Expression of inhibin alpha in adrenocortical tumours reflects the hormonal status of the neoplasm

Abstract

Inhibins are gonadal glycoprotein hormones whose main endocrine function is to inhibit pituitary FSH secretion. In addition to testes and ovaries, other steroid-producing organs are sites of inhibin subunit expression. To study the role of inhibins in human adrenal gland, we screened a panel of 150 adrenals (10 normal adrenals, 25 adrenocortical hyperplasias, 65 adrenocortical adenomas, 30 adrenocortical carcinomas and 20 phaeochromocytomas) for inhibin expression. mRNA levels of inhibin subunit were studied in 57 samples and all tissues were stained immunohistochemically with an inhibin subunit-specific antibody. Inhibin mRNA was detected in all adrenocortical tissues. Virilizing adenomas possessed a 10-fold higher median inhibin mRNA expression than did normal adrenals. Bilaterally and nodularly hyperplastic adrenals and other than virilizing adrenocortical tumours had their median inhibin mRNA levels close to those of normal adrenals. Immunohistochemically, inhibin subunit was detectable in all normal and hyperplastic adrenals, as well as in 73% of the adrenocortical tumours. However Our data show that inhibin subunit is highly expressed in both normal and neoplastic androgenproducing adrenocortical cells, with less expression in cortisol-producing and hardly any in aldosteroneproducing cells. This suggests a specific role for inhibins in the regulation of adrenal androgen production. We did not find any significant difference in inhibin expression between benign and malignant adrenocortical tumours. Thus inhibin gene does not seem to have a tumour suppressor role in human adrenal cortex.

Rodent adrenocortical cells display high affinity binding sites and proteins for inhibin A, and express components required for autocrine signalling by activins and bone morphogenetic proteins

“…By secreting inhibins, the AC cell line resembles the adrenal cortex and tumours arising from it, which strongly express the inhibin -subunit and weakly express both -subunits (Crawford et al 1987, Voutilainen et al 1991, Munro et al 1999, Arola et al 2000, and the human AC H295R cell line, which also makes and secretes activin A and both inhibin A and inhibin B (Vanttinen et al 2002). The present results also show that AC cells express mRNA encoding several BMP/GDF ligands (BMP-2, -3, -4, -6 and -8a; GDF-1, -3, -5 and -9) and Lefty A and B, for which autocrine roles in the adrenal cortex are yet to be identified.…”

Expression of activin/inhibin signaling components in the human adrenal gland and the effects of activins and inhibins on adrenocortical steroidogenesis and apoptosis

“…The significance of differential expression of activin receptors and Smads in the adrenocortical zones is not known but it may represent a regulatory mechanism for activin actions. Interestingly, the innermost ZF and ZR have previously been shown to express inhibin -and -subunit peptides (Munro et al 1999, Arola et al 2000. In connection with G expression, this suggests that adrenal inhibins may interfere with activin signaling in the adrenal gland.…”

“…Stimulation of androgen production in ovarian theca cells in response to inhibins (reviewed in Findlay 1993) and high inhibin -subunit mRNA and peptide expression in adrenal virilizing tumors (Nishi et al 1995, Arola et al 2000, Vänttinen et al 2002, suggest that inhibins might stimulate adrenal androgen production. On the other hand, inhibins have not been found to have any direct effects in adrenal cells.…”

“…The mechanisms controlling apoptosis in the adrenal cortex are complicated, but it is possible that activins play a role in this process as their signaling system is expressed in the same area as the most active apoptosis (Sasano et al 1995). Interestingly, increased inhibin -subunit expression has been detected in cortisol-producing and virilizing tumors probably originating from the inner cortical cells (Pelkey et al 1998, Arola et al 2000. Therefore, it is possible that decreased activin production or disturbed activin signal transduction in these inhibin -subunit overexpressing cells could contribute to increased steroidogenesis and cell mass in these tumors.…”

“…However, later studies showed that inhibins do not have marked tumorsuppressor activity in human adrenals, although loss of immunopositivity was reported in a subgroup of adrenocortical carcinomas (Munro et al 1999). In contrast, increased inhibin -subunit mRNA and peptide expression, and increased secretion of immunoreactive inhibins, were reported in virilizing and, to some extent, in cortisol-producing tumors (Nishi et al 1995, Pelkey et al 1998, Arola et al 2000, Vänttinen et al 2002.…”