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Testicular adrenal rest tumors (TARTs), commonly occurring in males with congenital adrenal hyperplasia, may arise from chronic stimulation of adrenocorticotropic hormone (ACTH)–sensitive cells in the testes. It is not yet established whether the human fetal testis (HFT) is responsive to ACTH. To investigate this, we cultured HFT tissue with and without ACTH for up to 5 days, and quantified adrenal steroid hormones and expression of adrenal steroidogenic enzymes. Fetal testis and adrenal tissue produced high levels of testosterone and cortisol, respectively, indicating viability. In contrast to fetal adrenal tissues, the expression of ACTH receptor MC2R was either absent or expressed at extremely low levels in ex vivo HFT tissue and no clear response to ACTH in gene expression or steroid hormone production was observed. Altogether, this study suggests that the HFT is unresponsive to ACTH, which would indicate that a TART does not arise from fetal testicular cells chronically exposed to ACTH in utero. [ABSTRACT FROM AUTHOR]

Cortisol and growth hormone (GH) deficiencies are causes of neonatal hypoglycemia. When they coexist, a pituitary disorder is suspected. We present an infant with hypoglycemia in whom an ACTH receptor defect was associated with transient GH deficiency. A full-term boy with consanguineous parents presented with hypoglycemia (serum glucose 18 mg/dL) at 4 hours of life with undetectable serum cortisol (<1 μg/dL). Examination showed diffuse hyperpigmentation with normal male genitalia. Patient developed hyperbilirubinemia and elevated transaminase levels. GH levels of 6.8 ng/mL and 7.48 ng/mL during episodes of hypoglycemia, peak of 9.2 ng/mL with glucagon stimulation, and undetectable IGF-1 suggested GH deficiency. Thyroid function, prolactin, and gonadotropins were normal. Baseline ACTH was elevated at 4868 pg/mL, whereas serum cortisol remained undetectable with ACTH stimulation. Hydrocortisone replacement resulted in normalization of blood glucose and cholestasis with decline in ACTH level. GH therapy was not initiated, given improvement in cholestasis and euglycemia. An ACTH receptor defect was confirmed with molecular genetic testing that revealed homozygosity for a known mutation of the melanocortin 2 receptor (MC2R) gene. At 12 weeks, a random GH level was 10 ng/mL. IGF-1 was 75 ng/mL and 101 ng/mL at 7 and 9 months, respectively. This report describes glucocorticoid deficiency from an MC2R mutation associated with GH deficiency. With glucocorticoid replacement, GH secretion normalized. Our findings are consistent with a previously stated hypothesis that physiologic glucocorticoid levels may be required for optimal GH secretion [ 1 ]. [ABSTRACT FROM AUTHOR]

Background: Testicular adrenal rest tumors (TART) are a common complication of unknown cellular origin in patients with congenital adrenal hyperplasia (CAH). These benign tumors have both adrenal and testicular characteristics and are hypothesized to either derive from cells of adrenal origin from the fetal adrenogonadal primordium or by atypical differentiation of adult Leydig-progenitor cells. Objective: This study aims to unravel the identity and etiology of TART. Methods: Co-expression of adrenal-specific CYP11B1 and Leydig cell-specific HSD17B3 in TART was studied using immunohistochemistry. We studied the possibility of TART being derived from atypical differentiation of adult Leydigprogenitor cells by the quantification of adrenal-specific enzyme expression upon adrenocorticotrophic hormone (ACTH)-like stimulation of ex vivo cultured platelet-derived growth factor receptor alpha-positive cells. By comparing the transcriptome of TART (n = 16) with the transcriptome of fetal adrenal (n = 13), fetal testis (n = 5), adult adrenal (n = 11), and adult testis (n = 10) tissues, we explored the identity of TART. Results: We demonstrate co-expression of adrenal-specific CYP11B1 and testis-specific HSD17B3 in TART cells, indicating the existence of a distinct TART cell exhibiting both adrenal and testicular characteristics. Ex vivo cultured adult Leydigprogenitor cells did not express the ACTH-receptor MC2R but did express CYP11B1 upon stimulation. Unsupervised clustering of transcriptome data showed that TART was most similar to adult adrenal tissue, followed by adult testis tissue, and least similar to either fetal tissue. Conclusion: Our data suggest that TART is induced - most likely via activation of a cAMP/protein kinase A-dependent receptor - from a progenitor cell into a unique mature adrenal-like cell type, sometimes exhibiting both adrenal and testicular features. [ABSTRACT FROM AUTHOR]

OBJECTIVE: ACTH resistance syndromes are rare, autosomal, and genetically heterogeneous diseases that include familial glucocorticoid deficiency (FGD) and triple A syndrome. FGD has been shown to segregate with mutations in the gene coding for ACTH receptor (MC2R) or melanocortin 2 receptor accessory protein (MRAP), whereas mutations in the triple A syndrome (AAAS, Allgrove syndrome) gene have been found in segregation with triple A syndrome. We describe the clinical findings and molecular analysis of MC2R, MRAP, and AAAS genes in five Brazilian patients with ACTH resistance syndrome. DESIGN AND METHODS: Genomic DNA from patients and their unaffected relatives was extracted from peripheral blood leucocytes and amplified by PCR, followed by automated sequencing. Functional analysis was carried out using Y6 cells expressing wild-type and mutant MC2R. RESULTS: All five patients showed low cortisol and elevated plasma ACTH levels. One patient had achalasia and alacrima, besides the symptoms of adrenal insufficiency. The molecular analysis of FGD patients revealed a novel p.Gly116Val mutation in the MC2R gene in one patient and p.Met1Ile mutation in the MRAP gene in another patient. Expression of p.Gly116Val MC2R mutant in Y6 cells revealed that this variant failed to stimulate cAMP production. The analysis of the AAAS gene in the patient with triple A syndrome showed a novel g.782_783delTG deletion. The molecular analysis of DNA from other two patients showed no mutation in MC2R, MRAP, or AAAS gene. CONCLUSIONS: In conclusion, the molecular basis of ACTH resistance syndrome is heterogeneous, segregating with genes coding for proteins involved with ACTH receptor signaling/expression or adrenal gland development and other unknown genes. [ABSTRACT FROM AUTHOR]

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder that causes isolated glucocorticoid deficiency. Here, we report on 22-month-old twin females of Native American ancestry who presented within 1 week of each other in adrenal crisis and were ultimately diagnosed with FGD because of a novel pathogenic variant, c1924G>T (p. Gly642*), in the nicotinamide nucleotide transhydrogenase (NNT) gene. This is the first report of FGD in a Native American population. The process of reaching the final diagnosis was complicated by several social determinants including geographic rurality, access to subspecialists, financial constraints, and challenges obtaining approval for genetic testing despite having insurance. Concerted efforts by the family, the local pediatrician, the Indian Health Service, and our tertiary care pediatric health system were required to reach the final diagnosis and develop an appropriate plan of care for the patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease caused by ACTH resistance and leads to isolated glucocorticoid deficiency. Although FGD patients typically have normal mineralocorticoid secretion, subtle alterations in the renin–angiotensin–aldosterone axis have been reported in a subset of patients at presentation. Anecdotally, some patients with FGD have been initially diagnosed as having Addison's disease (AD), with implications for treatment and genetic counselling. Currently, mutations in three genes: the ACTH receptor (MC2R); the melanocortin 2 receptor accessory protein (MRAP); and the steroidogenic acute regulatory protein (STAR) are known to give rise to FGD types 1–3. We investigated a cohort of autoantibody-negative AD patients for mutations in these genes. METHODS: Forty patients with known AD without evidence of autoimmune disease were screened for mutations in MC2R, MRAP and STAR. In addition, patients were genotyped for the MC2R promoter polymorphism previously associated with reduced responsiveness to ACTH. RESULTS: No mutations in MC2R, MRAP or STAR were identified in any patient. The frequencies of the MC2R promoter polymorphism were similar to those reported in healthy controls. CONCLUSIONS: FGD does not appear to be underdiagnosed in the AD population. However, in ∼50% of patients with FGD, no genetic cause has yet been identified and it is possible that the other, as yet unidentified, genes giving rise to FGD may be implicated in AD. [ABSTRACT FROM AUTHOR]

Melanocortin 4 receptor (MC4R), a canonical melanocyte-stimulating hormone receptor, is the main responsible for monogenic obesity in humans. Previous studies in fish and avian species showed that MC4R becomes an ACTH receptor after interaction with the melanocortin receptor accessory protein 2 (MRAP2). We show that human MC4R behaves in a similar way through its interaction with MRAP2. This evolutionary conservation of MRAP2-induced ligand selectivity supports a physiological role for the interaction with MC4R. Both proteins are coexpressed in the same hypothalamic neurons, providing an anatomical substrate and molecular mechanism for the central therapeutic actions of ACTH in the treatment of infantile spasms. These neurons may link the effects of stress on the energy balance independently of glucocorticoid secretion. The complex MC4R-MRAP2 throws light on the action of ACTH and, by extension, on the relay of stress-related information to additional biological systems. [ABSTRACT FROM AUTHOR]

Context Type 1 familial glucocorticoid deficiency (FGD) (OMIM #607397) is a rare autosomal recessive disorder due to mutations in melanocortin-2-receptor (MC2R) gene encoding the G protein-coupled adrenocorticotropic (ACTH) transmembrane receptor. Objective The aim of the study is to describe 2 siblings born to a healthy consanguineous family presenting with clinical and biochemical features of FGD, harboring a novel homozygous MC2R variant. Methods Both patients are siblings born at term via normal delivery with normal birth weights. The first sibling presented with symptoms of hypoglycemia, repeated episodes of infections starting from 2 days of age. At 18 months of age, low serum cortisol was found, and he was started on hydrocortisone replacement therapy. The second sibling developed hypoglycemia on day 1 after birth, investigations revealed low serum sodium and cortisol levels and was also commenced on hydrocortisone treatment. Whole exome sequencing (WES) and in vitro functional studies on cell line transfected with wild-type and mutant plasmid clones were undertaken. Results WES revealed a novel homozygous missense mutation c.326T>A, p.Leu109Gln in the MC2R gene. In-silico prediction tools predicted the effect of this mutation to be deleterious. In vitro study using HEK293 cells transfected with MC2R wild-type and mutant clones showed a defect in protein expression and cAMP generation when stimulated with ACTH. Conclusion Homozygous semiconserved p.Leu109Gln mutation disrupts cAMP production and MC2R protein expression leading to ACTH resistance. This study provides additional evidence that this novel pathogenic variant in MC2R results in FGD phenotypes. [ABSTRACT FROM AUTHOR]

CONTEXT: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease, characterised by isolated glucocorticoid deficiency in the absence of mineralocorticoid deficiency. Inactivating mutations in the ACTH receptor (melanocortin-2-receptor, MC2R) are well described and account for ∼25% of cases. By contrast, activating MC2R mutations are extremely rare. PATIENT: We report a child of Saudi Arabian origin who was diagnosed with FGD following hypoglycaemic episodes that resulted in spastic quadriplegia. METHODS AND RESULTS: MC2R gene analysis revealed an unusual combination of two homozygous missense mutations, consisting of the novel mutation Y129C and the previously described F278C activating mutation. Parents were heterozygous at both of these sites. In vitro analysis of the Y129C mutation using a fluorescent cell surface assay showed that this mutant was unable to reach the cell surface in CHO cells stably transfected with MC2R accessory protein (MRAP), despite the demonstration of an interaction with MRAP by co-immunoprecipitation. The double mutant Y129C-F278C also failed to traffic to the cell surface. CONCLUSION: The tyrosine residue at position 129 in the second intracellular loop is critical in MC2R folding and/or trafficking to the cell surface. Furthermore, the absence of cell surface expression of MC2R would account for the lack of activation of the receptor due to the F278C mutation located at the C-terminal tail. We provide a novel molecular explanation for a child with two opposing mutations causing severe FGD. [ABSTRACT FROM AUTHOR]

Familial glucocorticoid deficiency (FGD) is a rare inherited disorder which may be caused by mutations in the ACTH receptor (melanocortin 2 receptor, MC2R) named FGD type 1 or by mutations in the MC2R accessory protein (MRAP) named FGD type 2. We report the case history of a male patient from birth until adulthood with FGD type 2, confirmed by a mutation of the MRAP gene. [ABSTRACT FROM AUTHOR]

Dioxins and polychlorinated biphenyls (PCBs) have been shown to accumulate in the adrenal glands when incorporated into the body. However, the impacts of exposure on adrenal steroidogenesis have not been thoroughly investigated. In this study, we demonstrated that dioxin-like PCB126 altered androgen, cortisol, and aldosterone biosynthesis differentially in human adrenocortical H295R cells. PCB126 diminished basal and cAMP-induced androstenedione production as well as CYP17 mRNA expression in a dose-dependent and time-dependent manner. The CYP17 repression was accompanied with decreases in the encoded 17α-hydroxylase and 17,20-lyase activities, particularly the latter. In contrast, high concentrations of PCB126 stimulated basal cortisol and aldosterone biosynthesis, including induction of CYP21B, CYP11B1, and CYP11B2 mRNA expression and elevation of the conversion of cortisol from 17-OH-progesterone and aldosterone from progesterone. cAMP abolished the positive effect of PCB126 on cortisol synthesis, while it synergistically enhanced PCB126 stimulation on CYP11B2 expression and aldosterone production. It seemed likely that the downregulation of CYP21B caused by the combination of PCB126 and cAMP counteracted the CYP11B1 induction stimulated by the co-treatment. In addition, high concentrations of PCB126 might sensitize the regulation of adrenocorticotropin (ACTH) on the adrenocortical cells by increasing ACTH receptor levels. Because adrenal steroids have profound influences on glucose tolerance, insulin sensitivity, lipid metabolism, obesity, vascular function, and cardiac remodeling, this article also discusses the potential association of the detected adrenocortical alterations with increased diabetic and cardiovascular risk found among highly exposed people. [ABSTRACT FROM AUTHOR]

Primary adrenal insufficiency (PAI) is potentially life threatening, but rare. In children, genetic defects prevail whereas adults suffer more often from acquired forms of PAI. The spectrum of genetic defects has increased in recent years with the use of next-generation sequencing methods and now has reached far beyond genetic defects in all known enzymes of adrenal steroidogenesis. Cofactor disorders such as P450 oxidoreductase (POR) deficiency manifesting as a complex form of congenital adrenal hyperplasia with a broad clinical phenotype have come to the fore. In patients with isolated familial glucocorticoid deficiency (FGD), in which no mutations in the genes for the ACTH receptor (MC2R) or its accessory protein MRAP have been found, non-classic steroidogenic acute regulatory protein (StAR) and CYP11A1 mutations have been described; and more recently novel mutations in genes such as nicotinamide nucleotide transhydrogenase (NNT) and thioredoxin reductase 2 (TRXR2) involved in the maintenance of the mitochondrial redox potential and generation of NADPH important for steroidogenesis and ROS detoxication have been discovered. In addition, whole exome sequencing approach also solved the genetics of some syndromic forms of PAI including IMAGe syndrome (CDKN1C), Irish traveler syndrome (MCM4), MIRAGE syndrome (SAMD9); and most recently a syndrome combining FGD with steroid-resistant nephrotic syndrome and ichthyosis caused by mutations in the gene for sphingosine-1-phosphate lyase 1 (SGPL1). This review intends do give an update on novel genetic forms of PAI and their suggested mechanism of disease. It also advocates for advanced genetic work-up of PAI (especially in children) to reach a specific diagnosis for better counseling and treatment. [ABSTRACT FROM AUTHOR]

Primary aldosteronism, characterized by the dysregulated production of aldosterone from 1 or both adrenal glands, is the most common endocrine cause of hypertension. It confers a high risk of cardiovascular, renal, and metabolic complications that can be ameliorated with targeted medical therapy or surgery. Diagnosis can be achieved with a positive screening test (elevated aldosterone to renin ratio) followed by confirmatory testing (saline, captopril, fludrocortisone, or oral salt challenges) and subtyping (adrenal imaging and adrenal vein sampling). However, the diagnostic pathway may be complicated by interfering medications, intraindividual variations, and concurrent autonomous cortisol secretion. Furthermore, once diagnosed, careful follow-up is needed to ensure that treatment targets are reached and adverse effects, or even recurrence, are promptly addressed. These challenges will be illustrated in a series of case studies drawn from our endocrine hypertension clinic. We will offer guidance on strategies to facilitate an accurate and timely diagnosis of primary aldosteronism together with a discussion of treatment targets which should be achieved for optimal patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterised by isolated glucocorticoid deficiency. Mutations in the ACTH receptor/melanocortin 2 receptor (MC2R), the MC2Raccessory protein (MRAP) or the STAR protein (STAR) cause FGD types 1, 2 and 3, respectively, accounting for w50% of all cases. Patient and methods: We report a neonate of Indian origin, who was diagnosed with FGD in the first few days of life. He presented with hypoglycaemic seizures and was noted to have generalised intense hyperpigmentation and normal male genitalia. Biochemical investigations revealed hypocortisolaemia (cortisol 0.223 mg/dl; NR 1-23 mg/dl) and elevated plasma ACTH (170 pg/ml). Serum electrolytes, aldosterone and plasma renin activity were normal. Peak cortisol following a standard synacthen test was 0.018 mg/dl. He responded to hydrocortisone treatment and continues on replacement. Patient DNA was analysed by direct sequencing. The effect of the novel mutation was assessed by an in vitro splicing assay using wild type and mutant heterologous minigenes Results: Anovelhomozygousmutation c.106C2_3dupTAwas found in theMRAPgene.Bothparentswere heterozygous for the mutation. In an in vitro splicing assay, the mutation resulted in the skipping of exon 3. Conclusion:Wehave identifiedanovelMRAPmutationwhere disruption of the intron 3 splice-site results in a prematurely terminated translation product. This protein (if produced) would lack the transmembrane domain that is essential for MC2R interaction. We predict that this would cause complete lack of ACTH response thus explaining the early presentation in this case. [ABSTRACT FROM AUTHOR]

Investigates the importance of the natural birth process in regulating the postnatal development and function of the hypothalamus-pituitary-adrenal (HPA) axis in young pigs. Gestational age and birth weights of pigs delivered by cesarean section or vaginally; Basal serum concentration of cortisone at birth.

Purified cholera enterotoxin was as effective as adrenocorticotropin (ACTH) in stimulating steroidogenesis in adrenal tumor cells in tissue culture. In contrast to the rapid response to ACTH, there was a 60-min lag before increased steroidogenesis could be detected. Ten minutes of exposure to cholera toxin followed by removal of toxin resulted in maximal stimulation of steroidogenesis after incubation for 2 hr. Equine antiserum to choleragenoid or mixed gangliosides effectively blocked cholera toxin-induced steroidogenesis. Further studies suggested that cholera enterotoxin induced steroidogenesis in adrenal tumor cells by interacting with a membrane receptor distinctive from the ACTH receptor. Half maximal doses of cholera enterotoxin and ACTH produced an additive effect on steroidogenesis. There was no calcium requirement for cholera enterotoxin-induced steroidogenesis as opposed to stimulation by ACTH. A mutant cell line unresponsive to ACTH was stimulated by cholera enterotoxin. [ABSTRACT FROM PUBLISHER]

Objective: The data on clinical, biochemical, radiological characteristics, and outcomes in paediatric ectopic adrenocorticotropic hormone syndrome (EAS) are limited owing to rarity of the condition. We report three new cases and perform a systematic review of paediatric EAS. Design and Method: Case records of paediatric and adolescent EAS patient’s ≤20 years presenting at our centre between 1997 and 2021 were retrospectively reviewed, and a systematic review of the literature published between January 1970 and December 2022 was performed. Results: A total of 161 patients including 3 new patients from our centre were identified. Bronchial neuroendocrine tumours (NET) (28.5%), thymic NET (22.9%), primitive cell-derived tumours (18.6%), and gastro-entero-pancreatic-NET (13.7%) were the common causes. Primitive cell-derived tumours were the most common in the first decade (24/45, 53.4%) and were the largest (82 [60-100] mm), whereas bronchial NETs predominated during the second decade (42/116, 36.2%) and were the smallest (15 [10-25] mm). Computed tomography localized 92.9% (118/127) of paediatric EAS patients. Immediate postoperative remission was attained in 77.9% (88/113) patients, whereas 30.4% (24/ 79) relapsed over a median (IQR) period of 13 (8-36) months. Over a median (IQR) follow-up of 2 (0.6-4.6) years, 31.4% of patients died. The median survival was higher in bronchial NET than in other tumour groups. Distant metastasis and tumour size were independent negative predictors of survival. Conclusions: Aetiological profile of paediatric and adolescent EAS is distinct from that of adults. Bronchial NETs have the best long-term survival, whereas distant metastasis and tumour size predict poor survival. [ABSTRACT FROM AUTHOR]

Importance: Testicular adrenal rest tumors (TARTs), often found in male patients with congenital adrenal hyperplasia (CAH), are benign lesions causing testicular damage and infertility. We hypothesize that chronically elevated adrenocorticotropic hormone exposure during early life may promote TART development.Objective: This study aimed to examine the association between commencing adequate glucocorticoid treatment early after birth and TART development. Design and participants: This retrospective multicenter (n = 22) open cohort study collected longitudinal clinical and biochemical data of the first 4 years of life using the I-CAH registry and included 188 male patients (median age 13 years; interquartile range: 10-17) with 21-hydroxylase deficiency (n = 181) or 11-hydroxylase deficiency (n = 7). All patients underwent at least 1 testicular ultrasound. Results: TART was detected in 72 (38%) of the patients. Prevalence varied between centers. When adjusted for CAH phenotype, a delayed CAH diagnosis of >1 year, compared with a diagnosis within 1 month of life, was associated with a 2.6 times higher risk of TART diagnosis. TART onset was not predicted by biochemical disease control or bone age advancement in the first 4 years of life, but increased height standard deviation scores at the end of the 4-year study period were associated with a 27% higher risk of TART diagnosis. Conclusions and relevance: A delayed CAH diagnosis of >1 year vs CAH diagnosis within 1 month after birth was associated with a higher risk of TART development, which may be attributed to poor disease control in early life. [ABSTRACT FROM AUTHOR]

Adverse effects associated with exposure to brominated flame retardants have led to regulations for their use and their replacement with organophosphate esters (OPEs). However, little is known about the impact of OPEs on the adrenal, a vital endocrine gland. Here, we used a high-content screening approach to elucidate the effects of OPEs on H295R human adrenal cell phenotypic endpoints and function. The effects of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), a legacy brominated flame retardant, on H295R cell cytotoxicity, oxidative stress, mitochondria, lysosomes, and lipid droplets were compared with those of 6 OPEs. Most OPEs reduced oxidative stress, increased the numbers of mitochondria, decreased lysosomes, and increased lipid droplets. Two potency ranking approaches, the lowest benchmark concentration/administered equivalent dose methods and Toxicological Prioritization Index analyses, revealed that the triaryl-OPEs (isopropylated triphenyl phosphate [IPPP], tris(methylphenyl) phosphate [TMPP], and triphenyl phosphate [TPHP]) and 1 nontriaryl OPE (tris(1,3-dichloro-2-propyl) phosphate [TDCIPP]) were more potent than BDE-47. The steroidogenic activity of adrenal cells in the presence or absence of forskolin, a steroidogenic stimulus, was determined after exposure to triaryl-OPEs. The basal production of cortisol and aldosterone was increased by IPPP but decreased by TPHP or TMPP exposure; the response to forskolin was not affected by these OPEs. All 3 triaryl OPEs altered the expression of rate-limiting enzymes involved in cholesterol and steroid biosynthesis; CYP11B1 and CYP11B2 were the most prominently affected targets. The OPE chemical-specific effects on cortisol and aldosterone production were best explained by alterations in STAR expression. Thus, the adrenal may be an important target for these endocrine-disrupting chemicals. [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]

Aims High salt intake is common and contributes to poor cardiovascular health. Urinary sodium excretion correlates directly with glucocorticoid excretion in humans and experimental animals. We hypothesized that high salt intake activates the hypothalamic–pituitary–adrenal axis activation and leads to sustained glucocorticoid excess. Methods and results In male C57BL/6 mice, high salt intake for 2–8 weeks caused an increase in diurnal peak levels of plasma corticosterone. After 2 weeks, high salt increased Crh and Pomc mRNA abundance in the hypothalamus and anterior pituitary, consistent with basal hypothalamic–pituitary–adrenal axis activation. Additionally, high salt intake amplified glucocorticoid response to restraint stress, indicative of enhanced axis sensitivity. The binding capacity of Corticosteroid-Binding Globulin was reduced and its encoding mRNA downregulated in the liver. In the hippocampus and anterior pituitary, Fkbp5 mRNA levels were increased, indicating increased glucocorticoid exposure. The mRNA expression of the glucocorticoid-regenerating enzyme, 11β-hydroxysteroid dehydrogenase Type 1, was increased in these brain areas and in the liver. Sustained high salt intake activated a water conservation response by the kidney, increasing plasma levels of the vasopressin surrogate, copeptin. Increased mRNA abundance of Tonebp and Avpr1b in the anterior pituitary suggested that vasopressin signalling contributes to hypothalamic–pituitary–adrenal axis activation by high salt diet. Conclusion Chronic high salt intake amplifies basal and stress-induced glucocorticoid levels and resets glucocorticoid biology centrally, peripherally and within cells. [ABSTRACT FROM AUTHOR]

Primary adrenal insufficiency (PAI) occurs in 1 in 5 to 7000 adults. Leading etiologies are autoimmune adrenalitis in adults and congenital adrenal hyperplasia (CAH) in children. Oral replacement of cortisol is lifesaving, but poor quality of life, repeated adrenal crises, and dosing uncertainty related to lack of a validated biomarker for glucocorticoid sufficiency persists. Adrenocortical cell therapy and gene therapy may obviate many of the shortcomings of adrenal hormone replacement. Physiological cortisol secretion regulated by pituitary adrenocorticotropin could be achieved through allogeneic adrenocortical cell transplantation, production of adrenal-like steroidogenic cells from either stem cells or lineage conversion of differentiated cells, or for CAH, gene therapy to replace or repair a defective gene. The adrenal cortex is a high-turnover organ and thus failure to incorporate progenitor cells within a transplant will ultimately result in graft exhaustion. Identification of adrenocortical progenitor cells is equally important in gene therapy, for which new genetic material must be specifically integrated into the genome of progenitors to ensure a durable effect. Delivery of gene-editing machinery and a donor template, allowing targeted correction of the 21-hydroxylase gene, has the potential to achieve this. This review describes advances in adrenal cell transplants and gene therapy that may allow physiological cortisol production for children and adults with PAI. [ABSTRACT FROM AUTHOR]

We report a unique case of a 44-year-old man with paraneoplastic hyperparathyroidism due to an oncocytic adrenocortical carcinoma (stage pT3N0R0M0, ENSAT 2 with a 4% Ki-67). Paraneoplastic hyperparathyroidism was associated with mild adrenocorticotropic hormone (ACTH)- independent hypercortisolism and increased estradiol secretion responsible for gynecomastia and hypogonadism. Biological investigations performed in blood samples from peripheral and adrenal veins revealed that the tumor secreted parathyroid hormone (PTH) and estradiol. Ectopic PTH secretion was confirmed by abnormally high expression of PTH mRNA and clusters of PTH immunoreactive cells in the tumor tissue. Double-immunochemistry studies and analysis of contiguous slides for the expression of PTH and steroidogenic markers (scavenger receptor class B type 1 [SRB1], 3ß-hydroxysteroid dehydrogenase [3ß-HSD], and aromatase) were performed. The results suggested the presence of two tumor cells subtypes with large cells with voluminous nuclei producing only PTH and that were distinct from steroidproducing cells. [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]

The adrenal is a small, anatomically unimposing structure that escaped scientific notice until 1564 and whose existence was doubted by many until the 18th century. Adrenal functions were inferred from the adrenal insufficiency syndrome described by Addison and from the obesity and virilization that accompanied many adrenal malignancies, but early physiologists sometimes confused the roles of the cortex and medulla. Medullary epinephrine was the first hormone to be isolated (in 1901), and numerous cortical steroids were isolated between 1930 and 1949. The treatment of arthritis, Addison's disease, and congenital adrenal hyperplasia (CAH) with cortisone in the 1950s revolutionized clinical endocrinology and steroid research. Cases of CAH had been reported in the 19th century, but a defect in 21-hydroxylation in CAH was not identified until 1957. Other forms of CAH, including deficiencies of 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, and 17α-hydroxylase were defined hormonally in the 1960s. Cytochrome P450 enzymes were described in 1962-1964, and steroid 21-hydroxylation was the first biosynthetic activity associated with a P450. Understanding of the genetic and biochemical bases of these disorders advanced rapidly from 1984 to 2004. The cloning of genes for steroidogenic enzymes and related factors revealed many mutations causing known diseases and facilitated the discovery of new disorders. Genetics and cell biology have replaced steroid chemistry as the key disciplines for understanding and teaching steroidogenesis and its disorders. [ABSTRACT FROM AUTHOR]

Primary aldosteronism (PA) is a major cause of secondary hypertension. Aldosterone-producing adenoma (APA) is a subtype of PA, and adrenalectomy is the gold-standard treatment. Recently, a high prevalence of the KCNJ5 gene mutation has been reported in APA, particularly in Japan. Herein, we present 2 extremely rare cases of PA recurrence more than 10 years after adrenalectomy for APA. In the first case, a 52-year-old woman was examined for hypertension 22 years after total adrenalectomy of the right adrenal gland. Recurrent PA was diagnosed based on high aldosterone-renin-ratio (ARR), identification of left adrenal gland tumor by computed tomography (CT), and a confirmatory test. In the second case, a 65-year-old man was examined for hypertension 17 years after total adrenalectomy of the left adrenal gland. He had maintained his blood pressure using medication since the onset of hypertension 4 years after the surgery. A year later, a high ARR was observed. PA recurrence was determined by a right adrenal gland tumor noted on CT and a confirmatory test. Somatic mutations in KCNJ5 were detected in the resected tissues in both cases. We recommend careful follow-ups after adrenalectomy in APA cases, especially in those with a KCNJ5 gene mutation. [ABSTRACT FROM AUTHOR]

Objective: Congenital defects of androgen synthesis or action in 46,XY individuals can result in impaired virilisation, despite the apparent testicular development. In a recent case, report of a young adult with complete androgen insensitivity syndrome (CAIS), tumourous gonadal tissue was shown to express HSD17B3 in Sertoli cells (SCs) and not in Leydig cells (LCs). This expression pattern differs from the typical adult human testis and resembles a foetal mouse testis, suggesting an underlying testicular development and function defect. Here, we investigate the effect of altered androgen signalling in gonads from five 46,XY individuals with defects in androgen synthesis or action. Methods: Gonadal tissue sections from four patients with CAIS, one with CYP17A1 deficiency, and one control were immunostained for LC developmental and steroidogenic markers. The expression of some of these markers during development was investigated by reanalysing previously published single-cell RNA sequencing (scRNA-seq) data from normal human testicular tissues. Results: All gonadal tissues from the patients show an exclusive expression of HSD17B3 in SCs and an expression of the foetal/immature LC marker DLK1 in a subset of LCs, suggesting an androgen-dependent differentiation defect of adult SCs and LCs. Furthermore, reanalysis of scRNA-seq data reveals an expression of HSD17B3 in foetal and neonatal SCs that is downregulated in adult SCs. Conclusions: Androgen signalling may affect the differentiation of adults, but possibly not foetal SCs or LCs, and may induce a shift of testosterone production from the tubular compartment in the foetal phase to the interstitial compartment in the adult phase. [ABSTRACT FROM AUTHOR]

The adrenal glands are paired endocrine organs that produce steroid hormones and catecholamines required for life. Adrenocortical carcinoma (ACC) is a rare and often fatal cancer of the peripheral domain of the gland, the adrenal cortex. Recent research in adrenal development, homeostasis, and disease have refined our understanding of the cellular and molecular programs controlling cortical growth and renewal, uncovering crucial clues into how physiologic programs are hijacked in early and late stages of malignant neoplasia. Alongside these studies, genome-wide approaches to examine adrenocortical tumors have transformed our understanding of ACC biology, and revealed that ACC is composed of distinct molecular subtypes associated with favorable, intermediate, and dismal clinical outcomes. The homogeneous transcriptional and epigenetic programs prevailing in each ACC subtype suggest likely susceptibility to any of a plethora of existing and novel targeted agents, with the caveat that therapeutic response may ultimately be limited by cancer cell plasticity. Despite enormous biomedical research advances in the last decade, the only potentially curative therapy for ACC to date is primary surgical resection, and up to 75% of patients will develop metastatic disease refractory to standard-of-care adjuvant mitotane and cytotoxic chemotherapy. A comprehensive, integrated, and current bench-to-bedside understanding of our field's investigations into adrenocortical physiology and neoplasia is crucial to developing novel clinical tools and approaches to equip the one-in-a-million patient fighting this devastating disease. [ABSTRACT FROM AUTHOR]

Encoded by SerpinA6 , plasma corticosteroid-binding globulin (CBG) transports glucocorticoids and regulates their access to cells. We determined how CBG influences plasma corticosterone and adrenal development in rats during the pubertal to adult transition using CRISPR/cas9 to disrupt SerpinA6 gene expression. In the absence of CBG, total plasma corticosterone levels were ∼80% lower in adult rats of both sexes, with a greater absolute reduction in females than in males. Notably, free corticosterone and adrenocorticotropic hormone were comparable between all groups. Between 30 and 90 days of age, wild-type female rats showed increases in adrenal weight and the size of the corticosterone-producing region, the zona fasciculata (zf), in tandem with increases in plasma CBG and corticosterone concentrations, whereas no such changes were observed in males. This sex difference was lost in rats without CBG, such that adrenal growth and zf expansion were similar between sexes. The sex-specific effects of CBG on adrenal morphology were accompanied by remarkable changes in gene expression: ∼40% of the adrenal transcriptome was altered in females lacking CBG, whereas almost no effect was seen in males. Over half of the adrenal genes that normally exhibit sexually dimorphic expression after puberty were similarly expressed in males and females without CBG, including those responsible for cholesterol biosynthesis and mobilization, steroidogenesis, and growth. Rat adrenal SerpinA6 transcript levels were very low or undetectable. Thus, sex differences in adrenal growth, morphology and gene expression profiles that emerge during puberty in rats are dependent on concomitant increases in plasma CBG produced by the liver. [ABSTRACT FROM AUTHOR]

Objective: Patients with pro-opiomelanocortin (POMC) defects generally present with early-onset obesity, hyperphagia, hypopigmentation and adrenocorticotropin (ACTH) deficiency. Rodent models suggest that adequate cleavage of ACTH to α-melanocortin–stimulating hormone (α-MSH) and desacetyl-α-melanocortin–stimulating hormone (d-α-MSH) by prohormone convertase 2 at the KKRR region is required for regulating food intake and energy balance. Methods: We present 2 sisters with a novel POMC gene variant, leading to an ACTH defect at the prohormone convertase 2 cleavage site, and performed functional studies of this variant. Results: The patients had obesity, hyperphagia and hypocortisolism, with markerly raised levels of ACTH but unaffected pigmentation. Their ACTH has reduced potency to stimulate the melanocortin (MC) 2 receptor, explaining their hypocortisolism. Conclusion: The hyperphagia and obesity support evidence that adequate cleavage of ACTH to α-MSH and d-α-MSH is also required in humans for feeding control. [ABSTRACT FROM AUTHOR]

The 5 known melanocortin receptors (MCs) have established physiological roles. With the exception of MC2, these receptors can behave unpredictably, and since they are more widely expressed than their established roles would suggest, it is likely that they have other poorly characterized functions. The aim of this review is to discuss some of the less well-explored aspects of the 4 enigmatic members of this receptor family (MC1,3-5) and describe how these are multifaceted G protein–coupled receptors (GPCRs). These receptors appear to be promiscuous in that they bind several endogenous agonists (products of the proopiomelanocortin [ POMC ] gene) and antagonists but with inconsistent relative affinities and effects. We propose that this is a result of posttranslational modifications that determine receptor localization within nanodomains. Within each nanodomain there will be a variety of proteins, including ion channels, modifying proteins, and other GPCRs, that can interact with the MCs to alter the availability of receptor at the cell surface as well as the intracellular signaling resulting from receptor activation. Different combinations of interacting proteins and MCs may therefore give rise to the complex and inconsistent functional profiles reported for the MCs. For further progress in understanding this family, improved characterization of tissue-specific functions is required. Current evidence for interactions of these receptors with a range of partners, resulting in modulation of cell signaling, suggests that each should be studied within the full context of their interacting partners. The role of physiological status in determining this context also remains to be characterized. [ABSTRACT FROM AUTHOR]

Objective: Provide insights into the defective POMC processing and invasiv e behavior in silent pituitary corticotroph tumors. Design and methods: Single-cell RNAseq was used to compare the cellular makeup and transcriptome of silent and active corticotroph tumors. Results: A series of transcripts related to hormone processing peptidas es and genes involved in the structural organization of secretory vesicles were reduced in silent compa red to active corticotroph tumors. Most relevant to their invasive behavior, silent corticotroph tumors exhibited s everal features of epithelial-to-mesenchymal transition, with increased expression of mesenchymal genes along with the l oss of transcripts that regulate hormonal biogenesis and secretion. Silent corticotroph tumor vascular smooth muscle cell and pericyte stromal cell populations also exhibited plasticity in their mesenchymal features. Conclusions: Our findings provide novel insights into the mechanisms of impa ired POMC processing and invasion in silent corticotroph tumors and suggest that a common transcript ional reprogramming mechanism simultaneously impairs POMC processing and activates tumor invasion. [ABSTRACT FROM AUTHOR]

Context: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive ACTH-resistance syndrome characterized by glucocorticoid deficiency in the absence of mineralocorticoid deficiency. Here, we report the case of a young woman with a corticotroph pituitary adenoma as the initial presentation of FGD. Case report: A 15-year-old girl was referred to our institution for a 16 mm pituitary adenoma associated with glucocorticoid deficiency. Clinical and biological features were evocative of FGD. DNA sequencing did not identify mutations in either the melanocortin 2 receptor (MC2R) or the MC2R accessory protein genes, indicating type 3 FGD. Despite adequate glucocorticoid replacement, plasma ACTH levels remained increased and pituitary magnetic resonance imaging (MRI) showed a progression of the tumour size resulting in optic chiasm compression with intra-tumoural haemorrhaging. When the patient was 26 years old, it was decided that she would undergo transsphenoidal surgery. The histomorphological analysis identified a well-individualized pituitary adenoma immunoreactive for ACTH. The proband's sister also exhibited type 3 FGD associated with pituitary hyperplasia upon MRI. Conclusion: This case highlights the relationship between FGD and hyperplasia of ACTH-producing cells, potentially leading to histologically proven pituitary corticotroph adenomas. This observation raises the question of the pituitary MRI's significance in the follow-up of FGD. [ABSTRACT FROM AUTHOR]

Primary macronodular adrenal hyperplasia (PMAH) is considered a rare cause of adrenal Cushing syndrome, is pituitary ACTH-independent, generally results from bilateral adrenal macronodules (>1 cm), and is often associated with variable cortisol secretion, resulting in a heterogeneous clinical presentation. Recent advances in the molecular pathogenesis of PMAH have offered new insights into the comprehension of this heterogeneous and complex adrenal disorder. Different molecular mechanisms involving the actors of the cAMP/protein kinase A pathway have been implicated in the development of PMAH, including germline and/or somatic molecular defects such as hyperexpression of the G-protein aberrant receptors and pathogenic variants of MC2R , GNAS , PRKAR1A , and PDE11A. Nevertheless, since 2013, the ARMC5 gene is believed to be a major genetic cause of PMAH, accounting for more than 80% of the familial forms of PMAH and 30% of apparently sporadic cases, except in food-dependent Cushing syndrome in which ARMC5 is not involved. Recently, 2 independent groups have identified that the tumor suppressor gene KDM1A is responsible for PMAH associated specifically with food-dependent Cushing syndrome. Consequently, PMAH has been more frequently genetically associated than previously assumed. This review summarizes the most important aspects, including hormone secretion, clinical presentation, radiological imaging, and molecular mechanisms, involved in familial Cushing syndrome associated with PMAH. [ABSTRACT FROM AUTHOR]

Context: Adrenarche reflects the developmental growth of the adrenal zona reticularis, which produces increasing adrenal androgen secretion (eg, dehydroepiandrosterone [DHEA]/dehydroepiandrosterone sulfate [DHEAS]) from approximately age 5 to 15 years. Objective: We hypothesized that the study of the genetic determinants associated with variations in serum DHEAS during adrenarche might detect genetic variants influencing the rate or timing of this process. Methods: Genome-wide genotyping was performed in participants of the Chilean pediatric Growth and Obesity Chilean Cohort Study (GOCS) cohort (n = 788). We evaluated the genetic determinants of DHEAS levels at the genome-wide level and in targeted genes associated with steroidogenesis. To corroborate our findings, we evaluated a polygenic risk score (PRS) for age at pubarche, based on the discovered variants, in children from the same cohort. Results: We identified one significant variant at the genome-wide level in the full cohort, close to the GALR1 gene (P = 3.81 × 10–8). In addition, variants suggestive of association (P < 1 × 10–5) were observed in PRLR, PITX1, PTPRD, NR1H4, and BCL11B. Stratifying by sex, we found variants suggestive of association in SERBP1 and CAMTA1/VAMP3 for boys and near ZNF98, TRPC6, and SULT2A1 for girls. We also found significant reductions in age at pubarche in those children with higher PRS for greater DHEAS based on these newly identified variants. Conclusion: Our results disclose one variant associated with DHEAS concentrations at the level of genome-wide association study significance, and several variants with a suggestive association that may be involved in the genetic regulation of adrenarche. [ABSTRACT FROM AUTHOR]

Examines the effect of feeding spray-dried plasma (SDP) after weaning on the stress response of the pig to a lipopolysaccharide challenge. Quantification of messenger RNA; Potential mechanisms by which SDP may prevent activation of the hypothalamic-pituitary-adrenal axis.

Chronic food restriction (FR), which retards many aging processes, enhances the endogenous diurnal peak of plasma total corticosterone (B) in young rats. Although the FR-dependent enhancement of total B disappears in aged rats, increased levels of the bioavailable fraction, free B, appear to be maintained. In young rats, we previously found that the FR-induced increase in the diurnal peak of total B is associated with increased adrenal response to corticotropin, also known as adrenocorticotropic hormone (ACTH). Here we show that the FR-enhanced adrenal response of total B to ACTH disappears with age but that the enhanced response of free B is maintained. We measured the endogenous diurnal peak and the response to ACTH of total and free B in 10-, 16-, and 22-month-old ad-libitum fed and FR male Fischer 344 rats in the afternoon, when plasma B peaks. At 10 and 16 months, FR rats showed enhanced total plasma B responses to ACTH relative to ad-libitum fed rats, but not at 22 months. By contrast, the response of free B to ACTH was enhanced by FR at all ages. The effect of FR on patterns of endogenous total and free diurnal B in these three age groups paralleled the ACTH-response data. The enhanced adrenocortical response of FR rats to ACTH does not reflect an increased expression of ACTH-receptor (ACTH-R) mRNA, because ACTH-R mRNA/microg adrenal RNA and ACTH-R mRNA/mg adrenal weight did not differ between ad-libitum fed and FR rats at any age. [ABSTRACT FROM AUTHOR]

Context: Somatic gene mutations have been identified in only about half of cortisolproducing adenomas (CPAs). Affected genes include PRKACA, GNAS, PRKAR1A, and CTNNB1. Objective: This work aims to expand our understanding of the prevalence of somatic mutations in CPAs from patients with overt Cushing syndrome (OCS) and “subclinical” mild autonomous cortisol excess (MACE), with an immunohistochemistry (IHC)‒guided targeted amplicon sequencing approach using formalin-fixed paraffin-embedded (FFPE) tissue Methods: We analyzed FFPE adrenal tissue from 77 patients (n = 12 men, 65 women) with either OCS (n = 32) or MACE (n = 45). Using IHC for 17α-hydroxylase/17,20-lyase (CYP17A1) and 3β-hydroxysteroid dehydrogenase (HSD3B2), we identified 78 CPAs (32 OCS CPAs and 46 MACE CPAs). Genomic DNA was isolated from the FFPE CPAs and subjected to targeted amplicon sequencing for identification of somatic mutations. Results: Somatic mutations were identified in 71.8% (56/78) of the CPAs. While PRKACA was the most frequently mutated gene in OCS CPAs (14/32, 43.8%), somatic genetic aberrations in CTNNB1 occurred in 56.5% (26/46) of the MACE CPAs. Most GNAS mutations were observed in MACE CPAs (5/7, 71.4%). No mutations were observed in PRKAR1A. In addition to the known mutations, we identified one previously unreported mutation in PRKACA. Two patients with MACE harbored 2 adjacent tumors within the same adrenal gland - one patient had 2 CPAs, and the other patient had a CPA and an aldosterone-producing adenoma (identified by IHC for aldosterone synthase). Conclusion: A comprehensive FFPE IHC-guided gene-targeted sequencing approach identified somatic mutations in 71.8% of the CPAs. OCS CPAs demonstrated a distinct mutation profile compared to MACE CPAs. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) are critical modulators of the immune system. The hypothalamic-pituitary-adrenal (HPA) axis regulates circulating GC levels and is stimulated by endotoxins. Lymphoid organs also produce GCs; however, it is not known how lymphoid GC levels are regulated in response to endotoxins. We assessed whether an acute challenge of lipopolysaccharide (LPS) increases lymphoid levels of progesterone and GCs, and expression of steroidogenic enzymes and key HPA axis components (eg, corticotropin-releasing hormone [CRH], adrenocorticotropic hormone [ACTH]). We administered LPS (50 µg/kg intraperitoneally) or vehicle control to male and female C57BL/6J neonatal (postnatal day [PND] 5) and adult (PND90) mice and collected blood, bone marrow, thymus, and spleen 4 hours later. We measured progesterone, 11-deoxycorticosterone, corticosterone, and 11-dehydrocorticosterone via liquid chromatography–tandem mass spectrometry. We measured gene expression of key steroidogenic enzymes (Cyp11b1 , Hsd11b1 , and Hsd11b2) and HPA axis components (Crh , Crhr1 , Pomc , and Mc2r) via quantitative polymerase chain reaction. At PND5, LPS induced greater increases in steroid levels in lymphoid organs than in blood. In contrast, at PND90, LPS induced greater increases in steroid levels in blood than in lymphoid organs. Steroidogenic enzyme transcripts were present in all lymphoid organs, and LPS altered steroidogenic enzyme expression predominantly in the spleen. Lastly, we detected transcripts of key HPA axis components in all lymphoid organs, and there was an effect of LPS in the spleen. Taken together, these data suggest that LPS regulates GC production by lymphoid organs, similar to its effects on the adrenal glands, and the effects of LPS might be mediated by local expression of CRH and ACTH. [ABSTRACT FROM AUTHOR]

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 CAH with special attention to these new developments. [ABSTRACT FROM AUTHOR]

Context: Testicular adrenal rest tumors (TART) are a common complication in males with classic 21-hydroxylase deficiency (21OHD). TART are likely to contribute to the androgen excess in 21OHD patients, but a direct quantification of steroidogenesis from these tumors has not been yet done. Objective: We aimed to define the production of 11-oxygenated 19-carbon (11oxC19) steroids by TART. Methods: Using liquid chromatography-tandem mass spectrometry, steroids were measured in left (n = 7) and right (n = 4) spermatic vein and simultaneously drawn peripheral blood (n = 7) samples from 7 men with 21OHD and TART. For comparison, we also measured the peripheral steroid concentrations in 5 adrenalectomized patients and 12 age- and BMI-matched controls. Additionally, steroids were quantified in TART cell- and adrenal cell-conditioned medium, with and without adrenocorticotropic hormone (ACTH) stimulation. Results: Compared with peripheral blood from 21OHD patients with TART, the spermatic vein samples displayed the highest gradient for 11ß-hydroxytestosterone (11OHT; 96-fold) of the 11oxC19 steroids, followed by 11-ketotestosterone (47-fold) and 11ß-hydroxyandrostenedione (11OHA4; 29-fold), suggesting production of these steroids in TART. TART cells produced higher levels of testosterone and lower levels of A4 and 11OHA4 after ACTH stimulation compared with adrenal cells, indicating ACTH-induced production of testosterone in TART. Conclusion: In patients with 21OHD, TART produce 11oxC19 steroids, but in different proportions than the adrenals. The very high ratio of 11OHT in spermatic vs peripheral vein blood suggests the 11-hydroxylation of testosterone by TART, and the in vitro results indicate that this metabolism is ACTH-sensitive. [ABSTRACT FROM AUTHOR]