With this Research Topic, we want to celebrate 80 years of research on the role of adrenocorticot... more With this Research Topic, we want to celebrate 80 years of research on the role of adrenocorticotropic hormone (ACTH) on the adrenal cortex, from the pioneering work by Selye, who introduced the concept of "general adaptation syndrome" in a short Letter to Nature (1). Selye described the general adaptation syndrome, later renamed stress, as a response of the body to demands placed upon it. The system whereby the body copes with stress, the hypothalamo-pituitary-adrenal (HPA) axis, was also first described by Szabo et al. (2). From a historical standpoint, Selye actively avoided using the term "stress" until 1946. It was Walter Cannon who actually developed the term stress in his work relating to the fight-or-flight response in 1914 (2, 3). Because it was clear that most people viewed stress as some unpleasant threat, Selye had to create a new word, "stressor, " in order to distinguish between stimulus and response (3). It is also important to remember that Selye was the first to describe "corticoids" and to propose that glucocorticoids and mineralocorticoids (also named by Selye) regulated not only carbohydrate and electrolyte metabolism, respectively, but also exerted anti-or pro-inflammatory effects . By stimulating adrenal corticosteroids synthesis, the ACTH, first isolated in 1943 ( ) and then synthesized in 1960s and 1970s (see the review by Ghaddhab et al.), plays a central role in homeostasis and stress response and thus is a key component of the HPA axis. This Research Topic is a compendium of reviews and original contributions, which summarize classical views, novel findings, and challenges on the various mechanisms involved in ACTH action, from the binding of ACTH to its receptor to steroid secretion. The Research Topic also reviews the pathological consequences of the disruption of specific components of these pathways. The adult mammalian adrenal cortex is composed of three concentric layers, each having specific functional and morphological properties. ACTH is the main stimulus of the zona fasciculata and zona reticularis, stimulating glucocorticoids secretion, while angiotensin II and potassium are the main stimuli of aldosterone secretion by the zona glomerulosa. Glucocorticoids (cortisol, corticosterone, cortisone) are implicated in a broad range of metabolic functions, including antiinflammatory responses, stress response, and behavior. However, chronically elevated glucocorticoid levels alter body protein synthesis, fat distribution, increase visceral adiposity, and are responsible for metabolic abnormalities, such as hypertension, type 2 diabetes, or sleep disturbance. On the other hand, aldosterone stimulates sodium reabsorption, hence maintaining blood volume and pressure in sodium-depleted conditions. Excessive aldosterone secretion not only leads to hypertension and
ACTH-independent Cushing's syndrome (CS) usually results from a solitary adrenocortical adenoma. ... more ACTH-independent Cushing's syndrome (CS) usually results from a solitary adrenocortical adenoma. We recently encountered a patient with ACTH-independent CS associated with bilateral adrenal enlargement. The evaluation led us to consider some rare but interesting entities. The patient was a 69 year-old woman who had a 10-15 year history of controlled hypertension, back pain associated with osteoporosis, easy bruising, and truncal obesity. Her medications included conjugated estrogens. Physical examination revealed classical features of CS. She had a raised blue lesion on her buccal mucosa. Plasma cortisol concentrations were elevated at 36 (a.m.) and 38 (p.m.) µg/dL. Urinary free cortisol was normal at baseline (65 µg/24 hours) but failed to suppress adequately in response to the low-dose dexamethasone suppression test (75 µg/24 hours). The plasma ACTH concentration was undetectable. Plasma cortisol concentrations failed to suppress (37 µg/dL) with an 8 mg overnight dexamethasone test. A CT scan of the abdomen revealed bilateral adrenal masses. The possibilities of food-induced CS and primary pigmented nodular adrenal disease were excluded by a lack of marked stimulation in cortisol secretion to a mixed-meal and dermatologic confirmation of the buccal mucosa lesion as an angioma and not a blue nevus. Adrenal venous sampling showed cortisol secretion from both adrenals. The patient underwent bilateral adrenalectomy with pathology confirming bilateral adenomas. This case illustrates an unusual application of selective venous sampling in the CS evaluation and raises questions about the pathogenesis of cortisol-secreting adrenocortical adenomas.(Endocr Pract.
The Journal of Clinical Endocrinology and Metabolism, Sep 30, 2020
Context: In primary aldosteronism (PA), aldosterone secretion is relatively independent of the re... more Context: In primary aldosteronism (PA), aldosterone secretion is relatively independent of the renin-angiotensin system, but can be regulated by several other stimuli. Objective: To evaluate aldosterone response to several stimuli in a series of patients with PA secondary either to bilateral adrenal hyperplasia (BAH) or unilateral aldosteroneproducing adenoma (APA). Design and setting: Prospective cohort study conducted in a university teaching hospital research center. Patients: Forty-three patients with confirmed PA and subtyped by adrenal vein sampling (n = 39) were studied, including 11 with BAH, 28 with APA, and 4 with undefined etiology. We also studied 4 other patients with aldosterone and cortisol cosecretion. Interventions: We systematically explored aberrant regulation of aldosterone using an in vivo protocol that included the following stimulation tests performed over 3 days under dexamethasone suppression: upright posture, mixed meal, adrenocorticotropin (ACTH) 1-24, gonadotropin-releasing hormone (GnRH), vasopressin, and serotonin R4 agonist. Main outcome measures: Positive response was defined as >50% renin or ACTHindependent increase in plasma aldosterone/cortisol concentration following the various stimulation tests. Results: Renin-independent aldosterone secretion increased in response to several aberrant stimuli (upright posture, GnRH
Arquivos Brasileiros De Endocrinologia E Metabologia, Nov 1, 2007
ACTH-Independent macronodular adrenal hyperplasia (AIMAH) is a rare cause of endogenous Cushing's... more ACTH-Independent macronodular adrenal hyperplasia (AIMAH) is a rare cause of endogenous Cushing's syndrome (CS), in which clinical features usually become apparent only after several decades of life. This form of adrenal hyperplasia typically produces excess cortisol with overt or subclinical CS, but concurrent secretion of mineralocorticoids or sexual steroids can also occur. The diagnosis is suspected by bilateral adrenal nodules larger than 1 cm on incidental imaging studies or following the demonstration of ACTH-independent hormonal hypersecretion. The pathophysiology of this entity is heterogeneous and has been intensely explored in recent years. Several G-protein coupled receptors aberrantly expressed in the adrenal cortex have been implicated in the regulation of steroidogenesis and in the initial cell proliferation in AIMAH. Several familial cases of AIMAH have been recently described with the same pattern of aberrant hormone receptors in all affected members of the family. It is probable that additional somatic genetic events related to cell cycle regulation, adhesion and transcription factors occur in addition over time in the various nodules; other mechanisms, as Gsp or ACTH receptor mutations and paracrine adrenal hormonal secretion have been rarely identified as the molecular mechanism in some cases. When systematically screened, most patients with AIMAH exhibit an in vivo aberrant cortisol response to one or various ligands suggesting the presence of aberrant adrenal receptors. The identification of these receptors creates the possibility of a specific pharmacological treatment isolated or associated with adrenalectomy.
Best Practice & Research Clinical Endocrinology & Metabolism, May 1, 2020
Adrenocortical hyperplasia may develop in different contexts. Primary adrenal hyperplasia may be ... more Adrenocortical hyperplasia may develop in different contexts. Primary adrenal hyperplasia may be secondary to primary bilateral macronodular adrenocortical hyperplasia (PBMAH) or micronodular bilateral adrenal hyperplasia (MiBAH) which may be divided in primary pigmented nodular adrenocortical disease (PPNAD) and isolated micronodular adrenocortical disease (i-MAD). Both lead to oversecretion of cortisol and potentially to Cushing's syndrome. Moreover, adrenocortical hyperplasia may be secondary to longstanding ACTH stimulation in ACTH oversecretion as in Cushing's disease, ectopic ACTH secretion or glucocorticoid resistance syndrome and congenital adrenal hyperplasia secondary to various enzymatic defects within the cortex. Finally, idiopathic bilateral adrenal hyperplasia is the most common cause of primary aldosteronism. We will discuss recent findings on the multifaceted forms of adrenocortical hyperplasia.
The investigation and management of unilateral adrenal incidentalomas have been extensively consi... more The investigation and management of unilateral adrenal incidentalomas have been extensively considered in the last decades. While bilateral adrenal incidentalomas represent about 15% of adrenal incidentalomas (AIs), they have been less frequently discussed. The differential diagnosis of bilateral incidentalomas includes metastasis, primary bilateral macronodular adrenal hyperplasia and bilateral cortical adenomas. Less frequent etiologies are bilateral pheochromocytomas, congenital adrenal hyperplasia (CAH), Cushing's disease or ectopic ACTH secretion with secondary bilateral adrenal hyperplasia, primary malignancies, myelolipomas, infections or hemorrhage. The investigation of bilateral incidentalomas includes the same hormonal evaluation to exclude excess hormone secretion as recommended in unilateral AI, but diagnosis of CAH and adrenal insufficiency should also be excluded. This review is focused on the differential diagnosis, investigation and treatment of bilateral AIs.
Thirty years ago, we identified that cortisol secretion in some patients with unilateral adenoma ... more Thirty years ago, we identified that cortisol secretion in some patients with unilateral adenoma or primary bilateral macronodular adrenal hyperplasia (PBMAH) was stimulated by food intake; this was secondary to the abnormal adrenocortical responsiveness to physiological postprandial increase in glucose-dependent insulinotropic peptide (GIP). This resulted from the ectopic expression of non-mutated GIP receptor in the pathological adrenal tissues of those patients. Although ectopic GIP receptor (GIPR) was confirmed in a relatively limited number of cases to date, its elucidation leads to the identification of a wide diversity of aberrant G-protein-coupled receptors regulating steroidogenesis and cell proliferation in a high proportion of patients with PBMAH or cortisol-secreting adenomas. In addition, ectopic GIPR was identified in other endocrine tumors including somatotroph pituitary tumors with paradoxical growth hormone response to oral glucose, medullary thyroid carcinomas, and other neuroendocrine tumors. The first molecular pathogenic mechanism responsible for ectopic GIPR expression was elucidated in unilateral GIP-dependent adenomas in which somatic duplication and rearrangements in chromosome region 19q13.32 containing the GIPR locus lead to increased expression of GIPR which was enhanced by the activity of a glucocorticoid response element. Recently, germline lysine demythylase 1A (KDMIA) mutations combined with somatic chromosome 1p deletions were found to be specifically responsible for ectopic GIPR in sporadic or familial GIP-dependent PBMAH and can be associated with adrenal myelolipoma, monoclonal gammopathy of unknown significance (MGUS), or multiple myeloma. Screening for ectopic GIPR should be conducted in all patients with PBMAH; genetic studies to identify KDM1A mutations should be offered to such patients in order to detect affected members and provide early detection of PBMAH and other potential associated neoplasias. The elucidation of GIP-dependent Cushing's syndrome (CS) illustrates that careful bedside phenotyping of rare conditions can lead to identification of genetically determined diseases requiring personalized approaches to investigation and therapy.
AIMAH. When systematically screened, most patients with AIMAH and CS or subclinical CS exhibit an... more AIMAH. When systematically screened, most patients with AIMAH and CS or subclinical CS exhibit an in vivo aberrant cortisol response to one or various ligands suggesting the presence of aberrant adrenal receptors. A protocol designed to screen patients for the presence of these aberrant receptors should be undertaken in all patients with AIMAH. The identifi cation of these receptors provides the potential for novel pharmacological therapies by suppressing the endogenous ligands or blocking the receptor with specifi c antagonists.
Background: Pheochromocytoma (PHEO) and paragangliomas (PGL) (PPGL) may recur after initial surge... more Background: Pheochromocytoma (PHEO) and paragangliomas (PGL) (PPGL) may recur after initial surgery and the long-term postoperative management is unclear. Recent guidelines suggested screening for recurrence with yearly metanephrines for 10 years and lifelong in high risk patients (young, genetic disease, large tumors and/or PGL). In addition, very recent data suggest that recurrence rate is lower than previously estimated and mainly occur within the first five years of follow-up. Objective: To evaluate the characteristics and delay of recurrent PPGL in our center. Methods: We retrospectively analysed characteristics of patients with PPGL who had recurrent disease between 1994 and 2017. We collected data on clinical presentation, imaging, functional status, genetic testing, treatment and outcomes of patients with recurrent disease. Results: Our cohort included 29 patients. The mean age at diagnosis was 45.9 and 54.5 at recurrence. Thirteen patients had PHEO and 16 had PGL. The mean delay of recurrence was 7.8 years, with 13 patients (44.8%) recurring before 5 years of follow-up, 10 (34, 5%) between 5-10 years, 4 (13,8%) between 10-15 years and 2 at 21 (PGL) and 48 (PHE) years of follow up respectively. Nine of the 14 patients (64,3%) genetically tested had an identifiable germline mutation. Four patients with PHEO had initial tumors size of less than 5 cm. Conclusion: In our cohort, postoperative recurrence of apparently benign PPGL occurred after more than 10 years of follow up in 20,7% of cases, supporting that patients operated for PPGL should have a lifelong follow-up surveillance.
Current Opinion in Endocrinology, Diabetes and Obesity, Jun 1, 2007
Endogenous Cushing's syndrome is adrenocorticotropic hormone (or corticotropin)-independent ... more Endogenous Cushing's syndrome is adrenocorticotropic hormone (or corticotropin)-independent in 15-20% of cases. Primary Cushing's syndrome is most often secondary to adrenocortical adenomas or carcinomas, and more rarely to bilateral adrenal hyperplasias. Corticotropin-independent cortisol-producing hyperplasia is caused by micronodular diseases, including primary pigmented nodular adrenocortical disease and nonpigmented micronodular hyperplasia and adrenocorticotropic hormone-independent macronodular adrenal hyperplasia. Primary pigmented nodular adrenocortical disease can be found either alone or in the context of Carney complex, a multiple endocrine neoplasia syndrome.
In recent years, a novel understanding of the pathophysiology of adrenal Cushing's syndrome has e... more In recent years, a novel understanding of the pathophysiology of adrenal Cushing's syndrome has emerged. The ectopic or aberrant expression of G-proteincoupled hormone receptors in the adrenal cortex was found to play a central role in the regulation of cortisol secretion in ACTH-independent macronodular adrenal hyperplasia (AIMAH) and in some unilateral adrenal adenomas. Various aberrant receptors, functionally coupled to steroidogenesis, have been reported: GIP, vasopressin, β-adrenergic, LH/hCG, and serotonin receptors have been best characterized, but angiotensin, leptin, glucagon, IL-1 and TSH receptors have also been described. The molecular mechanisms responsible for the aberrant expression of these receptors are currently unknown. One or many of these aberrant receptors are present in most cases of AIMAH and in some cases of adrenal adenomas with overt or sub-clinical secretion of cortisol. Clinical protocols to screen for such aberrant receptors have been developed and should be performed in all patients with AIMAH. The identification of such aberrant regulation of steroidogenesis in AIMAH provides the novel opportunity to treat some of these patients with pharmacological agents that either suppress the endogenous ligand or block the aberrant receptor, thus avoiding bilateral adrenalectomy.
The Journal of Clinical Endocrinology and Metabolism, Sep 1, 2006
The mechanisms responsible for the ectopic adrenal expression of glucose-dependent insulinotropic... more The mechanisms responsible for the ectopic adrenal expression of glucose-dependent insulinotropic peptide (GIP) receptor (GIPR) in GIP-dependent Cushing's syndrome (CS) are unknown. Chronic adrenal stimulation by ACTH in Cushing's disease or GIP in GIP-dependent ACTH-independent macronodular adrenal hyperplasia both lead to the induction of genes implicated in adrenal proliferation and steroidogenesis. The objective of the study was to identify genes differentially expressed specifically in GIP-dependent CS that could be implicated in the ectopic expression of GIPR. Methods: We used the Affymetrix U133 plus 2.0 microarray oligochips to compare the whole genome expression profile of adrenal tissues from five cases of GIP-dependent bilateral ACTH-independent macronodular adrenal hyperplasia with CS, one case of GIP-dependent unilateral adenoma with CS, five cases of ACTH-dependent hyperplasias, and a pool of adrenals from 62 normal individuals. Results: After data normalization and statistical filtering, 723 genes with differential expression were identified, including 461 genes or sequences with a known functional implication, classified in eight dominant functional classes. Specific findings include repression of perilipin, the overexpression of 13 G protein-coupled receptors, and the potential involvement of Rho-GTPases. We also isolated 94 probe sets potentially linked to the formation of GIP-dependent nodules adjacent to the diffuse hyperplasia. These included probe sets related to the linker histone H1 and repression of RXRa and CCND2. The expression profiles for eight genes were confirmed by real-time RT-PCR. This study identified an extensive series of potentially novel target candidate genes that could be implicated in the molecular mechanisms of ectopic expression of the GIPR as well as in the multistep progression of GIP-dependent CS.
Needle tract seeding is a potential, albeit rare, complication following transcutaneous biopsies,... more Needle tract seeding is a potential, albeit rare, complication following transcutaneous biopsies, leading to the seeding of tumor cells along the path of the needle. Biopsies of adrenal masses are not routinely recommended and are only indicated, after exclusion of pheochromocytoma, when an adrenal metastasis of a primary extra-adrenal cancer is suspected or when pathological confirmation of inoperable adrenocortical cancer (ACC) may impact treatment. Despite guideline recommendations to avoid primary adrenal biopsy, very few needle tract seeding cases have been reported and none were in the context of an ACC. We report the occurrence of needle tract seeding in a patient following adrenal transcutaneous biopsy leading to ACC abdominal wall recurrence.
Journal of Vascular and Interventional Radiology, Feb 1, 2010
PowerWireTM (Baylis Medical Company, Montreal, QC, Canada) RF wire was advanced within a 5-Fr KMP... more PowerWireTM (Baylis Medical Company, Montreal, QC, Canada) RF wire was advanced within a 5-Fr KMP catheter. A straight wire tip combined with a semi-curved catheter provides higher precision during the tissue puncture. Once in contact with the occlusion site, the RF energy was delivered while the wire was gently advanced for a few millimeters at a time towards a target catheter placed in the opposite venous side. Once RF wire access was obtained to the contra-lateral side of the obstruction, a loop snare was used to assist the catheterization. The KMP catheter was advanced and the RF wire was exchanged for a stiffer wire and six/eight millimeters balloon angioplasties were followed by stent or stent-graft placement. If the puncture was inadequate, a new location was pursued. Results: Four patients were successfully treated with RF wire after previous failed attempts at recanalization using mechanical catheter/wire techniques. In two patients the procedure was aborted, in one due to hemothorax successfully treated with chest tube without clinical repercussions. All the successfully treated patients had resolution of symptoms in a 4(2-8)months mean follow up. RF wire offers a promising alternative in the recanalization of benign chronic central venous occlusions when conventional techniques failed.
The Journal of Clinical Endocrinology and Metabolism, Sep 30, 2022
Background Adrenal tumors are found in up to 40% of patients with multiple endocrine neoplasia ty... more Background Adrenal tumors are found in up to 40% of patients with multiple endocrine neoplasia type 1 (MEN1). However, adrenocortical carcinomas (ACC) and primary aldosteronism (PA) are rare in MEN1. Case A 48-year-old woman known to have primary hyperparathyroidism and hypertension with hypokalemia was referred for a right complex 8-cm adrenal mass with a 38.1 SUVmax uptake on 18F-FDG PET/CT. PA was confirmed by saline suppression test (aldosterone 1948 pmol/L-1675 pmol/L; normal range [N]: <165 post saline infusion) and suppressed renin levels (<5 ng/L; N: 5-20). Catecholamines, androgens, 24-hour urinary cortisol, and pituitary panel were normal. A right open adrenalectomy revealed a concomitant 4-cm oncocytic ACC and a 2.3-cm adrenocortical adenoma. Immunohistochemistry showed high expression of aldosterone synthase protein in the adenoma but not in the ACC, supporting excess aldosterone production by the adenoma. Genetic analysis After genetic counseling, the patient underwent genetic analysis of leucocyte and tumoral DNA. Sequencing of MEN1 revealed a heterozygous germline pathogenic variant in MEN1 (c.1556delC, p.Pro519Leufs*40). The wild-type MEN1 allele was lost in the tumoral DNA of both the resected adenoma and carcinoma. Sequencing analysis of driver genes in PA revealed a somatic pathogenic variant in exon 2 of the KCNJ5 gene (c.451G>A, p.Gly151Arg) only in the aldosteronoma. Conclusion To our knowledge, we describe the first case of adrenal collision tumors in a patient carrying a germline pathogenic variant of the MEN1 gene associated with MEN1 loss of heterozygosity in both oncocytic ACC and adenoma and a somatic KCNJ5 pathogenic variant leading to aldosterone-producing adenoma. This case gives new insights on adrenal tumorigenesis in MEN1 patients.
With this Research Topic, we want to celebrate 80 years of research on the role of adrenocorticot... more With this Research Topic, we want to celebrate 80 years of research on the role of adrenocorticotropic hormone (ACTH) on the adrenal cortex, from the pioneering work by Selye, who introduced the concept of "general adaptation syndrome" in a short Letter to Nature (1). Selye described the general adaptation syndrome, later renamed stress, as a response of the body to demands placed upon it. The system whereby the body copes with stress, the hypothalamo-pituitary-adrenal (HPA) axis, was also first described by Szabo et al. (2). From a historical standpoint, Selye actively avoided using the term "stress" until 1946. It was Walter Cannon who actually developed the term stress in his work relating to the fight-or-flight response in 1914 (2, 3). Because it was clear that most people viewed stress as some unpleasant threat, Selye had to create a new word, "stressor, " in order to distinguish between stimulus and response (3). It is also important to remember that Selye was the first to describe "corticoids" and to propose that glucocorticoids and mineralocorticoids (also named by Selye) regulated not only carbohydrate and electrolyte metabolism, respectively, but also exerted anti-or pro-inflammatory effects . By stimulating adrenal corticosteroids synthesis, the ACTH, first isolated in 1943 ( ) and then synthesized in 1960s and 1970s (see the review by Ghaddhab et al.), plays a central role in homeostasis and stress response and thus is a key component of the HPA axis. This Research Topic is a compendium of reviews and original contributions, which summarize classical views, novel findings, and challenges on the various mechanisms involved in ACTH action, from the binding of ACTH to its receptor to steroid secretion. The Research Topic also reviews the pathological consequences of the disruption of specific components of these pathways. The adult mammalian adrenal cortex is composed of three concentric layers, each having specific functional and morphological properties. ACTH is the main stimulus of the zona fasciculata and zona reticularis, stimulating glucocorticoids secretion, while angiotensin II and potassium are the main stimuli of aldosterone secretion by the zona glomerulosa. Glucocorticoids (cortisol, corticosterone, cortisone) are implicated in a broad range of metabolic functions, including antiinflammatory responses, stress response, and behavior. However, chronically elevated glucocorticoid levels alter body protein synthesis, fat distribution, increase visceral adiposity, and are responsible for metabolic abnormalities, such as hypertension, type 2 diabetes, or sleep disturbance. On the other hand, aldosterone stimulates sodium reabsorption, hence maintaining blood volume and pressure in sodium-depleted conditions. Excessive aldosterone secretion not only leads to hypertension and
ACTH-independent Cushing's syndrome (CS) usually results from a solitary adrenocortical adenoma. ... more ACTH-independent Cushing's syndrome (CS) usually results from a solitary adrenocortical adenoma. We recently encountered a patient with ACTH-independent CS associated with bilateral adrenal enlargement. The evaluation led us to consider some rare but interesting entities. The patient was a 69 year-old woman who had a 10-15 year history of controlled hypertension, back pain associated with osteoporosis, easy bruising, and truncal obesity. Her medications included conjugated estrogens. Physical examination revealed classical features of CS. She had a raised blue lesion on her buccal mucosa. Plasma cortisol concentrations were elevated at 36 (a.m.) and 38 (p.m.) µg/dL. Urinary free cortisol was normal at baseline (65 µg/24 hours) but failed to suppress adequately in response to the low-dose dexamethasone suppression test (75 µg/24 hours). The plasma ACTH concentration was undetectable. Plasma cortisol concentrations failed to suppress (37 µg/dL) with an 8 mg overnight dexamethasone test. A CT scan of the abdomen revealed bilateral adrenal masses. The possibilities of food-induced CS and primary pigmented nodular adrenal disease were excluded by a lack of marked stimulation in cortisol secretion to a mixed-meal and dermatologic confirmation of the buccal mucosa lesion as an angioma and not a blue nevus. Adrenal venous sampling showed cortisol secretion from both adrenals. The patient underwent bilateral adrenalectomy with pathology confirming bilateral adenomas. This case illustrates an unusual application of selective venous sampling in the CS evaluation and raises questions about the pathogenesis of cortisol-secreting adrenocortical adenomas.(Endocr Pract.
The Journal of Clinical Endocrinology and Metabolism, Sep 30, 2020
Context: In primary aldosteronism (PA), aldosterone secretion is relatively independent of the re... more Context: In primary aldosteronism (PA), aldosterone secretion is relatively independent of the renin-angiotensin system, but can be regulated by several other stimuli. Objective: To evaluate aldosterone response to several stimuli in a series of patients with PA secondary either to bilateral adrenal hyperplasia (BAH) or unilateral aldosteroneproducing adenoma (APA). Design and setting: Prospective cohort study conducted in a university teaching hospital research center. Patients: Forty-three patients with confirmed PA and subtyped by adrenal vein sampling (n = 39) were studied, including 11 with BAH, 28 with APA, and 4 with undefined etiology. We also studied 4 other patients with aldosterone and cortisol cosecretion. Interventions: We systematically explored aberrant regulation of aldosterone using an in vivo protocol that included the following stimulation tests performed over 3 days under dexamethasone suppression: upright posture, mixed meal, adrenocorticotropin (ACTH) 1-24, gonadotropin-releasing hormone (GnRH), vasopressin, and serotonin R4 agonist. Main outcome measures: Positive response was defined as >50% renin or ACTHindependent increase in plasma aldosterone/cortisol concentration following the various stimulation tests. Results: Renin-independent aldosterone secretion increased in response to several aberrant stimuli (upright posture, GnRH
Arquivos Brasileiros De Endocrinologia E Metabologia, Nov 1, 2007
ACTH-Independent macronodular adrenal hyperplasia (AIMAH) is a rare cause of endogenous Cushing's... more ACTH-Independent macronodular adrenal hyperplasia (AIMAH) is a rare cause of endogenous Cushing's syndrome (CS), in which clinical features usually become apparent only after several decades of life. This form of adrenal hyperplasia typically produces excess cortisol with overt or subclinical CS, but concurrent secretion of mineralocorticoids or sexual steroids can also occur. The diagnosis is suspected by bilateral adrenal nodules larger than 1 cm on incidental imaging studies or following the demonstration of ACTH-independent hormonal hypersecretion. The pathophysiology of this entity is heterogeneous and has been intensely explored in recent years. Several G-protein coupled receptors aberrantly expressed in the adrenal cortex have been implicated in the regulation of steroidogenesis and in the initial cell proliferation in AIMAH. Several familial cases of AIMAH have been recently described with the same pattern of aberrant hormone receptors in all affected members of the family. It is probable that additional somatic genetic events related to cell cycle regulation, adhesion and transcription factors occur in addition over time in the various nodules; other mechanisms, as Gsp or ACTH receptor mutations and paracrine adrenal hormonal secretion have been rarely identified as the molecular mechanism in some cases. When systematically screened, most patients with AIMAH exhibit an in vivo aberrant cortisol response to one or various ligands suggesting the presence of aberrant adrenal receptors. The identification of these receptors creates the possibility of a specific pharmacological treatment isolated or associated with adrenalectomy.
Best Practice & Research Clinical Endocrinology & Metabolism, May 1, 2020
Adrenocortical hyperplasia may develop in different contexts. Primary adrenal hyperplasia may be ... more Adrenocortical hyperplasia may develop in different contexts. Primary adrenal hyperplasia may be secondary to primary bilateral macronodular adrenocortical hyperplasia (PBMAH) or micronodular bilateral adrenal hyperplasia (MiBAH) which may be divided in primary pigmented nodular adrenocortical disease (PPNAD) and isolated micronodular adrenocortical disease (i-MAD). Both lead to oversecretion of cortisol and potentially to Cushing's syndrome. Moreover, adrenocortical hyperplasia may be secondary to longstanding ACTH stimulation in ACTH oversecretion as in Cushing's disease, ectopic ACTH secretion or glucocorticoid resistance syndrome and congenital adrenal hyperplasia secondary to various enzymatic defects within the cortex. Finally, idiopathic bilateral adrenal hyperplasia is the most common cause of primary aldosteronism. We will discuss recent findings on the multifaceted forms of adrenocortical hyperplasia.
The investigation and management of unilateral adrenal incidentalomas have been extensively consi... more The investigation and management of unilateral adrenal incidentalomas have been extensively considered in the last decades. While bilateral adrenal incidentalomas represent about 15% of adrenal incidentalomas (AIs), they have been less frequently discussed. The differential diagnosis of bilateral incidentalomas includes metastasis, primary bilateral macronodular adrenal hyperplasia and bilateral cortical adenomas. Less frequent etiologies are bilateral pheochromocytomas, congenital adrenal hyperplasia (CAH), Cushing's disease or ectopic ACTH secretion with secondary bilateral adrenal hyperplasia, primary malignancies, myelolipomas, infections or hemorrhage. The investigation of bilateral incidentalomas includes the same hormonal evaluation to exclude excess hormone secretion as recommended in unilateral AI, but diagnosis of CAH and adrenal insufficiency should also be excluded. This review is focused on the differential diagnosis, investigation and treatment of bilateral AIs.
Thirty years ago, we identified that cortisol secretion in some patients with unilateral adenoma ... more Thirty years ago, we identified that cortisol secretion in some patients with unilateral adenoma or primary bilateral macronodular adrenal hyperplasia (PBMAH) was stimulated by food intake; this was secondary to the abnormal adrenocortical responsiveness to physiological postprandial increase in glucose-dependent insulinotropic peptide (GIP). This resulted from the ectopic expression of non-mutated GIP receptor in the pathological adrenal tissues of those patients. Although ectopic GIP receptor (GIPR) was confirmed in a relatively limited number of cases to date, its elucidation leads to the identification of a wide diversity of aberrant G-protein-coupled receptors regulating steroidogenesis and cell proliferation in a high proportion of patients with PBMAH or cortisol-secreting adenomas. In addition, ectopic GIPR was identified in other endocrine tumors including somatotroph pituitary tumors with paradoxical growth hormone response to oral glucose, medullary thyroid carcinomas, and other neuroendocrine tumors. The first molecular pathogenic mechanism responsible for ectopic GIPR expression was elucidated in unilateral GIP-dependent adenomas in which somatic duplication and rearrangements in chromosome region 19q13.32 containing the GIPR locus lead to increased expression of GIPR which was enhanced by the activity of a glucocorticoid response element. Recently, germline lysine demythylase 1A (KDMIA) mutations combined with somatic chromosome 1p deletions were found to be specifically responsible for ectopic GIPR in sporadic or familial GIP-dependent PBMAH and can be associated with adrenal myelolipoma, monoclonal gammopathy of unknown significance (MGUS), or multiple myeloma. Screening for ectopic GIPR should be conducted in all patients with PBMAH; genetic studies to identify KDM1A mutations should be offered to such patients in order to detect affected members and provide early detection of PBMAH and other potential associated neoplasias. The elucidation of GIP-dependent Cushing's syndrome (CS) illustrates that careful bedside phenotyping of rare conditions can lead to identification of genetically determined diseases requiring personalized approaches to investigation and therapy.
AIMAH. When systematically screened, most patients with AIMAH and CS or subclinical CS exhibit an... more AIMAH. When systematically screened, most patients with AIMAH and CS or subclinical CS exhibit an in vivo aberrant cortisol response to one or various ligands suggesting the presence of aberrant adrenal receptors. A protocol designed to screen patients for the presence of these aberrant receptors should be undertaken in all patients with AIMAH. The identifi cation of these receptors provides the potential for novel pharmacological therapies by suppressing the endogenous ligands or blocking the receptor with specifi c antagonists.
Background: Pheochromocytoma (PHEO) and paragangliomas (PGL) (PPGL) may recur after initial surge... more Background: Pheochromocytoma (PHEO) and paragangliomas (PGL) (PPGL) may recur after initial surgery and the long-term postoperative management is unclear. Recent guidelines suggested screening for recurrence with yearly metanephrines for 10 years and lifelong in high risk patients (young, genetic disease, large tumors and/or PGL). In addition, very recent data suggest that recurrence rate is lower than previously estimated and mainly occur within the first five years of follow-up. Objective: To evaluate the characteristics and delay of recurrent PPGL in our center. Methods: We retrospectively analysed characteristics of patients with PPGL who had recurrent disease between 1994 and 2017. We collected data on clinical presentation, imaging, functional status, genetic testing, treatment and outcomes of patients with recurrent disease. Results: Our cohort included 29 patients. The mean age at diagnosis was 45.9 and 54.5 at recurrence. Thirteen patients had PHEO and 16 had PGL. The mean delay of recurrence was 7.8 years, with 13 patients (44.8%) recurring before 5 years of follow-up, 10 (34, 5%) between 5-10 years, 4 (13,8%) between 10-15 years and 2 at 21 (PGL) and 48 (PHE) years of follow up respectively. Nine of the 14 patients (64,3%) genetically tested had an identifiable germline mutation. Four patients with PHEO had initial tumors size of less than 5 cm. Conclusion: In our cohort, postoperative recurrence of apparently benign PPGL occurred after more than 10 years of follow up in 20,7% of cases, supporting that patients operated for PPGL should have a lifelong follow-up surveillance.
Current Opinion in Endocrinology, Diabetes and Obesity, Jun 1, 2007
Endogenous Cushing's syndrome is adrenocorticotropic hormone (or corticotropin)-independent ... more Endogenous Cushing's syndrome is adrenocorticotropic hormone (or corticotropin)-independent in 15-20% of cases. Primary Cushing's syndrome is most often secondary to adrenocortical adenomas or carcinomas, and more rarely to bilateral adrenal hyperplasias. Corticotropin-independent cortisol-producing hyperplasia is caused by micronodular diseases, including primary pigmented nodular adrenocortical disease and nonpigmented micronodular hyperplasia and adrenocorticotropic hormone-independent macronodular adrenal hyperplasia. Primary pigmented nodular adrenocortical disease can be found either alone or in the context of Carney complex, a multiple endocrine neoplasia syndrome.
In recent years, a novel understanding of the pathophysiology of adrenal Cushing's syndrome has e... more In recent years, a novel understanding of the pathophysiology of adrenal Cushing's syndrome has emerged. The ectopic or aberrant expression of G-proteincoupled hormone receptors in the adrenal cortex was found to play a central role in the regulation of cortisol secretion in ACTH-independent macronodular adrenal hyperplasia (AIMAH) and in some unilateral adrenal adenomas. Various aberrant receptors, functionally coupled to steroidogenesis, have been reported: GIP, vasopressin, β-adrenergic, LH/hCG, and serotonin receptors have been best characterized, but angiotensin, leptin, glucagon, IL-1 and TSH receptors have also been described. The molecular mechanisms responsible for the aberrant expression of these receptors are currently unknown. One or many of these aberrant receptors are present in most cases of AIMAH and in some cases of adrenal adenomas with overt or sub-clinical secretion of cortisol. Clinical protocols to screen for such aberrant receptors have been developed and should be performed in all patients with AIMAH. The identification of such aberrant regulation of steroidogenesis in AIMAH provides the novel opportunity to treat some of these patients with pharmacological agents that either suppress the endogenous ligand or block the aberrant receptor, thus avoiding bilateral adrenalectomy.
The Journal of Clinical Endocrinology and Metabolism, Sep 1, 2006
The mechanisms responsible for the ectopic adrenal expression of glucose-dependent insulinotropic... more The mechanisms responsible for the ectopic adrenal expression of glucose-dependent insulinotropic peptide (GIP) receptor (GIPR) in GIP-dependent Cushing's syndrome (CS) are unknown. Chronic adrenal stimulation by ACTH in Cushing's disease or GIP in GIP-dependent ACTH-independent macronodular adrenal hyperplasia both lead to the induction of genes implicated in adrenal proliferation and steroidogenesis. The objective of the study was to identify genes differentially expressed specifically in GIP-dependent CS that could be implicated in the ectopic expression of GIPR. Methods: We used the Affymetrix U133 plus 2.0 microarray oligochips to compare the whole genome expression profile of adrenal tissues from five cases of GIP-dependent bilateral ACTH-independent macronodular adrenal hyperplasia with CS, one case of GIP-dependent unilateral adenoma with CS, five cases of ACTH-dependent hyperplasias, and a pool of adrenals from 62 normal individuals. Results: After data normalization and statistical filtering, 723 genes with differential expression were identified, including 461 genes or sequences with a known functional implication, classified in eight dominant functional classes. Specific findings include repression of perilipin, the overexpression of 13 G protein-coupled receptors, and the potential involvement of Rho-GTPases. We also isolated 94 probe sets potentially linked to the formation of GIP-dependent nodules adjacent to the diffuse hyperplasia. These included probe sets related to the linker histone H1 and repression of RXRa and CCND2. The expression profiles for eight genes were confirmed by real-time RT-PCR. This study identified an extensive series of potentially novel target candidate genes that could be implicated in the molecular mechanisms of ectopic expression of the GIPR as well as in the multistep progression of GIP-dependent CS.
Needle tract seeding is a potential, albeit rare, complication following transcutaneous biopsies,... more Needle tract seeding is a potential, albeit rare, complication following transcutaneous biopsies, leading to the seeding of tumor cells along the path of the needle. Biopsies of adrenal masses are not routinely recommended and are only indicated, after exclusion of pheochromocytoma, when an adrenal metastasis of a primary extra-adrenal cancer is suspected or when pathological confirmation of inoperable adrenocortical cancer (ACC) may impact treatment. Despite guideline recommendations to avoid primary adrenal biopsy, very few needle tract seeding cases have been reported and none were in the context of an ACC. We report the occurrence of needle tract seeding in a patient following adrenal transcutaneous biopsy leading to ACC abdominal wall recurrence.
Journal of Vascular and Interventional Radiology, Feb 1, 2010
PowerWireTM (Baylis Medical Company, Montreal, QC, Canada) RF wire was advanced within a 5-Fr KMP... more PowerWireTM (Baylis Medical Company, Montreal, QC, Canada) RF wire was advanced within a 5-Fr KMP catheter. A straight wire tip combined with a semi-curved catheter provides higher precision during the tissue puncture. Once in contact with the occlusion site, the RF energy was delivered while the wire was gently advanced for a few millimeters at a time towards a target catheter placed in the opposite venous side. Once RF wire access was obtained to the contra-lateral side of the obstruction, a loop snare was used to assist the catheterization. The KMP catheter was advanced and the RF wire was exchanged for a stiffer wire and six/eight millimeters balloon angioplasties were followed by stent or stent-graft placement. If the puncture was inadequate, a new location was pursued. Results: Four patients were successfully treated with RF wire after previous failed attempts at recanalization using mechanical catheter/wire techniques. In two patients the procedure was aborted, in one due to hemothorax successfully treated with chest tube without clinical repercussions. All the successfully treated patients had resolution of symptoms in a 4(2-8)months mean follow up. RF wire offers a promising alternative in the recanalization of benign chronic central venous occlusions when conventional techniques failed.
The Journal of Clinical Endocrinology and Metabolism, Sep 30, 2022
Background Adrenal tumors are found in up to 40% of patients with multiple endocrine neoplasia ty... more Background Adrenal tumors are found in up to 40% of patients with multiple endocrine neoplasia type 1 (MEN1). However, adrenocortical carcinomas (ACC) and primary aldosteronism (PA) are rare in MEN1. Case A 48-year-old woman known to have primary hyperparathyroidism and hypertension with hypokalemia was referred for a right complex 8-cm adrenal mass with a 38.1 SUVmax uptake on 18F-FDG PET/CT. PA was confirmed by saline suppression test (aldosterone 1948 pmol/L-1675 pmol/L; normal range [N]: <165 post saline infusion) and suppressed renin levels (<5 ng/L; N: 5-20). Catecholamines, androgens, 24-hour urinary cortisol, and pituitary panel were normal. A right open adrenalectomy revealed a concomitant 4-cm oncocytic ACC and a 2.3-cm adrenocortical adenoma. Immunohistochemistry showed high expression of aldosterone synthase protein in the adenoma but not in the ACC, supporting excess aldosterone production by the adenoma. Genetic analysis After genetic counseling, the patient underwent genetic analysis of leucocyte and tumoral DNA. Sequencing of MEN1 revealed a heterozygous germline pathogenic variant in MEN1 (c.1556delC, p.Pro519Leufs*40). The wild-type MEN1 allele was lost in the tumoral DNA of both the resected adenoma and carcinoma. Sequencing analysis of driver genes in PA revealed a somatic pathogenic variant in exon 2 of the KCNJ5 gene (c.451G>A, p.Gly151Arg) only in the aldosteronoma. Conclusion To our knowledge, we describe the first case of adrenal collision tumors in a patient carrying a germline pathogenic variant of the MEN1 gene associated with MEN1 loss of heterozygosity in both oncocytic ACC and adenoma and a somatic KCNJ5 pathogenic variant leading to aldosterone-producing adenoma. This case gives new insights on adrenal tumorigenesis in MEN1 patients.
Uploads
Papers by Andre Lacroix