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You are looking at 1 - 10 of 41 items for :
- Abstract: Adrenal x
- Abstract: Adrenaline x
- Abstract: Androgens x
- Abstract: Catecholamines x
- Abstract: hyperplasia x
- Abstract: Cortex x
- Abstract: Cushings x
- Abstract: Glucocorticoids x
- Abstract: Medulla x
- Abstract: Noradrenaline x
- Adrenal x
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Glucocorticoids have short- and long-term effects on adrenal gland function and development. RNA sequencing (RNA-seq) was performed to identify early transcriptomic responses to the synthetic glucocorticoid, dexamethasone (Dex), in vitro and in vivo. In total, 1711 genes were differentially expressed in the adrenal glands of the 1-h Dex-treated mice. Among them, only 113 were also considered differentially expressed genes (DEGs) in murine adrenocortical Y-1 cells treated with Dex for 1 h. Gene ontology analysis showed that the upregulated DEGs in the adrenal gland of the 1-h Dex-treated mice were highly associated with the development of neuronal cells, suggesting the adrenal medulla had a rapid response to Dex. Interestingly, only 4.3% of Dex-responsive genes in the Y-1 cell line under Dex treatment for 1 h were differentially expressed under Dex treatment for 24 h. The heatmaps revealed that most early responsive DEGs in Y-1 cells during 1 h of treatment exhibited a transient response. The expression of these genes under treatment for 24 h returned to basal levels similar to that during control treatment. In summary, this research compared the rapid transcriptomic effects of Dex stimulation in vivo and in vitro. Notably, adrenocortical Y-1 cells had a transient early response to Dex treatment. Furthermore, the DEGs had a minimal overlap in the 1-h Dex-treated group in vivo and in vitro.
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The overproduction of adrenocorticotropic hormone (ACTH), in conditions such as Cushing’s disease and congenital adrenal hyperplasia (CAH), leads to significant morbidity. Current treatment with glucocorticoids does not adequately suppress plasma ACTH, resulting in excess adrenal androgen production. At present, there is no effective medical treatment in clinical use that would directly block the action of ACTH. Such a therapy would be of great clinical value. ACTH acts via a highly selective receptor, the melanocortin-2 receptor (MC2R) associated with its accessory protein MRAP. ACTH is the only known naturally occurring agonist for this receptor. This lack of redundancy and the high degree of ligand specificity suggest that antagonism of this receptor could provide a useful therapeutic strategy in the treatment of conditions of ACTH excess. To this end, we screened an extensive library of low-molecular-weight drug-like compounds for MC2R antagonist activity using a high-throughput homogeneous time-resolved fluorescence cAMP assay in Chinese hamster ovary cells stably co-expressing human MC2R and MRAP. Hits that demonstrated MC2R antagonist properties were counter-screened against the β2 adrenergic receptor and dose–response analysis undertaken. This led to the identification of a highly specific MC2R antagonist capable of antagonising ACTH-induced progesterone release in murine Y-1 adrenal cells and having selectivity for MC2R amongst the human melanocortin receptors. This work provides a foundation for the clinical investigation of small-molecule ACTH antagonists as therapeutic agents and proof of concept for the screening and discovery of such compounds.
Department of Endocrinology, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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Department of Endocrinology, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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Autoimmune Addison’s disease (AAD) is defined as primary adrenal insufficiency due to immune-mediated destruction of the adrenal cortex. This destruction of steroid-producing cells has historically been thought of as an irreversible process, with linear progression from an ACTH-driven compensated phase to overt adrenal insufficiency requiring lifelong glucocorticoid replacement. However, a growing body of evidence suggests that this process may be more heterogeneous than previously thought, with potential for complete or partial recovery of glucocorticoid secretion. Although patients with persistent mineralocorticoid deficiency despite preserved or recovered glucocorticoid function are anecdotally mentioned, few well-documented cases have been reported to date. We present three patients in the United Kingdom who further challenge the long-standing hypothesis that AAD is a progressive, irreversible disease process. We describe one patient with a 4-year history of mineralocorticoid-only Addison’s disease, a patient with spontaneous recovery of adrenal function and one patient with clinical features of adrenal insufficiency despite significant residual cortisol function. All three patients show varying degrees of mineralocorticoid deficiency, suggesting that recovery of zona fasciculata function in the adrenal cortex may occur independently to that of the zona glomerulosa. We outline the current evidence for heterogeneity in the natural history of AAD and discuss possible mechanisms for the recovery of adrenal function.
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Department of Endocrinology, Diabetes and Metabolism, Karolinska University Hospital, Stockholm, Sweden
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Department of Medicine, Haukeland University Hospital, Bergen, Norway
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Adrenal insufficiency is a life-threatening condition requiring chronic glucocorticoid replacement therapy, as well as stress adaptation to prevent adrenal crises. To increase patients’ self-sustainability, education on how to tackle an adrenal crisis is crucial. All patients should carry the European Emergency Card.
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Background
There is no consensus regarding markers of optimal treatment or timing between glucocorticoid intake and assessment of hormone levels in the follow-up of female 21-hydroxylase deficient patients.
Objective
To examine visit-to-visit repeatability in levels of adrenal hormones in adult female patients, to identify predictors of repeatability in hormone levels and to examine concordance between levels of different adrenal hormones.
Method
All patients with confirmed 21-hydroxylase deficiency treated with glucocorticoids, were included. The two most recent blood samples collected on a stable dose of glucocorticoid replacement were compared. Complete concordance was defined as all measured adrenal hormones either within, below or above normal range evaluated in a single-day measurement.
Results
Sixty-two patients, median age of 35 (range 18–74) years were included. All hormone levels showed moderate to excellent repeatability with an intraclass correlation coefficient between 0.80 and 0.99. Repeatability of hormone levels was not affected by the use of long-acting glucocorticoids or time of day for blood sample collection. The median difference in time between the two sample collections was 1.5 (range 0–7.5) h. Complete concordance between 17-hydroxyprogesterone, androstenedione, and testosterone was found in 21% of cases.
Conclusion
During everyday, clinical practice hormone levels in adult female patients with 21-hydroxylase deficiency showed a moderate to excellent repeatability, despite considerable variation in time of day for blood sample collection. We found no major predictors of hormone level variation. Future studies are needed to address the relationship between the timing of glucocorticoid intake vs adrenal hormone levels and clinical outcome in both adults and children.
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Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy
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First-trimester prenatal treatment with glucocorticoid (GC) dexamethasone (DEX) in pregnancies at risk for classic congenital adrenal hyperplasia (CAH) is associated with ethical dilemmas. Though effective in reducing virilisation in girls with CAH, it entails exposure to high doses of GC in fetuses that do not benefit from the treatment. The current paper provides an update on the literature on outcomes of prenatal DEX treatment in CAH cases and unaffected subjects. Long-term follow-up research is still needed to determine treatment safety. In addition, advances in early prenatal diagnostics for CAH and sex-typing as well as studies assessing dosing effects of DEX may avoid unnecessary treatment and improve treatment safety.
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Glucocorticoids represent a key element in the treatment of pediatric acute lymphoblastic leukemia (ALL) and lead to adrenal suppression. We aimed to assess the differential response profile of adrenal steroids in children with ALL during BFM (Berlin–Frankfurt–Münster) induction treatment. Therefore, we performed liquid chromatography tandem–mass spectrometry (LC–MS/MS)-based steroid profiling of up to seven consecutive leftover morning serum samples derived from 11 patients (pts) with ALL before (day 0) and during induction therapy at days 1–5, 6–12, 13–26, 27–29, 30–35 and 36–40. 17-hydroxyprogesterone (17OHP), 11-deoxycortisol (11S), cortisol, 11-deoxycorticosterone (DOC), corticosterone and aldosterone were determined in parallel. Subsequently, steroid concentrations were normalized by multiples of median (MOM) to adequately consider pediatric age- and sex-specific reference ranges. MOM-cortisol and its precursors MOM–11S and MOM–17OHP were significantly suppressed by glucocorticoid treatment until day 29 (P < 8.06 × 10−10, P < 5.102 × 10−5, P < 0.0076, respectively). Cortisol recovered in one of four pts at days 27–29 and in two of five pts at days 36–40. Among the mineralocorticoids, corticosterone was significantly suppressed (P < 3.115 × 10−6). Aldosterone and DOC showed no significant changes when comparing day 0 to the treatment time points. However, two ALL patients with ICU treatment due to the sepsis showed significantly lower MOM–DOC (P = 0.006436) during that time and almost always the lowest aldosterone compared to all other time points. Suppression of mineralocorticoid precursors under high-dose glucocorticoid therapy suggests a functional cross talk of central glucocorticoid regulation and adrenal mineralocorticoid synthesis. Our data should stimulate prospective investigation to assess potential clinical relevance.
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In critically ill adults, high plasma cortisol in the face of low ACTH coincides with high pro-opiomelanocortin (POMC) levels. Glucocorticoids further lower ACTH without affecting POMC. We hypothesized that in pediatric cardiac surgery-induced critical illness, plasma POMC is elevated, plasma ACTH transiently rises intraoperatively but becomes suppressed post-operatively, and glucocorticoid administration amplifies this phenotype. From 53 patients (0–36 months), plasma was obtained pre-operatively, intraoperatively, and on post-operative days 1 and 2. Plasma was also collected from 24 healthy children. In patients, POMC was supra-normal pre-operatively (P < 0.0001) but no longer thereafter (P > 0.05). ACTH was never high in patients. While in glucocorticoid-naive patients ACTH became suppressed by post-operative day 1 (P < 0.0001), glucocorticoid-treated patients had already suppressed ACTH intraoperatively (P ≤ 0.0001). Pre-operatively high POMC, not accompanied by increased plasma ACTH, suggests a centrally activated HPA axis with reduced pituitary processing of POMC into ACTH. Increasing systemic glucocorticoid availability with glucocorticoid treatment accelerated the suppression of plasma ACTH.
Significance statement
Glucocorticoids are often administered during pediatric cardiac surgery. In critically ill children, endogenous systemic glucocorticoid availability is elevated already upon ICU admission while ACTH levels are normal. This hormonal constellation suggests the presence of active feedback inhibition of ACTH. In this study, we have documented that intraoperative administration of glucocorticoids accelerates the suppression of ACTH, resulting in low plasma ACTH already upon ICU admission. Pre-operative plasma POMC, the ACTH precursor, but not ACTH, was increased. This is compatible with a centrally activated HPA axis prior to surgery in young children but reduced processing of POMC into ACTH within the pituitary. These findings suggest that glucocorticoid treatment in the context of pediatric cardiac surgery may amplify pre-existing impaired pituitary processing of the prohormone POMC.
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Pediatric Endocrinology Clinic, Department of Pediatrics, Aretaeio Hospital, Nicosia, Cyprus
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International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Department of Clinical Medicine, University of Copenhagen, Denmark
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Congenital adrenal hyperplasia (CAH) is a recessive condition that affects the adrenal glands. Despite life-long replacement therapy with glucocorticoids and mineralocorticoids, adult patients with CAH often experience impaired gonadal function. In pubertal boys and in men with CAH, circulating testosterone is produced by the adrenal glands as well as the testicular, steroidogenic cells. In this European two-center study, we evaluated the function of Leydig and Sertoli cells in 61 boys and men with CAH, primarily due to 21-hydroxylase deficiency. Despite conventional hormone replacement therapy, our results indicated a significant reduction in serum concentrations of both Leydig cell-derived hormones (i.e. insulin-like factor 3 (INSL3) and testosterone) and Sertoli cell-derived hormones (i.e. inhibin B and anti-Müllerian hormone) in adult males with CAH. Serum concentrations of INSL3 were particularly reduced in those with testicular adrenal rest tumors. To our knowledge, this is the first study to evaluate circulating INSL3 as a candidate biomarker to monitor Leydig cell function in patients with CAH.
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Sphingosine-1-phosphate lyase (SGPL1) insufficiency syndrome (SPLIS) is an autosomal recessive multi-system disorder, which mainly incorporates steroid-resistant nephrotic syndrome and primary adrenal insufficiency. Other variable endocrine manifestations are described. In this study, we aimed to comprehensively annotate the endocrinopathies associated with pathogenic SGPL1 variants and assess for genotype–phenotype correlations by retrospectively reviewing the reports of endocrine disease within our patient cohort and all published cases in the wider literature up to February 2022. Glucocorticoid insufficiency in early childhood is the most common endocrine manifestation affecting 64% of the 50 patients reported with SPLIS, and a third of these individuals have additional mineralocorticoid deficiency. While most individuals also have nephrotic syndrome, SGPL1 variants also account for isolated adrenal insufficiency at presentation. Primary gonadal insufficiency, manifesting with microphallus and cryptorchidism, is reported in less than one-third of affected boys, all with concomitant adrenal disease. Mild primary hypothyroidism affects approximately a third of patients. There is paucity of data on the impact of SGPL1 deficiency on growth, and pubertal development, limited by the early and high mortality rate (approximately 50%). There is no clear genotype–phenotype correlation overall in the syndrome, with variable disease penetrance within individual kindreds. However, with regards to endocrine phenotype, the most prevalent disease variant p.R222Q (affecting 22%) is most consistently associated with isolated glucocorticoid deficiency. To conclude, SPLIS is associated with significant multiple endocrine disorders. While endocrinopathy in the syndrome generally presents in infancy, late-onset disease also occurs. Screening for these is therefore warranted both at diagnosis and through follow-up.
