Role of serotonin in the paracrine control of adrenal steroidogenesis in physiological and pathophysiological conditions

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Role of serotonin in the paracrine control of adrenal steroidogenesis in physiological and pathophysiological conditions Estelle Louiset1, Céline Duparc1 and Hervé Lefebvre1,2 Abstract

Serotonin (5-hydroxytryptamine, 5-HT) and 5-HT receptors are present in adrenals from various species. In rats and humans, 5-HT mainly stimulates aldosterone secretion through activation of 5-HT7 and 5-HT4 receptors, respectively. The 5-HT-ergic control of adrenal steroidogenesis is strengthened in extreme physiological conditions such as sodium depletion and chronic stress. Especially, the emergence of a 5-HT regulatory loop in glucocorticoid-producing cells may be regarded as an adaptive mechanism aimed at potentiating the glucocorticoid response to stress. In humans, upregulation of the 5-HT signalling pathway occurs in aldosterone-producing adenomas and cortisol-producing hyperplasias and adenomas in response to overactivation of protein kinase A. These data suggest that the intra-adrenal 5-HT-ergic regulatory system represents a potential target for pharmacological treatments of primary adrenocortical diseases. Addresses 1 Normandie Univ, UNIROUEN, INSERM, U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, F76000 Rouen, France 2 Rouen University Hospital, Department of Endocrinology, Diabetes and Metabolic Diseases, F76000, Rouen, France Corresponding author: Louiset, Estelle ([email protected])

Current Opinion in Endocrine and Metabolic Research 2019, 8:50–59 This review comes from a themed issue on Adrenal Cortex Edited by André Lacroix and Enzo Lalli For a complete overview see the Issue and the Editorial Available online 18 July 2019 https://doi.org/10.1016/j.coemr.2019.07.003 2451-9650/© 2019 Elsevier Ltd. All rights reserved.

Keywords Adrenal, Steroidogenesis, Serotonin, Primary aldosteronism, Cushing’s syndrome, Paracrine communication, PKA pathway.

Introduction Serotonin (5-hydroxytryptamine, 5-HT) is synthesized from tryptophan which is first converted into 5hydroxytryptophan (5-HTP) by the rate-limiting enzyme tryptophan hydroxylase (TPH). Then, 5-HTP Current Opinion in Endocrine and Metabolic Research 2019, 8:50–59

is metabolized into 5-HT by a ubiquitous aromatic Lamino acid decarboxylase. TPH exists as two isoforms, namely TPH1 and TPH2, which differ in their distribution patterns [1,2]. TPH1 is expressed in nonneuronal tissues, whereas the presence of TPH2 is restricted to neurons. 5-HT is an important neurotransmitter involved in the regulation of multiple brain functions. However, only 5% of the endogenous 5-HT body content is found in the central nervous system [1]. In fact, the remaining 5-HT is localized in peripheral organs, especially in enterochromaffin cells of the gastrointestinal tract. In addition, intensive studies performed in the last decade have demonstrated that 5HT acts as a paracrine factor to regulate various physiological functions, including adaptation of the pancreatic b-cell mass during pregnancy and placental development [3,4]. In both human central nervous system and peripheral organs, 5-HT actions are mediated by 13 receptor subtypes classified into 7 types (5HT1 to 5-HT7). Six of the seven types of receptors belong to the G proteinecoupled receptor family [5]. In mammals, the adrenal gland is composed of two distinct structures, that is, the central medulla formed by catecholamine-producing chromaffin cells and the cortex constituted by steroidogenic cells at the periphery. In humans, the adult cortex is organized into three distinct layers, named glomerulosa, fasciculata and reticularis zonae. Zona glomerulosa cells synthesize aldosterone, a mineralocorticoid involved in sodium and potassium homeostasis. The zona fasciculata contains cells that produce glucocorticoids essential for glucose homeostasis, stress response and immunomodulation, while zona reticularis cells mainly secrete the androgen dehydroepiandrosterone (DHEA) and its sulfate. It is well established that adrenal steroidogenesis is stimulated by circulating factors. In particular, production of aldosterone is activated by the renin angiotensin system (RAS), whereas secretion of cortisol is regulated by corticotropin (adrenocorticotropic hormone [ACTH]) released by pituitary cells in response to the corticotropin-releasing hormone produced by hypothalamic neurons. Some data have provided evidence that 5-HT also regulates adrenal steroidogenesis through both indirect and direct actions. In particular, clinical www.sciencedirect.com

Serotonergic paracrine regulation in adrenal Louiset et al.

trials have revealed that administration of 5-HT precursors, 5-HT or 5-HT reuptake inhibitors to healthy volunteers and/or depressed patients results in an increase in plasma renin activity, which secondarily enhances aldosterone production [6e8]. 5-HT also exerts an indirect effect on glucocorticoid secretion by stimulating corticotropin-releasing hormone release from hypothalamic neurons and ACTH secretion by pituitary corticotrophs [9]. In addition, numerous data indicate that 5-HT produced in the adrenal gland directly stimulates steroidogenesis by adrenocortical cells through a paracrine mechanism. Interestingly, reinforcement of the 5-HT signalling pathway has been reported in adrenal lesions responsible for steroid hypersecretion, suggesting that the 5-HT-ergic control of corticosteroidogenesis may play a role in the pathogenesis of primary adrenal diseases [10e14]. The present review summarizes our current knowledge on the implication of 5-HT in the regulation of adrenal steroid hormone production in physiological and pathological conditions. It also discusses the potential interest of targeting the intra-adrenal 5-HT-ergic regulatory system for clinical management of patients with adrenocortical disorders.

Physiological role of 5-HT in adrenal steroidogenesis Occurrence of 5-HT in normal adrenal

The presence of 5-HT in the adrenal glands has been demonstrated in various species including fish, frogs, mice, rats, pigs, cattle and humans [15e21]. The cell types that contain 5-HT differ among species. For instance, 5-HT is exclusively detected in adrenal subcapsular mast cells in humans, whereas the monoamine is localized in chromaffin cells in fish, frogs, cattle and pigs, in both mast cells and chromaffin cells in rats as well as nerve fibres in mice [14e16,19,20,22] (Figure 1). 5-HT can be taken up from the plasma through the serotonin transporter (SERT) which is expressed in mouse, rat and human adrenals and/or de novo synthesized by the adrenal tissue from tryptophan under the influence of TPH [14,23,24]. In fact, in vivo experiments have demonstrated that the adrenal 5-HT content is dramatically reduced in SERT-deficient mice or rats [23,24]. In addition, internalization of 5HT in frog adrenal cells has been confirmed in vitro by using fluoxetine, an inhibitor of 5-HT uptake [25]. Because SERT is predominantly expressed in chromaffin cells, 5-HT uptake mainly occurs in the medulla. However, frog chromaffin cells are also able to synthesize 5-HT from 3H-labelled tryptophan [25]. Finally, the occurrence of TPH1 and 5-HT has been reported in adrenocortical cells from rats exposed to chronic stress [26]. www.sciencedirect.com

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Role of 5-HT in normal adrenal

5-HT secreted by the different cell types controls adrenal steroidogenesis through diverse mechanisms. For instance, the monoamine released by nerve fibres or mast cells in the vicinity of blood vessels [16,27] modulates blood flow, which is known to influence steroid synthesis [28]. Owing to the intermingling of chromaffin and steroidogenic cells in fish and amphibian adrenals, 5-HT secreted by chromaffin cells exerts a paracrine control on steroidogenesis [19] (Figure 1). In this regard, it has been demonstrated that 5-HT stimulates cortisol production in fish and increases both aldosterone and corticosterone secretion in frogs [19,29]. It must be noticed that such intercellular communication system may not occur in higher vertebrates because of the zonation of the adrenal gland and the centripetal direction of the blood flow. Conversely, cell-to-cell interactions exist between mast cells immunoreactive to TPH1 and 5-HT and aldosteroneproducing cells in the human zona glomerulosa [18,27]. Indeed, we have observed that mast cell secretory products upregulate expression of CYP11B2, encoding aldosterone synthase, and activate aldosterone secretion by the adrenocortical cell line H295R [27]. The decrease in the aldosterone response to mast celle conditioned medium induced by concomitant application of 5-HT receptor antagonists has revealed the important contribution of 5-HT to this intercellular communication process [27]. Similarly, experiments conducted ex vivo on explants of human adrenals have demonstrated that degranulation of intra-adrenal mast cells stimulates aldosterone production through release of 5-HT [18] (Figure 1). Consistently, 5-HT turns out to be more efficient on aldosterone than cortisol or DHEA secretion from cultured adrenocortical cells [30e32]. In addition, an increase in adrenal mast cell density precedes aldosterone synthase expression in the human foetal adrenal gland, suggesting that mast cells favour differentiation of aldosterone-producing cells during adrenal development [33]. Finally, it has been reported that the steroidogenic effects of 5-HT on the human adult adrenal is counteracted by monoamine oxidase type A which metabolizes 5-HT into inactive compounds as observed in serotonergic synapses [18]. Until now, the physiological stimulus eliciting 5-HT release by intra-adrenal mast cells remains unknown. The observation that nerve fibres establish connections with adrenal mast cells suggests that 5-HT may be produced in response to activation of the sympathetic system [27]. On the other hand, expression of angiotensin 2 receptors (AT2Rs) by rat mast cells [34] leads us to speculate on a potential role of RAS on 5-HT secretion by adrenal mast cells. In support of this hypothesis, our recent in vivo experiments conducted in mice have revealed that activation of circulating RAS by low-sodium diet is associated with adrenal upregulation Current Opinion in Endocrine and Metabolic Research 2019, 8:50–59

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Figure 1

Serotonergic control of adrenal steroidogenesis in different species. (A) In fish and amphibian adrenals, serotonin (5-HT) produced by chromaffin cells stimulates steroid secretion through a paracrine mechanism involving the 5-HT4 receptor. (B–C) In rodent and human adrenals, 5-HT released by mast cell located in zona glomerulosa (ZG) increases aldosterone synthesis via activation of 5-HT7 and 5-HT4 receptors, respectively. In mice, sodium depletion provokes activation of mast cells which might reinforce 5-HT secretion, and subsequently aldosterone production (B). In mammal adrenals, 5HT influences glucocorticoid secretion little or not in basal conditions. By contrast, huge and prolonged increase in plasma ACTH concentration, due to chronic stress or Cushing’s disease, favours expression of genes encoding the rate-limiting enzyme tryptophan hydroxylase (TPH) and 5-HT4, 5-HT6 and/ or 5-HT7 receptors in the zona fasciculata (ZF). Upregulation of the 5-HT signalling pathway may thus represent an adaptive mechanism potentiating the glucocorticoid response to ACTH. ZR, zona reticularis; MC2R, melanocortin type 2 receptor/ACTH receptor; DHEA, dehydroepiandrosterone; 5-HT, 5hydroxytryptamine; ACTH, adrenocorticotropic hormone.

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of Tpsb2 gene encoding tryptase, a mast cellespecific protease which reflects mast cell activation [35]. Moreover, Tpsb2 transcript level is positively correlated with Cyp11b2 gene expression, suggesting a common mechanism controlling these genes or an interdependent relationship between the two. Interestingly, the mast celledeficient KitW-sh/W-sh mouse strain develops an exaggerated aldosterone response to sodium restriction, consecutive to adrenal renin and angiotensin type 1 receptor overexpression [35]. Activation of adrenal RAS may be regarded as a compensatory mechanism enhancing aldosterone production in the absence of mast cells. It is not known whether similar regulatory system also occurs in human adrenal. Thus, it would be relevant to evaluate the mineralocorticoid function in response to sodium restriction in patients treated with mast cell stabilizers to prevent allergic disorders or in subjects with mast cell deficiency due to inactivating KIT mutation (i.e. patients with piebaldism). Altogether, the present data indicate that adrenal mast cells contribute to the control of mineralocorticoid synthesis in concert with circulating RAS. Nevertheless, the implication of 5-HT in this regulatory system remains to be investigated. Thus, it would be interesting to examine the aldosterone response to sodium restriction in 5-HTedeficient animals, such as TPH inhibitoretreated or TPH1-knockout mice [3]. Similarly, it would be worthy of note to test the effect of peripheral TPH inhibitors, currently used in the treatment of carcinoid syndrome, on plasma aldosterone concentration in healthy volunteers under normal- and low-sodium diets. 5-HT receptors in normal adrenal

Combinations of reverse transcriptase-polymerase chain reaction studies (RT-PCR), immunohistochemical and pharmacological experiments have revealed species specificities in the adrenal expression of 5-HT receptor subtypes. In particular, the steroidogenic effect of 5-HT is mediated by 5-HT4 receptors in fish, frogs and humans, whereas 5-HT7 receptors are involved in the aldosterone response to 5-HT in rats [19,36e38] (Figure 1). In contrast, the 5-HT receptors expressed in mouse adrenal have not yet been identified. In all species studied, both adrenal 5-HT4 and 5-HT7 receptors are positively coupled to AMPc/protein kinase A and membrane calcium channels, two transduction pathways that are known to activate steroidogenesis [31,37,38]. In humans, the distribution of the 5-HT4 receptor, which is abundant in the zona glomerulosa and weakly expressed in zonae fasciculata and reticularis, explains the higher efficacy of 5-HT to stimulate mineralocorticoid than glucocorticoid and androgen production [11,14,32]. The predominant effect of 5-HT on www.sciencedirect.com

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mineralocorticoid synthesis has been confirmed by clinical trials showing that 5-HT4 receptors agonists, such as metoclopramide, cisapride, zacopride, tegaserod and mosapride, increase plasma aldosterone levels without modifying circulating cortisol concentration in healthy volunteers [39e42]. Inhibition of the plasma aldosterone response to cisapride by piboserod, a 5-HT4 receptor antagonist, gave evidence for expression of functional 5-HT4 receptors in aldosterone-producing cells [43]. Unfortunately, the current lack of specific 5-HT4 receptor antagonists available for clinical use hampers in vivo investigation aimed at understanding the physiological role of adrenal 5-HT4 receptors. This problem could be circumvented by submitting healthy volunteers to a diet enriched with L-lysine which has been shown to act as a weak 5-HT4 receptor antagonist [44]. We observed that L-lysine supplementation expectedly decreased the plasma aldosterone response to the 5-HT4 receptor agonist metoclopramide but had no impact on plasma aldosterone adaptation to lowsodium diet and upright position [30]. Thus, the physiological role of adrenal 5-HT released by mast cells and 5-HT4 receptors remains to be established by conducting clinical studies with potent and selective 5-HT receptor antagonists. It is possible that a serotonergic control of glucocorticoid synthesis may be activated during specific physiological stimuli. In fact, ectopic synthesis of 5HT and 5-HT7 receptor overexpression in zona fasciculata has been described in rats submitted to chronic immobilization stress [26] (Figure 1). This process might result from activation of the adrenal cortex by the high plasma ACTH levels related to stress. In agreement with this interpretation, adrenals removed from patients with increased plasma ACTH concentrations, that is, patients with 21-hydroxylase deficiency, Cushing disease or paraneoplastic Cushing syndrome, harbour overexpression of TPH and 5-HT4/ 6/7 receptors [32]. Recent data obtained in the rat adrenal suggest that 5-HT synthesis and 5-HT7 receptor expression in the zona fasciculata may also result from the increase in glucocorticoid production induced by stress [45]. Upregulation of the 5-HT signalling pathway in the adrenal may thus be regarded as an adaptive mechanism aimed at potentiating the glucocorticoid response to stress through recruitment of intra-adrenal stimulatory signals whose action adds to that of circulating ACTH (Figure 2). Similar serotonergic paracrine-inducible systems have been previously reported in other organs. For instance, prolactin and placental lactogen produced during pregnancy stimulate production of TPH and 5-HT in b-pancreatic cells, a process which results in an increase in b-pancreatic cell mass and activation of insulin secretion [3]. In addition, oestrogens upregulate the serotonergic signalling pathway in placenta, as glucocorticoids in adrenals [46]. Current Opinion in Endocrine and Metabolic Research 2019, 8:50–59

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Figure 2

The serotonergic signalling pathway as an inducible paracrine process in endocrine tissues. (A) In response to chronic stress, the increase in plasma ACTH concentration upregulates the 5-HT signalling pathway in mammalian adrenals. Activation of the 5-HT regulatory loop enhances glucocorticoid synthesis. (B) During pregnancy, prolactin and placental lactogen stimulate the expression of TPH and 5-HT receptors in b-cells, a phenomenon which results in increased cell proliferation and insulin secretion. Upregulation of 5-HT synthesis and serotonergic receptors represents an adaptive mechanism aimed to potentiate the glucocorticoid response to stress through recruitment of intra-adrenal stimulatory signals and to enhance insulin production to counteract insulin resistance related to pregnancy, respectively. ACTH, adrenocorticotropic hormone; 5-HT, 5-hydroxytryptamine; TPH, tryptophan hydroxylase.

Globally, the observation that the adrenocortical function is controlled by 5-HT in adrenals of all studied species emphasizes its physiological importance. The action of 5-HT seems to be crucial for mineral and/or metabolic homeostasis, in particular, conditions linked to extreme events such as sodium depletion or chronic stress.

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Pathophysiological role of 5-HT in adrenal tumours Role of 5-HT in aldosterone-producing adenoma

There is increasing evidence that 5-HT plays a significant role in the aldosterone excess in patients with primary aldosteronism, in whom mineralocorticoid secretion is independent of the RAS. In particular, an increase in

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mast cell density has been reported in aldosteroneproducing adenomas (APAs), which likely leads to an enhancement of intra-adrenal production of 5-HT [11,27] (Figure 3). The strengthening of the 5-HTergic control of the mineralocorticoid function in APAs is also due to abnormal synthesis of 5-HT by a subpopulation of steroidogenic cells [11]. Furthermore, in vitro and in vivo studies revealed that adenoma cells are overresponsive to 5-HT. Indeed, patients with APAs show exaggerated plasma aldosterone responses to the 5-HT4 receptor agonists cisapride, metoclopramide and tegaserod in comparison with healthy volunteers [47e50]. Hypersensitivity of APAs to 5-HT4 receptor ligands results from overexpression of 5-HT4 receptors. For instance, many reports have described upregulation of 5HT4 receptors in APAs [11,49,51e54], which may be explained by hypomethylation of the promoter region of the HTR4 gene, encoding the 5-HT4 receptor [54]. Hypersensitivity of APA tissues to 5-HT4 receptor ligands may also be consecutive to abnormal splicing of HT4R transcripts giving rise to an expression pattern of 5HT4 receptor isoforms different to that observed in normal adrenals [11]. Collectively, these data suggest that targeting the 5-HT pathway may represent an efficient therapeutic approach to decrease aldosterone production in primary aldosteronism. Especially, clinical trials should be conducted to evaluate the effect of peripheral TPH inhibitors and/or 5-HT4 receptor antagonists (when available for human clinical studies) on plasma aldosterone concentrations in patients with APAs. Finally, clinical scientists may also take advantage of overexpression of 5-HT4 receptors in APAs to develop new adrenal imaging methods in vivo aimed at determining the lateralization of aldosterone secretion in primary aldosteronism. In fact, positron emission Figure 3

Serotonergic control of aldosterone secretion in primary aldosteronism. In aldosterone-producing adenomas (APAs), the intra-adrenal 5-HT signalling pathway is enhanced as a result of mast cell proliferation, ectopic synthesis of 5-HT in steroidogenic cells and overexpression of the 5-HT4 receptor. 5-HT, 5-hydroxytryptamine

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tomography scan imaging with radiolabeled 5-HT4Re specific ligands has already been used for functional brain imaging in humans, and adrenals have been successfully visualized in monkeys through this approach [55]. Role of 5-HT in primary Cushing’s syndrome

Owing to the weak effect of 5-HTon cortisol synthesis in physiological conditions, it was not expected that a 5-HTergic regulatory system could significantly influence glucocorticoid secretion by benign adrenal lesions in patients with primary Cushing’s syndrome. However, ectopic 5-HT production has been reported in steroidogenic cells in cortisol-producing adenomas (CPAs), primary bilateral macronodular adrenal hyperplasia (PBMAH) and primary pigmented nodular adrenocortical disease (PPNAD), responsible for cortisol overproduction [12,14,32,56]. This observation seems to result from local synthesis of the monoamine, as shown by abnormal expression of TPH in the adrenal tissues [14,32]. There is now a growing body of evidence showing that locally produced 5-HTexerts a paracrine stimulatory tone on glucocorticoid secretion: (1) 5-HT is detectable in the incubation medium of PPNAD tissue explants demonstrating the ability of steroidogenic cells to release the amine [14]; (2) 5-HT dose-dependently increases cortisol synthesis in cultured cells derived from patients with CPA, PBMAH and PPNAD, with higher potency and/or efficacy than normal adrenal [12,14,32,56]; (3) the TPH inhibitor p-chlorophenylalanine reduces cortisol production from CPA and PPNAD tissues in vitro [14,32]; (4) the action of 5-HT can be ascribed to abnormal expression of 5-HT4, 5-HT6 and/or 5-HT7 receptors evidenced by reverse transcription-quantitative polymerase chain reaction (RT-Q-PCR) and immunohistochemical studies [14,32,57]. The role of the 5-HT4 receptor in the control of glucocorticoid production was first evidenced in vivo by Lacroix et al [10] in a patient with PBMAH who showed an abnormal plasma cortisol response to the 5-HT4 receptor agonists cisapride and metoclopramide. Similar observations were subsequently reported in a series of patients with CPA and PBMAH associated with subclinical or overt hypercortisolism [12,58e62]. Owing to the lack of specific ligands for 5-HT6 and 5-HT7 receptors available for clinical studies, the contribution of these receptor subtypes to cortisol overproduction remains unknown. Recent studies have focused on the mechanism underlying the formation of illicit 5-HT regulatory loop in adrenal lesions. We have previously mentioned that the 5-HT signalling pathway in zona fasciculata represents an inducible system induced by high plasma ACTH levels. Because ACTH acts through melanocortin 2 receptors (MC2Rs) positively coupled to the cAMP/PKA pathway, we have hypothesized that chronic stimulation Current Opinion in Endocrine and Metabolic Research 2019, 8:50–59

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of the cAMP/PKA pathway may also trigger this adaptive process (Figure 4). In this respect, it is well established that CPA, PBMAH or PPNAD is frequently associated with constitutive activation of PKA resulting from germline or somatic mutations affecting proteins of the pathway. These mutations include gain-of-function mutations of MC2R, GNAS, PRKACA and PRKACB genes and inactivation mutations of the PRKAR1A,

PDE11A and PDE8B genes [63e65]. Stimulation of the cAMP/PKA pathway in PBMAH can also result from activation of both MC2R by locally produced ACTH [66] and illicit receptors by their natural ligands [13]. It is also possible that, as in rats under chronic stress, glucocorticoid overproduction in adrenal lesions may favour the emergence of the local 5-HT regulatory system. This process seems to be particularly probable

Figure 4

Serotonergic control of cortisol secretion in primary adrenal Cushing’s syndrome. (A) In physiological conditions, ACTH produced by pituitary cells stimulates cortisol synthesis through activation of MC2R positively coupled to the adenylyl cyclase (AC)/protein kinase A (PKA) pathway. PKA is an inactive tetramer composed by regulatory (R1a) and catalytic (Ca or Cb) subunits. In response to ACTH, cAMP produced by AC binds to regulatory subunits resulting in the release of catalytic subunits. Catalytic subunits then phosphorylate proteins leading to an increase in cortisol synthesis and transcription of target genes. Phosphodiesterases (PDEs) degrade cAMP to stop signal transduction. (B) In patients with primary adrenal Cushing’s syndrome, the adrenal cAMP/PKA pathway is reinforced due to (i) gain-of-function mutations of PRKACA and PRKACB genes (encoding Ca and Cb), (ii) inactivating mutations of PRKAR1A, PDE11A and PDE8B genes (encoding R1a and PDEs), (iii) intra-adrenal ACTH production in PBMAH and (iv) activation of illicit receptors (LH or GIP receptors). Reinforcement of the cAMP/PKA pathway stimulates expression of genes encoding TPH, 5HT4, 5-HT6 and/or 5-HT7 receptors giving rise to an illicit 5-HT stimulatory loop that participates in activation of cortisol synthesis. ACTH, adrenocorticotropic hormone; 5-HT, 5-hydroxytryptamine; TPH, tryptophan hydroxylase; PBMAH, primary bilateral macronodular adrenal hyperplasia; MC2R, melanocortin type 2 receptor; LH, Luteinizing hormone; GIP, Glucose-dependent insulinotropic peptide.

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in PPNAD tissues, in which glucocorticoid receptors are overexpressed [67]. In addition, the presence of glucocorticoid-responsive elements in the promoter of the HTR6 gene might lead to its upregulation in cortisolproducing adrenal neoplasia [68]. In conclusion, all these data indicate that the illicit paracrine serotonergic mechanism occurring in benign adrenal neoplasias may play a role in the pathogenesis of corticosteroid excess and consequently represent a potential target for pharmacological treatments of hypercorticisms. In this respect, because different 5-HT receptor types are expressed in cortisol-producing adenomas and hyperplasias, the most efficient therapeutic strategy aimed at counteracting in vivo the 5-HT-ergic tone on cortisol production would be to reduce 5-HT synthesis by using TPH inhibitors rather than blocking 5-HT receptors by specific antagonists. In contrast, 5HT4 receptor antagonists may be regarded as new potential antialdosterone drugs for the clinical management of primary aldosteronism.

Acknowledgements ´ et de la This work was supported by the Institut National de la Sante ´dicale, the Conseil Re ´gional de Haute Normandie, the Recherche Me ´te ´ Franc¸aise European Regional Development Fund and the Socie d’Endocrinologie.

Conflict of interest statement Nothing declared.

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