Corticotropin-releasing hormone (CRH) is produced and acts both within the central nervous system and at several peripheral sites. However, it is not known whether CRH is able to cross the blood-brain barrier (BBB) in either direction, or whether the central and peripheral compartments are independent. We studied the transport across the BBB of both human/rat CRH (hCRH) and ovine CRH (oCRH) using the native peptides labeled with ¹²⁵I at the histidine residue, thereby avoiding the use of other synthetic modifications. No apparent transport of either hCRH or oCRH into the brain from blood was found, as measured by multiple-time regression analysis after intravenous injection of the labeled peptides. There were no significant differences between the two forms of the CRH peptide. However, both hCRH and oCRH were rapidly transported out of the brain after intracerebroventricular injection, with half-time (t½) disappearances of 11.1 (hCRH) and 15.1 min (oCRH); the transport rate was significantly different for the human and ovine forms. The transport of hCRH could be specifically inhibited by 5 nmol of unlabeled hCRH (t½ = 17.7 min) but not by the same dose of the synthetic analog αCRH_12–41. The process could also be inhibited by pretreatment with aluminum chloride (t½ = 18.8 min). An indirect influence of the endogenous opiate modulating peptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH₂ 5 nmol) was apparent by a change in the initial distribution within the brain. In conclusion, there is a specific unidirectional brain to blood transport system for CRH. This transport system in the mouse has a greater affinity for the human/rat than for the ovine form of the peptide, is inhibited by hCRH itself, and can be disrupted by pretreatment with aluminum. By facilitating the rapid clearance of central CRH, this transport system could be involved in the regulation of central CRH levels and could allow central CRH to reach the general circulation and act at peripheral sites.

The unidirectional brain-to-blood transport system for corticotropin-releasing hormone (CRH) across the blood-brain barrier could be instrumental in the homeostasis of central CRH. To characterize this system, the intracerebroventricular injection of 125I-CRH was used in mice. CRH was rapidly transported out of the brain with a half-time disappearance (t1/2) of 15 min, much faster than albumin (t1/2 = 50 min). Kinetic analysis revealed a saturable component with a low maximum velocity (apaproximately 0.020 nmol x min(-1) x brain(-1)) and low capacity (Michaelis constant approximately 1.4 nmol/brain). Transport was inhibited by verapamil, ouabain, and colchicine but not by cyclosporin. Transport was increased by corticosterone and inhibited by tumor necrosis factor-alpha and beta-endorphin. These results suggest that the specific unidirectional brain-to-blood transport system for CRH is dependent on energy and calcium channels, involves microtubules, is independent of the P-glycoprotein transporter, and is acutely modulated by adrenal steroids, cytokines, and endogenous opiates. This suggests its participation in the control of the stress response.

The blood-brain barrier (BBB) regulates the passage of substances between the brain and the periphery. It has not been shown that the secretion from the brain of a small amount of a substance can directly affect the periphery by transport across the BBB. We found that central injection of radioactively labeled corticotropin-releasing hormone (CRH) resulted in the accumulation of intact CRH in the spleen. CRH also increased splenic β-endorphin, an effect not blocked by pretreatment with dexamethasone. Inhibition of the secretion of CRH from the brain by colchicine resulted in decreased accumulation of CRH in the spleen and also decreased splenic β-endorphin. Similar findings occurred in the pituitary gland. The results show that the passage of labeled CRH from the brain can directly affect a peripheral organ, thus emphasizing the regulatory function of the BBB.

Development of some immune-mediated disorders may depend on dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. To explore neuropsychologic mechanisms in relation to the abnormal endocrine reactivity in patients with systemic lupus erythematosus (SLE) and chronic hepatitis C (CHC) we used the corticotropin releasing hormone (CRH) test, the Minnesota Multiphasic Personality Inventory (MMPI), and the Edinburgh Inventory of Manual Preference Inventory (EIMP). Compared to controls, the adrenocorticotrophic hormone (ACTH) response to CRH was reduced in CHC, while SLE presented reduced baseline dehydroepiandrosterone sulfate levels; higher neurotic scores were found in SLE and higher behavior deviant scores in CHC. Peak ACTH levels were a significant factor for the MMPI profile variability, while the manual preference score was a significant factor for the ACTH response. Personality and manual preference contribute to neuroendocrine abnormalities. Different behavioral and neuroimmunoendocrine models emerge for these disorders.

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulphate (DHEAS) have been reported to have memory enhancement effects in humans. A neuro-stimulatory action and an anti-cortisol mechanism of action may contribute to that relation. In order to study DHEA, DHEAS and cortisol relations to working memory and distraction, we recorded the electroencephalogram of 23 young women performing a discrimination (no working memory load) or 1-back (working memory load) task in an audio-visual oddball paradigm. We measured salivary DHEA, DHEAS and cortisol both before each task and at 30 and 60 min. Under working memory load, a higher baseline cortisol/DHEA ratio was related to higher distraction as indexed by an enhanced novelty P3. This suggests that cortisol may lead to increased distraction whereas DHEA may hinder distraction by leading to less processing of the distractor. An increased DHEA production with consecutive cognitive tasks was found and higher DHEA responses attributed to working memory load were related to enhanced working memory processing as indexed by an enhanced visual P300. Overall, the results suggest that in women DHEA may oppose cortisol effects reducing distraction and that a higher DHEA response may enhance working memory at the electrophysiological level.

AimsTo understand the paradox of an increased fracture risk despite increased bone mineral density (BMD) in persons with type 2 diabetes (DM2).Patients and MethodsWe studied 80 old persons with DM2. Mineral metabolism, parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), bone turnover – osteocalcin, procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) – were measured and BMD was assessed at the lumbar spine (LS) and femoral neck (FN). Data was analyzed with the Statistical Package for the Social Sciences Program.ResultsLow levels of 25OHD (84%) and high values of PTH (20%) were found. Osteocalcin was directly related to CTX, p < 0.001, with increased bone formation and increased BMD (z-score) at LS and FN. PTH was directly related to osteocalcin and CTX and inversely related to BMD at the FN, p < 0.05. Patients with dyslipidemia presented higher P1NP, p < 0.05 and patients with hypertension presented higher BMD at LS and FN, p < 0.01.ConclusionOld type 2 diabetics present increased bone formation, PTH-driven. Low grade secondary hyperparathyroidism may explain the paradox of an increased fracture risk despite increased BMD.

OBJECTIVE: To characterize serum lipid abnormalities in overweight and obese female patients and to quantify the relative importance of associated factors. METHODS: Cross sectional study at the ®rst visit to the out-patient department. 237 consecutive overweight and obese female patients (age 31 AE 14 y, body mass index (BMI) 34.2 AE 6.0 kg/m 2 ) were studied. Evaluation included a questionnaire-based assessment of dietary and physical activity habits, determination of anthropometric indexes (BMI, abdominal/thigh ratio (A/T) and conicity index (CI)) and endocrine evaluation. Statistical analysis by factorial ANOVA and multiple regression. RESULTS: Dyslipidaemia was present in 46% of the patients, with hypercholesterolaemia (35%) being more frequent than hypertriglyceridaemia (10%). Age but not dietary habits or physical activity patterns was signi®cantly related to serum lipid concentrations, independently accounting for 6±10% of their variability. Pharmacological drug use resulted in increased serum triglyceride concentrations, explaining less than 5% of their variability. Serum cholesterol concentrations were not signi®cantly related either to anthropometric or to endocrine indexes. For serum triglyceride concentrations, anthropometric indexes accounted for 6% of their variability and endocrine indexes±postprandial insulin, serum cortisol, testosterone and androstenedione together accounted for 32%. CONCLUSION: In mild to moderate female obesity of the peripheral type, dyslipidaemia is common. However the most common abnormality, hypercholesterolaemia is not signi®cantly related to anthropometric or endocrine indexes, while these together account for more than one third of variability in serum triglyceride concentrations.

OBJECTIVE: To relate psychological pro®les, cerebral asymmetry and the hypothalamus ± pituitary ± adrenal axis (HPA) reactivity to clinical characteristics of common obesity. METHODS: Sixty consecutive adult female overweight and obese patients attending the outpatient endocrine department were included in this study. Clinical evaluation speci®cally selected a priori the following indexes: obesity age of onset, parenthood obesity, carbohydrate craving, binge eating with purging, obesity degree (de®ned by the body mass index (BMI) Ð weight (kg)aheight (m 2 )), body fat distribution (de®ned by the abdominal ± thigh ratio (AaT)) and initial weight loss after medical treatment. Psychological evaluation was performed with the Minnesota Multiphasic Personality Inventory (MMPI). In the last 30 patients, the Edinburgh Inventory of Manual Preference (EIMP) and the corticotrophin-releasing hormone (CRH) test were also performed. RESULTS: Clinical characteristics de®ned a priori were independent variables as evaluated by contingency table analysis. Factorial analysis of variance (ANOVA) revealed a signi®cantly different MMPI pro®le, according to parental obesity, with posthoc signi®cantly higher scores on the hypochondriasis (Hs), paranoia (Pa), psychasthenia (Pt) and schizophrenia (Sc) scales in patients with obese parents. Obese patients presented signi®cantly higher dichotomized manual preference indexes in relation to overweight patients. Parental obesity, binge eating behaviour with purging, body fat distribution and the dichotomized manual preference index were independent signi®cant factors for the ACTH response in the CRH test, together explaining 41% of the response variability. Age of onset of obesity and the dichotomized manual preference index were independent and signi®cant factors for the cortisol response, together explaining 37% of its variability. A non-normal distribution was found for the ACTH response: high-and low-responders presented signi®cantly different MMPI pro®les, with high-responders presenting higher scores on all clinical scales except masculinityafemininity (Mf). CONCLUSION: Overweightaobese subjects with parental obesity present a distinctive personality pro®le and a higher ACTH response in the CRH test. Cerebral asymmetry may be a relevant factor for obesity development and is associated with the HPA reactivity. HPA reactivity is a sensitive index integrating clinical, psychological and neural asymmetric factors. International Journal of Obesity (2001) 25, 24 ± 32