Plasma Adrenocorticotropin Hormone Research Articles

The Melanocortin and Endorphin Neuropeptides in Patients with Restless Legs Syndrome.

Based upon similarities between the urge to move and sensory discomfort of restless legs syndrome (RLS) and properties of melanocortin hormones, including their incitement of movement and hyperalgesia, we assessed plasma and cerebrospinal fluid (CSF) α-melanocyte-stimulating hormone (α-MSH) and β-endorphin in RLS patients and controls. Forty-two untreated moderate-to-severe RLS patients and 44 matched controls underwent venipuncture at 19:00, 20:30, and 22:00; 37 RLS and 36 controls had lumbar puncture at 21:30. CSF and plasma were analyzed for pro-opiomelanocortin (POMC), adrenocorticotropin hormone (ACTH), α-MSH, β-MSH, and β-endorphin by immunoassay. RLS severity was assessed by International RLS Study Group Severity Scale. RLS participants were 52.7 ± 12.0 years old, 61.9% were women, 21.4% had painful RLS, and RLS severity was 24.8 ± 9.0. Controls had similar age and sex. Plasma ACTH, α-MSH, and β-endorphin were similar between groups. Plasma POMC was significantly greater in RLS than controls (17.0 ± 11.5 vs 12.7 ± 6.1fmol/ml, p = 0.048). CSF ACTH was similar between groups. CSF β-MSH was significantly higher in painful than nonpainful RLS or controls (48.2 ± 24.8 vs 32.1 ± 14.8 vs 32.6 ± 15.2pg/ml, analysis of variance [ANOVA] p = 0.03). CSF α-MSH was higher in RLS than controls (34.2 ± 40.9 vs 20.3 ± 11.0pg/ml, p = 0.062). CSF β-EDP was lowest in painful RLS, intermediate in nonpainful RLS, and highest in controls (8.0 ± 3.4 vs 10.8 ± 3.1 vs 12.3 ± 5.0pg/ml, ANOVA p = 0.049). The ratio of the sum of CSF α- and β-MSH to CSF β-endorphin was highest, intermediate, and lowest in painful RLS, nonpainful RLS, and controls (p = 0.007). CSF β-MSH is increased and CSF β-endorphin decreased in RLS patients with painful symptoms. ANN NEUROL 2024;95:688-699.

Autoimmune Primary Adrenal Insufficiency in Children

Objective:Primary adrenal insufficiency (PAI) is a rare condition in children, and is potentially life-threatening. The most common cause is congenital adrenal hyperplasia, and autoimmune etiology is the most frequent acquired cause in this age group. Symptoms are usually non-specific and, when suspected, investigation should include adrenocorticotropin hormone (ACTH) and morning serum cortisol measurement and, in some cases, a cosyntropin test to confirm the diagnosis. Prompt treatment is essential to prevent an adverse outcome.Methods:We retrospectively collected clinical and laboratory data from adrenal insufficiency due to autoimmune adrenalitis, observed from 2015 to 2020 in a pediatric endocrinology department of a tertiary care hospital.Results:Eight patients were identified, seven males and one female, with age at diagnosis between 14 and 17 years. The symptoms at presentation ranged from non-specific symptoms, such as chronic fatigue and weight loss, to a severe presentation, with altered mental status and seizures. The median duration of symptoms was 4.5 months. The diagnosis was confirmed by serum cortisol and plasma ACTH measurement and all were confirmed to have autoimmune etiology (positive anti-adrenal antibodies). At diagnosis, the most common laboratory abnormality was hyponatremia. All patients were treated with hydrocortisone and fludrocortisone. One patient presented with evidence of type 2 autoimmune polyglandular syndrome.Conclusion:PAI is a rare condition in the pediatric age group. Due to non-specific symptoms, a high index of suspicion is necessary to establish a prompt diagnosis. Once an autoimmune etiology is confirmed, it is important to initiate the appropriate treatment and search for signs and symptoms of other autoimmune diseases during follow-up.

Alcohol Use Disorder Masks the Effects of Childhood Adversity, Lifetime Trauma, and Chronic Stress on Hypothalamic-Pituitary-Adrenal Axis Reactivity.

Individuals with alcohol use disorder (AUD) and those who have experienced traumas or chronic stress exhibit dysregulated hypothalamic-pituitary-adrenal (HPA) axis reactivity. Whether and how trauma and stress histories interact with AUD to affect HPA axis reactivity has not been assessed. In the present study, 26 healthy male controls and 70 abstinent men with AUD were administered a pharmacologic probe [ovine corticotropin-releasing hormone (oCRH)] and psychosocial stressor to assess HPA axis reactivity. Plasma adrenocorticotropin hormone (ACTH) and cortisol were assessed every 10-20minutes. Hierarchical clustering of multiple measures of trauma and stress identified 3 distinct clusters: childhood adversity, lifetime trauma, and chronic stress. General linear model procedures were used to examine main effects of group (AUD/control) and interaction effects of the 3 clusters upon net-integrated ACTH and cortisol response. We found that higher levels of childhood adversity, lifetime trauma, and chronic stress were each associated with blunted oCRH-induced ACTH reactivity in controls, but not in the AUD group. Recent chronic stress within the prior 6months had the strongest influence upon ACTH reactivity in the control group, and lifetime trauma, the least. Childhood adversity, lifetime trauma, and chronic stress likely exert persistent, measurable effects upon HPA axis functioning in healthy controls. This association appears to be masked in individuals with AUD, potentially confounding studies examining the effects of stress, adversity, and/or trauma upon the HPA axis in this population during the protracted withdrawal phase of recovery. Future work targeting stress exposure and reactivity should consider the heightened effect of previous alcohol use relative to past adversity and trauma.

An unusual case of ectopic corticotrophin-releasing hormone syndrome caused by an adrenal noncatecholamine-secreting pheochromocytoma: a case report

BackgroundPheochromocytoma, especially for noncatecholamine-secreting pheochromocytoma, is an extremely rare cause of ectopic corticotrophin-releasing hormone (CRH) syndrome.Case presentationA 27-year-old Chinese woman was administered dexamethasone for a skin allergy, but her general condition rapidly deteriorated over a month. She was subsequently hospitalized for typical clinical features of Cushing’s syndrome. Endocrinological investigation confirmed severe hypercortisolism along with elevated plasma adrenocorticotropin hormone (ACTH). However, magnetic resonance imaging (MRI) revealed no pituitary adenoma. Abdominal contrast-enhanced computed tomography (CT) revealed a 6.5 cm heterogeneous right adrenal mass with mildly contrast enhancement. The tumor was found during a routine physical check-up at a local hospital 16 months ago; however, the patient did not have any symptoms and did not seek further medical attention at that time. Laparoscopic resection of the right adrenal tumor led to a rapid remission of Cushing’s syndrome. Based on pathological findings and the presence of normal catecholamine metabolites in her serum and urine, the patient was diagnosed with noncatecholamine-secreting pheochromocytoma. Immunohistochemical staining of the adrenal tumor revealed positive staining for CRH and negative staining for ACTH.ConclusionsThis is an extremely rare case of ectopic CRH syndrome caused by an adrenal noncatecholamine-secreting pheochromocytoma. Both ectopic ACTH syndrome and ectopic CRH syndrome should be considered in patients presenting with ACTH-dependent Cushing’s syndrome caused by extrapituitary diseases.

Abstract 2810: Pterostilbene, a natural phytoalexin, weakens the antioxidant defenses of aggressive cancer cells in vivo: a pituitary gland- and Nrf2-dependent mechanism

Abstract Polyphenolic phytochemicals have anticancer properties. However, in mechanistic studies lack of correlation to the bioavailable concentrations is a critical issue. We studied the underlying mechanisms using different human melanomas (A2058, MeWo and MelJuso) and pancreatic cancers (AsPC-1 and BxPC-3) (with genetic backgrounds correlating with most tumors in patients), growing in nude mice as xenografts, and pterostilbene (Pter, 3’,5’-dimethoxy-4-stilbenol; abundant in e.g. blueberries and a natural dimethoxylated analog of resveratrol). RESULTS: Intravenous administration of Pter decreased human melanoma and pancreatic cancer growth (an effect associated with lower rates of tumor cell proliferation and increased apoptosis) in vivo. However Pter, at levels measured within the tumors, did not affect cancer growth or viability in vitro. Pter inhibited pituitary production of the adrenocorticotropin hormone (ACTH), decreased plasma levels of corticosterone and, thereby, down regulated the glucocorticoid receptor- and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent antioxidant defense system in growing cancers (i.e. the glutathione and thioredoxin systems, superoxide dismutases, catalase, and NADPH supplying dehydrogenases). Exogenous corticosterone or genetically-induced Nrf2 overexpression in the cancer cells prevented the inhibition of tumor growth and antioxidant defenses in these malignant cells. Glutathione depletion (selected as a potential anti-cancer strategy) facilitated the complete elimination by chemotherapy of cancer cells isolated from mice treated with Pter. CONCLUSIONS: This report shows a novel link between a neuroendocrine system- and stress response-dependent mechanism and the regulation of cancer growth in vivo. Natural polyphenols can interfere with the growth and defense of cancer cells by down-regulating the pituitary gland-dependent ACTH synthesis. Lower levels of plasma ACTH cause a decrease in the suprarenal glands-dependent glucocorticoid production, thus decreasing the glucocorticoid receptor and Nrf2-dependent signaling/transcription and the antioxidant protection of melanoma and pancreatic cancer cells. Hence facilitating identification of molecular targets to sensitize aggressive cancers to oncotherapy. Citation Format: Maria Benlloch, Soraya L. Valles, Maria L. Rodriguez, J. Antoni Sirerol, Javier Alcacer, Jose Pellicer, Rosario Salvador, Concha Cerda, Guillermo T. Saez, Jose M. Estrela. Pterostilbene, a natural phytoalexin, weakens the antioxidant defenses of aggressive cancer cells in vivo: a pituitary gland- and Nrf2-dependent mechanism. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2810.

Cushing syndrome.

Cushing syndrome.

Paradoxical Results after Inadvertent Use of Cosyntropin [Adrenocorticotropin Hormone (1-24)] Rather than Acthrel (Ovine Corticotropin Releasing Hormone) during Inferior Petrosal Sinus Sampling

The use of ovine corticotropin releasing hormone (oCRH) maximizes the diagnostic accuracy of inferior petrosal sinus sampling (IPSS) in patients with adrenocorticotropin hormone (ACTH)-dependent Cushing's syndrome (CS). oCRH is marketed as ACTHrel and, understandably, may be confused with cosyntropin [ACTH (1-24)]. The inadvertent substitution of synthetic ACTH(1-24) for oCRH (ACTHrel) during IPSS may cause unexpected and misleading results. The aim of this report is to raise awareness of the potential confounding results created when synthetic ACTH(1-24) is mistakenly used during IPSS. We present 3 patients treated at 3 different centers with ACTH-dependent CS in whom ACTH(1-24) was mistakenly substituted for oCRH (ACTHrel) during IPSS. In all patients, there was an abrupt and unexpected decrease in plasma ACTH in the inferior petrosal sinus (IPS) samples after presumptive stimulation with oCRH. Re-evaluation of the patients' pharmacy records confirmed that synthetic ACTH(1-24) had been used rather than oCRH during each procedure. Because "sandwich" immunometric assays for ACTH measure the entire pool of endogenous ACTH, the administration of synthetic ACTH(1-24) artifactually decreases the endogenous plasma ACTH(1-39) measurement by binding only to the N-terminal antibody raised against ACTH(1-17) and not to the C-terminal antibody raised against ACTH(34-39). This results in a lack of a detectable sandwich complex and explains the apparent reduction in ACTH concentration. An abrupt decrease in ACTH during IPSS suggests that synthetic ACTH(1-24) rather than oCRH (ACTHrel) has been administered. The labeling of oCRH as ACTHrel poses a potential patient safety problem about which endocrinologists, interventional radiologists, and pharmacists should be aware.

Effects of resistance exercise on the HPA axis response to psychological stress during short-term smoking abstinence in men

PurposeThe purpose of this study was to examine the effects of resistance exercise on the hypothalamic–pituitary–adrenal axis (HPA) response to mental challenge, withdrawal symptoms, urge to smoke, and cognitive stress during 24-hour smoking abstinence. Methods8 sedentary smokers (mean±SD age: 20.1±1.7y; height: 171.6±10.8cm; body mass: 70.4±12.0kg; smoking history: 2.9±0.8y) completed a 24-hour ad libitum smoking trial (SMO) followed by two 24-hour smoking abstinence trials. During abstinence trials, participants performed six whole body resistance exercises (EX) or a control condition (CON) in the morning, followed by mental challenge tasks in the afternoon. Plasma adrenocorticotropin hormone (ACTH), and salivary and serum cortisol were measured during each visit at rest (REST), and then before (PRE-EX), immediately after (IP-EX), and 30min after exercise (30-EX); and before (PRE-MC), immediately after (IP-MC), and 30min after mental challenge (30-MC). ResultsResistance exercise significantly (p≤0.05) elevated plasma ACTH and serum cortisol at IP-EX during EX compared with SMO and CON trials. Resting ACTH, salivary and serum cortisol concentrations at Pre-MC did not differ between EX and CON trials. The HPA axis response to mental challenge was similar after EX and CON trials. Finally, resistance exercise did not reduce withdrawal symptoms, urge to smoke, or stress. ConclusionResistance exercise did not substantially alter resting HPA hormones or the HPA response to mental challenge tasks during 24h of smoking abstinence.

Adrenal reserve function after unilateral adrenalectomy in patients with primary aldosteronism

After unilateral adrenalectomy (uADX) in patients with a unilateral aldosterone-producing adenoma (APA), the remaining contralateral adrenal gland is generally considered sufficient to support life. However, few studies have compared adrenal reserve function before and after uADX. Therefore, we closely evaluated adrenal cortisol secretory function before and after uADX in patients with unilateral APA. Patients who were diagnosed with APA and underwent uADX for unilateral APA were initially included in this study. Patients with subclinical Cushing's syndrome (SCS) or Cushing's syndrome were excluded on suspicion of autonomous cortisol secretion. Fourteen patients were finally evaluated. Morning basal serum cortisol and plasma adrenocorticotropin hormone (ACTH) levels were measured, and ACTH stimulation tests under 1-mg dexamethasone suppression (dex-ACTH test) were performed before and after uADX. No patient developed clinical adrenal insufficiency. Basal cortisol levels were not significantly different before and after uADX. However, basal ACTH levels were significantly elevated after uADX. In addition, peak cortisol levels on the dex-ACTH test decreased in all patients after uADX. The peak cortisol level after uADX was 86.6 (81.4-92.4)% of the level before uADX. The adrenal cortisol secretory response to ACTH stimulation is mildly reduced after uADX in patients with unilateral APA without SCS or Cushing's syndrome, although their basal cortisol level is sustained by elevated ACTH. These data will be important as a point of discussion when patients with unilateral APA consider either uADX or specific pharmacotherapy as treatment options.

Cortisol: ACTH ratio to test for primary hypoadrenalism: a pilot study

IntroductionA standard short Synacthen test (SST) is the conventional diagnostic test for primary hypoadrenalism. Measuring simultaneous plasma cortisol and adrenocorticotrophin hormone (ACTH) and using the cortisol: ACTH ratio as a...

Involvement of melanocortin receptor accessory proteins (MRAPs) in the function of melanocortin receptors

The melanocortin system integrates different agonists, competitive or inverse agonists, and receptors. Recent investigations have also discovered a specific system of melanocortin receptor accessory proteins (MRAPs) that are involved in the regulation of the functional expression of these receptors. MRAP1 mutations are responsible for type 2 familial glucocorticoid deficiency (FGD2), a rare autosomal disorder characterized by high plasma adrenocorticotropin hormone (ACTH) levels but severe cortisol deficiency. ACTH binds melanocortin 2 receptor (MC2R), a G protein-coupled receptor, in the adrenal gland to promote corticosteroid synthesis. In the absence of MRAP1, MC2R cannot translocate from the endoplasmic reticulum to the plasma membrane and ACTH-induced signaling is extinguished. A second MRAP protein, called MRAP2, also modulates MC2R activity. MRAPs also interact with the other melanocortin receptors, adjusting their pharmacological properties. In this paper, we briefly review the MRAP system and its interaction with melanocortin receptors.

Blunted salivary and plasma cortisol response in patients with panic disorder under psychosocial stress

BackgroundPanic disorder (PD) has been associated with an altered activity of the hypothalamic–pituitary–adrenal–cortical (HPA) axis. Recent findings from a patient sample with PD with secondary depression on psychotropic medication using salivary cortisol as outcome measure suggest a non-responsiveness of the HPA-axis under acute psychosocial stress. Salivary cortisol does not necessarily reflect the total plasma cortisol due to interfering variables. Whether the present findings can be replicated on a patient sample with pure PD using both salivary cortisol and total plasma cortisol as outcome variables remains to be elucidated. MethodsFor this study, the Trier Social Stress Test (TSST) was implemented to assess the HPA-axis reactivity indicated by the plasma adreno-corticotropin-hormone (ACTH), plasma cortisol, and salivary cortisol release. The sample included 32 patients diagnosed with PD in a Structured Clinical Interview (SCID). Twelve male and fifteen female patients [mean age=32.87years, SD=11.23] were matched with 32 healthy controls by age and gender. ResultsThe plasma ACTH, total plasma cortisol and salivary cortisol release increased significantly in both groups due to the psychosocial stress test. The patients with PD showed a decreased plasma and salivary cortisol response as compared to the healthy controls. Plasma cortisol and salivary cortisol were highly correlated in both groups. ConclusionThese findings provide strong evidence for a hypo-responsiveness of the HPA-axis as measured in both blood and saliva. Salivary and total plasma cortisol showed a strong concordance of results. Thus, future investigations could consider salivary cortisol as reliable marker of the HPA-axis under psychosocial stress.

Acute adrenal insufficiency due to primary antiphospholipid antibody syndrome

Introduction:We report a case of acute adrenal insufficiency (AAI) in a patient with antiphospholipid syndrome (APS).Case Report:A 44-year-old female patient presented to us with acute abdominal pain associated with recurrent vomiting and giddiness. On examination, her blood pressure was 80/50 mm Hg. Systemic examination was normal. Further evaluation revealed hypocortisolemia with elevated plasma adrenocorticotropin hormone indicative of primary adrenal insufficiency. Her abdominal computed tomography scan showed features of evolving bilateral adrenal infarction. Etiological work-up revealed prolonged activated thromboplastin time, which didn’t correct with normal plasma, her anti-cardiolipin antibody and lupus anticoagulant were also positive. She was diagnosed to have APS with adrenal insufficiency and she was started on intravenous steroids and heparin infusion.Conclusion:AAI due to the APS can present with acute abdominal pain followed by hypotension. A high index of suspicion is needed to make the correct diagnosis and to initiate appropriate treatment.

Antifungal azoles - new antidote for chronic pelvic pain?

0.88–1.79); voiding: 0.59 (95% CI: 0.33–0.84); quality of life: 0.95 (95% CI: 0.62–1.27). There was no evidence of a changing placebo effect over time [2]. For this reason, only placebo–controlled trials may prove efficacy of a specific treatment in CP/CPPS. Chronic pain conditions coexist with increased anxiety, perceived stress, and a higher profile of global distress when compared to asymptomatic controls. Both these disturbances and chronic central sensitization by nociceptive stimuli affect hypothalamic– pituitary–adrenal (HPA) axis, causing a decrease of plasma adrenocorticotropin hormone and blunting its stress response curve. In patients with CP/CPPS, cortisol levels remain intact under stress conditions but the slope of the awakening cortisol is steeper [3]. Both ketoconazole and, to the lesser extent, fluconazole also influence this hormonal axis by in hibiting synthesis of cortisol and other steroids [4]. Hormonal effects of azoles may modulate HPA axis reversing the vicious circle of pain, stress, and hormonal dysregulation. Two drugs affecting hormonal milieu of the prostate, finasteride and mepartricin, have been proven to improve symptoms in CP/CPPS patients. Azoles may be a new hormonally–active group of agents used in this indication. The most recent possible explanation of fluconazole efficacy in CP/CPPS comes from the Texas Health Science Center whose researchers have reported on potential analgesic effects of ketoconazole [5].This drug has been used in their experiment as a broad– spectrum cytochrome P450 (CYP) inhibitor. CYP is involved in oxidation of linoleic acid into its metabolites (OLAMs) and OLAMs are agonists of the TRPV1 ion channel involved in transmitting pain signals from inflammation or injury involving tissue. In this study it has also been found that ketoconazole possesses an unexpected antihyperalgesic effect. Treatment with ketoconazole inhibited a release of endogenous TRPV1 agonists from the inflamed tissue. However, since ketoconazole inhibits multiple oxidative enzymes including CYPs, the biochemical mechanism of action requires further evaluation. Fluconazole

Recurrent Acute-Onset Cushing’s Syndrome 6 Years after Removal of a Thymic Neuroendocrine Carcinoma: From Ectopic ACTH to CRH

We describe a rare case of ectopic Cushing's syndrome that recurred 6 years after resection of a thymic neuroendocrine carcinoma. We discuss reasons for the differing clinical presentations, management, hormone profiles, as well as immunopathology. A 41-year-old male developed acute-onset Cushing's syndrome. Clinical presentation and laboratory results were compatible with ectopic adrenocorticotropin hormone (ACTH) production. Computerized tomography (CT) showed a 3.6 cm thymic tumor which was successfully resected. Plasma ACTH (P-ACTH) normalized the first postoperative day. Histopathology demonstrated a well-differentiated neuroendocrine carcinoma with diffuse positivity for ACTH and focal corticotropin-releasing hormone (CRH) reactivity in a few scattered cells. The patient was in remission for 6 years. He then again presented with acute-onset Cushing's syndrome. Fluorine-labeled dihydroxyphenylalanine ((18)F-DOPA) PET/CT showed local uptake in the mediastinum and he underwent repeat resection. However, P-ACTH remained increased (613 ng/l) and 24-h urinary cortisol was 36,720 nmol, suggesting incomplete tumor removal or metastatic spread. Metyrapone treatment was initiated but then withdrawn because the patient spontaneously recovered and cortisol metabolism gradually normalized within 3 weeks. Histopathology demonstrated a recurrent neuroendocrine carcinoma with the same features as the previous lesion but this time CRH was strongly positive in more numerous cells. Normalization of P-ACTH after primary surgery was compatible with ectopic ACTH production. However, the delayed fall in P-ACTH and serum cortisol is compatible with ectopic CRH production and stimulation of pituitary ACTH secretion, which gradually resolved. Although ectopic CRH production is very rare, the unusual dynamics illustrated here should raise the possibility of CRH production by a neuroendocrine tumor.

The effects of palm vitamin E on stress hormone levels and gastric lesions in stress-induced rats

IntroductionThis study examines the effects of palm vitamin E (PVE) or α-tocopherol (α-TF) supplementation on adrenocorticotropin hormone (ACTH), corticosterone and gastric lesions in rats exposed to water-immersion restraint stress (WIRS).Material and methodsSixty male Sprague-Dawley rats (200-250 g) were divided into three groups. Group I: 20 rats as a control group were given a normal diet. Group II: 20 rats received oral supplementation of PVE at 60 mg/kg body weight. Group III: 20 rats received oral supplementation of α-TF at 60 mg/kg body weight. After the treatment period of 28 days, each group was further subdivided into two groups: 10 rats not exposed to stress, and the other 10 rats subjected to WIRS for 3.5 h. Blood samples were taken to measure the ACTH and corticosterone levels. The rats were then sacrificed and the stomach excised and opened along the greater curvature and examined for lesions.ResultsRats exposed to WIRS had lesions in their stomach mucosa. Our findings showed that dietary supplementation of PVE or α-TF was able to reduce gastric lesions significantly in comparison to the stressed controls. The WIRS increased plasma ACTH and corticosterone significantly. Palm vitamin E and α-TF treatments reduced these parameters significantly compared to the stressed controls.ConclusionsSupplementation with either PVE or α-TF reduces the formation of gastric lesions, probably by inhibiting the elevation of ACTH and corticosterone levels induced by stress.

Dysfunction of the Hypothalamic-Pituitary-Adrenal axis in STX1A Knockout Mice

HPC-1/syntaxin1A (STX1A) is considered to regulate exocytosis in neurones and endocrine cells. Previously, we reported that STX1A null mutant (STX1A KO) mice unexpectedly showed normal glutamatergic and GABAergic fast synaptic transmission but exhibited disturbances in monoaminergic transmission, such as serotonin, 5-hydroxytryptamine (5-HT), which may induce attenuation of latent inhibition. These results suggest that STX1A may contribute to dense-core vesicle exocytosis in vivo. Thus, we hypothesised that the lack of STX1A might affect the secretion of several hormones, as also mediated by dense-core vesicles exocytosis. In the present study, we focused on the hypothalamic-pituitary-adrenal (HPA) axis, which is a neuroendocrine system that regulates responses to stress stimuli and is considered to be associated with neuropsychiatric disorders. Specifically, we examined whether the HPA axis is impaired in STX1A KO mice. Interestingly, plasma concentrations of both corticosterone (CORT) and adrenocorticotrophin hormone (ACTH) during the resting condition decreased in STX1A KO mice compared to WT mice. Additionally, elevated plasma CORT, ACTH and corticotrophin-releasing hormone (CRH) which were usually observed after acute restraint stress, were also reduced in STX1A KO mice. We also observed the suppression of 5-HT-induced CRH release in STX1A KO mice in vitro. Furthermore, an in vivo microdialysis study revealed that the elevation of extracellular 5-HT in the hypothalamus, which was induced by the selective serotonin reuptake inhibitor, fluoxetine, was significantly reduced in STX1A KO mice compared to WT mice. 5-HT elevation in the hypothalamus, which was induced by acute restraint stress, was also reduced in STX1A KO mice. Finally, STX1A KO mice showed abnormal behavioural responses after mild restraint stress. These results indicate that the lack of STX1A could induce dysfunction of the HPA axis, and the deficit may result in abnormal behavioural properties, such as unusual responses to stress stimuli.

Increased morning adrenocorticotrophin hormone (ACTH) levels in women with postpartum thoughts of harming the infant

Some postpartum women experience intrusive thoughts of harming the infant. The hypothalamic-pituitary-adrenal (HPA) axis, which has been linked to postpartum depression, may play a role in the aetiology of postpartum thoughts of harming the infant. We aimed to study whether HPA axis hormones measured early postpartum are related to postpartum intrusive thoughts. 132 women who delivered a child at a university hospital participated in a follow-up study with visits at 2-3 days postpartum and 8th week postpartum. Participants were assessed for trait anxiety, social support, peripartum or postpartum anxiety or depression, stressful life events and obstetric variables including perinatal complications and lactation. Postpartum thoughts of harming the infant were assessed with a semi-structured interview. Serum cortisol, and plasma CRH and ACTH levels were measured within 48 h postpartum at 8-9 AM. A logistic regression was performed to explore the relationship between clinical variables, hormonal measures and postpartum intrusive thoughts. Patients with postpartum thoughts of harming the infant had, when compared to those women without intrusive thoughts, higher ACTH levels (7.59 pmol/L vs 5.09 pmol/L, p<0.05) without significant differences in CRH or cortisol levels. In the logistic regression analysis, adjusted for breast-feeding and psychopathological status, only ln ACTH was associated with the presence of postpartum thoughts of harming the infant (OR=5.2, CI 95% 1.2-22.6, p=0.029). No other clinical variables were associated with postpartum intrusive thoughts. Our study suggests that a dysregulation of the hypothalamic-pituitary-adrenal axis may play a role in the aetiology of postpartum thoughts of harming the infant.

Cadmium chronotoxicity at pituitary level: effects on plasma ACTH, GH, and TSH daily pattern

Cadmium is an endocrine disruptor that has been shown to induce chronotoxic effects. The present study was designed to evaluate the possible cadmium effects on the daily secretory pattern of adrenocorticotropin hormone (ACTH), growth hormone (GH), and thyroid-stimulating hormone (TSH) in adult male Sprague-Dawley rats. For this purpose, animals were treated with cadmium at two different doses [25 and 50 mg/l cadmium chloride (CdCl(2))] in the drinking water for 30 days. Control age-matched rats received cadmium-free water. After the treatment, rats were killed at six different time intervals throughout a 24-h cycle. Cadmium exposure modified the 24-h pattern of plasma ACTH and GH levels, as the peak of ACTH content between 12:00 and 16:00 h in controls appeared at 12:00 h in the group treated with the lowest dose used, while it appeared between 16:00 and 20:00 h in rats exposed to 50 mg/l CdCl(2). In addition, the peak of GH content found at 04:00 h in controls moved to 16:00 h in rats exposed to 25 mg/l CdCl(2), and the highest dose used abolished 24-h changes of GH secretion. The metal treatment did not modify ACTH secretory pattern. Exposure to cadmium also increased ACTH and TSH medium levels around the clock with both doses used. These results suggest that cadmium modifies ACTH and TSH medium levels around the clock, as well as disrupted ACTH and GH secretory pattern, thus confirming the metal chronotoxicity at pituitary level.

Adiponectin Modulates Excitability of Rat Paraventricular Nucleus Neurons by Differential Modulation of Potassium Currents

The adipocyte-derived hormone adiponectin acts at two seven-transmembrane domain receptors, adiponectin receptor 1 and adiponectin receptor 2, present in the paraventricular nucleus of the hypothalamus to regulate neuronal excitability and endocrine function. Adiponectin depolarizes rat parvocellular preautonomic neurons that secrete either thyrotropin releasing hormone or oxytocin and parvocellular neuroendocrine corticotropin releasing hormone neurons, leading to an increase in plasma adrenocorticotropin hormone concentrations while also hyperpolarizing a subgroup of neurons. In the present study, we investigate the ionic mechanisms responsible for these changes in excitability in parvocellular paraventricular nucleus neurons. Patch clamp recordings of currents elicited from slow voltage ramps and voltage steps indicate that adiponectin inhibits noninactivating delayed rectifier potassium current (I(K)) in a majority of neurons. This inhibition produced a broadening of the action potential in cells that depolarized in the presence of adiponectin. The depolarizing effects of adiponectin were abolished in cells pretreated with tetraethyl ammonium (0/15 cells depolarize). Slow voltage ramps performed during adiponectin-induced hyperpolarization indicate the activation of voltage-independent potassium current. These hyperpolarizing responses were abolished in the presence of glibenclamide [an ATP-sensitive potassium (K(ATP)) channel blocker] (0/12 cells hyperpolarize). The results presented in this study suggest that adiponectin controls neuronal excitability through the modulation of different potassium conductances, effects which contribute to changes in excitability and action potential profiles responsible for peptidergic release into the circulation.