Endothelin-1-immunoreactive protein and neuroendocrine differentiation and nerve supply in human non-neoplastic and neoplastic adrenal cortex : Immunohistochemical, ultrastructural, and biochemical findings

Abstract: The occurrence and distribution of endothelin (ET)-1-immunoreactive (ir) protein, neuro-endocrine markers and neurohormonal peptides in endocrine cells and nerves in human non-neoplastic and neoplastic adrenal cortex are described.ET-1-ir cell groups were regularly seen in human adrenal cortex, mainly in zona fasciculata, but not in the medulla. The ir protein appeared in the cytoplasm and focally also on the cell membrane. All cortical adenomas displayed ET-1-ir cells but only three of ten cortical carcinomas. Electron microscopy revealed the ET-1-ir protein adjacent to the outer surface of lipid bodies, in the membrane of mitochondria and endoplasmic reticulum and focally on the cell membrane. The molecular weight of the ET-1-ir protein, determined by SDS-polyacrylamide gel electrophoresis and immunoblotting, was 9 kD, which is different from ET-1 and its precursor, indicating that the substance may constitute a protein not earlier described. The localization suggests that this peptide is synthesized in the cortical cells and takes part in synthesis and/or secretion of steroid hormones.The significance of the neuroendocrine differentiation was analysed with different neuroendocrine markers. The findings evidently showed that neuroendocrine differentiation is a feature related to parenchymal cells in adrenal cortex and cortical lesions. The findings suggest that neuroendocrine differentiated cortical cells particularly play a role in the hormonal regulation, may be via an interaction with the medulla.Interestlingly, there was a notable difference in the distribution pattern of the neuroendocrine markers in nerves between cortex and different lesions. Cortex and slight hyperplastic cortical tissue had a moderate - to rich - supply of nerves containing the "general" neuronal markers, protein gene product (PGP) 9.5, neuron-specific enolase (NSE), synaptic vesicle protein 2 (SV2), and of fibres showing immunoreactivity to the adrenergic marker tyrosine-hydroxylase (TH). In hyperplasias, the innervation became more sparse with increasing degree of hyperplasia. These markers were only occasionally observed in cortical adenomas and carcinomas, while these lesions demonstrated fibres containing neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) in a varying number. The ir nerve fibres were predominantly located along blood vessels but also among parenchymal cells. Several types of co-existence and co-localization occurred. Our results suggest that NPY- and VIP-containing nerves mayhave some role in the regulation of cortical steroid secretion, particurlarly in neoplastic lesions.The present findings point to a complex hormonal regulation particularly in cortex and hyperplasia.