Çocukluk Çağında Farmakolojik Dozda Glukokortikoid Kullanımına Bağlı Adrenal Baskılanma ve Buna Etkiyen Unsurların İncelenmesi

Abstract

Glucocorticoids (GCs) are hormones produced in the zona fasiculata region of the adrenal cortex, and have been widely used in the treatment of various diseases since the discovery of their anti-inflammatory properties. One of the most important and life-threatening side effects of GC treatment is adrenal insufficiency. Exogenous GCs inhibit the production of endogenous GCs by creating negative feedback suppression on the hypothalamus-pituitary-adrenal (HPA) axis. In this study, we aimed to identify the factors that influence the recovery time of the HPA axis by comparing the characteristics of patients and systemic GC treatments administered for different reasons. In this retrospective study, we included patients who received pharmacological doses of GC treatment and were referred to the Pediatric Endocrinology Department of Hacettepe University Faculty of Medicine Children's Hospital for adrenal insufficiency related to GCs between January 2017 and December 2020. The diagnoses, age at the onset of treatment, anthropometric measurements at the onset of treatment, type and duration of GC treatment, cumulative and average daily doses, and the presence of Cushingoid features on physical examination were analyzed for the included patients. Of the 186 patients included in the study, 99 (55.5%) were male and 87 (45.5%) were female. Of the patients, 19 (17 with ALL, one with a hematological disease, and one with a respiratory failure diagnosis) received GC treatment at three different times, thus total of 207 cases were included in the study. The median age of the cases was 6.8 years. Of the 207 cases included in the study, 168 (81%) received MPZ/PDZ treatment and 39 (19%) received DXM treatment. The median duration of GC treatment was 52 days, the median daily GC dose was 94 mg/m2 HC equivalent, and the median duration of HPA axis suppression was 95 days. In our study, the recovery of the HPA axis took longer in cases with a longer duration of treatment, but this relationship was weak (p=0.051; r=0.194). However, no statistically significant difference was found between the median cumulative GC treatment doses of the cases with the earliest and latest recovery of the HPA axis (5420 and 6800 mg/m2, respectively; p=0.112). Although cumulative dose is a parameter directly related to the duration of treatment, our findings suggest that the dose of pharmacological GC use does not affect the recovery time of the HPA axis as much as duration. In our study, we also compared cases using MPZ/PDZ and DXM treatment for less than two months to evaluate the effect of GC types on the suppression of the HPA axis. There was no significant difference in the recovery time of the HPA axis between the two groups using GC for similar treatment duration, although basal cortisol levels were lower in the DXM group (p=0.483). In 25 ALL patients, cases that used PDZ in Protocol 1 and DXM in Protocol 2 were compared. Despite the shorter treatment duration in the DXM protocol compared to the PDZ protocol (median 31 and 37 days, respectively; p<0.001), the recovery time of the HPA axis after DXM was longer (p=0.005). Seven cases that used 5 mg/kg/day of fluconazole for periods of 6-15 days during PDZ treatment in Protocol 1 or maintenance HC treatment after PDZ were compared to 22 cases that received the same protocol but did not use fluconazole and it was found that the recovery time of the HPA axis in cases using fluconazole was significantly longer than in those who did not use it (log rank, p=0.068). In our study, it was found that the recovery of the HPA axis in cases with Cushingoid features, that is, cases with striking systemic GC-related side effects, took longer and this difference had a small-to-medium effect size (p<0.001; r=0.235). A medium-to-large negative correlation was found between basal cortisol level and the recovery time of the HPA axis (p<0.001; r=-0.410). Our results suggest that the initial basal cortisol level in cases using GC treatment may be a predictive parameter for the recovery time of the HPA axis as a first-level evaluation. In our study, a medium-level positive correlation was found between basal and peak cortisol levels during the low-dose ACTH test performed in the morning (p<0.001; r=0.36). As one of the few studies examining the recovery time of the HPA axis after GC treatment in childhood, our study contributes to the literature. Randomized, controlled, prospective studies are requiered to better understand the nature of this clinical picture and to determine the factors that influence the recovery of the HPA axis in secondary adrenal insufficiency due to glucocorticoids in childhood.