Basal Adrenocorticotropic Hormone Levels Research Articles

Gender-affirming hormone therapy effect on cortisol levels in trans males and trans females.

Previous studies have shown differences in baseline and stimulated cortisol levels between men and women. Whether this difference is secondary to sex hormones or to other factors, such as genetic or epigenetic changes, is unknown. We investigated the effect of gender-affirming hormone treatment (GAHT) on the hypothalamo-pituitary-adrenal axisof transgender subjects in an effort to throw light on this question. Ten transgender males (TM) and eighttransgender females (TF) underwent a low-dose (1 µg) adrenocorticotropic hormone (ACTH) stimulation test before and 6 months after GAHT initiation. Serum total, free and salivary cortisol (SC) levels were measured at baseline and at 20, 30and 40 min. For the TM, all three levels were significantly lower at several time points after ACTH injection compared to pretreatment levels following 6 months of treatment (p < .05). Likewise, the overall SCresponse as calculated by the area under the curve was significantly lower (p = .0053). For the TF, the basal total cortisol (TC) level increased after 6 months of treatment (p < .01) while ACTH-stimulated SClevels decreased significantly. The basal ACTH levels were significantly lower following hormonal therapy (p < .001). Stimulated salivary cortisol levels decreased significantly after 6 months of GAHT in both male and female transgender subjects, possibly reflecting a decreased state of anxiety associated with treatment initiation. Additionally, basal and stimulated serum TC levels increased after hormonal treatment in the TF, probably secondary to the effect of oestrogen on cortisol-binding globulin.

ODP301 Corticotroph Macroadenomas with Extensions to Third Ventricle: Four Case Reports

Abstract Background Pathophysiology of corticotroph macroadenomas has not been elucidated. In this study, we present four cases of adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas with extensions to the third ventricle (TV) and investigate their clinical and pathological characteristics. Case 1 A male in his seventies went to a hospital because of a fall. Upon performing computed tomography, a tumor was incidentally noted. Pituitary MRI revealed a macroadenoma with extension to TV. He presented with Cushingoid features (CF). His basal ACTH level was 112 pg/mL, and urinary free cortisol (UFC) was 129.1 μg/day. Cortisol was not suppressed in the 0.5 mg dexamethasone suppression test (0.5 mg DST). ACTH level increased in the corticotropin-releasing hormone (CRH) stimulation test and the desmopressin (DDAVP) stimulation test. He was diagnosed with Cushing's disease (CD), and endoscopic transsphenoidal surgery (ETSS) was performed. Pathological findings showed densely granulated corticotroph adenoma (DGCA). Somatostatin receptor type 5 (SSTR5) was negative, and ubiquitin-specific protease 8 (USP8) was not mutated. Case 2 A female in her fifties had a visual field defect and pigmentation of the face. MRI revealed a macroadenoma with extension to TV. She presented with CF. Her basal ACTH level was 57.9 pg/mL, and UFC was 259.7 μg/day. Cortisol was not suppressed in the 0.5 mg DST. ACTH level increased in the CRH test and the DDAVP test. She was diagnosed with CD. Pathological findings showed DGCA. SSTR5 was moderate positive, and USP8 was suspected to be mutated. Case 3 A female in her fifties had a throbbing headache. MRI showed a macroadenoma with extension to TV. She did not present with CF. Her basal ACTH level was 71.8 pg/mL, and UFC was 134.3 μg/day. Cortisol was not suppressed in the 0.5 mg DST. ACTH showed response to the CRH test and the DDAVP test. She was diagnosed with subclinical Cushing's disease (SCD) and sparsely granulated corticotroph adenoma (SGCA). SSTR5 was slightly positive, and USP8 was not mutated. Case 4 A male in his fifties had general malaise and polyuria. MRI showed a macroadenoma with extension to TV. He did not present with CF. His basal ACTH level was 179 pg/mL, and UFC was 187.4 μg/day. Cortisol was not suppressed in the 0.5 mg DST. ACTH did not show response to the CRH test and the DDAVP test. He was diagnosed with SCD, and the tumor had oncocytic changes. SSTR5 was negative, and USP8 was not mutated. Conclusion The findings from these case reports suggest that phenotypes of CD and SCD are associated with the differences between SGCA and DGCA. Moreover, it is also suggested that USP8 mutations correlate with SSTR5 expression in macroadenomas that extend to the TV. Presentation: No date and time listed

Postpartum maternal exposure to predator odor alters offspring antipredator behavior, basal HPA axis activity and immunoglobulin levels in adult Brandt’s voles

Predation risk can program offspring behavior, physiology, and fitness through maternal effect, but most studies have mainly focused on this effect during pregnancy; little is known about the effect of postpartum predation risk on offspring’s phenotype. Here, we compared the antipredator behaviors of adult offspring (approximately 90 days old) produced by female Brandt’s voles (Lasiopodomys brandtii) exposed to one of three treatments: cat odor (CO), rabbit odor (RO), and distilled water (DW) for 60 min daily from postpartum day 1–18. Basal levels of plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT), hypothalamic corticotrophin releasing hormone (CRH), as well as spleen immunoglobulins (IgA, IgM, and IgG) were also measured. Our data showed that the offspring of CO-exposed mothers displayed less head-out behavior to acute 15-min CO exposure, and female offspring showed more freezing behavior. CO offspring showed significantly lower basal ACTH and CORT levels than the RO and DW offspring. Additionally, female but not male CO offspring had higher hypothalamic CRH expression and spleen IgG levels than controls, showing a sex-specific effect. These findings demonstrate that postpartum maternal predator risk exposure promotes a passive-avoidant response to these cues in adult offspring, showing a cross-generational maternal effect of postpartum predation risk. Further, these changes may be associated with alterations in the hypothalamic-pituitary-adrenal axis and immune function.

GHS-R1a Deficiency Alleviates Depression-Related Behaviors After Chronic Social Defeat Stress

Ghrelin is an important orexigenic hormone that regulates feeding, metabolism and glucose homeostasis in human and rodents. Ghrelin functions by binding to its receptor, the growth hormone secretagogue receptor 1a (GHS-R1a), which is widely expressed inside and outside of the brain. Recent studies suggested that acyl-ghrelin, the active form of ghrelin, is a persistent biomarker for chronic stress exposure. However, how ghrelin/GHS-R1a signaling contributes to stress responses and mood regulation remains uncertain. In this study, we applied the chronic social defeat stress (CSDS) paradigm to both GHS-R1a knock-out (Ghsr-/-) mice and littermate control (Ghsr+/+) mice, and then measured their depression- and anxiety-related behaviors. We found that Ghsr+/+ mice, but not Ghsr-/- mice, displayed apparent anxiety and depression after CSDS, while two groups mice showed identical behaviors at baseline, non-stress state. By screening the central and peripheral responses of Ghsr-/- mice and Ghsr+/+ mice to chronic stress, we found similar elevations of total ghrelin and adrenocorticotropic hormone (ACTH) in the serum of Ghsr-/- mice and Ghsr+/+ mice after CSDS, but decreased interleukin-6 (IL-6) in the serum of defeated Ghsr-/- mice compared to defeated Ghsr+/+ mice. We also found increased concentration of brain derived neurotropic factor (BDNF) in the hippocampus of Ghsr-/- mice compared to Ghsr+/+ mice after CSDS. The basal levels of ghrelin, ACTH, IL-6, and BDNF were not different between Ghsr-/- mice and Ghsr+/+ mice. Our findings thus suggested that the differential expressions of BDNF and IL-6 after CSDS may contribute to less anxiety and less despair observed in GHS-R1a-deficient mice than in WT control mice. Therefore, ghrelin/GHS-R1a signaling may play a pro-anxiety and pro-depression effect in response to chronic stress, while GHS-R1a deficiency may provide resistance to depressive symptoms of CSDS.

Особенности функционального состояния гипоталамо-гипофизарно-адренокортикальной системы у крыс линии Крушинского–Молодкиной

The aim of present work was to evaluate functional state of the hypothalamic–pituitary–adrenal axis (HPA) in both naive control Wistar rats and Krushinsky-Molodkina (KM) rats, genetically prone to audiogenic epilepsy, and analyzed the changes of activity of HPA in KM rats during and after expression of audiogenic seizure (AGS). Obtained data demonstrated that the activity of corticotropin-releasing hormone (CRH) neurons in KM rats was reduced, due to the increased inhibitory effect of GABAergic neurons. In the anterior pituitary, we observed accumulation of proopiomelanocortin and adrenocorticotropic hormone (ACTH). However, basal levels of ACTH and corticosterone were equal in the blood in both naive KM rats and Wistar rats. Thus, the data indicate the disturbances in the interaction between the hypothalamus and the pituitary gland in KM rats, which can be one of the regulatory mechanisms for maintaining hormone concentrations in the blood. Analysis of AGS effects on HPA demonstrated increasing secretion of CRH and vasopressin into the portal system of KM rats and ACTH in the blood at clonus-tonus stages, which expresses in 6-10 seconds after sound stimulation. Therein corticosterone level was increased in KM rats during 24 hours. In Wistar rats, the sound stimulation did not change the levels of ACTH and corticosterone in the blood. Thus, we demonstrated specific activation of HPA in KM rats by AGS as a result of epileptiform activity overspreading in the brain that revealed participation of HPA is the expression of seizure activity.

Delayed peak response of cortisol to insulin tolerance test in patients with Prader-Willi syndrome.

Deaths among children with Prader-Willi syndrome (PWS) are often related to only mild or moderate upper respiratory tract infections, and many causes of death remain unexplained. Several reports have hypothesized that patients with PWS may experience latent central adrenal insufficiency. However, whether PWS subjects suffer from alteration of the hypothalamus-pituitary-adrenal (HPA) axis remains unclear. This study aimed to explore the HPA axis on PWS. We evaluated the HPA axis in 36 PWS patients (24 males, 12 females; age range, 7 months to 12 years; median age 2.0 years; interquartile range [IQR], 1.5-3.4 years) using an insulin tolerance test (ITT) in the morning between 08:00 and 11:00. For comparison, ITT results in 37 age-matched healthy children evaluated for short stature were used as controls. In PWS patients, basal levels of adrenocorticotropic hormone (ACTH) were 13.5 pg/ml (IQR, 8.3-27.5 pg/ml) and basal levels of cortisol were 18.0 μg/dl (IQR, 14.2-23.7 μg/dl). For all patients, cortisol levels at 60 min after stimulation were within the reference range (>18.1 μg/dl), with a median peak of 41.5 μg/dl (IQR, 32.3-48.6 μg/dl). Among control children, basal level of ACTH and basal and peak levels of cortisol were 10.9 (IQR, 8.5-22.0 pg/ml), 15.6 (IQR, 11.9-21.6 μg/dl), and 27.8 μg/dl (IQR, 23.7-30.5 μg/dl), respectively. Basal and peak levels of cortisol were all within normal ranges, but peak response of cortisol to ITT was delayed in the majority of PWS patients (64%). Although the mechanismremains unclear, this delay may signify the existence of central obstacle in adjustment of the HPA axis.

Predicting Recovery Of The Hypothalamic-Pituitary-Adrenal Axis After Prolonged Glucocorticoid Use

Prolonged exposure to glucocorticoids lead to hypothalamic-pituitary-adrenal (HPA) axis suppression that recovers after cessation of treatment. We aimed to identify the predictive factors for HPA axis recovery after prolonged glucocorticoid use. Retrospective review of patients who had undergone first short Synacthen test (SST) to assess HPA axis recovery after prolonged use of glucocorticoids. A total of 61% (20/33) of patients had adequate SST response at a median time of 2 years after diagnosis of adrenal insufficiency. Those who had adequate response during SST had higher ambulatory early morning cortisol ( P<.01), shorter duration of exposure to glucocorticoids ( P = .01), and lower final cumulative hydrocortisone replacement dose ( P = .03). Age, gender, body mass index, indications for glucocorticoid use, and basal adrenocorticotropic hormone levels were not predictive of HPA axis recovery. On multivariate analysis, ambulatory early morning cortisol was the only independent predictor of adequate SST response (odds ratio, 1.02; 95% confidence interval, 1.01 to 1.04; P = .02). Using receiver operating characteristic curve analysis, ambulatory early morning cortisol of 8.8 μg/dL predicted a positive SST response with a sensitivity of 70% and specificity of 93%. Early morning ambulatory cortisol could be used to decide on timely SST in order to prevent complications from unnecessary replacement with glucocorticoids. ACTH = adrenocorticotropic hormone; BMI = body mass index; CV = coefficient of variation; HPA = hypothalamic-pituitary-adrenal; SST = short Synacthen test.

Basal serum cortisol and adrenocorticotropic hormone levels in patients with atopic dermatitis.

BackgroundCertain studies suggest that percutaneous absorption of topical steroids may cause suppression of hypothalamic–pituitary–adrenal axis (HPAA) in atopic dermatitis (AD) patients. This study aimed to investigate the basal serum cortisol, adrenocorticotropic hormone (ACTH), and IgE levels in patients with AD and their correlation with the disease severity.MethodsLevels of basal serum cortisol, ACTH, and IgE were assessed by ELISA in 31 patients with AD and 31 controls. Clinical severity of AD was evaluated by the scoring of atopic dermatitis (SCORAD) index.ResultsNo statistical difference was observed between the two groups for basal serum cortisol and ACTH levels. The serum IgE level was significantly higher in the AD group. The SCORAD index was correlated with serum IgE level.ConclusionsBasal serum cortisol and ACTH levels are normal in AD patients. Serum IgE level is significantly higher in AD patients and is correlated with the disease severity.

Apparent Hypothalamic-Pituitary-Adrenal Axis Suppression via Reduction of Interleukin-6 by Glucocorticoid Therapy in Systemic Autoimmune Diseases.

ContextSuppression of the hypothalamic-pituitary-adrenal (HPA) axis is a serious complication of systemic glucocorticoid therapy.ObjectiveTo clarify the influence of proinflammatory cytokines on the HPA axis after onset of glucocorticoid therapy in patients with systemic autoimmune diseases.Patients and MethodsForty-eight glucocorticoid-naïve patients with systemic autoimmune diseases (28 women) who were starting prednisolone therapy according to our standard regimens were prospectively observed. Patients were classified into high-dose and low-dose groups depending on the dose of prednisolone administered as indicated for their diseases. Plasma adrenocorticotropic hormone (ACTH) and serum cortisol levels were measured by electrochemiluminescence immunoassay. The corticotropin-releasing hormone (CRH) test was performed at baseline and second and forth weeks after starting glucocorticoid therapy. The increased levels of ACTH (ΔACTH) and cortisol (Δcortisol) were investigated. Serum levels of 10 proinflammatory cytokines were measured simultaneously by a multi-spot assay system.ResultsIn the high-dose group, both basal and stimulated levels of ACTH and cortisol were significantly decreased by glucocorticoid therapy. In the low-dose group, basal ACTH and cortisol levels were also significantly decreased by glucocorticoid therapy, but ΔACTH and Δcortisol were unchanged. Among 10 cytokines, only interleukin (IL)-6 was significantly decreased by glucocorticoid therapy in both groups and was more closely correlated with cortisol than ACTH. Basal cortisol level was positively correlated with serum IL-6 level in all patients before glucocorticoid therapy.ConclusionIn patients with systemic autoimmune diseases, apparent suppression of cortisol during glucocorticoid therapy may be partly mediated by reduced production of IL-6.

Evaluation of Basal Serum Adrenocorticotropic Hormone and Cortisol Levels and Their Relationship with Nonalcoholic Fatty Liver Disease in Male Patients with Idiopathic Hypogonadotropic Hypogonadism.

Background:Prolonged gonadal hormone deficiency in patients with idiopathic hypogonadotropic hypogonadism (IHH) may produce adverse effects on the endocrine homeostasis and metabolism. This study aimed to compare basal serum adrenocorticotropic hormone (ACTH) and cortisol levels between male IHH patients and healthy controls. Moreover, this study compared the basal hypothalamic-pituitary-adrenal (HPA) axis in patients with and without nonalcoholic fatty liver disease (NAFLD), and also evaluated the relationship between basal HPA axis and NAFLD in male IHH patients.Methods:This was a retrospective case-control study involving 75 Chinese male IHH patients (mean age 21.4 ± 3.8 years, range 17–30 years) and 135 healthy controls after matching for gender and age. All subjects underwent physical examination and blood testing for serum testosterone, luteinizing hormone, follicle-stimulating hormone, ACTH, and cortisol and biochemical tests.Results:Higher basal serum ACTH levels (8.25 ± 3.78 pmol/L vs. 6.97 ± 2.81 pmol/L) and lower cortisol levels (366.70 ± 142.48 nmol/L vs. 452.82 ± 141.53 nmol/L) were observed in male IHH patients than healthy subjects (all P <0.05). IHH patients also showed higher metabolism parameters and higher prevalence rate of NAFLD (34.9% vs. 4.4%) than the controls (all P < 0.05). Basal serum ACTH (9.91 ± 4.98 pmol/L vs. 7.60 ± 2.96 pmol/L) and dehydroepiandrosterone sulfate (2123.7 ± 925.8 μg/L vs. 1417.1 ± 498.4 μg/L) levels were significantly higher in IHH patients with NAFLD than those without NAFLD (all P < 0.05). We also found that basal serum ACTH levels were positively correlated with NAFLD (r = 0.289, P <0.05) and triglyceride levels (r = 0.268, P < 0.05) in male IHH patients. Furthermore, NAFLD was independently associated with ACTH levels in male IHH patients by multiple linear regression analysis.Conclusions:The male IHH patients showed higher basal serum ACTH levels and lower cortisol levels than matched healthy controls. NAFLD was an independent associated factor for ACTH levels in male IHH patients. These preliminary findings provided evidence of the relationship between basal serum ACTH and NAFLD in male IHH patients.

Basal Serum Cortisol and Adrenocorticotropic Hormone Levels in Patients with Atopic Dermatitis

Background: Atopic dermatitis (AD) is an inflammatory skin disease with eczematous pruritic lesions. Topical corticosteroids are the most widely used and the mainstay of treatment for AD. There are some studies that percutaneous systemic absorption of topical steroids may occur and lead to suppression of hypothalamic-pituitaryadrenal axis (HPAA). However, almost in all of these studies, “basic” HPAA function (before application of topical steroids) was not evaluated. Aim: The aim of this study was to investigate basal serum cortisol, adrenocorticotropic hormone (ACTH), and IgE levels in patients with AD and their correlation with disease severity. Methods: Levels of basal serum cortisol, ACTH, and IgE were assessed by ELISA in 31 patients with AD and 31 control subjects. Clinical severity of AD was evaluated by the SCORAD (SCORing Atopic Dermatitis) index. Results: Data analysis showed no statistical difference for basal serum cortisol and ACTH levels between two groups. The serum IgE level was significantly higher in AD group (P=0.02). The SCORAD index was correlated with serum IgE level, but not with the basal serum cortisol level and ACTH level. Conclusions: Basal serum cortisol and ACTH levels are normal in AD patients. Serum IgE level is significantly higher in AD patients and correlated with disease severity.

A case of posttraumatic acth deficiency that initial skin finding suggesting cushing syndrome /Baslangic cilt bulgulari cushing sendromunu dusunduren posttravmatik ACTH eksikligi olgusu

Pituitary adrenocorticotropic hormone (ACTH) deficiency is one cause of secondary adrenal insufficiency. Genetic factors, autoimmunity, infiltrative disease, cranial trauma may cause ACTH deficiency. Hyperpigmented skin lesions are expected in primary adrenal insufficiency while they are very rare in secondary adrenal insufficiency. Striae are characterized by linear smooth bands of atrophic appearing skin and pathogenesis is not understood. They are mostly associated with obesity, pregnancy, hypercortisolism. Striae are not an expected finding in hypocortisolemia. We presented a 34-year-old male patient that evaluated for striae on both axillas. He had head trauma and operation 12 years ago. Basal hypophysis hormone levels and dynamic tests were conducted. Basal cortisol and ACTH level were 0,18 ug/dl and

The Recovery of Hypothalamic-Pituitary-Adrenal Axis Is Rapid in Subclinical Cushing Syndrome.

BackgroundIn subclinical Cushing syndrome (SC), it is assumed that glucocorticoid production is insufficient to cause a clinically recognizable syndrome. Differences in hormonal levels or recovery time of the hypothalamic-pituitary-adrenocortical (HPA) axis after adrenalectomy between patients with overt Cushing syndrome (OC) and SC remain unknown.MethodsThirty-six patients (10 with OC and 26 with SC) with adrenal Cushing syndrome who underwent adrenalectomy from 2004 to 2014 were reviewed retrospectively. Patients were treated with glucocorticoid after adrenalectomy and were reevaluated every 1 to 6 months using a rapid adrenocorticotropic hormone (ACTH) stimulation test.ResultsLevels of basal 24-hour urine free cortisol (UFC), serum cortisol after an overnight dexamethasone suppression test (DST), and serum cortisol and 24-hour UFC after low-dose DST and high-dose DST were all significantly lower in patients with SC compared with OC. Basal ACTH levels showed significantly higher in patients with SC compared with OC. The probability of recovering adrenal function during follow-up differed significantly between patients with OC and SC (P=0.001), with significant correlations with the degree of preoperative cortisol excess. Patients with OC required a longer duration of glucocorticoid replacement to recover a normal ACTH stimulation test compared with patients with SC (median 17.0 months vs. 4.0 months, P<0.001).ConclusionThe HPA axis recovery time after adrenalectomy in patients with SC is rapid and is dependent on the degree of cortisol excess. More precise definition of SC is necessary to achieve a better management of patients and to avoid the risk of under- or over-treatment of SC patients.

Adrenocorticotropic hormone (ACTH)-producing pheochromocytoma presented as Cushing syndrome and complicated by invasive aspergillosis

Adrenocorticotropic hormone (ACTH)-producing pheochromocytoma has been rarely reported, whereas only a few cases of Cushing syndrome accompanied by opportunistic infections have been reported. We experienced a patient with pheochromocytoma with ectopic Cushing syndrome complicated by invasive aspergillosis. A 35-year-old woman presented with typical Cushingoid features. Her basal plasma cortisol, ACTH, and 24-hour urine free cortisol levels were significantly high, and 24-hour urine metanephrine and catecholamine levels were slightly elevated. The endogeneous cortisol secretion was not suppressed by either low- or high-dose dexamethasone. Abdominal computed tomography (CT) revealed a heterogeneous enhancing mass measuring approximately 2.5 cm in size in the left adrenal gland. No definitive mass lesion was observed on sellar magnetic resonance imaging. On fluorine-18 fluorodeoxyglucose positron emission tomography/CT, a hypermetabolic nodule was observed in the left upper lung. Thus, we performed a percu- taneous needle biopsy, which revealed inflammation, not malignancy. Thereafter, we performed a laparo- scopic left adrenalectomy, and its pathologic finding was a pheochromocytoma with positive immunohisto- staining for ACTH. After surgery, the biochemistry was normalized, but the clinical course was fatal despite intensive care because of the invasive aspergillosis that included the lungs, retina, and central nervous system.

Acylated ghrelin as provocative test for the diagnosis of ACTH deficiency in patients with hypothalamus-pituitary disease.

The insulin tolerance test (ITT) is the gold standard to evaluate adrenocorticotropic hormone (ACTH) insufficiency. However, alternative tests have been proposed such as metyrapone, glucagon, and ACTH stimulation test. We determined the diagnostic reliability of testing with ghrelin, the natural GH secretagogue that is a potent stimulus exploring the integrity of hypothalamic-pituitary-adrenal axis. We studied the ACTH and cortisol response to acylated ghrelin in 49 patients with history of pituitary disease. The best cortisol and ACTH cut offs to ghrelin test, defined as those with the best sensitivity (SE) and specificity (SP), were identified using the ROC analysis. We also compared accuracy of ghrelin test with that of a simple and cheap test like basal cortisol and ACTH levels. The best cortisol and ACTH cut offs to ghrelin test were ≤11.6 µg/dl (SE 86.4%, SP 77.8%) and ≤32.5 pg/ml (SE 72.7%, SP 51.9%), respectively; the best basal cortisol and ACTH cut offs were ≤10.7 µg/dl (SE 90.9%, SP 70.4%) and ≤25.0 pg/ml (SE 85%, SP 37%), respectively. The diagnostic accuracy was 81.6, 60.9, 79.6, and 57.4%, respectively. A comparison between ROC AUC showed a great diagnostic power for cortisol, both stimulated and basal, versus ACTH, both stimulated and basal, but no difference between stimulated and basal cortisol evaluation. Our data show that testing with acylated ghrelin is not a useful diagnostic tool for the diagnosis of central hypocortisolism; particularly ghrelin test adds no more information that basal cortisol evaluation in the diagnosis of ACTH deficiency in patients with hypothalamus-pituitary disease.

Mu‐opioid receptor A118G polymorphism in healthy volunteers affects hypothalamic–pituitary–adrenal axis adrenocorticotropic hormone stress response to metyrapone

The mu-opioid receptor encoded by the gene OPRM1 plays a primary role in opiate, alcohol, cocaine and nicotine addiction. Studies using opioid antagonists demonstrate that the mu-opioid receptor (MOP-r) also mediates the hypothalamic-pituitary-adrenal (HPA) axis stress response. A common polymorphism in exon one of the MOP-r gene, A118G, has been shown to significantly alter receptor function and MOP-r gene expression; therefore, this variant likely affects HPA-axis responsivity. In the current study, we have investigated whether the presence of the 118AG variant genotype affects HPA axis responsivity to the stressor metyrapone, which transiently blocks glucocorticoid production in the adrenal cortex. Forty-eight normal and healthy volunteers (32 men, 16 women) were studied, among whom nine men and seven women had the 118AG genotype. The 118G allele blunted the adrenocorticotropic hormone (ACTH) response to metyrapone. Although there was no difference in basal levels of ACTH, subjects with the 118AG genotype had a more modest rise and resultant significantly lower ACTH levels than those with the prototype 118AA at the 8-hour time point (P < 0.02). We found no significant difference between genders. These findings suggest a relatively greater tonic inhibition at hypothalamic-pituitary sites through the mu-opioid receptor and relatively less cyclical glucocorticoid inhibition in subjects with the 118G allele.

Genetic variation of TLR4 influences immunoendocrine stress response: an observational study in cardiac surgical patients

IntroductionSystemic inflammation (for example, following surgery) involves Toll-like receptor (TLR) signaling and leads to an endocrine stress response. This study aims to investigate a possible influence of TLR2 and TLR4 single nucleotide polymorphisms (SNPs) on perioperative adrenocorticotropic hormone (ACTH) and cortisol regulation in serum of cardiac surgical patients. To investigate the link to systemic inflammation in this context, we additionally measured 10 different cytokines in the serum.MethodsA total of 338 patients admitted for elective cardiac surgery were included in this prospective observational clinical cohort study. Genomic DNA of patients was screened for TLR2 and TLR4 SNPs. Serum concentrations of ACTH, cortisol, interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α and granulocyte macrophage-colony stimulating factor (GM-CSF) were determined before surgery, immediately post surgery and on the first postoperative day.ResultsThirteen patients were identified as TLR2 SNP carriers, 51 as TLR4 SNP carriers and 274 patients as non-carriers. Basal levels of ACTH, cortisol and cytokines did not differ among groups. In all three groups a significant, transient perioperative rise of cortisol could be observed. However, only in the non-carrier group this was accompanied by a significant ACTH rise. TLR4 SNP carriers had significant lower ACTH levels compared to non-carriers (mean (95% confidence intervals)) non-carriers: 201.9 (187.7 to 216.1) pg/ml; TLR4 SNP carriers: 149.9 (118.4 to 181.5) pg/ml; TLR2 SNP carriers: 176.4 ((110.5 to 242.3) pg/ml). Compared to non-carriers, TLR4 SNP carriers showed significant lower serum IL-8, IL-10 and GM-CSF peaks (mean (95% confidence intervals)): IL-8: non-carriers: 42.6 (36.7 to 48.5) pg/ml, TLR4 SNP carriers: 23.7 (10.7 to 36.8) pg/ml; IL-10: non-carriers: 83.8 (70.3 to 97.4) pg/ml, TLR4 SNP carriers: 54.2 (24.1 to 84.2) pg/ml; GM-CSF: non-carriers: 33.0 (27.8 to 38.3) pg/ml, TLR4 SNP carriers: 20.2 (8.6 to 31.8) pg/ml). No significant changes over time or between the groups were found for the other cytokines.ConclusionsRegulation of the immunoendocrine stress response during systemic inflammation is influenced by the presence of a TLR4 SNP. Cardiac surgical patients carrying this genotype showed decreased serum concentrations of ACTH, IL-8, IL-10 and GM-CSF. This finding might have impact on interpreting previous and designing future trials on diagnosing and modulating immunoendocrine dysregulation (for example, adrenal insufficiency) during systemic inflammation and sepsis.

Expression of pituitary glucocorticoid receptor and 11β-hydroxysteroid dehydrogenase 1 in obese diabetic rats

Diabetic rat model was induced by high fat diet combined with streptozotocin (STZ). After the model was established, blood samples were taken from jugular veins to examine plasma adrenocorticotropic hormone (ACTH) and corticosterone, and hypothalamus and pituitary were removed for real-time PCR. There were no significant differences in basal plasma ACTH and corticosterone level among control, obese, and obese diabetic rats (P=0.07). The corticosterone rhythm in obese and obese diabetic rats was impaired. Hypothalamus glucocorticoid receptors (GR) mRNA expressions yielded similar results in the groups, but 11β-HSD1 mRNA expression in obese diabetic rats was up-regulated ( vs control rats, P<0.05 ). The expressions of GR and 11β-HSD1 in pituitary of obese diabetic and obese rats were significantly down-regulated (both P<0.05). In the obese diabetic rats, the impaired glucocorticoid negative feedback was partly due to down-regulation of 11 β-HSD1 and GR expressions in pituitary. Key words: Diabetes mellitus, type 2; Pituitary; Negative feedback; 11β-hydroxysteroid dehydrogenase type 1; Glucocorticoid receptors

Dopamine-Regulated Adrenocorticotropic Hormone Secretion in Lactating Rats: Functional Plasticity of Melanotropes

Pro-opiomelanocortin (POMC) is processed to adrenocorticotropic hormone (ACTH) and β-lipotropin in corticotropes of the anterior lobe, and to α-melanocyte-stimulating hormone (α-MSH) and β-endorphin in melanotropes of the intermediate lobe (IL) of the pituitary gland. While ACTH secretion is predominantly under the stimulatory influence of the hypothalamic factors, hormone secretion of the IL is tonically inhibited by neuroendocrine dopamine (NEDA) neurons. Lobe-specific POMC processing is not absolute. For example, D₂ type DA receptor (D2R)-deficient mice have elevated plasma ACTH levels, although it is known that corticotropes do not express D2R(s). Moreover, observations that suckling does not influence α-MSH release, while it induces an increase in plasma ACTH is unexplained. The aim of the present study was to investigate the involvement of the NEDA system in the regulation of ACTH secretion and the participation of the IL in ACTH production in lactating rats. Untreated and estradiol (E₂)-substituted ovariectomized (OVX) females were also studied. The concentration of ACTH in the IL was higher in lactating rats than in OVX rats, while the opposite change in α-MSH level of the IL was observed. DA levels in the IL and the neural lobe were lower in lactating rats than in OVX rats. Suckling-induced ACTH response was eliminated by pretreatment with the DA receptor agonist, bromocriptine (BRC). Inhibition of DA biosynthesis by α-methyl-p-tyrosine (αMpT) and blockade of D2R by domperidone (DOM) elevated plasma ACTH levels, but did not influence plasma α-MSH levels in lactating rats. The same drugs had opposite effects in OVX and OVX + E₂ animals. In lactating mothers, BRC was able to block ACTH responses induced by both αMpT and DOM. Surgical denervation of the IL elevated basal plasma levels of ACTH. Taken together, these data indicate that melanotropes synthesize ACTH during lactation and its release from these cells is regulated by NEDA neurons.

Comparisons between Macroadenomas and Microadenomas in Cushing's Disease: Characteristics of Hormone Secretion and Clinical Outcomes

It has been suggested that the patients with Cushing's disease secondary to pituitary macroadenomas (>10 mm) have higher basal adrenocorticotropic hormone (ACTH) levels, which are less suppressible on high-dose dexamethasone suppression tests (HDDST). We compared the clinical and biochemical characteristics of patients with macroadenomas (N=7) and microadenomas (N=23) who were diagnosed at Samsung Medical Center in Korea between 1996 and 2006. Basal morning plasma ACTH levels were 101.5±23.2 pg/mL for macroadenoma patients and 83.6±11.1 pg/mL for microadenoma patients (mean±SEMs) (p=0.44). Morning serum cortisol levels were 26.8±3.2 µg/dL for macroadenoma patients and 29.5±2.9 µg/dL for microadenoma patients (p=0.77). The proportion of patients who showed suppressibility on HDDST was almost identical in the two groups (71.4% [5/7] for macroadenoma patients vs. 72.7% [16/22] for microadenoma patients, p=1.00). Furthermore, the remission rate with trans-sphenoidal surgery was similar between the two groups (100% [5/5] for macroadenoma patients vs. 73.3% [11/15] for microadenoma patients, p=0.53). Thus, tumor size is not a major determinant of hormone secretion or clinical outcomes in patients with Cushing's disease.