Adrenal steroids in adrenomyeloneuropathy

Abstract

Adrenoleukodystrophy (ALD) and its adult variant adrenomyeloneuropathy (AMN) are X-linked diseases associated with a deficiency in the peroxisomal degradation of saturated very long chain fatty acids (VLCFA) resulting in an accumulation of VLCFA in the central and peripheral myelin, the adrenal cortex and the testis. Adrenal insufficiency with clinical hypocortisolism occurs in approximately two thirds of the patients with AMN. We studied the circulating adrenal hormones 17alpha-hydroxyprogesterone (17alpha-OHP), androstenedione and dehydroepiandrosterone sulphate (DHEAS) in 63 male AMN patients (age 17-65 years) and the DHEAS serum levels in 95 healthy male controls (age 30-65 years). 34 of the patients presented with the phenotype of only spinal cord and peripheral nerve disability without hypocortisolism, 29 of the patients presented with the phenotype of either additional hypocortisolism or Addison's syndrome only. Normal 17alpha-OHP concentrations were found in all patients with no significant difference between patients without and with hypocortisolism (6.07 +/- 0.61 nmol/l and 4.76 +/- 0.37 nmol/l). Androstenedione concentration was significantly (p < 0.01) lower in patients with hypocortisolism (2.99 +/- 0.65 pmol/l versus 5.71 +/- 0.68 pmol/l). As serum levels of DHEAS are agedependent we divided the two groups into two subgroups each (subgroup one: age 17-40 years, subgroup two: age 41-65 years). The DHEAS concentration of patients without and with hypocortisolism was significantly (p < 0.01) lower in both subgroups (1. 4.35 +/- 0.84 micromol/l, n = 15, 2. 15 +/- 0.28 micromol/l, n = 19; 1. 1.90 +/- 0.57 micromol/, n = 21, 2. 0.96 +/- 0.29 micromol/l, n = 8) compared to controls (1. 9.0 +/- 0.96 micromol/l; 2. 5.21 +/- 0.25 micromol/l). In conclusion, androstenedione and DHEAS serum concentrations are subnormal in all AMN patients and may therefore serve as sensitive markers of the adrenal function in adrenomyeloneuropathy.

X-linked Adrenoleukodystrophy

“…These inclusions and markedly elevated levels of VLCFA are also seen in the fetal adrenal gland [109]. As a result steroid hormone production by the adrenal cortex and the testis is impaired [52,[110][111][112][113]. As a result steroid hormone production by the adrenal cortex and the testis is impaired [52,[110][111][112][113].…”

“…DHEA and its sulfate ester (DHEA-S) represent the most abundant steroid in humans. Altogether and since low levels of circulating DHEA-S are observed in X-ALD patients [112,113], a treatment with DHEA was likely able to yield beneficial effects for X-ALD patients. DHEA mediates its effects through several nuclear receptors including PPARa and has been shown to induce peroxisome proliferation in rodents [467][468][469].…”

Oxidative stress and adrenocortical insufficiency

“…2012). Adrenocortical insufficiency can be the presenting symptom of adrenomyeloneuropathy years or even decades before the onset of neurological symptoms (Wichers-Rothers et al 2005). …”