Serum Cortisol and 17-Hydroxyprogesterone Interrelation in Classic 21-Hydroxylase Deficiency: Is Current Replacement Therapy Satisfactory?

Abstract

One of the main aims in the management of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency is to achieve adequate suppression of the adrenal cortex with the smallest possible dose of glucocorticoid substitution. To evaluate the administration schedule of current replacement therapy regimens, we investigated the cortisol-17-hydroxyprogesterone interrelation in 36 patients (13 males and 23 females; median age, 12.3 yr; range, 6.1-18.8 yr) with salt-wasting congenital adrenal hyperplasia. As sufficient variation in 17-hydroxyprogesterone concentrations was required to allow analysis of the cortisol-17-hydroxyprogesterone interrelation, patients were divided into 2 groups depending on the adequacy of hypothalamic-pituitary-adrenal axis suppression. The first group consisted of 17 patients with suppressed 17-hydroxyprogesterone concentrations (group 1), and the second group consisted of 19 patients with nonsuppressed 17-hydroxyprogesterone concentrations (group 2).We determined serum cortisol and 17-hydroxyprogesterone concentrations at 20-min intervals for a total of 24 h while patients were receiving their usual replacement treatment with hydrocortisone and 9␣-fludrocortisone. We also determined the lowest dose of dexamethasone required to suppress the 0800 h serum ACTH concentrations when administered as a single dose (0.3 or 0.5 mg/m 2 ) the night before. Mean 24-h cortisol and 17-hydroxyprogesterone concentrations were 3.9 g/dl (SD ‫؍‬ 2.1) and 66.2 ng/dl (SD ‫؍‬ 92.7), respectively, in group 1 and 4.1 g/dl (SD ‫؍‬ 2.5) and 4865.7 ng/dl (SD ‫؍‬ 6951) in group 2. The 24-h 17-hydroxyprogesterone concentrations demonstrated circadian variation, with peak values observed between 0400 -0900 h. In group 2, 17-hydroxyprogesterone concentrations decreased gradually in response to the rise in cortisol concentrations during the day, but remained low during the night despite the almost undetectable cortisol concentrations between 1600 -2000 h. Mean 0800 h androstenedione concentrations correlated strongly with integrated 17-hydroxyprogesterone concentrations (r ‫؍‬ 0.81; P < 0.0001), but not with integrated cortisol concentrations. There was a significant negative correlation between cortisol and 17-hydroxyprogesterone at lag time 0 min (r ‫؍‬ ؊0.187; P < 0.0001), peaking at lag time 60 min (r ‫؍‬ ؊0.302; P < 0.0001), with cortisol leading 17-hydroxyprogesterone by these time intervals. Finally, 0800 h serum ACTH concentrations were sufficiently suppressed after a dexamethasone dose of 0.3 mg/m 2 in all but three patients. These findings indicate that in classic 21-hydroxylase deficiency, hydrocortisone should be administered during the period of increased hypothalamic-pituitary-adrenal axis activity, between 0400 -1600 h, with the biggest dose given in the morning. Blood investigations performed as part of monitoring of congenital adrenal hyperplasia patients should include androstenedione and 17-hydroxyprogesterone concentrations determined in the morning before the administration of hydrocor...

Duration of Suppression of Adrenal Steroids after Glucocorticoid Administration

“…In treated patients with CAH, a similar pattern is observed. Charmandari et al studied steroid secretory patterns in 36 treated children and adolescents with CAH [9]. They divided the 24-hour day into two periods: daytime, defined as 0400–1600, and nighttime, defined as 1600-0400.…”

“…Thus, timing of administration of the steroid relative to adrenal hormone secretion becomes a critical factor when interpreting subsequent levels. There have been limited studies of the effectiveness of hydrocortisone administration at suppressing endogenous hormone concentrations in subjects with CAH [8, 9, 19, 20]. The studies have been performed almost exclusively in individuals receiving hydrocortisone treatment, with only a few subjects receiving prednisone.…”

“…Charmandari et al [9] studied 36 prepubertal and pubertal subjects with CAH, all of whom were receiving hydrocortisone. They obtained samples at 20 minute intervals over a 24-hour time period.…”

“…This has led to different opinions regarding how best to approach the administration of hydrocortisone. As discussed above, 17OHP and androstenedione reach their highest concentrations in serum early in the morning, and some authors have recommended administering hydrocortisone in split doses with the largest share given early in the morning [9]. While this will lead to rapid suppression of the high 17OHP and androstenedione levels, it does not address the increasing concentrations of adrenal hormones that begins at about 0400.…”

An Evidence-Based Model of Multidisciplinary Care for Patients and Families Affected by Classical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

“…Blood samples are obtained in the morning before the first medication dose to improve consistency of the 17-OHP measurement as this varies greatly with respect to time of day and glucocorticoid dose [30]. We aim for levels of androstenedione, testosterone, and plasma renin activity to be in the normal range for prepubertal children, whereas modest elevations of 17-OHP are accepted.…”