Extra-adrenal glucocorticoids and mineralocorticoids: evidence for local synthesis, regulation, and function

Abstract

Glucocorticoids and mineralocorticoids are steroid hormones classically thought to be secreted exclusively by the adrenal glands. However, recent evidence has shown that corticosteroids can also be locally synthesized in various other tissues, including primary lymphoid organs, intestine, skin, brain, and possibly heart. Evidence for local synthesis includes detection of steroidogenic enzymes and high local corticosteroid levels, even after adrenalectomy. Local synthesis creates high corticosteroid concentrations in extra-adrenal organs, sometimes much higher than circulating concentrations. Interestingly, local corticosteroid synthesis can be regulated via locally expressed mediators of the hypothalamic-pituitary-adrenal (HPA) axis or renin-angiotensin system (RAS). In some tissues (e.g., skin), these local control pathways might form miniature analogs of the pathways that regulate adrenal corticosteroid production. Locally synthesized glucocorticoids regulate activation of immune cells, while locally synthesized mineralocorticoids regulate blood volume and pressure. The physiological importance of extra-adrenal glucocorticoids and mineralocorticoids has been shown, because inhibition of local synthesis has major effects even in adrenal-intact subjects. In sum, while adrenal secretion of glucocorticoids and mineralocorticoids into the blood coordinates multiple organ systems, local synthesis of corticosteroids results in high spatial specificity of steroid action. Taken together, studies of these five major organ systems challenge the conventional understanding of corticosteroid biosynthesis and function.

Fig. 1.

Simplified diagram of the classical corticosteroid synthetic pathway. Enzyme gene names are in italics and gray. StAR (steroidogenic acute regulatory protein) is required for translocation of cholesterol from the outer to the inner mitochondrial membrane, where CYP11A1 (P450 side-chain cleavage, or P450scc) catalyzes the conversion of cholesterol to pregnenolone. Further steroid conversions are performed by 3β-HSD (3β-hydroxysteroid dehydrogenase/Δ5–Δ4 isomerase), CYP17 (17α-hydroxylase/17,20-lyase, or P450c17), CYP21 (21-hydroxylase, or P450c21), CYP11B1 (11β-hydroxylase or P450c11β), CYP11B2 (aldosterone synthase or P450c11AS), 11β-HSD types 1 and 2.

Fig. 2.

Baseline endogenous glucocorticoid levels in plasma (A) and bursa of Fabricius (bursa; B) of developing zebra finches at ages 0, 3, and 30 days posthatch. The bursa is the site of B lymphocyte development, similar to mammalian bone marrow. Adapted with permission from Ref. .

Fig. 3.

Regulation and functions of local glucocorticoid synthesis. A: in the thymus, glucocorticoids and T cell receptor (TCR) signaling each function independently as proapoptotic stimuli in developing thymocytes. Glucocorticoids also antagonize TCR signaling and alter the threshold of TCR affinity for self peptide:MHC that results in survival and proliferation vs. apoptosis. B: in the intestine, activated macrophages and T_H1 cells secrete the proinflammatory cytokine TNFα, which upregulates the transcription factor LRH-1 in epithelial cells of the intestinal crypt. LRH-1 induces local production of glucocorticoids, which downregulate immune cell activation and resulting inflammation. C: activation of keratinocytes (and other types of skin cells) results in production of CRH, which stimulates production of ACTH and proinflammatory cytokines such as IL-1β and TNFα. ACTH then stimulates local synthesis of glucocorticoids, which inhibit further production of CRH and proinflammatory cytokines, thus downregulating inflammation. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; GCs, glucocorticoids; IFNγ, interferon-γ; IGF-1, insulin-like growth factor I; IL, interleukin; LRH-1, liver receptor homolog-1; MHC, major histocompatibility complex; T_H1, type I helper T cell; TNFα, tumor necrosis factor-α.

Fig. 4.

Effects of FAD286 (FAD, an inhibitor of CYP11B2 activity and aldosterone synthesis) on systolic blood pressure. Intracerebroventricular (icv) but not subcutaneous (sc) FAD administration decreases systolic blood pressure in hypertensive Dahl salt-sensitive rats. Crossover treatment demonstrates the reversibility of this effect. Importantly, all subjects were adrenal intact, and circulating aldosterone levels were similar in all groups at the conclusion of the experiment. Reprinted with permission from Ref. .