The Role of Inhibin and Activin in Adrenal Tumorigenesis

Abstract

Inhibin and activin are members of the TGFβ family of ligands, which were initially cloned as opposing hormones regulating pituitary FSH secretion. Since their initial characterization, both inhibin and activin have also been shown to play a critical role as paracrine and autocrine factors in regulating growth and differentiation of a variety of tissues including the adrenal cortex. While inhibin is mainly expressed and secreted by the adrenal cortex and gonads, activin expression is more widespread where it exerts its effects by modulating cellular differentiation, survival, proliferation, and apoptosis. Much of our knowledge about the physiological function of inhibin originates from studies on mice with targeted deletion of the inhibin alpha subunit gene (INH-/-). INH-/- mice develop gonadal tumors and – when gonadectomized (GDX) – X-zone-derived adrenal tumors. These findings suggest that inhibin functions as a tumor suppressor in both the gonads and adrenals in vivo. The mechanisms leading to adrenal tumorigenesis after GDX in INH-/- have been proposed to involve the lack of a gonadal factor and/or compensatory increase of gonadotropins. Crossing experiments of INH-/- mice with a transgenic mouse strain that has chronically elevated LH levels (LH-CTP) reveals a growth promoting effect of high levels of LH upon gonadal tumorigenesis. In contrast, ovarian tumor presence in compound INH-/-:LH-CTP is associated with smaller adrenals with a regressed x-zone, suggesting that elevated LH levels are not sufficient to induce adrenal tumor formation. However, following gonadectomy, INH-/-:LH-CTP mice develop large adrenal tumors, indicating a direct growth-promoting effect of LH on the adrenal cortex in the absence of ovarian tumors. Activin, which is secreted in high quantities from ovarian tumors in compound INH-/-:LH-CTP mice, has been reported to induce apoptosis in human fetal adrenal cells. Expression of Smad2, which has a pivotal role within the activin signaling cascade, is restricted to cells of the adrenal x-zone suggesting that the main site of activin action in the adrenal could be the x-zone. Accordingly, activin induces apoptosis specifically in the adrenal x-zone when injected in intact adrenals. Taken together, these findings support the concept that activin prevents adrenal tumor growth by inducing x-zone regression in contrast to LH, which exerts a growth promoting effect on adrenocortical tumors in INH-/- mice. Further clinical studies are needed to evaluate the role of the activin/inhibin/Smad system in patients with benign and malignant adrenal tumors.