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Objective To assess the usefulness of the upright posture stimulation test (UPT) in the confirmation of primary aldosteronism (PA) in patients in whom saline tests (ST) were inconclusive. Methods One hundred eighty-seven adult patients with possible PA were retrospectively included and compared to 25 control subjects. Blood samples were obtained after a 1-hour supine posture and during 2 hours of ambulation. An increase in plasma aldosterone concentration (PAC) ≥ 50% with a suppressed renin (≤10.1 ng/L; ≤1 ng/mL/hour) and a cortisol increase ≤50% were considered abnormal. Results PA patients had higher basal PAC and lower basal direct renin concentration (DRC) (P <.0001) and a higher maximal PAC (P =.0025) and lower maximal DRC (DRCmax) (P <.0001) during UPT compared to controls. PA was confirmed in 145 patients (77.5%), based on either oral/IV ST or UPT. DRCmax ≤12 ng/L during UPT was a predictor of PA (receiver operating characteristic curve sensitivity 93.8%, specificity 88%), and 95.6% of PA patients increased PAC ≥50% on UPT (median 222.2%), while renin remained suppressed. All 41 PA patients with false-negative IV ST (PAC < 162 pmol/L) and 88.9% with borderline response (162-240 pmol/L) had a DRCmax ≤12, while, respectively, 97.6% and 100% increased aldosterone by ≥50%. Similar responses to UPT were found in lateralized (28/63) and bilateral PA source (35/63). PA diagnosis increased from 23.6% to 88.8% using UPT results instead of IV ST and were confirmed at pathology and clinical outcome after adrenalectomy (n = 22). Conclusion UPT can be useful to confirm PA, particularly in patients with suspected false-negative ST. [ABSTRACT FROM AUTHOR]

Desmopressin is increasingly used for the diagnosis of Cushing disease (CD) since corticotropin-releasing hormone became unavailable. We report the case a 32-year-old man who presented with overt Cushing syndrome. Morning blood cortisol, ACTH, 1 mg dexamethasone suppression test, 24-hour urinary free cortisol, and bedtime salivary cortisol were highly variable, reaching markedly elevated values. Intravenous desmopressin administration produced no ACTH or cortisol increase. Pituitary magnetic resonance imaging, thoracic computed tomography, and DOTATATE positron emission tomography scan identified no lesion. Inferior petrosal sinus sampling (IPSS) with desmopressin stimulation resulted in elevated central-to-peripheral ACTH ratio and prolactin co-secretion, while peripheral ACTH remained stable. No corticotroph tumor was identified on pituitary surgery pathology. Hypercortisolism persisted postoperatively. Cabergoline was initiated, after which the patient rapidly developed transient severe adrenal insufficiency (AI). Bilateral adrenalectomy was performed in view of persistent hypercortisolism. This is an unusual case of petrosal sinus ACTH response to desmopressin without any peripheral response, suggesting a central source of ACTH. Thus, desmopressin should still be used during IPSS in patients with no peripheral response. It is unclear whether the AI episode resulted from a combination of nadir of cyclic hypercortisolism, partial apoplexy, and response to cabergoline of an occult corticotroph tumor. [ABSTRACT FROM AUTHOR]

Adrenal crisis (AC) is a life threatening acute adrenal insufficiency (AI) episode which can occur in patients with primary AI but also secondary AI (SAI), tertiary AI (TAI) and iatrogenic AI (IAI). In SAI, TAI and IAI, AC may develop when the HPA axis is unable to mount an adequate glucocorticoid response to severe stress due to pituitary or hypothalamic disruption. It manifests as an acute deterioration in multi-organ homeostasis that, if untreated, leads to shock and death. Despite the availability of effective preventive strategies, its prevalence is increasing in patients with SAI, TAI and IAI due to more frequent exogenous steroid administration, pituitary immune-related effects of immune checkpoint inhibitors and opioid use in pain management. The delayed diagnosis of acute AI which remains infrequently suspected increases the risk of AC. Its main precipitating factors are infections, emotional distress, surgery, cessation or reduction in GC doses, pituitary infarction or surgical cure of endogenous Cushing's syndrome. In patients not known previously to have SAI/TAI/IAI, recognition of its symptoms, signs, and biochemical abnormalities can be challenging and cause delay in proper diagnosis and therapy. Effective therapy of AC is rapid intravenous administration of hydrocortisone (initial bolus of 100 mg followed by 200 mg/24 h as continuous infusion or bolus of 50 mg every 6 h) and 0.9% saline. In diagnosed patients, preventive education in sick-day rules adjustment of glucocorticoid replacement and hydrocortisone parenteral self-administration must be performed repeatedly by trained health care providers. Strategies to improve the adequate preventive education in patients at risk for secondary AI should be promoted in collaboration with various medical specialist societies and patients support associations. [ABSTRACT FROM AUTHOR]

BACKGROUND: Primary aldosteronism (PA) has been broadly dichotomized into unilateral and bilateral forms. Adrenal vein sampling (AVS) lateralization indices (LI) ≥2 to 4 are the standard-of-care to recommend unilateral adrenalectomy for presumed unilateral PA. We aimed to assess the rates and characteristics of residual PA after AVS-guided adrenalectomy. METHODS: We conducted an international, retrospective, cohort study of patients with PA from 7 referral centers who underwent unilateral adrenalectomy based on LI≥4 on baseline and/or cosyntropin-stimulated AVS. Aldosterone synthase (CYP11B2) immunohistochemistry and next generation sequencing were performed on available formalin-fixed paraffin-embedded adrenal tissue. RESULTS: The cohort included 283 patients who underwent AVS-guided adrenalectomy, followed for a median of 326 days postoperatively. Lack of PA cure was observed in 16% of consecutive patients, and in 22 patients with lateralized PA on both baseline and cosyntropin-stimulated AVS. Among patients with residual PA postoperatively, 73% had multiple CYP11B2 positive areas within the resected adrenal tissue (versus 23% in those cured), wherein CACNA1D mutations were most prevalent (63% versus 33% in those cured). In adjusted regression models, independent predictors of postoperative residual PA included Black versus White race (odds ratio, 5.10 [95% CI, 1.45–17.86]), AVS lateralization only at baseline (odds ratio, 8.93 [95% CI 3.00–26.32] versus both at baseline and after cosyntropin stimulation), and CT-AVS disagreement (odds ratio, 2.75 [95% CI, 1.20–6.31]). CONCLUSIONS: Multifocal, asymmetrical bilateral PA is relatively common, and it cannot be excluded by robust AVS lateralization. Long-term postoperative monitoring should be routinely pursued, to identify residual PA and afford timely initiation of targeted medical therapy. [ABSTRACT FROM AUTHOR]

Context: Central hypothyroidism was described previously in mitotane-treated patients but data on its prevalence and time of occurrence are limited. Objective: To better characterize thyroid hormone insufficiency in patients exposed to mitotane. Methods: We reviewed medical records of patients from 2 academic centers in Montreal (Canada) and Toulouse (France) with exposure to mitotane therapy for adrenocortical cancer between 1995 and 2020. We analyzed the thyroid function parameters during and after treatment. Results: In our cohort of 83 patients, 17 were excluded because of preexisting primary hypothyroidism or drug-induced hypothyroidism. During follow-up, 3/66 patients maintained a normal thyroid function and 63/66 developed central hypothyroidism. Among those 63 patients, 56 presented with an inappropriately normal or low TSH and 7 with a mildly elevated TSH. The onset of hypothyroidism was: <3 months in 33.3%, 3 to 6 months in 19.1%, 6 to 9 months in 14.3%, and 9 to 12 months in 9.5%. At least 14.3% of cases occurred after 12 months of exposure, and 6 patients had an undetermined time of occurrence. Over time, 27 patients stopped mitotane and partial (42.3%) or complete (23.1%) recovery from hypothyroidism was observed, mainly in the first 2 years after mitotane discontinuation. Conclusion: Mitotane therapy is frequently associated with new onset of central hypothyroidism with a prevalence of 95.5%. Most cases occurred in the first year of treatment. Partial or full recovery of thyroid function occurs in 65.4% of cases. This study supports the importance of systematic monitoring of TSH and free T4 levels during and following discontinuation of mitotane therapy. [ABSTRACT FROM AUTHOR]

This study investigated the effectivity and sustainability of a physical activity (PA) promotion and motor training programs and analyzed predictors for PA changes in persons with dementia. A total of 122 participants with mild-to-moderate dementia were randomized to the intervention program designed for persons with dementia (intervention group) or a motor placebo activity (control group). The primary outcome was the Physical Activity Questionnaire for the Elderly assessed at the baseline, after the 3-month intervention, and at a 3-month follow-up. The PA promotion program significantly increased PA in the intervention group compared with the control group during the training intervention phase. Both groups showed an increase in habitual PA when intervention-induced activities were excluded. PA was sustainably increased in both groups at follow-up. Low baseline PA was predictive for increased PA after the intervention and low baseline PA, high motor performance, and low comorbidity for increased PA at follow-up. [ABSTRACT FROM AUTHOR]

Patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) usually present bilateral benign adrenocortical macronodules at imaging and variable levels of cortisol excess. PBMAH is a rare cause of primary overt Cushing's syndrome but may represent up to one-third of bilateral adrenal incidentalomas with evidence of cortisol excess. The increased steroidogenesis in PBMAH is often regulated by various G protein–coupled receptors (GPCRs) aberrantly expressed in PBMAH tissues; some receptor ligands are ectopically produced in PBMAH tissues, creating aberrant autocrine/paracrine regulation of steroidogenesis. The bilateral nature of PBMAH and familial aggregation led to the identification of germline heterozygous inactivating mutations of the ARMC5 gene, in 20% to 25% of the apparent sporadic cases and more frequently in familial cases; ARMC5 mutations/pathogenic variants can be associated with meningiomas. More recently, combined germline mutations/pathogenic variants and somatic events inactivating the KDM1A gene were specifically identified in patients affected by glucose-dependent insulinotropic peptide (GIP)-dependent PBMAH. Functional studies demonstrated that inactivation of KDM1A leads to GIP-receptor (GIPR) overexpression and over- or downregulation of other GPCRs. Genetic analysis is now available for early detection of family members of index cases with PBMAH carrying identified germline pathogenic variants. Detailed biochemical, imaging, and comorbidity assessment of the nature and severity of PBMAH is essential for its management. Treatment is reserved for patients with overt or mild cortisol/aldosterone or other steroid excesses, taking in account comorbidities. It previously relied on bilateral adrenalectomy; however, recent studies tend to favor unilateral adrenalectomy or, less frequently, medical treatment with cortisol synthesis inhibitors or specific blockers of aberrant GPCR. [ABSTRACT FROM AUTHOR]

Adrenal vein sampling (AVS) is recommended for subtyping primary aldosteronism (PA) to identify lateralized or bilateral sources of aldosterone excess, allowing for better decision-making in regard to medical or surgical management on a case-by-case basis. To date, no consensus exists on protocols to be used during AVS, especially concerning sampling techniques, the timing of sampling, and whether or not to use adrenocorticotropic hormone (ACTH) stimulation. Interpretation criteria for selectivity, lateralization, and contralateral suppression vary from one expert center to another, with some favoring strict cut-offs to others being more permissive. Clinical and biochemical post-operative outcomes can also be influenced by AVS criteria utilized to indicate surgical therapy. In this review, we reanalyze studies on AVS highlighting the recent pathological findings of frequent micronodular hyperplasia adjacent to a dominant aldosteronoma (APA) overlapping with bilateral idiopathic hyperaldosteronism (IHA) etiologies, as opposed to the less frequent unilateral single aldosteronoma. The variable expression of melanocortin type 2 receptors in the nodules and hyperplasia may explain the frequent discordance in lateralization ratios between unstimulated and ACTH- stimulated samples. We conclude that aldosterone values collected during simultaneous bilateral sampling, both at baseline and post-ACTH stimulation, are required to adequately evaluate selectivity, lateralization, and contralateral suppression during AVS, to better identify all patients with PA that can benefit from a surgical indication. Recommended cut-offs for each ratio are also presented. [ABSTRACT FROM AUTHOR]

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 post-prandial 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. [ABSTRACT FROM AUTHOR]

Endogenous Cushing's syndrome (CS) is rare during pregnancy, probably because hypercortisolism induces anovulation and infertility. To date, slightly above 200 cases have been reported in the literature. The most frequent etiology of CS diagnosed during gestation is from primary adrenal causes, namely adrenal adenomas and an entity called pregnancy-induced CS. The latter can be secondary to the aberrant adrenal expression of luteinizing hormone/human chorionic gonadotropin receptor (LHCGR) in the adrenal lesions. Diagnosis of CS during pregnancy is extremely challenging, as a consequence of the physiologic hypercortisolism normally present during pregnancy. Assessment of excess cortisol production tests should be interpreted cautiously using adapted upper limits of normal criteria for pregnant patients and a high index of suspicion is required for diagnosis. Imaging is also limited due to high risk of radiation exposure with computed tomography and teratogenicity with contrast agents. The optimal treatment strategy is surgical resection of adrenal adenoma or pituitary adenoma, ideally before 24 weeks of gestation to reduce the risk of maternal and fetal complications. In mild cases, surgery can be postponed until after delivery and treatment should focus on controlling metabolic complications of hypercortisolism, such as hypertension and dysglycemia. Maternal and fetal outcomes of excess cortisol exposure, except fetal loss, are not readily improved by successful treatment of hypercortisolism. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In this narrative review, we present data gathered over four decades (1980–2020) on the epidemiology, pathophysiology and genetics of primary hyperparathyroidism (PHPT). PHPT is typically a disease of postmenopausal women, but its prevalence and incidence vary globally and depend on a number of factors, the most important being the availability to measure serum calcium and parathyroid hormone levels for screening. In the Western world, the change in presentation to asymptomatic PHPT is likely to occur, over time also, in Eastern regions. The selection of the population to be screened will, of course, affect the epidemiological data (ie, general practice as opposed to tertiary center). Parathyroid hormone has a pivotal role in regulating calcium homeostasis; small changes in extracellular Ca++ concentrations are detected by parathyroid cells, which express calcium‐sensing receptors (CaSRs). Clonally dysregulated overgrowth of one or more parathyroid glands together with reduced expression of CaSRs is the most important pathophysiologic basis of PHPT. The spectrum of skeletal disease reflects different degrees of dysregulated bone remodeling. Intestinal calcium hyperabsorption together with increased bone resorption lead to increased filtered load of calcium that, in addition to other metabolic factors, predispose to the appearance of calcium‐containing kidney stones. A genetic basis of PHPT can be identified in about 10% of all cases. These may occur as a part of multiple endocrine neoplasia syndromes (MEN1–MEN4), or the hyperparathyroidism jaw‐tumor syndrome, or it may be caused by nonsyndromic isolated endocrinopathy, such as familial isolated PHPT and neonatal severe hyperparathyroidism. DNA testing may have value in: confirming the clinical diagnosis in a proband; eg, by distinguishing PHPT from familial hypocalciuric hypercalcemia (FHH). Mutation‐specific carrier testing can be performed on a proband's relatives and identify where the proband is a mutation carrier, ruling out phenocopies that may confound the diagnosis; and potentially prevention via prenatal/preimplantation diagnosis. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

The desmopressin test was first described 30 years ago. Based on the differential secretagogue properties of desmopressin on adrenocorticotropin (ACTH) release between normal and corticotroph tumor cells, this test was intended to facilitate the diagnosis of Cushing syndrome (CS). The distinct expression of the various arginine vasopressin receptors between normal pituitary, corticotroph tumors, or neuroendocrine tumors cells secreting ACTH ectopically suggested that this test could facilitate the etiological diagnosis of ACTH-dependent CS. In this review, we analyze the merits and pitfalls of desmopressin use in the diagnostic procedures of CS. Desmopressin response is not able to completely differentiate the various etiologies of CS; its wider availability has allowed its use for inferior petrosal sinus sampling confirmation of a pituitary source of ACTH excess. In addition, desmopressin can be useful to demonstrate adequate corticotroph tumor resection when its stimulatory effect is lost following pituitary surgery of patients with Cushing disease. Desmopressin response can also be a marker of the risk of longer-term postoperative recurrence. However, this review also highlights the lack of consensual criteria of normal or abnormal response to desmopressin in its various uses and requirement for further research on its usefulness. [ABSTRACT FROM AUTHOR]

Context Preparation of patients with iodine contrast media (ICM) allergy who require adrenal vein sampling (AVS) to establish source of aldosterone excess of their confirmed primary aldosteronism (PA) is controversial. Usual premedication with high-dose prednisone can interfere with cortisol determinations, possibly altering the aldosterone to cortisol ratios for the identification of lateralized aldosterone excess. Objective We aimed to evaluate the efficacy and safety of premedication with high-dose dexamethasone to perform AVS in patients with ICM. Methods One hundred and seventy-seven consecutive patients with confirmed PA who underwent bilateral simultaneous basal and post-ACTH bolus AVS at our center between January 2010 and December 2020 were retrospectively analyzed for history of ICM allergy. A total of 7 patients (4%) with previous allergic reactions to ICM were prepared with 3 doses of 7.5 mg dexamethasone premedication rather than the usual 50 mg of prednisone. Results No breakthrough allergic reactions were reported in the 7 patients. Despite adequate serum cortisol suppression following dexamethasone, the basal and post-ACTH selectivity index were respectively > 2 and > 5 bilaterally in all patients, confirming adequate cannulation of both adrenal veins. Four patients had lateralized ratios (A/C ratio > 2 basally and > 4 post-ACTH), while 3 had bilateral source during AVS study. In the 3 patients undergoing unilateral adrenalectomy for lateralized source and contralateral suppression and adequate follow-up data, cure of PA was achieved at mean 58 months postoperatively. Conclusion AVS using dexamethasone premedication is safe and accurate for diagnosing the source of aldosterone excess in patients with PA and ICM allergy. [ABSTRACT FROM AUTHOR]

Simple Summary: At least 10% of pheochromocytomas (PHEOs) and paragangliomas (PPGLs) may recur after the initial surgery. The optimal follow-up time for these tumors remains unknown. We present a cohort of recurrent PPGLs in a clinical care setting of a quaternary center. In this paper, we describe recurrence patterns based on tumor location (head and neck paragangliomas, thoracoabdominal paragangliomas, and pheochromocytomas). We report that the overall mean delay of recurrence was 9.7 years and that one-third of the cohort had a recurrence more than 10 years after the initial surgery. Additionally, 17.6% of recurrent PHEOs were smaller than the predicted cutoff for recurrence (5 cm). Finally, more than 50% of recurrent PPGLs harbored a germline mutation in a susceptibility gene. In sum, this paper supports that overall, the safest option remains a lifelong follow-up. At least 10% of pheochromocytomas (PHEOs) and paragangliomas (PGLs) (PPGLs) may recur after the initial surgery. Guidelines recommend annual screening for recurrence in non-metastatic tumors for at least 10 years after the initial surgical resection and lifelong screening in high-risk patients. However, recent data suggest that a shorter follow-up might be appropriate. We performed a retrospective analysis on patients with PPGLs who had local and/or metastatic recurrences between 1995 and 2020 in our center. Data were available for 39 cases of recurrence (69.2% female) including 20 PHEOs (51.3%) and 19 PGLs (48.7%) (13 head and neck (HNPGL) and 6 thoracoabdominal (TAPGL)). The overall average delay of recurrence was 116.6 months (14–584 months) or 9.7 years and the median was 71 months or 5.9 years. One-third of the cohort had a recurrence more than 10 years after the initial surgery (10–48.7 years). The average tumor size at initial diagnosis was 8.2 cm for PHEOs, 2.7 cm for HNPGLs, and 9.6 cm for TAPGLs. Interestingly, 17.6% of PHEOs were under 5 cm at the initial diagnosis. Metastatic recurrence was identified in 75% of PHEOs, 15.4% of HNPGLs, and 66.7% of TAPGLs. Finally, 12/23 (52.2%) patients with recurrence who underwent genetic testing carried a germline mutation. Overall, the safest option remains a lifelong follow-up. [ABSTRACT FROM AUTHOR]

Objective: Pheochromocytomas (PHEOs) and paragangliomas (PGLs), collectively known as PPGLs, are tumours with high heritability. The prevalence of germline mutations in apparently sporadic PPGLs varies depending on the study population. The objective of this study was to determine the spectrum of germline mutations in a cohort of patients with apparently sporadic PPGLs over time. Design: We performed a retrospective review of patients with apparently sporadic PPGLs who underwent genetic testing at our referral centre from 2005 to 2020. Patients: We included patients with apparently sporadic PPGLs who underwent genetic testing at our referral center. Measurements: Genetic analysis included sequential gene sequencing by Sanger method or next generation sequencing (NGS) with a multigene panel. Results: The prevalence of germline mutations was 26.2% (43/164); 40.0% (30/75) in PGLs and 14.6% (13/89) in PHEOs. We identified four novel pathogenic variants (two SDHB and two SDHD). Patients carrying germline mutations were younger (38.7 vs. 49.7 years old) than patients with no identified germline mutations. From 2015 to 2020, we performed NGS with a multigene panel on 12 patients for whom the initial genetic analysis was negative. Germline mutations in previously untested genes were found in four (33.3%) of these patients (two MAX and two SDHA), representing 9.3% (4/43) of the mutation carriers. Conclusion: The prevalence of germline mutations in our cohort of patients with apparently sporadic PPGLs was 26.2%. Genetic re‐evaluation over time using multigene sequencing by NGS assay in a subgroup of patients leads to an increase in the detection of mutations. [ABSTRACT FROM AUTHOR]

Context: Acylated ghrelin (AG) stimulates appetite and is elevated compared to its unacylated (UAG) counterpart in Prader-Willi syndrome (PWS). GLWL-01 is a selective, reversible inhibitor of ghrelin O-acyltransferase (GOAT), the enzyme that converts UAG into AG. Objective: This work aimed to assess the efficacy, pharmacokinetics, pharmacodynamics, and safety of GLWL-01 in the treatment of PWS patients. Methods: A double-blind, placebo-controlled, phase 2 crossover study was conducted with 2 active treatment periods of 28 days in 19 patients (aged 16-65 years; body mass index (BMI) ≥ 28) with genetically confirmed PWS. The study took place in 7 hospital-based study centers in the United States and Canada. Patients received placebo or GLWL-01 (450 mg twice daily) orally after lead-in placebo and washout periods. The Hyperphagia Questionnaire for Clinical Trials and Caregiver Global Impression of Change were used to measure reductions in hyperphagia. Plasma concentrations of AG and UAG were evaluated as correlates. Results: Treatment resulted in statistically significant differences compared to placebo in plasma AG (P = .0002), UAG (P = .0488), and AG/UAG (P = .0003). GLWL-01 did not statistically significantly reduce hyperphagia-related behavior or bring about changes in global clinical end points, as assessed by caregivers. Anthropometric and clinical parameters correlated with obesity did not statistically significantly change in response to treatment. Less than half of patients reported a treatment-emergent adverse event (TEAE). No deaths, serious adverse events, or severe TEAEs were reported. Conclusion: GLWL-01 is safe and well tolerated. Pharmacological parameters confirmed the inhibition of GOAT following administration of GLWL-01. Patients' eating behaviors, BMI, blood glucose, and total cholesterol, among other similar measures, were not modified. [ABSTRACT FROM AUTHOR]

Progress in our understanding of adrenal disorders affecting pregnant women has been hindered by three major hurdles: the phenotypical and biochemical overlap between pregnancy and adrenal pathology, the infrequent presentation of adrenal disorders during pregnancy, and the scarcity of human studies that include pregnant women. Pregnancy-specific adrenal hormone calibrations are lacking. Thus, the evaluation and management of adrenal disorders presenting during pregnancy are challenging. In this thematic issue, prominent experts in adrenal physiology and pathology have joined forces to offer a comprehensive collection of articles covering the current knowledge on adrenal disorders affecting reproductive-age women. This superb collection of reviews makes the perfect clinical companion on pregnancy-related adrenal pathology for a broad range of healthcare providers, from primary care physicians and internists to endocrinologists and gynecologist-obstetricians, regardless of career stage or practice setting. [ABSTRACT FROM AUTHOR]