Regeneration of Functional Adrenal Tissue Following Bilateral Adrenalectomy

It is assumed that after complete bilateral adrenalectomy (ADX), no adrenal tissue will redevelop and adrenal hormone levels will remain low and unaffected by stress. However, anecdotal observations in animals and in patients suggest that under some unknown circumstances the opposite can occur. Herein, we studied whether adrenalectomized rats can develop an alternative source of systemic corticosterone after complete bilateral ADX with minimal replacement therapy. Male and female rats underwent either a standard ADX, in which the glands were removed with minimal surrounding adipose tissue, or an extensive ADX, in which glands were removed with most surrounding adipose tissue. Excised glands were histologically tested for completeness, and corticosterone replacement was nullified within 1 to 3 weeks postoperatively. In four experiments and in both excision approaches, some rats gradually reestablished baseline corticosterone levels and stress response in a time-dependent manner, but differences were observed in the reestablishing rates: 80% in standard ADX vs 20% in extensive ADX. Upon searching for the source of corticosterone secretion, we were surprised to find functional macroscopic foci of adrenocortical tissue without medullary tissue, mostly proximal to the original location. Chronic stress accelerated corticosterone level reestablishment. We hypothesized that underlying this phenomenon were preexisting ectopic microscopic foci of adrenocortical-like tissue or a few adrenal cells that were pre-embedded in surrounding tissue or detached from the excised gland upon removal. We concluded that adrenalectomized animals may develop compensatory mechanisms and suggest that studies employing ADX consider additional corticosterone supplementation, minimize stress, and verify the absence of circulating corticosterone.