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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.

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.

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.

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.

ObjectiveTo assess the efficacy and safety after 48 weeks of treatment with pasireotide long-acting-release (PAS-LAR) alone or in combination with pegvisomant in patients with acromegaly. In addition, we assessed the relation between insulin secretion and pasireotide-induced hyperglycemia.DesignThe PAPE extension study is a prospective follow-up study until 48 weeks after the core study of 24 weeks.MethodsFifty-nine out of 61 patients entered the extension study. Efficacy was defined as the percentage of patients achieving IGF-I normalization (≤1.2× the upper limit of normal (ULN)) at 48 weeks through protocol-based adjustment of pegvisomant and PAS-LAR doses. At baseline, insulin secretion was assessed by an oral glucose tolerance test (OGTT).ResultsAt the end of the study, median IGF-I was 0.98× ULN, and 77% of patients achieved normal IGF-I levels with a mean pegvisomant dose of 64 mg/week, and an overall cumulative pegvisomant dose reduction of 52%. Frequency of diabetes mellitus increased from 68% at 24 weeks to 77% at 48 weeks, and nine patients discontinued PAS-LAR treatment, mainly because of severe hyperglycemia. Pasireotide-induced hyperglycemia was inversely correlated with baseline insulin secretion (r = −0.37,P ConclusionsPAS-LAR normalizes IGF-I levels in most acromegaly patients, with a 50% pegvisomant-sparing effect. However, PAS-LAR treatment coincided with a high incidence of diabetes mellitus. The risk for developing diabetes during PAS-LAR treatment seems inversely related to insulin secretion at baseline.

Objectives ACROSTUDY is an international, non-interventional study of acromegaly patients treated with pegvisomant (PEGV), a growth hormone receptor antagonist and has been conducted since 2004 in 15 countries to study the long-term safety and efficacy of PEGV. This report comprises the second interim analysis of 2090 patients as of May 12, 2016. Methods Descriptive analyses of safety, pituitary imaging and outcomes on PEGV treatment up to 12 years were performed. Results Prior to starting PEGV, 96% of patients had reported surgery, radiation, medical therapy or any combinations of those. At start of PEGV, 89% of patients had IGFI levels above the upper limit of normal (ULN). The percentage of patients with normal IGFI levels increased from 53% at year 1 to 73% at year 10, and the average daily dose of PEGV increased from 12.8 mg (year 1) to 18.9 mg (year 10). A total of 4832 adverse events (AEs) were reported in 1137 patients (54.4%), of which 570 were considered treatment related in 337 patients (16.1%). Serious AEs were reported in 22% of patients, of which 2.3% were considered treatment related. Locally reported MRIs showed most patients (72.2%) had no change in tumor size relative to the prior scan; 16.8% had a decrease, 6.8% an increase and 4.3% both. In patients with normal liver tests at PEGV start, an ALT or AST elevation of >3× ULN at any time point during their follow-up was reported in 3%. Conclusions This second interim analysis confirms that long-term use of PEGV is an effective and safe treatment in patients with acromegaly.

Introduction: Patients with complex rare genetic syndromes (CRGS) have, by definition, combined medical problems affecting multiple organ systems. Intellectual disability (ID) is often part of the syndrome. During childhood, most patients with CRGS receive multidisciplinary (MD) and specialized pediatric care in tertiary centers. As improvement of medical care has improved life expectancy, more and more patients are now reaching adult age. While the complexity of the syndromes persist into adulthood, adequate multidisciplinary syndrome-specific care is rarely available for adults with CRGS. Although multiple organ systems are usually affected, internists are rarely involved. Pediatricians have expressed the urgent need for adequate, syndrome-specific, MD tertiary healthcare for adults with CRGS. Methods: In 2015 we have launched the Center for Adults with CRGS, a specialized MD outpatient clinic (MOPC) within the Endocrinology unit of the department of Internal Medicine. As adult manifestations are unknown for most CRGS, all CRGS patients who visit our MOPC undergo a systematic health screening (followed by treatment, if indicated). Before visiting the MOPC, caregivers fill out a medical questionnaire. We gathered the physical complaints, medication use and missed diagnoses of 726 adults with CRGS. Results: Between 2015 and 2020, 256 males and 470 females with over 60 syndromes visited the Center for Adults with CRGS. The main features of this population, as compared with general internal medicine patients, were intellectual disability, polypharmacy and use of psychotropic drugs. Missed diagnoses were common and many patients had undergone extensive diagnostic tests for symptoms that could actually be explained by their syndrome. Fatigue (52%), abdominal discomfort (23%) and hypertension (10%) were among the most frequent reasons for referral to Internal Medicine. Based on the literature and our clinical findings, 73% of the syndromes was associated with endocrine problems. We provide an algorithm for the clinical approach to CRGS adults, in order to prevent unnecessary diagnostics as well as missed diagnoses. Conclusion: Our overview of 726 adults with CRGS shows that missed diagnosed and needless invasive tests are common in this patient population. As more and more CRGS patients are now reaching adult age and transfer to Internal Medicine, internists and endocrinologists should be aware of the special needs of adults with CRGS and of the medical pitfalls. Knowledge about syndrome-specific health problems and multidisciplinary expert care is crucial to prevent the personal and financial burden of unnecessary diagnostics and under- and overtreatment.

Prader–Willi syndrome (PWS) is a complex genetic syndrome combining hypotonia, hyperphagia, a PWS-specific neurocognitive phenotype, and pituitary hormone deficiencies, including hypothyroidism. The low muscle mass associated with PWS causes a low energy expenditure due to a low basal metabolic rate. Combined with increased energy intake due to hyperphagia, this results in a high risk of obesity and associated cardiovascular disease. To reduce the high mortality in PWS (3% yearly), exercise is extremely important. As hypothyroidism can impair exercise tolerance, early detection is crucial. We performed a literature search for articles on hypothyroidism in PWS, measured thyroid hormone (TH) levels in 122 adults with PWS, and performed a medical file search for medication use. Hypothyroidism (low free thyroxin) was present in 17%, and often central in origin (80%). Triiodothyronine levels were lower in patients who used psychotropic drugs, while other TH levels were similar. One in six patients in our cohort of adults with PWS had hypothyroidism, which is more than in non-PWS adults (3%). We recommend yearly screening of free thyroxin and thyroid-stimulating hormone levels to avoid the negative effects of untreated hypothyroidism on basal metabolic rate, body mass index, and cardiovascular risk. Additionally, we recommend measuring TH concentrations 3–4 months after the start of growth hormone treatment.

Aim: To assess the efficacy and safety of pasireotide long-Acting release (PAS-LAR) alone or in combination with pegvisomant by switching patients with acromegaly who were well controlled with long-Acting somatostatin analogues (LA-SSAs) and pegvisomant to PAS-LAR with or without pegvisomant. Methods: Sixty-one patients with acromegaly were enrolled in a prospective open-label study. We included patients with an insulin-like growth factor I (IGF-I) #1.2 3 upper limit of normal (ULN) during treatment with LA-SSAs and pegvisomant. At baseline, the pegvisomant dose was reduced by 50% up to 12 weeks. When IGF-I remained#1.23ULN after 12 weeks, patients were switched to PAS-LAR 60 mg monotherapy. When IGF-I was .1.2 3 ULN, patients were switched to PAS-LAR 60 mg, and they continued with the 50% reduced pegvisomant dose. Results: At baseline, mean IGF-I was 0.97 3 ULN, and the median pegvisomant dose was 80 mg/wk. At 12 weeks, mean IGF-I increased to 1.59 3 ULN, and IGF-I levels #1.2 ULN were observed in 24.6% of participants. At 24 weeks, IGF-I levels were reduced into the reference range in 73.8% of patients. Between baseline and 24 weeks, the pegvisomant dose was reduced by 66.1%. PAS-LAR was well tolerated, but hyperglycemia was the most frequent adverse event. The frequency of diabetes increased from 32.8% at baseline to 68.9% at 24 weeks. Conclusions: Switching to PAS-LAR, either as monotherapy or combination with pegvisomant, can control IGF-I levels in most patients. PAS-LAR demonstrated a pegvisomant-sparing effect of 66% compared with the combination with LA-SSAs. Hyperglycemia was the most important safety issue.

La terapia medica dell’acromegalia, con analoghi della somatostatina a prolungata durata di azione (LA-SMSA) e con l’antagonista recettoriale dell’ormone della crescita Pegvisomant (PEGV), rende possibile il raggiungimento di normali livelli circolanti di IGF-I nella maggioranza dei pazienti acromegalici. Le due classi di farmaci, comunque, hanno un differente impatto sull’asse GH-IGF-I, il che complica la tradizionale valutazione biochimica della risposta alla terapia. In questa rassegna si postula che la terapia con LA-SMSA in certi pazienti normalizzi i livelli circolanti di IGF-I senza influenzare gli effetti dell’aumento del GH a livello di tessuti extraepatici. Tale eventualita puo risultare nella persistenza dell’attivita della malattia, per la quale si propone la definizione di acromegalia extra-epatica. Il Pegvisomant, d’altra parte, blocca gli effetti sistemici del GH, evento che non e necessariamente e attendibilmente testimoniato dai livelli circolanti di IGF-I; inoltre, il trattamento con Pegvisomant causa ulteriore aumento dei livelli circolanti di GH. Il monitoraggio della terapia medica, basato su marcatori bioumorali tradizionali, e quindi complicato. Peraltro, il differente meccanismo d’azione di LA-SMSA e PEGV incoraggia l’impiego dei due farmaci in combinazione, rendendo necessaria una revisione critica dei correnti concetti relativi al trattamento dell’acromegalia e al monitoraggio degli effetti della terapia.

Background: Growth hormone-secreting pituitary adenomas (somatotroph adenoma) predominantly express somatostatin receptors (SSTRs) subtypes 2 and 5. Higher SSTR2 expression on somatotroph adenomas results in a better response to somatostatin analogues (SSAs), which preferentially bind, but also downregulate, SSTR2. The effect of the combined treatment with SSAs and the GH receptor antagonist pegvisomant (PEGV) on SSTR expression in somatotroph adenomas is currently unknown. Aim of the Study: To assess SSTR2 and SSTR5 expression in three groups of somatotroph adenomas: drug-naive, treated with long-acting (LA) SSA monotherapy, or LA-SSA/PEGV combination therapy before surgery. Additionally, we evaluated the required PEGV dose to achieve insulin-like growth factor I (IGF-I) normalization in relation to the SSTR expression. Materials and Methods: At our Pituitary Center Rotterdam, we selected acromegalic patients who underwent transsphenoidal neurosurgery. All patients were eventually treated with LA-SSA/PEGV combination therapy during their medical history. SSTR2 and SSTR5 expression in somatotroph adenoma tissues was determined using immunohistochemistry. Results: Out of 39 somatotroph adenoma tissue samples, 23 were drug-naive, 9 received pretreatment with LA-SSA and 7 LA-SSA/PEGV combined treatment. SSTR2 expression was significantly higher in treatment-naive compared to combined treatment somatotroph adenomas (p = 0.048), while SSTR5 expression did not differ. Noteworthy, SSTR2 expression in naive somatotroph adenoma tissues was inversely correlated with the required PEGV dose to achieve IGF-I normalization during postsurgical medical treatment (ρ = -0.538, p = 0.024). Conclusion: In our specific cohort, the SSTR2 expression was lower in patients pretreated with LA-SSA/PEGV compared to the drug-naive acromegalic patients. Additionally, the SSTR2 expression in treatment-naive somatotroph adenoma tissues was inversely correlated with the required PEGV dose to achieve IGF-I normalization.

Objective Studies investigating long-term health conditions in patients with craniopharyngioma are limited by short follow-up durations and generally do not compare long-term health effects according to initial craniopharyngioma treatment approach. In addition, studies comparing long-term health conditions between patients with childhood- and adult-onset craniopharyngioma report conflicting results. The objective of this study was to analyse a full spectrum of long-term health effects in patients with craniopharyngioma according to initial treatment approach and age group at craniopharyngioma presentation. Design Cross-sectional study based on retrospective data. Methods We studied a single-centre cohort of 128 patients with craniopharyngioma treated from 1980 onwards (63 patients with childhood-onset disease). Median follow-up since craniopharyngioma presentation was 13 years (interquartile range: 5–23 years). Initial craniopharyngioma treatment approaches included gross total resection (n = 25), subtotal resection without radiotherapy (n = 44), subtotal resection with radiotherapy (n = 25), cyst aspiration without radiotherapy (n = 8), and 90Yttrium brachytherapy (n = 21). Results Pituitary hormone deficiencies (98%), visual disturbances (75%) and obesity (56%) were the most common long-term health conditions observed. Different initial craniopharyngioma treatment approaches resulted in similar long-term health effects. Patients with childhood-onset craniopharyngioma experienced significantly more growth hormone deficiency, diabetes insipidus, panhypopituitarism, morbid obesity, epilepsy and psychiatric conditions compared with patients with adult-onset disease. Recurrence-/progression-free survival was significantly lower after initial craniopharyngioma treatment with cyst aspiration compared with other therapeutic approaches. Survival was similar between patients with childhood- and adult-onset craniopharyngioma. Conclusions Long-term health conditions were comparable after different initial craniopharyngioma treatment approaches and were generally more frequent in patients with childhood- compared with adult-onset disease.

Context First-generation somatostatin analogs (SSAs), such as octreotide (OCT), are the first line medical therapy for acromegaly. Pasireotide (PAS), a newly developed SSA, has shown promising results in the treatment of acromegaly. Objective To compare the antisecretory effect of OCT and PAS in primary cultures of growth hormone (GH)-secreting pituitary adenomas (GH-omas). To correlate responses with the adenoma somatostatin receptor (SSTR) profile. Design The effect of OCT and PAS on GH (and PRL) secretion was tested in 33 GH-oma cultures. SSTR expression was evaluated in adenoma samples. Setting and Patients Patients with acromegaly referred to the Erasmus Medical Center (Rotterdam, The Netherlands). Interventions OCT and PAS treatment for 72 hours (10 nM). Main Outcome Measures GH (and PRL) concentrations in cell culture media. SSTR expression in adenoma samples. Results The overall effect of OCT (-36.8%) and PAS (-37.1%) on GH secretion was superimposable. We identified three adenoma groups: PAS+ (PAS more effective than OCT), n = 6; PAS = OCT, n = 22; and OCT+ (OCT more effective than PAS), n = 5. PAS+ adenomas showed lower somatostatin receptor subtype (sst)2 messenger RNA (mRNA) and sst2/sst5 mRNA ratio, compared with the other groups (P < 0.05). PAS inhibited PRL hypersecretion more than OCT (P < 0.01). Conclusions Overall, OCT and PAS equally reduced GH secretion in vitro. Adenomas with lower sst2 mRNA expression and lower sst2/sst5 mRNA ratio were better responders to PAS compared with OCT. SSTR evaluation in GH-omas may become a tool for tailored SSA treatment in acromegaly.

Background: The common exon 3 deletion polymorphism of the growth hormone receptor (d3-GHR) is associated with disease severity in acromegaly patients. The GHR antagonist pegvisomant (PEGV) is highly effective in treating severe acromegaly. Response to PEGV treatment seems to be influenced by d3-GHR and appears to be more responsive to PEGV, although available results remain conflicting. Objective: To assess the influence of d3-GHR on the responsiveness of acromegaly patients to PEGV by compiling the evidence derived from the largest available studies. Design: A systematic review of the literature identified three published studies and one conference abstract. Acromegaly patients (n = 324, 49.7% d3-GHR carriers) were treated with either PEGV monotherapy or PEGV combined with long-acting somatostatin analogues and/or cabergoline. A meta-analysis of raw data from these studies was performed. Results: No significant effect of the d3-GHR was observed while bringing insulin-like growth factor I (IGF-I) levels below the upper limit of normal with PEGV, which was defined as the lowest IGF-I level during PEGV treatment (mean difference: -2.3%; 95% CI: -6.5 to 1.8, p = 0.270). The PEGV dose required to achieve the lowest IGF-I levels was also not significantly influenced by individuals carrying d3-GHR (mean difference: 4.1 mg weekly; 95% CI: -5.1 to 13.2, p = 0.385). For both outcomes, separate analysis of PEGV monotherapy and combination treatment gave similar results. Conclusion: Our findings suggest that the d3-GHR polymorphism has no effect on biochemical disease control in acromegaly, as it is not of added value for either the prediction of PEGV responsiveness or the determination of the required PEGV dose.

Objective Insulin-like growth factor-binding protein-2 (IGFBP-2) concentrations are low in subjects with metabolic syndrome and type 2 diabetes. Intriguingly, recent studies have demonstrated an association between high IGFBP-2 concentrations and increased mortality not only in populations with certain types of cancer, but also in relatively healthy populations. We evaluated the role of IGFBP-2 in relation to BMI and mortality. Design and Participants BMI, insulin sensitivity, insulin-like growth factor 1 (IGF-I) and IGFBP-2 were assessed repeatedly in 539 participants of the Baltimore Longitudinal Study of Aging around the ages of 55, 65 and 75 years. Results IGFBP-2 concentrations positively correlated with insulin sensitivity and inversely with BMI, both at baseline and follow-up. Independent of IGF-I, sex, BMI and insulin sensitivity, circulating IGFBP-2 levels positively correlated with age (P P = 0.02) as well as serial (P 0.001) measurements of IGFBP2. Finally, in this longitudinal study, we found that IGF-I concentrations increased with age (0.82 ± 0.2 (µg/L)/year, P Conclusion This is the first study investigating the relationship between IGFBP-2 levels and age in a longitudinal setting. Serum IGFBP-2 levels increase with age after the age of 50 years and evolve in parallel with insulin sensitivity. IGFBP-2 may therefore be a potential marker for insulin sensitivity. We further show that IGFBP-2 levels can predict mortality in this aging population. However, its predictive value for mortality can only be interpreted in relation to insulin sensitivity. After adjustment for insulin sensitivity, high IGFBP-2 levels are predictive of increased mortality.

Background: The response to first-generation somatostatin receptor ligands (SRLs) treatment in acromegaly correlates with expression of somatostatin receptor subtype 2 (SSTR2). However, pasireotide shows the highest binding affinity for SSTR subtype 5 (SSTR5). It has been suggested that in acromegaly, SSTR5 expression is better at predicting the response to pasireotide long-acting release (PAS-LAR) treatment than SSTR2 expression. Aim: To investigate in patients with active acromegaly whether response to SRL treatment correlates to PAS-LAR treatment and to what extent SSTR2 and SSTR5 expression are correlated to the response to PAS-LAR treatment. Methods: We included 52 patients from a cohort that initially received SRL treatment, followed by SRL and pegvisomant combination treatment, and finally PAS-LAR treatment. The long-term response to PAS-LAR was evaluated using a PAS-LAR score. In 14 out of 52 patients, somatotroph adenoma tissue samples were available to evaluate SSTR2 and SSTR5 expression using a previously validated immunoreactivity score (IRS). Results: The percentage IGF-I (times the upper limit of normal) reduction, which was observed after SRL treatment, correlated with PAS-LAR response score during follow-up (r = 0.40; P = 0.003; n = 52). After exclusion of SRL-pretreated patients, SSTR2 IRS was positively correlated to PAS-LAR score (r = 0.58; P = 0.039; n = 9), whereas SSTR5 IRS showed no relation (r = 0.35; P = 0.36; n = 9). Conclusions: In a cohort of patients partially responsive to SRLs, the IGF-I–lowering effects of PASLAR treatment correlated with the effect of SRL treatment and seemed to be mainly driven by SSTR2 expression instead of SSTR5.

PurposeTo explore the effects of pegvisomant (PEGV) on glucose metabolism in patients with acromegaly within ACROSTUDY, an international, observational, prospective safety surveillance study.MethodsPatients were retrospectively divided into two cohorts, with (DM group) or without diabetes mellitus (no-DM). Parameters of glucose metabolism and IGF-I values were analyzed yearly both cross-sectionally for 4 years (yrs) and longitudinally at 1 and 4-5yrs of PEGV treatment.ResultsAmong 1762 patients, 510 (28.9%) had DM before PEGV start. At cross-sectional analyses, in the DM group mean blood glucose was 140.058.7mg/dl at baseline, 116.4 +/- 44.8mg/dl at year 1 and 120.0 +/- 44.3mg/dl at yr 4. Mean HbA1c was 6.6 +/- 1.2 % at yr 1 vs. 7.0 +/- 1.4 % at baseline. HbA1c was above 6.5% in 61.9% at baseline and ranged from 45.4 to 53.8% at subsequent yearly time points. At the 4-yr longitudinal analysis, in the DM group (n=109), mean blood glucose decreased by 20.2mg/dl at yr 4, mean HbA1c was 7.0 +/- 1.5% at baseline vs. 6.8 +/- 1.4%. Patients achieved IGF-I normalization in 52.1% and 57.4% of cases in the DM and no-DM groups, respectively at 1 year. The mean daily PEGV dose (mg/day) was higher in the DM group (18.2 vs. 15.3) while the absolute change of IGF-I values from baseline was similar in both groups. PEGV was well tolerated in both groups without any unexpected AEs.Conclusions p id=Par4 Patients with DM had a moderate decrease in mean fasting glucose values during PEGV treatment.

Background: Primary antibody deficiencies (PADs) and anterior pituitary dysfunction are both rare conditions. However, recent studies have remarkably reported the occurrence of anterior pituitary dysfunction in PAD patients. Methods: In this cross-sectional, single-center study we evaluated the prevalence of endocrine disorders in adult PAD patients. Our study focused on common variable immunodeficiency (CVID), immunoglobulin G (IgG) subclass deficiency (IgGSD), and specific anti-polysaccharide antibody deficiency (SPAD). We assessed hormone levels, performed provocative tests and genetic testing in a subset of patients by direct sequencing of the nuclear factor kappa beta subunit 2 (NFKB2) gene and primary immunodeficiency (PID) gene panel testing by whole exome sequencing (WES). Results: Our results demonstrated that one out of 24 IgGSD/SPAD patients had secondary hypothyroidism and three out of 9 men with IgGSD/SPAD had secondary hypogonadism. Premature ovarian failure was observed in four out of 9 women with CVID and primary testicular failure in one out of 15 men with CVID. In two out of 26 CVID patients we found partial adrenal insufficiency (AI) and in one out of 18 patients with IgGSD/SPAD secondary AI was found. Moreover, in one out of 23 patients with CVID and in two out of 17 patients with IgGSD/SPAD severe growth hormone deficiency (GHD) was found, while one patient with IgGSD/SPAD showed mild GHD. Combined endocrine disorders were detected in two women with CVID (either partial secondary AI or autoimmune thyroiditis with primary hypogonadism) and in three men with IgGSD/SPAD (two with either mild GHD or secondary hypothyroidism combined with secondary hypogonadism, and one man with secondary AI and severe GHD). Genetic testing in a subset of patients did not reveal pathogenic variants in NFKB2 or other known PID-associated genes. Conclusion: This is the first study to describe a high prevalence of both anterior pituitary and end-organ endocrine dysfunction in adult PAD patients. As these endocrine disorders may cause considerable health burden, assessment of endocrine axes should be considered in PAD patients.

Introduction: Prader-Willi syndrome (PWS) is a complex genetic syndrome in which hypothalamic dysfunction leads to extreme appetite (hyperphagia) and pituitary hormone deficiencies (PHD), among others. Compared with the ‘general endocrine population’, the population of adults with PWS is characterized by a high prevalence of intellectual disability (ID) and frequent use of psychotropic drugs. Due to hypotonia and the low muscle mass associated with the syndrome, adults with PWS have a low basal metabolic rate (BMR) and a high risk of developing obesity. Therefore, exercising is extremely important. However, PHD like hypothyroidism can cause fatigue and exercise intolerance. If left untreated, hypothyroidism can lead to a further decrease in BMR, an increase in Body Mass Index (BMI) and increased cardiovascular risk. As mortality in PWS is high (3% yearly) and often related to cardiovascular problems and obesity, it is of utmost importance to optimize thyroid function and other factors affecting BMR. Methods: In 122 adults with PWS (median age 29 y [IQR 21-39], median BMI 29 kg/m2 [IQR 26-36]), we measured TSH, free T4 and T3 (the active form of thyroid hormone) and searched the medical history for use of medication and any pre-existing diagnosis of hypothyroidism. Moreover, we performed an extensive literature search and summarized the current literature on hypothyroidism, T3 and T4 levels in adults with PWS. Results: Hypothyroidism was present in 17% and more prevalent in females (23%) than in males (10%), even though this was not statistically significant (P=0.06). Although within the reference range, serum T3 levels were relatively high compared to free T4 levels. T3 levels were significantly lower in patients that used psychotropic medication (n=45) than in patients that did not (median 1.7 [IQR 1.5-2.0] vs 2.1 [IQR 1.7-2.3], P=0.013). Conclusion: We found a prevalence of hypothyroidism of 17% (compared to 3% in the non-PWS population). T3 levels were relatively high, which might be explained by increased peripheral conversion of T4 to T3 by deiodinase type 2. Levels of the active thyroid hormone T3 were significantly lower in patients using psychotropic medication. Based on our findings, we recommend 1) yearly screening of thyroid hormone levels in adults with PWS to avoid negative effects of untreated hypothyroidism on BMR, BMI and cardiovascular risk and 2) extra monitoring of the active thyroid hormone T3 in patients using psychotropic drugs.

IntroductionAcromegaly is a rare disorder in which, due to the high incidence of secondary hypogonadism, pregnancies are relatively rare. However, some women with acromegaly do get pregnant, which brings along questions about medication, complications and follow-up. This review tries to address these issues and provide the reader with practical information.MethodsThis review summarizes published data.ConclusionsAcromegaly is a disorder that is characterized by changes in growth hormone (GH), insulin-like growth factor-1 (IGF-1) and insulin concentrations and actions. All these hormones are important in pregnancy as well. In principle, the fetal-placental collaboration between mother and child more-or-less takes over the control over GH and IGF-1, not only in normal physiology but also to a certain extend in acromegaly. When medication for the high GH levels or actions is continued during pregnancy, both dopamine agonists, somatostatin analogs and GH receptor antagonists have been used and the available data suggest that there are no adverse consequences on mother or fetus to date. However, it is strongly advised to stop any medical intervention during pregnancy until more data are available on the safety of these compounds. Also, medical treatment is not needed as tumor size and disease activity are not reported to escape.