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London Centre for Paediatric Endocrinology, University College London (E.C., P.C.H., C.G.D.B.) and Department of Clinical Pharmacology, St. Bartholomew’s, and The Royal London School of Medicine and Dentistry (A.J.), London, United Kingdom W1N 8AA
Address all correspondence and requests for reprints to: Evangelia Charmandari, M.D., National Institute of Child Health and Human Development, National Institutes of Health, Pediatric and Reproductive Endocrinology Branch, 10 Center Drive, Building 10, Suite 9D42, Bethesda, Maryland 20892-1583. E-mail: charmane{at}mail.nih.gov
Abstract
In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, treatment with glucocorticoid and mineralocorticoid substitution is not always satisfactory. Suboptimal control is often observed in pubertal patients, despite adequate replacement doses and adherence to treatment. We investigated whether the pubertal process is associated with alterations in cortisol pharmacokinetics resulting in a loss of control of the hypothalamic-pituitary-adrenal axis.
We determined the pharmacokinetics of hydrocortisone administered iv as
a bolus. A dose of 15 mg/m2 body surface area was given to
14 prepubertal (median age, 9.4 yr; range, 6.1–10.8 yr), 20 pubertal
(median, 13.5 yr; range, 10.6–16.8 yr), and 6 postpubertal (median,
18.2 yr; range, 17.2–20.3 yr) patients with salt-wasting CAH. All
patients were on standard replacement therapy with hydrocortisone and
9
-fludrocortisone. Serum total cortisol concentrations were measured
at 10-min intervals for 6 h following iv hydrocortisone bolus and
analyzed using a solid-phase RIA.
The serum total cortisol clearance curve was monoexponential. Mean clearance was significantly higher in the pubertal group (mean, 427.0 mL/min; SD, 133.4) compared with the prepubertal (mean, 248.7 mL/min; SD, 100.6) and postpubertal (mean, 292.4 mL/min; SD, 106.3) (one-way ANOVA, F = 9.8, P < 0.001) groups. This effect persisted after adjustment for body mass index. The mean volume of distribution was also significantly higher in the pubertal (mean, 49.5 L; SD, 12.2) than the prepubertal (mean, 27.1 L; SD, 8.4) patients but not in the postpubertal (mean, 40.8 L; SD, 16) (ANOVA, F = 15.2, P < 0.001) patients. The significance remained after correction for body mass index. There was no significant difference in mean half-life of total cortisol in prepubertal (mean, 80.2 min; SD, 19.4), pubertal (mean, 84.4 min; SD, 24.9), and postpubertal (mean, 96.7 min; SD, 9.9) patients. Similar differences between groups were observed when the pharmacokinetic parameters of free cortisol were examined. In addition, the half-life of free cortisol was significantly shorter in females compared with males (P = 0.04).
These data suggest that puberty is associated with alterations in cortisol pharmacokinetics resulting in increased clearance and volume of distribution with no change in half-life. These alterations probably reflect changes in the endocrine milieu at puberty and may have implications for therapy of CAH and other conditions requiring cortisol substitution in the adolescent years.
CONGENITAL ADRENAL HYPERPLASIA (CAH) due to 21-hydroxylase deficiency is an autosomal recessive condition in which deletions or mutations of the cytochrome P450 21-hydroxylase gene (CYP21) cause glucocorticoid and mineralocorticoid deficiency. This leads to an excess of ACTH secretion by the anterior pituitary, adrenal hyperplasia, accumulation of steroid precursors before the enzymatic defect, and increased production of androgens for which 21 hydroxylation is not necessary (1, 2). Two main aims in the management of CAH are to provide adequate glucocorticoid and mineralocorticoid substitution to prevent adrenal crises and to suppress the abnormal secretion of androgens and androgen precursors from the adrenal cortex. Achieving and maintaining adrenal suppression is far more challenging than preventing adrenal crises and, in many patients, it is impossible to control hyperandrogenism without using supraphysiologic doses of glucocorticoids leading to an undesirable degree of hypercortisolism (1, 2, 3). Suboptimal control is observed more often in pubertal patients than prepubertal or adult patients, despite adequate replacement therapy and adherence to treatment. The result is hirsutism, impaired growth and fertility, and the risk of addisonian crisis.
The aim of this study was to investigate whether the pubertal process is associated with an alteration in cortisol pharmacokinetics resulting in a loss of control of the hypothalamic-pituitary-adrenal (HPA) axis and a significant increase in the concentrations of androgens and androgen precursors.
Subjects and Methods
Patients
Forty patients (14 males and 26 females; age range, 6.1–20.3
yr) attending the London Centre for Paediatric Endocrinology were
studied prospectively. Patients were consecutive attendees at the
Outpatient Clinics and consisted of 14 prepubertal children
(male/female, 5/9; median age, 9.4 yr; age range, 6.1–11.0 yr) (Tanner
stage I), 20 pubertal (male/female, 7/13; median age, 13.5 yr; age
range, 10.6–16.8 yr) (Tanner stage III-V), and 6 postpubertal
(male/female, 2/4; median age, 18.2 yr; age range, 17.2–20.3 yr)
patients. Each group of patients was further subdivided into adequately
and inadequately controlled depending on the suppression of HPA axis as
defined by the 0800 h ACTH concentrations (ACTH <71 pg/mL)
and/or serial measurements of 17-hydroxyprogesterone (17OHP)
concentrations (17OHP <6.6 ng/mL) determined 1 day before the study.
The clinical characteristics of all CYP21-deficient patients are
summarized in Table 1
.
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-fludrocortisone given once
daily. Table 1
details daily hydrocortisone and 9-fludrocortisone
replacement doses in the prepubertal, pubertal, and postpubertal
groups. Patients were excluded from the study if there was evidence of
central precocious puberty or other associated endocrine disorder. No
patient had clinical or biochemical evidence of hepatic or renal
disease, and none was taking drugs known to alter corticosteroid
binding globulin concentrations (CBG) or to induce mixed function
oxidase enzymes. The study was approved by the University College London Hospitals Committee on the Ethics of Human Research, and informed written consent was obtained in all cases.
Methods
Patients were admitted to the Endocrine Unit 1 day before the investigations and a complete physical examination, including Tanner pubertal staging (4, 5) and anthropometry, was performed by the same observer. Skeletal maturity was estimated according to the Tanner and Whitehouse method (6). Baseline investigations, including serum CBG, ACTH, 17OHP, androgens, insulin-like growth factor (IGF)-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) concentrations, were obtained on this day at 0800 h. Two indwelling venous catheters, one for the iv administration of hydrocortisone and the other for blood sampling, were inserted at least 12 h before sampling to allow a period of adaptation. Urine steroid profile analysis was also performed on 24-h urine collections, while patients were receiving their usual replacement therapy.
On the day of the study, patients were given their usual dose of mineralocorticoid substitution at 0800 h, and 1 h later iv hydrocortisone sodium succinate was administered as a bolus in a dose of 15 mg/m2 body surface area through the first cannula. Blood samples for cortisol concentrations were collected through the second cannula at 10-min intervals for a total of 6 h following the injection of hydrocortisone. Blood samples were spun, separated, and stored at -20 C before assay.
Assays
Total cortisol. Serum total cortisol was measured using the Coat-A-Count RIA (Coat-A-Count, DPC, Los Angeles, CA). This is a solid-phase RIA with a sensitivity of 0.2 µg/dL. The within-assay coefficients of variation (CV) were 5.7% and 2.6% at serum concentrations of 1.0 µg/dL and 20.0 µg/dL, respectively, and the between-assay CV were 6.3% and 4.5% at serum concentrations of 5.0 µg/dL and 10.0 µg/dL, respectively.
CBG. CBG was assayed with the CBG-RIA-100 Diagnostic kit (Biosource Technologies, Inc., Nivelles, Belgium). The minimum detectable concentration of transcortin (CBG) was 0.25 µg/mL. The within-assay CV were 7.7% and 3.3% at serum concentrations of 33.1 µg/mL and 109.4 µg/mL, respectively. The between-assay CV were 5.0% and 4.5% at serum concentrations of 31.9 and 105.0 µg/mL, respectively.
Free cortisol. Free cortisol was calculated according to Biosource Technologies, Inc. protocol using the following formula: U = (Z2 + 0.0122C)1/2 - Z µM, where Z = 1/2K + (T - C)/2(1 + N) = 0.0167 + 0.182(T - C) µM. In this equation, U represents the molar concentration of unbound cortisol, C the molar concentration of total cortisol, and T the concentration of CBG. K corresponds to the affinity of transcortin for cortisol at 37 C, and N to the proportion of albumin bound to non-CBG bound cortisol.
IGF-I. IGF-I concentrations were measured using an immunoradiometric assay (IGF-I IRMA; Nichols Institute Diagnostics, San Juan Capistrano, CA) with a sensitivity of 6 ng/mL, intraassay variations of 4.6% and 4.1% at serum concentrations of 61.0 ng/mL and 547.9 ng/mL, respectively, and interassay variations of 15.8% and 9.3% at serum concentrations of 60.1 ng/mL and 594.3 ng/mL, respectively.
IGF-II. IGF-II concentrations were determined using an IRMA (DSL-2600 ACTIVE IGF-II IRMA kit; Diagnostics Systems Laboratories, Inc. Webster, TX) with a sensitivity of 12 ng/mL. The intraassay CV were 6.5% and 4.7% at serum concentrations of 245 ng/mL and 1432 ng/mL, respectively. The interassay CV were 5.3% and 4.5% at serum concentrations of 245 ng/mL and 1383 ng/mL, respectively.
IGFBP-3. IGFBP-3 was measured using an IRMA (DSL-6600 ACTIVE IGFBP-3 IRMA kit; Diagnostics Systems Laboratories, Inc.) with a sensitivity of 0.5 ng/mL, intraassay CV of 3.9% and 1.8% at serum concentrations of 7.35 ng/mL and 82.72 ng/mL, respectively, and interassay CV of 0.6% and 1.9% at 8.04 ng/mL and 76.90 ng/mL, respectively.
Urine steroid profile analysis. Urine steroid profile
analysis was performed by gas chromatography and mass spectrometry as
described previously (7). Steroid metabolites measured
included androsterone, aetiocholanolone, 17-hydroxypegnanolone,
tetrahydrocortisol (THF), allo-THF, -cortol, tetrahydrocortisone
(THE), -cortolone, and ß-cortol + ß-cortolone.
Pharmacokinetics
The pharmacokinetic parameters of total and free cortisol examined included clearance, volume of distribution, and half-life. Clearance (CL) and volume of distribution (V) are the two primary pharmacokinetic parameters in terms of fundamental physiological processes, whereas the half-life is a composite parameter derived from the clearance and volume of distribution.
Clearance was calculated following estimation of the area under the drug concentration vs. time curve (AUC) from time (t) 0 min to infinite time (inf.) as follows: CL = dose (iv)/AUC0-inf. (8, 9). The elimination rate constant (k) was calculated from the slope of the regression line of the log transformed cortisol data vs. time. The volume of distribution was estimated by dividing cortisol clearance by the elimination rate constant: V = CL/k (10). Finally, half-life (t1/2) was estimated by dividing 0.693 (loge2) by the elimination rate constant: t1/2 = 0.693/k (11). Half-life is a composite pharmacokinetic parameter determined by both clearance and volume of distribution (t1/2 = 0.693 x V/CL) and, therefore, it is increased by an increase in volume of distribution or a decrease in clearance and vice versa.
Statistical analysis
All data were natural log (loge) transformed before statistical analysis. Clearance, volume of distribution, and half-life of total and free cortisol were estimated as described above. One-way ANOVA with the Student’s-Newman-Keuls post hoc test were used to compare the mean clearance, volume of distribution, and half-life in the three groups of patients. Student’s t test was used for comparisons between adequately and inadequately controlled prepubertal and pubertal patients as well as for comparisons between males and females.
Results
Initial analysis included all three groups of CYP21-deficient
patients and was followed by comparisons between adequately controlled
prepubertal and pubertal patients. The pharmacokinetic parameters of
total and free cortisol in all patients are summarized in Table 2.
|
All CYP21-deficient patients. The serum total cortisol
clearance curve was monoexponential (Fig. 1, A and C). A maximum serum total
cortisol concentration of 98.0 µg/dL was achieved at a maximum time
of 10 min. Mean peak total cortisol concentration was 67.0 µg/dL
(SD, 21.5). The mean clearance of total cortisol was 248.7
mL/min (SD, 100.6) in the prepubertal, 427.0 mL/min
(SD, 133.4) in the pubertal, and 292.4 mL/min
(SD, 106.3) in the postpubertal patients. Mean total
cortisol clearance was significantly higher in the pubertal group
compared with the prepubertal and postpubertal groups (one-way ANOVA,
F = 9.8, P < 0.001; Student’s-Newman-Keuls,
P < 0.05) but there was no significant difference
between prepubertal and postpubertal groups (Fig. 2A). Similarly, mean total cortisol
clearance corrected for body mass index (BMI) was higher in the
pubertal than the prepubertal and postpubertal patients (ANOVA, F
= 5.0, P = 0.012; Student’s-Newman-Keuls,
P < 0.05) with no significant difference between
prepubertal and postpubertal groups.
|
|
). The mean
volume of distribution in the pubertal patients was significantly
greater than the mean volume of distribution in the prepubertal
patients (ANOVA, F = 15.2, P < 0.001;
Student’s-Newman-Keuls, P < 0.05), whereas comparison
between prepubertal and postpubertal as well as pubertal and
postpubertal groups did not reach statistical significance. Similar
observations were made when the mean volume of distribution was
corrected for BMI (ANOVA, F = 7.0, P = 0.003;
Student’s-Newman-Keuls, P < 0.05).
The mean total cortisol half-life was 80.2 min (SD, 19.4)
in the prepubertal group of patients, 84.5 min (SD, 24.9)
in the pubertal and 96.7 min (SD, 10.0) in the postpubertal
group. Comparison between groups showed no significant difference
in total cortisol half-life (ANOVA, F = 1.2, P =
0.3) (Fig. 2C).
Effect of control on total cortisol pharmacokinetics. There was no significant difference in mean serum total cortisol clearance, volume of distribution, and half-life between adequately and inadequately controlled prepubertal or pubertal patients. This effect persisted even when cortisol clearance and volume of distribution were corrected for BMI.
Effect of sex on total cortisol pharmacokinetics. When all patients were considered, no significant difference in total cortisol clearance between males (mean, 386.5 mL/min; SD, 138.5) and females (mean, 321.8 mL/min; SD, 28.3) was noted. However, when corrected for BMI, cortisol clearance was higher in males than females [males (mean, 16.8 mL/m2 per kilogram per min; SD, 5.0); females (mean, 13.2 mL/m2 per kilogram per min; SD, 5.1)] (P = 0.04). Similarly, although there was no significant difference in the volume of distribution between males (mean, 45.7 L; SD, 3.9) and females (mean, 37.5 L; SD, 15.2), when adjusted for BMI, the volume of distribution was found to be greater in males than females [males, (mean, 2.0 L/m2·kg; SD, 0.5); females (mean, 1.5 L/m2·kg; SD, 0.4)] (P = 0.01). There was no difference in the half-life of total cortisol between males (mean, 84.9 min; SD, 25.8) and females (mean, 84.7 min; SD, 19.6).
Comparison of the pharmacokinetic parameters of total cortisol between sexes in each separate group of patients (prepubertal, pubertal, and postpubertal) revealed no significant difference in clearance, volume of distribution, and half-life.
Adequately controlled patients. To exclude a possible effect of ACTH on cortisol metabolic clearance rate, data were analyzed including the adequately controlled patients only. The postpubertal patients have been excluded from subsequent analysis because of the small sample size.
The mean total cortisol clearance was 232.9 mL/min (SD, 99.5) in the prepubertal and 409.3 mL/min (SD, 122.5) in the pubertal adequately controlled patients (P = 0.002). Total cortisol clearance corrected for BMI was also significantly higher in the pubertal group (P < 0.05). The mean volume of distribution was 25.1 L (SD, 7.3) in prepubertal patients and 49.2 L (SD, 11.6) in pubertal patients (P < 0.001), and the significance remained after correction for BMI (P = 0.004). There was no difference in the mean half-life of total cortisol between prepubertal (mean, 80.6 min; SD, 22.0) and pubertal (mean, 86.3 min; SD, 22.1) patients.
Pharmacokinetics of free cortisol
All CYP21-deficient patients. The free cortisol clearance
curve was also monoexponential (Fig. 1, B and C). Mean peak free
cortisol concentration was 13.8 µg/dL (SD, 7.5). The mean
clearance of free cortisol was significantly higher in the pubertal
patients (mean, 4787.7 mL/min; SD, 2386.8) compared with
the prepubertal (mean, 2477.4; SD, 988.6) and postpubertal
(mean, 3001.8; SD, 1090.4) patients (one-way ANOVA,
F = 6.9, P = 0.003; Student’s-Newman-Keuls,
P < 0.05). Free cortisol clearance corrected for BMI
was higher in the pubertal than the prepubertal but not than the
postpubertal group (ANOVA, F = 4.2, P = 0.023;
SKN, P < 0.05).
The mean volume of distribution was significantly greater in the pubertal patients (mean, 540.7 L; SD, 493.3) than the prepubertal (mean, 237.0 L; SD, 95.3) but not than the postpubertal (mean, 276.6 L; SD, 116.4) patients (ANOVA, F = 3.3, P = 0.048; Student’s-Newman-Keuls, P < 0.05). However, when the volume of distribution was corrected for BMI, comparison between groups did not reach statistical significance (ANOVA, F = 3.0, P = 0.06).
Finally, the half-life of free cortisol was 67.2 min (SD, 9.4) in the prepubertal, 77.1 min (SD, 44.4) in the pubertal, and 62.5 min (SD, 6.6) in the postpubertal patients. Comparison between groups suggested no significant difference in half-life (ANOVA, F = 0.6, P = 0.52).
Effect of control on free cortisol pharmacokinetics. The mean clearance and volume of distribution of free cortisol did not differ between adequately and inadequately controlled prepubertal or pubertal patients, even when corrected for BMI. No significant difference was noted in half-life of free cortisol between adequately and inadequately controlled patients.
Effect of sex on free cortisol pharmacokinetics. When all
patients were considered, free cortisol clearance did not differ
significantly between males (mean, 4148.8 mL/min; SD,
1676.6) and females (mean, 3475.6 mL/min; SD, 2312.9), even
when corrected for BMI. The volume of distribution of free cortisol was
also not different between male (mean, 550.1 L; SD, 567.2)
and female (mean, 311.1 L; SD, 196.5) patients. However,
when adjusted for BMI, the volume of distribution was higher in males
than females [males (mean, 22.6 L/m2·kg;
SD, 19.8); females (mean, 13.0
L/m2·kg; SD, 8.0)]
(P = 0.02). The half-life of free cortisol was
significantly shorter in females (mean, 64.0 min;
SD, 15.1) than males (mean, 85.3 min;
SD, 48.3) (P = 0.04) (Fig. 3).
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Adequately controlled patients. In adequately controlled patients the mean free cortisol clearance was significantly higher in the pubertal (mean, 4832.7 mL/min; SD, 1638.7) compared with the prepubertal (mean, 2405.5 mL/min; SD, 1039.8) group (P = 0.001) and the difference persisted after correction for BMI [prepubertal (mean, 123.2 mL/m2 per kilogram per min; SD, 52.7); pubertal (mean, 201.6 mL/m2 per kilogram per min; SD, 90.4)] (P < 0.02). The mean volume of distribution was also higher in the pubertal (mean, 414.2 L; SD, 110.1) than the prepubertal patients (mean, 238.3 L; SD, 107.0) (P = 0.002), but not so when corrected for BMI. No significant difference in the mean half-life of free cortisol in prepubertal (mean, 69.1 min; SD, 10.0) and pubertal (mean, 61.0 min; SD, 9.9) patients was noted.
Biochemical parameters
The biochemical parameters determined in the 40 CYP21-deficient
patients are shown in Table 2. IGF-I concentrations were significantly
higher in the pubertal (mean, 371.1 ng/mL; SD, 104.6) than
the prepubertal (mean, 227.3 ng/mL; SD, 95.2) and
postpubertal (mean, 250.6 ng/mL; SD, 73.6) patients
(one-way ANOVA, F = 12.1, P < 0.001;
Student’s-Newman-Keuls, P < 0.05). IGF-II
concentrations were significantly higher in the postpubertal group
(mean, 925.4 ng/mL; SD, 330.3) compared with the
prepubertal (mean, 648.0 ng/mL; SD, 125.9) and
pubertal (mean, 626.7 ng/mL; SD, 118.2) groups
(ANOVA, F = 6.7, P = 0.003;
Student’s-Newman-Keuls, P < 0.05). No difference in
IGFBP-3 concentrations was noted between groups. THE concentrations
were higher in the pubertal (mean, 4501.1 µg per 24 h;
SD, 2636.3) than the prepubertal (mean, 2462.1
µg per 24 h; SD, 994.6) and postpubertal
(mean, 1860.0 µg per 24 h; SD, 308.1)
patients (ANOVA, F = 4.8, P = 0.014;
Student’s-Newman-Keuls, P < 0.05). However, the (THF
plus allo-THF) to THE ratio did not differ between the three groups of
patients [prepubertal (mean, 1.0; SD, 0.3);
pubertal (mean, 0.9; SD, 0.3); postpubertal
(mean, 1.2; SD, 0.2)] (ANOVA, F = 1.5,
P = 0.2).
Discussion
These data demonstrate differences in the pharmacokinetic parameters of total and free cortisol in patients with classical 21-hydroxylase deficiency and provide evidence for a significant rise in cortisol clearance at puberty, which is associated with an increase in volume of distribution but no change in half-life.
The primary site of cortisol metabolism in humans is the liver and a
number of cytosolic and microsomal enzymes, including cytochrome P450,
5/5ß-reductase, 3/3ß-oxidoreductase, and
11ß-hydroxysteroid dehydrogenase (11ß-HSD), play an important role
in the hepatic metabolism of cortisol (12, 13, 14). The major
routes of hepatic metabolism determined from both urinary analysis and
in vitro studies involve A-ring and side-chain reduction
followed in vivo by conjugation with glucuronic acid and
sulfate (15). The inactive glucuronide and sulfate
metabolites are excreted by the kidneys, whereas only less than 1% of
cortisol is excreted unchanged in the urine. Therefore, the metabolic
clearance of cortisol is influenced primarily by factors altering
hepatic clearance and to a much lesser degree by factors affecting
renal excretion.
Changes in the endocrine milieu at puberty may affect cortisol clearance in a number of ways. Puberty results from increased secretion of sex steroids by the gonads in response to gonadotropin secretion from the anterior pituitary. Rising sex steroid concentrations are associated with increased pulse amplitude of GH secretion, resulting in increased IGF-I concentrations (16, 17). The rise in serum GH concentration is also associated with a marked decrease in insulin sensitivity and a parallel elevation in serum insulin concentrations (18, 19). At the tissue level, insulin reduces IGFBP-1 concentrations, thus further increasing the concentration of IGF-I (20, 21).
The increase in cortisol clearance observed in the pubertal patients may be explained by an alteration in 11ß-HSD activity secondary to the rise in GH and IGF-I concentrations at puberty. It is now well documented that an increase in GH and IGF-I concentrations is associated with inhibition of the activity of type 1 isoform of 11ß-HSD (11ß-HSD1), which acts predominantly as an oxo-reductase, converting inactive cortisone to active cortisol (22, 23, 24, 25). Studies in hypopituitary adults showed a significant, dose-independent, persistent decrease in the activity of 11ß-HSD1 following treatment with GH (22, 24). Similarly in acromegalic patients, withdrawal from medical therapy resulted in a significant rise in GH and IGF-I concentrations and a concomitant decrease in 11ß-HSD1 activity whereas complete removal of the pituitary tumor by transphenoidal surgery resulted in a decrease in GH concentrations and a parallel increase in 11ß-HSD1 activity (23). These findings are supported by in vitro studies, which suggest that the GH effects on 11ß-HSD1 activity are mediated by IGF-I (23) and are specific as no effect on 11ß-HSD2 activity is observed. By inhibiting 11ß-HSD1 activity, GH effectively increases the metabolic clearance rate of cortisol (23).
In addition to GH and IGF-I, there is evidence to suggest that gonadal steroids also influence 11ß-HSD1 activity. In rats, a sexually dimorphic pattern in the activity of 11ß-HSD1 (males have increased 11ß-HSD1 activity) exists (26, 27, 28, 29). Gonadectomy and estradiol treatment leads to a dramatic decrease in both 11ß-HSD1 activity and messenger RNA expression in male rat liver, whereas gonadectomy and testosterone replacement has no effect on type 1 isoform activity (26). However, gonadectomy resulted in a marked increase in 11ß-HSD1 activity in female rat liver, which was reversed by estradiol replacement therapy but not testosterone treatment (26). A similar situation may operate in man as female hypopituitary subjects receiving optimal replacement therapy have lower activity of the type 1 isoform (30, 31). This reduction was directly related to insulin sensitivity, suggesting that a fall in insulin sensitivity at puberty may be associated with a decrease in 11ß-HSD1 activity (31). Although caution must be exercised in extrapolating inferences about 11ß-HSD1 regulation from rodents to man, the above observations suggest a similar role of gonadal steroids in humans with estrogen inhibiting 11ß-HSD1 activity and, hence, increasing cortisol clearance, and testosterone exerting no effect on reductase activity.
The concept of decreased 11ß-HSD1 activity at puberty as a result of a rise in GH/IGF-I concentrations and/or gonadal steroids is supported by the fact that there was an increase in the urinary cortisone metabolites (THE) in pubertal patients compared with pre and postpubertal patients, with no concomitant rise in the (THF plus allo-THF) to THE ratio, which represents an index of the overall activity of 11ß-HSD1 (22). The decrease in 11ß-HSD1 activity in CAH patients will result in decreased conversion of cortisone to cortisol and hypocortisolaemia, which will further activate the HPA axis and potentiate increased androgen production.
Except for alterations in the activity of 11ß-HSD1, hormonal changes
at puberty may result in alterations in the activity of other enzymes
that play an important role in cortisol metabolism. The effects of
IGF-I, IGF-II, and insulin on adrenal steroidogenesis and regulation of
steroidogenic enzymes have long been recognized. In cultured human
adrenal fasciculata/reticularis cells pretreated with IGF-I or IGF-II
an increase in cytochrome P450 17-hydroxylase and 3ß-HSD messenger
RNA levels can be demonstrated (32, 33). IGF-II seems to
be more potent than IGF-I in this respect (34, 35). These
observations indicate that patients with an enzymatic defect in adrenal
steroidogenesis, such as 21-hydroxylase deficiency, will have a more
pronounced adrenal androgen production in response to the pubertal rise
in GH, IGF-I, and insulin concentrations and, therefore, will be at
increased risk for developing hyperandrogenism.
Finally, the increase in cortisol clearance observed in pubertal patients may also be due to an increase in renal clearance of cortisol secondary to an increase in glomerular filtration rate (GFR) (8, 36). GH and IGF-I both increase GFR although the action of GH is likely to be mediated by IGF-I. IGF-I seems to increase GFR via a direct effect on the glomerular vasculature and a decrease in renal glomerular afferent and efferent arteriolar resistance (37, 38).
The increase in the volume of distribution in the pubertal and postpubertal patients was probably due to the increase in body surface area in these two groups compared with the prepubertal group (10). Except for body size, the volume of distribution is also determined by the relative strength of binding of the drug to tissue components as compared with plasma proteins. Drugs that are tightly bound to plasma proteins and not to tissues have volume of distribution that is very close to blood volume. Conversely, drugs that are very tightly bound by tissues and not by plasma proteins are held mostly in the tissues and their volume of distribution is large. The dependency of volume of distribution on both plasma protein binding and body surface area is illustrated by the fact that the volume of distribution of free cortisol, which takes into consideration plasma protein binding, adjusted for BMI was not significantly different between the three groups of patients.
Despite the increase in cortisol clearance at puberty, no difference in half-life of total and free cortisol was observed between prepubertal, pubertal, and postpubertal patients. This is because the elimination of a drug from the body does not depend on clearance only. It is a function of both clearance and volume of distribution as is the half-life (8). Therefore, a concomitant rise in both cortisol clearance and volume of distribution may not result in a significant change in half-life. However, it is worth noting that the half-life of free cortisol was significantly shorter in pubertal female patients compared with pubertal male patients and resulted in a significant difference in half-life between the two sexes when all patients were considered. These observations may explain why management of female patients at puberty is often problematic and indicate a more frequent regimen than twice daily hydrocortisone replacement in pubertal female patients.
We conclude that, in patients with CAH due to 21-hydroxylase deficiency, puberty is associated with alterations in cortisol pharmacokinetics that primarily reflect alterations in the endocrine milieu. The increase in cortisol clearance is associated with an increase in volume of distribution but no change in half-life. The above observations may have implications for therapy and may indicate glucocorticoid replacement with more frequent than two or three daily doses at puberty. Further studies are required to investigate independent predictors of cortisol clearance and to examine the inter-relation between cortisol and 17OHP concentrations in these patients.
Acknowledgments
We thank Ms. Brankica Leonard for her technical support and Ms. Jane Pringle, Ms. Jane McLean, and the staff on Carousel Ward, The Middlesex Hospital (London, UK), for their support and contribution to the successful completion of this study.
Footnotes
1 E.C. was supported by Children Nationwide Medical Research Fund. 
Received August 30, 2000.
Revised January 3, 2001.
Accepted January 11, 2001.
References
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  E. CHARMANDARI and G. P CHROUSOS Metabolic Syndrome Manifestations in Classic Congenital Adrenal Hyperplasia: Do They Predispose to Atherosclerotic Cardiovascular Disease and Secondary Polycystic Ovary Syndrome? Ann. N.Y. Acad. Sci., November 1, 2006; 1083(1): 37 - 53. [Abstract] [Full Text] [PDF]
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 G. Pinto, V. Tardy, C. Trivin, C. Thalassinos, S. Lortat-Jacob, C. Nihoul-Fekete, Y. Morel, and R. Brauner Follow-Up of 68 Children with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency: Relevance of Genotype for Management J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2624 - 2633. [Abstract] [Full Text] [PDF]
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R. S. Legro, H. M. Lin, L. M. Demers, and T. Lloyd Urinary Free Cortisol Increases in Adolescent Caucasian Females during Perimenarche J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 215 - 219. [Abstract] [Full Text] [PDF]
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E. Charmandari, K. A. Calis, M. F. Keil, M. R. Mohassel, A. Remaley, and D. P. Merke Flutamide Decreases Cortisol Clearance in Patients with Congenital Adrenal Hyperplasia J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3197 - 3200. [Abstract] [Full Text] [PDF]
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E. Charmandari Author's Response: Serum Cortisol and 17-Hydroxyprogesterone Concentrations in Children with Classic Congenital Adrenal Hyperplasia J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2993 - 2993. [Full Text] [PDF]
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E. Charmandari, S. M. Pincus, D. R. Matthews, A. Johnston, C. G. D. Brook, and P. C. Hindmarsh Oral Hydrocortisone Administration in Children with Classic 21-Hydroxylase Deficiency Leads to More Synchronous Joint GH and Cortisol Secretion J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2238 - 2244. [Abstract] [Full Text] [PDF]
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 E Charmandari, C G D Brook, and P C Hindmarsh Why is management of patients with classical congenital adrenal hyperplasia more difficult at puberty? Arch. Dis. Child., April 1, 2002; 86(4): 266 - 269. [Abstract] [Full Text] [PDF]
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