In vivo and in vitro evidence for the production of inhibin-like immunoreactivity in human adrenocortical adenomas and normal adrenal glands: relatively high secretion from adenomas manifesting Cushing's syndrome

Abstract

To clarify whether adrenal gland secretes inhibin in vivo in physiological or pathological conditions, we measured the levels of inhibin-like immunoreactivity (inhibin-LI) in adrenal veins (A-vein) and compared them with those in inferior vena cava (IVC) using blood samples obtained at catheterization of adrenal vein in the patients with adrenal adenoma manifesting Cushing's syndrome (Cs), aldosterone-producing adenoma, clinically non-functioning adenoma and normal adrenal gland. The tumor sides of A-veins in the patients with adenomas and also both sides of A-veins in subjects with normal adrenal glands showed significantly higher contents of inhibin-LI than their IVC. When the inhibin-LI secretion rate from adrenal gland was estimated by the difference between the levels of A-vein (tumor side) and IVC, Cs adenomas showed the highest secretion rate. Similarly, the tissue inhibin-LI content and the basal secretion rate of inhibit-LI from primary cultured cells were the highest in Cs adenomas. These findings indicated that normal adrenal glands and adrenocortical adenomas produced and secreted inhibin-LI into the general circulation in vivo and Cs adenomas have relatively high capacity for secreting inhibin-LI, and the present study provided the first in vivo evidence for adrenal inhibin-LI production in pathological conditions.

The expression of inhibin/activin subunits in the human adrenal cortex and its tumours

“…We have, however, demonstrated centripetal extension of immunoreactivity for inhibin in the ACTH-stimulated hyperplastic cortex in the cases with Cushing's disease. These changes would fit with the observations that secretion of inhibin-like immunoreactive material and expression of inhibin mRNA can be regulated in vitro by ACTH in human (Voutilainen et al 1991, Spencer et al 1992, Nishi et al 1995 and ovine (Crawford et al 1987) glands. Interestingly, a circadian rhythm of circulating inhibin has been reported which correlates closely with that of cortisol (Yamaguchi et al 1991).…”

“…The observation that the same pattern of tumour development occurred in mice bearing a SV40 T-antigen transgene, driven by the inhibin promoter (Kananen et al 1996), indicates physiological activation of the promoter for the inhibin subunit gene in the adrenal gland, which leads to the immortalisation of cells by expression of the SV-40 T antigen. In addition, there is evidence that, in the human, adrenocortical adenomas secrete inhibin-like immunoreactive material (Nishi et al 1995) and that both adenomas and carcinomas immunostain positively for inhibin (Chivite et al 1998, McCluggage et al 1998, Munro et al 1998, Pelkey et al 1998. This would suggest that inhibin is not a tumour suppressor for the adrenal cortex in man.…”

“…Quantitative analysis of tumour extracts would be of interest to confirm the relative levels of expression. Nishi et al (1995) provided data to suggest that tumours associated with Cushing's syndrome secreted higher levels of inhibin-like material than those causing other clinical syndromes again linking inhibin to cortisol production. In our analysis, which was performed blind with respect to the clinical data, we demonstrated higher intensity of staining for inhibin in the Cushing's cases.…”

“…Plasma immunoreactive inhibin levels are higher in the adrenal veins than in vena cava or the peripheral circulation (Nishi et al 1995) and normal adrenocortical cells in culture secrete inhibin-like immunoreactive material (Haji et al 1991, Spencer et al 1992. While this may reflect production of mature inhibin dimer it may also indicate the presence of free subunit which may crossreact in the assay.…”

MECHANISMS IN ENDOCRINOLOGY: Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism

“…Nevertheless, the role of these findings in adrenocortical tumorigenesis remains to be elucidated. Inhibin production by adrenocortical cortisol-or estrogen-secreting tumors has been observed in vivo (219,220,221). The main endocrine consequence of this process is inhibition of pituitary FSH release (219,220).…”