Adrenocortical Functions in Women With Nonclassical 21-hydroxylase Deficiency. (EVAF-21)

Evaluation of Adrenocortical Functions by Insulin Tolerance Test and Sodium Depletion in Women With Nonclassical Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency in Comparison With Healthy Volunteers.

The risk of adrenal insufficiency in patients with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency is not well documented. Indication of cortisol replacement therapy in situation of acute stress or at long term is thus controversial. The mineralocorticoid reserve of these patients has never been evaluated.

Hypothesis: The glucocorticoid and mineralocorticoid function of the adrenal glands in women with nonclassical 21-hydroxylase deficiency is comparable with the adrenal functions of healthy age- sexe- and BMI-matched subjects.

Study Overview

• Status: Unknown
• Conditions: Adrenal Hyperplasia, Congenital; 21-hydroxylase Deficiency
• Intervention / Treatment: Other: Functional explorations

Detailed Description

The primary end-point of the study is to evaluate the glucocorticoid function of the adrenal glands in women with nonclassical 21-hydroxylase deficiency (= patients) by comparing the maximal cortisol concentrations obtained during insulin tolerance test (ITT) in the patients and in the healthy volunteers.

The secondary end-point of the study is to determine the % of patients with a maximal plasma cortisol concentration greater or equal to 18μg/dL during ITT; compare the maximal plasma ACTH and salivary cortisol concentration during ITT in the two study groups; to evaluate the mineralocorticoid function of the patients by comparing the variations (changes from baseline) of the plasma renin, aldosterone, urinary aldosterone, systolic and diastolic blood pressure and pulse wave velocity in response to sodium depletion in the patients and in the healthy volunteers.

Women with nonclassical 21-hydroxylase deficiency followed in the Endocrinology and reproduction illnesses Service of the BICETRE Hospital, LE KREMLIN-BICETRE, France and female healthy volunteers will be proposed to participate.

Before inclusion patients must be genotyped and both patients and healthy volunteers must undergo an ACTH (Synacthen 250 μg IV) test for plasma cortisol and 17-hydroxyprogesterone concentration assessments.

After inclusion:

• ITT: IV injection of 0.10-0.2U/kg of insulin (ACTRAPID) at 09h00, dose adapted to BMI, with repeated measures 15, 30, 45, 60, 90 and 120 minutes after insulin injection for assessment of the glucocorticoid function, at the One Day Hospital of the Endocrinology and reproduction illnesses Service of the BICETRE Hospital, LE KREMLIN BICETRE.
• Sodium depletion test: obtained by PO administration of 40 mg of furosemide (LASILIX) at 09h00 in combination with low sodium diet (20mmol of Na/day) with repeated measures for assessment of the mineralocorticoid function during 24 hours after the drug administration at the Clinical Investigation Center of The George POMPIDOU Hospital, Paris.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Le Kremlin-bicetre, France, 94 275
    • Assistance Publique - Hôpitaux de Paris, Bicêtre Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

Groupe of patients:

• women aged 18-50 years with nonclassical 21-hydroxylase deficiency with homozygous or compound heterozygous mutations of CYP21A2 and plasma 17-hydroxyprogesterone concentration after stimulation with synacthen >= 10ng/mL

Groupe of healthy volunteers :

• age matched female healthy volunteers with plasma 17-hydroxyprogesterone concentration after stimulation with synacthen < 2ng/mL

Exclusion Criteria:

• treatment with oral or local glucocorticoids < 1 year
• oral estroprogestative contraception < 3 months
• spironolactone < 3 months
• cyproterone acetate < 3 months
• treatment modifying the activity of the renin - angiotensine - aldosterone system < 2 weeks
• pregnancy and lactation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Cases; Functional explorations of cortisol and aldosterone production during stimulation by ITT and sodium depletion respectively in female patients with non classical 21-hydroxylase deficiency.	Other: Functional explorations; Functional explorations of cortisol and aldosterone production during stimulation by ITT and sodium depletion respectively
EXPERIMENTAL: Control; Functional explorations of cortisol and aldosterone production during stimulation by ITT and sodium depletion respectively in healthy female controls.	Other: Functional explorations; Functional explorations of cortisol and aldosterone production during stimulation by ITT and sodium depletion respectively

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximal plasma cortisol concentration	Repeated measures 15, 30, 45, 60, 90 and 120 minutes after insulin IV injection	Before and up to two hours after Insulin injection (Insulin tolerance test)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
% of patients with maximal plasma cortisol concentration >=18microg/dl	Repeated measures 15, 30, 45, 60, 90 and 120 minutes after insulin IV injection	Before and up to two hours after Insulin injection (Insulin tolerance test)
Maximal plasma ACTH concentration	Repeated measures 15, 30, 45, 60, 90 and 120 minutes after insulin IV injection	Before and up to two hours after Insulin injection (Insulin tolerance test)
Maximal salivary cortisol concentration	Repeated measures 15, 30, 45, 60, 90 and 120 minutes after insulin IV injection	Before and up to two hours after Insulin injection (Insulin tolerance test)
Variation (change from baseline) of plasma rennin and plasma aldosterone concentration	Repeated measures 1, 2, 3, 6, 9, 12, 24 hours after oral furosemide administration	Before and up to 24 hours after oral furosemide administration (Sodium depletion test)
Variation (change from baseline) of urinary aldosterone concentration	Repeated measures in 4-hour urine portions after oral furosemide administration	Before and up to 24 hours after oral furosemide administration (Sodium depletion test)
Variation (change from baseline) of the systolic, diastolic blood pressure and pulse wave velocity	Repeated measures 1, 2, 3, 6, 9, 12, 24 hours after oral furosemide administration	Before and up to 24 hours after oral furosemide administration (Sodium depletion test)

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Peter Kamenicky, MD, PhD, Assistance Publique Hôpitaux de Paris - Bicêtre Hospital

Publications and helpful links

General Publications

• Kamenicky P, Blanchard A, Lamaziere A, Piedvache C, Donadille B, Duranteau L, Bry H, Gautier JF, Salenave S, Raffin-Sanson ML, Genc S, Pietri L, Christin-Maitre S, Thomas J, Lorthioir A, Azizi M, Chanson P, Le Bouc Y, Brailly-Tabard S, Young J. Cortisol and Aldosterone Responses to Hypoglycemia and Na Depletion in Women With Non-Classic 21-Hydroxylase Deficiency. J Clin Endocrinol Metab. 2020 Jan 1;105(1):dgz005. doi: 10.1210/clinem/dgz005.

Study record dates

Study Major Dates

• Study Start: February 1, 2013
• Primary Completion (ACTUAL): December 1, 2015
• Study Completion (ANTICIPATED): November 1, 2016

Study Registration Dates

• First Submitted: May 22, 2013
• First Submitted That Met QC Criteria: May 23, 2013
• First Posted (ESTIMATE): May 24, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): September 29, 2016
• Last Update Submitted That Met QC Criteria: September 28, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: cortisol; deficiency; Healthy people; Woman; Adrenocortical function; Adrenal hyperplasia, Congenital; 21-hydroxylase; replacement therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Endocrine System Diseases; Gonadal Disorders; Disorders of Sex Development; Urogenital Abnormalities; Congenital Abnormalities; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Adrenal Gland Diseases; Steroid Metabolism, Inborn Errors; Hyperplasia; Adrenal Hyperplasia, Congenital; Adrenogenital Syndrome; Adrenocortical Hyperfunction
• Other Study ID Numbers: P111005