Glucocorticoid Excess Research Articles

Diagnostic and management challenges in paediatric Cushing's syndrome.

Cushing syndrome (CS) is the result of chronic exposure to glucocorticoid excess. CS in children is most often caused by the administration of exogenous steroids. Endogenous CS is rare in the paediatric population and is caused mainly by tumours of the pituitary and adrenal glands, with ectopic sources being extraordinarily rare before the age of 18 years. In addition, children and young adults with CS present with different epidemiology, management issues, prognosisand outcomes than older adult patients. This complex disorder needs early diagnosis and management to avoid the significant morbidity and even mortality that can result from chronic untreated CS. In this review, we present the complex case of a 7-year-old boy with CS that highlights the diagnostic and management challenges of paediatric CS patients, including the considerations for genetic predisposition and life-long consequences of CS in children and young adults. The diagnostic protocols for the evaluation of CS have been devised for adults and tested predominantly on adults. In this review, we discuss necessary modifications so that the testing can be adjusted for use in children. Additionally, pituitary adenomas in children are generally smaller and thus more difficult to recognize on pituitary imaging. The management of the case and its complexities underline the need for children with CS to be managed in a centre with experienced paediatric endocrinologists and skilled neurosurgeons both for their initial diagnosis and treatment as well as for their long-term follow-up and management.

Diagnosis and Management of Adrenocortical Carcinoma with co-secretion of Cortisol and Aldosterone

Adrenocortical carcinoma (ACC) accounts for 0.05-2% of all malignant tumors. Forty-five percent of ACCs with secretory function have excess glucocorticoids alone and only less than 1% secrete aldosterone. This is a case of a 44-year-old Filipino female with hypertension and a 12-year-history of an incidentaloma of the left adrenal gland, with recent-onset complaints of increasing abdominal girth, purple striae, amenorrhea, moon facies and a dorsocervical fat pad. Laboratory findings revealed low potassium levels, non-suppressed cortisol on dexamethasone test suggesting Cushing’s syndrome and elevated aldosterone-renin ratio and plasma aldosterone concentration pointing to primary hyperaldosteronism. A computed tomography scan revealed a left-sided adrenal mass measuring approximately 23 cm in largest diameter suggestive of carcinoma without metastasis or lymph node involvement. Complete resection via open adrenalectomy was performed and histopathologic assessment revealed Adrenocortical Carcinoma with Weiss score of 4. The Ki-67 proliferative index was found to be >20%. Radiotherapy was done as an adjuvant treatment. Although rare, co-secretion of cortisol and aldosterone can occur in functional tumors of adrenocortical carcinoma. Malignancy should always be considered in patients who present with a history of a unilateral adrenal mass and/ or in those with signs and symptoms of adrenal hormone excess. Thus, a proper assessment derived from a thorough medical history, physical examination and laboratory work-up is warranted in patients with an adrenal mass to ascertain the diagnosis and provide adequate management.

Glucocorticoid modulates oxidative and thermogenic function of rat brown adipose tissue and human brown adipocytes.

Chronic and excessive glucocorticoid (GC) exposure can cause Cushing's syndrome, resulting in fat accumulation in selected body areas. Particularly in the brown adipose tissue (BAT), GC acts negatively, resulting in whitening of the tissue. We hypothesized that dysregulation of microRNAs by GC could be an additional mechanism to explain its negative actions in BAT. Male Wistar rats were divided into two groups: (1) Control sham and (2) GC group that was administered dexamethasone 6.25 mg/200 μL via osmotic pump implantation over 28 days. After this period, the animals were euthanized and BAT tissue was properly stored. Human fat cells treated with dexamethasone were used to translate the experimental results found in animals to human biology. GC-treated rat BAT presented with large lipid droplets, severely impaired thermogenic activation, and reduced glucose uptake measured by 18F-FDG PET/CT. GC exposure induced a reduction in the mitochondrial OXPHOS system and oxygen consumption. MicroRNA profiling of BAT revealed five top-regulated microRNAs and among them miR-21-5p was the most significantly upregulated in GC-treated rats compared to the control group. Although upregulation of miR-21-5p in the tissue, differentiated primary brown adipocytes from GC-treated rats had decreased miR-21-5p levels compared to the control group. To translate these results to the clinic, human brown adipocytes were treated with dexamethasone and miR-21-5p inhibitor. In human brown cells, inhibition of miR-21-5p increased brown adipocyte differentiation and prevented GC-induced glucose uptake, resulting in a lower glycolysis rate. In conclusion, high-dose GC therapy significantly impacts brown adipose tissue function, with a notable association between glucose uptake and miR-21-5p.

Effects of improved on-farm crop storage on DNA methylation of mothers and their infants: evidence from a randomized controlled trial in Kenya

BackgroundStress during pregnancy can lead to adverse maternal and infant health outcomes through epigenetic changes in the hypothalamic–pituitary–adrenal axis. Among farmers in low-income countries, one important stressor is food insecurity, which can be reduced using hermetic storage bags. This study aimed to determine, for the first time, whether a hermetic storage bag intervention during pregnancy positively affects maternal and infant DNA methylation of the hypothalamic–pituitary–adrenal axis-related genes FKBP5 and NR3C1. We further analyzed whether anthropometrics, stress, and mental health were associated with DNA methylation.MethodsThis study was part of a larger matched-pair randomized controlled trial focusing on the impact of improved on-farm storage on food security, poverty, and net income of smallholder farming households. A total of N = 149 mothers were recruited by telephone and invited to attend a study appointment at health facilities in Kakamega County, Western Kenya, with their infants in April or May 2021. During the appointment, anthropometric measurements were taken, questionnaires on stress and mental health were administered, and saliva samples were collected. Logistic and multiple linear regression were used to examine the effect of the intervention and related measures on DNA methylation.ResultsMothers in the intervention group showed higher mean NR3C1 methylation levels than those in the control group, corrected for multiple testing. Maternal postpartum body mass index was positively associated with infant NR3C1 CpG3 DNA methylation. The more stressful life events a mother had experienced in the previous 12 months (including during pregnancy), the lower her FKBP5 CpG3 methylation levels.ConclusionsFood insecurity and stressful life events during pregnancy seem to exert significant effects on maternal DNA methylation. While these stressors did not appear to impact infant DNA methylation in the present study, maternal postpartum body mass index was significantly related to infant methylation. These findings suggest that while infants may be protected from excessive maternal glucocorticoids by placental barrier activity, maternal metabolic status is still reflected in their epigenetic make-up.Trial registration This study was part of a larger matched-pair randomized controlled trial on the impact of improved on-farm crop storage on welfare, nutrition, and human health. Registration can be found in the American Economic Association (AEA) RCT Registry, RCT ID: AEARCTR-0005845.

Augmented Cortisol and Antiglucocorticoid Therapy in Mood Disorders: the Hippocampus as a Potential Drug Target

The pathophysiology of many mood disorders is closely relatedto abnormal stress response associated with the dysfunction of thehypothalamic–pituitary–adrenal (HPA) axis and cortisol overproduction. Thehippocampus, a key structure of the limbic system responsible forboth cognitive and emotional spheres, is selectively vulnerableto excess of glucocorticoids (GCs) inducing neuroinflammation and neurodegeneration.The antiGC therapy of psychiatric diseases, in particular depressivedisorders, may be a useful additional treatment. Among other approaches,targeting glucocorticoid receptors, abounded in the hippocampus,is regarded as highly promising. However, though the preclinicaldata provide fairly firm evidence to the concept of antiGC therapyfor stress-related diseases, clinical studies still are at the proof-of-conceptstage. Noteworthy, chronic GC excess is associated not only withmood diseases, but also with cognitive decline, metabolic disorders,diabetes. Potentially, antiGC (HPA axis modifying) therapy may alleviateaffective symptoms, cognitive disturbances, GC and insulin resistanceand adverse side effects of conventional drugs through beneficialeffects on the hippocampus mitigating its dysfunction and neurodegeneration,neuroinflammation, and impairment of neurogenesis. Since stress/GC-associatedneuroinflammation-mediated pathology of the limbic system and, specifically,the hippocampus, is a general feature typical for many brain diseases,the concept of antiGC therapy may be extended, tested and validatedin a wider spectrum of cerebral pathologies.

A Review of Fetal Development in Pregnancies with Maternal Type 2 Diabetes Mellitus (T2DM)-Associated Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysregulation: Possible Links to Pregestational Prediabetes.

Research has identified fetal risk factors for adult diseases, forming the basis for the Developmental Origins of Health and Disease (DOHaD) hypothesis. DOHaD suggests that maternal insults during pregnancy cause structural and functional changes in fetal organs, increasing the risk of chronic diseases like type 2 diabetes mellitus (T2DM) in adulthood. It is proposed that altered maternal physiology, such as increased glucocorticoid (GC) levels associated with a dysregulated hypothalamic-pituitary-adrenal (HPA) axis in maternal stress and T2DM during pregnancy, exposes the fetus to excess GC. Prenatal glucocorticoid exposure reduces fetal growth and programs the fetal HPA axis, permanently altering its activity into adulthood. This programmed HPA axis is linked to increased risks of hypertension, cardiovascular diseases, and mental disorders in adulthood. With the global rise in T2DM, particularly among young adults of reproductive age, it is crucial to prevent its onset. T2DM is often preceded by a prediabetic state, a condition that does not show any symptoms, causing many to unknowingly progress to T2DM. Studying prediabetes is essential, as it is a reversible stage that may help prevent T2DM-related pregnancy complications. The existing literature focuses on HPA axis dysregulation in T2DM pregnancies and its link to fetal programming. However, the effects of prediabetes on HPA axis function, specifically glucocorticoid in pregnancy and fetal outcomes, are not well understood. This review consolidates research on T2DM during pregnancy, its impact on fetal programming via the HPA axis, and possible links with pregestational prediabetes.

Medical Therapy of Endogenous Cushing's Syndrome with Steroidogenesis Inhibitors: Treatment Rationale, Available Drugs, and Therapeutic Effects.

Endogenous Cushing's syndrome (CS) is a rare disease characterized by a glucocorticoid excess. If inadequately treated, hypercortisolism can lead to increased morbidity and mortality. Surgical removal of the underlying tumor is the first-line treatment but is sometimes not feasible or even contraindicated. Additionally, in cases with severe CS, rapid control of hypercortisolism may be required. In these scenarios, steroidogenesis inhibitors represent a therapeutic alternative to surgery. Over the last years, the knowledge of the broad therapeutic effects of steroidogenesis inhibitors per se and the number of available drugs have increased. However, large comparative studies are still lacking. Accordingly, the decision on which drug to be used in a certain patient or clinical setting may be difficult. This review aims to summarize the main characteristics of steroidogenesis inhibitors.

HOW I DO IT: Cushing’s disease—selective adenomectomy via an endoscopic transsphenoidal approach

BackgroundAn ACTH-secreting pituitary adenoma is the most common cause of excessive endogenous glucocorticoid production resulting in Cushing’s Syndrome. A multidisciplinary approach is paramount. Selective adenomectomy is the treatment of choice.MethodEndoscopic transnasal transsphenoidal approach to the tumour, along with techniques for resection, are demonstrated.ConclusionEndoscopic transsphenoidal approaches with its magnified view of the pituitary gland allows precise microsurgical dissection during selective adenomectomy. This technique increases the possibility of proving a gross total resection, leading to clinical and biochemical cure in these patients.

Hipercortisolismo de origen adrenal

Hypercortisolism of adrenal origin is a hormonal disorder caused by chronic exposure to excess glucocorticoids due to adrenal overproduction of cortisol. There is a wide spectrum of clinical presentations of hypercortisolism, from apparently subclinical to full-blown cases depending on the duration and intensity of the hypercortisolism. Consequently, the diagnosis can be complex, given that most of the signs and symptoms are nonspecific. The clinical manifestations are related to an unfavorable cardiometabolic profile, which leads to increased morbidity and mortality in these patients. The biochemical diagnosis is based on confirming autonomous glucocorticoid production by demonstrating the absence of physiological cortisol suppression via a dexamethasone suppression test. The adrenocorticotropic hormone (ACTH) concentration is requested in order to establish the etiological diagnosis. Once the biochemical diagnosis is confirmed, the next step is a radiological study, with the first imaging technique being a computed tomography (CT) scan of the adrenal gland without contrast. The most common cause of endogenous ACTH-independent hypercortisolism is a unilateral cortisol-producing adrenal adenoma. Treatment will be individualized according to the cause and degree of hypercortisolism as well as associated comorbidities.

DNA methylation-mediated 11βHSD2 downregulation drives the increases in angiotensin-converting enzyme and angiotensin II within preeclamptic placentas.

Preeclampsia (PE) is a complex human-specific complication frequently associated with placental pathology. The local renin-angiotensin system (RAS) in the human placenta, which plays a crucial role in regulating placental function, has been extensively documented. Glucocorticoids (GCs) are a class of steroid hormones. PE cases often have abnormalities in GCs levels and placental GCs barrier. Despite extensive speculation, there is currently no robust evidence indicating that GCs regulate placental RAS. This study aims to investigate these potential relationships. Plasma and placental samples were collected from both normal and PE pregnancies. The levels of angiotensin-converting enzyme (ACE), angiotensin II (Ang II), cortisol, and 11β-hydroxysteroid dehydrogenases (11βHSD) were analyzed. In PE placentas, cortisol, ACE, and Ang II levels were elevated, while 11βHSD2 expression was reduced. Interestingly, a positive correlation was observed between ACE and cortisol levels in the placenta. A significant inverse correlation was found between the methylation statuses within the 11βHSD2 gene promoter and its expression, meanwhile, 11βHSD2 expression was negatively correlated with cortisol and ACE levels. Invitro experiments using placental trophoblast cells confirmed that active GCs can stimulate ACE transcription and expression through the GR pathway. Furthermore, 11βHSD2 knockdown could enhance this activating effect. An invivo study using a rat model of intrauterine GCs overexposure during mid-to-late gestation suggested that excess GCs in utero lead to increased ACE and Ang II levels in the placenta. Collectively, this study provides the first evidence of the relationships between 11βHSD2 expression, GCs barrier, ACE, and Ang II levels in the placenta. It not only contributes to understanding the pathological features of the placental GCs barrier and RAS under PE conditions, also provides important information for revealing the pathological mechanism of PE.

Deletion of Hsd11b1 suppresses caloric restriction-induced bone marrow adiposity in male but not female mice.

Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass in healthy humans. It increases in diverse conditions, including ageing, obesity, osteoporosis, glucocorticoid therapy, and notably, during caloric restriction (CR). BMAT potentially influences skeletal, metabolic, and immune functions, but the mechanisms of BMAT expansion remain poorly understood. Our hypothesis is that, during CR, excessive glucocorticoid activity drives BMAT expansion. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies glucocorticoid activity by catalysing intracellular regeneration of active glucocorticoids from inert 11-keto forms. Mice lacking 11β-HSD1 resist metabolic dysregulation and bone loss during exogenous glucocorticoid excess; thus, we hypothesised that 11β-HSD1 knockout mice would also resist excessive glucocorticoid action during CR, thereby restrining BMAT expansion and bone loss. To test this, we first confirmed that 11β-HSD1 is expressed in mouse and human bone marrow. We then investigated the effects of CR in male and female control and 11β-HSD1 knockout mice from 9 to 15 weeks of age. CR increased Hsd11b1 mRNA in adipose tissue and bone marrow. Deletion of Hsd11b1 did not alter bone or BMAT characteristics in mice fed a control diet and had little effect on tibial bone microarchitecture during CR. Notably, Hsd11b1 deletion attenuated the CR-induced increases in BMAT and prevented increases in bone marrow corticosterone in males but not females. This was not associated with suppression of glucocorticoid target genes in bone marrow. Instead, knockout males had increased progesterone in plasma and bone marrow. Together, our findings show that knockout of 11β-HSD1 prevents CR-induced BMAT expansion in a sex-specific manner and highlights progesterone as a potential new regulator of bone marrow adiposity.

Infertility risk assessment with ultrasound in congenital adrenal hyperplasia male patients.

Testicular adrenal rest tumor (TART) is a prevalent complication associated with congenital adrenal hyperplasia (CAH), culminating in gonadal dysfunction and infertility. Early hormonal intervention is preventive, but excessive glucocorticoid poses risks. Developing reliable methods for early TART diagnosis and monitoring is crucial. The present study aims to formulate a scoring system to identify high-risk infertility through analysis of TART ultrasound features. Grayscale and power Doppler ultrasound were employed in this retrospective study to evaluate testicular lesions in male CAH patients. Lesion assessment encompassed parameters such as range, echogenicity, and blood flow, and these were subsequently correlated with semen parameters. Results of 49 semen analyzes from 35 patients demonstrated a notable inverse correlation between lesion scores and both sperm concentration (rs = - 0.83, P < 0.001) and progressive motility (rs = - 0.56, P < 0.001). The ROC curve areas for evaluating oligospermia and asthenozoospermia were calculated as 0.94 and 0.72, respectively. Establishing a lesion score threshold of 6 revealed a sensitivity of 75.00% and specificity of 93.94% for oligospermia and a sensitivity of 53.85% and specificity of 100.00% for asthenozoospermia. These findings underscore the potential utility of incorporating ultrasound into routine CAH patient management, facilitating timely interventions to preserve male fertility.

Cardiac magnetic resonance reveals biventricular impairment in Cushing’s syndrome: a multicentre case-control study

PurposeCushing’s syndrome (CS) is associated with severe cardiovascular (CV) morbidity and mortality. Cardiac magnetic resonance (CMR) is the non-invasive gold standard for assessing cardiac structure and function; however, few CMR studies explore cardiac remodeling in patients exposed to chronic glucocorticoid (GC) excess. We aimed to describe the CMR features directly attributable to previous GC exposure in patients with cured or treated endogenous CS.MethodsThis was a prospective, multicentre, case-control study enrolling consecutive patients with cured or treated CS and patients harboring non-functioning adrenal incidentalomas (NFAI), comparable in terms of sex, age, CV risk factors, and BMI. All patients were in stable condition and had a minimum 24-month follow-up.ResultsSixteen patients with CS and 15 NFAI were enrolled. Indexed left ventricle (LV) end-systolic volume and LV mass were higher in patients with CS (p = 0.027; p = 0.013); similarly, indexed right ventricle (RV) end-diastolic and end-systolic volumes were higher in patients with CS compared to NFAI (p = 0.035; p = 0.006). Morphological alterations also affected cardiac function, as LV and RV ejection fractions decreased in patients with CS (p = 0.056; p = 0.044). CMR features were independent of metabolic status or other CV risk factors, with fasting glucose significantly lower in CS remission than NFAI (p < 0.001) and no differences in lipid levels or blood pressure.ConclusionCS is associated with biventricular cardiac structural and functional impairment at CMR, likely attributable to chronic exposure to cortisol excess independently of known traditional risk factors.

Impact of etiology, sex, diabetes mellitus and remission status on erythrocytic profile in patients with cushing's syndrome: a large population database study.

The study aimed to characterize the erythrocytic profile in patients with cushing's syndrome (CS) versus controls from the normal population according to etiology, sex, presence of diabetes mellitus (DM) and hypercortisolemia remission status. This retrospective cohort analysis compared erythrocytic parameters between patients with CS of pituitary (CD) and adrenal (aCS) etiology and age, sex, body mass index (BMI) and socioeconomic status-matched controls in a 1:5 ratio. Laboratory values at baseline were calculated as mean values during the year preceding CS diagnosis, and over one year thereafter. The cohort included 397 CS patients (68.26% female; mean age 51.11 ± 16.85years) and 1970 controls. Patients with CS had significantly higher baseline median levels of hemoglobin (Hgb) (13.70g/dL vs. 13.12g/dL [p < 0.0001]) and hematocrit (Hct) (41.64% vs. 39.80% [p < 0.0001]) compared to controls. These differences were observed for both CD and aCS and for both sexes. Patients who attained remission had Hgb and Hct levels comparable to controls (13.20g/dL and 40.08% in patients with CD and aCS vs. 13.20g/dL and 39.98% in controls). Meanwhile, those with persistent/recurrent disease maintained elevated levels. Patients with comorbid DM had similar Hgb but higher Hct (p = 0.0419), while patients without DM showed elevated erythrocytic values compared to controls (p < 0.0001). Our data illustrates that erythrocytic parameters are directly influenced by glucocorticoid excess as Hgb and Hct are higher in patients with CS, and normalize after remission. We have identified the influence of DM on erythrocytic parameters in patients with CS for the first time.

Astaxanthin-mediated Nrf2 activation ameliorates glucocorticoid-induced oxidative stress and mitochondrial dysfunction and impaired bone formation of glucocorticoid-induced osteonecrosis of the femoral head in rats

BackgroundOsteonecrosis of the femoral head caused by glucocorticoids (GIONFH) is a significant issue resulting from prolonged or excessive clinical glucocorticoid use. Astaxanthin, an orange-red carotenoid present in marine organisms, has been the focus of this study to explore its impact and mechanism on osteoblast apoptosis induced by dexamethasone (Dex) and GIONFH.MethodsIn this experiment, bioinformatic prediction, molecular docking and dynamics simulation, cytotoxicity assay, osteogenic differentiation, qRT-PCR analysis, terminal uridine nickend labeling (TUNEL) assay, determination of intracellular ROS, mitochondrial function assay, immunofluorescence, GIONFH rat model construction, micro-computed tomography (micro-CT) scans were performed.ResultsOur research demonstrated that a low dose of astaxanthin was non-toxic to healthy osteoblasts and restored the osteogenic function of Dex-treated osteoblasts by reducing oxidative stress, mitochondrial dysfunction, and apoptosis. Furthermore, astaxanthin rescued the dysfunction in poor bone quality, bone metabolism and angiogenesis of GIONFH rats. The mechanism behind this involves astaxanthin counteracting Dex-induced osteogenic damage by activating the Nrf2 pathway.ConclusionAstaxanthin shields osteoblasts from glucocorticoid-induced oxidative stress and mitochondrial dysfunction via Nrf2 pathway activation, making it a potential therapeutic agent for GIONFH treatment.

Primary unilateral macronodular adrenal hyperplasia with concomitant glucocorticoid and androgen excess and KDM1A inactivation

Primary unilateral macronodular adrenal hyperplasia with concomitant glucocorticoid and androgen excess and KDM1A inactivation

Glucocorticoid Resistance Increases PPARγ Activity and Drives Hepatic Lipid Accumulation via Increased Eicosanoid and Monoacylglyceride Synthesis

A diet high in fat induces adiposity and obesity, and chronic feeding can lead to multiple metabolic complications, including type II diabetes, non-alcoholic fatty liver disease, and cardiovascular disease. The glucocorticoid receptor (GR) regulates genes that control metabolism. The GR has two isoforms (GRα and GRβ) that arise from the GR gene ( NR3C1) due to the alternative splicing of exon 9. The GRα isoform is the classical receptor that binds to glucocorticoids. However, the GRβ isoform has a truncated C-terminus. It cannot bind glucocorticoid steroids, and as a result, this isoform induces a glucocorticoid-resistant state when its expression is increased. We hypothesized that increasing levels of GRβ from long-term excess glucocorticoid exposure or a high-fat diet induces adiposity by affecting lipid metabolism and lipogenesis, causing fat to accumulate in the adipose and liver tissues. We first overexpressed GRβ (GRβ-Ad) or control (Vec-Ad) using adenovirus delivery and fed the mice a normal chow diet. The GRβ-Ad mice had significantly higher lipid accumulation within five days. Western blotting analysis revealed a significant increase (p-value &lt;0.05) in the GRβ-Ad livers for fatty acid synthase (FAS) expression, and there was a remodeling of the hepatic lipid content as measured by mass spectrometry lipidomic analysis. The data indicate an increased level of monoacylglyceride lipid species and some species of long-chain triacylglycerides and diacylglycerides. mRNA analysis revealed a significant increase (p-value &lt;0.05) in Carbohydrate-responsive element-binding protein (ChREBP), PPARγ, and Cyp2j6, indicating an increase in de novo lipogenesis and eicosanoid synthesis. We conclude that glucocorticoid resistance due to increased levels of GRβ drives de novo lipogenesis and increases eicosanoid synthesis, possibly via synergism with PPARγ. A better understanding of the GR isoforms and glucocorticoid resistance could benefit people with obesity and other metabolic disorders to improve obesity-associated comorbidities. R01DK121797 (T.D.H.J.), R01DA058933 (T.D.H.J.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Association of Lower Rostral Anterior Cingulate GABA+ and Dysregulated Cortisol Stress Response With Altered Functional Connectivity in Young Adults With Lifetime Depression: A Multimodal Imaging Investigation of Trait and State Effects.

Preclinical work suggests that excess glucocorticoids and reduced cortical γ-aminobutyric acid (GABA) may affect sex-dependent differences in brain regions implicated in stress regulation and depressive phenotypes. The authors sought to address a critical gap in knowledge, namely, how stress circuitry is functionally affected by glucocorticoids and GABA in current or remitted major depressive disorder (MDD). Multimodal imaging data were collected from 130 young adults (ages 18-25), of whom 44 had current MDD, 42 had remitted MDD, and 44 were healthy comparison subjects. GABA+ (γ-aminobutyric acid and macromolecules) was assessed using magnetic resonance spectroscopy, and task-related functional MRI data were collected under acute stress and analyzed using data-driven network modeling. Across modalities, trait-related abnormalities emerged. Relative to healthy comparison subjects, both clinical groups were characterized by lower rostral anterior cingulate cortex (rACC) GABA+ and frontoparietal network amplitude but higher amplitude in salience and stress-related networks. For the remitted MDD group, differences from the healthy comparison group emerged in the context of elevated cortisol levels, whereas the MDD group had lower cortisol levels than the healthy comparison group. In the comparison group, frontoparietal and stress-related network connectivity was positively associated with cortisol level (highlighting putative top-down regulation of stress), but the opposite relationship emerged in the MDD and remitted MDD groups. Finally, rACC GABA+ was associated with stress-induced changes in connectivity between overlapping default mode and salience networks. Lifetime MDD was characterized by reduced rACC GABA+ as well as dysregulated cortisol-related interactions between top-down control (frontoparietal) and threat (task-related) networks. These findings warrant further investigation of the role of GABA in the vulnerability to and treatment of MDD.

Dissecting the networks underlying diverse brain disorders after prenatal glucocorticoid overexposure.

New human life begins in the uterus in a period of both extreme plasticity and sensitivity to environmental disturbances. The fetal stage is also a vital period for central nervous system development, with experiences at this point profoundly and permanently shaping brain structure and function. As such, some brain disorders may originate in utero. Glucocorticoids, a class of essential stress hormones, play indispensable roles in fetal development, but overexposure may have lasting impacts on the brain. In this review, we summarize data from recent clinical and non-clinical studies regarding alterations in fetal brains due to prenatal glucocorticoid overexposure that are associated with nervous system disorders. We discuss relevant changes to brain structure and cellular functions and explore the underlying molecular mechanisms. In addition, we summarize factors that may cause differential outcomes between varying brain regions, and outline clinically feasible intervention strategies that are expected to minimize negative consequences arising from fetal glucocorticoid overexposure. Finally, we highlight the need for experimental evidence aided by new technologies to clearly determine the effects of excessive prenatal glucocorticoid exposure. This review consolidates diverse findings to help researchers better understand the relationship between the prenatal glucocorticoid overexposure and the effects it has on various fetal brain regions, promoting further development of critical intervention strategies.

Elevated glucocorticoid alters the developmental dynamics of hypothalamic neurogenesis in zebrafish

Exposure to excess glucocorticoid (GC) during early development is implicated in adult dysfunctions. Reduced adult hippocampal neurogenesis is a well-known consequence of exposure to early life stress or elevated GC, however the effects on neurogenesis during development and effects on other brain regions are not well understood. Using an optogenetic zebrafish model, here we analyse the effects of GC exposure on neurogenesis during development in the whole brain. We identify that the hypothalamus is a highly GC-sensitive region where elevated GC causes precocious development. This is followed by failed maturation and early decline accompanied by impaired feeding, growth, and survival. In GC-exposed animals, the developmental trajectory of hypothalamic progenitor cells is strikingly altered, potentially mediated by direct regulation of transcription factors such as rx3 by GC. Our data provide cellular and molecular level insight into GC-induced alteration of the hypothalamic developmental trajectory, a process crucial for health across the life-course.