Taves MD, Gomez-Sanchez CE, Soma KK. Extra-adrenal glucocorticoids and mineralocorticoids: evidence for local synthesis, regulation, and function. Am J Physiol Endocrinol Metab 301: E11-E24, 2011. First published May 3, 2011; doi:10.1152/ajpendo.00100.2011.-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.aldosterone; brain; bursa of Fabricius; corticosterone; cortisol; heart; immunosteroids; intestine; neurosteroids; skin; stress; thymus CORTICOSTEROIDS ARE STEROID HORMONES produced in the adrenal cortex and are of two types, glucocorticoids and mineralocorticoids. Glucocorticoids, such as corticosterone and cortisol, have numerous effects and can act on nearly all cells in the body. For example, glucocorticoids regulate metabolic activity, immune function, and behavior (84). Circulating glucocorticoid levels increase in response to a variety of stressors under control of the hypothalamic-pituitary-adrenal (HPA) axis. Hypothalamic release of corticotropin-releasing hormone (CRH) triggers pituitary release of adrenocorticotropic hormone (ACTH), which stimulates glucocorticoid production by the zona fasciculata of the adrenals. The adrenals can secrete cortisol, corticosterone, or both, depending on the species.Mineralocorticoids, such as aldosterone, promote sodium reabsorption in transporting epithelia of the kidneys, salivary glands, and large intestine. Sodium reabsorption is followed by passive reabsorption of water. Circulating aldosterone concentrations...

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Glucocorticoids (GCs) are produced by the adrenal glands and circulate in the blood to coordinate organismal physiology. In addition, different tissues may independently regulate their local GC levels via local GC synthesis. Here, we find that in the mouse, endogenous GCs show tissue-specific developmental patterns, rather than mirroring GCs in the blood. Using solid-phase extraction, HPLC, and specific immunoassays, we quantified endogenous steroids and found that in tissues of female and male mice, (1) local GC levels can be much higher than systemic GC levels, (2) local GCs follow age-related patterns different from those of systemic GCs, and (3) local GCs have identities different from those of systemic GCs. For example, whereas corticosterone is the predominant circulating adrenal GC in mice, high concentrations of cortisol were measured in neonatal thymus, bone marrow, and heart. The presence of cortisol was confirmed with liquid chromatography-tandem mass spectrometry. In addition, gene expression of steroidogenic enzymes was detected across multiple tissues, consistent with local GC production. Our results demonstrate that local GCs can differ from GCs in circulating blood. This finding suggests that steroids are widely used as local (paracrine or autocrine) signals, in addition to their classic role as systemic (endocrine) signals. Local GC regulation may even be the norm, rather than the exception, especially during development.