Background: There is a major lack of randomized controlled trials (RCTs) evaluating the effects of hydrocortisone (HC) substitution therapy in patients with secondary adrenal insufficiency. Therefore, we evaluated the effects of two different replacement doses of HC on health-related quality of life (HRQoL) in a RCT. Methods: This RCT with a double-blind cross-over design was performed at the University Medical Center Groningen. Forty-seven patients (29 men, age 51 ± 14 years, range 19-73 years) with secondary adrenal insufficiency participated. Patients received both a lower and a higher dose of HC (0.2-0.3 and 0.4-0.6 mg/kg body weight/day) for 10 weeks in random order. HRQoL was assessed with a daily mood and symptom checklist (Patient Health Questionnaire-15 [PHQ-15], Generalized Anxiety Disorder-7 [GAD-7], Patient Health Questionnaire-9 [PHQ-9]) and with questionnaires assessing general well-being (RAND 36-Item Health Survey [RAND-36]), mood (Hospital Anxiety and Depression Scale [HADS]) and fatigue (Multidimensional Fatigue Inventory-20 [MFI-20]). ClinicalTrials.gov identifier: NCT01546922. Results: Patients receiving the higher dose of HC reported significantly fewer symptoms of depression (p = 0.016 and p = 0.045 for HADS and PHQ-9, respectively), less general and mental fatigue (p = 0.004 and p = 0.003, respectively, both MFI-20), increased motivation (p = 0.021, MFI-20), better physical functioning (p = 0.041), better general health (p = 0.013) and more vitality (p = 0.025) (all RAND-36). In addition, while on the higher dose, fewer somatic symptoms (p = 0.022) and less pain (p < 0.001) (both PHQ-15) were experienced. Conclusions: On the higher dose of HC, patients reported a better HRQoL on various domains as compared to the lower dose of HC. The fact that a higher dose of HC may improve patient well-being should be taken into consideration when individualizing the HC substitution dose.

Journal Section:
Editor's choice
Keywords:
Hydrocortisone, Adrenal insufficiency, Quality of life, Pain, Depression, Fatigue
1.
Arlt W, Rosenthal C, Hahner S, Allolio B: Quality of glucocorticoid replacement in adrenal insufficiency: clinical assessment vs. timed serum cortisol measurements. Clin Endocrinol (Oxf) 2006;64:384-389.
[PubMed]
https://doi.org/10.1111/j.1365-2265.2006.02473.x
2.
Grossman A, Johannsson G, Quinkler M, Zelissen P: Therapy of endocrine disease: perspectives on the management of adrenal insufficiency: clinical insights from across Europe. Eur J Endocrinol 2013;169:R165-R175.
[PubMed]
https://doi.org/10.1530/EJE-13-0450
3.
Filipsson H, Monson JP, Koltowska-Haggstrom M, Mattsson A, Johannsson G: The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients. J Clin Endocrinol Metab 2006;91:3954-3961.
[PubMed]
https://doi.org/10.1210/jc.2006-0524
4.
Mah PM, Jenkins RC, Rostami-Hodjegan A, Newell-Price J, Doane A, Ibbotson V, Tucker GT, Ross RJ: Weight-related dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency. Clin Endocrinol (Oxf) 2004;61:367-375.
[PubMed]
https://doi.org/10.1111/j.1365-2265.2004.02106.x
5.
Bancos I, Hahner S, Tomlinson J, Arlt W: Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol 2015;3:216-226.
[PubMed]
https://doi.org/10.1016/S2213-8587(14)70142-1
6.
Johannsson G, Falorni A, Skrtic S, Lennernas H, Quinkler M, Monson JP, Stewart PM: Adrenal insufficiency: review of clinical outcomes with current glucocorticoid replacement therapy. Clin Endocrinol (Oxf) 2015;82:2-11.
[PubMed]
https://doi.org/10.1111/cen.12603
7.
Tiemensma J, Andela CD, Kaptein AA, Romijn JA, van der Mast RC, Biermasz NR, Pereira AM: Psychological morbidity and impaired quality of life in patients with stable treatment for primary adrenal insufficiency: cross-sectional study and review of the literature. Eur J Endocrinol 2014;171:171-182.
[PubMed]
https://doi.org/10.1530/EJE-14-0023
8.
Hahner S, Loeffler M, Fassnacht M, Weismann D, Koschker AC, Quinkler M, Decker O, Arlt W, Allolio B: Impaired subjective health status in 256 patients with adrenal insufficiency on standard therapy based on cross-sectional analysis. J Clin Endocrinol Metab 2007;92:3912-3922.
[PubMed]
https://doi.org/10.1210/jc.2007-0685
9.
Ragnarsson O, Mattsson AF, Monson JP, Filipsson Nystrom H, Akerblad AC, Koltowska-Haggstrom M, Johannsson G: The relationship between glucocorticoid replacement and quality of life in 2737 hypopituitary patients. Eur J Endocrinol 2014;171:571-579.
[PubMed]
https://doi.org/10.1530/EJE-14-0397
10.
Bleicken B, Hahner S, Loeffler M, Ventz M, Decker O, Allolio B, Quinkler M: Influence of hydrocortisone dosage scheme on health-related quality of life in patients with adrenal insufficiency. Clin Endocrinol (Oxf) 2010;72:297-304.
[PubMed]
https://doi.org/10.1111/j.1365-2265.2009.03596.x
11.
Alonso N, Granada ML, Lucas A, Salinas I, Reverter J, Oriol A, Sanmarti A: Evaluation of two replacement regimens in primary adrenal insufficiency patients. Effect on clinical symptoms, health-related quality of life and biochemical parameters. J Endocrinol Invest 2004;27:449-454.
[PubMed]
https://doi.org/10.1007/BF03345290
12.
Wichers M, Springer W, Bidlingmaier F, Klingmuller D: The influence of hydrocortisone substitution on the quality of life and parameters of bone metabolism in patients with secondary hypocortisolism. Clin Endocrinol (Oxf) 1999;50:759-765.
[PubMed]
https://doi.org/10.1046/j.1365-2265.1999.00723.x
13.
Behan LA, Rogers B, Hannon MJ, O'Kelly P, Tormey W, Smith D, Thompson CJ, Agha A: Optimizing glucocorticoid replacement therapy in severely adrenocorticotropin-deficient hypopituitary male patients. Clin Endocrinol (Oxf) 2011;75:505-513.
[PubMed]
https://doi.org/10.1111/j.1365-2265.2011.04074.x
14.
Benson S, Neumann P, Unger N, Schedlowski M, Mann K, Elsenbruch S, Petersenn S: Effects of standard glucocorticoid replacement therapies on subjective well-being: a randomized, double-blind, crossover study in patients with secondary adrenal insufficiency. Eur J Endocrinol 2012;167:679-685.
[PubMed]
https://doi.org/10.1530/EJE-12-0351
15.
Dullaart RP, Pasterkamp SH, Beentjes JA, Sluiter WJ: Evaluation of adrenal function in patients with hypothalamic and pituitary disorders: comparison of serum cortisol, urinary free cortisol and the human-corticotrophin releasing hormone test with the insulin tolerance test. Clin Endocrinol (Oxf) 1999;50:465-471.
[PubMed]
https://doi.org/10.1046/j.1365-2265.1999.00679.x
16.
Werumeus Buning J, Brummelman P, Koerts J, Dullaart RP, van den Berg G, van der Klauw MM, Tucha O, Wolffenbuttel BH, van Beek AP: The effects of two different doses of hydrocortisone on cognition in patients with secondary adrenal insufficiency - results from a randomized controlled trial. Psychoneuroendocrinology 2015;55:36-47.
[PubMed]
https://doi.org/10.1016/j.psyneuen.2015.02.001
17.
Zigmond AS, Snaith RP: The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand 1983;67:361-370.
[PubMed]
https://doi.org/10.1111/j.1600-0447.1983.tb09716.x
18.
Smets EM, Garssen B, Bonke B, De Haes JC: The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res 1995;39:315-325.
[PubMed]
https://doi.org/10.1016/0022-3999(94)00125-O
19.
van der Zee KI, Sanderman R: The Measurement of the General Health with the RAND-36, a Handbook. Groningen, Rijks Universiteit Groningen, Noordelijk Centrum voor Gezondsheidsvraagstukken, 2012.
20.
Wallace JC, Kass SJ, Stanny CJ: The Cognitive Failures Questionnaire revisited: dimensions and correlates. J Gen Psychol 2002;129:238-256.
[PubMed]
https://doi.org/10.1080/00221300209602098
21.
Broadbent DE, Cooper PF, FitzGerald P, Parkes KR: The Cognitive Failures Questionnaire (CFQ) and its correlates. Br J Clin Psychol 1982;21:1-16.
[PubMed]
https://doi.org/10.1111/j.2044-8260.1982.tb01421.x
22.
Kroenke K, Spitzer RL, Williams JB: The PHQ-15: validity of a new measure for evaluating the severity of somatic symptoms. Psychosom Med 2002;64:258-266.
[PubMed]
https://doi.org/10.1097/00006842-200203000-00008
23.
Spitzer RL, Kroenke K, Williams JB, Lowe B: A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med 2006;166:1092-1097.
[PubMed]
https://doi.org/10.1001/archinte.166.10.1092
24.
Lowe B, Kroenke K, Herzog W, Grafe K: Measuring depression outcome with a brief self-report instrument: sensitivity to change of the Patient Health Questionnaire (PHQ-9). J Affect Disord 2004;81:61-66.
[PubMed]
https://doi.org/10.1016/S0165-0327(03)00198-8
25.
Altman D: Practical Statistics for Medical Research. London, Chapman and Hall, 1991.
https://doi.org/10.1002/sim.4780101015
26.
Cohen J: Statistical Power Analysis for the Behavioral Sciences, ed 2. Hillsdale, Lawrence Erlbaum Associates, 1988.
27.
Dekkers OM, van der Klaauw AA, Pereira AM, Biermasz NR, Honkoop PJ, Roelfsema F, Smit JW, Romijn JA: Quality of life is decreased after treatment for nonfunctioning pituitary macroadenoma. J Clin Endocrinol Metab 2006;91:3364-3369.
[PubMed]
https://doi.org/10.1210/jc.2006-0003
28.
Plihal W, Krug R, Pietrowsky R, Fehm HL, Born J: Corticosteroid receptor mediated effects on mood in humans. Psychoneuroendocrinology 1996;21:515-523.
[PubMed]
https://doi.org/10.1016/S0306-4530(96)00011-X
29.
Hays RD, Morales LS: The RAND-36 measure of health-related quality of life. Ann Med 2001;33:350-357.
[PubMed]
https://doi.org/10.3109/07853890109002089
30.
al'Absi M, Petersen KL, Wittmers LE: Adrenocortical and hemodynamic predictors of pain perception in men and women. Pain 2002;96:197-204.
[PubMed]
https://doi.org/10.1016/S0304-3959(01)00447-X
31.
Kuehl LK, Michaux GP, Richter S, Schachinger H, Anton F: Increased basal mechanical pain sensitivity but decreased perceptual wind-up in a human model of relative hypocortisolism. Pain 2010;149:539-546.
[PubMed]
https://doi.org/10.1016/j.pain.2010.03.026
32.
Goodin BR, Smith MT, Quinn NB, King CD, McGuire L: Poor sleep quality and exaggerated salivary cortisol reactivity to the cold pressor task predict greater acute pain severity in a non-clinical sample. Biol Psychol 2012;91:36-41.
[PubMed]
https://doi.org/10.1016/j.biopsycho.2012.02.020
33.
Crettaz B, Marziniak M, Willeke P, Young P, Hellhammer D, Stumpf A, Burgmer M: Stress-induced allodynia - evidence of increased pain sensitivity in healthy humans and patients with chronic pain after experimentally induced psychosocial stress. PLoS One 2013;8:e69460.
[PubMed]
https://doi.org/10.1371/journal.pone.0069460
34.
Choi JC, Chung MI, Lee YD: Modulation of pain sensation by stress-related testosterone and cortisol. Anaesthesia 2012;67:1146-1151.
[PubMed]
https://doi.org/10.1111/j.1365-2044.2012.07267.x
35.
Wingenfeld K, Wolf S, Kunz M, Krieg JC, Lautenbacher S: No effects of hydrocortisone and dexamethasone on pain sensitivity in healthy individuals. Eur J Pain 2015;19:834-841.
[PubMed]
https://doi.org/10.1002/ejp.610
36.
Yehuda R, Seckl J: Minireview: Stress-related psychiatric disorders with low cortisol levels: a metabolic hypothesis. Endocrinology 2011;152:4496-4503.
[PubMed]
https://doi.org/10.1210/en.2011-1218
37.
Jezova D, Vigas M, Hlavacova N, Kukumberg P: Attenuated neuroendocrine response to hypoglycemic stress in patients with panic disorder. Neuroendocrinology 2010;92:112-119.
[PubMed]
https://doi.org/10.1159/000283560
38.
Tak LM, Cleare AJ, Ormel J, Manoharan A, Kok IC, Wessely S, Rosmalen JG: Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders. Biol Psychol 2011;87:183-194.
[PubMed]
https://doi.org/10.1016/j.biopsycho.2011.02.002
39.
Manenschijn L, van den Akker EL, Lamberts SW, van Rossum EF: Clinical features associated with glucocorticoid receptor polymorphisms. An overview. Ann NY Acad Sci 2009;1179:179-198.
[PubMed]
https://doi.org/10.1111/j.1749-6632.2009.05013.x
40.
Zelissen PM: Effect of glucocorticoid replacement therapy on bone mineral density in patients with Addison disease. Ann Intern Med 1994;120:207-210.
[PubMed]
https://doi.org/10.7326/0003-4819-120-3-199402010-00005
41.
Ragnarsson O, Nystrom HF, Johannsson G: Glucocorticoid replacement therapy is independently associated with reduced bone mineral density in women with hypopituitarism. Clin Endocrinol (Oxf) 2012;76:246-252.
[PubMed]
https://doi.org/10.1111/j.1365-2265.2011.04174.x
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