1 cells: a comparison of their glucocorticoid and mineralocorticoid properties. Eur J Endocrinol 151(3):397–406

    Article  CAS  PubMed  Google Scholar 

  10. Reul JM, de Kloet ER (1985) Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology 117(6):2505–2511

    Article  CAS  PubMed  Google Scholar 

  11. Reul JM, Gesing A, Droste S, Stec IS, Weber A, Bachmann C, Bilang-Bleuel A, Holsboer F, Linthorst AC (2000) The brain mineralocorticoid receptor: greedy for ligand, mysterious in function. Eur J Pharmacol 405(1–3):235–249

    Article  CAS  PubMed  Google Scholar 

  12. Dallman MF, Levin N, Cascio CS, Akana SF, Jacobson L, Kuhn RW (1989) Pharmacological evidence that the inhibition of diurnal adrenocorticotropin secretion by corticosteroids is mediated via type I corticosterone-preferring receptors. Endocrinology 124(6):2844–2850

    Article  CAS  PubMed  Google Scholar 

  13. Spencer RL, Miller AH, Moday H, Stein M, McEwen BS (1993) Diurnal differences in basal and acute stress levels of type I and type II adrenal steroid receptor activation in neural and immune tissues. Endocrinology 133(5):1941–1950

    Article  CAS  PubMed  Google Scholar 

  14. Kalman BA, Spencer RL (2002) Rapid corticosteroid-dependent regulation of mineralocorticoid receptor protein expression in rat brain. Endocrinology 143(11):4184–4195

    Article  CAS  PubMed  Google Scholar 

  15. Otte C, Jahn H, Yassouridis A, Arlt J, Stober N, Maass P, Wiedemann K, Kellner M (2003) The mineralcorticoid receptor agonist, fludrocortisone, inhibits pituitary-adrenal activity in humans after pre-treatment with metyrapone. Life Sci 73(14):1835–1845

    Article  CAS  PubMed  Google Scholar 

  16. Otte C, Yassouridis A, Jahn H, Maass P, Stober N, Wiedemann K, Kellner M (2003) Mineralocorticoid receptor-mediated inhibition of the hypothalamic-pituitary-adrenal axis in aged humans. J Gerontol A Biol Sci Med Sci 58(10):900–905

    Article  Google Scholar 

  17. Herman JP, Prewitt CM, Cullinan WE (1996) Neuronal circuit regulation of the hypothalamo-pituitary-adrenocortical stress axis. Crit Rev Neurobiol 10(3–4):371–394

    Article  CAS  PubMed  Google Scholar 

  18. Herman JP, Watson SJ, Spencer R (1999) Defense of adrenocorticosteroid receptor expression in rat hippocampus: effects of stress and strain. Endocrinology 140(9):3981–3991

    Article  CAS  PubMed  Google Scholar 

  19. Swanson LW, Sawchenko PE, Lind RW, Rho JH (1987) The CRH motoneuron: differential peptide regulation in neurons with possible synaptic, paracrine, and endocrine outputs. Ann NY Acad Sci 512:12–23

    Article  CAS  PubMed  Google Scholar 

  20. Swanson LW (1991) Biochemical switching in hypothalamic circuits mediating responses to stress. Prog Brain Res 87:181–200

    Article  CAS  PubMed  Google Scholar 

  21. Oitzl MS, Van Haarst AD, Sutanto W, De Kloet ER (1995) Corticosterone, brain mineralocorticoid receptor (MRs) and the activity of the hypothalamic-pituitary-adrenal (HPA) axis: the Lewis rat as an example of increased central MR capacity and a hyporesponsive HPA axis. Psychoneuroendocrinology 20(6):655–675

    Article  CAS  PubMed  Google Scholar 

  22. Ratka A, Sutanto W, Bloemers M, De Kloet ER (1989) On the role of brain mineralocorticoid (type I) and glucocorticoid (type II) receptors in neuroendocrine regulation. Neuroendocrinology 50(2):117–123

    Article  CAS  PubMed  Google Scholar 

  23. Deuschle M, Weber B, Colla M, Muller M, Kniest A, Heuser I (1998) Mineralocorticoid receptor also modulates basal activity of hypothalamus-pituitary-adrenocortical system in humans. Neuroendocrinology 68(5):355–360

    Article  CAS  PubMed  Google Scholar 

  24. Young EA, Lopez JF, Murphy-Weinberg V, Watson SJ, Akil H (1998) The role of mineralcorticoid receptors in hypothalamo-pituitary-adrenocortical axis regulation in humans. J Clin Endocrinol Metab 83(9):3339–3345

    Article  CAS  PubMed  Google Scholar 

  25. Born J, De Kloet ER, Wenz H, Kern W, Fehm HL (1991) Gluco- and antimineralocorticoid effects on human sleep: a role of central corticosteroid receptors. Am J Physiol 260:183–188

    Google Scholar 

  26. Wellhoener P, Born J, Fehm HL, Dodt C (2004) Elevated resting and exercise-induced cortisol levels after mineralocorticoid receptor blockade with canrenoate in healthy humans. J Clin Endocrinol Metab 89(10):5048–5052

    Article  CAS  PubMed  Google Scholar 

  27. Giordano R, Bo M, Pellegrino M, Vezzari M, Baldi M, Picu A, Balbo M, Bonelli L, Migliaretti G, Ghigo E, Arvat E (2005) Hypothalamus-pituitary-adrenal hyperactivity in human aging is partially refractory to stimulation by mineralcorticoid receptor blockade. J Clin Endocrinol Metab 90(10):5656–5662

    Article  CAS  PubMed  Google Scholar 

  28. Dodt C, Kern W, Fehm HL, Born J (1993) Antimineralocorticoid canrenoate enhances secretory activity of the hypothalamus-pituitary-adrenocortical (HPA) axis in humans. Neuroendocrinology 58(5):570–574

    Article  CAS  PubMed  Google Scholar 

  29. Funder JW, Carey RM, Fardella C, Gomez-Sanchez GE, Mantero F, Stowasser M, Young FW Jr, Montori VM (2008) Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 93:3266–3281

    Article  CAS  PubMed  Google Scholar 

  30. Berardelli R, Karamouzis I, Marinazzo E, Prats E, Picu A, Giordano R, Ghigo E, Arvat E (2010) Effect of acute and prolonged mineralocorticoid receptor blockade on spontaneous and stimulated hypothalamic-pituitary-adrenal axis in humans. Eur J Endocrinol 162(6):1067–1074

    Article  CAS  PubMed  Google Scholar 

  31. Giordano R, Pellegrino M, Picu A, Bonelli L, Oleandri SE, Pellissetto C, Limone P, Migliaretti G, Maccario M, Ghigo E, Arvat E (2007) Primary hyperaldosteronism is associated with derangement in the regulation of the hypothalamus-pituitary-adrenal axis in humans. J Endocrinol Invest 30(7):558–563

    CAS  PubMed  Google Scholar 

  32. Heuser I, Deuschle M, Weber B, Stalla GK, Holsboer F (2000) Increased activity of the hypothalamus–pituitary–adrenal system after treatment with the mineralocorticoid receptor antagonist spironolactone. Psychoneuroendocrinology 25(5):513–518

    Article  CAS  PubMed  Google Scholar 

  33. Vogt W, Fischer I, Ebenroth S, Appel S, Knedel M, Lücker PW, Rennekamp H (1971) Pharmacokinetics of 9-fluorhydrocortisone. Arzneimittelforschung 21(8):1133–1143

    PubMed  Google Scholar 

  34. Buckley TM, Mullen BC, Schatzberg AF (2007) The acute effects of a mineralocorticoid receptor (MR) agonist on nocturnal hypothalamic-adrenal-pituitary (HPA) axis activity in healthy controls. Psychoneuroendocrinology 32(8–10):859–864

    Article  CAS  PubMed  Google Scholar 

  35. Arvat E, Maccagno B, Ramunni J, Di Vito L, Giordano R, Gianotti L, Broglio F, Camanni F, Ghigo E (1999) The inhibitory effect of alprazolam, a benzodiazepine, overrides the stimulatory effect of metyrapone-induced lack of negative cortisol feedback on corticotroph secretion in humans. J Clin Endocrinol Metab 84:2611–2615

    Article  CAS  PubMed  Google Scholar 

  36. Grottoli S, Maccagno B, Ramunni J, Di Vito L, Giordano R, Gianotti L, Destefanis S, Camanni F, Ghigo E, Arvat E (2002) Alprazolam, a benzodiazepine, does not modify the ACTH and cortisol response to hCRH and AVP, but blunts the cortisol response to ACTH in humans. J Endocrinol Invest 25:420–425

    CAS  PubMed  Google Scholar 

  37. Hügin-Flores ME, Steimer T, Aubert ML, Schulz P (2004) Mineralo- and glucocorticoid receptor mrnas are differently regulated by corticosterone in the rat hippocampus and anterior pituitary. Neuroendocrinology 79(4):174–184

    Article  PubMed  Google Scholar 

  38. Roubos EW, Kuribara M, Kuipers-Kwant FJ, Coenen TA, Meijer KH, Cruijsen PM, Denver RJ (2009) Dynamics of glucocorticoid and mineralocorticoid receptors in the Xenopus laevis pituitary pars intermedia. Ann NY Acad Sci 1163:292–295

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by Grants from the University of Turin and Foundation for the Study of Endocrine and Metabolic Diseases of Turin, Italy.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Endocrinology, Diabetology and Metabolism, Department of Internal Medicine, Ospedale San Giovanni Battista-Molinette, C.so Dogliotti 14, 10126, Turin, Italy

    Ioannis Karamouzis, Rita Berardelli, Elisa Marinazzo, Valentina D’Angelo, Domenico Zinnà, Marco Alessandro Minetto, Clizia Zichi, Beatrice Fussotto, Ezio Ghigo & Emanuela Arvat

  2. Department of Clinical and Biological Science, University of Turin, Turin, Italy

    Roberta Giordano

Authors
  1. Ioannis Karamouzis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rita Berardelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elisa Marinazzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Valentina D’Angelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Domenico Zinnà
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marco Alessandro Minetto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Clizia Zichi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Beatrice Fussotto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Roberta Giordano
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ezio Ghigo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Emanuela Arvat
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ioannis Karamouzis.

Additional information

Ioannis Karamouzis and Rita Berardelli equally contributed as first author.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Karamouzis, I., Berardelli, R., Marinazzo, E. et al. The acute effect of fludrocortisone on basal and hCRH-stimulated hypothalamic–pituitary–adrenal (HPA) axis in humans. Pituitary 16, 378–385 (2013). https://doi.org/10.1007/s11102-012-0435-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-012-0435-3

Keywords

Search

Navigation