Long-term outcomes of osilodrostat in Cushing’s disease: LINC 3 study extension

Objective To investigate the long-term efficacy and tolerability of osilodrostat, a potent oral 11β-hydroxylase inhibitor, for treating Cushing’s disease (CD). Design/methods A total of 137 adults with CD and mean 24-h urinary free cortisol (mUFC) > 1.5 × upper limit of normal (ULN) received osilodrostat (starting dose 2 mg bid; maximum 30 mg bid) during the prospective, Phase III, 48-week LINC 3 (NCT02180217) core study. Patients benefiting from osilodrostat at week 48 could enter the optional extension (ending when all patients had received ≥ 72 weeks of treatment or discontinued). Efficacy and safety were assessed for all enrolled patients from the core study baseline. Results Median osilodrostat exposure from the core study baseline to study end was 130 weeks (range 1–245) and median average dose was 7.4 mg/day (range 0.8–46.6). The reduction in mean mUFC achieved during the core was maintained during the extension and remained ≤ ULN. Of 106 patients, 86 (81%) patients who entered the extension had mUFC ≤ ULN at week 72. Improvements in cardiovascular/metabolic-related parameters, physical manifestations of hypercortisolism (fat pads, central obesity, rubor, striae, and hirsutism in females), and quality of life in the core study were also maintained or improved further during the extension. No new safety signals were reported; 15/137 (10.9%) and 12/106 (11.3%) patients discontinued for adverse events during the core and extension, respectively. Mean testosterone in females decreased towards baseline levels during the extension. Conclusions Data from this large, multicentre trial show that long-term treatment with osilodrostat sustains cortisol normalisation alongside clinical benefits in most patients with CD and is well tolerated

Long-term cardiometabolic morbidity in young adults with classic 21-hydroxylase deficiency congenital adrenal hyperplasia

Purpose To study the current practice for assessing comorbidity in adults with 21-hydroxylase CAH and to assess the prevalence of comorbidity in these adults. Methods A structured questionnaire was sent to 46 expert centres managing adults with CAH. Information collected included current therapy and surveillance practice with a particular focus on osteoporosis/osteopaenia, hyperlipidaemia, type 2 diabetes/hyperinsulinaemia, hypertension, CV disease, obesity. Results Of the 31 (67%) centres from 15 countries that completed the survey, 30 (97%) screened for hypertension by measuring blood pressure, 30 (97%) screened for obesity, 26 (84%) screened for abnormal glucose homoeostasis mainly by using Hb1Ac (73%), 25 (81%) screened for osteoporosis mainly by DXA (92%), 20 (65%) screened for hyperlipidaemia and 6 (19%) screened for additional CV disease. Of the 31 centres, 13 provided further information on the six co-morbidities in 244 patients with a median age of 33 yrs (range 19, 94). Of these, 126 (52%) were females and 174 (71%) received fludrocortisone in addition to glucocorticoids. Of the 244 adults, 73 (30%) were treated for at least one comorbidity and 15 (21%) for more than 2 co-morbidities. Of 73, the patients who were treated for osteoporosis/osteopaenia, hyperlipidaemia, type 2 diabetes/hyperinsulinaemia, hypertension, CV disease, obesity were 43 (59%), 17 (23%), 16 (22%), 10 (14%), 8 (11), 3 (4%) respectively. Conclusion Cardiometabolic and bone morbidities are not uncommon in adults with CAH. There is a need to standardise the screening for these morbidities from early adulthood and to explore optimal therapy through routine collection of standardised data

Phenotypic variability in 17β-hydroxysteroid dehydrogenase-3 deficiency and diagnostic pitfalls

10.1111/j.1365-2265.2007.02829.xClinical Endocrinology67120-2

An expert consensus statement on use of adrenal vein sampling for the subtyping of primary aldosteronism

Item does not contain fulltextAdrenal venous sampling is recommended by current guidelines to identify surgically curable causes of hyperaldosteronism but remains markedly underused. Key factors contributing to the poor use of adrenal venous sampling include the prevailing perceptions that it is a technically challenging procedure, difficult to interpret, and can be complicated by adrenal vein rupture. In addition, the lack of uniformly accepted standards for the performance of adrenal venous sampling contributes to its limited use. Hence, an international panel of experts working at major referral centers was assembled to provide updated advice on how to perform and interpret adrenal venous sampling. To this end, they were asked to use the PICO (Patient or Problem, Intervention, Control or comparison, Outcome) strategy to gather relevant information from the literature and to rely on their own experience. The level of evidence/recommendation was provided according to American Heart Association gradings whenever possible. A consensus was reached on several key issues, including the selection and preparation of the patients for adrenal venous sampling, the procedure for its optimal performance, and the interpretation of its results for diagnostic purposes even in the most challenging cases

Response to implementation of rapid cortisol during adrenal vein sampling

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Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors

In our article “Production of 11-oxygenated androgens by testicular adrenal rest tumors” we defined the production of 11-oxygenated 19-carbon steroids by testicular adrenal rest tumors (TART) in men with 21-hydroxylase deficiency (21OHD), by the quantification of these steroid hormones in the spermatic vein blood and corresponding peripheral vein blood samples of men with 21OHD. Eleven steroid hormones were quantified in left (n=7) and right (n=4) spermatic vein- and simultaneously taken peripheral blood (n=7) samples from seven men with 21OHD and TART using liquid chromatography-tandem mass spectrometry. These samples were previously obtained by Claahsen-van der Grinten et al. (DOI:10.1210/jc.2007-0337). All patients had bilateral TART, but for three patients (2, 3, and 7) no material was longer available from the right spermatic vein. For comparison, we also measured the peripheral steroid concentrations in five adrenalectomized patients and twelve age, sex, and BMI-matched controls. Additionally, steroids were measured in previously collected media (Turcu et al. DOI:10.1210/jc.2015-1023) of in vitro cultured TART cells and adrenal cells, that were treated for 24 or 48 hours with adrenocorticotropic hormone (ACTH; 10 nmol/L) or Luteinizing Hormone (LH; 25 ng/mL). In this repository we provide the raw data files and the supplementary data files. The abbreviations of the quantified steroid hormones are listed in “Abbreviations_quantified_hormones.pdf”. The raw data can be found in three different files: Schroder_2021_peripheral_vein.csv contains the peripheral steroid hormone concentrations (ng/dL) of seven men with 21OHD and TART (P1-P7), five adrenalectomized controls (C1-C5), and twelve BMI- and age-matched healthy men (M1-M12). Schroder_2021_spermatic_vein.csv contains the steroid hormone concentrations (ng/dL) in left (n=7) and right (n=4) spermatic vein blood samples of seven men with 21OHD and TART. The corresponding numbers of the spermatic vein samples and peripheral vein samples belong to the same patient. Schroder_2021_TART_Adrenal.csv contains the steroid hormone concentrations (pg/mL) in TART-cell- or normal adrenal cell-conditioned medium under basal conditions or 24 or 48 hours of treatment with ACTH or LH. Three supplementary Tables are provided: Schroder_2021_SupplementaryTable1.pdf contains Supplementary Table 1, presenting the concentrations (nmol/L) of eleven steroid hormones in vena spermatica (v.Sp) and peripheral plasma (P) samples with corresponding ratios (R) of seven men with 21OHD and TART with left and/or right cannulated spermatic veins. Steroid concentrations below the lower limit of quantification (LLOQ) were set at 0.5*LLOQ for calculation of the ratios. Schroder_2021_SupplementaryTable2.pdf contains Supplementary Table 2, presenting the concentrations (nmol/L) of steroid hormones in TART-cell- or normal adrenal cell-conditioned medium under basal conditions or after 24 hours of treatment with ACTH. Schroder_2021_SupplementaryTable3.pdf contains Supplementary Table 3, presenting the concentrations (nmol/L) of steroid hormones in TART-cell- or normal adrenal cell-conditioned medium under basal conditions or after 48 hours of treatment with ACTH

Mediastinal paragangliomas: association with mutations in the succinate dehydrogenase genes and aggressive behavior

Extra-adrenal pheochromocytomas, otherwise known as paragangliomas (PGLs), account for about 20% of catecholamine-producing tumors. Catecholamine excess and mutations in the genes encoding succinate dehydrogenase subunits (SDHx) are frequently found in patients with PGLs. Only 2% of PGLs are found in the mediastinum, and little is known about genetic alterations in patients with mediastinal PGLs, catecholamine production by these tumors, or their clinical behavior. We hypothesized that most mediastinal PGLs are associated with germ line SDHx mutations, norepinephrine and/or dopamine excess, and aggressive behavior. The objective of this study was to characterize genetic, biochemical, and clinical data in a series of ten patients with mediastinal PGLs. All ten primary mediastinal PGL patients had germ line SDHx mutations, six in SDHB, and four in SDHD genes. Chest or back pain were the most common presenting symptoms (five patients), and catecholamines and/or their metabolites were elevated in seven patients. Additional tumors included head and neck PGLs in four patients, pheochromocytoma in one patient, and bladder PGL in another. Metastatic disease was documented in six patients (60%), and a concurrent abdominal mass was found in one patient. We conclude that mediastinal PGLs are strongly associated with SDHB and SDHD gene mutations, noradrenergic phenotype, and aggressive behavior. The present data suggest that all patients with mediastinal PGLs should be screened for SDHx gene mutations, regardless of age

Supplementary Material for: Severe aldosterone synthase deficiency in a nine-day old Lebanese boy: the importance of functional studies to establish pathogenicity of seemingly benign variants in CYP11B2

Introduction Aldosterone synthase deficiency is a rare autosomal recessive disease characterized by vomiting, dehydration, salt wasting, life-threatening hyperkalemia in infancy, followed by failure to thrive. It results from pathogenic variants in CYP11B2. Case Presentation A boy, born in Montreal to Lebanese parents who are first cousins, was referred at nine days of life for severe dehydration. A diagnosis of primary adrenal insufficiency was made, and treatment was started with fludrocortisone and hydrocortisone. Exome sequencing revealed a homozygous variant p.(Asn201Asp)(N201D). In silico, this variant was considered benign, but in vitro functional expression studies established it caused the severe aldosterone deficiency. It ended the diagnostic odyssey and allowed to safely stop hydrocortisone replacement. Conclusion If a gene variant co-segregates with a phenotype, in vitro functional studies are required even if in silico studies are negativ

Congenital adrenal hyperplasia - current insights in pathophysiology, diagnostics and management

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21- hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000 there have been numerous new developments. These include more detailed understanding of steroidogenic pathways, refinements in neonatal screening, improved diagnostic measurements utilizing chromatography and mass spectrometry coupled with steroid profiling, and improved genotyping methods. Clinical trials of alternative medications and modes of delivery have been recently completed or are under way. Genetic and cell-based treatments are being explored. A large body of data concerning long-term outcomes in patients affected by CAH, including psychosexual well-being, has been enhanced by the establishment of disease registries. This review provides the reader with current insights in congenital adrenal hyperplasia with special attention to these new developments