Androgen synthesis cell-specific CREBZF deficiency alters adrenal cortex steroid secretion and develops behavioral abnormalities in adult male mice.

The global challenge of male infertility is escalating, notably due to the decreased testosterone (T) synthesis in testicular Leydig cells under stress, underscoring the critical need for a more profound understanding of its regulatory mechanisms. CREBZF, a novel basic region-leucine zipper transcription factor, regulates testosterone synthesis in mouse Leydig cells in vitro; however, further validation through in vivo experiments is essential. Our study utilized Cyp17a1-Cre to knock out CREBZF in androgen-synthesis cells and explored the physiological roles of CREBZF in fertility, steroid hormone synthesis, and behaviors in adult male mice. Conditional knockout (cKO) CREBZF did not affect fertility and serum testosterone level in male mice. Primary Leydig cells isolated from CREBZF-cKO mice showed impaired testosterone secretion and decreased mRNA levels of Star, Cyp17a1, and Hsd3b1. Loss of CREBZF resulted in thickening of the adrenal cortex, especially X-zone, with elevated serum corticosterone and dehydroepiandrosterone levels and decreased serum dehydroepiandrosterone sulfate levels. Immunohistochemical staining revealed increased expression of StAR, Cyp11a1, and 17ß-Hsd3 in the adrenal cortex of CREBZF-cKO mice, while the expression of AR was significantly reduced. Along with the histological changes and abnormal steroid levels in the adrenal gland, CREBZF-cKO mice showed higher anxiety-like behavior and impaired memory in the elevated plus maze and Barnes maze, respectively. In summary, CREBZF is dispensable for fertility, and CREBZF deficiency in Leydig cells promotes adrenal function in adult male mice. These results shed light on the requirement of CREBZF for fertility, adrenal steroid synthesis, and stress response in adult male mice, and contribute to understanding the crosstalk between testes and adrenal glands.

Artificial light at night suppresses the day-night cardiovascular variability: evidence from humans and rats.

Artificial light at night (ALAN) affects most of the population. Through the retinohypothalamic tract, ALAN modulates the activity of the central circadian oscillator and, consequently, various physiological systems, including the cardiovascular one. We summarised the current knowledge about the effects of ALAN on the cardiovascular system in diurnal and nocturnal animals. Based on published data, ALAN reduces the day-night variability of the blood pressure and heart rate in diurnal and nocturnal animals by increasing the nocturnal values of cardiovascular variables in diurnal animals and decreasing them in nocturnal animals. The effects of ALAN on the cardiovascular system are mainly transmitted through the autonomic nervous system. ALAN is also considered a stress-inducing factor, as glucocorticoid and glucose level changes indicate. Moreover, in nocturnal rats, ALAN increases the pressure response to load. In addition, ALAN induces molecular changes in the heart and blood vessels. Changes in the cardiovascular system significantly depend on the duration of ALAN exposure. To some extent, alterations in physical activity can explain the changes observed in the cardiovascular system after ALAN exposure. Although ALAN acts differently on nocturnal and diurnal animals, we can conclude that both exhibit a weakened circadian coordination among physiological systems, which increases the risk of future cardiovascular complications and reduces the ability to anticipate stress.

Bile acids regulate SF-1 to alter cholesterol balance in adrenocortical cells via S1PR2.

Glucocorticoid synthesis typically occurs in adrenal cortex and is influenced by cholesterol balance, since cholesterol is the sole precursor of steroids. Bile acids as the signaling molecules, have been shown to promote steroidogenesis in steroidogenic cells. However, whether bile acids directly regulate cholesterol balance remains elusive. In this study, we prepared cholestatic mouse models and cultured human adrenocortical cells (H295R) treated with taurochenodeoxycholic acid (TCDCA) to determine transcription levels of cholesterol metabolism associated genes and cholesterol concentrations in adrenocortical cells. Results showed that common bile duct ligation (CBDL) and chenodeoxycholic acid (CDCA) feeding elevated the mRNA levels of Abca1, Cyp51, Hmgcr, Srb1, and Mc2r in adrenals of mice. Meanwhile, the concentrations of total cholesterol and cholesteryl ester in adrenals of CBDL and CDCA-fed mice were dramatically lowered. The total and phosphorylation levels of HSL in adrenal glands of CBDL mice were also enhanced. Similarly, TCDCA treatment in H295R cells decreased intracellular concentrations of total cholesterol and cholesteryl ester and increased transcription levels of SRB1, MC2R, and HSL as well. Inhibition of bile acids' receptor sphingosine 1-phosphate receptor 2 (S1PR2), extracellular signal-regulated kinase (ERK) phosphorylation, and steroidogenic factor 1 (SF-1) respectively successfully abolished effect of TCDCA on H295R cells. SF-1s was found to be phosphorylated at Thr75 in TCDCA-treated H295R cells. While a mild increase of intracellular cAMP concentration was detected upon TCDCA treatment, inhibition of PKA activity with Rp-Isomer in H295R cells failed to decrease the expression of SF-1 and its target genes. Our findings suggest that conjugated bile acids affect cholesterol balance through regulation of SF-1 in adrenocortical cells so as to provide an adequate cholesterol supply for glucocorticoid synthesis, which improves and enriches our understanding of the mechanism whereby bile acids regulate cholesterol balance to affect adrenal function.

Metastatic adrenal gland neuroblastoma in an infant with trisomy 18: A case report.

I present a patient with trisomy 18 associated with neuroblastoma. To the best of my knowledge, this is the second report of such an individual in the relevant literature. A 19-month-old girl known to have trisomy 18 presented with respiratory distress secondary to pleural effusion. Work-up showed metastatic neuroblastoma to multiple sites, and the patient's clinical situation was critical. The physician-parent's decision was not to proceed with treatment of the malignancy. Based on this report, I recommend that physicians remain vigilant and have a high level of suspicion about the potential association between neuroblastoma and trisomy 18. Accordingly, it may be necessary to consider performing serial abdominal ultrasounds and biochemical tests to screen children with trisomy 18 who survive beyond infancy.

Neurochemical Anatomy of Cushing's Syndrome.

The neurochemical anatomy underlying Cushing's syndrome is examined for regional brain metabolism as well as neurotransmitter levels and receptor binding of biogenic amines and amino acids. Preliminary studies generally indicate that glucose uptake, blood flow, and activation on fMRI scans decreased in neocortical areas and increased in subcortical areas of patients with Cushing's syndrome or disease. Glucocorticoid-mediated increases in hippocampal metabolism occurred despite in vitro evidence of glucocorticoid-induced decreases in glucose uptake or consumption, indicating that in vivo increases are the result of indirect, compensatory, or preliminary responses. In animal studies, glucocorticoid administration decreased 5HT levels and 5HT1A receptor binding in several brain regions while adrenalectomy increased such binding. Region-specific effects were also obtained in regard to the dopaminergic system, with predominant actions of glucocorticoid-induced potentiation of reuptake blockers and releasing agents. More in-depth neuroanatomical analyses are warranted of these and amino acid-related neurotransmission.

Feasibility of spectral CT-derived extracellular volume fraction for differentiating aldosterone-producing from nonfunctioning adrenal nodules.

OBJECTIVE: To assess the feasibility of spectral CT-derived extracellular volume (ECV) for differentiating aldosterone-producing nodules (APN) from nonfunctioning adrenal nodules (NFN). METHODS: Sixty-nine patients with biochemically and histologically confirmed unilateral APN (34) and NFN (35) as well as 23 patients with bilateral APN (19) and NFN (27) confirmed biochemically and by adrenal vein sampling (AVS) were enrolled in this retrospective study from October 2020 to April 2022. All patients underwent contrast-enhanced spectral CT of the adrenal glands with a 10-min delayed phase. The haematocrit level was measured within 2 days of CT. An iodine density map was derived from the delayed CT. The ECV fractions of the APN and NFN were calculated and compared in the test cohort of 69 patients with unilateral adrenal nodules. The optimal cut-off value was determined to evaluate the diagnostic efficacy of the ECV fraction for differentiating APN from NFN in the validation cohort of 23 patients with bilateral adrenal nodules. RESULTS: The ECV fractions of the APN (11.17 ± 4.57%) were significantly lower (p < 0.001) than that of the NFN (24.79 ± 6.01%) in the test cohort. At cut-off ECV value of 17.16%, the optimal area under the receiver operating characteristic curve was 0.974 (95% confidence interval: 0.942-1) with 91.4% sensitivity, 93.9% specificity, and 92.8% accuracy in the test cohort and 89.5% sensitivity, 96.3% specificity, and 93.5% accuracy in the validation cohort for differentiating APN from NFN. CONCLUSION: The spectral CT-derived ECV fraction can differentiate APN from NFN with high diagnostic performance. CLINICAL RELEVANCE STATEMENT: Spectral CT-derived extracellular volume fraction could accurately differentiate between adrenal aldosterone-producing nodules and nonfunctioning nodules. It might serve as a noninvasive alternative to adrenal vein sampling in primary aldosteronism patients with bilateral adrenal nodules. KEY POINTS: • Conventional CT cannot differentiate aldosterone-producing adrenal nodules from nonfunctioning nodules. • Extracellular volume of adrenal aldosterone-producing nodules was significantly lower than that of nonfunctioning nodules and normal adrenal glands. It can accurately differentiate between aldosterone-producing and nonfunctioning adrenal nodules. • Extracellular volume may be a novel, noninvasive biomarker alternative to adrenal vein sampling for determining the functional status of bilateral adrenal nodules in patients with primary aldosteronism.

Adrenal Mass Biopsy in Patients Without Extraadrenal Primary Malignancy: A Multicenter Study.

BACKGROUND. Adrenal washout CT is not useful for evaluating incidental adrenal masses in patients without known or suspected primary extraadrenal malignancy. OBJECTIVE. The purpose of our study was to evaluate the diagnostic utility of adrenal mass biopsy in patients without known or suspected extraadrenal primary malignancy. METHODS. This retrospective six-center study included 69 patients (mean age, 56 years; 32 men, 37 women) without known or suspected extraadrenal primary malignancy who underwent image-guided core needle biopsy between January 2004 and June 2021 of a mass suspected to be arising from the adrenal gland. Biopsy results were classified as diagnostic or nondiagnostic. For masses resected after biopsy, histopathologic concordance was assessed between diagnoses from biopsy and resection. Masses were classified as benign or malignant by resection or imaging follow-up, and all nondi-agnostic biopsies were classified as false results. RESULTS. The median mass size was 7.4 cm (range, 1.9-19.2 cm). Adrenal mass biopsy had a diagnostic yield of 64% (44/69; 95% CI, 51-75%). After biopsy, 25 masses were resected, and 44 had imaging follow-up. Of the masses that were resected after diagnostic biopsy, diagnosis was concordant between biopsy and resection in 100% (12/12). Of the 13 masses that were resected after nondiagnostic biopsy, the diagnosis from re-section was benign in eight masses and malignant in five masses. The 44 masses with imaging follow-up included one mass with diagnostic biopsy yielding benign adenoma and two masses with nondiagnostic biopsy results that were classified as malignant by imaging follow-up. Biopsy had overall sensitivity and specificity for malignancy of 73% (22/30) and 54% (21/39), respectively; diagnostic biopsies had sensitivity and specificity for malignancy of 96% (22/23) and 100% (21/21), respectively. Among nine nondi-agnostic biopsies reported as adrenocortical neoplasm, six were classified as malignant by the reference standard (resection showing adrenocortical carcinoma in four, resection showing adrenocortical neoplasm of uncertain malignant potential in one, imaging follow-up consistent with malignancy in one). CONCLUSION. Adrenal mass biopsy had low diagnostic yield, with low sensitivity and low specificity for malignancy. A biopsy result of adrenocortical neoplasm did not reliably differentiate benign and malignant adrenal masses. CLINICAL IMPACT. Biopsy appears to have limited utility for the evaluation of incidental adrenal masses in patients without primary extraadrenal malignancy.

Bacteremia caused by Nocardia farcinica: a case report and literature review.

BACKGROUND: Nocardia farcinica is one of the most common Nocardia species causing human infections. It is an opportunistic pathogen that often infects people with compromised immune systems. It could invade human body through respiratory tract or skin wounds, cause local infection, and affect other organs via hematogenous dissemination. However, N. farcinica-caused bacteremia is uncommon. In this study, we report a case of bacteremia caused by N. farcinica in China. CASE PRESENTATION: An 80-year-old woman was admitted to Peking Union Medical College Hospital with recurrent fever, right abdominal pain for one and a half month, and right adrenal gland occupation. N. farcinica was identified as the causative pathogen using blood culture and plasma metagenomics next-generation sequencing (mNGS). The clinical considerations included bacteremia and adrenal gland abscess caused by Nocardia infection. As the patient was allergic to sulfanilamide, imipenem/cilastatin and linezolid were empirically administered. Unfortunately, the patient eventually died less than a month after the initiation of anti-infection treatment. CONCLUSION: N. farcinica bacteremia is rare and its clinical manifestations are not specific. Its diagnosis depends on etiological examination, which can be confirmed using techniques such as Sanger sequencing and mNGS. In this report, we have reviewed cases of Nocardia bloodstream infection reported in the past decade, hoping to improve clinicians' understanding of Nocardia bloodstream infection and help in its early diagnosis and timely treatment.

Adrenal volumes in fetuses delivering prior to 32 weeks' gestation: An MRI pilot study.

INTRODUCTION: Spontaneous preterm birth prior to 32 weeks' gestation accounts for 1% of all deliveries and is associated with high rates of morbidity and mortality. A total of 70% are associated with chorioamnionitis which increases the incidence of morbidity, but for which there is no noninvasive antenatal test. Fetal adrenal glands produce cortisol and dehydroepiandosterone-sulphate which upregulate prior to spontaneous preterm birth. Ultrasound suggests that adrenal volumes may increase prior to preterm birth, but studies are limited. This study aimed to: (i) demonstrate reproducibility of magnetic resonance imaging (MRI) derived adrenal volumetry; (ii) derive normal ranges of total adrenal volumes, and adrenal: body volume for normal; (iii) compare with those who have spontaneous very preterm birth; and (iv) correlate with histopathological chorioamnionitis. MATERIAL AND METHODS: Patients at high risk of preterm birth prior to 32 weeks were prospectively recruited, and included if they did deliver prior to 32 weeks; a control group who delivered an uncomplicated pregnancy at term was also recruited. T2 weighted images of the entire uterus were obtained, and a deformable slice-to-volume method was used to reconstruct the fetal abdomen. Adrenal and body volumes were obtained via manual segmentation, and adrenal: body volume ratios generated. Normal ranges were created using control data. Differences between groups were investigated accounting for the effect of gestation by use of regression analysis. Placental histopathology was reviewed for pregnancies delivering preterm. RESULTS: A total of 56 controls and 26 cases were included in the analysis. Volumetry was consistent between observers. Adrenal volumes were not higher in the case group (p = 0.2); adrenal: body volume ratios were higher (p = 0.011), persisting in the presence of chorioamnionitis (p = 0.017). A cluster of three pairs of adrenal glands below the fifth centile were noted among the cases all of whom had a protracted period at risk of preterm birth prior to MRI. CONCLUSIONS: Adrenal: body volume ratios are significantly larger in fetuses who go on to deliver preterm than those delivering at term. Adrenal volumes were not significantly larger, we hypothesize that this could be due to an adrenal atrophy in fetuses with fulminating chorioamnionitis. A straightforward relationship of adrenal size being increased prior to preterm birth should not be assumed.

A novel likely pathogenetic variant p.(Cys235Arg) of the MEN1 gene in multiple endocrine neoplasia type 1 with multifocal glucagonomas.

PURPOSE: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary endocrine syndrome caused by pathogenic variants in MEN1 tumor suppressor gene. Diagnosis is commonly based on clinical criteria and confirmed by genetic testing. The objective of the present study was to report on a MEN1 case characterized by multiple pancreatic glucagonomas, with particular concern on the possible predisposing genetic defects. METHODS: While conducting an extensive review of the most recent scientific evidence on the unusual glucagonoma familial forms, we analyzed the MEN1 gene in a 35-year-old female with MEN1, as well as her son and daughter, using Sanger and next-generation sequencing (NGS) approaches. We additionally explored the functional and structural consequences of the identified variant using in silico analyses. RESULTS: NGS did not show any known pathogenic variant in the tested regions. However, a new non-conservative variant in exon 4 of MEN1 gene was found in heterozygosity in the patient and in her daughter, resulting in an amino acid substitution from hydrophobic cysteine to hydrophilic arginine at c.703T > C, p.(Cys235Arg). This variant is absent from populations databases and was never reported in full papers: its characteristics, together with the high specificity of the patient's clinical phenotype, pointed toward a possible causative role. CONCLUSION: Our findings confirm the need for careful genetic analysis of patients with MEN1 and establish a likely pathogenic role for the new p.(Cys235Arg) variant, at least in the rare subset of MEN1 associated with glucagonomas.

SDHB variant type impacts phenotype and malignancy in pheochromocytoma-paraganglioma.

BACKGROUND: Traditional genotype-phenotype correlations for the succinate dehydrogenase-complex II (SDH) genes link SDHB variants to thoracic-abdominal pheochromocytoma-paraganglioma (PPGL) and SDHD variants to head and neck paraganglioma (HNPGL). However, in a recent study we found strong and specific genotype-phenotype associations for SDHD variants. In the present study we zoom in on the genotype-phenotype associations of SDHB gene variants, considering the impact of individual gene variants on disease risk and risk of malignancy. METHODS: We analysed two large independent data sets, including a total of 448 patients with PPGL and HNPGL, and studied the association of missense or truncating SDHB variants with tumour incidence, age of onset and malignancy risk using binomial testing and Kaplan-Meier analysis. RESULTS: Compared with missense variants, truncating SDHB variants were significantly and consistently more common in patients with PPGL, by a 20 percentage point margin. Malignancy was also significantly more common in truncating versus missense variant carriers. No overall differences in age of PPGL onset were noted between carriers of the two variant types, although some individual variants may differ in certain cases. Missense variants were marginally over-represented among patients with HNPGL, but the difference was not statistically significant. CONCLUSION: SDHB truncating variants convey an elevated risk for development of both PPGL and malignancy compared with missense variants. These results further support earlier robust associations between truncating variants and PPGL, and also suggest that the two variant types differ in their impact on complex II function, with PPGL/HNPGL tissues displaying differing sensitivities to changes in complex II function.

Genetic and phenotypic spectrum of non-21-hydroxylase-deficiency primary adrenal insufficiency in childhood: data from 111 Chinese patients.

BACKGROUND: Primary adrenal insufficiency (PAI) is a rare but life-threatening condition. Differential diagnosis of numerous causes of PAI requires a thorough understanding of the condition. METHODS: To describe the genetic composition and presentations of PAI. The following data were collected retrospectively from 111 patients with non-21OHD with defined genetic diagnoses: demographic information, onset age, clinical manifestations, laboratory findings and genetic results. Patients were divided into four groups based on the underlying pathogenesis: (1) impaired steroidogenesis, (2) adrenal hypoplasia, (3) resistance to adrenocorticotropic hormone (ACTH) and (4) adrenal destruction. The age of onset was compared within the groups. RESULTS: Mutations in the following genes were identified: NR0B1 (n=39), STAR (n=33), CYP11B1 (n=12), ABCD1 (n=8), CYP17A1 (n=5), HSD3B2 (n=4), POR (n=4), MRAP (n=2), MC2R (n=1), CYP11A1 (n=1), LIPA (n=1) and SAMD9 (n=1). Frequent clinical manifestations included hyperpigmentation (73.0%), dehydration (49.5%), vomiting (37.8%) and abnormal external genitalia (23.4%). Patients with adrenal hypoplasia typically presented manifestations earlier than those with adrenal destruction but later than those with impaired steroidogenesis (both p<0.01). The elevated ACTH (92.6%) and decreased cortisol (73.5%) were the most common laboratory findings. We generated a differential diagnosis flowchart for PAI using the following clinical features: 17-hydroxyprogesterone, very-long-chain fatty acid, external genitalia, hypertension and skeletal malformation. This flowchart identified 84.8% of patients with PAI before next-generation DNA sequencing. CONCLUSIONS: STAR and NR0B1 were the most frequently mutated genes in patients with non-21OHD PAI. Age of onset and clinical characteristics were dependent on aetiology. Combining clinical features and molecular tests facilitates accurate diagnosis.

Prolactin as an adrenocorticotropic hormone: Prolactin signalling is a conserved key regulator of sexually dimorphic adrenal gland function in health and disease.

A large number of previous reports described an effect of the pituitary hormone prolactin (PRL) on steroid hormone production by the adrenal cortex. However, those studies remained anecdotal and were never converted into a conceptual and mechanistic framework, let alone being translated into clinical care. In the light of our recently published landmark study where we described PRL signalling as a pivotal regulator of the sexually dimorphic adrenal phenotype in mouse and of adrenal androgen production in humans, we present here the overarching hypothesis that PRL signalling increases the activity of Steroidogenic Factor-1 (SF-1/NR5A1), a transcription factor that has an essential role in adrenal gland development and function, to regulate adrenal cortex growth and hormonal production in physiological and pathological conditions. PRL can then be considered as a bona fide adrenocorticotropic hormone synergizing with ACTH in the endocrine control of adrenal cortex function.

The effect of mass functionality on laparoscopic adrenalectomy outcomes.

PURPOSE: This study aimed to determine the effect of adrenal mass functionality and different hormone subtypes synthesized by the adrenal masses on laparoscopic adrenalectomy (LA) outcomes. MATERIALS AND METHODS: The study included 298 patients, 154 of whom were diagnosed with nonfunctional masses. In the functional group, 33, 62, and 59 patients had Conn syndrome, Cushing's syndrome, and pheochromocytoma, respectively. The variables were analyzed between the functional and nonfunctional groups and then compared among functional masses through subgroup analysis. RESULTS: The incidence of diabetes mellitus, hypertension, and obesity, blood loss, and length of hospital stay (LOH) were significantly higher in the functional group than in the nonfunctional group. In the subgroup analysis, patients with pheochromocytoma had significantly lower body mass index but significantly higher mass size, blood loss, and LOH than the other two groups. A positive correlation was found between mass size and blood loss in patients with pheochromocytoma (p ≤ 0.001, r = 0.761). However, no significant difference in complications was found among the groups. CONCLUSIONS: In this study, patients with functional adrenal masses had higher comorbidity rates and American Society of Anesthesiologists scores. Moreover, blood loss and LOH were longer on patients with functional adrenal masses who underwent LA. Mass size, blood loss, and LOH in patients with pheochromocytoma were significantly longer than those in patients with other functional adrenal masses. Thus, mass functionality did not increase the complications.

Brain tissue heterotopic in the adrenal gland in a child: a scarce case report.

Heterotopic brain tissue is rare and has not been reported. Our center made the first report. 4 years and 2 months old Girl presented with a cystic mass in the right adrenal gland 2 weeks after right upper abdominal pain. The operation was successful, and the diagnosis was confirmed by postoperative pathology. 6 months after the procedure, the incision healed well without recurrence. This case report has a detailed diagnosis and treatment process and satisfactory examination results. It can provide a reference for diagnosing and treating clinical HBT and reduce the risk of misdiagnosis and mistreatment.

Single-cell atlas of developing murine adrenal gland reveals relation of Schwann cell precursor signature to neuroblastoma phenotype.

Neuroblastoma is the most common extracranial solid tumor and accounts for ∼10% of pediatric cancer-related deaths. The exact cell of origin has yet to be elucidated, but it is generally accepted that neuroblastoma derives from the neural crest and should thus be considered an embryonal malignancy. About 50% of primary neuroblastoma tumors arise in the adrenal gland. Here, we present an atlas of the developing mouse adrenal gland at a single-cell level. Five main cell cluster groups (medulla, cortex, endothelial, stroma, and immune) make up the mouse adrenal gland during fetal development. The medulla group, which is of neural crest origin, is further divided into seven clusters. Of interest is the Schwann cell precursor ("SCP") and the "neuroblast" cluster, a highly cycling cluster that shares markers with sympathoblasts. The signature of the medullary SCP cluster differentiates neuroblastoma patients based on disease phenotype: The SCP signature score anticorrelates with ALK and MYCN expression, two indicators of poor prognosis. Furthermore, a high SCP signature score is associated with better overall survival rates. This study provides an insight into the developing adrenal gland and introduces the SCP gene signature as being of interest for further research in understanding neuroblastoma phenotype.

Enhanced Ca2+ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1hM1560V/+ ).

Gain-of-function mutations in the CACNA1H gene (encoding the T-type calcium channel CaV3.2) cause autosomal-dominant familial hyperaldosteronism type IV (FH-IV) and early-onset hypertension in humans. We used CRISPR/Cas9 to generate Cacna1hM1560V/+ knockin mice as a model of the most common FH-IV mutation, along with corresponding knockout mice (Cacna1h-/- ). Adrenal morphology of both Cacna1hM1560V/+ and Cacna1h-/- mice was normal. Cacna1hM1560V/+ mice had elevated aldosterone:renin ratios (a screening parameter for primary aldosteronism). Their adrenal Cyp11b2 (aldosterone synthase) expression was increased and remained elevated on a high-salt diet (relative autonomy, characteristic of primary aldosteronism), but plasma aldosterone was only elevated in male animals. The systolic blood pressure of Cacna1hM1560V/+ mice was 8 mmHg higher than in wild-type littermates and remained elevated on a high-salt diet. Cacna1h-/- mice had elevated renal Ren1 (renin-1) expression but normal adrenal Cyp11b2 levels, suggesting that in the absence of CaV3.2, stimulation of the renin-angiotensin system activates alternative calcium entry pathways to maintain normal aldosterone production. On a cellular level, Cacna1hM1560V/+ adrenal slices showed increased baseline and peak intracellular calcium concentrations in the zona glomerulosa compared to controls, but the frequency of calcium spikes did not rise. We conclude that FH-IV, on a molecular level, is caused by elevated intracellular Ca2+ concentrations as a signal for aldosterone production in adrenal glomerulosa cells. We demonstrate that a germline Cacna1h gain-of-function mutation is sufficient to cause mild primary aldosteronism, whereas loss of CaV3.2 channel function can be compensated for in a chronic setting.

Prenatal diagnosis of intrathoracic kidney and adrenal gland in left-sided congenital diaphragmatic hernia.

A 29-year-old primigravida at 31 weeks of gestation was referred for intrathoracic kidney (ITK). Ultrasound revealed left kidney intrathoracic placement with an anteriorly positioned ectopic adrenal gland. Magnetic resonance imaging confirmed diaphragmatic interruption and colon herniation. A female neonate, delivered at 37 weeks, underwent successful thoracoscopic repair for a left Bochdalek hernia. Despite compression of the left lung, notably optimistic lung-to-head ratio (LHR) values were observed, correlating with favorable outcomes. This case underscores the rare occurrence of ITK, its association with Bochdalek hernia, and the importance of comprehensive prenatal evaluations.

The Role of the Gap Junction Protein Connexin in Adrenal Gland Tumorigenesis.

Gap junctions (GJs) are important in the regulation of cell growth, morphology, differentiation and migration. However, recently, more attention has been paid to their role in the pathogenesis of different diseases as well as tumorigenesis, invasion and metastases. The expression pattern and possible role of connexins (Cxs), as major GJ proteins, under both physiological and pathological conditions in the adrenal gland, were evaluated in this review. The databases Web of Science, PubMed and Scopus were searched. Studies were evaluated if they provided data regarding the connexin expression pattern in the adrenal gland, despite current knowledge of this topic not being widely investigated. Connexin expression in the adrenal gland differs according to different parts of the gland and depends on ACTH release. Cx43 is the most studied connexin expressed in the adrenal gland cortex. In addition, Cx26, Cx32 and Cx50 were also investigated in the human adrenal gland. Cx50 as the most widespread connexin, along with Cx26, Cx29, Cx32, Cx36 and Cx43, has been expressed in the adrenal medulla with distinct cellular distribution. Considerable effort has recently been directed toward connexins as therapeutically targeted molecules. At present, there exist several viable strategies in the development of potential connexin-based therapeutics. The differential and hormone-dependent distribution of gap junctions within adrenal glands, the relatively large gap junction within this gland and the increase in the gap junction size and number following hormonal treatment would indicate that gap junctions play a pivotal role in cell functioning in the adrenal gland.

Anatomy and anatomical variations of adrenal veins and its application to adrenal venous sampling.

PURPOSE: Our aim was to study the anatomy of the left and right main adrenal veins (LAV and RAV) and to identify their anatomical variations in order to see the practical application of these findings to adrenal venous sampling (AVS). METHODS: Our work is based on dissection of 80 adrenal glands from fresh corpses in the forensic medicine department. We studied the number, the drainage, the direction and the level of termination of the main adrenal veins. RESULTS: The average length of the LAV was 21 mm. It ended in 100% of cases at the upper edge of the left renal vein with a mean connection angle of 70° and after an anastomosis with the lower phrenic vein in 36 cases(90%). The average length of the RAV was 9 mm. It ended in 100% of cases at the level of the retro hepatic inferior vena cava (IVC) mainly on its posterior face in 21 cases (53%) and on its right lateral border in 18 cases (45%). The mean angle of the RAV in relation to the vertical axis of the IVC was 40°, with extremes ranging from 15° to 90°. CONCLUSIONS: AVS seems to be easier on the left than on the right side because of the greater length of the adrenal vein (21 mm vs. 9 mm) and a greater angle of connection (70° with the left renal vein vs. 40° with the IVC), which explains the lower success rate of cannulation and the more frequent occurrence of blood sample contamination on the right side.