Sarah Bocchini

Use of GLP-1 Receptor Agonists in Prader-Willi Syndrome: Report of Six Cases

A high incidence of glucose metabolism alterations (impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes) has been observed in Prader-Willi syndrome (PWS) (7–40%), particularly after pubertal age and in obese subjects (1). Glucagon-like peptide 1 (GLP-1) receptor agonist (exenatide) and analog (liraglutide) are the new drugs recently introduced for type 2 diabetes that simultaneously reduce appetite and body weight, and their beneficial effects have been reported only in few cases with PWS (2–5). We report, for the first time, the effects of long-term liraglutide or exenatide treatment in six genetically confirmed (3 deletion and 3 uniparental disomy of chromosome 15) (UPD) adult PWS patients (3 males, aged 20.7–37.7 years; all but one obese, BMI 28–57.2 kg/m2) never treated with growth hormone, affected by type 2 diabetes. All patients were treated at least …

Growth Hormone Response to Standard Provocative Stimuli and Combined Tests in Very Young Children with Prader-Willi Syndrome

Background: In Prader-Willi syndrome (PWS) a reduced growth hormone (GH) response to several stimulators has been documented in many studies, but none have focused on very young children. We evaluated the pattern of GH secretion in very young PWS patients. Patients and Methods: Twenty-seven genetically confirmed PWS children (10 females, aged 0.4-5 years, mean: 2.2 ± 1.4 years) were included. All subjects underwent standard provocative tests (clonidine, CLO; and arginine, ARG) and one combined test [growth hormone-releasing hormone (GHRH) plus pyridostigmine (13 patients) or GHRH plus arginine (14 patients)]. Insulin-like growth factor-1 (IGF-1) levels were also measured. Results: While standard tests (CLO and ARG) showed low GH peak in 85.2 and 70.4% of the patients, respectively, the combined test was found to be normal in 85.2%. IGF-1 was low in 66.7% of patients. Out of 27 patients, 3 (11%) showed a normal GH peak with both standard tests (group A), 6 (22%) to one of the standard tests (group B) and 18 (67%) presented a low response to both standard tests (group C). Four subjects showed low response to both the combined and standard tests and reduced IGF-1. Conclusion: Our data suggest that very young PWS children seem to have impaired hypothalamic GHRH secretion with a normal GH pituitary reserve.

Non-Alcoholic Fatty Liver Disease (NAFLD) in children and adolescents with Prader-Willi Syndrome (PWS)

We tested the hypothesis that patients with Prader–Willi syndrome (PWS) may be at lower risk of developing non‐alcoholic fatty liver disease (NAFLD) because of a higher insulin sensitivity. Twenty‐one PWS patients and 42 control subjects closely similar for age, gender, pubertal stage and body mass index (CNT), were studied. Metabolic profile and body composition were assessed. NAFLD was established by a validated method of US grading (range from G0 to G3). PWS patients showed a significantly better metabolic profile (lower waist circumference, fasting glucose levels, HOMA‐IR, cholesterol, transaminase levels and trunk fat mass/fat mass ratio). Furthermore, NAFLD G1stage was significantly more frequent in PWS subjects (P < 0.05), whereas G2 stage was significantly more frequent in control patients (P < 0.05). NAFLD grading seems to correlate with body composition in PWS, also after adjustment for sex and GH treatment. To our knowledge, this is the first report suggesting a reduced risk of NAFLD in PWS children.

AZP-531, an unacylated ghrelin analog, improves food-related behavior in patients with Prader-Willi syndrome: A randomized placebo-controlled trial

Context and objective Prader-Willi syndrome (PWS) is characterized by early-onset hyperphagia and increased circulating levels of the orexigenic Acylated Ghrelin (AG) hormone with a relative deficit of Unacylated Ghrelin (UAG). AZP-531, a first-in-class UAG analog, was shown to inhibit the orexigenic effect of AG in animals, to improve glycemic control and decrease body weight in humans. We aimed to investigate the safety and efficacy of AZP-531 in patients with PWS for whom no approved treatment for hyperphagia is currently available. Methods and design Multi-center, randomized, double-blind, placebo-controlled trial. Forty-seven patients with genetically confirmed PWS and evidence of hyperphagia received daily subcutaneous injections of AZP-531 (3 and 4 mg for 50–70 kg and >70 kg body weight, respectively) or matching placebo for 14 days. Assessments included adverse events, vital signs, safety laboratory tests, the Hyperphagia Questionnaire (HQ), patient-reported appetite, body composition and glycemic measures. Results AZP-531 was well tolerated. There was a significant improvement with AZP-531 versus placebo in the mean total score, the 9-item score and the severity domain score of the HQ (p < .05). The highest reduction in the total and 9-item scores was observed in AZP-531 subjects with the highest hyperphagia score at baseline. Findings were supported by a reduction in appetite scores observed with AZP-531 only. Body weight did not change in both groups while a significant reduction in waist circumference and fat mass was observed only with AZP-531. AZP-531 significantly decreased post-prandial glucose levels in a baseline glucose dependent fashion. Conclusions AZP-531 may constitute a new treatment strategy to improve hyperphagia and metabolic issues in patients with PWS. These findings support further investigation in longer-term clinical trials.

Autoimmune pituitary involvement in Prader–Willi syndrome: new perspective for further research

The role of antipituitary antibodies in the pathophysiology of pituitary hormone deficiency has been increasingly elucidated over the last decade. Prader-Willi syndrome is a genetic disorder which includes hypothalamic/pituitary dysfunction as one of its main features. We looked for autoimmune pituitary involvement in 55 adults with Prader-Willi syndrome, discovering that about 30% of them have a positive titer of antipituitary antibodies. Although the presence of these autoantibodies could only be an “epiphenomenon”, our results suggest that autoimmune mechanisms might contribute, at least in part, to the pituitary impairment of Prader-Willi syndrome, and in addition to genetically determined dysfunction of the central nervous system. This paper provides a new perspective on pituitary impairment in these patients, suggesting that the search for hypophisitis could be a reasonable and interesting field for further research.

Obesity management in Prader–Willi syndrome: current perspectives

Prader–Willi syndrome (PWS) is a complex multisystem disorder due to the absent expression of the paternally active genes in the PWS critical region on chromosome 15 (15q11.2-q13). The syndrome is considered the most common genetic cause of obesity, occurring in 1:10,000–1:30,000 live births. Its main characteristics include neonatal hypotonia, poor feeding, and lack of appetite in infancy, followed by weight gain, lack of satiety, and uncontrolled appetite, frequently after the age of 2–3 years. The clinical picture includes short stature, multiple endocrine abnormalities (hypogonadism, growth hormone/insulin-like growth factor-I axis dysfunction, hypothyroidism, central adrenal insufficiency), dysmorphic features, scoliosis, osteoporosis, mental retardation, and behavioral and psychiatric problems. Subjects with PWS will become severely obese unless their food intake is strictly controlled. Constant and obsessive food seeking behavior can make life very difficult for both the family and caretakers. Prevention of obesity is mandatory in these patients from the first years of life, because once obesity develops it is difficult to maintain the control of food intake. In fact, PWS subjects die prematurely from complications conventionally related to obesity, including diabetes mellitus, metabolic syndrome, sleep apnea, respiratory insufficiency, and cardiovascular disease. The mechanisms underlying hyperphagia in PWS are not completely known, and to date no drugs have proven their efficacy in controlling appetite. Consequently, dietary restriction, physical activity, and behavior management are fundamental in the prevention and management of obesity in PWS. In spite of all available therapeutic tools, however, successful weight loss and maintenance are hardly accomplished. In this context, clinical trials with new drugs have been initiated in order to find new possibilities of a therapy for obesity in these patients. The preliminary results of these studies seem to be encouraging. On the other hand, until well-proven medical treatments are available, bariatric surgery can be taken into consideration, especially in PWS patients with life-threatening comorbidities.

GHRH plus arginine and arginine administration evokes the same ratio of GH isoforms levels in young patients with Prader-Willi syndrome

Human GH is present in pituitary and circulation as several isoforms, the prevalent being 22kDa- and 20kDa-GH. Recently, we have demonstrated the preservation of a normal balance in GH isoforms after GH releasing hormone (GHRH) plus arginine (ARG) administration in adult patients with Prader-Willi syndrome (PWS), one of the most common causes of syndromic obesity, often associated with GH deficiency (GHD). Aim of the present study was to measure circulating levels of 22kDa- and 20kDa-GH in young PWS patients (n=24; F/M: 10/14; genotype UPD/DEL/met+: 11/11/2; age: 10.8±5.3years; BMI SDS: 2.0±2.0; GHD: 16/24; obesity: 12/24) after combined GHRH+ARG or ARG administration. The results were analysed subdividing the GHRH+ARG and ARG groups on the basis of PWS genotype, GHD status and obesity. Circulating levels of 22kDa- and 20kDa-GH were measured by a chemiluminescent or fluorescent method based on specific pairs of monoclonal antibodies. GHRH+ARG or ARG significantly stimulated the secretion of 22kDa-GH but not that of 20kDa-GH in all PWS patients. No significant GHRH+ARG- vs. ARG-induced changes in the ratios of 22kDa- to 20kDa-GH peaks were observed in all PWS patients, although 22kDa- or 20kDa-GH peaks were significantly higher in the GHRH+ARG than ARG group. When subdividing PWS patients in UPD vs. DEL, obese vs. non obese and GHD vs. non GHD subgroups, GH peaks were significantly higher in nonobese than obese patients and in non GHD than GHD patients administered with either GHRH+ARG or ARG test, apart from the comparisons in the DEL/UPD subgroups. Anyway, the ratios of peak levels of 22kDa- to 20kDa-GH were similar after GHRH+ARG vs. ARG in all subgroups investigated. In conclusion, this study shows that administration of two different pharmacological tests, i.e. ARG, capable of reducing hypothalamic somatostatinergic tone, and GHRH (+ARG), that directly acts at pituitary level on the somatotropic cell, evokes the same ratios of GH isoforms in young PWS patients, suggesting that the hypothalamic dysfunction in this genetic disorder does not alter the qualitative and quantitative composition of GH isoforms present in circulation.

Prader–Willi syndrome: clinical problems in transition from pediatric to adult care

php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Research and Reports in Endocrine Disorders 2016:6 49–57 Research and Reports in Endocrine Disorders Dovepress

Assessment of the hypothalamus-pituitary-adrenal axis with different corticotropin tests in adult patients with Prader-Willi syndrome

Hypothalamic-pituitary anomalies are well proven in Prader-Willi syndrome (PWS), consistent with deficiency of many pituitary hormones. In this context, we have previously demonstrated that central adrenal insufficiency (CAI) may be part of the PWS phenotype. However, the diagnostics of CAI insufficiency is a critical issue, due to the variety of the diagnostic stimulations available, to the lack of flawless and fully reliable tests, and to the difficulties in their interpretation. The hypothalamus-pituitary-adrenal (HPA) axis response to insulin hypoglycemia (ITT) is still considered the gold standard in the evaluation of suspected CAI, even though its validity has been recently questioned. Several studies have looked at the clinical usefulness of the low dose (1 μg) short synacthen test (LDSST) compared to the conventional dose (250 μg) test (SDSST) in patients with pituitary disease. Actually, the dose used in the conventional SDSST is considered supraphysiological and might produce a deceivingly adequate cortisol (F) response. Nevertheless, other reports suggested no difference between the LDSST and SDSST in patients with multiple pituitary hormone deficiency.