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  • Abstract: Adrenal x
  • Abstract: Addisons x
  • Abstract: Androgens x
  • Abstract: Catecholamines x
  • Abstract: hyperplasia x
  • Abstract: Cushings x
  • Abstract: Glucocorticoids x
  • Abstract: Medulla x
  • Abstract: Noradrenaline x
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Huifei Sophia Zheng Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama

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Jeffrey G Daniel Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama

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Julia M Salamat Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama

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Laci Mackay Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama

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Chad D Foradori Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama

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Robert J Kemppainen Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama

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Satyanarayana R Pondugula Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama

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Ya-Xiong Tao Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama

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Chen-Che Jeff Huang Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama

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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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Henrik Falhammar Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

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Magnus Kjellman Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Department of Breast and Endocrine Surgery, Karolinska University Hospital, Stockholm, Sweden

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Jan Calissendorff Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

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Background

With the increasing access to imaging more pheochromocytomas are diagnosed in the workup of adrenal incidentalomas. This may have changed the occurrence of the classic presentation with hypertension and the classic triad (headaches, sweating and palpitation).

Methods

We reviewed 94 consecutive cases of pheochromocytomas. Two cases of ectopic ACTH-syndrome were subsequently excluded.

Results

Of the 92 cases included 64% had presented as an incidentaloma, 32% as a suspected pheochromocytoma and 4% had been screened because of previously diagnosed MEN2A. Those screened were youngest while those with incidentalomas were oldest. The females were more common in the incidentaloma and the screening groups, and males in the suspected pheochromocytoma group. Measurements of noradrenaline/normetanephrine levels were highest in the suspected pheocromocytoma group and lowest in the screening group. Hypertension was present in 63% of the incidentalomas, 79% of suspected pheochromocytomas and in none of the screening group. Paroxysmal symptoms were present in almost all with suspected pheochromocytoma while only in half of the other groups. The suspected pheocromocytoma group had most symptoms and the screening group least. The classic triad was present in 14% of the incidentalomas, in 28% of the suspected and in none of the screening group, while no symptoms at all was present in 12%, 0% and 25%, respectively. Pheochromocytoma crisis occurred in 5%. There was a positive correlation between tumor size vs hormone levels, and catecholamine levels vs blood pressure.

Conclusion

Clinicians need to be aware of the modern presentation of pheochromocytomas since early identification can be life-saving.

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Rachel Forfar Centre for Therapeutics Discovery, LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, UK

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Mashal Hussain Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK

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Puneet Khurana Centre for Therapeutics Discovery, LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, UK

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Jennifer Cook Centre for Therapeutics Discovery, LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, UK

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Steve Lewis Centre for Therapeutics Discovery, LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, UK

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Dillon Popat Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK

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David Jackson Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK

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Ed McIver Centre for Therapeutics Discovery, LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, UK

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Jeff Jerman Centre for Therapeutics Discovery, LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, UK

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Debra Taylor Centre for Therapeutics Discovery, LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, UK

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Adrian JL Clark Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK

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Li F Chan Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK

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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.

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Anastasia P Athanasoulia-Kaspar Clinical Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany

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Matthias K Auer Clinical Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany
Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany

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Günter K Stalla Clinical Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany

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Mira Jakovcevski Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany

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Objective

Patients with non-functioning pituitary adenomas exhibit high morbidity and mortality rates. Growth hormone deficiency and high doses of glucocorticoid substitution therapy have been identified as corresponding risk factors. Interestingly, high levels of endogenous cortisol in, e.g., patients with post-traumatic stress disorder or patients with Cushing’s disease have been linked to shorter telomere length. Telomeres are noncoding DNA regions located at the end of chromosomes consisting of repetitive DNA sequences which shorten with aging and hereby determine cell survival. Therefore, telomere length can serve as a predictor for the onset of disease and mortality in some endocrine disorders (e.g., Cushing’s disease).

Design/methods

Here, we examine telomere length from blood in patients (n = 115) with non-functioning pituitary adenomas (NFPA) in a cross-sectional case–control (n = 106, age-, gender-matched) study using qPCR. Linear regression models were used to identify independent predictors of telomere length.

Results

We show that patients with NFPA exhibited shorter telomeres than controls. No significant association of indices of growth hormone deficiency (IGF-1-level-SDS, years of unsubstituted growth hormone deficiency etc.) with telomere length was detected. Interestingly, linear regression analysis showed that hydrocortisone replacement dosage in patients with adrenal insufficiency (n = 52) was a significant predictor for shorter telomere length (β = 0.377; P = 0.018) independent of potential confounders (gender, age, BMI, arterial hypertension, systolic blood pressure, number of antihypertensive drugs, total leukocyte count, waist-to-hip ratio, waist circumference, diabetes mellitus type 2, HbA1c, current statin use). Median split analysis revealed that higher hydrocortisone intake (>20 mg) was associated with significantly shorter telomeres.

Conclusion

These observations strengthen the importance of adjusted glucocorticoid treatment in NFPA patients with respect to morbidity and mortality rates.

Open access
Ivar Følling Department of Endocrinology, Akershus University Hospital, Lørenskog, Norway
Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway

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Anna B Wennerstrøm Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway

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Tor J Eide Division of Laboratory Medicine, Department of Pathology, Oslo University Hospital, Oslo, Norway

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Hilde Loge Nilsen Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway

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Introduction

Phaeochromocytomas are tumours originating in the medulla of the adrenal gland. They produce catecholamines, and some tumours also produce ectopic hormones. Two types of glucose imbalances occur in phaeochromocytoma patients, hyperglycaemia and hypoglycaemic attacks. Therefore, we tested whether insulin transcript (INS), insulin, and a hybrid read-through transcript between exons from insulin and insulin-like growth factor 2 (INS-IGF2) were expressed in phaeochromocytomas.

Methods

We measured the expression of insulin using immunohistochemistry. The expression of INS-IGF2 was determined by qRT-PCR in formalin-fixed and paraffin-embedded tissue from 20 phaeochromocytomas. The expression of INS and INS-IGF2 transcriptswas also analysed in 182 phaeochromocytomas and paragangliomas using publicly available datasets in The Cancer Genome Atlas (TCGA) Database.

Results

Of 20 phaeochromocytomas, 16 stained positive for insulin. The distribution of positive cells was mostly scattered, with some focal expression indicating clonal expansion. Nineteen tumours expressed high levels of INS and INS-IGF2 transcripts. The expression of the two transcripts corresponded closely. In the TCGA dataset, phaeochromocytoma expresses higher levels of INS and INS-IGF2 transcripts compared to the normal non-tumour adrenal glands. Thus, the expression of INS and INS-IGF2 seems to be a general phenomenon in phaeochromocytoma.

Conclusion

Most phaeochromocytomas contain cells that overexpress INS and INS-IGF2 transcripts. Most tumours also display heterogeneous expression of polypeptides immunoreactive to monoclonal anti-insulin antibodies. Clinically this may relate to both hyperglycaemia and hypoglycaemic attacks seen in patients with phaeochromocytoma as well as autocrine tumour growth.

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Ailsa Maria Main Department of Medical Endocrinology and Metabolism, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

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Maria Rossing Center for Genomic Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

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Line Borgwardt Center for Genomic Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

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Birgitte Grønkær Toft Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

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Åse Krogh Rasmussen Department of Medical Endocrinology and Metabolism, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

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Ulla Feldt-Rasmussen Department of Medical Endocrinology and Metabolism, Copenhagen University Hospital, Rigshospitalet, and Faculty of Health, Institute of Clinical and Scientific Research, Copenhagen, Denmark

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Phaeochromocytomas and paragangliomas (PPGLs) are tumours of the adrenal medulla and extra-adrenal sympathetic nervous system which often secrete catecholamines. Variants of the SDHX (SDHA, -AF2, -B, -C, -D) genes are a frequent cause of familial PPGLs. In this study from a single tertiary centre, we aimed to characterise the genotype–phenotype associations in patients diagnosed with germline variants in SDHX genes. We also assessed whether systematic screening of family members resulted in earlier detection of tumours. The study cohort comprised all individuals (n = 59) diagnosed with a rare variant in SDHX during a 13-year period. Patient- and pathology records were checked for clinical characteristics and histopathological findings. We found distinct differences in the clinical and histopathological characteristics between genetic variants in SDHB. We identified two SDHB variants with distinct phenotypical patterns. Family screening for SDHB variants resulted in earlier detection of tumours in two families. Patients with SDHA, SDHC and SDHD variants also had malignant phenotypes, underlining the necessity for a broad genetic screening of the proband. Our study corroborates previous findings of poor prognostic markers and found that the genetic variants and clinical phenotype are linked and, therefore, useful in the decision of clinical follow-up. Regular tumour screening of carriers of pathogenic variants may lead to an earlier diagnosis and expected better prognosis. The development of a combined algorithm with clinical, genetic, morphological, and biochemical factors may be the future for improved clinical risk stratification, forming a basis for larger multi-centre follow up studies.

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Yiqiang Huang Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, People’s Republic of China

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Lin-ang Wang Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, People’s Republic of China

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Qiubo Xie Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, People’s Republic of China

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Jian Pang Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, People’s Republic of China

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Luofu Wang Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, People’s Republic of China

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Yuting Yi Geneplus-Beijing Institute, Beijing, People’s Republic of China

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Jun Zhang Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, People’s Republic of China

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Yao Zhang Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, People’s Republic of China

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Rongrong Chen Geneplus-Beijing Institute, Beijing, People’s Republic of China

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Weihua Lan Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, People’s Republic of China

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Dianzheng Zhang Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania, USA

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Jun Jiang Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, People’s Republic of China

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Pheochromocytoma and paragangliomas (PCC/PGL) are neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and sympathetic/parasympathetic ganglia, respectively. Of clinical relevance regarding diagnosis is the highly variable presentation of symptoms in PCC/PGL patients. To date, the clear-cut correlations between the genotypes and phenotypes of PCC/PGL have not been entirely established. In this study, we reviewed the medical records of PCC/PGL patients with pertinent clinical, laboratory and genetic information. Next-generation sequencing (NGS) performed on patient samples revealed specific germline mutations in the SDHB (succinate dehydrogenase complex iron-sulfur subunit B) and SDHD (succinate dehydrogenase complex subunit D) genes and these mutations were validated by Sanger sequencing. Of the 119 patients, two were identified with SDHB mutation and one with SDHD mutation. Immunohistochemical (IHC) staining was used to analyze the expression of these mutated genes. The germline mutations identified in the SDH genes were c343C>T and c.541-542A>G in the SDHB gene and c.334-337delACTG in the SDHD gene. IHC staining of tumors from the c.343C>T and c.541-2A>G carriers showed positive expression of SDHB. Tumors from the c.334-337delACTG carrier showed no expression of SDHD and a weak diffused staining pattern for SDHB. We strongly recommend genetic testing for suspected PCC/PGL patients with a positive family history, early onset of age, erratic hypertension, recurrence or multiple tumor sites and loss of SDHB and/or SDHD expression. Tailored personal management should be conducted once a patient is confirmed as an SDHB and/or SDHD mutation carrier or diagnosed with PCC/PGL.

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Annelies van’t Westeinde Department of Women’s and Children’s Health, Karolinska Institutet and Division of Pediatrics, Unit for Pediatric Endocrinology and Metabolic Disorders, Karolinska University Hospital, Stockholm, Sweden

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Leif Karlsson Department of Women’s and Children’s Health, Karolinska Institutet and Division of Pediatrics, Unit for Pediatric Endocrinology and Metabolic Disorders, Karolinska University Hospital, Stockholm, Sweden

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Valeria Messina Department of Women’s and Children’s Health, Karolinska Institutet and Division of Pediatrics, Unit for Pediatric Endocrinology and Metabolic Disorders, Karolinska University Hospital, Stockholm, Sweden

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Lena Wallensteen Department of Women’s and Children’s Health, Karolinska Institutet and Division of Pediatrics, Unit for Pediatric Endocrinology and Metabolic Disorders, Karolinska University Hospital, Stockholm, Sweden

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Manuela Brösamle European Patient Advocacy Group for Adrenal Diseases, European Reference Network on Rare Endocrine Conditions (Endo ERN), Endo ERN Coordinating Centre, Leiden, The Netherlands

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Giorgio Dal Maso ArfSAG (Associazione Refionale Famiglie Sindrome Adreno Genitale) c/o Unita Operativa di Pediatria, Azienda Ospedaliero Universitaria di Bologna, Policlinico S Orsala-Malpighi, Bologna, Italy

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Alessandro Lazzerini Spanish Association of Congenital Adrenal Hyperplasia (CAH), Spain

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Jette Kristensen ePAG & Chair of Danish Addison Patient Association, Aarhus, Denmark

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Diana Kwast Dutch Adrenal Society NVACP, Nijkerk, The Netherlands

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Lea Tschaidse Department of Endocrinology, Medizinische Klinik IV, Klinikum der Universität München, Munich, Germany

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Matthias K Auer Department of Endocrinology, Medizinische Klinik IV, Klinikum der Universität München, Munich, Germany

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Hanna F Nowotny Department of Endocrinology, Medizinische Klinik IV, Klinikum der Universität München, Munich, Germany

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Luca Persani Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy

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Nicole Reisch Department of Endocrinology, Medizinische Klinik IV, Klinikum der Universität München, Munich, Germany

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Svetlana Lajic Department of Women’s and Children’s Health, Karolinska Institutet and Division of Pediatrics, Unit for Pediatric Endocrinology and Metabolic Disorders, Karolinska University Hospital, Stockholm, Sweden

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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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Ida Staby Department of Medical Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

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Jesper Krogh Department of Medical Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

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Marianne Klose Department of Medical Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

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Jonas Baekdal Department of Medical Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

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Ulla Feldt-Rasmussen Department of Medical Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Department of Clinical Medicine, Faculty of Health and Clinical Sciences, Copenhagen University, Copenhagen, Denmark

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Lars Poulsgaard Department of Neurosurgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

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Jacob Bertram Springborg Department of Neurosurgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

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Mikkel Andreassen Department of Medical Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Department of Clinical Medicine, Faculty of Health and Clinical Sciences, Copenhagen University, Copenhagen, Denmark

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Introduction

Patients with pituitary adenomas undergoing transsphenoidal surgery require pre- and post-surgery examination of pituitary hormones. There is currently no consensus on how to evaluate the adrenal axis post-surgery. The aims of this study were to investigate factors that may predict postoperative adrenal insufficiency (AI) and to investigate the overall effect of transsphenoidal surgery on pituitary function.

Methods

One hundred and forty-three consecutive patients who had undergone transsphenoidal surgery for pituitary adenomas were included. Data on tumour size, pituitary function pre-surgery, plasma basal cortisol measured within 48 h post-surgery and pituitary function 6 months post-surgery were collected. Patients with AI prior to surgery, perioperative glucocorticoid treatment, Cushing’s disease and no re-evaluation after 1 month were excluded (n = 93) in the basal cortisol analysis.

Results

Low plasma basal cortisol post-surgery, tumour size and previous pituitary surgery were predictors of AI (all P < 0.05). A basal cortisol cut-off concentration of 300 nmol/L predicted AI 6 months post-surgery with sensitivity and negative predictive value of 100%, specificity of 81% and positive predictive value of 25%. New gonadal, thyroid and adrenal axis insufficiencies accounted for 2, 10 and 10%, respectively. The corresponding recovery rates were 17, 7 and 24%, respectively

Conclusion

Transsphenoidal surgery had an overall beneficial effect on pituitary endocrine function. Low basal plasma cortisol measured within 48 h after surgery, tumour size and previous surgery were identified as risk factors for AI. Measurement of basal cortisol post-surgery may help to identify patients at risk of developing AI.

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Tatiana V Novoselova Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK

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Peter J King Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK

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Leonardo Guasti Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK

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Louise A Metherell Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK

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Adrian J L Clark Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK

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Li F Chan Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK

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The melanocortin-2-receptor (MC2R), also known as the ACTH receptor, is a critical component of the hypothalamic–pituitary–adrenal axis. The importance of MC2R in adrenal physiology is exemplified by the condition familial glucocorticoid deficiency (FGD), a potentially fatal disease characterised by isolated cortisol deficiency. MC2R mutations cause ~25% of cases. The discovery of a MC2R accessory protein MRAP, mutations of which account for ~20% of FGD, has provided insight into MC2R trafficking and signalling. MRAP is a single transmembrane domain accessory protein highly expressed in the adrenal gland and essential for MC2R expression and function. Mouse models helped elucidate the action of ACTH. The Mc2r-knockout (Mc2r / ) mice was the first mouse model developed to have adrenal insufficiency with deficiencies in glucocorticoid, mineralocorticoid and catecholamines. We recently reported the generation of the Mrap / mice which better mimics the human FGD phenotype with isolated glucocorticoid deficiency alone. The adrenal glands of adult Mrap / mice were grossly dysmorphic with a thickened capsule, deranged zonation and deranged WNT4/beta-catenin and sonic hedgehog (SHH) pathway signalling. Collectively, these mouse models of FGD highlight the importance of ACTH and MRAP in adrenal progenitor cell regulation, cortex maintenance and zonation.

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