| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Endocrine Care |
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development (E.C., M.F.K., D.P.M.), The Warren Grant Magnuson Clinical Center (D.P.M.), and Clinical Center Pharmacy Department (K.A.C., M.R.M., A.R.), National Institutes of Health, Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Evangelia Charmandari, M.D., Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Building 10, Suite 9D42, Bethesda, Maryland 20892-1583.
Abstract
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency is characterized by a defect in cortisol and aldosterone secretion and adrenal hyperandrogenism. Current treatment is to provide adequate glucocorticoid and mineralocorticoid substitution to prevent adrenal crises and to suppress excess adrenal androgen secretion. Satisfactory adrenocortical suppression often requires supraphysiological doses of hydrocortisone, which may produce an unacceptable degree of hypercortisolism. A new four-drug treatment regimen of flutamide, testolactone, reduced hydrocortisone dose, and 9
-fludrocortisone has been shown to achieve normal growth and development after 2 yr of therapy and may, therefore, represent a potential alternative approach to the treatment of children with classic congenital adrenal hyperplasia.
We investigated the effect of flutamide and testolactone, and flutamide alone, on cortisol clearance by performing clearance studies twice in 13 children (6 males and 7 females; age range, 7.0–14.5 yr) with classic 21-hydroxylase deficiency. All studies were conducted at least 3 months after institution of the four-drug treatment regimen. In eight patients (group 1), the first cortisol clearance study was performed on the four-drug regimen, and the second study was performed after a 48-h washout period off flutamide and testolactone. In five patients (group 2), the first study was conducted 1 wk after discontinuation of testolactone and while patients were receiving flutamide, hydrocortisone and 9-fludrocortisone, and the second study was performed after a 48-h washout period off flutamide. Oral hydrocortisone was held on the day of the clearance studies, and all patients received a continuous infusion of hydrocortisone (0.6 mg/m2·h) from 1800 h to 0200 h, with cortisol concentrations measured once hourly. In addition, an in vitro study was conducted to exclude the possibility of an analytical interference of flutamide, 2-hydroxyflutamide, and testolactone with the serum cortisol immunoassay.
Total body cortisol clearance was significantly lower during treatment with the four-drug regimen than during treatment with hydrocortisone and 9-fludrocortisone (153.5 ± 26.8 vs.355.4 ± 65.8 ml/min; P = 0.001). Similar results were obtained comparing flutamide, hydrocortisone, and 9-fludrocortisone therapy to hydrocortisone and 9-fludrocortisone therapy (155.8 ± 26.5 vs. 281.8 ± 96.2 ml/min; P = 0.037). The in vitro study indicated that an interference with the serum cortisol immunoassay was unlikely.
These findings indicate that the addition of flutamide and testolactone to the treatment regimen of hydrocortisone and 9-fludrocortisone decreases cortisol clearance in patients with classic 21-hydroxylase deficiency, and this effect seems to be due to flutamide. Glucocorticoid replacement doses should be reduced when flutamide is added to the treatment regimen of patients receiving hydrocortisone.
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 result in impaired glucocorticoid and mineralocorticoid biosynthesis. This leads to increased secretion of CRH and ACTH, adrenal hyperplasia, and excessive production of adrenal androgens and steroid precursors for which 21-hydroxylation is not necessary (1). Current treatment is to provide adequate glucocorticoid and mineralocorticoid substitution to prevent adrenal crises and to suppress the excess secretion of androgens and androgen precursors from the adrenal cortex (1).
Achieving and maintaining adrenal androgen suppression in classic CAH is far more challenging than preventing adrenal crises, and increased doses of glucocorticoid are often necessary to achieve satisfactory androgen suppression (2). Existing treatment has often failed to normalize the growth and development of children with CAH. Thus, the use of alternative treatment options has been proposed, especially for severely affected children in whom it is difficult to maintain satisfactory adrenal suppression without producing hypercortisolism (3, 4). An alternative approach to the treatment of children with CAH using a combination of an antiandrogen (flutamide), an inhibitor of androgen to estrogen conversion (testolactone), reduced hydrocortisone dose, and 9-fludrocortisone has been reported with promising results (5, 6). After 2 yr of therapy, children receiving this new four-drug treatment maintained normal growth velocity and bone maturation, despite elevated androgen levels (6). Therefore, this regimen may represent a potential alternative medical approach to the treatment of children with classic CAH.
The aim of the present study was to investigate the effect of flutamide and testolactone on cortisol clearance. The influence of these medications on glucocorticoid metabolism has important clinical implications in the development of new treatment approaches for patients with classic 21-hydroxylase deficiency.
Subjects and Methods
Subjects
Thirteen children with classic 21-hydroxylase deficiency (six males and seven females; median age, 10.0 yr; range, 7.0–14.5 yr) were studied prospectively. Patients were receiving reduced doses of hydrocortisone (10.9 ± 1.0 mg/m2/d), standard doses of 9-fludrocortisone (206 ± 22 µg/d), flutamide (10 mg/kg/d), and testolactone (40 mg/kg/d). The clinical characteristics of all subjects are summarized in Table 1
. Patients were excluded from the study if there was evidence of central precocious puberty or any other associated medical condition. No subject had evidence of hepatic or renal disease, and none was taking any other medications known to alter corticosteroid-binding globulin concentrations or to induce hepatic enzymes.
|
Methods
Cortisol clearance studies were performed twice, at least 3 months after institution of the four-drug treatment regimen. All patients received their usual doses of hydrocortisone and 9-fludrocortisone during the studies. In eight patients (group 1), the first cortisol clearance study was conducted on the four-drug regimen, and the second study was performed after a 48-h washout period off flutamide and testolactone. In five patients (group 2), the first study was performed 1 wk after discontinuation of testolactone and while they were receiving flutamide, hydrocortisone and 9-fludrocortisone, and the second study was performed after a 48-h washout period off flutamide.
Patients were admitted to the pediatric ward 1 d before the study. An indwelling venous catheter for frequent blood sampling was inserted at least 12 h before sampling to allow a period of adaptation. Oral hydrocortisone was held on the day of the clearance studies, all patients received a continuous infusion of hydrocortisone in a dose of 0.6 mg/m2·h from 1800 h to 0200 h, and serum cortisol concentrations were determined at 1-h intervals from 1800 h to 0300 h (7). There was no alteration in the administration schedule of 9-fludrocortisone. Samples were centrifuged and separated immediately after collection, and were stored at -80 C until assayed.
Assays: cortisol
In the first group of patients with CAH and the in vitro study, serum cortisol concentrations were measured using an immunoassay (Abbott Laboratories, Abbott Park, IL) with a sensitivity of 1 µg/dl. At a serum concentration of 20 µg/dl, the intra-assay coefficient of variation (CV) was 4.1% and the interassay CV was less than 10%. In the second group of patients studied 1 yr later, serum cortisol was measured using a chemiluminescent assay (Diagnostic Products, Los Angeles, CA) because of changes in the cortisol assay used at our institution. This assay has a sensitivity of 1 µg/dl. The intra-assay CV was 4.7% at a serum concentration of 24 µg/dl whereas the interassay CV was 7.5% at a serum concentration of 22.4 µg/dl. The two assays used for the measurement of cortisol concentrations were very similar to each other (r = 0.9829).
In vitro study
Serum from 10 healthy volunteers was pooled, and testolactone, flutamide, and 2-hydroxyflutamide (the active metabolite of flutamide) were added to the serum samples at a concentration of 100 µg/ml, which is well in excess of the physiological concentrations of these agents. All samples were assayed for cortisol and compared with a control. Cross-reactivity of tested drugs was determined by adding the drugs to a serum pool and comparing the cortisol value to the untreated serum pool.
Pharmacokinetic analysis
Total body cortisol clearance (CL) was estimated using the equation: CL = Ro/Css, where Ro is the hydrocortisone infusion rate and Css is the steady state serum cortisol concentration (8). Because hydrocortisone has a half-life of approximately 1 h (9), patients were considered to have reached steady state concentrations 6 h after initiation of the infusion. The steady state serum cortisol concentration for each patient was estimated as the mean value of the last three steady state serum cortisol concentrations, if the difference between them was less than 5%. For those patients in whom baseline cortisol concentrations were detectable, steady state cortisol concentrations were adjusted using the following equation: Cadjusted = Css - Cbaseline (8).
Statistical analysis
Data that were not normally distributed were logarithmically transformed before analysis. Comparisons between groups were performed using the t test or the paired t test. Values are expressed as mean ± SEM.
Results
There were no significant differences in gender distribution, age, body mass index (BMI), and treatment doses between children with CAH in the two groups, although the children in group 2 were larger.
Total body cortisol clearance was significantly (P = 0.001) lower when patients were receiving the four-drug regimen than during treatment with hydrocortisone and 9-fludrocortisone (Fig. 1A). Similar results were obtained comparing flutamide, hydrocortisone, and 9-fludrocortisone therapy to hydrocortisone and 9-fludrocortisone therapy (P = 0.04) (Fig. 1B). Cortisol clearance while receiving the two-drug regimen of hydrocortisone and 9-fludrocortisone was higher in group 1 than in group 2, most likely due to differences in BMI between the two groups. However, these differences were not statistically significant. When compared with hydrocortisone and 9-fludrocortisone therapy alone, cortisol steady state concentrations were significantly higher when patients were receiving the additional medications of either flutamide and testolactone (8.5 ± 1.1 vs. 4.1 ± 0.7 ng/dl; P = 0.002) or flutamide (10.3 ± 1.4 vs. 6.8 ± 1.3 ng/dl; P = 0.024). The addition of flutamide or flutamide and testolactone to the two-drug treatment regimen resulted in higher serum cortisol concentrations measured hourly (Fig. 2).
|
|
Discussion
Our findings demonstrate that the addition of flutamide and testolactone to the treatment regimen of hydrocortisone and 9-fludrocortisone significantly decreases cortisol clearance in patients with classic 21-hydroxylase deficiency, and this effect seems to be due to flutamide.
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) play an important role in the hepatic metabolism of cortisol (10, 11, 12). The major routes of hepatic metabolism of cortisol involve A-ring and side-chain reduction, followed by conjugation with glucuronic acid and sulfate (13). 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.
The effect of flutamide on cortisol metabolism has been studied previously in patients with prostate cancer receiving high doses of flutamide (750–1500 mg/d) after iv administration of radioactive cortisol [14C] (14, 15). In elderly men with prostate cancer, treatment with flutamide resulted in a decrease in cortisol metabolic clearance rate, prolongation of the half-life of serum cortisol, decreased formation of the 5ß-metabolites, tetrahydrocortisol and tetrahydrocortisone, and increased formation of the 5-metabolite, allo-tetrahydrocortisol. These changes were attributed to alterations in the activity of 5- and 5ß-reductase caused by flutamide and a subsequent alteration in cortisol pharmacokinetics.
Despite the marked decrease in cortisol clearance, patients with prostate cancer treated with flutamide maintained normal daily serum cortisol concentrations because of the decreased cortisol production rates, which reflected normal hypothalamic-pitutary-adrenal axis function and preservation of the negative feedback of cortisol at the hypothalamic and pituitary levels (14). Patients with classic CAH, however, are on fixed doses of glucocorticoid substitution, and the addition of flutamide to their treatment regimen would place them at risk for developing hypercortisolism and iatrogenic Cushing’s syndrome, if the hydrocortisone dose remained unchanged. Therefore, a reduction in the daily dose of hydrocortisone replacement should be considered at the time of introduction of antiandrogen therapy with flutamide in patients with classic 21-hydroxylase deficiency or any other condition that compromises the integrity and function of the hypothalamic-pitutary-adrenal axis.
The concept of flutamide-induced suppression of the activity of hepatic microsomal enzymes is also supported by studies that investigated the effect of flutamide on testosterone (16) and estradiol (17) metabolism, which showed an alteration of the relative activities of steroid 5- and 5ß-reductase in favor of the former. Although in the present study the urinary cortisol metabolites were not determined because of the short washout period off medication, our findings support previous observations and provide additional evidence that low-to-moderate doses of flutamide also affect cortisol metabolic clearance rates.
The reduction of the hydrocortisone dose in the new four-drug treatment approach was intended to prevent hypercortisolism, a common iatrogenic complication of classic CAH. Overall reduction of cortisol levels has been achieved in patients receiving this new treatment regimen, as evidenced by the observation of reduced urinary-free cortisol concentrations and an increase in androgen production in these patients. However, the reduction in cortisol clearance observed in patients receiving the regimen containing flutamide may explain the ability to reduce hydrocortisone dose to as low as 5 mg/m2/d in some patients (observation of D.P.M.).
An increase in cortisol half-life may have potential treatment benefits. The short half-life of hydrocortisone makes this drug suboptimal in the management of patients with CAH (18), and longer-acting glucocorticoid preparations are often advocated in the treatment of adults with CAH (19). Thus, the addition of flutamide to the standard glucocorticoid and mineralocorticoid replacement regimen in patients with CAH may suppress androgens in two ways: through androgen receptor blockade, and improved suppression of CRH and ACTH secretion via an increase in the cortisol half-life. However, an increase in the cortisol half-life may also increase the risk of iatrogenic Cushing’s syndrome.
We conclude that treatment with flutamide decreases cortisol clearance in patients with classic 21-hydroxylase deficiency. Glucocorticoid replacement doses should be reduced when flutamide is added to the treatment regimen of patients receiving hydrocortisone, and failure to adjust the hydrocortisone dose may result in iatrogenic Cushing’s syndrome. Whenever medications are added to the standard adrenal replacement regimen of hydrocortisone and 9-fludrocortisone, potential influences on glucocorticoid metabolism should be considered.
Note Added in Proof
Since this study was accepted for publication, a single case report on the effect of flutamide on cortisol clearance has been published with similar findings [Charmandari E, Johnston A, Honour JW, Brook CG, Hindmarsh PC. J Pediatr Endocrinol Metab, 2002, 15(4):435–439].
Acknowledgments
We thank the patients and their families for participation in this study, Donna Peterson for assistance in data management, and the 9 West Nursing Staff of the Warren Grant Magnuson Clinical Center for assistance in the care of these patients.
Footnotes
D.P.M. is a Commissioned Officer in the United States Public Health Service.
Abbreviations: BMI, Body mass index; CAH, congenital adrenal hyperplasia; CV, coefficient of variation.
Received January 14, 2002.
Accepted March 26, 2002.
References
4-5ß-reductase and dihydrocortisol-3-oxidoreductase(s). Steroids 55:495–500[CrossRef][Medline]
This article has been cited by other articles:
 |
|
 |
|
  M. Hero, O. A. Janne, K. Nanto-Salonen, L. Dunkel, and T. Raivio Circulating Antiandrogenic Activity in Children with Congenital Adrenal Hyperplasia during Peroral Flutamide Treatment J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5141 - 5145. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
). The addition of flutamide to their treatment regimen significantly decreased cortisol clearance, resulting in longer cortisol half-life and higher serum cortisol concentrations. Error bars represent SEM.