Natacha Germain

Ghrelin/obestatin ratio in two populations with low bodyweight: Constitutional thinness and anorexia nervosa

Constitutional thinness (CT) and anorexia nervosa (AN) are two categories of severely underweight subjects. Some appetite-regulating hormones display opposite levels in AN and CT. While levels of ghrelin, an orexigenic hormone, fit with the normal food intake in CT, the lack of efficacy of increased ghrelin levels in AN is not clear. Obestatin is a recently described peptide derived from the preproghrelin gene, reported to inhibit appetite in contrast to ghrelin. The aim of this study was to determine whether the circadian profile of obestatin, total and acylated ghrelin levels is different in CT subjects when compared with AN patients. Six-points circadian profiles of plasma obestatin, acylated ghrelin, total ghrelin and other hormonal and nutritional parameters were evaluated in four groups of young women: 10 CT, 15 restricting-type AN, 7 restored from AN and 9 control subjects. Obestatin circadian levels were significantly higher in AN (p<0.0001) while no difference was found between CT and control subjects. Acylated and total ghrelin were found increased in AN. Acylated ghrelin/obestatin and total ghrelin/obestatin were found decreased in AN compared to CT or C subjects (p<0.05). The percentage of acylated ghrelin was found decreased in CT group (p<0.05). The decreased ghrelin/obestatin ratio found in AN might participate in the restraint in nutriment intake of these patients. In contrast, in CT a lower percentage of acylated over total ghrelin might be considered in the aetiology of this condition.

Hormonal Profile Heterogeneity and Short-Term Physical Risk in Restrictive Anorexia Nervosa

CONTEXT The relevance of hormonal assessment in anorexia nervosa (AN) management is still unclear. The short-term physical risk during undernutrition period of the disease is partially predicted by anthropometric and electrolytic parameters. OBJECTIVE The objective of the study was to evaluate hormonal profiles in a large cohort of AN and their relationship with critical states. DESIGN AND SETTING This was an observational monocentric cross-sectional study performed in the endocrinological unit. PATIENTS AND OTHER PARTICIPANTS Participants included 210 young female subjects with restrictive-type AN and 42 female controls of comparable age. MAIN OUTCOME MEASURES The following hormonal parameters were measured: thyroid hormones, GH, IGF-I, cortisol, oestradiol, FSH, LH, SHBG, dehydroepiandrosterone sulfate, plasma metanephrines, and bone markers. Their relation with registered short-term evolution of AN subjects after hormonal assessment was evaluated. RESULTS Except for metanephrines and dehydroepiandrosterone sulfate, most of the hormonal abnormalities previously reported in AN were confirmed. The manifestation of these hormonal abnormalities started below different body mass index (BMI) levels, ranging between 17 and 15 kg/m(2), even though an important percentage of normal values for every parameter was still noticed for very low BMIs. All patients who developed critical states during the 3 months after the hormonal assessment presented with BMI less than 15 kg/m(2) and a very increased level of cortisol, GH, and increased values of metanephrines. CONCLUSIONS The hormonal response to undernutrition is heterogeneous in a large population with restrictive AN. In clinical practice, metanephrines, GH, and/or cortisol data could be used as important predictors for severe short-term outcome.

Ghrelin and Obestatin Circadian Levels Differentiate Bingeing-Purging from Restrictive Anorexia Nervosa

CONTEXT Anorexia nervosa (AN) patients present with restrictive food behavior (AN-R). Some of them develop episodes of bulimia (AN-BP) without any clear pathophysiological explanation to date. Their clinical differentiation is important but not easily performed. Orexigenic/anorexigenic peptides measurements could provide some clues for that matter. OBJECTIVE The objective of the study was to determine whether the circadian profile of total and acylated ghrelin, obestatin, and peptide YY (PYY) levels is different in AN-R subjects when compared with AN-BP patients. DESIGN AND SETTINGS This was a cross-sectional study in an endocrinological unit. PATIENTS AND CONTROL SUBJECTS Four groups of age-matched young women: 22 AN-R, 10 AN-BP, 16 normal-weight bulimia nervosa (BN), and nine controls. MAIN OUTCOME MEASURES Twelve-point circadian profiles of plasma total and acylated ghrelin, obestatin, and PYY were measured. RESULTS Total and acylated ghrelin and obestatin circadian levels were increased in AN-R when compared with controls but decreased in both AN-BP and BN groups (P < 0.001). PYY was decreased in all groups with eating disorders. Acylated to total ghrelin ratio was decreased in AN-BP and BN (P < 0.001), whereas obestatin to acylated ghrelin and PYY to acylated ghrelin ratios were increased in both groups with bingeing-purging behavior (P < 0.0001). CONCLUSIONS Patients with AN-associated bingeing-purging behavior present a very different profile of appetite regulatory peptides when compared with the pure restrictive type. The assessment of ghrelin (and eventually obestatin) could be of particular interest for differential diagnosis. Very low ghrelin levels and increased anorexigenic to orexigenic peptide ratios suggest either a lack of adaptation to a starvation state or a higher facility to cope with undernutrition.

Orexigenic Neuropeptide 26RFa: New Evidence for an Adaptive Profile of Appetite Regulation in Anorexia Nervosa

CONTEXT Restrictive anorexia nervosa (AN) presents an adaptive appetite regulating profile including mainly high levels of ghrelin. Because this adaptive mechanism is not effective on food intake, other appetite-regulating peptides need to be explored. 26RFa is a hypothalamic neuropeptide that stimulates appetite, gonadotropin release, and bone metabolism. OBJECTIVE The objective of the study was to evaluate the circadian levels of 26RFa in AN patients compared with healthy subjects, other eating disorders, and constitutional thinness (CT). DESIGN AND SETTINGS This was a cross-sectional study performed in an endocrine unit and an academic laboratory. INVESTIGATED SUBJECTS Five groups of age-matched young women were included in the study: 19 restrictive AN, 10 AN with bingeing/purging episodes, 14 with CT, 10 bulimic, and 10 normal-weight controls. MAIN OUTCOME MEASURES Twelve-point circadian profiles of plasma 26RFa levels were measured in each subject. RESULTS Significant circadian variations of 26 RFA were noticed in controls with higher values in the morning and abrupt decrease at noon. Twenty-four-hour mean 26RFa levels were significantly increased in restrictive AN and AN with bingeing/purging episodes (P < 0.001), predominantly in the afternoon and evening when compared with controls. Preprandial rises of 26 RFA were noticed in AN patients. Mean 26RFa levels trend to be higher in CT than in controls (P = 0.06) and significantly lower than in AN. The bulimic patients presented a circadian profile of 26RFa similar to that of controls. CONCLUSION High levels of circulating 26RFa observed in AN patients might reflect an adaptive mechanism of the organism to promote energy intake and to increase fat stores in response to undernutrition.

Diminution de la mortalité et stabilité du taux de guérison dans le suivi de l’anorexie mentale

Resume Objectif L’anorexie mentale (AM) est un trouble du comportement alimentaire associant une denutrition, une amenorrhee et un trouble de l’image corporelle selon les criteres du DSM-IV. Peu d’etudes de suivi ont ete publiees. Nous avons realise une etude retrospective, portant sur la population de patientes anorexiques mentales restrictives ayant ete prises en charge de 1979 a 2004. Methodes Les donnees necessaires, elaborees a partir de l’inventaire de Morgan et Russell, ont ete recueillies entre mai et juillet 2004 a l’aide du dossier clinique et d’une enquete telephonique. Pour chaque patiente, ont ete notes la chronologie de la maladie, les caracteristiques morphologiques, le type de l’anorexie, le mode de prise en charge, l’histoire gynecologique et la situation professionnelle et conjugale. Resultats La population etudiee representait 206 patientes pour lesquelles la duree moyenne de suivi a ete de 8,3 ± 5,3 ans ; 55,8 % ont ete gueries sur les criteres IMC > 17,5 kg/m2 maintenu pendant 1 an et reprise de l’activite genitale ; 18,5 % sont entrees dans une forme chronique de la maladie et 25,7 % avaient encore une des deux composantes citees ci-dessus. Le taux de mortalite a ete de 1,8 %. En termes d’evolution de la maladie, l’âge de debut precoce lors de l’adolescence etait de bon pronostic. Par contre, l’intensite de la maigreur, un delai de prise en charge long, une frequence faible de consultation semblaient predictifs d’une issue defavorable. Conclusions La gravite de cette maladie est plutot liee a ses formes chronicisees qu’au nombre de deces qui lui sont directement imputables. Par contre, le versant psychopathologique n’a pas ete pris en compte et il semble important a evaluer puisque certains traits de personnalite sous-jacents apparaissent comme des facteurs de comorbidite.

Constitutional Thinness and Anorexia Nervosa: A Possible Misdiagnosis?

Clinical and biological aspects of restrictive anorexia nervosa (R-AN) are well documented. More than 10,000 articles since 1911 and more than 600 in 2013 have addressed R-AN psychiatric, somatic, and biological aspects. Genetic background, ineffectiveness of appetite regulating hormones on refeeding process, bone loss, and place of amenorrhea in the definition are widely discussed and reviewed. Oppositely, constitutional thinness (CT) is an almost unknown entity. Only 32 articles have been published on this topic since 1953. Similar symptoms associating low body mass index, low fat, and bone mass are reported in both CT and R-AN subjects. Conversely, menses are preserved in CT women and almost the entire hormonal profile is normal, except for leptin and PYY. The aim of the present review is to alert the clinician on the confusing clinical presentation of these two situations, a potential source of misdiagnosis, especially since R-AN definition has changed in DSM5.

No Loss of Chance of Diabetic Retinopathy Screening by Endocrinologists With a Digital Fundus Camera

OBJECTIVE To compare the efficacy of the diabetic retinopathy (DR) screening with digital camera by endocrinologists with that by specialist and resident ophthalmologists in terms of sensitivity, specificity, and level of “loss of chance.” RESEARCH DESIGN AND METHODS In a cross-sectional study, 500 adult diabetic patients (1,000 eyes) underwent three-field retinal photography with a digital fundus camera following pupillary dilatation. Five endocrinologists and two ophthalmology residents underwent 40 h of training on screening and grading of DR and detection of associated retinal findings. A κ test compared the accuracy of endocrinologist and ophthalmology resident screening with that performed by experienced ophthalmologists. Screening efficiency of endocrinologists was evaluated in terms of “loss of chance,” i.e., missed diagnoses that required ophthalmologist referrals. RESULTS The mean weighted κ of DR screening performed by endocronologists was similar to that of ophthalmology residents (0.65 vs. 0.73). Out of 456 DR eyes, both endocrinologists and ophthalmology residents misdiagnosed only stage 1 DR (36 and 14, respectively), which did not require ophthalmologist referral. There were no significant differences between endocrinologists and ophthalmology residents in terms of diabetic maculopathy and incidental findings except for papillary cupping and choroidal lesions, which were not the main purpose of the study or of the training. CONCLUSIONS The endocrinologist with specific training for DR detection using a three-field digital fundus camera with pupillary dilatation can perform a reliable DR screening without any loss of chance for the patients when compared with identical evaluation performed by experienced ophthalmologists.

Neuropeptide Y and α-MSH circadian levels in two populations with low body weight: anorexia nervosa and constitutional thinness.

Context Anorexia nervosa (AN) presents an adaptive appetite regulating profile including high levels of ghrelin and 26RFa (orexigenic) and low levels of leptin and PYY (anorexigenic). However, this adaptive mechanism is not effective in promoting food intake. The NPY/proopiomelanocortin (POMC) system plays a crucial role in the regulation of feeding behavior as NPY is the most potent orexigenic neuropeptide identified so far and as the POMC-derived peptide α-MSH drastically reduces food intake, and this peptidergic system has not been thoroughly studied in AN. Objective The aim of the present study was thus to investigate whether a dysfunction of the NPY/POMC occurs in two populations with low body weight, AN and constitutional thinness (CT). Design and Settings This was a cross-sectional study performed in an endocrinological unit and in an academic laboratory. Investigated Subjects Three groups of age-matched young women were studied: 23 with AN (AN), 22 CT and 14 normal weight controls. Main Outcome Measures Twelve-point circadian profiles of plasma NPY and α-MSH levels were measured in the three groups of investigated subjects. Results No significant circadian variation of NPY was detected between the three groups. Plasma α-MSH levels were significantly lower in AN (vs controls) all over the day. The CT group, compared to controls, presented lower levels of α-MSH in the morning and the evening, and an important rise during lunchtime. Conclusion In AN patients, the NPY system is not up-regulated under chronic undernutrition suggesting that this may play a role in the inability of anorectic women to adapt food intake to their energy demand. In contrast, low circadian α-MSH levels integrate the adaptive profile of appetite regulation of this disease. Finally, in CT women, the important α-MSH peak detected during lunchtime could explain why these patients are rapidly food satisfied.

Normal Inhibin B Levels Suggest Partial Preservation of Gonadal Function in Adult Male Patients with Anorexia Nervosa

INTRODUCTION The impact of undernutrition on endocrine and exocrine gonadatrope function is poorly known in male anorexia nervosa (AN) patients. AIM The aim of this study was to compare the pituitary-gonadal function of male AN subjects with that of healthy controls, Kallmann syndrome (KS) patients, and female AN subjects. METHODS Observational monocentric cross-sectional study performed in 31 male and 25 female subjects with restrictive-type AN, 22 male and 20 female controls, and nine male KS patients. MAIN OUTCOME MEASURES Hormonal parameters are as follows: follicule stimulating hormone (FSH), luteinizing hormone (LH), sex hormone binding globulin, estradiol, testosterone, inhibin B, thyroid hormones, growth hormone (GH), insulin-like growth factor 1 (IGF-1), cortisol, adrenocorticotropic hormone (ACTH), dehydroepiandrosterone sulfate, and leptin. RESULTS Similar abnormalities of free T3, GH, IGF-I, cortisol, and leptin were found in men as in AN women with equivalent undernutrition status when compared with corresponding controls. Low levels of LH, FSH were found in both male and female AN patients. In male AN, total testosterone was found lower than in controls but higher than in KS, while a lack of estradiol was noticed in AN women. Sex hormones variations were directly related to weight gain only in AN men. No relationship was found between sex hormones and leptin variation for both sexes. In AN men, inhibin B levels were similar to that of controls and did not correlate with testosterone levels. CONCLUSIONS Significant differences of undernutrition impact on gonadal status were noticed between male and female AN subjects, including partial preservation of testosterone release and probable preservation of exocrine function, according to the normal inhibin B levels.

Degradation Paradigm of the Gut Hormone, Pancreatic Polypeptide, by Hepatic and Renal Peptidases

Pancreatic polypeptide (PP) is a gut hormone that acts on Y4 receptors to reduce appetite. Obese humans display a reduced postprandial increase in PP and remain fully sensitive to the anorectic effects of exogenous PP. The utility of PP as an anti-obesity treatment is limited by its short circulating half-life. Insight into the mechanisms by which PP is degraded could aid in the design of long-acting PP analogs. We investigated the role of peptidases in PP degradation to determine whether inhibition of these enzymes enhanced PP plasma levels and bioactivity in vivo. Dipeptidyl peptidase IV (DPPIV) and neprilysin (NEP) were two peptidase found to cleave PP. Limiting the effect of both peptidases improved the in vivo anorectic effect of PP and PP-based analogs. These findings suggest that inhibiting the degradation of PP using specific inhibitors and/or the design of analogs resistant to cleavage by DPPIV and NEP might be useful in the development of PP as an anti-obesity pharmacotherapy.