Hypothalamic pituitary adrenal function in patients with anorexia nervosa.

Hypothalamic pituitary adrenal function was studied in 14 patients with anorexia nervosa. Although basal plasma cortisol levels in the morning were elevated in most cases, basal plasma ACTH levels were not suppressed. Oral administration of 1 mg dexamethasone 10 hr before blood sampling failed to suppress plasma ACTH and cortisol levels in most patients with anorexia nervosa. Apparent biological half-life of exogenous cortisol was prolonged in all 4 patients with anorexia nervosa tested. The cortisol response to insulin-induced hypoglycemia and exogenous ACTH appeared to be blunted in these patients. It is concluded that anorexia nervosa has dysfunctions of hypothalamic pituitary adrenal axis, especially an abnormal feedback mechanism on ACTH secretion.     

alpha-MSH enhances activity-based anorexia

Activity-based anorexia (ABA) is considered an animal model of anorexia nervosa (AN). In ABA, scheduled feeding in combination with voluntary access to running wheels, results in hyperactivity, hypophagia, body weight loss and activation of the HPA axis. Since stimulation of the melanocortin (MC) system has similar effects, this system is a candidate system involved in ABA. Here it is shown that chronic alpha-MSH treatment enhances ABA by increasing running wheel activity (RWA), decreasing food intake and increasing HPA axis activation.     

Disturbed cholecystokinin secretion in patients with eating disorders

It has been shown that the gastrointestinal hormone cholecystokinin (CCK) induces satiety and reduces food intake in laboratory animals and humans. In the light of this evidence we studied CCK release in patients suffering from eating disorders. The secretion of CCK into the general circulation was measured in 10 anorectic, in 7 bulimic patients, and in 8 healthy controls before and after a high-caloric liquid testmeal. Baseline CCK values were similar in controls (0.6 +/- 0.2 pmol/l) and bulimics (0.6 +/- 0.1 pmol/l) and were significantly increased in the anorectic group (1.8 +/- 0.4 pmol/l) (p less than or equal to 0.005). After eating peak plasma levels increased to 6.1 +/- 0.9 pmol/l in the anorectic, to 3.8 +/- 0.5 pmol/l in the bulimic and to 2.7 +/- 0.6 pmol/l in the control group. All postprandial CCK values were significantly higher in the anorectic group. The secretion of CCK-8-S, an important peptide in the CCK family, was significantly elevated, too. This disturbed CCK secretion in patients suffering from anorexia nervosa, even if it is a secondary, diet-induced defect, may perpetuate this disorder.     

Secretory dynamics of leptin in adolescent girls with anorexia nervosa and healthy adolescents

Leptin, an adipocytokine that suppresses appetite and may regulate neuroendocrine pathways, is low in undernourished states like anorexia nervosa (AN). Although leptin exhibits pulsatility, secretory characteristics have not been well described in adolescents and in AN, and the contribution of hypoleptinemia to increased growth hormone (GH) and cortisol in AN has not been explored. We hypothesized that hypoleptinemia in AN reflects decreased basal and pulsatile secretion and may predict increased GH and cortisol levels. Sampling for leptin, GH, cortisol, and ghrelin was performed every 30 min (from 2000 to 0800) in 23 AN and 21 controls 12-18 yr old, and data were analyzed using Cluster and deconvolution methods. Estradiol, thyroid hormones, and body composition were measured. AN girls had lower pulsatile and total leptin secretion than controls (P < 0.0001) subsequent to decreased burst mass (P < 0.0001) and basal secretion (P = 0.02). Nutritional markers predicted leptin characteristics. In a regression model including BMI, body fat, and ghrelin, leptin independently predicted GH burst interval and frequency. Valley leptin contributed to 56% of the variability in GH burst interval, and basal leptin and fasting ghrelin contributed to 42% of variability in burst frequency. Pulsatile leptin independently predicted urine free cortisol/creatinine (15% of variability). Valley leptin predicted cortisol half-life (22% of variability). Leptin predicted estradiol and thyroid hormone levels. In conclusion, hypoleptinemia in AN is subsequent to decreased basal and pulsatile secretion and nutritionally regulated. Leptin predicts GH and cortisol parameters and with ghrelin predicts GH burst frequency. Low leptin and high ghrelin may be dual stimuli for high GH concentrations in undernutrition.     

Comparison of estrogen priming effects with body weight restoration effects on the gonadotropin pattern of patients with anorexia nervosa

Plasma estradiol (E2), serum LH and FSH, and the gonadotropin response to two consecutive LHRH administrations (10 and 100 micrograms with an interval of 2 h) were determined in 19 patients with anorexia nervosa (AN) at the emaciation phase, before and after estradiol benzoate (E2B) injections (3 micrograms/kg/day for 7 days). The same investigations were repeated after weight restoration in 9 AN patients who remained amenorrheic. Both at the emaciation phase and after weight restoration, E2B enhanced the second LH response to LHRH and decreased serum FSH, suggesting that the functional capacities of the pituitary gonadotrophs are normal in AN. Unlike E2B injections, weight restoration increased all the hormone values, suggesting that the weight restoration effects on the abnormal gonadotropin secretory pattern of AN depend on another mechanism than the E2 lowering. That mechanism is probably a disorder of the hypothalamic LHRH secretion, the consequences of which could be reinforced by the low E2 levels.     

Changes of plasma obestatin, ghrelin and NPY in anorexia and bulimia nervosa patients before and after a high-carbohydrate breakfast

Peptides ghrelin, obestatin and neuropeptide Y (NPY) play an important role in regulation of energy homeostasis, the imbalance of which is associated with eating disorders anorexia (AN) and bulimia nervosa (BN). The changes in ghrelin, obestatin and NPY plasma levels were investigated in AN and BN patients after administration of a high-carbohydrate breakfast (1604 kJ). Eight AN women (aged 25.4+/-1.9, BMI: 15.8+/-0.5), thirteen BN women (aged 22.0+/-1.05, BMI: 20.1+/-0.41) and eleven healthy women (aged 25.1+/-1.16, BMI: 20.9+/-0.40) were recruited for the study. We demonstrated increased fasting ghrelin in AN, but not in BN patients, while fasting obestatin and NPY were increased in both AN and BN patients compared to the controls. Administration of high-carbohydrate breakfast induced a similar relative decrease in ghrelin and obestatin plasma levels in all groups, while NPY remained increased in postprandial period in both patient groups. Ghrelin/obestatin ratio was lower in AN and BN compared to the controls. In conclusions, increased plasma levels of fasting NPY and its unchanged levels after breakfast indicate that NPY is an important marker of eating disorders AN and BN. Different fasting ghrelin and obestatin levels in AN and BN could demonstrate their diverse functions in appetite and eating suppression.     

The role of insulin, glucagon and growth hormone in the regulation of plasma glucose and free fatty acid levels in anorexia nervosa

It is well established that glucagon plays an important role in the regulation of fuel supplies as its plasma level increases during the first days of a complete fast. However, it is not certain that glucagon is involved in the adaptation to chronic starvation. In the present study, this problem was investigated by the determination of the changes in the plasma glucagon level elicited by an i.v. glucose tolerance test followed by an i.v. arginine perfusion in 26 self starved patients suffering from anorexia nervosa (AN) and 14 control patients having only minor neurotic disorders. The basal plasma glucagon level tended to be higher in the AN patients than in the controls; but the difference was not statistically significant. Glucagon responses to glucose and arginine observed in the AN patients were not significantly different from those seen in the control patients. In the AN patients, the insulin response to both loads was reduced and the plasma GH level increased paradoxically after the glucose load, whereas it rose normally after the arginine load. It may be concluded that in chronic starvation by AN the regulation of fuel supplies depends mainly on decreased insulin and increased growth hormone secretion. The role of glucagon seems to be of minor importance in this condition.     

Effect of nutritional rehabilitation on circulating ghrelin and growth hormone levels in patients with anorexia nervosa

Circulating ghrelin and growth hormone (GH) are up-regulated in anorexia nervosa (AN) as a consequence of prolonged starvation. The current study examines the effect of nutritional rehabilitation with improvement of eating behavior on ghrelin and GH levels in AN patients during the course of inpatient treatment. The subjects included 34 female AN patients and 9 age-matched female controls. Fasting blood samples were collected before, during and after treatment. For data analysis, AN subjects were divided into three subtypes. The first group included seven patients with emergent hospitalization (E-AN), who were accompanied by severe emaciation due to their inability for food intake for more than a month. The other two groups included 14 AN with restricting (AN-R) and 13 AN with binge-eating/purging (AN-BP) patients. There were significant correlations between ghrelin, GH and body mass index (BMI) before treatment in all subjects. However, ghrelin levels were not significantly correlated with BMI and GH although there was a relationship between GH and BMI after treatment. Before treatment, E-AN patients had the highest levels of ghrelin and GH with the lowest glucose levels and liver dysfunction. The AN-BP group had a higher level of ghrelin than the AN-R group. During treatment, comparing with the controls group only the AN-R group showed higher level of ghrelin. Contrarily, the ghrelin levels in the E-AN group, who showed improved glucose levels, and the AN-BP group, who stopped vomiting behavior due to our treatment, decreased ghrelin levels. After treatment, only the AN-BP group showed a higher ghrelin level as compared to the controls. Although GH levels of the three AN groups decreased gradually according to our treatment progress, it still showed the higher value than the control group at the end of the treatment because every AN patients could not reach to more than 80% of their ideal body weight at discharge. These findings suggest that (1) severe emaciation with abnormal fasting hypoglycemia in AN patients may cause very high levels of GH and ghrelin, (2) that GH levels in AN patients may relate to nutritional status and (3) that ghrelin may be influenced by not only nutritional status but also the eating behavior of the patients.     

Cholecystokinin, vasoactive intestinal peptide and peptide histidine methionine responses to feeding in anorexia nervosa.

Anorexia nervosa (AN) is a syndrome of unknown cause characterized by voluntary starvation. Cholecystokinin has been implicated as a neuroendocrine regulatory factor in control of satiety. Relatively little information is known about gastrointestinal hormone responses to feeding in subjects with anorexia nervosa. In the present studies, we examine fasting and postprandial levels of cholecystokinin (CCK), vasoactive intestinal peptide (VIP) and peptide histidine methionine (PHM) in anorexia nervosa subjects and in control individuals. Results of these studies indicate that plasma CCK response to a liquid meal (Ensure Plus) in untreated AN subjects was distinctly different from that observed in healthy controls, both in terms of temporal pattern of peptide released and the amount of CCK secreted into the circulation. Peak levels of CCK release occurred at 30 min following meal ingestion in AN patients and at 60 min in control subjects. Integrated CCK release in untreated AN patients was approximately twice that measured in control individuals. Renutrition therapy was associated with reversion of the pattern of CCK release to that observed in control subjects. Plasma VIP levels were unchanged following meal ingestion in both control and anorexic subjects. In contrast, PHM levels in AN subjects were significantly greater than that observed in control individuals. The pattern of PHM release following liquid meal ingestion was similar to that observed with plasma CCK; namely, peak release of peptide was observed at 30 min which was significantly greater than corresponding control values (P less than 0.05). In conclusion, these results demonstrate distinctive differences in plasma CCK and PHM levels in response to feeding in AN subjects when compared to control individuals. These findings suggest that the earlier and greater rise in plasma CCK levels in AN subjects following meal ingestion may contribute to the abnormal sensation of satiety in this condition.     

The melanocortins and melanin-concentrating hormone in the central regulation of feeding behavior and energy homeostasis

A number of different neuropeptides exert powerful concerted controls on feeding behavior and energy balance, most of them being produced in hypothalamic neuronal networks under stimulation by anabolic and catabolic peripheral hormones such as ghrelin and leptin, respectively. These peptide-expressing neurons interconnect extensively to integrate the multiple opposing signals that mediate changes in energy expenditure. In the present review I have summarized our current knowledge about two key peptidic systems involved in regulating appetite and energy homeostasis, the melanocortin system (alpha-MSH, agouti and Agouti-related peptides, MC receptors and mahogany protein) and the melanin-concentrating hormone system (proMCH-derived peptides and MCH receptors) that contribute to satiety and feeding-initiation, respectively, with concurrent effects on energy expenditure. I have focused particularly on recent data concerning transgenic mice and the ongoing development of MC/MCH receptor antagonists/agonists that may represent promising drugs to treat human eating disorders on both sides of the energy balance (anorexia, obesity).     

Neuronal effects of orexins: relevant to sympathetic and cardiovascular functions

Orexin A and B, also called hypocretin 1 and 2, were recently discovered in the hypothalamus. This organ, in which a number of neuropeptides have been demonstrated to stimulate or suppress food intake, is considered important for the regulation of appetite and energy homeostasis. Orexins were initially reported as a regulator of food intake. More recent reports suggest their possible important roles in the multiple functions of neuronal systems, such as narcolepsy, a sleep disorder. Orexins and their receptors are distributed in neural tissue and brain regions involved in the autonomic and neuroendocrine control. Functional studies have shown that these peptides evoke changes in cardiovascular and sympathetic responses. The data from our in vivo and in vitro studies suggest that the peptide acting on neurons in the hypothalamic paraventricular nucleus increases the cardiovascular responses. This review will focus on the neural effects of orexins and how these peptides may participate in the regulation of cardiovascular and sympathetic functions.     

GLP-1 as a satiety factor in children with eating disorders.

GLP-1, with its insulinotropic properties and direct action on satiety center in the brain, may be the main hormone regulating the amount of ingested food. In this study, GLP-1 secretion was investigated in age-matched adolescent girls (14 +/- 2 years): 13 with anorexia nervosa (BMI 14.8 +/- 1.4 kg/m(2)), 13 with simple obesity (BMI 33.0 +/- 3.3 kg/m(2)) and 10 healthy girls as a control group (BMI 21.6 +/- 0.7 kg/m(2)). Each girl was subjected to OGTT and standard meal tests after a 12 h overnight fast. Blood samples were collected before and 15, 30, 60, and 120 min after the stimulation. The mean fasted GLP-1 levels in simple obesity group (1.6 +/- 0.3 pmol/l) and in anorexia nervosa group (1.7 +/- 0.3 pmol/l) were significantly lower than those in the control group (2.6 +/- 0.4 pmol/l) (p < 0.05 in both cases). The highest peak concentration of GLP-1 was observed in the control group after both stimuli. In each group, the mean integrated GLP-1 outputs were almost twice as high after OGTT than after the test meal (p < 0.001 in each case). In our opinion, low secretion of GLP-1 in girls with simple obesity may seriously and negatively influence the course of this disease. On the other hand, low GLP-1 levels in girls with anorexia nervosa are beneficial and promote appetite.     

Possible involvement of brain-derived neurotrophic factor in eating disorders

Eating disorders (EDs) manifest as abnormal patterns of eating behavior and weight regulation driven by low self-esteem due to weight preoccupation and perceptions toward body weight and shape. Two major groups of such disorders are anorexia nervosa (AN) and bulimia nervosa (BN). The etiology of EDs is complex and evidence indicates that both biological/genetic and psychosocial factors are involved. Several lines of evidence indicate that brain-derived neurotrophic factor (BDNF) plays a critical role in regulating eating behaviors and cognitive impairments in the EDs. BDNF is involved in neuronal proliferation, differentiation, and survival during development. BDNF and its tyrosine kinase receptor (TrkB) are expressed in hypothalamic nuclei associated with eating behaviors. A series of studies using BDNF knockout mice and the human BDNF gene indicate an association of BDNF and EDs with predisposition and vulnerability. In the previous studies, serum BDNF levels in subjects with EDs are reduced significantly compared with healthy controls, hence, we proposed that levels of serum BDNF would be a useful diagnostic indicator for EDs.     

Disruption of Spatial Task Performance in Anorexia Nervosa

In anorexia nervosa (AN), body distortions have been associated with parietal cortex (PC) dysfunction. The PC is the anatomical substrate for a supramodal reference framework involved in spatial orientation constancy. Here, we sought to evaluate spatial orientation constancy and the perception of body orientation in AN patients. In the present study, we investigated the effect of passive lateral body inclination on the visual and tactile subjective vertical (SV) and body Z-axis in 25 AN patients and 25 healthy controls. Subjects performed visual- and tactile-spatial judgments of axis orientations in an upright position and tilted 90° clockwise or counterclockwise. We observed a significant deviation of the tactile and visual SV towards the body (an A-effect) under tilted conditions, suggesting a multisensory impairment in spatial orientation. Deviation of the Z-axis in the direction of the tilt was also observed in the AN group. The greater A-effect in AN patients may reflect reduced interoceptive awareness and thus inadequate consideration of gravitational inflow. Furthermore, marked body weight loss could decrease the somatosensory inputs required for spatial orientation. Our study results suggest that spatial references are impaired in AN. This may be due to particular integration of visual, tactile and gravitational information (e.g. vestibular and proprioceptive cues) in the PC.     

Characteristics of suicide attempts in anorexia and bulimia nervosa: a case-control study

Objective

Compared to other eating disorders, anorexia nervosa (AN) has the highest rates of completed suicide whereas suicide attempt rates are similar or lower than in bulimia nervosa (BN). Attempted suicide is a key predictor of suicide, thus this mismatch is intriguing. We sought to explore whether the clinical characteristics of suicidal acts differ between suicide attempters with AN, BN or without an eating disorders (ED).

Method

Case-control study in a cohort of suicide attempters (n = 1563). Forty-four patients with AN and 71 with BN were compared with 235 non-ED attempters matched for sex, age and education, using interview measures of suicidal intent and severity.

Results

AN patients were more likely to have made a serious attempt (OR = 3.4, 95% CI 1.4–7.9), with a higher expectation of dying (OR = 3.7,95% CI 1.1–13.5), and an increased risk of severity (OR = 3.4,95% CI 1.2–9.6). BN patients did not differ from the control group. Clinical markers of the severity of ED were associated with the seriousness of the attempt.

Conclusion

There are distinct features of suicide attempts in AN. This may explain the higher suicide rates in AN. Higher completed suicide rates in AN may be partially explained by AN patients'' higher desire to die and their more severe and lethal attempts.     

Hormonal regulation of energy-protein homeostasis in hemodialysis patients: an anorexigenic profile that may predispose to adverse cardiovascular outcomes

To assess whether endocrine dysfunction may cause derangement in energy homeostasis in patients undergoing hemodialysis (HD), we profiled hormones, during a 3-day period, from the adipose tissue and the gut and the nervous system around the circadian clock in 10 otherwise healthy HD patients and 8 normal controls. The protocol included a 40-h fast. We also measured energy-protein intake and output and assessed appetite and body composition. We found many hormonal abnormalities in HD patients: 1) leptin levels were elevated, due, in part, to increased production, and nocturnal surge in response to daytime feeding, exaggerated. 2) Peptide YY (PYY), an anorexigenic gut hormone, was markedly elevated and displayed an augmented response to feeding. 3) Acylated ghrelin, an orexigenic gut hormone, was lower and did not exhibit the premeal spike as observed in the controls. 4) neuropeptide Y (NPY), a potent orexigenic peptide, was markedly elevated and did not display any circadian variation. 5) Norepinephrine, marginally elevated, did not exhibit the normal nocturnal dip. By contrast, α-melanocyte-stimulating hormone and glucagon-like peptide-1 were not different between the two groups. Despite these hormonal abnormalities, HD patients maintained a good appetite and had normal body lean and fat mass, and there was no evidence of increased energy expenditure or protein catabolism. We explain the hormonal abnormalities as well as the absence of anorexia on suppression of parasympathetic activity (vagus nerve dysfunction), a phenomenon well documented in dialysis patients. Unexpectedly, we noted that the combination of high leptin, PYY, and NPY with suppressed ghrelin may increase arterial blood pressure, impair vasodilatation, and induce cardiac hypertrophy, and thus could predispose to adverse cardiovascular events that are the major causes of morbidity and mortality in the HD population. This is the first report attempting to link hormonal abnormalities associated with energy homeostasis to adverse cardiovascular outcome in the HD patients.     

Responses of pituitary and adrenal medulla to insulin-induced hypoglycemia in patients with anorexia nervosa

The responses of pituitary and adrenomedullary hormones to insulin-induced hypoglycemia were studied in 10 patients with anorexia nervosa and 7 control females of comparable age. The increases in plasma GH and PRL were significantly smaller in the patients, while the responses of GH to arginine and of PRL to TRH were indistinguishable. Plasma cortisol attained similar peak levels in both groups with higher basal levels and smaller increments in the patients. The response of plasma epinephrine was markedly lower in the patients, although urinary epinephrine showed similar increase in both groups. These results suggest the possibility that the process by which hypoglycemic stimulus causes pituitary and adrenomedullary hormone secretion is deranged in patients with anorexia nervosa.     

Anorexia nervosa and bulimia nervosa.

No definitive therapy exists for anorexia nervosa (AN) or bulimia nervosa (BN). Nevertheless, biologic and psychologic research into these disorders has increased over the last decade. We examine the various drugs available for treatment. Advances in pharmacotherapy for AN have been modest and have reflected efforts either to stimulate hunger and weight gain or to control complications of the starvation process. Food remains the "drug" of choice. Antidepressants have been found to be beneficial in the treatment of BN. The meaning of this in the context of a relation between BN and mood disorders remains unclear, since coexistent depression does not predict a positive response to these drugs. Pharmacotherapy represents a single but important dimension of the management of patients with eating disorders. The optimal integration of drug therapy and psychotherapy and the identification of predictors of a positive response to drugs have yet to be addressed by clinical research.     

Increased subcutaneous abdominal tissue norepinephrine levels in patients with anorexia nervosa: an in vivo microdialysis study

The present study was designed to measure interstitial levels of norepinephrine-regulating lipolysis (NE) in subcutaneous abdominal adipose tissue of anorexia nervosa (AN) patients and control subjects under basal conditions and after the local administration of an inhibitor of NE re-uptake, maprotiline. In vivo microdialysis technique was used to assess subcutaneous adipose NE levels in five women with AN (body mass index 14.62+/-0.47 kg/m(2)) and six age-matched controls (22.1+/-0.52 kg/m(2)). NE was assayed using high performance liquid chromatography with electrochemical detection after batch alumina extraction. Measured basal adipose tissue NE levels reflecting its interstitial levels were significantly increased in AN patients compared to the controls (106.0+/-20.9 vs. 40.0+/-5.0 pg/ml). The local maprotiline administration resulted in a significant increase in adipose tissue NE levels (AN patients: 440.0+/-28.6 vs. 202.0+/-33.0 pg/ml in the controls) in both groups. Markedly increased subcutaneous abdominal adipose tissue NE levels in AN patients compared to control subjects reflect increased sympathetic nervous system activity but not altered membrane noradrenergic transporter system in anorexia nervosa patients.