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Assessment of Adrenal Function in Women Heterozygous for Adrenoleukodystrophy¹

Division of Endocrinology and Metabolism (S.S.E., P.W.L.) and Kennedy Krieger Institute (S.N.), Johns Hopkins Medical Institutions, Baltimore, Maryland 21287; and the Section of Endocrinology and Metabolism, Emory Clinic (L.S.B.), Atlanta, Georgia 30322

Address all correspondence and requests for reprints to: Dr. Paul W. Ladenson, Division of Endocrinology and Metabolism, Department of Medicine, Johns Hopkins Hospital, 600 North Wolfe Street, Blalock 904, Baltimore, Maryland 21287-4904.

Abstract

Adrenoleukodystrophy (ALD) is an X-linked recessive disorder that destroys the white matter of the brain and is associated with adrenal insufficiency. The prevalence of adrenal dysfunction in 71 women carriers of the X-linked ALD gene was studied. These subjects were identified initially on the basis of being obligate carriers of the X-linked trait by pedigree analysis and were confirmed by plasma very long chain fatty acid levels consistent with a heterozygote status. One subject had well documented overt adrenal insufficiency, diagnosed and treated since age 9 yr. Among the remaining women, the mean serum 0800 h and 1 h post-ACTH cortisol concentrations [16 ± 7 (±SD) and 34 ± 8 µg/dL, respectively] were normal. All subjects had normal ACTH-stimulated serum cortisol levels, i.e. more than 20 µg/dL. However, 4 subjects (6%) had subnormal ACTH-stimulated aldosterone concentrations (mean, 9 ± 6 vs. 42 ± 16 ng/dL for other subjects; P = 0.001, by Mann Whitney rank sum test). Three of these women (75%) were taking nonsteroidal antiinflammatory agents (NSAIDs), whereas only 4 of 67 (6%) subjects with normal aldosterone responsiveness were NSAIDs users (P < 0.01, by Fisher’s exact test). Thus, NSAIDs use was associated with increased risk of hypoaldosteronism (odds ratio, 50.2; 95% confidence interval, 3.3–266; P < 0.002). Three of these four women had symptoms consistent with mineralocorticoid deficiency. Serum sodium and potassium concentrations were normal in all subjects. Basal and metyrapone-stimulated plasma ACTH concentrations were also normal in adequately tested subjects with and without mineralocorticoid insufficiency.

Five of eight subjects (63%) who underwent testing with synthetic ovine CRH (oCRH) had abnormalities. Three did not meet the criteria for adequate cortisol stimulation (i.e. >20 µg/dL) and had peak ACTH levels greater than 30 pg/mL. Two other subjects had exaggerated ACTH responses with normal cortisol levels.

There were no significant differences in the mean or median levels of very long chain fatty acid, C26:0, C24/22 ratios, or C26/22 ratios among the entire subject group, the subgroup with blunted aldosterone responses to ACTH, and the subgroup with blunted responses to oCRH (P > 0.05, by ANOVA and Kruskall-Wallis test for C26, C24/22 ratio, and C26/22 ratio).

We conclude that 1) adrenal cortical insufficiency rarely develops in ALD heterozygotes; 2) isolated mineralocorticoid insufficiency can occur in ALD heterozygotes, as has been previously reported to occur with autoimmune and acquired immunodeficiency syndrome-related adrenal dysfunction; 3) ALD heterozygosity may predispose these individuals to NSAID-related hypoaldosteronism; and 4) a subclinical decrease in glucocorticoid reserve, as measured by oCRH testing, may be present in a majority of these women. Aldosterone levels should be included in the ACTH stimulation testing when seeking evidence of adrenal insufficiency in affected women. NSAIDs should be considered a risk factor for the development of hypoaldosteronism in women heterozygous for ALD.

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