Differential effects of hydrocortisone, prednisone, and dexamethasone on hormonal and pharmacokinetic profiles: a pilot study in children with congenital adrenal hyperplasia

This pilot study compared the hormonal effects and pharmacokinetic profiles of HC, PDN, and DEX in nine prepubertal children with classic CAH. We used a potency conversion between HC to PDN to DEX of 1 to 5 to 50. However, our data demonstrate that DEX was more potent than both HC and PDN as children on the DEX arm had significantly lower adrenal hormone levels compared to those on either HC or PDN. Although glucocorticoid equivalencies are debatable, our findings are in line with other studies suggesting that DEX is at least 70 times [3] and up to 80 to 100 times or more [7–9] potent than HC in regards to suppressing adrenal androgen production. Unlike for DEX, we did not find any difference in ACTH or androstenedione concentrations during treatment with HC and PDN. In contrast, 17-OHP values were significantly higher when children were receiving PDN than when they were treated with HC. This suggests that PDN may be ??5 fold more potent than HC and conflicts with other reports suggesting that PDN is 10 to 15 times more potent than HC [9, 10]. It is important to note that these findings may not reflect what is seen with prednisolone, which is the active metabolite of PDN.

Laboratory monitoring during glucocorticoid therapy in children with CAH is difficult since hormone concentrations can vary widely depending on the time of day and most recent glucocorticoid dose [11]. By measuring frequent hormone levels during each inpatient stay, we were able to characterize the degree of hormone variability. In particular, there were wide fluctuations in 17-OHP levels within individual subjects demonstrating that a single 17-OHP measurement is problematic in terms of reflecting the degree of biochemical control. This marked variability in 17-OHP has been attributed to circadian patterns [12, 13] and exaggerated responses to stress [14, 15]. Androstenedione also has a circadian rhythm but the magnitude of variability is less than that seen with 17-OHP [16] and levels often correlate better with overall CAH control [17]. Although not routinely used in the management of CAH, ACTH levels have been shown to be a useful adjunct [18], and as seen in our study, often correlate with other hormone markers of biochemical control.

Nightly dosing of DEX can lead to overtreatment with greater suppression of early morning adrenal steroid concentrations [19, 20]. All but one of our subjects had an undetectable trough DEX level, but many of our subjects on DEX had low 17-OHP and androstenedione levels. This implies that trough DEX levels do not accurately reflect the biological effect at a tissue or cellular level. Despite disparities in adrenal steroids, there was no difference in GH, IGF-1, or BMI during treatment with the three glucocorticoids. However, given the short duration of our study, any presumption regarding the implication of this observation on long-term growth would be premature.

Very few studies, also with small sample sizes, have compared different glucocorticoids in either children or adults with CAH [7, 20–22], and ours is the only one to compare three different preparations in a prepubertal cohort. While overall results have been conflicting, other investigators have also noted a greater degree of suppression than expected with DEX [7], as was the case in our study. In our study, significant correlations were found between ABCB1, NR3C1, IPO13 and GLCCI1 genotypes and hormone concentrations and/or clearance. While such findings could be spurious, it is intuitive that differences in glucocorticoid-related genes could impact individual physiologic responses. The ABCB1 gene encodes for P-glycoprotein, which is a transmembrane transporter that acts as a cellular drug efflux pump for various substances, including glucocorticoids [23]. Clinical response to glucocorticoids has been shown to be influenced by individual SNPs as well as haplotypes in ABCB1 [24, 25]. For example, polymorphisms in ABCB1 have been associated with steroid resistance in children with nephrotic syndrome [26, 27] and steroid response in those with inflammatory bowel disease [28, 29]. In our study, subjects with specific ABCB1 genetic variants were found to metabolize and clear cortisol faster when on HC. Polymorphisms in ABCB1 and other relevant genes might explain why some patients with CAH require unexpectedly low or high doses of glucocorticoids to achieve optimal biochemical control, and preemptive genetic testing may facilitate selection of a more appropriate starting dose for individual patients. Furthermore, experimental regimens and novel medical therapies currently under investigation may eventually make a one glucocorticoid approach obsolete in the treatment of CAH.

The NR3C1 gene encodes for the glucocorticoid receptor (GR). Other research has shown that individuals with the BclI (rs41423247) polymorphism have increased sensitivity and responsiveness to glucocorticoids [30, 31]. This SNP has also been associated with increased BMI, hypertension, and cardiovascular disease in the general population [32]. Adults with CAH who possess the BclI polymorphism have also been found to have a higher BMI, waist circumference, and systolic blood pressure [33] but this has not been found in children [34]. We did not evaluate for correlations with BMI in our subjects with this SNP given the small size of our population. However, we did find significant associations between the rs41423247 variant and androstenedione concentrations when subjects were on PDN.

Subjects in our study with genetic variants in IPO13 and GLCCI1 had variable exposure to glucocorticoids when on PDN. Both IPO13 and GLCCI1 genotypes are associated with glucocorticoid exposure in children on PDN [35, 36]. IPO13 regulates the nuclear translocation of the GR. Polymorphisms of IPO13 have been associated with airway hyper-responsiveness and reactivity in children with asthma, suggesting that IPO13 variation might improve endogenous glucocorticoid bioavailability in the cell nucleus [35]. The function of GLCCI1 is not well understood. SNPs in GLCCI1 in patients with asthma have been associated with a decreased response to inhaled glucocorticoids [36]. However, differences in gene variants of GLCCI1 have not been shown to be significant in other diseases, such as steroid resistant nephrotic syndrome [37].

Limitations of our pilot study include the small sample size, lack of a washout period, previous treatment with different glucocorticoids, and short exposure to each glucocorticoid. Although significant pharmacogenetic correlations were detected, it is premature to draw firm conclusions about the possible functional role of these genetic variants [38]. Another limitation is that hormone levels were measured using RIA and ELISA instead of more precise techniques, such as liquid chromatography and tandem mass spectrometry; however, this is similar to the clinical setting. Finally, we acknowledge that the potency conversion used in our study is open to debate. Determining equivalent glucocorticoid dosing is complex, varies between individuals and can be based on anti-inflammatory effect, growth-retarding effect, and/or androgen-suppressive effect. For example, while DEX may be up to 80 times more potent than cortisol for growth-retarding effect, it appears to be only 30 times more potent than cortisol in regards to anti-inflammatory effect [39]. While extremely preliminary, our findings are intriguing and warrant replication in a larger population to see if there is a true differential versus a dose or equivalency-related effect.