Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency: Alterations in Cortisol Pharmacokinetics at Puberty

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 9α-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.

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Classic congenital adrenal hyperplasia and puberty

Acta Endocrinologica ◽

10.1530/eje.0.151u077 ◽

2004 ◽

pp. U77-U82 ◽

Cited By ~ 32

Author(s):

E Charmandari ◽

CG Brook ◽

PC Hindmarsh

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Serum Insulin ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Autosomal Recessive Disorders ◽

The Metabolic Syndrome ◽

Adrenal Hyperandrogenism ◽

Free Cortisol ◽

21 Hydroxylase Deficiency ◽

And Function

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders resulting from deficiency of one of the five enzymes required for synthesis of cortisol in the adrenal cortex. The most common form of the disease is classic 21-hydroxylase deficiency, which is characterized by decreased synthesis of glucocorticoids and often mineralocorticoids, adrenal hyperandrogenism and impaired development and function of the adrenal medulla. The clinical management of classic 21-hydroxylase deficiency is often suboptimal, and patients are at risk of developing in tandem iatrogenic hypercortisolism and/or hyperandogenism. Limitations of current medical therapy include the inability to control hyperandrogenism without employing supraphysiologic doses of glucocorticoid, hyperresponsiveness of the hypertrophied adrenal glands to adrenocorticotropic hormone (ACTH) and difficulty in suppressing ACTH secretion from the anterior pituitary. Puberty imposes increased difficulty in attaining adrenocortical suppression despite optimal substitution therapy and adherence to medical treatment. Alterations in the endocrine milieu at puberty may influence cortisol pharmacokinetics and, consequently, the handling of hydrocortisone used as replacement therapy. Recent studies have demonstrated a significant increase in cortisol clearance at puberty and a shorter half-life of free cortisol in pubertal females compared with males. Furthermore, children with classic CAH have elevated fasting serum insulin concentrations and insulin resistance. The latter may further enhance adrenal and/or ovarian androgen secretion, decrease the therapeutic efficacy of glucocorticoids and contribute to later development of the metabolic syndrome and its complications.

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Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Journal of Endocrinology ◽

10.1677/joe.0.1690065 ◽

2001 ◽

Vol 169 (1) ◽

pp. 65-70 ◽

Cited By ~ 66

Author(s):

E Charmandari ◽

A Johnston ◽

CG Brook ◽

PC Hindmarsh

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Intravenous Administration ◽

Cortisol Concentration ◽

Absolute Bioavailability ◽

Pharmacokinetic Parameters ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Total Cortisol ◽

Hydrocortisone Administration ◽

21 Hydroxylase Deficiency

The management of congenital adrenal hyperplasia due to 21-hydroxylase (CYP21) deficiency requires glucocorticoid substitution with oral hydrocortisone given twice or thrice daily. In paediatric practice little is known of the bioavailability of oral hydrocortisone tablets used in these patients. The aim of this study was to assess the bioavailability of oral hydrocortisone and to evaluate current replacement therapy in the light of cortisol pharmacokinetic properties. We determined the bioavailability of hydrocortisone following oral and intravenous administration in sixteen (median age: 10.9 years, range: 6.0-18.4 years) adequately controlled CYP21 deficient patients. Serum total cortisol concentrations were measured at 20-min intervals for 24 h while patients were on oral substitution therapy, and at 10-min intervals for 6 h following an intravenous bolus of hydrocortisone in a dose of 15 mg/m(2) body surface area. The area under the serum total cortisol concentration versus time curve (AUC) following oral and intravenous administration of hydrocortisone was calculated using the trapezoid method. The bioavailability was estimated by dividing the corrected for dose AUC after oral hydrocortisone administration by the corrected for dose AUC after the intravenous hydrocortisone administration and was exemplified as a percentage. After oral administration of hydrocortisone in the morning, median serum total cortisol concentrations reached a peak of 729.5 nmol/l (range: 492-2520 nmol/l) at 1.2 h (range: 0.3-3.3 h) and declined monoexponentially thereafter to reach undetectable concentrations 7 h (range: 5-12 h) after administration. Following administration of the evening hydrocortisone dose, median peak cortisol concentration of 499 nmol/l (range: 333-736 nmol/l) was attained also at 1.2 h (range: 0.3-3.0 h) and subsequently declined gradually, reaching undetectable concentrations at 9 h (5-12 h) after administration of the oral dose. After the intravenous hydrocortisone bolus a median peak serum total cortisol concentration of 1930 nmol/l (range: 1124-2700 nmol/l) was observed at 10 min (range: 10-20 min). Serum cortisol concentrations fell rapidly and reached undetectable levels 6 h after the hydrocortisone bolus. The absolute bioavailability of oral hydrocortisone in the morning was 94.2% (90% confidence interval (CI): 82.8-105.5%) whereas the apparent bioavailability in the evening was estimated to be 128.0% (90% CI: 119.0-138.0%). We conclude that the bioavailability of oral hydrocortisone is high and may result in supraphysiological cortisol concentrations within 1-2 h after administration of high doses. The even higher bioavailability in the evening, estimated using as reference the data derived from the intravenous administration of hydrocortisone bolus in the morning, is likely to reflect a decrease in the hydrocortisone clearance in the evening. Decisions on the schedule and frequency of administration in patients with congenital adrenal hyperplasia should be based on the knowledge of the bioavailability and other pharmacokinetic parameters of the hydrocortisone formulations currently available.

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Taking it with a Grain of Salt: A Woman with ‘PCOS’ and Infertility Diagnosed with Nonclassic Congenital Adrenal Hyperplasia and a Large Renal Mass

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.322 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A159-A160

Author(s):

Marcos D Villarreal ◽

Viraj Desai ◽

Pratima V Kumar

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Renal Mass ◽

Laboratory Evaluation ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Adrenal Rest Tumor ◽

Free Cortisol ◽

Classic Cah ◽

Adrenal Rest ◽

21 Hydroxylase Deficiency

Abstract Background: Clinical manifestations of Nonclassic CAH (NCCAH) in women may range from asymptomatic to hirsutism, oligo-menorrhea, or infertility. Testicular adrenal rest tumors are common in men with classic CAH though uncommon in NCCAH. In women with classic CAH, ovarian adrenal rest tumors are even rarer. 11–58% of patients with classic CAH will have at least one adrenal nodule but the prevalence is unknown in NCCAH (1). Clinical Case: A 34-year-old Hispanic woman was seen by reproductive endocrinology for evaluation of infertility. She had been unable to conceive for the past 7 years. She was diagnosed with PCOS by her PCP. She was referred to our clinic for further workup. The patient denied galactorrhea. Laboratory evaluation revealed prolactin 49.3 (< 20.0 ng/ml), TSH 2.290 (0.5–5.0 μU/mL), fT4 1.14 (0.9–2.3 ng/dL), total testosterone 92 (15 -70 ng/dL for women), DHEAS 361 (45 -270 µg/dL), 8 AM cortisol 20.0 (5–23 μg/dL), ACTH 59.0 (6–76 pg/ml), 17-hydroxyprogesterone (17OHP) >2000 ng/dL, and A1c 5%. 24-hour urinary free cortisol was 26.4 (3.5–45 mcg/day). MRI of the pituitary did not show any adenoma. Pelvic ultrasound did not reveal any ovarian cysts. Cosyntropin stimulation test showed baseline 17OHP 1076 ng/dL, 30 minutes 8812 ng/dL, and 60 minutes 9452 ng/dL. She was begun on hydrocortisone and cabergoline. CT of the abdomen did not reveal any adrenal masses but showed mildly thickened adrenal limbs suggesting adrenal hyperplasia. A 4.5 cm exophytic enhancing mass on the left kidney was noted representing an adrenal rest tumor versus angiomyolipoma. Given the exophytic nature of the mass and increased risk of hemorrhage with angiomyolipomas greater than 4 cm, the patient was referred to urology and interventional radiology for radioembolization and possible biopsy of the mass. We are unsure if this renal mass is an angiomyolipoma or an adrenal rest tumor, which are uncommon in the kidneys. The patient was also referred for genetic counseling. Patients with CAH typically have CYP21A2 gene mutations, and the chance that a patient with NCCAH will have a child with classic CAH is reported to be 1 to 2% in two large cohort studies (2). Conclusion: This case is a reminder that evaluation of infertility/subfertility includes less common diagnoses, such as NCCAH. This genetic disorder is seen more frequently in certain ethnic groups, including Hispanics; and after diagnosis, patients should be referred to a genetic specialist. Additional abdominopelvic imaging should be considered in both men and women with a new diagnosis of NCCAH to evaluate for rare but clinically significant tumors. Reference: 1. Nordenström, A., Falhammar H. Diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency Eur J Endocrinol. 2019 Mar;180(3):R127-R145.2. Merke, D, Auchus, R Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. NEJM 2020;383:1248–61.

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