Current guidelines suggest proving angiotensin-independent aldosterone secretion in patients with primary aldosteronism (PA). It is further recommended to demonstrate unilateral disease because of its consequence for therapy. A general screening for excess secretion of other hormones is not recommended. However, clinically relevant autonomous aldosterone production rarely originates in adrenal tumors, compromised of zona glomerulosa cells only. This article reviews published data on aldosterone- and cortisol-co-secreting tumors and shows that pre-operative diagnosis of such a lesion is beneficial for patients. Overt or subclinical glucocorticoid hypersecretion may interfere with diagnostic studies, e.g. adrenal venous sampling, screening of familial forms of PA on the basis of serum 18-hydroxy-cortisol (18-OH-F) determination, and provoke glucocorticoid deficiency after surgical removal of the tumor. In addition, knowledge from histological and molecular studies in patients with aldosterone- and cortisol-co-secreting tumors challenges some concepts of the development of adrenal autonomy. The presence of an aldosterone- and cortisol-co-secreting adrenocortical tumor should be considered if a patient has i) PA and an adenoma that is larger than 2.5 cm, ii) cortisol that is nonsuppressible with overnight low-dose dexamethasone, or iii) grossly elevated serum levels of hybrid steroids, such as 18-OH-F.
