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Context: Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing's syndrome, usually characterized by functioning adrenal macronodules and increased cortisol production. Familial clustering of PMAH has been described, suggesting an inherited genetic cause for this condition., Objective: The aim of the present study was to identify the gene responsible for familial PMAH., Patients and Methods: Forty-seven individuals of a Brazilian family with PMAH were evaluated. A single-nucleotide polymorphism-based genome-wide linkage analysis followed by whole-exome sequencing were then performed in selected family members. Additionally, 29 other patients with PMAH and 125 randomly selected healthy individuals were studied to validate the genetic findings. Moreover, PMAH tissue was also analyzed through whole-exome sequencing, conventional sequencing, and microsatellite analysis., Results: A heterozygous germline variant in the ARMC5 gene (p.Leu365Pro) was identified by whole-exome sequencing in a candidate genomic region (16p11.2). Subsequently, the same variant was confirmed by conventional sequencing in all 16 affected family members. The variant was predicted to be damaging by in silico methods and was not found in available online databases or in the 125 selected healthy individuals. Seven additional ARMC5 variants were subsequently identified in 5 of 21 patients with apparently sporadic PMAH and in 2 of 3 families with the disease. Further molecular analysis identified a somatic mutational event in 4 patients whose adrenal tissue was available., Conclusions: Inherited autosomal dominant mutations in the ARMC5 gene are a frequent cause of PMAH. Biallelic inactivation of ARMC5 is consistent with its role as a potential tumor suppressor gene.

Purpose: Many adrenal venous sampling (AVS) protocols require repeated samplings before and after adrenocorticotrophic hormone (ACTH) stimulation. Maintaining catheter selectivity in the adrenal vein over time is essential but can be challenging, especially in the short right adrenal vein, where the catheter is often in an unstable position. The aim of our study was to evaluate guide wire insertion into the right adrenal vein catheter to sustain AVS selectivity (adrenal/peripheral cortisol ratio [Ca/Cp]) over time., Methods: This retrospective investigation was approved by our institutional review board, and informed consent was obtained. A 0.014-inch guide wire was inserted in the right adrenal vein 5F catheter to secure its positioning and to facilitate blood sampling. Plasma cortisol levels from the left and right adrenal veins and left iliac vein were assessed in 117 consecutive patients undergoing bilateral, simultaneous sets of AVS at -5 and 0 min (baseline) and 5, 10, and 15 min after intravenous bolus of 250 μg ACTH (stimulated). Ca/Cp ratios of ≥2 for baseline and >10 for stimulated AVS were considered selective., Results: The first sampling, at time -5 min, was nonselective in 41 of 116 (35.3 %) right and 30 of 116 (25.9 %) left AVSs retained for analysis. In patients with a selective first sampling, 74 of 75 (98.7 %) right and 85 of 86 (98.8 %) left AVSs were selective in all post-ACTH samplings. Right and left selectivity rates were not statistically different (p > 0.87). No complications arose from guide wire insertion., Conclusion: Guide wire insertion into the right adrenal vein catheter is safe and effective to maintain AVS selectivity over time.

Purpose of Review: Primary bilateral macronodular adrenal hyperplasia is a rare cause of Cushing's syndrome and is more often diagnosed as bilateral adrenal incidentalomas with subclinical cortisol production. We summarize the recent insights concerning its epidemiology, diagnosis, genetics, pathophysiology, and therapeutic options., Recent Findings: Recent publications have modified our notions on the genetics and pathophysiology of bilateral macronodular adrenal hyperplasia. Combined germline and somatic mutations of armadillo repeat containing 5 gene were identified in familial cases, in approximately 50% of apparently sporadic cases and in the relatives of index cases; genetic testing should allow early diagnosis in the near future. The recent finding of ectopic adrenocortical production of adrenocorticotropic hormone in clusters of bilateral macronodular adrenal hyperplasia tissues and its regulation by aberrant hormone receptors opens new horizons for eventual medical therapy using melanocortin-2 receptor and G-protein-coupled receptor antagonists. Finally, some medical and surgical treatments have been updated., Summary: Recent findings indicate that bilateral macronodular adrenal hyperplasia is more frequently genetically determined than previously believed. Considering the role of paracrine adrenocorticotropic hormone production on cortisol secretion, the previous nomenclature of adrenocorticotropic hormone-independent macronodular adrenal hyperplasia appears inappropriate, and this disease should now be named primary bilateral macronodular adrenal hyperplasia.

Purpose of Review: Adrenocortical cancer (ACC) is a rare and often aggressive malignancy. The overall 5-year survival rate of ACC is less than 30% in part owing to advanced stage of the disease at diagnosis and limited efficiency of therapies when initial surgery is not curative. So far, studies with large cohorts of patients affected by ACC were lacking because of the rarity of the disease; however, recent international and multicenter collaborative studies provide new insights in the management of ACC., Recent Findings: This review summarizes recent findings in the genetic, hormonal evaluation, imaging, and therapies of ACC in adults. There is new promise for the use of 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography and metomidate in initial diagnosis and follow-up. Limited studies support benefit of specific surgical approaches such as loco-regional lymph node dissection and metastasectomy in specific subgroups. New developments in the use of mitotane therapy and its drug interactions, on adjuvant radiotherapy and prospective data on combined chemotherapy, have appeared recently., Summary: These recent findings will provide more evidence-based recommendations in the future to better assist clinicians in the management of patients with ACC. However, there is still an important need to understand the molecular mechanisms underlying this disease to design better therapeutic approaches.

Background: Cabergoline is a long-acting dopamine receptor agonist used to treat prolactinomas. Identification of D(2) receptors in corticotroph tumors led to clinical trials of cabergoline therapy in limited cases of Nelson's syndrome, ectopic ACTH-secreting tumors, and recently Cushing's disease (CD)., Objective: To evaluate the long-term efficacy of cabergoline monotherapy in patients with CD., Methods: Retrospective analysis of non-randomized clinical therapy with cabergoline in 30 patients with CD treated in academic centers of Buenos Aires and Montreal. Cabergoline was initiated at 0.5-1.0 mg/week and adjusted up to a maximal dose of 6 mg/week based on urinary free cortisol (UFC) levels. Complete response to cabergoline was defined as a sustained normalization of UFC with at least two normal values measured at 1-3 months interval; partial response was defined as a decrease of UFC to <125% of the upper limit of normal, and treatment failure as UFC ≥ 125% of it., Results: Within 3-6 months, complete response was achieved in 11 patients (36.6%) and partial response in 4 patients (13.3%). After long-term therapy, nine patients (30%) remain with a complete response after a mean of 37 months (range from 12 to 60 months) with a mean dose of 2.1 mg/week of cabergoline. Two patients escaped after 2 and 5 years of complete response, but one patient transiently renormalized UFC after an increase in cabergoline dosage. No long-term response was maintained in four initial partial responders., Conclusions: Cabergoline monotherapy can provide an effective long-term medical therapy for selected patients with CD, but requires close follow-up for dose adjustments.

Adrenocortical cancer (ACC) is a rare and often aggressive malignancy that requires multidisciplinary expertise for optimal management. It can present with symptoms of rapidly appearing excess steroid secretion or an abdominal mass, or it can be discovered incidentally. Thorough imaging and endocrine evaluations can identify the majority of ACCs amongst adrenal tumors; however, some smaller ACCs are better identified using fluorodeoxyglucose-positron emission tomography/computed tomography scan. Complete resection by an expert surgeon is the only potentially curative treatment for ACC, and tumor spillage should be avoided. Histopathology is important for diagnosis, but immunohistochemistry markers and gene profiling of the resected tumor may become superior to current staging systems to stratify prognosis. Despite complete resection in stage I-III tumors, approximately 40% of patients develop metastasis within 2 yr. Some retrospective studies indicate that adjuvant mitotane therapy prolongs disease-free survival, leading several centers to recommend its administration; prospective studies are under way to provide future evidence-based recommendations. For locally invading ACC, extensive en bloc resection is attempted, followed by adjuvant mitotane and, in selected cases, adjuvant radiotherapy. When ACC is not surgically resectable, mitotane therapy is adjusted to reach serum levels of 14-20 μg/ml. Careful replacement of glucocorticoid and mineralocorticoid deficiency after surgery or mitotane therapy is important; steroid excess from remaining tumor burden should also be controlled to avoid its morbidities. For metastatic disease, combination chemotherapy should be administered, if possible, in the context of multicenter collaborative research protocols. New insights in the molecular pathogenesis of ACC should allow the development of improved targeted therapies.

Cushing's disease is caused by glucocorticoid-resistant pituitary corticotroph adenomas. We have previously identified the loss of nuclear Brg1 as one mechanism that may lead to partial glucocorticoid resistance: this loss is observed in about 33% of human corticotroph adenomas. We now show that Brg1 loss of function correlates with cyclin E expression in corticotroph adenomas and with loss of the cell cycle inhibitor p27(Kip1) expression. Because Brg1 is thought to have tumor suppressor activity, the present study was undertaken to understand the putative contribution of cyclin E derepression produced by loss of Brg1 expression on adenoma development. Overexpression of cyclin E in pituitary proopiomelanocortin cells leads to abnormal reentry into cell cycle of differentiated proopiomelanocortin cells and to centrosome instability. These alterations are consistent with the intermediate lobe hyperplasia and anterior lobe adenomas that were observed in these pituitaries. When combined with the p27(Kip1) knockout, overexpression of cyclin E increased the incidence of pituitary tumors, their size, and their proliferation index. These results suggest that cyclin E up-regulation and p27(Kip1) loss-of-function act cooperatively on pituitary adenoma development.

While the role of corticosterone in mediating the response of birds to acute stress is well established, it has recently been proposed that a decrease in prolactin levels following stress may complement corticosterone in redirecting resources away from breeding activities and towards behaviors promoting immediate survival. Here, for the first time, we detail changes in the prolactin stress response of birds throughout the breeding cycle. We then discuss the modulation of the corticosterone and prolactin stress responses over successive stages of breeding, differing in reproductive value and parental effort. In a long-lived Procellariiform seabird, the Manx shearwater Puffinus puffinus, we found that prolactin levels decreased in response to acute stress during incubation and mid chick-rearing but increased in response to stress during late chick-rearing and in non parenting birds, a pattern similar to that previously described for mammals. The high corticosterone stress response in pre-breeders was consistent with predictions based on reproductive value, but a similar response during late chick-rearing was not. This probably reflected foraging effort and a heightened importance of the parents' own nutritional status at this stage of the season, in advance of post-breeding migration. We also found that baseline prolactin levels were maintained at high levels during chick-rearing and were only slightly lower during late chick-rearing and in failed breeders and non-breeders. These data suggest that prolactin may play a role in nestling care long beyond the brooding phase, that this is not due to birds spending long periods away from the colony and that prolactin secretion may be necessary for nest-guarding behavior., (Copyright 2010 Elsevier Inc. All rights reserved.)

The aberrant adrenal expression and function of one or several G-protein coupled receptors can lead to cell proliferation and abnormal regulation of steroidogenesis in unilateral adenomas, carcinomas or in ACTH-independent macronodular adrenal hyperplasia (AIMAH). Excess cortisol secretion leading to either sub-clinical or overt Cushing's syndrome is the most prevalent phenotype reported to date. In a few patients, aberrant regulation of androgen excess has been reported. More recently, initial studies suggest that similar mechanisms are involved in the renin-independent regulation of aldosterone secretion in primary aldosteronism. In recent years, cases of familial AIMAH have been identified, and specific aberrant hormone receptors are functional in the adrenal of affected members. The identification of aberrant receptors can offer specific pharmacological approach to prevent disease progression and control abnormal steroidogenesis; alternatively, unilateral or bilateral adrenalectomy remains the treatment of choice.

Objective: ACTH-independent macronodular adrenal hyperplasia (AIMAH) is often associated with subclinical cortisol secretion or atypical Cushing's syndrome (CS). We characterized a large series of patients of AIMAH and compared them with patients with other adrenocortical tumors., Design and Patients: We recruited 82 subjects with: 1) AIMAH (n = 16); 2) adrenocortical cortisol-producing adenoma with CS (n = 15); 3) aldosterone-producing adenoma (n = 19); and 4) single adenomas with clinically nonsignificant cortisol secretion (n = 32)., Methods: Urinary free cortisol (UFC) and 17-hydroxycorticosteroid (17OHS) were collected at baseline and during dexamethasone testing; aberrant receptor responses was also sought by clinical testing and confirmed molecularly. Peripheral and/or tumor DNA was sequenced for candidate genes., Results: AIMAH patients had the highest 17OHS excretion, even when UFCs were within or close to the normal range. Aberrant receptor expression was highly prevalent. Histology showed at least two subtypes of AIMAH. For three patients with AIMAH, there was family history of CS; germline mutations were identified in three other patients in the genes for menin (one), fumarate hydratase (one), and adenomatosis polyposis coli (APC) (one); a PDE11A gene variant was found in another. One patient had a GNAS mutation in adrenal nodules only. There were no mutations in any of the tested genes in the patients of the other groups., Conclusions: AIMAH is a clinically and genetically heterogeneous disorder that can be associated with various genetic defects and aberrant hormone receptors. It is frequently associated with atypical CS and increased 17OHS; UFCs and other measures of adrenocortical activity can be misleadingly normal.

Purpose of Review: Adrenal incidentaloma has become a frequent clinical dilemma. Even in the absence of specific clinical features of Cushing's syndrome, adrenocortical incidentalomas may display steroid secretory activity at different degrees. The recognition of endocrine and metabolic dysfunctions associated with subclinical hypercortisolism leads to current awareness about its potential consequences., Recent Findings: Different protocols and threshold values to define normal cortisol secretion and diagnosis of subclinical Cushing's syndrome have been proposed, including recent practice guidelines for the diagnosis of overt Cushing's syndrome. Follow-up studies have provided additional data about the natural course of the disease and related cardiovascular and metabolic consequences. The study of bilateral adrenocorticotropin-independent macronodular adrenocortical hyperplasia in some familial cases offers a new approach to understanding the spectrum of subclinical cortisol hypersecretion., Summary: The prevalence of subclinical hypercortisolism may be higher than previously reported as more sensitive diagnostic criteria are now recommended. The absence of a single gold standard test, the diversity of diagnostic criteria and the requirement of subsequent meticulous biochemical evaluations before a decision for treatment represent a challenge for the clinical management of this condition.

Adrenocorticotropic hormone- (ACTH-)independent macronodular adrenal hyperplasia (AIMAH) is an infrequent cause of Cushing's syndrome (CS). AIMAH presents as incidental radiological finding or with subclinical or overt CS, occasionally with secretion of mineralocorticoids or sex steroids. The pathophysiology of this entity is heterogeneous. The aberrant adrenal expression and function of one or several G-protein-coupled receptors can lead to cell proliferation and abnormal regulation of steroidogenesis. In several familial cases of AIMAH, specific aberrant hormone receptors are functional in the adrenal of affected members. Additional somatic genetic events related to cell cycle regulation, adhesion and transcription factors occur in addition in the various nodules over time. Other mechanisms, such as Gsp or ACTH receptor mutations and paracrine adrenal hormonal secretion, have been rarely identified in other cases of AIMAH. The identification of aberrant receptors can offer a specific pharmacological approach to prevent progression and control abnormal steroidogenesis; alternatively, unilateral or bilateral adrenalectomy becomes the treatment of choice.

Context: Primary adrenal Cushing's syndrome can result from the aberrant adrenal expression of several hormone receptors; this mechanism has not been explored in detail in aldosterone-producing tumors., Objective: The objective of the study was to evaluate a 56-yr-old male patient with an aldosteronoma for the regulation of aldosterone secretion by aberrant hormone receptors., Results: Renin-independent stimulation of aldosterone secretion was observed in vivo after a mixed meal, oral glucose, or administration of glucose-dependent insulinotropic peptide (GIP), vasopressin, and tegaserod. The mixed meal-mediated stimulation of aldosterone was not present in five other cases of aldosteronoma. A smaller response of aldosterone after GIP infusion was observed in a normal subject. Aldosterone secretion was stimulated by GIP in primary cultures of this patient's aldosteronoma. Increased expression of GIP receptor was found in this aldosteronoma by real-time RT-PCR and immunohistochemistry. The GIP receptor protein was also found at lower levels in zona glomerulosa cells of the normal adjacent adrenal gland. Increased expression of serotonin 4 and ACTH receptors was also present in this aldosteronoma., Conclusions: This case report provides new evidence of the implication of aberrant hormone receptors in the regulation of this aldosteronoma and suggests that further detailed studies of the role of aberrant hormone receptors in this frequent pathology should be undertaken.

After testosterone, dehydroepiandrosterone (DHEA) is the main hormone involved in aggressive behaviour in birds. While the role of DHEA has been verified for wintering territorial passerines, it has not been shown for gregarious species. In wintering geese species, both sexes present very low testosterone levels and aggression in a non-sexual context is not testosterone-related. Therefore, testosterone does not seem to be responsible for aggressive behaviour by geese during winter and the role of DHEA must be explored. We used brent geese (Branta bernicla bernicla) to examine the roles of testosterone and DHEA in dominance relationships. For the first time, we highlighted the presence of plasma DHEA in free-living geese. As the level of DHEA was lower than that of testosterone, and there was no obvious impact of DHEA level on dominance status, our results failed to confirm the role of plasma DHEA in the social hierarchies of this species during winter. Nevertheless, because DHEA levels were greater in singletons than in paired birds, we discuss the need to explore hormonal and/or behavioural mechanisms implicated within dominance status acquisition and maintenance within each reproductive status class, to underline the role of the presence of relatives as a signal of dominance abilities. We also acknowledge and discuss the possibility that the long handling time may have affected DHEA levels and masked subtle differences between individuals.

Various exogenous or endogenous factors may induce an emergency response in birds, redirecting current activity towards survival. In fasting, breeding penguins, the achievement of a critical energy depletion was suggested to induce egg abandonment and departure to sea for re-feeding. How such a behavioral shift is hormonally controlled remains unknown. The possible involvement of corticosterone and prolactin was examined by characterizing the nutritional and hormonal states of king penguins at egg abandonment. Further, we tested if these states differ according to whether an egg or a chick is abandoned, and according to the timing of breeding. In every case of abandonment, birds were in phase III fasting characterized by accelerated protein catabolism. However, body condition at egg abandonment was lower in early than in late breeders, suggesting that king penguins are willing to tolerate a larger energy depletion when their potential breeding success is high. At egg and chick abandonment, plasma corticosterone levels were, respectively, increased by 2- and 4-fold, whereas plasma prolactin levels were, respectively, depressed by 3- and 1.4-fold. The increase in plasma corticosterone and the decrease in plasma prolactin could be involved in the control of abandonment by, respectively, stimulating the drive to re-feed and diminishing the drive to incubate or brood. The smaller decrease in prolactin levels and the greater increase in corticosterone levels observed at chick vs egg abandonment suggest that, in addition to nutritionally-related stimuli, tactile or audible stimuli from the egg or chick could intervene in the endocrine control of abandonment.

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.

Purpose of Review: 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., Recent Findings: In recent years, the pathophysiology of adrenocortical tumors and hyperplasias became better understood following the identification of genes responsible for syndromes associated with corticotropin-independent Cushing's syndrome and the demonstration of aberrant expression and function of various hormone receptors in adrenocortical adenomas and adrenocorticotropic hormone-independent macronodular adrenal hyperplasia. This article reviews findings on the molecular and genetic aspects of corticotropin-independent Cushing's syndrome including recent gene expression profiling studies of adrenocortical tumors and hyperplasias and animal models that provided clues on the pathogenesis of primary Cushing's syndrome., Summary: A better understanding of molecular mechanisms involved in adrenocortical tumors and hyperplasias may lead to improved diagnostic and prognostic markers and treatment strategies to assist clinicians in the management of corticotropin-independent Cushing's syndrome.

Context: 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., Objective: 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., Conclusion: 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.

The purpose of this study was: (i) to provide additional evidence regarding the existence of human voice parameters, which could be reliable indicators of a speaker's physical characteristics and (ii) to examine the ability of listeners to judge voice pleasantness and a speaker's characteristics from speech samples. We recorded 26 men enunciating five vowels. Voices were played to 102 female judges who were asked to assess vocal attractiveness and speakers' age, height and weight. Statistical analyses were used to determine: (i) which physical component predicted which vocal component and (ii) which vocal component predicted which judgment. We found that men with low-frequency formants and small formant dispersion tended to be older, taller and tended to have a high level of testosterone. Female listeners were consistent in their pleasantness judgment and in their height, weight and age estimates. Pleasantness judgments were based mainly on intonation. Female listeners were able to correctly estimate age by using formant components. They were able to estimate weight but we could not explain which acoustic parameters they used. However, female listeners were not able to estimate height, possibly because they used intonation incorrectly. Our study confirms that in all mammal species examined thus far, including humans, formant components can provide a relatively accurate indication of a vocalizing individual's characteristics. Human listeners have the necessary information at their disposal; however, they do not necessarily use it.

Introduction: There is a need to create, disseminate, and implement new knowledge in the work disability prevention (WDP) field. Training programs attracting high-quality applicants and taking into account the complexity of this emerging field are urgently needed., Methods: An advanced training program, funded by the Canadian Institutes of Health Research (CIHR), was developed by 24 mentors affiliated with nine different universities. The main objective of this program is to develop transdisciplinary knowledge, skills, and attitudes regarding WDP. This program has been developed for PhD students or post-doctoral fellows already registered full-time in a Canadian or recognized foreign university whose main interest is WDP, regardless of the health problem., Results: Since its implementation, the program received two successive cohorts of 10 students. They were registered in 13 universities in five countries and trained in nine different disciplines. CONCLUSIONS AND SIGNIFICANCES: Appropriate WDP research may save major societal costs attributable to prolonged work disability. The proposed training program will contribute to developing tomorrow's research workforce.

The best characterized effect of glucose-dependent insulinotropic polypeptide (GIP) is its stimulatory effect on insulin secretion by pancreatic beta-cells. Recently, it was demonstrated that some cases of primary adrenal Cushing's syndrome were secondary to the ectopic expression of non-mutated GIP receptor (GIP-R) in bilateral adrenal hyperplasias or unilateral adrenal adenomas, resulting in food-dependent steroidogenesis. Using a human multiple-expression tissue array, GIP-R was found to be expressed in a large number of human adult and fetal tissues, but not in the adrenal gland. The analysis of the promoter region of human (h) GIP-R gene revealed six consensus sequences important in regulating the reporter gene activity and capable of binding to Sp1 and Sp3 transcription factors. Data obtained by gene array and semi-quantitative RT-PCR showed an increase in the expression of Sp3 and CRSP9 (co-regulator of Sp1 transcription factor, subunit 9) in the adrenal adenomas or bilateral macronodular hyperplasias of patients with GIP-dependent Cushing's syndrome; they were, however, also increased in some patients with non-GIP-dependent cortisol-secreting adenomas or with ACTH-dependent Cushing's disease. This study represents the first step in our understanding of the mechanisms involved in the regulation of the expression of the hGIP-R gene.

Corticotropin (ACTH)-independent bilateral macronodular adrenal hyperplasia (AIMAH) and primary pigmented nodular adrenocortical disease (PPNAD) are responsible for approximately 10% of adrenal Cushing's syndrome. AIMAH also can be present as subclinical bilateral incidentalomas in sporadic or familial forms. Diverse aberrant hormone receptors have been found to be implicated in the regulation of steroidogenesis and pathophysiology of AIMAH. PPNAD can be found alone or in the context of Carney complex, a multiple endocrine neoplasia syndrome. Additionally, it can be secondary to mutations of type 1 alpha-regulatory subunit of cAMP-dependent protein kinase A (PRKARIA). Strategies for the investigation and treatment of AIMAH and PPNAD are discussed.

Cushing's syndrome (CS) is a relevant model to better understand the effects of glucocorticoid (GC) excess on the human brain. The importance of GC excess on the central nervous system is highlighted by the high prevalence of neuropsychiatric disorders such as depression and cognitive impairment in patients who have CS. In addition, there is a high incidence of apparent diffuse loss of brain volume in patients who have CS. Recent studies indicate at least partial reversibility of these abnormalities following correction of hypercortisolism.

We tested the hypothesis that parental effort modulates the magnitude of corticosterone and prolactin responses to stress in a long-lived bird, the Black-legged kittiwake (Rissa tridactyla). To do so, we compared corticosterone and prolactin responses to capture/restraint stress between chick-rearing birds and failed breeders (no parental effort). We predicted that (1) the increase in plasma corticosterone levels in response to stress should be lower in chick-rearing birds, (2) the decrease in plasma prolactin levels in response to stress should be lower in chick-rearing birds, and (3) as both sexes care for the chick, there should be no sex difference in the hormonal response to stress. Baseline plasma corticosterone and prolactin levels were higher in chick-rearing birds and were not influenced by body condition. Failed breeders were in better condition than chick-rearing individuals. Corticosterone response to stress was unaffected by parental effort as both chick-rearing and failed birds exhibited a robust corticosterone increase. Prolactin response to stress was however clearly influenced by parental effort: chick-rearing birds showed a modest 9% prolactin decrease whereas in failed birds prolactin concentrations fell by 41%. Body condition did not influence hormonal responses to stress. When facing stressful condition, breeding kittiwakes attenuate their prolactin response to stress while enhancing their secretion of corticosterone. Increasing corticosterone secretion triggers foraging efforts and diminishes nest attendance whereas an attenuation of prolactin response to stress maintains parental behavior. We suggest that this hormonal mechanism facilitates a flexible time-budget that has been interpreted as a buffer against environmental variability.

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a very rare cause of endogenous Cushing's syndrome (CS). In this review, the clinical characteristics, the pathophysiology, and the management of AIMAH are described. AIMAH typically presents with overt CS, but subclinical oversecretion of cortisol has been increasingly described. The diagnosis is suspected by adrenal nodular enlargement on conventional imaging following the demonstration of ACTH-independent hypercortisolism. Final diagnosis is established by histological examination of the adrenal tissue. Bilateral adrenalectomy is the treatment of choice but unilateral adrenalectomy has been proposed in selected cases. In patients with subclinical CS, the decision to treat should be individualized. The pathophysiology of this condition has begun to be elucidated in recent years. Diverse aberrant membrane-bound receptors expressed in a non-mutated form in the adrenal gland have been found to be implicated in the regulation of steroidogenesis in 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 identification of these receptors provides the potential for novel pharmacological therapies by suppressing the endogenous ligands or blocking the receptor with specific antagonists., (Copyright (c) 2005 S. Karger AG, Basel.)

AIMAH is a clinical condition characterized by the presence of adrenal macronodules even in the absence of ACTH. Usually the clinical overt syndrome only becomes apparent after several decades of life; this is probably due to the low steroidogenic enzyme capacity of the hyperplastic tissue. However, in asymptomatic individuals in whom the AIMAH was incidentally discovered, the HHA axis is usually disrupted. In the great majority of AIMAH cases, cortisol secretion is aberrantly regulated by hormones such as GIP, AVP, beta-adrenergic agonists, LH/hCG and in some cases by serotonin, acting through their specific receptors. The molecular mechanisms responsible by ectopic expression of such hormone receptors and/or their aberrant coupling to steroidogenesis are still largely unknown. Although this aberrant expression may have an important role in the augmented cell proliferation initiation, as well as in the steroidogenesis, it is probable that additional genetic events involving cell cycle regulation, adhesion and transcription occur. In rare cases GNAS1 mutations not related to McCune-Albright syndrome may be found in this condition. In some patients, the presence of aberrant hormone receptors creates the possibility of specific pharmacological treatment, isolated or associated with unilateral adrenalectomy.

The secretion of cortisol and other steroids from adrenal tumors can be regulated by hormones other than corticotropin following the aberrant expression of several G-protein-coupled receptors (GPCRs). To date, ectopic receptors for gastric inhibitory polypeptide, beta-adrenergic receptor agonists, vasopressin (V(2) and V(3) receptors), 5-hydroxytryptamine (5-HT(7) receptor) and, probably, angiotensin II (AT(1) receptor) have been identified. Either increased expression or altered activity of eutopic receptors for vasopressin (V(1)), luteinizing hormone/human chorionic gonadotropin, 5-HT (5-HT(4) receptor) and leptin might also be involved. One or more aberrant receptors can be present in unilateral tumors and bilateral macronodular adrenal hyperplasia, at either the early subclinical or overt stages of hormone secretion. The identification of aberrant adrenal GPCRs offers the potential for novel pharmacological therapies that either suppress the endogenous ligands or block the receptor with specific antagonists.

In recent years, a novel understanding of the pathophysiology of adrenal Cushing's syndrome has emerged. The ectopic or aberrant expression of G-protein-coupled 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, beta-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.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent adrenal Cushing's syndrome (CS), which is often associated with Carney complex (CNC). We have recently described a paradoxical increase in cortisol excretion after dexamethasone administration in most patients with PPNAD. In the present study we investigated the hypothesis that this phenomenon is due to a primary abnormality of the tissues affected by PPNAD, rather than a defect of the patients' hypothalamic-pituitary-adrenal axis; as such it should be replicated in vitro by adrenal slices exposed directly to dexamethasone. We were able to study adrenal tissues from eight patients with CS caused by PPNAD; two patients were also studied in vivo according to a protocol first described in ACTH-independent macronodular adrenal hyperplasia (AIMAH) for the clinical detection of aberrant hormone receptor expression. Their DNA has been previously screened for inactivating mutations of the PRKAR1A gene, the most frequent molecular defect leading to PPNAD and/or CNC. We also investigated whether glucocorticoid receptor (GR) expression underlies paradoxical dexamethasone responses in PPNAD by immunohistochemistry and semiquantitative PCR, and we correlated GR expression with that of other markers for PPNAD (e.g. synaptophysin). Indeed, we demonstrated that dexamethasone induced cortisol secretion in vitro in five of these tumors; no such increase was seen in adenomatous or AIMAH tissues that were treated in the same manner. GR mRNA was expressed, and GR immunoreactivity was detected in PPNAD nodular cells. Staining for GR was not seen in surrounding cortical cells, and hence, it correlated with synaptophysin, which also stains PPNAD in a similar manner. In normal adrenal tissue, GR was detected mostly in medullary areas, whereas GR immunoreactivity was weak in adenomatous and AIMAH tissues. We conclude that 1) dexamethasone produces an increase in glucocorticoid synthesis by PPNAD adrenal slices in vitro, suggesting a direct effect on adrenocortical tissue, and 2) this phenomenon is accompanied by increased expression of the GR in PPNAD nodules. PPNAD and/or CNC patients with and without mutations leading to protein kinase A activation demonstrated in vitro and/or in vivo paradoxical dexamethasone responses and GR expression, indicating that PRKAR1A alterations are not necessary for these phenomena.

The serotonin4 (5-HT4) receptor agonists cisapride and/or metoclopramide have been shown to stimulate cortisol secretion in some patients with ACTH-independent bilateral macronodular adrenal hyperplasias (AIMAH) causing Cushing's syndrome. In the present study, we have investigated quantitatively and qualitatively the expression of the 5-HT4 receptor in both normal adrenal cortex and tissues removed from six patients (P1-P6) with cisapride-responsive AIMAH and Cushing's syndrome. Real-time quantitative PCR assay revealed that the 5-HT4 receptor was overexpressed in four of the six hyperplasias studied when compared with normal adrenal cortex. In these tissues, 5-HT4 receptor mRNA expression was 3 to 16 times higher than in normal glands, likely explaining the abnormal in vivo cortisol response to cisapride. Characterization of 5-HT4 receptor splice variants by RT-PCR in both hyperplastic and normal adrenals showed that the variants present in the two hyperplasias that did not overexpress the 5-HT4 receptor, i.e. P2 and P5, could also be detected in the normal adrenal tissue. In addition, sequencing of the full-length cDNAs encoding 5-HT4 receptors in hyperplasias P2 and P5 did not reveal any mutation. Taken together, our results show an overexpression of the 5-HT4 receptor in cisapride-responsive AIMAH. However, in two cases, the level of expression of the receptor in the hyperplastic adrenal cortex was similar to that of normal adrenal gland. The enhanced sensitivity of these two tissues to 5-HT4 receptor agonists was not due to ectopic expression of 5-HT4 receptor isoforms or to the occurrence of somatic gain-of-function mutation of the receptor.

This report presents a series of recommendations derived from deliberations of the G8 countries Subproject 4 Group (SP4 Group) of the Global Health Care Applications Project entitled, A Teleconsultation Practice Guideline. The recommendations provide an initial step toward developing a general guideline platform for the practice of telemedicine/teleconsultation.

The main objectives of the G-8 Global Healthcare Applications Subproject-4 (G-8 GHAP-SP-4) were to establish an international concerted action on collaboration in telemedicine, telehealth, and health telematics (hereafter referred in this paper as telemedicine). In order to promote and facilitate the implementation of telemedicine or health telematics networks around the world, it was considered necessary to address certain key issues. Five thematic solution-seeking forums were held between May 1998 and December 1999. Each addressed a key issue, including interoperability of telemedicine and telehealth systems, impact of telemedicine on health care management, evaluation and cost effectiveness of telemedicine, clinical and technical quality and standards, and medico-legal aspects of national and international applications. The main objectives of these forums were to establish best practices and a thorough review of the issues and discussions among experts to determine the best solutions for the facilitation of global international telemedicine networks. More than 650 invited participants from 16 countries attended the five forums, which were of 2-3 days in duration. These forums provided a foundation for the exchange of ideas resulting in the initiation of collaborative activities. Based on these deliberations, a series of 21 recommendations were prepared by the national representatives of the G-8 GHAP SP-4. These recommendations propose to political leaders and health care managers of the G-8 and other countries roadmaps to follow in order to accelerate the achievement of a Global Society of Healthcare via Telemedicine, Telehealth, and Health Telematics. The 21 recommendations are presented in this report.

Chronic exposure to excess glucocorticoids results in cognitive and psychological impairment. A few studies have indicated that cerebral atrophy can be found in patients with Cushing's syndrome (CS), but its evolution after cure has not been studied extensively. We report the presence of apparent cerebral atrophy in CS and its reversibility after the correction of hypercortisolism. Thirty-eight patients with CS, including 21 with Cushing's disease and 17 with adrenal CS were studied. The control groups consisted of 18 patients with other non-ACTH-secreting sellar tumors and 20 normal controls. Twenty-two patients with CS were reevaluated after cure. Subjective loss of brain volume was present in 86% of patients with Cushing's disease and 100% of patients with adrenal CS. The values for third ventricle diameter, bicaudate diameter, and subjective evaluation were significantly increased in CS groups in comparison with the control group (P < or = 0.001). Imaging reevaluated at 39.7 +/- 34.1 months after achieving eucortisolism showed an improvement of the third ventricle diameter (P = 0.001), bicaudate diameter (P < 0.0005), and subjective evaluation (P = 0.05). We conclude that brain volume loss is highly prevalent in CS and is at least partially reversible following correction of hypercortisolism.

Chronic exposure to elevated glucocorticoid (GC) levels in Cushing's syndrome (CS) is associated with deficits in cognitive function. It has already been shown that CS patients scored significantly lower than controls on several aspects of cognitive function (J. Int. Neuropsychol. Soc. 6 (2000) 20). In the present study, 13 subjects who presented with CS were investigated one year after surgical treatment to determine the extent to which the effects of hypercortisolism on cognitive function are reversible. Subjects were evaluated with a battery of tasks, similar to the original battery of a year earlier and including tests of attention, visuospatial processing, memory, reasoning and verbal fluency. Except for one task of visual organization, the results showed little change in performance, suggesting that prolonged exposure to high levels of GC can cause long-lasting deleterious effects on cognitive function. The data suggest that correction of hypercortisolism is not necessarily correlated with short-term improvement in cognitive function.

Endogenous Cushing's syndrome can result from excess adrenocorticotropic hormone (ACTH; corticotropin) production by a pituitary adenoma (Cushing's disease) or by ectopic tumors secreting ACTH or corticotro- pin-releasing hormone (CRH). ACTH-independent Cushing's syndrome is caused by adrenocortical tumors or hyperplasias. Initial diagnosis is performed using 24-hour urinary free cortisol, low-dose dexamethasone tests, salivary cortisol, or night-time plasma cortisol values. A dexamethasone CRH test can discriminate between Cushing's syndrome and pseudo-Cushing's syndrome. If ACTH is elevated, combinations of high-dose dexamethasone tests, CRH/desmopressin tests, and pituitary magnetic resonance imaging can indicate a pituitary source. Discrimination from an ectopic ACTH tumor often requires inferior petrosal sinus sampling to confirm the ACTH source. If ACTH is low, adrenal computed tomography scan will identify the adrenal lesion(s) implicated. Some cortisol-producing adrenal tumors or, more frequently, bilateral macronodular hyperplasias, are under the control of aberrant membrane hormone receptors, or altered activity of eutopic receptors. The initial therapy of choice for patients with Cushing's disease is the selective transsphenoidal removal of the corticotroph adenoma; this induces remission in approximately 80% of patients, but long-term relapse occurs in up to 30% of these cases. The choice of second-line therapy remains controversial. Repeat surgery can be successful when residual tumor is detectable on magnetic resonance imaging, but carries a high risk of hypopituitarism. Bilateral adrenalectomy may be a better choice in patients without visible residual tumors, particularly in women desiring fertility. Radiotherapy combined with ketoconazole or radiosurgery was recently found effective, but longer-term evaluation of hypopituitarism and brain function is required. Current studies do not support the systematic use of prophylactic radiotherapy after bilateral adrenalectomy to decrease the risk of Nelson's syndrome; however, as soon as the residual tumor progresses, surgery and radiotherapy should be initiated. Various drugs which inhibit steroid synthesis (ketoconazole, metyrapone, aminoglutethimide, mitotane) are often effective for rapidly controlling hypercortisolism either in preparation for surgery, after unsuccessful removal of the etiologic tumor, or while awaiting the full effect of radiotherapy or more definitive therapy. Surgery is usually the treatment of choice for removal of cortisol-secreting adrenal tumors or ectopic ACTH/CRH-secreting tumors. The identification of aberrant adrenal receptors has recently allowed normalization of cortisol secretion by specific ligand receptor antagonists in limited cases of Cushing's syndrome secondary to bilateral macronodular adrenal hyperplasia. The long-term follow-up of patients treated for Cushing's syndrome should include the adequate replacement of glucocorticoids and other hormones, treatment of osteoporosis, and detection of long-term relapse of Cushing's syndrome.