Edward Ram

Effects of early-life stress on behavior and neurosteroid levels in the rat hypothalamus and entorhinal cortex.

Recent evidence support the hypothesis that exposure to stress or trauma during early childhood may disturb the formation of functional brain pathways, in particular, of the limbic circuits. We examined the effects of exposure to early life trauma (juvenile stress) on emotional and cognitive aspects of behavior in adulthood as well as on dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) levels in relevant brain regions. Quantitative assessment of the effects of exposure to juvenile stress was made 1 month post-stress, and obtained by measuring: emotional (utilizing an open field and a startle response tests) and cognitive (Morris water-maze task) functions, as well as neurosteroids concentration (DHEA and its sulfate ester, DHEAS) in the hypothalamus and entorhinal cortex. We report here that an exposure to juvenile stress led to elevated levels of anxiety 1 month post-stress. Moreover, in a spatial learning task, the juvenile stress group performed poorer than the control group. Finally, an exposure to juvenile stress increased DHEAS but not DHEA concentrations both in the hypothalamus and the entorhinal cortex. These findings indicate that an exposure to juvenile stress has long-lasting effects on behavior and DHEAS levels in the hypothalamus and the entorhinal cortex. These effects may be of relevance to our understanding of early life stress-related disorders such as PTSD and major depression.

Alterations in DHEA metabolism in schizophrenia: Two-month case-control study

OBJECTIVE The goals of this study were to determine whether alterations in serum dehydroepiandrosterone (DHEA), its sulfated conjugate (DHEAS), androstenedione, testosterone, and progesterone concentrations occur in schizophrenia patients compared with healthy controls over two months, and their associations with psychopathology, emotional distress, and antipsychotic treatment. METHOD Serum hormones were repeatedly determined for 21 antipsychotic-treated male DSM-IV schizophrenia patients and 14 healthy controls. Observations were at four time points: upon entry into the study, and after 2, 4 and 8 weeks. RESULTS In schizophrenia patients compared with healthy controls serum concentration of DHEA and androstenedione found increased, but that of DHEAS decreased, while progesterone and testosterone showed normal levels. Schizophrenia patients were also characterized by elevated androstenedione/DHEAS molar ratios, and reduced DHEAS/DHEA and testosterone/androstenedione molar ratios compared with healthy controls. Concentrations and molar ratios of serum hormones did not significantly change during the study either among schizophrenia patients, or healthy controls. Among patients alterations in DHEA, DHEAS and androstenedione were associated with emotional distress, anxiety, dysphoric mood, positive and activation symptoms, serum prolactin levels, but were not related to age, antipsychotic agents, and extrapyramidal side effects. CONCLUSIONS Alterations in DHEA metabolism in schizophrenia are attributed to the distress, anxiety, severity of symptoms, prolactin levels, and may represent a marker for impaired hormonal responses to stress. These findings should be considered when evaluating the discrepancies in DHEA studies in schizophrenia.

Cortisol/Dehydroepiandrosterone Ratio and Responses to Antipsychotic Treatment in Schizophrenia

Dehydroepiandrosterone (DHEA) or their sulfate conjugate (DHEAS) (together abbreviated DHEA(S)) exert multiple effects in the central nervous system, and may be involved in the pathophysiological processes in schizophrenia. This prospective study aimed to investigate whether serum cortisol/DHEA(S) molar ratios are associated with response to antipsychotic treatment during the exacerbation of schizophrenia. Serum DHEA(S) and cortisol were determined at baseline, and 2 and 4 weeks later for 43 medicated schizophrenia inpatients with acute exacerbation. The patients were treated with stable doses of antipsychotic agents up to 2 weeks prior to entering the study and for the 4-week duration of the study after which they were classified as either responders or nonresponders to treatment. Findings suggest that responders had significantly higher serum cortisol levels and cortisol/DHEA(S) ratios compared with nonresponders. These differences remained significant at three time points controlling for gender, age, severity of symptoms and emotional distress, benzodiazepines, type or dosage of antipsychotic agents, and background variables. The logistic regression model shows advantages of both cortisol/DHEA(S) molar ratios vs serum cortisol and DHEA(S) concentrations for prediction of responsivity to antipsychotic treatment. No significant canonical correlations were observed between changes from baseline through end-of-study in hormonal values and severity of symptoms and emotional distress among responders and nonresponders. Thus, these data provide evidence that elevated serum cortisol and cortisol/DHEA(S) ratios may serve as markers of biological mechanisms that are involved in responsivity of schizophrenia patients to antipsychotic treatment.

Internal Anal Sphincter Function Following Lateral Internal Sphincterotomy for Anal Fissure: A Long-term Manometric Study

Background:Anal fissure is a common and painful disorder. Its relation to hypertonic anal sphincter is controversial. The most common surgical treatment of chronic anal fissure is lateral internal sphincterotomy. Objective:The aim of this study was to evaluate long-term manometric results of sphincter healing following lateral internal sphincterotomy. Patients and Methods:Between 2000 and 2003, 50 patients with anal fissure were included in this study and underwent sphincterotomy; 12 healthy patients served as controls. All patients with anal fissure underwent manometric evaluation using a 6-channel perfusion catheter. All patients were examined 1 month before surgery and 1, 3, 6, and 12 months following surgery. The control group had 3 manometric evaluations 6 months apart. Results:The mean basal resting pressure before surgery was 138 ± 28 mm Hg. One month after surgery, the pressure dropped to 86 ± 15 mm Hg (P < 0.0001) and gradually rose to a plateau at 12 months (110 ± 18 mm Hg, P < 0.0001). At 12 months, the manometric pressure was significantly lower than the baseline (P < 0.0001). However, manometric measurements in the fissure group were still significantly higher than in the control group (110 ± 18 versus 73 ± 4.8 mm Hg, P < 0.0001). All patients were free of symptoms at the 12-month follow-up. Conclusion:Lateral internal sphincterotomy caused a significant decline in the resting anal pressure. During the first year following surgery, the tone of the internal anal sphincter gradually increased, indicating recovery, but still remained significantly lower than before surgery. However, postoperative resting pressures were higher than those in the control, and no patient suffered any permanent problems with incontinence, so this decrease may not be clinically significant.

Impact of Gastric Banding on Plasma Ghrelin, Growth Hormone, Cortisol, DHEA and DHEA-S Levels

Background: Several endocrine abnormalities are reported in obesity. Some are considered as causative factors, whereas others are considered to be secondary effects of obesity. In the current study, we explored the changes in cortisol, growth hormone (GH), DHEA, DHEA-S and GH releasing hormone (ghrelin) plasma levels in morbidly obese subjects who lost abundant weight following laparoscopic adjustable gastric banding (LAGB). Methods: 12 morbidly obese adult patients (15 females), age 21-56 years with BMI 46.0±4.4 kg/cm2, were studied. Blood samples were collected before, 6 and 14 months after LAGB. The levels of DHEA, DHEA-S, cortisol, GH, and ghrelin were determined by commercial kits. Statistical analysis was based on one-way repeated measures ANOVA, followed by Student-Newman-Keuls post-hoc test. Results: Mean BMI reduced significantly along the study course (P=.000). Cortisol plasma levels significantly decreased 6 months after surgery (from 541.4±242.4 nM to 382.4±142.1 nM, P=.004), but did not change further after 14 months (460.2±244.9 nM), despite further reduction in BMI (P=.050). GH constantly increased throughout the study from 0.076±0.149ng/ml, to 0.410±0.509 ng/ml at 6 months (NS), to 1.224±1.738 ng/ml at 14 months after surgery (P=.001). DHEA, DHEA-S and ghrelin plasma levels remained stable throughout the study. Conclusions: GH levels showed a persistent increase during the 14 months following LAGB in association with the weight loss, while a transient decrease in cortisol levels occurred at the 6-months time-point. In contrast, ghrelin, DHEA and DHEA-S were not altered after surgery. The association between GH and cortisol secretion and surgical- and nonsurgical-induced weight reduction merits further investigation.

General Anesthesia for Surgery Influences Melatonin and Cortisol Levels

The purpose of this study was to investigate the effect of general anesthesia and surgery on melatonin production, and to assess the relationship between melatonin secretion and cortisol levels. Twenty (9 males and 11 females) consecutive otherwise healthy patients aged 27 to 52 years were included in this study. The patients underwent laparoscopic cholecystectomy or laparoscopic hernioplasty. All patients had general anesthesia with the same anesthetic drugs. Serum cortisol levels were measured at several time periods. Urine collections for melatonin were performed from 18:00 to 7:00 the day prior to surgery, on the operation day, and on the first postoperative day. Baseline melatonin metabolites were measured the night prior to surgery, and the level was found to be 1979 ± 1.76 ng. The value decreased to 1802 ± 1.82 ng (NS) on the night of surgery, and it became a significantly higher, reaching 2981 ± 1.55 ng the night after surgery (p = .003). The baseline daytime cortisol level was significantly lower than the baseline night cortisol level (6.87 ± 1.51 μg/dl, 14.89 ± 1.66 micrograms/dl, respectively, p < 0.0001). Surgery induced a significant increase in both day and night cortisol levels. Daytime cortisol levels increased from 6.89 ± 1.51μg/dl to 16.90 ± 1.27μg/dl (p < 0.0001), whereas right levels increased from 14.89 ± 1.66 μg/dl to 29.20 ± 1.24 μg/dl (p <0.0001). The morning after surgery, cortisol levels decreased to 10.16 ± 1.40 μg/dl, lower than the value obtained on the day of surgery (p < 0.0001). As was true of melatonin, cortisol levels did not reach the pre operative level (p < 0.005). The finding of the current study is that melatonin and cortisol levels show an inverse correlation after surgery.

The Relationship between BMI, Plasma Leptin, Insulin and Proinsulin Before and After Laparoscopic Adjustable Gastric Banding

Background: Morbid obesity is associated with over-secretion of leptin and insulin, and predisposes to development of carbohydrate intolerance. In the current study, we explored the impact of BMI after laparoscopic adjustable gastric banding (LAGB) on leptin, insulin and proinsulin levels. Methods: 23 obese patients (8 males, 15 females) were included in the study. Their mean age was 36±6 yrs (range 21–56 yrs). Blood samples were collected for measurement of plasma leptin, insulin and proinsulin before and 6 and 14 months after LAGB. Results: Mean BMI before surgery was 46.04 ± 4.44 kg/m2, with significant and equal reduction of 18% in each of the follow-up periods, with total BMI reduction of 33% (P <.0001). The levels of circulating leptin, insulin and proinsulin before intervention were 119.3 ± 53.1 ng/ml, 159 ± 13 pmol/l, and 36.36 ± 23.06 pmol/l respectively. Despite an equal BMI reduction in the 2 follow-up periods, the most significant decrease in hormone levels was observed in the immediate postoperative period (54, 53, and 45%, respectively), when compared to the second follow-up period (15, 30, 10%, respectively). The highest total decline in hormone level of 70% was obtained with insulin, compared to 52% in leptin, and 50% in proinsulin. Despite the significant decrease in proinsulin and insulin levels, their ratio increased from 0.22, to 0.28 and 0.36 after LAGB. Unlike insulin and proinsulin, leptin levels strongly and persistently correlated with BMI during the study. Conclusion: Following LAGB, weight loss was associated with decreased levels of circulating leptin, insulin and proinsulin, most prominent in the first follow-up period. Unlike insulin and proinsulin, leptin showed the most significant and persistent correlation with BMI, suggesting that morbid obesity acts through different feedback hormonal mechanisms which are probably not regulated only by absolute weight loss. Longer follow-up and larger numbers of patients are needed to clarify long-term hormonal profile, as well as the beneficial lasting effects of such interventions.

Impact of Gastric Banding on Plasma Adiponectin Levels

Background: Several endocrine abnormalities are reported in obesity. In an earlier study, we found that the changes in BMI following laparoscopic adjustable gastric banding (LAGB) were associated with changes in hormone profiles such as insulin and proinsulin. In the current study, we explored the changes in plasma adiponectin levels in morbidly obese subjects who lost abundant weight following LAGB. Methods: 23 adult morbidly obese patients (15 females), aged 21-56 years, were studied. Blood samples were collected before, and 6 and 14 months after LAGB. The plasma adiponectin levels were determined by commercial kit (B-Bridge International, Inc). Statistical analysis was based on one-way repeated measures ANOVA, followed by Student-NewmanKeuls post-hoc test. Regression model was used to look for predictors of adiponectin change after LAGB. Results: Mean BMI before surgery was 46.04±4.44 kg/m2, and decreased significantly by 18% 6 months after surgery to 37.67±4.47 kg/m2. BMI further decreased by 32% 14 months after surgery to a mean of 31.30±4.65 kg/m2 (P =.000). The mean adiponectin level before surgery was 3997±1766 μg/ml, and increased significantly by 16% to 4763±1776 μg/ml 6 months after surgery, and to 6336±3292 μg/ml (37%) 14 months after surgery. Although BMI persistently decreased, while adiponectin persistently increased, BMI did not correlate with adiponectin. Conclusion: In morbidly obese patients who underwent LAGB, adiponectin levels persistently increased, probably due to the reduction of visceral fat mass. Adiponectin plasma increase was correlated with proinsulin levels prior to the surgery. The interaction between adiponectin, proinsulin and BMI change in morbid obesity merits further investigation.

Resting Anal Pressure Following Hemorrhoidectomy and Lateral Sphincterotomy

PURPOSEThe role of high anal pressure in the pathophysiology of hemorrhoids and anal fissures is debated. We compared resting anal pressures following left lateral sphincterotomy and hemorrhoidectomy in a prospective manometric study with emphasis on the recovery of the internal anal sphincter activity.METHODSIncluded in the study were 38 patients with third-degree or fourth-degree symptomatic hemorrhoids who underwent hemorrhoidectomy, 50 patients with anal fissure who underwent sphincterotomy, and 12 healthy patients who served as controls. All patients with anal fissure or hemorrhoids underwent periodic manometric evaluation: 1 month before surgery and 1, 3, 6, and 12 months after surgery. The control group had three manometric evaluations 6 months apart.RESULTSBaseline pressure measurement in the fissure group was significantly higher than in the hemorrhoid group, which was significantly higher than in the control group (138 ± 28.4 mmHg vs. 108.4 ± 23 mmHg vs. 73 ± 5.9 mmHg, P < 0.0001). Twelve months after surgery, anal resting pressure remained significantly lower than the baseline measurements in both the fissure (110 ± 18.2 vs. 138 ± 28.4, P < 0.0001) and hemorrhoid groups (103.6 ± 21.5 vs. 108 ± 23, P < 0.0001), but both remained higher than the control group (103.6 ± 21.5 mmHg vs. 73 ± 5.9 mmHg, P < 0.0001).CONCLUSIONSResting pressure is elevated in hemorrhoid and anal fissure patients. After surgery the anal resting pressure is reduced but is still higher than in the control group. Further studies are required to investigate the protective effect of postsurgical reduction of anal resting pressure against recurrence.

Is brain dehydroepiandrosterone synthesis modulated by free radicals in mice

Dehydroepiandrosterone (DHEA) is a neurosteroid synthesized de novo in the brain, in addition to the periphery, modulating some membrane, ion-gated channel neurotransmitter receptors. P450-17alpha-hydroxylase activity converting pregnenolone to DHEA, has not yet been identified in the brain of rodents. Studies in brain-derived primary cultures and cell lines, suggest a possible alternative pathway for DHEA synthesis involving oxygenated hydroxyperoxides. We investigated DHEA synthesis in the brains of castrated male mice before and after treatment with N-acetylcysteine amide (AD4) (a newly developed brain penetrating antioxidant). We found a significant increase in brain DHEA level 24 h after castration, which was totally blocked by AD4. This blockade of castration-induced increased brain DHEA synthesis, supports the assumption that this synthesis may also be affected by free radicals. This is the first in vivo study indicating the possible existence of an in-brain oxidative stress-related pathway leading to brain DHEA production.