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Background/aims:
Growth failure is a difficult, but key aspect of care in children with anorexia nervosa (AN). The effects of hGH therapy have not been studied. The aim was to investigate the effect of hGH treatment on height velocity (HV) in children with AN.
Methods:
We carried out a retrospective observational study. Ten girls diagnosed with...
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Background: Growth hormone deficiency (GHD) is suspected in subjects with short stature (SS) and reduced growth velocity in whom other causes of poor growth have been excluded. Insulin-like growth factor-1 (IGF-1) measurements are relatively newer methods for evaluating GHD or GH adequacy. Objective: To study the relation between levels of leptin a...
Citations
... This treatment did not induce an increase in circulating insulin-like growth factor-1 levels but decreased fat mass without effect on body weight [93]. In adolescents with anorexia nervosa treatment with recombinant growth hormone induced an increase of insulin-like growth factor-1 and led to a stimulation of height velocity [94]. Data from this pilot study should be followed up in a larger and controlled manner. ...
Introduction:
Anorexia nervosa is a frequent eating disorder that affects predominantly young women and may take a severe and chronically worsening course of disease contributing to its high mortality rate. Although a multitude of treatment options exist, this disease still bears a high relapse rate. In light of these facts, an improvement of existing and development of new treatment targets and options is warranted.
Areas covered:
The present review article covers recent developments in psychotherapy associated with the respective neuropsychological and brain alterations as well as highlights current and future pharmacotherapeutic options.
Expert opinion:
Several encouraging developments in the field of psychotherapy such as interventions targeting neurocognitive profiles or addressing reward processing, brain stimulation as well as pharmacological modulation of hormones, namely leptin, oxytocin, ghrelin and nesfatin-1 signaling might be - most likely as part of a multimodal treatment approach - efficacious in order to improve treatment of patients with anorexia nervosa, especially those with a severe course of disease as well as comorbidities. As anorexia nervosa represents a complex and severe mental disorder, it seems most likely that a combination and integration of different evidence-based treatment approaches and settings will contribute to an improved prognosis of this eating disorder. This should be further explored in future studies.
... The above drugs are reported to affect blood glucose levels and improve depression (Kessing et al. 2020). Fourth, we did not measure the levels of insulin and glycosylated hemoglobin, which are more accurate indicators of abnormal glucose metabolism (Léger et al. 2017). Fifth, there is no healthy controls in this study. ...
Depressive symptoms and abnormal glycolipid metabolisms are common in patients with Parkinson’s disease (PD), but their relationship has not been fully reported. It is not clear whether glycolipid impairments lead to poor cognitive and motor function, and aggravate depressive symptoms. Therefore, we aimed to explore the relationships between glycolipid variables, cognition, motor and depressive symptoms in PD patients cross-sectionally. Two hundred ten PD patients were recruited. Glycolipid parameters and Uric acid (UA) were measured. Depressive symptoms, cognitive function and motor symptoms were assessed using the Hamilton Depression Rating Scale-17 (HAMD-17), the Montreal Cognitive Assessment (MOCA) and the Movement Disorder Society Unified Parkinson’s Disease Rating Scale Part-III (UPDRS-III). Depressive PD patients had significantly worse motor symptoms and higher levels of fasting plasma glucose (FPG) than those in non-depressive patients (F = 24.145, P < 0.001). Further, logistic regression analysis indicated that UPDRS-III (OR = 1.039, 95% CI 1.019–1.057, P = 0.044), FPG (OR = 1.447, 95% CI 1.050–1.994, P = 0.024) were independently associated with depression. In PD patients without depression, UA (β = − 0.068, t = − 2.913, P = 0.005) and cholesterol (CHOL) (β = − 3.941, t = − 2.518, P = 0.014) were independent predictors of the UPDRS-III score; in addition, UPDRS-III score was negatively associated with MOCA score (β = − 0.092, t = − 2.791, P = 0.007). FPG levels and motor symptoms were related to depressive symptoms in PD patients. Further, in non-depressive PD patients, UA and CHOL showed putative biomarkers of motor symptoms.
... The growth response to rhGH treatment in children with 3M syndrome is variable and modest [185]. Interestingly, GH treatment appears effective in increasing growth in girls with anorexia nervosa, despite the GHI associated with this condition [191]. ...
The current differential diagnosis for a short child with low insulin-like growth factor I (IGF-I) and a normal growth hormone (GH) peak in a GH stimulation test (GHST), after exclusion of acquired causes, includes the following disorders: (1) a decreased spontaneous GH secretion in contrast to a normal stimulated GH peak (“GH neurosecretory dysfunction,” GHND) and (2) genetic conditions with a normal GH sensitivity (e.g., pathogenic variants of GH1 or GHSR ) and (3) GH insensitivity (GHI). We present a critical appraisal of the concept of GHND and the role of 12- or 24-h GH profiles in the selection of children for GH treatment. The mean 24-h GH concentration in healthy children overlaps with that in those with GH deficiency, indicating that the previously proposed cutoff limit (3.0–3.2 μg/L) is too high. The main advantage of performing a GH profile is that it prevents about 20% of false-positive test results of the GHST, while it also detects a low spontaneous GH secretion in children who would be considered GH sufficient based on a stimulation test. However, due to a considerable burden for patients and the health budget, GH profiles are only used in few centres. Regarding genetic causes, there is good evidence of the existence of Kowarski syndrome (due to GH1 variants) but less on the role of GHSR variants. Several genetic causes of (partial) GHI are known ( GHR , STAT5B , STAT3 , IGF1 , IGFALS defects, and Noonan and 3M syndromes), some responding positively to GH therapy. In the final section, we speculate on hypothetical causes.
... We previously reported, in an open observational pilot study, the beneficial effect of growth hormone (GH) treatment for increasing HV in severely affected girls with AN and a prolonged low HV (13). However, these findings were obtained in a noncontrolled trial, which may have affected the results. ...
... To the best of our knowledge, our previous observational study (13) and this trial are the only studies to have investigated changes in HV in children with AN on GH treatment. However, this study is subject to several limitations. ...
... growth factors and bone metabolism parameters, SDS expressed for sex, age, and Tanner pubertal stage(13). ...
Context
Children with anorexia nervosa (AN) are at risk of adult height deficit due to prolonged low height velocity (HV).
Objective
To investigate the effects of human growth hormone (GH) injections on HV in children with AN and severe growth impairment.
Design and participants
In this prospective, randomized, double-blind, single-center, proof-of-concept trial, children with AN and low HV (≤2 cm/y) for at least 18 months, and a bone age ≤12 years for girls and 14 years for boys, were randomized to receive daily subcutaneous injections of hGH (0.050 mg/kg/d) or placebo for 12 months.
Main outcome measures
Change in HV after 12 months.
Results
In total, eight patients were assigned to the GH group and six to the placebo group. Patients had a median (25-75 th percentile) HV of 1.0 (0.5;1.5) cm/year. The effect of GH treatment increased strongly after six months, with a height gain after 12 months of 9.65 (8.0;11.6) cm for the GH group vs.3.85 (1.7;7.3) cm for the placebo group, with an absolute median (2.5 th-97.5 th percentile) difference between the groups of 5.8 (-1.85;9.68) cm after bootstrapping. The percentage of patients with a HV>5 cm/y during the study period was higher in the GH group than in the placebo group (100% vs.50%, p=0.05). Adverse events occurred in similar numbers in the two groups, were mild or non-fatal, and did not lead to treatment being stopped.
Conclusion
GH administration to improve HV is a potentially valid option for increasing HV in children with AN and prolonged severe growth failure.
... Indeed, in adolescent girls and women, one of the criteria for a minimum weight compatible with good health is the reappearance of menstruation. This criterion is not appropriate for use in young children with early-onset prepubertal AN, but, in this population, very specific growth failure [23] and pubertal delay or arrest can be considered a relevant clinical parameter, changes which can be used to assess the effectiveness of refeeding. Moreover, weight goals should be reviewed regularly during the refeeding of children and adolescents, to take into account their growth, given the limited time window available for potentially effective treatment [13]. ...
... Finally, AN is accompanied by multiple neuroendocrine dysfunctions involving the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis, thyroid function, hypercortisolemia, hypogonadotropic hypogonadism, and the levels of several adipokines and gut peptides, such as ghrelin and peptide YY [23], but the clinical relevance of monitoring this parameters is lacking; these laboratory tests are expansive. ...
... Finally, a recent pilot study showed that GH treatment in young adolescents with AN and severe growth failure was associated with significant improvements in linear growth [23]. These improvements in linear growth may, in turn, have a major impact on weight restoration and refeeding. ...
Refeeding in anorexia nervosa is a collaborative enterprise involving multidisciplinary care plans, but clinicians currently lack guidance, as treatment guidelines are based largely on clinical confidence rather than more robust evidence. It seems crucial to identify reproducible approaches to refeeding that simultaneously maximize weight recovery and minimize the associated risks, in addition to improving long-term weight and cognitive and behavioral recovery and reducing relapse rates. We discuss here various approaches to refeeding, including, among others, where, by which route, how rapidly patients are best refed, and ways of choosing between them, taking into account the precautions or the potential effects of medication or of psychological care, to define better care plans for use in clinical practice.Conclusion: The importance of early weight gain for long-term recovery has been demonstrated by several studies in both outpatient and inpatient setting. Recent studies have also provided evidence to support a switch in current care practices for refeeding from a conservative approach to higher calorie refeeding. Finally, the risks of undernutrition/“underfeeding syndrome” and a maintenance of weight suppression are now better identified. Greater caution should still be applied for more severely malnourished < 70% average body weight and/or chronically ill, adult patients.
What is Known:
• Refeeding is a central part of the treatment in AN and should be a multidisciplinary and collaborative enterprise, together with nutritional rehabilitation and psychological support, but there are no clear guidelines on the management of refeeding in clinical practice.
• The risk of a refeeding syndrome is well known and well managed in severely malnourished patients (“conservative approaches”).
What is New:
• There is evidence that early weight restoration has an impact on outcome, justifying an aggressive approach to refeeding in the early stages of the illness.
• The risks of “underfeeding syndrome” and of a maintenance of weight suppression are now better identified and there is sufficient evidence to support a switch in current care practices for refeeding from a conservative approach to higher calorie refeeding.
Graphical abstract
... To date, no systematic review concerning endocrine medications exists, but we found a few recent, innovative studies on promising hormone treatments conducted among female AN patients: one study concerned recombinant human growth hormone (rhGH) replacement among adult AN women [150], one study concerned rhGH treatment among AN children [151], one study concerned oestrogen replacement among adolescent AN girls [152], one study concerned GnRH among weight-recovered AN [153] and one study concerned recombinant human leptin among underweight women [154]. We report these five studies on these innovative hormone medications in the following sections, and they are summarized in Table S1. ...
... In a proof-of-concept study reported by Léger et al [151], recombinant human growth hormone (rhGH) treatment has recently been shown to greatly increase HV among AN adolescents with delayed puberty and prolonged severe growth failure (HV < 2.5 cm/year for at least 18 months at the age of 13.3 ± 1.1 years) within one year of treatment instatement. Serum IGF-I levels increased to the mid-normal range for all patients; HV increased significantly, from a median of 1.0 (0.7-2.1) to 7.1 (6.0-9.5) ...
... The evidence of a higher risk of osteoporosis and spontaneous fracture among AN subjects with amenorrhea [17,19] raised the question of the use of bisphosphonate or oestrogen replacement to treat low bone density [39,49,50]. Other hormone replacement therapies for the endocrine consequences of AN, such as growth or pubertal delay, appeared in the 2000s in association with endocrine-paediatric management in the context of a multidisciplinary approach [151,157]. Two recent narrative update reviews on endocrine mechanisms and repercussions in AN report on available treatments and innovative therapeutic strategies in endocrinology [189,190]. Physicians' interest in refeeding modalities [191], relating to optimal daily calorie requirements [42], the risk of over-feeding and that of under-feeding, high calorie oral supplementation [116], vitamin supplementation and functional digestive disorder medications [139], is fairly recent and corresponds to the development of specific nutritional and dietary expertise, alongside the publication of international guidelines [2,3]. ...
Drugs are widely prescribed for anorexia nervosa in the nutritional, somatic, and psychiatric fields. There is no systematic overview in the literature, which simultaneously covers all these types of medication. The main aims of this paper are (1) to offer clinicians an overview of the evidence-based data in the literature concerning the medication (psychotropic drugs and medication for somatic and nutritional complications) in the field of anorexia nervosa since the 1960s, (2) to draw practical conclusions for everyday practise and future research. Searches were performed on three online databases, namely MEDLINE, Epistemonikos and Web of Science. Papers published between September 2011 and January 2019 were considered. Evidence-based data were identified from meta-analyses, if there were none, from systematic reviews, and otherwise from trials (randomized or if not open-label studies). Evidence-based results are scarce. No psychotropic medication has proved efficacious in terms of weight gain, and there is only weak data suggesting it can alleviate certain psychiatric symptoms. Concerning nutritional and somatic conditions, while there is no specific, approved medication, it seems essential not to neglect the interest of innovative therapeutic strategies to treat multi-organic comorbidities. In the final section we discuss how to use these medications in the overall approach to the treatment of anorexia nervosa.
... Indeed, in ado- lescent girls and women, one of the criteria for a minimum weight compatible with good health is the reappearance of menstruation. This criterion is not appropriate for use in young children with early-onset prepubertal AN, but, in this popula- tion, very specific growth failure [23] and pubertal delay or arrest can be considered a relevant clinical parameter, changes which can be used to assess the effectiveness of refeeding. Moreover, weight goals should be reviewed regularly during the refeeding of children and adolescents, to take into account their growth, given the limited time window available for potentially effective treatment [13]. ...
... Finally, AN is accompanied by multiple neuroendocrine dysfunctions involving the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis, thyroid function, hypercortisolemia, hypogonadotropic hypogonadism, and the levels of several adipokines and gut peptides, such as ghrelin and peptide YY [23], but the clinical relevance of monitoring this parameters is lacking; these laboratory tests are expansive. ...
... Finally, a recent pilot study showed that GH treatment in young adolescents with AN and severe growth failure was associated with significant improvements in linear growth [23]. These improvements in linear growth may, in turn, have a major impact on weight restoration and refeeding. ...
Linear growth is a complex process and is considered one of the best indicators of children’s well-being and health. Genetics, epigenetics and environment (mainly stress and availability of nutrients) are the main regulators of growth. Nutrition exerts its effects on growth throughout the course of life with different, not completely understood mechanisms. Cells have a sophisticated sensing system, which allows growth processes to occur in the presence of an adequate nutrient availability. Most of the nutritional influence on growth is mediated by hormonal signals, in turn sensitive to nutritional cues. Both macro- and micro-nutrients are required for normal growth, as demonstrated by the impairment of growth occurring when their intake is insufficient. Clinical conditions characterized by abnormal nutritional status, including obesity and eating disorders, are associated with alterations of growth pattern, confirming the tight link between growth and nutrition. The precise molecular mechanisms connecting nutrition to linear growth are far from being fully understood and further studies are required. A better understanding of the interplay between nutrients and the endocrine system will allow one to develop more appropriate and effective nutritional interventions for optimizing child growth.
Growth hormone (GH) and insulin like growth factor-I (IGFI) are key bone trophic hormones, whose rising levels during puberty are critical for pubertal bone accrual. Conditions of GH deficiency and genetic resistance impact cortical and trabecular bone deleteriously with reduced estimates of bone strength. In humans, conditions of undernutrition (as in anorexia nervosa (AN), or subsequent to chronic illnesses) are associated with low IGF-I levels, which correlate with disease severity, and also with lower bone mineral density (BMD), impaired bone structure and lower strength estimates. In adolescents and adults with AN, studies have demonstrated a nutritionally acquired GH resistance with low IGF-I levels despite high concentrations of GH. IGF-I levels go up with increasing body weight, and are associated with rising levels of bone turnover markers. In short-term studies lasting 6–10 days, recombinant human IGF-I (rhIGF-I) administration in physiologic replacement doses normalized IGF-I levels and increased levels of bone formation markers in both adults and adolescents with AN. In a randomized controlled trial in adults with AN in which participants were randomized to one of four arms: (i) rhIGF-I with oral estrogen-progesterone (EP), (ii) rhIGF-I alone, (iii) EP alone, or (iv) neither for 9 months, a significant increase in bone formation markers was noted in the groups that received rhIGF-I, and a significant decrease in bone resorption markers in the groups that received EP. The group that received both rhIGF-I and EP had a significant increase in bone density at the spine and hip compared to the group that received neither. Side effects were minimal, with no documented fingerstick glucose of <50 mg/dl. These data thus suggest a potential role for rhIGF-I administration in optimizing bone accrual in states of undernutrition associated with low IGF-I.
Anorexia nervosa is a syndrome, i.e. collections of symptoms, which it is not defined by etiology. The severe cases are intractable. The syndrome is associated with multiple, profound endocrine alterations which may be adaptive, reactive or etiologic. Adaptive changes potentially may be inappropriate in clinical settings such as inpatient intensive re-nutrition or in a setting with somatic comorbidity. Electrolyte levels must be closely monitored during the refeeding process, and the need for weight gain must be balanced against potentially fatal refeeding complications. An important focus of clinical research should be to identify biomarkers associated with different stages of weight loss and re-nutrition combined with psychometric data. Besides well-established peripheral endocrine actions, several hormones also are released directly to different brain areas, where they may exert behavioral and psychogenic actions that could offer therapeutic targets. We need reliable biomarkers for predicting outcome and to ensure safe re-nutrition, however, first of all we need them to explore the metabolism in anorexia nervosa to open new avenues with therapeutic targets. A breakthrough in our understanding and treatment of this whimsical disease remains. Considering this, the aim of the present review is to provide an updated overview of the many endocrine changes in a clinical perspective.
