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Context Previous studies report that outcomes of growth hormone (GH) replacement therapy (GHRT) might be less beneficial in growth hormone deficient (GHD) women compared with men. Objective This study investigated possible contributing factors regarding this previously found sex difference. Methods This retrospective cohort study, conducted at a nationwide outpatient clinic (the Dutch National Registry of GH Treatment in Adults), included Dutch adult GHD men (n = 1335) and women (n = 1251) treated with GHRT. The patients’ baseline characteristics, details of GHRT, and the tolerability and long-term safety of GHRT were measured. Results During treatment, sensitivity analysis showed that insulin-like growth factor-1 (IGF-1) SD scores remained subnormal more often in women (P < 0.001), while scores above normal were more frequent in men (P < 0.001). Women reported more adverse events (P < 0.001), especially symptoms related to fluid retention, and more often needed a dose reduction or temporary stop of GHRT (P = 0.001). In percentages, both sexes equally discontinued GHRT, as was also true for the risk in developing type 2 diabetes mellitus, benign neoplasms, and tumor recurrence. The risk of developing malignant neoplasms was higher in men (P = 0.012). Conclusion Data obtained from the Dutch National Registry of GH Treatment in Adults indicate that GHD women might be treated suboptimally, reflected as lower IGF-1 status and lower GHRT tolerability, leading to more frequent changes in treatment regimen but not discontinuation of GHRT. Regarding long-term safety, we found a higher risk for development of malignancies in GHD men.

Objective Adolescents and young adults (AYA) with common endocrine disorders show a high dropout (up to 50%) after the transfer from paediatric to adult endocrinology. Little is known about transition readiness in rare endocrine conditions (rEC). This study aims to assess medical self-management skills (SMS) among AYA with rEC in relation to age and gender, in order to understand dropout and increase transition readiness. Design Cross-sectional study using web-based medical self-management questionnaires. Methods Questionnaires consisting of 54 questions in seven domains were filled out by the adolescents before the first shared appointment with both paediatric and adult endocrinologist. Results Fifty-seven patients (median age 17 years, 25/57 females) participated and generally scored well on most items. However, one out of seven did not know the name of their disorder, one sixth of the glucocorticoid users did not know that dose should be adapted in case of illness or surgery, over one-fifth had never ordered their repeat prescriptions themselves and two-thirds had never had a conversation alone with their doctor. Conclusions Several SMS among patients with rEC are insufficient, with regard to medical knowledge, practical skills and communication. As SMS are only weakly related to non-modifiable factors, such as age and gender, we recommend focussing on other factors to increase transition readiness. The timing, amount and ‘mode’ of medical information should be individualised. Transition checklists should be used to detect shortcomings in practical skills and communication, which can subsequently be trained with the help of parents, caregivers and/or e-technology.

Background Prader-Willi syndrome (PWS) is a complex rare genetic disorder associated with hypothalamic dysfunction, pituitary hormone deficiencies, hyperphagia and (morbid) obesity. PWS is caused by loss of expression of paternally expressed genes on chromosome 15q11.2-q13. The most common genetic mechanisms leading to PWS are paternal deletion (DEL) and maternal uniparental disomy (mUPD). DELs can be subdivided in type 1 and (smaller) type 2 deletions (DEL-1, DEL-2). Most research has focused on behavioral, cognitive and psychological differences between patients with a DEL-1, DEL-2 or mUPD. However, little is known about the genetic subtype differences in relation to physical health problems. Methods We reviewed the medical files of all adults with genetically confirmed PWS who visited the outpatient clinic of the Center for Adults with Complex Rare Genetic Syndromes at the Erasmus University Medical Center, Rotterdam, the Netherlands, between January 2015 and June 2021. All patients underwent a systematic health screening, including a structured interview, a medical questionnaire, a complete physical examination, biochemical measurements, and a review of the medical records. Health problems, physical complaints, symptoms of disease and behavioral challenges were compared between adults with an mUPD and DEL and between adults with a DEL-1 and DEL-2. Results Twenty-eight adults had an mUPD and 65 a DEL (13 DEL-1, 27 DEL-2, 25 unspecified). Gender, age and BMI did not differ between the genetic subgroups. Although psychiatric problems (psychotic episodes) were significantly more often present in adults with an mUPD (P < 0.001) and scoliosis was more prevalent among patients with DEL (P = 0.04), there was only a slight difference in prevalence of other medical problems like hypertension, cold intolerance, edema, hyperphagia, skin picking, abdominal pain and fatigue. There were no significant differences between DEL-1 and DEL-2. However, fatigue, cold intolerance, edema and hyperphagia were slightly more prevalent among adults with a DEL-1, whereas osteopenia, constipation and skin picking were more prevalent among adults with a DEL-2. Conclusion The differences in health problems between PWS adults with DEL-1, DEL-2 and mUPD are mostly present in the psychological domain. Especially psychotic episodes were more frequent in adults with an mUPD. Apart from scoliosis, there were no significant differences in physical health outcomes between the genetic subtypes. Presentation: Sunday, June 12, 2022 1:00 p.m. - 1:05 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Pasireotide, a multireceptor-targeted somatostatin analog with highest affinity for somatostatin receptor subtype (SST) 5, has demonstrated superior efficacy over the SST2-preferential somatostatin analogs octreotide and lanreotide. The safety profile is similar to those of octreotide and lanreotide, except for a higher frequency and degree of hyperglycemia. This analysis investigated baseline characteristics and occurrence and management of hyperglycemia during pasireotide treatment in patients with acromegaly treated in two prospective clinical studies, SOM230C2305 (C2305) and SOM230C2402 (C2402; PAOLA). One hundred and seventy-eight patients naïve to medical therapy at baseline (C2305) and 125 uncontrolled on first-generation somatostatin analogs at baseline (C2402) received long-acting pasireotide in these studies. Of patients treated with pasireotide in studies C2305 and C2402, respectively, 75.3 (134/178) and 65.6% (82/125) developed hyperglycemia or experienced worsening of existing hyperglycemia. Occurrence of hyperglycemia during pasireotide treatment was less frequent in patients with lower age (1c

Objective T2-signal intensity and somatostatin (SST) receptor expression are recognized predictors of therapy response in acromegaly. We investigated the relationship between these predictors and the hormonal and tumoral responses to long-acting pasireotide (PAS-LAR) therapy, which were also compared with responsiveness to first-generation somatostatin receptor ligands (SRLs). Design The PAPE study is a cohort study. Methods We included 45 acromegaly patients initially receiving SRLs, followed by combination therapy with pegvisomant, and finally PAS-LAR. We assessed tumor volume reduction (≥25% from baseline), IGF-1 levels (expressed as the upper limit of normal), and T2-weighted MRI signal and SST receptor expression of the adenoma. Results Patients with significant tumor shrinkage during PAS-LAR showed higher IGF-1 levels during PAS-LAR (mean (S.D.): 1.36 (0.53) vs 0.93 (0.43), P = 0.020), less IGF-1 reduction after first-generation SRLs (mean (S.D.): 0.55 (0.71) vs 1.25 (1.07), P = 0.028), and lower SST2 receptor expression (median (IQR): 2.0 (1.0–6.0) vs 12.0 (7.5–12.0), P = 0.040). Overall, T2-signal intensity ratio was increased compared with baseline (mean (S.D.): 1.39 (0.56) vs 1.25 (0.52), P = 0.017) and a higher T2-signal was associated with lower IGF-1 levels during PAS-LAR (β: −0.29, 95% CI: −0.56 to −0.01, P = 0.045). A subset of PAS-LAR treated patients with increased T2-signal intensity achieved greater reduction of IGF-1 (mean (S.D.): 0.80 (0.60) vs 0.45 (0.39), P = 0.016). Conclusions Patients unresponsive to SRLs with a lower SST2 receptor expression are more prone to achieve tumor shrinkage during PAS-LAR. Surprisingly, tumor shrinkage is not accompanied by a biochemical response, which is accompanied with a higher T2-signal intensity.

Purpose Although quality of life (QoL) is improved in patients with acromegaly after disease control, QoL correlates only weakly with traditional biomarkers. Our objective is to investigate a potential relation between the new serum biomarker soluble Klotho (sKlotho), GH and insulin-like growth factor 1 (IGF-1) levels, and QoL. Methods In this prospective cohort study, we investigated 54 acromegaly patients biochemically well-controlled on combination treatment with first-generation somatostatin receptor ligands (SRLs) and pegvisomant (PEGV) at baseline and 9 months after switching to pasireotide LAR (PAS-LAR; either as monotherapy, n = 28; or in combination with PEGV, n = 26). QoL was measured by the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) and Acromegaly Quality of Life (AcroQoL) questionnaire. Results Switching to PAS-LAR treatment significantly improved QoL without altering IGF-1 levels. QoL did not correlate with GH or IGF-1 levels, but sKlotho correlated with the observed improvements in QoL by the AcroQoL global (r = −0.35, p = 0.012) and physical subdimension (r = −0.34, p = 0.017), and with PASQ headache (r = 0.28, p = 0.048), osteoarthralgia (r = 0.46, p = 0.00080) and soft tissue swelling score (r = 0.29, p = 0.041). Parallel changes in serum sKlotho and IGF-1 (r = 0.31, p = 0.023) suggest sKlotho and IGF-1 to be similarly dependent on GH. Comparing the PAS-LAR combination therapy and the monotherapy group we did not observe a significant difference in improvement of QoL. Conclusions Patients experienced improved QoL during PAS-LAR, either as monotherapy or in combination with PEGV. Soluble Klotho concentrations appear to be a useful marker of QoL in acromegaly patients but the underlying mechanisms remain to be investigated.

Current guidelines recommend the use of long-acting somatostatin receptor ligands (SRLs) first when surgery fails to correct GH/IGF-I hypersecretion in patients with acromegaly. In this issue of the journal, a pro- and contra debate will outline which arguments are in favour and which are against positioning pegvisomant (PEGV), a GH receptor antagonist, as the first-line treatment modality of acromegaly. The task of the pros was to promote a paradigm shift towards repositioning PEGV as first-line treatment as PEGV is safe and more effective than the first- and second-generation of SRLs. SRLs, when prescribed together with PEGV can still reduce tumour size when necessary, while they decrease the necessary dose of PEGV by around 50% in the average patient. They conclude that PEGV must move up towards the first-line treatment. For the cons, SRLs remain the first-line medical treatment. Indeed, even if, in recent studies, the remission rate is lower than initially claimed, SRLs are still effective not only for normalizing GH/IGF-I levels in half of the patients but also for inducing tumour shrinkage, improving comorbidities and headaches and reversing excess mortality. They are more convenient for use with their monthly administration and have a remarkable safety profile as demonstrated by the very prolonged experience acquired by more than 30 years of use. Finally, the cost-effectiveness of first-generation SRLs is better than that of PEGV. For all these reasons, cons consider that SRLs remain the best first medical treatment in patients requiring medical therapy.

Context Craniopharyngioma is a sellar tumor associated with high rates of pituitary deficiencies (~98%) and hypothalamic obesity (~50%). Objective To determine the efficacy regarding long-term weight loss after bariatric surgery in obese craniopharyngioma patients with hypothalamic dysfunction. Design Retrospective case control study. Setting Multicenter international study. Patients and participants Obese craniopharyngioma patients (N = 16; of which 12 women) with a history of bariatric surgery [12 Roux-en-Y gastric bypass, 4 sleeve gastrectomy; median age of 21 years (range 15-52), median follow-up 5.2 years (range 2.0-11.3)] and age/sex/surgery/BMI-matched obese controls (N = 155). Main outcome measures Weight loss and obesity-related comorbidities up to 5 years after bariatric surgery were compared and changes in hormonal replacement therapy evaluated. Results Mean weight loss at 5-year follow-up was 22.0% (95% CI 16.1, 27.8) in patients versus 29.5% (28.0, 30.9) in controls (P = 0.02), which was less after Roux-en-Y gastric bypass (22.7% [16.9, 28.5] vs. 32.0% [30.4, 33.6]; P = 0.003) but at a similar level after sleeve gastrectomy (21.7% [–1.8, 45.2] vs. 21.8% [18.2, 25.5]; P = 0.96). No major changes in endocrine replacement therapy were observed after surgery. One patient died (unknown cause). One patient had long-term absorptive problems. Conclusions Obese patients with craniopharyngioma had a substantial mean weight loss of 22% at 5-year follow-up after bariatric surgery, independent of type of bariatric surgery procedure. Weight loss was lower than in obese controls after Roux-en-Y gastric bypass. Bariatric surgery appears effective and relatively safe in the treatment of obese craniopharyngioma patients.

Patients with complex rare genetic syndromes (CRGS) have combined medical problems affecting multiple organ systems. Pediatric multidisciplinary (MD) care has improved life expectancy, however, transfer to internal medicine is hindered by the lack of adequate MD care for adults. We have launched an MD outpatient clinic providing syndrome-specific care for adults with CRGS, which, to our knowledge, is the first one worldwide in the field of internal medicine. Between 2015 and 2020, we have treated 720 adults with over 60 syndromes. Eighty-nine percent of the syndromes were associated with endocrine problems. We describe case series of missed diagnoses and patients who had undergone extensive diagnostic testing for symptoms that could actually be explained by their syndrome. Based on our experiences and review of the literature, we provide an algorithm for the clinical approach of health problems in CRGS adults. We conclude that missed diagnoses and needless invasive tests seem common in CRGS adults. Due to the increased life expectancy, an increasing number of patients with CRGS will transfer to adult endocrinology. Internist-endocrinologists (in training) should be aware of their special needs and medical pitfalls of CRGS will help prevent the burden of unnecessary diagnostics and under- and overtreatment.

Context Cardiovascular (CV) risk profile might differ between growth hormone-treated patients with craniopharyngioma and non-functioning pituitary adenoma (NFPA), since patients with craniopharyngioma more frequently suffer from hypothalamic metabolic disruption. Objective The aim of this study is to investigate the CV risk profile in adult patients with craniopharyngioma compared to NFPA before and after treatment with growth hormone (GH) replacement therapy due to severe GH deficiency. Design A sub-analysis of the Dutch National Registry of Growth Hormone Treatment in Adults was performed, in which we compared 291 patients with craniopharyngioma to 778 patients with NFPA. CV risk profile and morbidity were evaluated at baseline and during long-term follow-up within and between both groups. Results At baseline, patients with craniopharyngioma demonstrated higher BMI than patients with NFPA, and men with craniopharyngioma showed greater waist circumference and lower HDL compared to men with NFPA. During follow-up, BMI, as well as diastolic blood pressure among patients using antihypertensive drugs, deteriorated in the craniopharyngioma group compared to the NFPA group. Lipid profile improved similarly in both groups over time. No differences were found between groups in the occurrence of diabetes mellitus, cerebrovascular accidents, CV disease, or overall mortality. Conclusion This study suggests that overall CV risk profile is worse in craniopharyngioma patients with GH deficiency compared to patients with NFPA. During GH replacement therapy, patients with craniopharyngioma demonstrated an increase in BMI over time, where BMI remained stable in patients with NFPA. Also, diastolic blood pressure did not improve with antihypertensive drugs in craniopharyngioma patients as seen in patients with NFPA.

With interest, we have read the article of Moriconi et al. [...]

Objective To report the final long-term safety and efficacy analyses of patients with acromegaly treated with pegvisomant from the ACROSTUDY. Design Global (15 countries), multicentre, non-interventional study (2004–2017). Methods The complete ACROSTUDY cohort comprised patients with acromegaly, who were being treated with pegvisomant (PEGV) prior to the study or at enrolment. The main endpoints were long-term safety (comorbidities, adverse events (AEs), pituitary tumour volumes, liver tests) and efficacy (IGF1 changes). Results Patients (n = 2221) were treated with PEGV for a median of 9.3 years (range, 0–20.8 years) and followed up for a median of 7.4 years (range, 0–13.9 years). Before PEGV, 96.3% had received other acromegaly treatments (surgery/radiotherapy/medications). Before PEGV treatment, 87.2% of patients reported comorbidities. During ACROSTUDY, 5567 AEs were reported in 56.5% of patients and of these 613 were considered treatment-related (in 16.5% of patients) and led to drug withdrawal in 1.3%. Pituitary imaging showed a tumour size increase in 7.1% of patients; the majority (71.1%) reported no changes. Abnormal AST or ALT liver tests occurred in 3.2% of patients. IGF1 normalization rate improved over time, increasing from 11.4% at PEGV start to 53.7% at year 1, and reaching 75.4% at year 10 with the use of ≥30 mg PEGV/day in an increasing proportion of patients. Conclusion This comprehensive review of the complete cohort in ACROSTUDY confirmed the overall favourable benefit-to-risk profile and high efficacy of PEGV as mono- and combination therapy in patients with an aggressive course/uncontrolled/active acromegaly requiring long-term medical therapy for control.

ContextFeatures of Prader-Willi syndrome (PWS) overlap with features of growth hormone (GH) deficiency, like small hands and feet, short stature, increased body fat, and low muscle mass and strength. In children with PWS, GH treatment (GHt) improves physical health and cognition. GHt has become the standard of care in PWS children, but in adults this is not yet the case.ObjectiveThis work aims to provide an overview of the current knowledge on GHt in PWS adults.MethodsMedline, Embase, and the Cochrane Central Register of Controlled Trials databases were searched. Study selection included randomized clinical trials (RCTs) and nonrandomized (un)controlled trials (NRCTs) that reported data for adults with PWS, who received GHt for at least 6 months. Data on body composition, body mass index (BMI), cardiovascular end points, bone, cognitive function, quality of life, and safety were extracted.ResultsNine RCTs and 20 NRCTs were included. Body composition improved during 12 months of GHt with an increase in mean (95% CI) lean body mass of 1.95 kg (0.04 to 3.87 kg) and a reduction of mean (95% CI) fat mass of –2.23% (–4.10% to –0.36%). BMI, low-density lipoprotein cholesterol levels, fasting glucose levels, and bone mineral density did not change during GHt. There were no major safety issues.ConclusionGHt appears to be safe and improves body composition in adults with PWS. Because poor body composition is closely linked to the observed high incidence of cardiovascular morbidity in adults with PWS, improving body composition might reduce cardiovascular complications in this vulnerable patient group.

Medical treatment of acromegaly is based on either suppressing pituitary GH secretion or inhibiting GH action by preventing interaction with its receptor in order to suppress the elevated levels of IGF1. AZP-3813 is a 16-amino acid, bicyclic peptide antagonist of the GH receptor (GHR) with a KD of 1.9nM for the human GHR, and 18.5nM for the rat GHR. The circulating half-life of AZP-3813 in the rat is 11.2 hours. In previous studies, AZP-3813 was demonstrated to suppress IGF1 secretion in juvenile rats in a dose-related manner, and to maintain IGF1 suppression when given over 4 days. To examine the ability of chronic AZP-3813 treatment to maintain suppression of IGF1 levels, we injected normal, 5-week old (∼150g), male Sprague Dawley rats subcutaneously either with vehicle or with AZP-3813 at doses of either 10 or 30mg/kg QD for 19 days (n=7/group). Blood samples were collected immediately prior to either vehicle or AZP-3813 injection on days 1, 2, 3, 7, 10, 15 and 19, and 24h after the last injection (day 20). Samples were assayed for total IGF1 content by radioimmunoassay, and samples collected on days 2, 10 and 19 were also analyzed for AZP-3813 content by LC-MS/MS. At the initiation of treatment, the average body weight of the rats was 150.3 + 3.0g, and over the 20 days of the study animals treated with vehicle gained an average of 158.4 + 4.9g. In contrast, rats treated QD with 10 or 30mg/kg AZP-3813 gained 23.6 + 2.1 and 27.9 + 2.2% less weight than the vehicle-treated controls, respectively. Accumulation of AZP-3813 levels in the blood was observed with repeated daily injections of both 10 and 30mg/kg, increasing from day 2 levels by 107.1 + 12.5 and 125.2 + 36.3%, respectively, by day 19. In the vehicle-treated control rats, IGF1 levels increased from an initial 395.1 +16.3ng/ml to 674.4 + 19.8ng/ml by day 20. Twenty-four hours after the first injections of 10 and 30mg/kg AZP-3813, IGF1 levels were suppressed by 27.6 + 3.4 and 29.2 + 3.3%, respectively, versus vehicle-treated control levels, and, with continued treatment, a similar magnitude of IGF1 suppression was maintained through day 20 despite the progressively increasing levels of IGF1 observed in the vehicle-treated rats. At study termination on day 20, animals treated with 10 and 30mg/kg AZP-3813 were observed to have 4.1 and 4.6% shorter femur length, 1.1 and 3.6% shorter body length, and 7.7 and 13.3% less liver weight, respectively, as compared with vehicle-treated control rats. These results demonstrate that with continued treatment, the potent GHR antagonist activity exhibited by AZP-3813 translates to sustained in vivo suppression of IGF1 levels and associated parameters, and support its development as a potential therapy for acromegaly. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:05 p.m. - 1:10 p.m.

Prader-Willi syndrome (PWS) is a complex genetic syndrome characterized by hyperphagia, intellectual disability, hypotonia and hypothalamic dysfunction. Adults with PWS often have hormone deficiencies, hypogonadism being the most common. Untreated male hypogonadism can aggravate PWS-related health issues including muscle weakness, obesity, osteoporosis, and fatigue. Therefore, timely diagnosis and treatment of male hypogonadism is important. In this article, we share our experience with hypogonadism and its treatment in adult males with PWS and present a review of the literature. In order to report the prevalence and type of hypogonadism, treatment regimen and behavioral issues, we retrospectively collected data on medical interviews, physical examinations, biochemical measurements and testosterone replacement therapy (TRT) in 57 Dutch men with PWS. Fifty-six (98%) of the patients had either primary, central or combined hypogonadism. Untreated hypogonadism was associated with higher body mass index and lower hemoglobin concentrations. TRT was complicated by behavioral challenges in one third of the patients. Undertreatment was common and normal serum testosterone levels were achieved in only 30% of the patients. Based on the Dutch cohort data, review of the literature and an international expert panel discussion, we provide a practical algorithm for TRT in adult males with PWS in order to prevent undertreatment and related adverse health outcomes.

Background Several studies have demonstrated suppressed levels of acylated (AG) and unacylated ghrelin (UAG) in patients with type 2 diabetes. However, the role of these hormones in type 1 diabetes has not been extensively studied. This study assessed the relationship between AG and UAG levels and body composition in patients with type 1 diabetes. Methods We selected eighteen patients with type 1 diabetes and divided them into two groups: non-obese (BMI 2) and overweight (BMI ≥ 25 kg/m2). Demographics, parameters of body composition and serum parameters including AG and UAG, were assessed. Results The patients with a BMI ≥ 25 kg/m2 were older and had a longer duration of diabetes. AG and UAG levels were not significantly different between non-obese and overweight groups (mean AG non-obese ± SD: 44.5 ± 29.4 pg/ml and mean UAG non-obese 42.4 ± 20.7 pg/ml vs mean AG overweight ± SD: 46.1 ± 29.6 pg/ml and mean UAG overweight 47.2 ± 18.2 pg/ml). AG/UAG ratios did not discriminate between these groups. There was a positive association of insuline dose/kg bodyweight with BMI (r2 = 0.45, p = 0.002). Conclusions Surprisingly, unlike non-diabetics and in T2D, we did not observe a difference in plasma levels of AG and UAG between normal weight and overweight adult type 1 diabetics. However, we did observe a positive correlation between BMI and insuline dose/kg bodyweight, suggesting that exogenous insulin is more important than the ghrelin system in the development of obesity in type 1 diabetes.

Prader-Willi syndrome (PWS) is a complex hypothalamic disorder. Features of PWS include hyperphagia, hypotonia, intellectual disability, and pituitary hormone deficiencies. The combination of growth hormone treatment and multidisciplinary care (GHMDc) has greatly improved the health of children with PWS. Little is known about the effects of childhood GHMDc on health outcomes in adulthood. We retrospectively collected clinical data of 109 adults with PWS. Thirty-nine had received GHMDc during childhood and adolescence (GHMDc+ group) and sixty-three had never received growth hormone treatment (GHt) nor multidisciplinary care (GHMDc− group). Our systematic screening revealed fewer undetected health problems in the GHMDc+ group (10%) than in the GHMDc− group (84%). All health problems revealed in the GHMDc+ group had developed between the last visit to the paediatric and the first visit to the adult clinic and/or did not require treatment. Mean BMI and the prevalence of diabetes mellitus type 2 were significantly lower in the GHMDc+ group compared to the GHMDc− group. As all patients who received GHt were treated in a multidisciplinary setting, it is unknown which effects are the result of GHt and which are the result of multidisciplinary care. However, our data clearly show that the combination of both has beneficial effects. Therefore, we recommend continuing GHMDc after patients with PWS have reached adult age.

Prolactinomas are the most commonly encountered pituitary adenomas in the clinical setting. While most can be controlled by dopamine agonists, a subset of prolactinomas are dopamine-resistant and very aggressive. In such tumors, the treatment of choice is neurosurgery and radiotherapy, with or without temozolomide. Here, we report a patient with an highly aggressive, dopamine-resistant prolactinoma, who only achieved biochemical and tumor control during pasireotide long-acting release (PAS-LAR) therapy, a second-generation somatostatin receptor ligand (SRL). Interestingly, cystic degeneration, tumor cell necrosis or both was observed after PAS-LAR administration suggesting an antitumor effect. This case shows that PAS-LAR therapy holds clinical potential in selective aggressive, dopamine-resistant prolactinomas that express somatostatin (SST) receptor subtype 5 and appears to be a potential new treatment option before starting temozolomide. In addition, PAS-LAR therapy may induce cystic degeneration, tumor cell necrosis or both in prolactinomas.

Advances in combination medical treatment have offer new perspectives for acromegaly patients with persistent disease activity despite receiving the available medical monotherapies. The outcomes of combination medical treatment may reflect both additive and synergistic effects. This review focuses on combination medical treatment and its current position in acromegaly, based on clinical studies evaluating the efficacy and safety of combined medical treatment(s) and our own experiences with combination therapy. Arch Endocrinol Metab. 2019;63(6):646-52

Context Pasireotide long-acting release (LAR) is a somatostatin multireceptor ligand, and in the current consensus criteria pasireotide LAR is considered the second-line medical treatment for acromegaly. We present in this article our recommendations to define the position of pasireotide LAR in the treatment of acromegaly and provide recommendations for the management of pasireotide-induced hyperglycemia. Evidence Acquisition Our recommendations are based on our experiences with the pasireotide LAR and pegvisomant (PEGV) combination study and the available basic or clinical articles published in peer-reviewed international journals on pasireotide LAR and acromegaly. Evidence Synthesis In accordance with the current consensus criteria, we recommend pasireotide LAR monotherapy as a second-line therapy in young patients who show tumor growth during first-generation somatostatin receptor ligand (SRL) therapy and in patients who show tumor growth during PEGV therapy. In addition, we recommend pasireotide LAR monotherapy in patients with headache not responsive to first-generation SRL therapy and in patients who experience side effects or are intolerant to PEGV monotherapy. In contrast to the current consensus criteria, we recommend considering combination therapy with pasireotide LAR and PEGV as third-line treatment in patients without diabetes at low PEGV dosages (≤80 mg/week) and in patients with tumor growth or symptoms of active acromegaly during first-generation SRL and PEGV combination therapy. With respect to pasireotide-induced hyperglycemia, we recommend a more liberal strategy of blood glucose monitoring during pasireotide treatment. Conclusions In contrast to the current consensus criteria, we recommend a more reluctant use of pasireotide LAR therapy for the treatment of acromegaly.

Objective Craniopharyngioma patients often have poor metabolic profiles due to hypothalamic–pituitary damage. Previously, using BMI as obesity marker, the occurrence of the metabolic syndrome in these patients was estimated at 46%. Our aim was to determine if dual X-ray absorptiometry (DXA) scan in evaluation of obesity and metabolic syndrome would be superior. Design Retrospective study of craniopharyngioma patients for whom DXA scan results were available. Methods BMI, fat percentage and fat mass index were used to evaluate obesity and as components for obesity in metabolic syndrome. Results Ninety-five craniopharyngioma patients were included (51% female, 49% childhood-onset disease). Metabolic syndrome occurred in 34–53 (45–51%) subjects (depending on the definition of obesity, although all definitions occurred in higher frequency than in the general population). Metabolic syndrome frequency was higher if obesity was defined by fat percentage (52 vs 42%) or fat mass index (51 vs 43%) compared to BMI. Misclassification appeared in 9% (fat percentage vs BMI) and 7% (fat mass index vs BMI) for metabolic syndrome and 29 and 13% for obesity itself, respectively. For metabolic syndrome, almost perfect agreement was found for BMI compared with fat percentage or fat mass index. For obesity, agreement was fair to moderate (BMI vs fat percentage). Conclusion Using BMI to evaluate obesity underestimates the true prevalence of metabolic syndrome in patients with craniopharyngioma. Furthermore, fat percentage contributes to a better evaluation of obesity than BMI. The contribution of DXA scan might be limited for identification of the metabolic syndrome.

Acromegaly is a rare disease and the clinical features of acromegaly develop insidiously; its diagnosis is often significantly delayed. Therefore, earlier diagnosis will improve the quality of life of the patient and reduce the need for other therapies to control the initial and ongoing damage that acromegaly presents. In this chapter, we describe the view of the patient and the clinician on the importance of earlier diagnosis, as well as on what can be done to speed up this process. Earlier diagnosis will not only improve quality of life and the burden of disease in acromegaly patients, but it will also have a positive impact in the economic burden of this rare disease.

Prader–Willi syndrome (PWS) is a rare genetic condition characterized by hypotonia, intellectual disability, and hypothalamic dysfunction, causing pituitary hormone deficiencies and hyperphagia, ultimately leading to obesity. PWS is most often caused by the loss of expression of a cluster of genes on chromosome 15q11.2-13. Patients with Prader–Willi-like syndrome (PWLS) display features of the PWS phenotype without a classical PWS genetic defect. We describe a 46-year-old patient with PWLS, including hypotonia, intellectual disability, hyperphagia, and pituitary hormone deficiencies. Routine genetic tests for PWS were normal, but a homozygous missense variant NM_003097.3(SNRPN):c.193C>T, p.(Arg65Trp) was identified. Single nucleotide polymorphism array showed several large regions of homozygosity, caused by high-grade consanguinity between the parents. Our functional analysis, the ‘Pipeline for Rapid in silico, in vivo, in vitro Screening of Mutations’ (PRiSM) screen, showed that overexpression of SNRPN-p.Arg65Trp had a dominant negative effect, strongly suggesting pathogenicity. However, it could not be confirmed that the variant was responsible for the phenotype of the patient. In conclusion, we present a unique homozygous missense variant in SNURF-SNRPN in a patient with PWLS. We describe the diagnostic trajectory of this patient and the possible contributors to her phenotype in light of the current literature on the genotype–phenotype relationship in PWS.

Introduction: Prader-Willi syndrome (PWS) is associated with several hypothalamic-pituitary hormone deficiencies. There is no agreement on the prevalence of central adrenal insufficiency (CAI) in adults with PWS. This is partly due to the variable results of the synacthen test, compared with the more robust metyrapone test (MTP) and insulin tolerance test (ITT). In some countries, patients with PWS receive stress-dose corticosteroids during physical or psychological stress. Side effects of frequent corticosteroids use are weight gain, osteoporosis, diabetes mellitus and hypertension, already major problems in adults with PWS. However, undertreatment of CAI can cause significant morbidity or even mortality. To prevent over- and undertreatment with corticosteroids, we assessed the prevalence of CAI in a large international cohort of adults with this rare disorder. Methods: The hypothalamic-pituitary-adrenal axis was tested in 81 adult subjects (55 Dutch, 10 British, 10 French, 6 Swedish) with genetically confirmed PWS. For multiple-dose MTP, 11-deoxycortisol >230 nmol/L (7.6 g/dL) was considered sufficient. For Dutch, French and Swedish patients who underwent ITT, cortisol >500 nmol/L (18.1 μg/dL) was considered sufficient. For British patients cortisol >450 nmol/L (16.3 μg/dL) was considered sufficient, as this center used a different assay. Additionally, we reviewed medical files of 645 adults with PWS from Italy (240), France (110), the Netherlands (110), Australia (60), Spain (45), Sweden (38) and the United Kingdom (42) for symptoms of hypocortisolism/adrenal crisis during surgery. Results: Data on 81 adult subjects (46 males and 35 females), median age (range) 25.2 yr (18.0 – 55.5), median BMI (range) 29.1 kg/m2 (20.0 – 62.0), with genetically confirmed PWS were collected. 33 subjects (41%) were using GH treatment since childhood. Multiple-dose MTP was performed in 45 subjects and ITT in 36 subjects. Both tests were well tolerated by all individuals. CAI was excluded in 80 of 81 patients. One patient with a peak cortisol level of 494 nmol/L (just below cut-off level of 500 nmol/L) was prescribed hydrocortisone for use during physical stress. There was no relation between baseline cortisol and ITT/multiple-dose MTP results. Even patients with a low baseline cortisol level (lowest: 102.0 nmol/L) had normal responses. Among the 645 patients whose medical files were reviewed, 200 had undergone surgery without perioperative corticosteroids treatment. None of them displayed any features of hypocortisolism/adrenal crisis. Conclusions: CAI is rare (1.2%) in adults with PWS. Based on these results, we recommend against routinely prescribing corticosteroids stress-doses in adults with PWS. Funding: CZ foundation.

Ghrelin, a 28-amino acid peptide gut hormone, occurs in acylated (AG) and unacylated (UAG) variants. AG is a GH secretagogue as well as being orexigenic and diabetogenic, acting via the growth hormone secretagogue receptor (GHSR1a) in the hypothalamus and pituitary. UAG counteracts these metabolic effects through unknown mechanisms. While screening for potential UAG receptor(s) we discovered previously uncharacterised interactions of AG and UAG with five cell membrane proteins (MPs), three of which are known to modulate metabolism. Here, we studied if two of these MPs (MP1 & 2) could modulate GHSR1a signalling by expressing their transgenes in HEK293 cells. As GHSR1a is coupled with calcium signalling via Gq proteins, aequorin luminescence was used to evaluate Ca2+ influx into the cells. Transfected cells were treated with either AG, UAG, or soluble parts of the MPs, or combinations thereof. MP2 markedly enhanced the efficacy (~5.5-fold), but not the potency, of AG-induced Ca2+ influx, whereas MP1 had no effect on Ca2+ influx. Neither MP1 nor MP2 overexpression altered cellular GHSR1a levels. In the absence of GHSR1a, MP2 was unable to stimulate an AG-induced Ca2+ influx. UAG treatment (100nM) had no effect on GHSR1a-mediated Ca2+ influx in the presence or absence of MP2. MP2 is post-translationally modified and we suspected this to be important for its activity. However, removal or blockade of these modifications had no effect on the ability of MP2 to enhance GHSR1a signalling. Moreover, incubating the cells with soluble ectodomain of MP2 did not alter its effect on GHSR1a signalling. Nevertheless, induction of ectodomain shedding with PMA (0.4-1µM) dose-dependently reduced the AG-induced Ca2+ response to 0.5-0.2 of control levels (DMSO) in MP2-GHSR1a co-transfected cells. Unlike MP2, which has a transmembrane and intracellular domain, MP1 is attached to the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor and lacks an intracellular domain. Since MP1 is otherwise structurally similar to MP2, we suspected that the intracellular domain of MP2 may be important for its function. Therefore, we expressed chimeras of MP2 and MP1 in which the GPI linkage site and the transmembrane/intracellular domains were exchanged. The MP2 ectodomain with a GPI-anchor had similar stimulatory effects on GHSR1a signalling as full-length MP2, whereas the MP1 ectodomain with MP2 transmembrane and intracellular domain only enhanced GHSR1a signalling by approximately 3-fold. In conclusion, we have identified a membrane protein as a novel component of the ghrelin signalling pathway that markedly enhances the response of the ghrelin receptor to AG. Our current data suggest its ectodomain is important in mediating this effect. Studies are ongoing to fully delineate the mode of interaction and to determine the role of MP2 in ghrelin signalling in vivo.

Introduction: Prader-Willi syndrome (PWS) is a complex hypothalamic disorder, combining hypotonia, intellectual disability (ID), pituitary hormone deficiencies and hyperphagia. In PWS, up to 3% of patients die every year. In half of the patients, the cause of death is obesity related and / or of cardiovascular (CV) origin. Obesity is caused by hyperphagia combined with a low energy expenditure. Untreated hormone deficiencies like hypogonadism and hypothyroidism can cause low muscle mass and low basal rest metabolism (BRM) leading to this low energy expenditure. Patients with PWS should exercise one hour daily to compensate for their low BRM. However, hormone deficiencies usually cause fatigue, leading to exercise intolerance. Musculoskeletal and / or behavioral problems can also cause reduced physical activity. The subsequent sedentary lifestyle can induce CV risk factors like hypertension, hypercholesterolemia and diabetes mellitus (DM). Another risk factor often present in PWS is sleep apnea, which can be central (CSA), obstructive (OSA) or both. Both CSA and OSA can lead to pulmonary hypertension and a further increase in obesity. The above mentioned health problems often remain unnoticed and untreated, which is partly due to the behavioral phenotype of PWS (patients seldomly report pain and hardly ever complain about physical problems). However, if left untreated, these risk factors can cause CV complications leading to hospital admission or even death. To reveal yet undiagnosed health problems, we performed a systematic health screening among adults with PWS. Methods: We systematically screened 115 adults with PWS (mean age 31.4 ± 12.1 y, mean BMI 31.8 ± 9,5 kg/m2) for the presence of undiagnosed health problems and cardiovascular risk factors. Based on a medical questionnaire, medical file search, extensive interview, thorough physical examination and biochemical measurements we made an overview of the undiagnosed health problems in adults with PWS. If possible, we performed polygraphy to test for sleep apnea. Results: Undiagnosed health problems (hypertension, DM, hypercholesterolemia, sleep apnea, hypothyroidism and hypogonadism) were present in 50% of the patients. 10% had multiple undiagnosed health problems simultaneously. All males and 94% of females had hypogonadism and 15% had hypothyroidism. Hypertension and / or hypercholesterolemia were present in 20% and DM was present in 16%. One third of patients was not on a diet and 22% exercised less than 30 minutes a day. Sleep apnea was present in 17 of 26 patients tested. Conclusion: We detected a striking number of undiagnosed health problems among adults with PWS which, if left untreated, can pose a serious health threat. Systematic screening is needed to detect these problems in an early phase. This will prevent burdensome and expensive complications and might even reduce mortality in this vulnerable patient population.

Introduction Transition from paediatric to adult endocrinology is a challenge for adolescents, their families and their healthcare professionals. Previous studies show that up to 25% of young adults with endocrine disorders are lost to follow-up once they move out of paediatric care. This poses a health risk for young adults, as lack of medical treatment and surveillance can have both psycho-social and physical consequences. Apart from absenteeism from school or work, this can lead to serious and expensive medical complications like Addison crisis. Methods In 2019 we studied electronic medical records of 387 patients who were over 15 years old when they attended the paediatric endocrine outpatient clinic (OPC) of our medical centre in 2013-2014. We collected data from medical charts, the hospital digital agenda and medical correspondence. Results Of 387 adolescents, 161 (42%) did not need adult endocrine follow-up because paediatric endocrine care was only puberty- or growth-related. Forty-six patients did not enter regular transition because they 1) participated in a pilot to improve transition (N=10), 2) had intellectual disability (ID) and transferred to ID care (N=28), or 3) died (N=8, mostly cancer-related). Hundred-and-eighty patients entered regular transition: 49 (27%) to a regional hospital and 131 (73%) within our university hospital. Of these 131 patients, 33 (25%) were lost to follow up; in 24 of them (73%), the invitation for the adult OPC had never been sent. Loss to follow up occurred when three subsequent critical steps failed: 1) the adult endocrinologist had not received or read the paediatrician’s referral letter and/or had not invited the patient; 2) the paediatrician had not checked whether the appointment was really made and received by the patient and 3) the patients and/or caregivers had not alarmed the hospital when no invitation for an appointment was received. Conclusion We found a 25% dropout during transfer from paediatric to adult tertiary endocrine care. Starting the transition process early and in a structured manner, as well as assigning a transition coordinator, can prevent part of the dropouts. However, 73% of all dropouts appeared to be attributable to failure of practical, logistic steps. In order to prevent this part of the dropouts, we provide practical recommendations for all three parties involved: 1) the adult endocrinologist should carefully read paediatricians’ letters and check whether action is required (i.e. check whether an appointment is requested) 2) the paediatrician should ascertain whether the appointment is really made and received by the patient 3) the patients and/or caregivers should be instructed to alarm the hospital when they do not receive the appointment. These actions require relatively little effort and may prevent the part of drop-outs that is caused by logistic failures.

ContextPrader–Willi syndrome (PWS) is associated with several hypothalamic-pituitary hormone deficiencies. There is no agreement on the prevalence of central adrenal insufficiency (CAI) in adults with PWS. In some countries, it is general practice to prescribe stress-dose hydrocortisone during physical or psychological stress in patients with PWS. Side effects of frequent hydrocortisone use are weight gain, osteoporosis, diabetes mellitus, and hypertension—already major problems in adults with PWS. However, undertreatment of CAI can cause significant morbidity—or even mortality.ObjectiveTo prevent both over- and undertreatment with hydrocortisone, we assessed the prevalence of CAI in a large international cohort of adults with PWS. As the synacthen test shows variable results in PWS, we only use the metyrapone test (MTP) and insulin tolerance test (ITT).DesignMetyrapone test or ITT in adults with PWS (N = 82) and review of medical files for symptoms of hypocortisolism related to surgery (N = 645).SettingOutpatient clinic.Patients or Other ParticipantsEighty-two adults with genetically confirmed PWS.Main Outcome MeasureFor MTP, 11-deoxycortisol > 230 nmol/L was considered sufficient. For ITT, cortisol > 500 nmol/L (Dutch, French, and Swedish patients) or > 450 nmol/L (British patients) was considered sufficient.ResultsCentral adrenal insufficiency was excluded in 81 of 82 patients. Among the 645 patients whose medical files were reviewed, 200 had undergone surgery without perioperative hydrocortisone treatment. None of them had displayed any features of hypocortisolism.ConclusionsCentral adrenal insufficiency is rare (1.2%) in adults with PWS. Based on these results, we recommend against routinely prescribing hydrocortisone stress-doses in adults with PWS.

Eucaloric Low-Carbohydrate Ketogenic Diet in Acromegaly This proof-of-concept study tested whether an adjuvant eucaloric very-low-carbohydrate diet for 2 weeks added to first-generation somatostati...

Context First-generation somatostatin receptor ligands (fg-SRLs) represent the mainstay of medical therapy for acromegaly, but they provide biochemical control of disease in only a subset of patients. Various pretreatment biomarkers might affect biochemical response to fg-SRLs. Objective To identify clinical predictors of the biochemical response to fg-SRLs monotherapy defined as biochemical response (insulin-like growth factor (IGF)-1 ≤ 1.3 × ULN (upper limit of normal)), partial response (>20% relative IGF-1 reduction without normalization), and nonresponse (≤20% relative IGF-1 reduction), and IGF-1 reduction. Design Retrospective multicenter study. Setting Eight participating European centers. Methods We performed a meta-analysis of participant data from 2 cohorts (Rotterdam and Liège acromegaly survey, 622 out of 3520 patients). Multivariable regression models were used to identify predictors of biochemical response to fg-SRL monotherapy. Results Lower IGF-1 concentration at baseline (odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.72–0.95 IGF-1 ULN, P = .0073) and lower bodyweight (OR = 0.99, 95% CI 0.98–0.99 kg, P = .038) were associated with biochemical response. Higher IGF-1 concentration at baseline (OR = 1.40, (1.19–1.65) IGF-1 ULN, P ≤ .0001), the presence of type 2 diabetes (oral medication OR = 2.48, (1.43–4.29), P = .0013; insulin therapy OR = 2.65, (1.02–6.70), P = .045), and higher bodyweight (OR = 1.02, (1.01–1.04) kg, P = .0023) were associated with achieving partial response. Younger patients at diagnosis are more likely to achieve nonresponse (OR = 0.96, (0.94–0.99) year, P = .0070). Baseline IGF-1 and growth hormone concentration at diagnosis were associated with absolute IGF-1 reduction (β = 0.90, standard error (SE) = 0.02, P ≤ .0001 and β = 0.002, SE = 0.001, P = .014, respectively). Conclusion Baseline IGF-1 concentration was the best predictor of biochemical response to fg-SRL, followed by bodyweight, while younger patients were more likely to achieve nonresponse.

Context Patients with craniopharyngioma suffer from obesity and impaired bone health. Little is known about longitudinal changes in body composition and bone mineral density (BMD). Objective To describe body composition and BMD (change). Design Retrospective longitudinal study. Setting Two Dutch/Swedish referral centers. Patients Patients with craniopharyngioma (n = 112) with a dual X-ray absorptiometry (DXA) scan available (2 DXA scans, n = 86; median Δtime 10.0 years; range 0.4-23.3) at age ≥ 18 years (58 [52%] male, 50 [45%] childhood onset). Main outcome measures Longitudinal changes of body composition and BMD, and associated factors of ΔZ-score (sex and age standardized). Results BMI (from 28.8 ± 4.9 to 31.2 ± 5.1 kg/m2, P Conclusions Z-scores of BMI, fat percentage, and FMI remained stable in patients with craniopharyngioma over time, while Z-scores of FFMI and BMD increased. Higher glucocorticoid dose and radiotherapy were associated with BMD loss and GHRT with increase.

Context Pituitary hormonal deficiencies in patients with craniopharyngioma may impair their bone health. Objective To investigate bone health in patients with craniopharyngioma. Design Retrospective cross-sectional study. Setting Dutch and Swedish referral centers. Patients Patients with craniopharyngioma (n = 177) with available data on bone health after a median follow-up of 16 years (range, 1-62) were included (106 [60%] Dutch, 93 [53%] male, 84 [48%] childhood-onset disease). Main outcome measures Fractures, dual X-ray absorptiometry-derived bone mineral density (BMD), and final height were evaluated. Low BMD was defined as T- or Z-score ≤-1 and very low BMD as ≤-2.5 or ≤-2.0, respectively. Results Fractures occurred in 31 patients (18%) and were more frequent in men than in women (26% vs. 8%, P = .002). Mean BMD was normal (Z-score total body 0.1 [range, -4.1 to 3.5]) but T- or Z-score ≤-1 occurred in 47 (50%) patients and T-score ≤-2.5 or Z-score ≤-2.0 in 22 (24%) patients. Men received less often treatment for low BMD than women (7% vs. 18%, P = .02). Female sex (OR 0.3, P = .004) and surgery (odds ratio [OR], 0.2; P = .01) were both independent protective factors for fractures, whereas antiepileptic medication was a risk factor (OR, 3.6; P = .03), whereas T-score ≤-2.5 or Z-score ≤-2.0 was not (OR, 2.1; P = .21). Mean final height was normal and did not differ between men and women, or adulthood and childhood-onset patients. Conclusions Men with craniopharyngioma are at higher risk than women for fractures. In patients with craniopharyngioma, a very low BMD (T-score ≤-2.5 or Z-score ≤-2.0) seems not to be a good predictor for fracture risk.

Context Prader-Willi syndrome (PWS) is a complex hypothalamic disorder, combining hyperphagia, hypotonia, intellectual disability, and pituitary hormone deficiencies. Annual mortality of patients with PWS is high (3%). In half of the patients, the cause of death is obesity related and/or of cardiopulmonary origin. Health problems leading to this increased mortality often remain undetected due to the complexity and rareness of the syndrome. Objective To assess the prevalence of health problems in adults with PWS retrospectively. Patients, Design, and Setting We systematically screened 115 PWS adults for undiagnosed health problems. All patients visited the multidisciplinary outpatient clinic for rare endocrine syndromes at the Erasmus University Medical Center, Rotterdam, Netherlands. We collected the results of medical questionnaires, interviews, physical examinations, biochemical measurements, polygraphy, polysomnography, and radiology. Main outcome measures Presence or absence of endocrine and nonendocrine comorbidities in relation to living situation, body mass index, genotype, and demographic factors. Results Seventy patients (61%) had undiagnosed health problems, while 1 in every 4 patients had multiple undiagnosed health problems simultaneously. All males and 93% of females had hypogonadism, 74% had scoliosis, 18% had hypertension, 19% had hypercholesterolemia, 17% had type 2 diabetes mellitus, and 17% had hypothyroidism. Unfavorable lifestyles were common: 22% exercised too little (according to PWS criteria) and 37% did not see a dietitian. Conclusions Systematic screening revealed many undiagnosed health problems in PWS adults. Based on patient characteristics, we provide an algorithm for diagnostics and treatment, with the aim to prevent early complications and reduce mortality in this vulnerable patient group.