Endocrine Abstracts

Familial glucocorticoid deficiency (FGD) results from the inability of the adrenal cortex to produce cortisol in response to ACTH stimulation and can be fatal if unrecognised. The disease manifests clinically with increased ACTH and reduced cortisol levels. Our group has recently demonstrated that oxidative stress is implicated in the pathogenesis of this disorder.

We previously identified mutations in nicotinamide nucleotide transhydrogenase (NNT) in patients with FGD by targeted exome sequencing. NNT supplies the high concentrations of NADPH needed for the glutathione and thioredoxin pathways to detoxify mitochondrial H₂O₂. Recently whole exome sequencing of FGD patients with unknown aetiology identified a novel homozygous mutation in the mitochondrial selenoprotein, thioredoxin reductase 2 (TXNRD2) in a large consanguineous kindred, and two further homozygous mutations in glutathione peroxidase 1 (GPX) and peroxiredoxin 3 (PRDX3) in one individual that may act synergistically to induce oxidative damage. RT-PCR revealed that NNT, GPX1, PRDX3 and TXNRD2 are highly expressed in human adrenals and knockdown of these genes in adrenocortical cell lines causes perturbation of redox homeostasis.

Oxidative stress impedes steroidogenesis but paradoxically steroidogenesis itself induces oxidative stress as a result of electron leak throughout the steroidogenic pathway. In fact the final step of cortisol production, catalysed by CYP11B1 within the mitochondria, accounts for ~40% of the total electron flow from NAPDH directed at ROS production during cortisol synthesis. An efficient ROS removal network is therefore of particular importance for the adrenal cortex and may explain why FGD patients with TXNRD2, NNT, GPX1 and PRDX3 mutations present with adrenal insufficiency. Our results suggest that both glutathione and thioredoxin antioxidant systems are critical for ROS detoxification in adrenocortical cells, with their loss leading to defective oxidative stress responses, an impairment of steroidogenesis and hence adrenal insensitivity to ACTH.