Skip to main content
SpringerLink
Log in

The Challenges of Cortisol Replacement Therapy in Childhood: Observations from a Case Series of Children Treated with Modified-Release Hydrocortisone

  • Short Communication
  • Published:
Pediatric Drugs Aims and scope Submit manuscript

Abstract

Background

Hydrocortisone is the preferred treatment for adrenal insufficiency in childhood. A small minority of children experience low cortisol concentrations and symptoms of cortisol insufficiency, poorly responsive to modifications in dosing. We speculated that treatment with modified-release hydrocortisone Plenadren® may be beneficial in these selected patients.

Objective

The aim of this article was to report cortisol profiles during treatment with standard formulation hydrocortisone and Plenadren, and growth and weight gain during treatment with Plenadren in selected children with adrenal insufficiency.

Patients and Methods

Data are reported as median (range). Eight patients (5 male) age 11.0 years (8.8–13.3), with adrenal insufficiency for 4.3 years (2.2–10.0) were treated with Plenadren in doses derived from cortisol concentrations measured during treatment with standard formulation hydrocortisone.

Results

Plasma cortisol was 262 nmol/L (114–654) 2 h after the morning dose (hydrocortisone dose 6.1 mg/m2 [4.3–7.1]) of standard formulation hydrocortisone. After 4 h, cortisol concentration was 81 nmol/L (56–104) and was < 100 nmol/L in six patients. Two hours after Plenadren administration (hydrocortisone dose 12.1 mg/m2 [8.3–17.6]), plasma cortisol concentration was 349 nmol/L (150–466), and after 4 h it was 239 nmol/L (99–375) and < 100 nmol/L in one patient. Six hours after the Plenadren dose, cortisol concentration was < 100 nmol/L in four patients and after 8 h cortisol concentration was < 100 nmol/L in seven patients (sample not obtained in one patient). Six patients elected to continue treatment with Plenadren. After 4.2 years (2.7–6.0), change in height standard deviation score (SDS) was 0.1 SD (− 0.2 to 0.2) and body mass index SDS was 0.3 SD (0–1.1).

Conclusion

Smoother cortisol profiles and more sustained cortisol exposure were achieved during treatment with Plenadren, which was the preferred treatment in most patients. Robust clinical trials are required to determine the place of this medication in paediatric practice.

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

References

  1. Perry R, Kecha O, Paquette J, Huot C, Van Vliet G, Deal C. Primary adrenal insufficiency in children: twenty years experience at the Sainte-Justine Hospital, Montreal. J Clin Endocrinol Metab. 2005;90:3243–50.

    Article  CAS  Google Scholar 

  2. Hindmarsh PC, Charmandari E. Variation in absorption and half-life of hydrocortisone influence plasma cortisol concentrations. Clin Endocrinol (Oxf). 2015;82:557–61.

    Article  CAS  Google Scholar 

  3. Werumeus Buning J, Touw DJ, Brummelman P, et al. Pharmacokinetics of oral hydrocortisone—results and implications from a randomized controlled trial. Metabolism. 2017;71:7–16.

    Article  CAS  Google Scholar 

  4. Lewis JG, Bagley CJ, Elder PA, Bachmann AW, Torpy DJ. Plasma free cortisol fraction reflects levels of functioning corticosteroid-binding globulin. Clin Chim Acta Int J Clin Chem. 2005;359(1–2):189–94.

    Article  CAS  Google Scholar 

  5. Tunn S, Mollmann H, Barth J, Derendorf H, Krieg M. Simultaneous measurement of cortisol in serum and saliva after different forms of cortisol administration. Clin Chem. 1992;38(8 Pt 1):1491–4.

    CAS  PubMed  Google Scholar 

  6. Toothaker RD, Craig WA, Welling PG. Effect of dose size on the pharmacokinetics of oral hydrocortisone suspension. J Pharm Sci. 1982;71(10):1182–5.

    Article  CAS  Google Scholar 

  7. Maguire AM, Ambler GR, Moore B, et al. Prolonged hypocortisolemia in hydrocortisone replacement regimens in adrenocorticotrophic hormone deficiency. Pediatrics. 2007;120(1):e164–71.

    Article  Google Scholar 

  8. Petersen KS, Rushworth RL, Clifton PM, Torpy DJ. Recurrent nocturnal hypoglycaemia as a cause of morning fatigue in treated Addison’s disease—favourable response to dietary management: a case report. BMC Endocr Disord. 2015;24(15):61. https://doi.org/10.1186/s12902-015-0058-6.

    Article  CAS  Google Scholar 

  9. Werumeus Buning J, Touw DJ, Brummelman P, Dullaart RPF, van den Berg G, van der Klauw MM, Kamp J, Wolffenbuttel BHR, van Beek AP. Pharmacokinetics of oral hydrocortisone—results and implications from a randomized controlled trial. Metabolism. 2017;71:7–16.

    Article  CAS  Google Scholar 

  10. Johannsson G, Nilsson AG, Bergthorsdottir R, Burman P, Dahlqvist P, Ekman B, Engström BE, Olsson T, Ragnarsson O, Ryberg M, Wahlberg J, Biller BM, Monson JP, Stewart PM, Lennernäs H, Skrtic S. Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective randomized trial of a novel hydrocortisone dual-release formulation. J Clin Endocrinol Metab. 2012;97(2):473–81.

    Article  CAS  Google Scholar 

  11. Tschöp M, Lahner H, Feldmeier H, Grasberger H, Morrison KM, Janssen OE, Attanasio AF, Strasburger CJ. Effects of growth hormone replacement therapy on levels of cortisol and cortisol-binding globulin in hypopituitary adults. Eur J Endocrinol. 2000;143(6):769–73.

    Article  Google Scholar 

  12. Rodríguez-Arnao J, Perry L, Besser GM, Ross RJ. Growth hormone treatment in hypopituitary GH deficient adults reduces circulating cortisol levels during hydrocortisone replacement therapy. Clin Endocrinol (Oxf). 1996;45(1):33–7.

    Article  Google Scholar 

  13. Gelding SV, Taylor NF, Wood PJ, Noonan K, Weaver JU, Wood DF, Monson JP. The effect of growth hormone replacement therapy on cortisol–cortisone interconversion in hypopituitary adults: evidence for growth hormone modulation of extrarenal 11 beta-hydroxysteroid dehydrogenase activity. Clin Endocrinol (Oxf). 1998;48(2):153–62.

    Article  CAS  Google Scholar 

  14. Frey FJ, Horber FF, Frey BM. Altered metabolism and decreased efficacy of prednisolone and prednisone in patients with hyperthyroidism. Clin Pharmacol Ther. 1988;44:510.

    Article  CAS  Google Scholar 

  15. Gangadharan A, McCoy P, Phyo A, McGuigan MP, Dharmaraj P, Ramakrishnan R, McNamara PS, Blair J. Recovery of hypothalamo–pituitary–adrenal axis suppression during treatment with inhaled corticosteroids for childhood asthma. J Asthma Allergy. 2017;15(10):317–26.

    Article  Google Scholar 

  16. Huizenga NA, De Herder WW, Koper JW, de Lange P, v Lely DAJ, Brinkmann AO, de Jong FH, Lamberts SW. Decreased ligand affinity rather than glucocorticoid receptor down-regulation in patients with endogenous Cushing’s syndrome. Eur J Endocrinol. 2000;142(5):472–6.

    Article  CAS  Google Scholar 

  17. Moreira RP, Gomes LG, Madureira G, et al. Influence of the A3669G glucocorticoid receptor gene polymorphism on the metabolic profile of pediatric patients with congenital adrenal hyperplasia. Int J Endocrinol. 2014;2014:594710.

    Article  Google Scholar 

  18. Moreira RP, Jorge AA, Gomes LG, et al. Pharmacogenetics of glucocorticoid replacement could optimize the treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Clinics (Sao Paulo). 2011;66(8):1361–6.

    Article  Google Scholar 

  19. Marra AM, Improda N, Capalbo D, Salzano A, Arcopinto M, De Paulis A, Alessio M, Lenzi A, Isidori AM, Cittadini A, Salerno M. Cardiovascular abnormalities and impaired exercise performance in adolescents with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2015;100(2):644–52.

    Article  CAS  Google Scholar 

  20. Peters CJ, Hill N, Dattani MT, Charmandari E, Matthews DR, Hindmarsh PC. Deconvolution analysis of 24-h serum cortisol profiles informs the amount and distribution of hydrocortisone replacement therapy. Clin Endocrinol (Oxf). 2013;78(3):347–51.

    Article  CAS  Google Scholar 

  21. Charmandari E, Weise M, Bornstein SR, Eisenhofer G, Keil MF, Chrousos GP, Merke DP. Children with classic congenital adrenal hyperplasia have elevated serum leptin concentrations and insulin resistance: potential clinical implications. J Clin Endocrinol Metab. 2002;87(5):2114–20.

    Article  CAS  Google Scholar 

  22. Williams RM, Deeb A, Ong KK, Bich W, Murgatroyd PR, Hughes IA, Acerini CL. Insulin sensitivity and body composition in children with classical and nonclassical congenital adrenal hyperplasia. Clin Endocrinol (Oxf). 2010;72(2):155–60.

    Article  CAS  Google Scholar 

  23. Han TS, Walker BR, Arlt W, Ross RJ. Treatment and health outcomes in adults with congenital adrenal hyperplasia. Nat Rev Endocrinol. 2014;10(2):115–24.

    Article  CAS  Google Scholar 

  24. Forss M, Batcheller G, Skrtic S, Johannsson G. Current practice of glucocorticoid replacement therapy and patient-perceived health outcomes in adrenal insufficiency—a worldwide patient survey. BMC Endocr Disord. 2012;13(12):8.

    Article  Google Scholar 

  25. Gilban DL, Alves Junior PA, Beserra IC. Health related quality of life of children and adolescents with congenital adrenal hyperplasia in Brazil. Health Qual Life Outc. 2014;12:107.

    Article  Google Scholar 

  26. Browne WV, Hindmarsh PC, Pasterski V, et al. Working memory performance is reduced in children with congenital adrenal hyperplasia. Horm Behav. 2015;67:83–8.

    Article  Google Scholar 

  27. Gan Y, Yang C, Tong X, et al. Shift work and diabetes mellitus: a meta-analysis of observational studies. Occup Environ Med. 2015;72:72–8.

    Article  Google Scholar 

  28. Vyas MV, Garg AX, Iansavichus AV, et al. Shift work and vascular events: systematic review and meta-analysis. BMJ. 2012;345:e4800.

    Article  Google Scholar 

  29. Giordano R, Guaraldi F, Marinazzo E, et al. Improvement of anthropometric and metabolic parameters, and quality of life following treatment with dual-release hydrocortisone in patients with Addison’s disease. Endocrine. 2016;51(2):360–8.

    Article  CAS  Google Scholar 

  30. Quinkler M, Miodini Nilsen R, Zopf K, Ventz M, Øksnes M. Modified-release hydrocortisone decreases BMI and HbA1c in patients with primary and secondary adrenal insufficiency. Eur J Endocrinol. 2015;172(5):619–26.

    Article  CAS  Google Scholar 

  31. Isidori AM, Venneri MA, Graziadio C, Simeoli C, Fiore D, Hasenmajer V, Sbardella E, Gianfrilli D, Pozza C, Pasqualetti P, Morrone S, Santoni A, Naro F, Colao A, Pivonello R, Lenzi A. Effect of once-daily, modified-release hydrocortisone versus standard glucocorticoid therapy on metabolism and innate immunity in patients with adrenal insufficiency (DREAM): a single-blind, randomised controlled trial. Lancet Diabetes Endocrinol. 2018;6(3):173–85.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Endocrinology, Alder Hey Children’s NHS Foundation Trust, Liverpool, L12 2AP, UK

    Julie Park, Urmi Das, Mohammed Didi, Renuka Ramakrishnan & Joanne Blair

  2. NIHR Alder Hey Clinical Research Facility, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

    Matthew Peak

  3. Department of Clinical Biochemistry, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

    Paul Newland

Authors
  1. Julie Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Urmi Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohammed Didi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Renuka Ramakrishnan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matthew Peak
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paul Newland
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Joanne Blair
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joanne Blair.

Ethics declarations

Funding

No funding was received to support the work reported in this manuscript.

Conflict of interest

JB has a paid advisory role for a study of modified-release hydrocortisone (Chronocort) in adult patients with congenital adrenal hyperplasia. Authors JP, UD, MP, RR, MD and PN report no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Park, J., Das, U., Didi, M. et al. The Challenges of Cortisol Replacement Therapy in Childhood: Observations from a Case Series of Children Treated with Modified-Release Hydrocortisone. Pediatr Drugs 20, 567–573 (2018). https://doi.org/10.1007/s40272-018-0306-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40272-018-0306-0

Search

Navigation