Hydrocortisone dose in adrenal insufficiency:Balancing harms and benefits

Patients with secondary adrenal insufficiency do not produce cortisol and are therefore treated with hydrocortisone tablets. The optimal substitution dose for hydrocortisone is unknown. We therefore performed this study, in which two different doses of hydrocortisone and its effect on cognition (observing, remembering, thinking), quality of life and blood pressure were studied. We further looked at how fast hydrocortisone was removed from the body. Patients received both a lower dose of hydrocortisone and the double amount of it, adjusted to body weight. Both doses were administered for 10 weeks and the order of the doses was random. Total daily doses were divided in three daily administrations. The most important findings of our study were that quality of life improved after treatment with the higher dose of hydrocortisone. Patients reported less symptoms of depression, less fatigue, more vitality and a better general health. They also reported less pain. Cognitive functioning (such as memory, attention and problem solving skills) was not influenced after 10 weeks of treatment with the higher dose of hydrocortisone. Blood pressure did increase after 10 weeks of treatment with the higher dose, but fats in blood such as cholesterol, did not change. Striking was the large difference in the way in which hydrocortisone was removed from the body between patients, which could differ up to 10-fold. This suggests that for some patients, thrice daily dosing is not enough to establish the correct blood level of hydrocortisone

Higher hydrocortisone dose increases bilirubin in hypopituitary patients- Results from an RCT

Background Bilirubin has anti-oxidative and anti-inflammatory properties, which may explain its proposed protective effects on the development of cardiometabolic disorders. Glucocorticoids affect heme oxygenase regulation in vitro, which plays a key role in bilirubin production. Effects of variations in glucocorticoid exposure on circulating bilirubin levels in humans are unknown. Here we tested whether a higher hydrocortisone replacement dose affects circulating bilirubin in hypopituitary patients. Materials and methods A randomized double-blind cross-over study (ClinicalTrials.gov, number NCT01546992) was performed in 47 patients with secondary adrenal failure [10-week exposure to a higher hydrocortisone dose (0.4-0.6 mg/kg body weight) vs. 10 weeks of a lower hydrocortisone dose (0.2-0.3 mg/kg body weight)]. Results Plasma total bilirubin was increased by 10% from 7 to 8 mu M in response to the higher hydrocortisone dose (P = 0.033). This effect was inversely related to age (P = 0.042), but was unaffected by sex, obesity and (replacement for) other hormonal insufficiencies. The higher hydrocortisone dose also resulted in lower alkaline phosphatase (P = 0.006) and aspartate aminotransferase activities (P = 0.001). Conclusion Bilirubin is modestly increased in response to higher glucocorticoid exposure in humans, in conjunction with lower alkaline phosphatase and aspartate aminotransferase activities, which are supposed to represent biomarkers of a pro-inflammatory state and enhanced liver fat accumulation

Somatosensory function in patients with secondary adrenal insufficiency treated with two different doses of hydrocortisone:Results from a randomized controlled trial

Background: Low cortisol levels are associated with several functional pain syndromes. In patients with secondary adrenal insufficiency (SAI), the lack in endogenous cortisol production is substituted by the administration of oral hydrocortisone (HC). Our previous study showed that a lower dose of HC led to an increase in reported subjective pain symptoms. Whether different doses of HC substitution alter somatosensory functioning in SAI patients has not been established yet. Methods: In this randomized double blind cross-over trial, forty-six patients with SAI participated. Patients randomly received either first a lower dose (0.2-0.3 mg HC/kg body weight/ day) for 10 weeks followed by a higher dose (0.4-0.6 mg HC/kg body weight/ day) for another 10 weeks, or vice versa. After each treatment period, blood samples were drawn and somatosensory functioning was assessed by determining the mechanical detection threshold (MDT), mechanical pain threshold (MPT), mechanical pain sensitivity (MPS) and the pain pressure threshold (PPT), according to the Quantitative Sensory Testing (QST) battery by the German Network on Neuropathic Pain. Results: The administration of the higher dose of HC resulted in significantly higher levels of cortisol (mean [SD] 748 [245] nmol/L) than the lower dose (537 [250] nmol/L, P Conclusions: The results suggest that the dose of HC has no impact on somatosensory functioning in response to mechanical stimuli in patients with SAI, despite previously found altered subjective pain reports

The Role of Cortisol in the Association Between Perceived Stress and Pain: stress and pain: A short report on secondary adrenal insufficiency patients

Background: Given the pain-dampening effect of cortisol, low cortisol levels have often been proposed to mediate the association between perceived stress and pain. However, studying causal effects is difficult given the complex interplay between perceived stress, cortisol release and pain levels in people with an intact hypothalamic-pituitary-adrenal axis. In the current study, we approached this problem by examining the association between perceived stress and pain levels in patients with secondary adrenal insufficiency (SAI) who were successively supplemented by lower and higher doses of hydrocortisone in a double-blinded cross-over design. Methods: Forty-seven patients with SAI (29 males, 18 females; mean [SD] age, 51 [14] years, range 19-73) participated in an RCT. Patients randomly received low doses of hydrocortisone (0.2-0.3 mg/kg body weight/day) during 10 weeks fol-lowed by high doses (0.4-0.6 mg/kg body weight/day) for another 10 weeks, or vice versa. Patients filled out a daily diary on perceived stress (GAD-7) and pain levels (PHQ-15) throughout the RCT. Non-seasonal autoregressive moving average (ARMA) modeling was performed to test associations between daily perceived stress levels and daily pain levels during low and high hydrocortisone dose. Results: Out of 47 study patients, twelve patients showed high enough fluctuations in perceived stress and pain levels (MSSD>0.01) to study their associations during intake of two different hydrocortisone doses. Six patients showed associa-tions between perceived stress and pain during both hydrocortisone doses, one showed this association only under the low dose, and two only under the high dose. Conclusion: This study does not suggest a role for lower cortisol levels in the association between perceived stress and pain

Hydrocortisone Affects Fatigue and Physical Functioning Through Metabolism of Tryptophan:A Randomized Controlled Trial

Context: Hydrocortisone (HC) treatment influences health-related quality of life (HRQOL) in secondary adrenal insufficiency (AI). Glucocorticoids regulate tryptophan metabolism through the kynurenine pathway which modulates mood and energy homeostasis. Objective: This study investigated whether tryptophan metabolism mediated the effect of HC dose on HRQOL in patients with secondary AI. Design, Setting and Patients: Forty-seven patients with secondary AI participated in this double-blind randomized controlled cross-over trial in the University Medical Center Groningen. Intervention: Patients were treated for two 10-week periods with a daily HC dose of 0.2 - 0.3 mg and 0.4 - 0.6 mg/kg body weight, respectively. Main outcome measures: Diary data and questionnaires were used to assess HRQOL. Tryptophan, kynurenine and 3-hydroxykynurenine were measured in serum and dialyzed plasma and the kynurenine to tryptophan (kyn/trp) ratio was calculated. Results: A higher dose HC was associated with increased levels of tryptophan (95% CI for mean difference 0.37 to 12.5, p= .038), reduced levels of kynurenine (95% CI -0.49 to -0.10, p= .004) and 3-hydroxykynurenine (95% CI -10.6 to -2.35, p= .003) and a reduced kyn/trp ratio (95% CI -0.84 to -0.50, p < .001). The kyn/trp ratio mediated the effect of a higher dose HC on fatigue (p = .041) and physical functioning (p = .005). Conclusion: Metabolism of tryptophan through the kynurenine pathway is reduced after a 10-week treatment with a higher dose HC and plays a role in the effect of HC on fatigue and physical functioning in patients with secondary AI

Downregulation of cholesteryl ester transfer protein by glucocorticoids:A randomised study on HDL

Background: High density lipoprotein (HDL) cholesterol is not decreased in hypercortisolism despite high triglycerides, which may be ascribed to effects on the cholesteryl ester transfer protein (CETP) pathway. We explored if CETP mRNA expression is modulated by glucocorticoid treatment in vitro. Effects of doubling the hydrocortisone (HCT) replacement dose on plasma CETP activity, and HDL characteristics were tested in patients with secondary adrenal insufficiency. Materials and methods: Human THP-1 macrophages were incubated with corticosterone in vitro in the presence or absence of a liver X receptor (LXR) agonist, followed by determination of CETP mRNA levels by quantitative real-time PCR. In addition, a randomised double-blind cross-over study was performed in 47 patients with secondary adrenal insufficiency (university medical setting; 10 weeks exposure to a higher HCT dose (0.4-0.6 mg/kg body weight) vs. 10 weeks of a lower HCT dose (0.2-0.3 mg/kg body weight). Results: Corticosterone dose dependently decreased CETP mRNA in THP-1 macrophages. Corticosterone also decreased CETP mRNA expression after LXR pretreatment. In patients, CETP activity decreased with doubling of the HCT dose (P = 0.049), coinciding with an increase in HDL cholesterol, apolipoprotein A-I and the HDL cholesterol/apolipoprotein A-I ratio (reflecting HDL size; P <0.01 for each). The increase in the HDL cholesterol/apolipoprotein A-I ratio was correlated with the decrease in plasma CETP activity (r = -0.442, P = 0.002). Conclusion: Glucocorticoids downregulate CETP gene expression in a human macrophage cell system. In line, a higher glucocorticoid replacement dose decreases plasma CETP activity in patients, thereby contributing to higher HDL cholesterol and an increase in estimated HDL size