Limits...
Cell-to-cell communication in bilateral macronodular adrenal hyperplasia causing hypercortisolism.

Lefebvre H, Duparc C, Prévost G, Bertherat J, Louiset E - Front Endocrinol (Lausanne) (2015)

Bottom Line: In addition, the genetic events, which cause the disease, favor abnormal adrenal differentiation that results in illicit expression of paracrine regulatory factors and their receptors in adrenocortical cells.All these defects constitute the molecular basis for aberrant autocrine/paracrine regulatory mechanisms, which are likely to play a role in the pathophysiology of BMAH-associated hypercortisolism.The present review summarizes the current knowledge on this topic as well as the therapeutic perspectives offered by this new pathophysiological concept.

View Article: PubMed Central - PubMed

Affiliation: INSERM Unité 982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication , Mont-Saint-Aignan , France ; Institute for Research and Innovation in Biomedicine, Rouen University , Mont-Saint-Aignan , France ; Department of Endocrinology, Diabetes and Metabolic Diseases, University Hospital of Rouen , Rouen , France.

ABSTRACT
It has been well established that, in the human adrenal gland, cortisol secretion is not only controlled by circulating corticotropin but is also influenced by a wide variety of bioactive signals, including conventional neurotransmitters and neuropeptides, released within the cortex by various cell types such as chromaffin cells, neurons, cells of the immune system, adipocytes, and endothelial cells. These different types of cells are present in bilateral macronodular adrenal hyperplasia (BMAH), a rare etiology of primary adrenal Cushing's syndrome, where they appear intermingled with adrenocortical cells in the hyperplastic cortex. In addition, the genetic events, which cause the disease, favor abnormal adrenal differentiation that results in illicit expression of paracrine regulatory factors and their receptors in adrenocortical cells. All these defects constitute the molecular basis for aberrant autocrine/paracrine regulatory mechanisms, which are likely to play a role in the pathophysiology of BMAH-associated hypercortisolism. The present review summarizes the current knowledge on this topic as well as the therapeutic perspectives offered by this new pathophysiological concept.

No MeSH data available.


Related in: MedlinePlus

Catecholaminergic pathway in bilateral macronodular adrenal hyperplasia (BMAH) associated with Cushing’s syndrome. (A) Chromogranin A-positive chromaffin cells (arrows), which represent the main source of catecholamines in the normal adrenal gland, were in close contact with steroidogenic cells (arrow heads) in BMAH tissue. (B) Clonidine, an α2 receptor agonist, dose-dependently stimulated cortisol secretion by cultured adrenocortical cells derived from a BMAH tissue. Adapted from Ref. (47). (C) The maximum cortisol responses of cultured BMAH adrenocortical cells to high concentrations of ACTH (10−10 M) and clonidine (10−6 M) were not additive, suggesting that α2 and MC2R receptors are coupled to a common transduction pathway.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4403554&req=5

Figure 2: Catecholaminergic pathway in bilateral macronodular adrenal hyperplasia (BMAH) associated with Cushing’s syndrome. (A) Chromogranin A-positive chromaffin cells (arrows), which represent the main source of catecholamines in the normal adrenal gland, were in close contact with steroidogenic cells (arrow heads) in BMAH tissue. (B) Clonidine, an α2 receptor agonist, dose-dependently stimulated cortisol secretion by cultured adrenocortical cells derived from a BMAH tissue. Adapted from Ref. (47). (C) The maximum cortisol responses of cultured BMAH adrenocortical cells to high concentrations of ACTH (10−10 M) and clonidine (10−6 M) were not additive, suggesting that α2 and MC2R receptors are coupled to a common transduction pathway.

Mentions: The catecholamines adrenaline and noradrenaline are secreted by adrenal chromaffin cells under control of splanchnic nerve and proinflammatory cytokines. It has been hypothesized that catecholamines released by chromaffin cells present at the corticomedullary junction and in the cortex, may influence steroid production by adrenocortical cells, in particular during stress and inflammation (25, 27, 69). In support of this hypothesis, in vitro experiments have demonstrated that adrenaline and noradrenaline are able to modulate glucocorticoid production in frog and bovine adrenocortical cells (70, 71). However, there is no clear evidence for catecholamine responsiveness in human adrenal, since noradrenaline did not affect in vitro cortisol secretion by human normal adrenocortical cells (72). By contrast, abnormal catecholaminergic control of steroidogenesis has been documented in some patients with macronodular adrenal hyperplasia-associated with Cushing’s syndrome. Indeed, immunohistochemical studies have revealed the presence of clusters of chromogranin A-immunopositive chromaffin cells in the vicinity of steroidogenic cells, indicating paracrine interactions between the two cell types in hyperplastic tissues (24) (Figure 2A). In addition, abnormal elevations of plasma cortisol have been detected in patients placed in physiological conditions associated with increases in endogenous catecholamine, such as upright posture or insulin-induced hypoglycemia (22, 73). Moreover, increases in circulating cortisol levels provoked by administration of isoproterenol, a β-adrenergic receptor agonist, as well as decreases in plasma cortisol concentrations in response to infusion of propranolol, a β blocker, have given evidence for illicit β-adrenergic control of steroidogenesis (73–76). Aberrant expression of β adrenergic receptors in BMAH tissues has been confirmed by binding, RT-PCR, and functional in vitro experiments (22, 59, 73, 77). In particular, hypersensitivities to salbutamol and isoproterenol, two β2 receptor agonists, have been observed on cultured cells derived from BMAH tissues (22, 59). Our group has also demonstrated, by using molecular and cellular biological approaches, the occurrence of illegitimate α2-adrenergic receptors in BMAHs (47). In particular, in vivo and in vitro experiments have revealed that administration of the α2 receptor agonist clonidine stimulated cortisol synthesis in one BMAH case (47) (Figure 2B). Pharmacological studies have shown that the positive effect of clonidine on cortisol production resulted from activation of α2 receptors positively coupled to the adenylyl cyclase/PKA pathway (47). The absence of additive effects of high concentrations of ACTH and clonidine on cortisol production is consistent with a common transduction pathway for α2 and MC2R receptors (Figure 2C). Altogether, these data indicate that, in some BMAH tissues, the presence of chromaffin cells intermingled with steroidogenic cells expressing illegitimate β- or α2-adrenergic receptors, give rise to a positive adrenergic regulatory loop, which likely contributes to the pathogenesis of hypercortisolism.


Cell-to-cell communication in bilateral macronodular adrenal hyperplasia causing hypercortisolism.

Lefebvre H, Duparc C, Prévost G, Bertherat J, Louiset E - Front Endocrinol (Lausanne) (2015)

Catecholaminergic pathway in bilateral macronodular adrenal hyperplasia (BMAH) associated with Cushing’s syndrome. (A) Chromogranin A-positive chromaffin cells (arrows), which represent the main source of catecholamines in the normal adrenal gland, were in close contact with steroidogenic cells (arrow heads) in BMAH tissue. (B) Clonidine, an α2 receptor agonist, dose-dependently stimulated cortisol secretion by cultured adrenocortical cells derived from a BMAH tissue. Adapted from Ref. (47). (C) The maximum cortisol responses of cultured BMAH adrenocortical cells to high concentrations of ACTH (10−10 M) and clonidine (10−6 M) were not additive, suggesting that α2 and MC2R receptors are coupled to a common transduction pathway.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403554&req=5

Figure 2: Catecholaminergic pathway in bilateral macronodular adrenal hyperplasia (BMAH) associated with Cushing’s syndrome. (A) Chromogranin A-positive chromaffin cells (arrows), which represent the main source of catecholamines in the normal adrenal gland, were in close contact with steroidogenic cells (arrow heads) in BMAH tissue. (B) Clonidine, an α2 receptor agonist, dose-dependently stimulated cortisol secretion by cultured adrenocortical cells derived from a BMAH tissue. Adapted from Ref. (47). (C) The maximum cortisol responses of cultured BMAH adrenocortical cells to high concentrations of ACTH (10−10 M) and clonidine (10−6 M) were not additive, suggesting that α2 and MC2R receptors are coupled to a common transduction pathway.
Mentions: The catecholamines adrenaline and noradrenaline are secreted by adrenal chromaffin cells under control of splanchnic nerve and proinflammatory cytokines. It has been hypothesized that catecholamines released by chromaffin cells present at the corticomedullary junction and in the cortex, may influence steroid production by adrenocortical cells, in particular during stress and inflammation (25, 27, 69). In support of this hypothesis, in vitro experiments have demonstrated that adrenaline and noradrenaline are able to modulate glucocorticoid production in frog and bovine adrenocortical cells (70, 71). However, there is no clear evidence for catecholamine responsiveness in human adrenal, since noradrenaline did not affect in vitro cortisol secretion by human normal adrenocortical cells (72). By contrast, abnormal catecholaminergic control of steroidogenesis has been documented in some patients with macronodular adrenal hyperplasia-associated with Cushing’s syndrome. Indeed, immunohistochemical studies have revealed the presence of clusters of chromogranin A-immunopositive chromaffin cells in the vicinity of steroidogenic cells, indicating paracrine interactions between the two cell types in hyperplastic tissues (24) (Figure 2A). In addition, abnormal elevations of plasma cortisol have been detected in patients placed in physiological conditions associated with increases in endogenous catecholamine, such as upright posture or insulin-induced hypoglycemia (22, 73). Moreover, increases in circulating cortisol levels provoked by administration of isoproterenol, a β-adrenergic receptor agonist, as well as decreases in plasma cortisol concentrations in response to infusion of propranolol, a β blocker, have given evidence for illicit β-adrenergic control of steroidogenesis (73–76). Aberrant expression of β adrenergic receptors in BMAH tissues has been confirmed by binding, RT-PCR, and functional in vitro experiments (22, 59, 73, 77). In particular, hypersensitivities to salbutamol and isoproterenol, two β2 receptor agonists, have been observed on cultured cells derived from BMAH tissues (22, 59). Our group has also demonstrated, by using molecular and cellular biological approaches, the occurrence of illegitimate α2-adrenergic receptors in BMAHs (47). In particular, in vivo and in vitro experiments have revealed that administration of the α2 receptor agonist clonidine stimulated cortisol synthesis in one BMAH case (47) (Figure 2B). Pharmacological studies have shown that the positive effect of clonidine on cortisol production resulted from activation of α2 receptors positively coupled to the adenylyl cyclase/PKA pathway (47). The absence of additive effects of high concentrations of ACTH and clonidine on cortisol production is consistent with a common transduction pathway for α2 and MC2R receptors (Figure 2C). Altogether, these data indicate that, in some BMAH tissues, the presence of chromaffin cells intermingled with steroidogenic cells expressing illegitimate β- or α2-adrenergic receptors, give rise to a positive adrenergic regulatory loop, which likely contributes to the pathogenesis of hypercortisolism.

Bottom Line: In addition, the genetic events, which cause the disease, favor abnormal adrenal differentiation that results in illicit expression of paracrine regulatory factors and their receptors in adrenocortical cells.All these defects constitute the molecular basis for aberrant autocrine/paracrine regulatory mechanisms, which are likely to play a role in the pathophysiology of BMAH-associated hypercortisolism.The present review summarizes the current knowledge on this topic as well as the therapeutic perspectives offered by this new pathophysiological concept.

View Article: PubMed Central - PubMed

Affiliation: INSERM Unité 982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication , Mont-Saint-Aignan , France ; Institute for Research and Innovation in Biomedicine, Rouen University , Mont-Saint-Aignan , France ; Department of Endocrinology, Diabetes and Metabolic Diseases, University Hospital of Rouen , Rouen , France.

ABSTRACT
It has been well established that, in the human adrenal gland, cortisol secretion is not only controlled by circulating corticotropin but is also influenced by a wide variety of bioactive signals, including conventional neurotransmitters and neuropeptides, released within the cortex by various cell types such as chromaffin cells, neurons, cells of the immune system, adipocytes, and endothelial cells. These different types of cells are present in bilateral macronodular adrenal hyperplasia (BMAH), a rare etiology of primary adrenal Cushing's syndrome, where they appear intermingled with adrenocortical cells in the hyperplastic cortex. In addition, the genetic events, which cause the disease, favor abnormal adrenal differentiation that results in illicit expression of paracrine regulatory factors and their receptors in adrenocortical cells. All these defects constitute the molecular basis for aberrant autocrine/paracrine regulatory mechanisms, which are likely to play a role in the pathophysiology of BMAH-associated hypercortisolism. The present review summarizes the current knowledge on this topic as well as the therapeutic perspectives offered by this new pathophysiological concept.

No MeSH data available.


Related in: MedlinePlus