Publications by authors named "Charlotte Höybye"

82 Publications

Effects of Growth Hormone treatment on sleep-related parameters in adults with Prader-Willi syndrome.

J Clin Endocrinol Metab 2021 May 5. Epub 2021 May 5.

Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.

Background: Prader-Willi Syndrome (PWS) is a rare, genetic, multi-symptom, neurodevelopmental disease, due to lack of the expression of the paternal genes in the q11-q13 region of chromosome 15. The main characteristics of PWS are muscular hypotonia, hyperphagia, obesity, behavioral problems, cognitive disabilities and endocrine deficiencies, including growth hormone (GH) deficiency. Sleep apnea and abnormal sleep patterns are common in PWS. GH treatment might theoretically have a negative impact on respiration. Here we present the effect of GH treatment on polysomnographic measurements.

Patients And Methods: Thirty-seven adults, 15 men and 22 women, with confirmed PWS were randomized to one year of GH treatment (n= 19) or placebo (n=18) followed by two years of GH treatment to all. Polysomnographic measurements were performed every 6 months. A mixed-effect regression model was used for comparison over time in the subgroup who received GH for three years.

Results: At baseline median age was 29.5 years, BMI 27.1 kg/m 2, IGF-I 115 µg/L, apnea-hypopnea index (AHI) 1.4 (0.0-13.9) and sleep efficiency (SE) 89.0 % (41.0 - 99.0). No differences in sleep or respiratory parameters were seen between GH and placebo treated patients. SE continuously improved throughout the study, also after adjustment for BMI, and the length of the longest apnea increased. AHI inconsistently increased within normal range.

Conclusion: SE improved during GH treatment and no clinical, significantly negative, impact on respiration was seen. The etiology of breathing disorders is multifactorial and awareness of them should always be present in adults with PWS with or without GH treatment.
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http://dx.doi.org/10.1210/clinem/dgab300DOI Listing
May 2021

Pituitary Apoplexy: A Retrospective Study of 33 Cases From a Single Center.

Front Endocrinol (Lausanne) 2021 15;12:656950. Epub 2021 Apr 15.

Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden.

Purpose: Acute symptomatic pituitary apoplexy is a rare and potentially life-threatening condition. However, pituitary apoplexy can also present with milder symptoms and stable hemodynamics. Due to the rarity of this inhomogeneous condition, clinical studies are important to increase the knowledge.

Methods: We retrospectively reviewed all consecutive cases of pituitary apoplexy being admitted between January 1, 2005 and December 31, 2019 at the Karolinska University Hospital, Stockholm, Sweden, for symptoms, results of magnetic resonance (MRI), biochemistry, management and mortality.

Results: Thirty-three patients were identified with pituitary apoplexy, 18 were men (55%) and mean age was 46.5 (17.2) years. The incidence of symptomatic pituitary apoplexy was 1.6 patients/year (0.76 patients/1,000,000 inhabitants/year). The majority presented with headache (n=27, 82%) and hormonal deficiencies (n=18, 55%), which were most frequent in men. ACTH deficiency was present in nine patients (27% but 50% of those with hormonal deficiencies). All had the characteristic findings on MRI. Only three patients (9%) required acute pituitary surgery, while eight were operated after more than one week. Seven (21%) were on antithrombotic therapy. None of the patients died in the acute course. During follow-up (7.6 ± 4.3 years) none of the hormonal deficiencies regressed and 3 patients died from non-related causes.

Conclusion: Our study confirmed the rarity and the symptoms of this condition. Surprisingly, only 3 patients needed acute neurosurgical intervention, perhaps due to milder cases and a general intensified treatment of precipitating factors. An early awareness and in severe cases decision on pituitary surgery is of utmost importance to avoid severe complications.
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http://dx.doi.org/10.3389/fendo.2021.656950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082680PMC
April 2021

Prader-Willi Syndrome and Hypogonadism: A Review Article.

Int J Mol Sci 2021 Mar 8;22(5). Epub 2021 Mar 8.

Centre for Paediatric Endocrinology Zurich (PEZZ), 8006 Zurich, Switzerland.

Prader-Labhart-Willi syndrome (PWS) is a rare genetic disorder characterized by intellectual disability, behavioural problems, hypothalamic dysfunction and specific dysmorphisms. Hypothalamic dysfunction causes dysregulation of energy balance and endocrine deficiencies, including hypogonadism. Although hypogonadism is prevalent in males and females with PWS, knowledge about this condition is limited. In this review, we outline the current knowledge on the clinical, biochemical, genetic and histological features of hypogonadism in PWS and its treatment. This was based on current literature and the proceedings and outcomes of the International PWS annual conference held in November 2019. We also present our expert opinion regarding the diagnosis, treatment, care and counselling of children and adults with PWS-associated hypogonadism. Finally, we highlight additional areas of interest related to this topic and make recommendations for future studies.
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http://dx.doi.org/10.3390/ijms22052705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962179PMC
March 2021

Safety and effectiveness of replacement with biosimilar growth hormone in adults with growth hormone deficiency: results from an international, post-marketing surveillance study (PATRO Adults).

Pituitary 2021 Mar 20. Epub 2021 Mar 20.

Department of Endocrinology, Sahlgrenska University Hospital, Göteborg, Sweden.

Purpose: To evaluate safety and effectiveness of biosimilar recombinant human growth hormone (rhGH; Omnitrope®) in adults with growth hormone deficiency (GHD), using data from the PATRO Adults study.

Methods: PATRO Adults was a post-marketing surveillance study conducted in hospitals and specialized endocrinology units across Europe. The primary objective was to assess the safety of rhGH in adults treated in routine clinical practice. All adverse events (AEs) were monitored and recorded for the complete duration of Omnitrope® treatment. Effectiveness was evaluated as a secondary objective.

Results: As of January 2020, 1447 patients (50.9% male) had been enrolled from 82 centers in 9 European countries. Most patients had adult-onset GHD (n = 1179; 81.5%); 721 (49.8%) were rhGH-naïve at study entry. Overall, 1056 patients (73.0%) reported adverse events (AEs; n = 5397 events); the majority were mild-to-moderate in intensity. Treatment-related AEs were reported in 117 patients (8.1%; n = 189 events); the most commonly reported (MedDRA preferred terms) were arthralgia (n = 19), myalgia (n = 16), headache (n = 14), and edema peripheral (n = 10). In total, 495 patients (34.2%) had serious AEs (SAEs; n = 1131 events); these were considered treatment-related in 28 patients (1.9%; n = 35 events). Mean (standard deviation) IGF-I SDS increased from - 2.34 (1.47) at baseline to - 0.23 (1.65) at 12 months, and remained relatively stable thereafter (up to 3 years). Body mass index remained stable between baseline and 3 years.

Conclusion: Data from PATRO Adults indicate biosimilar rhGH (Omnitrope) is not associated with any unexpected safety signals, and is effective in adults with GHD treated in real-world clinical practice.
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http://dx.doi.org/10.1007/s11102-021-01139-2DOI Listing
March 2021

Pregnancy outcomes in women receiving growth hormone replacement therapy enrolled in the NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program.

Pituitary 2021 Mar 12. Epub 2021 Mar 12.

Unit of Endocrinology, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz, Germany.

Purpose: Data on the safety of growth hormone (GH) replacement therapy during pregnancy are limited. We report a combined analysis of data from pregnant women treated with GH while enrolled in two non-interventional, multicenter studies: NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program.

Methods: Pregnancy data were pooled from NordiNet® IOS and the ANSWER Program. Data were collected during routine clinic visits by participating physicians using a web-based system. Patients exposed to GH replacement therapy during pregnancy were included in the analysis.

Results: The study population included 40 female patients with typical causes of adult GH deficiency (GHD). Overall, there were 54 pregnancies. Of these, 47 were exposed to GH between conception and delivery. In 48.9% of pregnancies exposed to GH, the dose was > 0.6 mg/day. GH was continued past conception and then stopped during the first, second, and third trimester, in 27.7%, 17.0%, and 2.1% of pregnancies, respectively. In 29.8%, GH was continued throughout pregnancy, with an unchanged dose in most cases. Of the 47 GH-exposed pregnancies, 37 (78.7%) progressed to normal delivery. There were three adverse events reported in two pregnancies.

Conclusion: These real-world data suggest that there were no new safety signals related to GH exposure in women with GHD during pregnancy. These results are consistent with findings from previous studies reporting data in pregnancies exposed to GH at conception or throughout pregnancy. This observational study in additional pregnancies provides further evidence that GH exposure does not adversely affect pregnancy outcome.

Clinical Trial Registration: ClinicalTrials.gov NCT00960128 (date of registration: August 13, 2009) and NCT01009905 (date of registration: November 5, 2009).
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http://dx.doi.org/10.1007/s11102-021-01138-3DOI Listing
March 2021

Endocrine disorders in Prader-Willi syndrome: a model to understand and treat hypothalamic dysfunction.

Lancet Diabetes Endocrinol 2021 04 26;9(4):235-246. Epub 2021 Feb 26.

International Prader-Willi Syndrome Organisation, Cambridge, UK; Department of Endocrinology, Karolinska University Hospital and Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.

Prader-Willi syndrome is a rare genetic neurodevelopmental disorder resulting from the loss of expression of maternally imprinted genes located in the paternal chromosomal region, 15q11-13. Impaired hypothalamic development and function is the cause of most of the phenotypes comprising the developmental trajectory of Prader-Willi syndrome: from anorexia at birth to excessive weight gain preceding hyperphagia, and early severe obesity with hormonal deficiencies, behavioural problems, and dysautonomia. Growth hormone deficiency, hypogonadism, hypothyroidism, premature adrenarche, corticotropin deficiency, precocious puberty, and glucose metabolism disorders are the main endocrine dysfunctions observed. Additionally, as a result of hypothalamic dysfunction, oxytocin and ghrelin systems are impaired in most patients. Standard pituitary and gonadal hormone replacement therapies are required. In this Review, we discuss Prader-Willi syndrome as a model of hypothalamic dysfunction, and provide a comprehensive description of the accumulated knowledge on genetics, pathophysiology, and treatment approaches of this rare disorder.
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http://dx.doi.org/10.1016/S2213-8587(21)00002-4DOI Listing
April 2021

Psychotropic Drugs in Patients with Cushing's Disease Before Diagnosis and at Long-Term Follow-Up: A Nationwide Study.

J Clin Endocrinol Metab 2021 May;106(6):1750-1760

Department of Endocrinology in Linköping and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.

Context: Psychiatric symptoms are common in Cushing's disease (CD) and seem only partly reversible following treatment.

Objective: To investigate drug dispenses associated to psychiatric morbidity in CD patients before treatment and during long-term follow-up.

Design: Nationwide longitudinal register-based study.

Setting: University Hospitals in Sweden.

Subjects: CD patients diagnosed between 1990 and 2018 (N = 372) were identified in the Swedish Pituitary Register. Longitudinal data was collected from 5 years before, at diagnosis, and during follow-up. Four matched controls per patient were included. Cross-sectional subgroup analysis of 76 patients in sustained remission was also performed.

Main Outcome Measures: Data from the Swedish Prescribed Drug Register and the Patient Register.

Results: In the 5-year period before and at diagnosis, use of antidepressants (odds ratio [OR] 2.2 [95% confidence interval (CI) 1.3-3.7]) and 2.3 [1.6-3.5]), anxiolytics [2.9 (1.6-5.3) and 3.9 (2.3-6.6)], and sleeping pills [2.1 (1.2-3.7) and 3.8 (2.4-5.9)] was more common in CD than controls. ORs remained elevated at 5-year follow-up for antidepressants [2.4 (1.5-3.9)] and sleeping pills [3.1 (1.9-5.3)]. Proportions of CD patients using antidepressants (26%) and sleeping pills (22%) were unchanged at diagnosis and 5-year follow-up, whereas drugs for hypertension and diabetes decreased. Patients in sustained remission for median 9.3 years (interquartile range 8.1-10.4) had higher use of antidepressants [OR 2.0 (1.1-3.8)] and sleeping pills [2.4 (1.3-4.7)], but not of drugs for hypertension.

Conclusions: Increased use of psychotropic drugs in CD was observed before diagnosis and remained elevated regardless of remission status, suggesting persisting negative effects on mental health. The study highlights the importance of early diagnosis of CD, and the need for long-term monitoring of mental health.
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http://dx.doi.org/10.1210/clinem/dgab079DOI Listing
May 2021

Time for a general approval of growth hormone treatment in adults with Prader-Willi syndrome.

Orphanet J Rare Dis 2021 02 8;16(1):69. Epub 2021 Feb 8.

Division of Pediatric Genetics and Metabolism, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA.

Prader-Willi syndrome (PWS) is a complex, multi-system, neurodevelopmental disorder characterised by neonatal muscular hypotonia, short stature, high risk of obesity, hypogonadism, intellectual disabilities, distinct behavioural/psychiatric problems and abnormal body composition with increased body fat and a deficit of lean body mass. Growth hormone (GH) deficiency and other hormone deficiencies are common due to hypothalamic dysfunction. In children with PWS GH treatment has been widely demonstrated to improve body composition, normalise height and improve psychomotor development. In adults with PWS, GH's main effects are to maintain normal body structure and metabolism. The positive effects of GH treatment on body composition, physical fitness and beneficial effects on cardiovascular risk markers, behaviour and quality of life in adults with PWS are also well established from several studies. GH treatment is approved for treatment of children with PWS in many countries, but until recently not as a treatment in young adults in the transition period or for adults in general. In this commentary we want to draw attention to the uneven global use of GH treatment, specifically in adults with PWS, and advocate for GH treatment to be approved internationally, not just for children, but also for adults with PWS and based only on the diagnosis of genetically confirmed PWS.
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http://dx.doi.org/10.1186/s13023-020-01651-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869190PMC
February 2021

ESE audit on management of Adult Growth Hormone Deficiency in clinical practice.

Eur J Endocrinol 2020 Dec 1. Epub 2020 Dec 1.

T Kocjan, Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre, Ljubljana, Slovenia.

Guidelines recommend adults with pituitary disease in whom GH therapy is contemplated, to be tested for GH deficiency (AGHD); however, clinical practice is not uniform.

Aims: 1) To record current practice of AGHD management throughout Europe and benchmark it against guidelines; 2) To evaluate educational status of healthcare professionals about AGHD.

Design: On-line survey in endocrine centres throughout Europe.

Patients And Methods: Endocrinologists voluntarily completed an electronic questionnaire regarding AGHD patients diagnosed or treated in 2017-2018.

Results: Twenty-eight centres from 17 European countries participated, including 2139 AGHD patients, 28% of childhood-onset GHD. Aetiology was most frequently non-functioning pituitary adenoma (26%), craniopharyngioma (13%) and genetic/congenital mid-line malformations (13%). Diagnosis of GHD was confirmed by a stimulation test in 52% (GHRH+arginine, 45%; insulin-tolerance, 42%, glucagon, 6%; GHRH alone and clonidine tests, 7%); in the remaining, ≥3 pituitary deficiencies and low serum IGF-I were diagnostic. Initial GH dose was lower in older patients, but only women <26 years were prescribed a higher dose than men; dose titration was based on normal serum IGF-I, tolerance and side-effects. In one country, AGHD treatment was not approved. Full public reimbursement was not available in four countries and only in childhood-onset GHD in another. AGHD awareness was low among non-endocrine professionals and healthcare administrators. Postgraduate AGHD curriculum training deserves being improved.

Conclusion: Despite guideline recommendations, GH replacement in AGHD is still not available or reimbursed in all European countries. Knowledge among professionals and health administrators needs improvement to optimize care of adults with GHD.
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http://dx.doi.org/10.1530/EJE-20-1180DOI Listing
December 2020

Hair cortisol-a method to detect chronic cortisol levels in patients with Prader-Willi syndrome.

BMC Endocr Disord 2020 Nov 10;20(1):166. Epub 2020 Nov 10.

Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.

Background: Prader-Willi syndrome (PWS) is a multisymptomatic, rare, genetic, neurodevelopmental disorder in adults mainly characterized by hyperphagia, cognitive dysfunction, behavioral problems and risk of morbid obesity. Although endocrine insufficiencies are common, hypocortisolism is rare and knowledge on long-term cortisol concentrations is lacking. The aim of this study was to evaluate long-term cortisol levels in PWS by measurements of hair cortisol.

Methods: Twenty-nine adults with PWS, 15 men and 14 women, median age 29 years, median BMI 27 kg/m, were included. Scalp hair samples were analyzed for cortisol content using liquid-chromatography tandem-mass spectrometry. In addition, a questionnaire on auxology, medication and stress were included. For comparison, 105 age- and sex-matched participants from the population-based Lifelines Cohort study were included as controls. The mean hair cortisol between the groups were compared and associations between BMI and stress were assessed by a generalized linear regression model.

Results: In the PWS group large variations in hair cortisol was seen. Mean hair cortisol was 12.8 ± 25.4 pg/mg compared to 3.8 ± 7.3 pg/mg in controls (p = 0.001). The linear regression model similarly showed higher cortisol levels in patients with PWS, which remained consistent after adjusting for BMI and stress (p = 0.023). Furthermore, hair cortisol increased with BMI (p = 0.012) and reported stress (p = 0.014).

Conclusion: Long-term cortisol concentrations were higher in patients with PWS compared to controls and increased with BMI and stress, suggesting an adequate cortisol response to chronic stress. Hair cortisol demonstrate promising applications in the context of PWS treatment and disease management.
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http://dx.doi.org/10.1186/s12902-020-00646-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654170PMC
November 2020

Simplified and improved fluid deprivation test for diagnosing diabetes insipidus.

Eur J Endocrinol 2021 Jan;184(1):123-131

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Objective: The challenge of finding patients with the rare conditon of diabetes insipidus in need of vasopressin treatment is demanding. The guidelines for performing the fluid deprivation test and interpreting the results are abundant. We evaluated the discriminative capacity of the fluid deprivation test in patients with polyuria to define a cut off for a more effective discrimination between diabetes insipidus and other polyuria syndromes.

Research Design And Methods: Retrospective review and data collection of all ambulatory fluid deprivation tests, of patients with mild polyuria and polydipsia (< 3 L/day), performed between 2000 and 2018. Serum osmolality, urine osmolality, urine volumes and clinical information of diagnosis were retrieved from the patient's medical records.

Results: The study group consisted of 153 patients, 123 were diagnosed with non-diabetes insipidus and 30 with diabetes insipidus. After 12 h fasting (baseline) median duration of the fluid deprivation test was 5 h (fasting range: 12-21 h). At baseline, there was a significant difference between median serum and urine osmolality between the groups (P < 0.05). The best cut-off for the diagnosis of diabetes insipidus, was the combination of < 400 mosmol/kg in urine and > 302 mosmol/kg in serum. With this cut-off a sensitivity of 90% and specificity of 98% was achieved.

Conclusion: After 12 h fasting our proposed cut off clearly differentiated between diabetes insipidus, and non-diabetes insipidus suggesting a possibility to considerably reduce the duration of the fluid deprivation test.
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http://dx.doi.org/10.1530/EJE-20-0759DOI Listing
January 2021

Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations.

J Clin Endocrinol Metab 2021 Mar;106(4):1183-1194

Department of Endocrinology, Skåne University Hospital, Malmö, Lund University, Sweden.

Context: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors.

Objective: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs.

Design: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored.

Results: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs.

Conclusion: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors.
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http://dx.doi.org/10.1210/clinem/dgaa749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993578PMC
March 2021

Safety of current recombinant human growth hormone treatments for adults with growth hormone deficiency and unmet needs.

Expert Opin Drug Saf 2020 Dec 27;19(12):1539-1548. Epub 2020 Oct 27.

Leeds Centre for Diabetes & Endocrinology, St James's University Hospital , Leeds, UK.

Introduction: Growth hormone (GH) deficiency (GHD) in adults is characterized by abnormal body composition, unfavorable cardiovascular risk factors, and poor quality of life. The diagnosis is made within appropriate clinical settings and according to established guidelines. Numerous studies have shown that GH treatment improves body composition, cardiovascular risk factors, physical capacity, and quality of life while issues on safety, in particular long-term safety, remain.

Areas Covered: Short- and long-term safety of GH replacement in adults with GHD.

Expert Opinion: Adults with GHD are an inhomogeneous group of patients and GH replacement requires individual considerations. Most adverse effects are mild and transient and related to fluid retention and GH dose. In patients without comorbidities long-term GH treatment is safe and development of diabetes, cardiovascular disease, or tumors are not increased. Furthermore, mortality is not increased. Patients with risk factors should be identified before GH treatment is initiated and an optimal balance between benefit and risk established. Studies with sufficient duration and power to identify the development of cardiovascular diseases and cancers are still awaited. Effective management of comorbidities can be expected to decrease morbidity and mortality and improve quality of life. Studies with long-acting GH formulations are ongoing and available data indicate similar effects and short-time safety.
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http://dx.doi.org/10.1080/14740338.2020.1839410DOI Listing
December 2020

Malignancy risk in adults with growth hormone deficiency undergoing long-term treatment with biosimilar somatropin (Omnitrope): data from the PATRO Adults study.

Ther Adv Endocrinol Metab 2020 10;11:2042018820943377. Epub 2020 Sep 10.

Medicover Neuroendokrinologie, Munich, Germany.

Background: To assess the safety (particularly the occurrence of malignancies) of growth hormone (GH) replacement (Omnitrope) in adults with GH deficiency, using data from the ongoing PATRO Adults post-marketing surveillance study.

Methods: PATRO Adults is being conducted in hospitals and specialized endocrinology clinics across Europe. All enrolled patients who receive ⩾1 dose of Omnitrope are included in the safety population. Malignancies are listed as adverse events under the MedDRA System Organ Class 'neoplasms, benign, malignant and unspecified (including cysts and polyps)'.

Results: As of July 2018, 1293 patients had been enrolled in the study and 983 (76.0%) remained active in the study. Approximately half [ = 637 (49.3%)] of the patients were GH treatment-naïve on study entry. The majority of enrolled patients had multiple pituitary hormone deficiency ( = 1128, 87.2%). A total of 41 on-study malignancies were reported in 33 patients (2.6%; incidence rate 7.94 per 1000 patient-years). The most common cancers were basal cell carcinoma ( = 13), prostate ( = 6), breast, kidney and malignant melanoma (each  = 3). Treatment with Omnitrope was discontinued following diagnosis of malignancy in 16 patients. The tumors occurred after a mean of 79.4 months of recombinant hormone GH (rhGH) treatment overall.

Conclusion: Based on this snapshot of data from PATRO Adults, Omnitrope treatment is tolerated in adult patients with GH deficiency in a real-life clinical practice setting. Our results do not generally support a carcinogenic effect of rhGH in adults with GH deficiency, although an increased risk of second new malignancies in patients with previous cancer cannot be excluded based on the current dataset.
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http://dx.doi.org/10.1177/2042018820943377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491215PMC
September 2020

Excess Morbidity Persists in Patients With Cushing's Disease During Long-term Remission: A Swedish Nationwide Study.

J Clin Endocrinol Metab 2020 08;105(8)

Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Context: Whether multisystem morbidity in Cushing's disease (CD) remains elevated during long-term remission is still undetermined.

Objective: To investigate comorbidities in patients with CD.

Design, Setting, And Patients: A retrospective, nationwide study of patients with CD identified in the Swedish National Patient Register between 1987 and 2013. Individual medical records were reviewed to verify diagnosis and remission status.

Main Outcomes: Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were calculated by using the Swedish general population as reference. Comorbidities were investigated during three different time periods: (i) during the 3 years before diagnosis, (ii) from diagnosis to 1 year after remission, and (iii) during long-term remission.

Results: We included 502 patients with confirmed CD, of whom 419 were in remission for a median of 10 (interquartile range 4 to 21) years. SIRs (95% CI) for myocardial infarction (4.4; 1.2 to 11.4), fractures (4.9; 2.7 to 8.3), and deep vein thrombosis (13.8; 3.8 to 35.3) were increased during the 3-year period before diagnosis. From diagnosis until 1 year after remission, SIRs (95% CI were increased for thromboembolism (18.3; 7.9 to 36.0), stroke (4.9; 1.3 to 12.5), and sepsis (13.6; 3.7 to 34.8). SIRs for thromboembolism (4.9; 2.6 to 8.4), stroke (3.1; 1.8 to 4.9), and sepsis (6.0; 3.1 to 10.6) remained increased during long-term remission.

Conclusion: Patients with CD have an increased incidence of stroke, thromboembolism, and sepsis even after remission, emphasizing the importance of early identification and management of risk factors for these comorbidities during long-term follow-up.
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http://dx.doi.org/10.1210/clinem/dgaa291DOI Listing
August 2020

Residual Corticosteroid Production in Autoimmune Addison Disease.

J Clin Endocrinol Metab 2020 07;105(7)

Department of Clinical Science, University of Bergen, Norway.

Context: Contrary to current dogma, growing evidence suggests that some patients with autoimmune Addison disease (AAD) produce corticosteroids even years after diagnosis.

Objective: To determine frequencies and clinical features of residual corticosteroid production in patients with AAD.

Design: Two-staged, cross-sectional clinical study in 17 centers (Norway, Sweden, and Germany). Residual glucocorticoid (GC) production was defined as quantifiable serum cortisol and 11-deoxycortisol and residual mineralocorticoid (MC) production as quantifiable serum aldosterone and corticosterone after > 18 hours of medication fasting. Corticosteroids were analyzed by liquid chromatography-tandem mass spectrometry. Clinical variables included frequency of adrenal crises and quality of life. Peak cortisol response was evaluated by a standard 250 µg cosyntropin test.

Results: Fifty-eight (30.2%) of 192 patients had residual GC production, more common in men (n = 33; P < 0.002) and in shorter disease duration (median 6 [0-44] vs 13 [0-53] years; P < 0.001). Residual MC production was found in 26 (13.5%) patients and associated with shorter disease duration (median 5.5 [0.5-26.0] vs 13 [0-53] years; P < 0.004), lower fludrocortisone replacement dosage (median 0.075 [0.050-0.120] vs 0.100 [0.028-0.300] mg; P < 0.005), and higher plasma renin concentration (median 179 [22-915] vs 47.5 [0.6-658.0] mU/L; P < 0.001). There was no significant association between residual production and frequency of adrenal crises or quality of life. None had a normal cosyntropin response, but peak cortisol strongly correlated with unstimulated cortisol (r = 0.989; P < 0.001) and plasma adrenocorticotropic hormone (ACTH; r = -0.487; P < 0.001).

Conclusion: In established AAD, one-third of the patients still produce GCs even decades after diagnosis. Residual production is more common in men and in patients with shorter disease duration but is not associated with adrenal crises or quality of life.
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http://dx.doi.org/10.1210/clinem/dgaa256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274491PMC
July 2020

Ten years with biosimilar rhGH in clinical practice in Sweden - experience from the prospective PATRO children and adult studies.

BMC Endocr Disord 2020 Apr 29;20(1):55. Epub 2020 Apr 29.

Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.

Background: In 2007, Omnitrope® was the first biosimilar recombinant human growth hormone (rhGH) to be approved in Sweden for treatment in adults and children. Over 10 years' safety and effectiveness data for biosimilar rhGH can now be presented.

Methods: PATRO Children and PATRO Adults are multicenter, longitudinal, observational, post-marketing surveillance studies. Eligible patients include children 0-18 years and adults receiving biosimilar rhGH treatment. Adverse events (AEs) are monitored for safety evaluation. Growth variables in children and metabolic data in adults are recorded for effectiveness evaluation.

Results: As of January 2019, data from 136 children (48% male) were reported from Swedish centers. Mean age in rhGH treatment-naïve patients at study entry (n = 114) was 7.5 years, with mean 3.6 years treatment duration. No severe AEs of diabetes, impaired glucose tolerance, or malignancy were reported. The most frequently reported AE was nasopharyngitis (n = 16 patients). No clinically relevant anti-hGH or neutralizing antibodies were observed. The mean change from baseline in height standard deviation score (SDS) in naïve prepubertal GH deficiency patients was + 0.79 at 1 year, + 1.27 at 2 years, and + 1.55 at 3 years. Data from 293 adults (44% rhGH-naïve, 51% male) were included. Fatigue was the most frequently reported AE (n = 26 patients). The incidence of new neoplasms or existing neoplasm progression was 23.8 patients per 1000 patient-years. Type 2 diabetes mellitus was reported in four patients. At baseline in rhGH-naïve adults, mean (SD) body mass index (BMI) was 29.1 (5.6) kg/m and mean (SD) insulin-like growth factor (IGF)-I SDS was - 3.0 (1.4). Mean daily dose increased from 0.1 mg at baseline to 0.3 mg after 4 years. IGF-I SDS normalized during the first year of treatment. Mean BMI and glucose were unchanged over 4 years, while low-/high-density lipoprotein cholesterol ratio decreased.

Conclusions: For the first time, Swedish data from the PATRO Children and Adults studies are presented. The 10-year data suggest that biosimilar rhGH is well tolerated across pediatric and adult indications. Safety and effectiveness were similar to previous reports for other rhGH preparations. These results need to be confirmed in larger cohorts, highlighting the importance of long-term post-marketing studies.
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http://dx.doi.org/10.1186/s12902-020-0535-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191769PMC
April 2020

Central Adrenal Insufficiency Is Rare in Adults With Prader-Willi Syndrome.

J Clin Endocrinol Metab 2020 07;105(7)

Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Context: 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. 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.

Objective: To 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).

Design: Metyrapone test or ITT in adults with PWS (N = 82) and review of medical files for symptoms of hypocortisolism related to surgery (N = 645).

Setting: Outpatient clinic.

Patients Or Other Participants: Eighty-two adults with genetically confirmed PWS.

Main Outcome Measure: For 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.

Results: Central 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.

Conclusions: Central 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.
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http://dx.doi.org/10.1210/clinem/dgaa168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211032PMC
July 2020

Reference intervals of salivary cortisol and cortisone and their diagnostic accuracy in Cushing's syndrome.

Eur J Endocrinol 2020 Jun;182(6):569-582

Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.

Objective: The challenge of diagnosing Cushing's syndrome (CS) calls for high precision biochemical screening. This study aimed to establish robust reference intervals for, and compare the diagnostic accuracy of, salivary cortisol and cortisone in late-night samples and after a low-dose (1 mg) dexamethasone suppression test (DST).

Design And Methods: Saliva samples were collected at 08:00 and 23:00 h, and at 08:00 h, after a DST, from 22 patients with CS and from 155 adult reference subjects. We also collected samples at 20:00 and 22:00 h from 78 of the reference subjects. Salivary cortisol and cortisone were analysed with liquid chromatography-tandem mass spectrometry. The reference intervals were calculated as the 2.5th and 97.5th percentiles of the reference population measurements. Diagnostic accuracies of different tests were compared, based on areas under the receiver-operating characteristic curves.

Results: The upper reference limits of salivary cortisol and cortisone at 23:00 h were 3.6 nmol/L and 13.5 nmol/L, respectively. Using these reference limits, CS was detected with a sensitivity (95% CI) of 90% (70-99%) and specificity of 96% (91-98%) for cortisol, and a 100% (84-100%) sensitivity and 95% (90-98%) specificity for cortisone. After DST, cortisol and cortisone upper reference limits were 0.79 nmol/L and 3.5 nmol/L, respectively. CS was detected with 95% (75-100%) sensitivity and 96% (92-99%) specificity with cortisol, and 100% (83-100%) sensitivity and 94% (89-97%) specificity with cortisone. No differences in salivary cortisol or cortisone levels were found between samples collected at 22:00 and 23:00 h.

Conclusion: Salivary cortisol and cortisone in late-night samples and after DST showed high accuracy for diagnosing CS, salivary cortisone being slightly, but significantly better.
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http://dx.doi.org/10.1530/EJE-19-0872DOI Listing
June 2020

Growth hormone replacement in adults: Real-world data from two large studies in US and Europe.

Growth Horm IGF Res 2020 02 26;50:71-82. Epub 2019 Oct 26.

Neuroendocrine Unit, Massachusetts General Hospital, Bulfinch 457B, Massachusetts General Hospital, Fruit St., Boston, MA 02114, USA.

Objective: This report describes the effectiveness and safety of growth hormone replacement in 3180 adult patients with growth hormone deficiency followed-up for 0.0-12.2 years in two completed, complementary, non-interventional, multicentre studies, NordiNet® International Outcome Study (IOS) (NCT00960128) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program (NCT01009905).

Design: In both studies, Norditropin® (somatropin; Novo Nordisk A/S, Denmark) was administered at the discretion of the treating physician and according to routine practice. We present data on baseline characteristics, growth hormone dose, safety data and change from baseline in waist circumference, body mass index and bioimpedance (NordiNet® IOS only).

Results: Mean (SD) baseline characteristics (effectiveness analysis set) in NordiNet® IOS (n = 971) and ANSWER (n = 304): females, 45%; 69%; mean growth hormone dose (mg/day) (female, 0.338 [0.177]; male, 0.289 [0.157]); (female, 0.501 [0.313]; male, 0.505 [0.351]). Most patients had BMI ≥25 kg/m. Median (P10,P90) exposure (females, 3.5 [0.42,11.0]; 1.6 [3.2; 0.3,8.6]; males, 4.1 [0.33,10.8]; 2.3 [2.9; 0.0,7.5] years). Mean (SD) change from baseline for waist circumference (-0.46 [6.38] cm [n = 403], BMI (0.30 [3.30] kg/m [n = 857]) and bioimpedance (-17.4 (59.19) ohm [n = 239]) were associated with growth hormone dose (waist/bioimpedance) and duration of follow-up (BMI/bioimpedance). No new safety signals were observed among patients in the full analysis set (NordiNet® IOS, n = 2321; ANSWER, n = 859).

Conclusions: Long-term growth hormone replacement is associated with an improvement in body composition. The accumulated data from >10 years of follow-up support the long-term effectiveness and safety of growth hormone replacement as prescribed in clinical practice.
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http://dx.doi.org/10.1016/j.ghir.2019.09.002DOI Listing
February 2020

No increased risk of glucose metabolism disorders in adults with growth hormone deficiency undergoing long-term treatment with biosimilar somatropin (Omnitrope®): data from an observational, longitudinal study.

BMC Endocr Disord 2019 Dec 11;19(1):138. Epub 2019 Dec 11.

Medicover Neuroendokrinologie, Orleansplatz 3, 81667, Munich, Germany.

Background: To evaluate the impact of treatment with recombinant human growth hormone (rhGH; Omnitrope®) on the risk of diabetes mellitus in adults with growth hormone deficiency (GHD), using data from the ongoing PATRO Adults post-marketing surveillance study.

Methods: PATRO Adults is an ongoing post-marketing surveillance study being conducted in hospitals and specialized endocrinology clinics across Europe. All enrolled patients who receive ≥1 dose of Omnitrope® are included in the safety population. Patient profiles, containing all available study database information for each specific patient, were generated for all patients with adverse events (AEs) of diabetes mellitus while participating in the study. Diabetes mellitus was confirmed if fasting plasma glucose was ≥7.0 mmol/L or 2-h plasma glucose ≥11.1 mmol/L during oral glucose tolerance test or glycated hemoglobin ≥6.5%.

Results: Up to July 2018, 1293 patients had been enrolled in the study, and 983 (76.0%) remained active. Just under half (n = 687, 49.3%) of the patients were growth hormone (GH) treatment-naïve on entering the study, and most (n = 1128, 87.2%) had multiple pituitary hormone deficiency (MPHD). Diabetes mellitus/inadequate control (worsening) of diabetes mellitus was reported in 21 patients (22 events). The cases were newly diagnosed in 15 patients (age 29-84 years; incidence rate 3.61 per 1000 patient-years) and occurred in 6 patients with pre-existing diabetes mellitus at baseline (age 45-72 years). Most cases of newly diagnosed diabetes mellitus occurred in patients with adult-onset MPHD (n = 13); the remaining cases of new-onset diabetes mellitus occurred in a patient with childhood-onset MPHD who had previously received GH replacement therapy (n = 1), and a patient with adulthood-onset isolated GHD who was naïve to GH replacement therapy (n = 1). All cases of inadequate control/worsening of diabetes mellitus occurred in patients with adult-onset MPHD.

Conclusions: Based on this snapshot of data from PATRO Adults, Omnitrope® treatment is tolerated in adult patients with GHD in a real-life clinical practice setting. No signals of an increased risk for diabetes mellitus have been noted so far, although continued follow-up (both during and after rhGH therapy) is required to confirm this.

Trial Registration: Not applicable.
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http://dx.doi.org/10.1186/s12902-019-0464-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907272PMC
December 2019

Change in baseline characteristics over 20 years of adults with growth hormone (GH) deficiency on GH replacement therapy.

Eur J Endocrinol 2019 Dec;181(6):629-638

Endocrine Care, Pfizer Health AB, Sollentuna, Sweden.

Objective: Clinical observations over time of adults with growth hormone (GH) deficiency (GHD) have indicated a shift in patient characteristics at diagnosis. The objective of this study was to compare baseline characteristics of patients diagnosed with adult-onset GHD naive to GH replacement during three study periods (1994-1999 (P1), 2000-2004 (P2), and 2005-2012 (P3)) using the KIMS (Pfizer's International Metabolic) database.

Methods: Data were retrieved for a total of 6069 patients with adult-onset GHD from six countries (Belgium, Germany, Netherlands, Spain, Sweden, and UK): P1 (n = 1705), P2 (n = 2397), and P3 (n = 1967).

Results: The proportions of patients with pituitary/hypothalamic tumors and patients with multiple pituitary hormone deficiencies decreased per entry year period, while the proportions with hypertension and diabetes increased. The lag time from diagnosis of pituitary disease to start of GH treatment decreased by 2.9 years over the entry year periods. IGF-1 increased by 0.1 standard deviation score per entry year period. Maximum GH following various stimulation tests, BMI, and waist circumference increased. The use of radiotherapy, glucocorticoid replacement doses, and the proportion of women >50 years on estrogen replacement therapy decreased. The effects of 1 year of GH replacement were similar over the entry year periods despite changes in the patients' baseline characteristics. An expected increase in fasting blood glucose was seen after 1 year of GH treatment.

Conclusions: The degree of confirmed GHD became less pronounced and more patients with co-morbidities and diabetes were considered for GH replacement therapy, possibly reflecting increased knowledge and confidence in GH therapy gained with time.
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http://dx.doi.org/10.1530/EJE-19-0576DOI Listing
December 2019

Letter regarding "Prevalence of growth hormone deficiency in previously GH-treated young adults with Prader-Willi syndrome" by Donze et al.

Clin Endocrinol (Oxf) 2019 10 26;91(4):578-579. Epub 2019 Jun 26.

President IPWSO, Department of Psychiatry, University of Cambridge, Cambridge, UK.

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http://dx.doi.org/10.1111/cen.14047DOI Listing
October 2019

Serum soluble urokinase plasminogen activator receptor (suPAR) in adults with growth hormone deficiency.

Endocr Connect 2019 Jun;8(6):772-779

Clinical Research Centre, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.

Growth hormone deficiency (GHD) syndrome is associated with adverse levels of several risk factors for cardiovascular diseases (CVD), including metabolic inflammation. However, the impact of GHD and GH treatment on low-grade inflammation is unknown. The aim of the study was to establish the level of the low-grade inflammation biomarker soluble urokinase plasminogen activator receptor (suPAR) in adults with GHD and the response to long-term GH treatment. Measurements of suPAR and CRP were performed in bio-bank serum samples from 72 adults, 34 males and 38 females, with GHD before and during at least 5 years of GH treatment. Mean age was 52.5 ± 15.5 years, BMI 27.3 ± 5 kg/m2. Clinical evaluations and blood sampling were performed at routine visits. Data on demography, anthropometry, lab results and clinical events were retrieved from post-marketing surveillance study databases and medical records. suPAR and high-sensitive (hs) CRP were analysed using ELISA and immunochemistry, respectively. At baseline blood pressure, lipid profile and fasting glucose were within the normal reference range. Baseline geometric mean and 95% CI of suPAR was 2.9 (2.7-3.3) ng/mL and of CRP 2.3 (0.6-4.0) mg/L. Mean follow-up was 8 ± 2 years. The suPAR levels remained stable during follow-up, although individual increases were seen on occurrence or presence of co-morbidities. In contrast, levels of CRP decreased. In conclusion, the decrease in CRP and indirectly the absence of an expected increase in suPAR over time indicates a favourable effect of GH on low-grade inflammation.
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http://dx.doi.org/10.1530/EC-19-0159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547304PMC
June 2019

Evaluation of different hydrocortisone treatment strategies in transsphenoidal pituitary surgery.

Acta Neurochir (Wien) 2019 08 7;161(8):1715-1721. Epub 2019 May 7.

Department of Otorhinolaryngology, Ryhov County Hospital, Futurum- the Academy for Health and Care, Jönköping, Sweden.

Background: Hydrocortisone treatment in transsphenoidal pituitary surgery has been debated. Although several publications advocate restrictive treatment, centers around the world administer stress doses of hydrocortisone in patients with presumed intact cortisol production. Our aim with this analysis was to compare postoperative hypocortisolism in patients who received three different protocols of hydrocortisone therapy during and after surgery.

Method: This was a retrospective observational study. Based on perioperative hydrocortisone dose given, patients were divided in three groups: high dose (HD), intermediate dose (ID), and low dose (LD). Postoperative evaluation of the pituitary function was performed using S-cortisol at day 4 and short Synacthen test (SST) at 6-8 weeks. Patients with ACTH-producing adenomas or preoperative hydrocortisone treatment were excluded.

Result: There was no difference between the groups regarding failure rate of SST. The rate of failed SST (all groups) was 51/186 (27%), 24/74 (32%) in the HD group and 26/74 (35%) and 11/38 (29%) in the ID and LD groups respectively. There was no significant difference between the ID and LD groups regarding S-cortisol at postoperative day 4 regarding serum cortisol level below 200 nmol/L. There was a significant but weak correlation, r 0.330 (P < 0.01) between S-cortisol day 4 and SST at 4-6 weeks.

Conclusions: Peri and postoperative hydrocortisone treatment did not affect SST response 6-8 weeks postoperatively, whereas the rate of patients with S-cortisol below 200 nmol/L at postoperative day 4 did. LD hydrocortisone therapy seems to favor a better endogenous production in the early postoperative phase.
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http://dx.doi.org/10.1007/s00701-019-03885-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616203PMC
August 2019

The incidence of Cushing's disease: a nationwide Swedish study.

Pituitary 2019 Apr;22(2):179-186

Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, and The Department of Endocrinology, Sahlgrenska University Hospital, Gröna Stråket 8, 413 45, Gothenburg, Sweden.

Background: Studies on the incidence of Cushing's disease (CD) are few and usually limited by a small number of patients. The aim of this study was to assess the annual incidence in a nationwide cohort of patients with presumed CD in Sweden.

Methods: Patients registered with a diagnostic code for Cushing's syndrome (CS) or CD, between 1987 and 2013 were identified in the Swedish National Patient Registry. The CD diagnosis was validated by reviewing clinical, biochemical, imaging, and histopathological data.

Results: Of 1317 patients identified, 534 (41%) had confirmed CD. One-hundred-and-fifty-six (12%) patients had other forms of CS, 41 (3%) had probable but unconfirmed CD, and 334 (25%) had diagnoses unrelated to CS. The mean (95% confidence interval) annual incidence between 1987 and 2013 of confirmed CD was 1.6 (1.4-1.8) cases per million. 1987-1995, 1996-2004, and 2005-2013, the mean annual incidence was 1.5 (1.1-1.8), 1.4 (1.0-1.7) and 2.0 (1.7-2.3) cases per million, respectively. During the last time period the incidence was higher than during the first and second time periods (P < 0.05).

Conclusion: The incidence of CD in Sweden (1.6 cases per million) is in agreement with most previous reports. A higher incidence between 2005 and 2013 compared to 1987-2004 was noticed. Whether this reflects a truly increased incidence of the disease, or simply an increased awareness, earlier recognition, and earlier diagnosis can, however, not be answered. This study also illustrates the importance of validation of the diagnosis of CD in epidemiological research.
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http://dx.doi.org/10.1007/s11102-019-00951-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418061PMC
April 2019

Impact of pituitary dysfunction on cognitive and global outcome after traumatic brain injury and aneurysmal subarachnoid haemorrhage.

J Rehabil Med 2019 Apr;51(4):264-272

Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.

Objective: To explore associations between pituitary dysfunction and clinical outcome at 12 months after traumatic brain injury and aneurysmal subarachnoid haemorrhage.

Methods: Prospective cohort study of 82 patients with traumatic brain injury and 45 with aneurysmal subarachnoid haemorrhage, included at one neurointensive care unit. Baseline data comprised age, sex, Glasgow Coma Scale (GCS) score, S100B and pupil light reactions. Hormone data were collected in the neurointensive care unit and after 3, 6 and 12 months. Outcome was assessed with Barrow Neurological Institute Screen for Higher Cerebral Functions (BNIS), Rancho Los Amigos Cognitive Scale-Revised (RLAS-R) and Glasgow Outcome Scale Extended (GOSE).

Results: The most frequent hormonal deviations were hypogonadotropic hypogonadism (38%) and hypercortisolism (52%). At 12 months, performance on BNIS was impaired in 54% and GOSE in 37%. Controlling for baseline variables, low levels of gonadal hormones were associated with lower GOSE score (b = -0.80, p = 0.033), high levels of prolactin with lower RLAS (b = -1.42, p = 0.034) and high levels of serum insulin-like growth factor I (S-IGF-I) with lower RLAS level (b = -1.78, p = 0.002) and lower GOSE score (b = -1.49, p = 0.006).

Conclusion: These data suggest that pituitary dysfunctions during the first year after traumatic brain injury and aneurysmal subarachnoid haemorrhage may have clinically relevant, independent effects on clinical outcome at 12 months.
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http://dx.doi.org/10.2340/16501977-2531DOI Listing
April 2019

Overall and Disease-Specific Mortality in Patients With Cushing Disease: A Swedish Nationwide Study.

J Clin Endocrinol Metab 2019 06;104(6):2375-2384

Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.

Context: Whether patients with Cushing disease (CD) in remission have increased mortality is still debatable.

Objective: To study overall and disease-specific mortality and predictive factors in an unselected nationwide cohort of patients with CD.

Design, Patients, And Methods: A retrospective study of patients diagnosed with CD, identified in the Swedish National Patient Registry between 1987 and 2013. Medical records were systematically reviewed to verify the diagnosis. Standardized mortality ratios (SMRs) with 95% CIs were calculated and Cox regression models were used to identify predictors of mortality.

Results: Of 502 identified patients with CD (n = 387 women; 77%), 419 (83%) were confirmed to be in remission. Mean age at diagnosis was 43 (SD, 16) years and median follow-up was 13 (interquartile range, 6 to 23) years. The observed number of deaths was 133 vs 54 expected, resulting in an overall SMR of 2.5 (95% CI, 2.1 to 2.9). The commonest cause of death was cardiovascular diseases (SMR, 3.3; 95% CI, 2.6 to 4.3). Excess mortality was also found associated with infections and suicide. For patients in remission, the SMR was 1.9 (95% CI, 1.5 to 2.3); bilateral adrenalectomy and glucocorticoid replacement therapy were independently associated with increased mortality, whereas GH replacement was associated with improved outcome.

Conclusion: Findings from this large nationwide study indicate that patients with CD have excess mortality. The findings illustrate the importance of achieving remission and continued active surveillance, along with adequate hormone replacement and evaluation of cardiovascular risk and mental health.
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http://dx.doi.org/10.1210/jc.2018-02524DOI Listing
June 2019

Temporal relationship of sleep apnea and acromegaly: a nationwide study.

Endocrine 2018 11 31;62(2):456-463. Epub 2018 Jul 31.

Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.

Purpose: Patients with acromegaly have an increased risk of sleep apnea, but reported prevalence rates vary largely. Here we aimed to evaluate the sleep apnea prevalence in a large national cohort of patients with acromegaly, to examine possible risk factors, and to assess the proportion of patients diagnosed with sleep apnea prior to acromegaly diagnosis.

Methods: Cross-sectional multicenter study of 259 Swedish patients with acromegaly. At patients' follow-up visits at the endocrine outpatient clinics of all seven university hospitals in Sweden, questionnaires were completed to assess previous sleep apnea diagnosis and treatment, cardiovascular diseases, smoking habits, anthropometric data, and S-IGF-1 levels. Daytime sleepiness was evaluated using the Epworth Sleepiness Scale. Patients suspected to have undiagnosed sleep apnea were referred for sleep apnea investigations.

Results: Of the 259 participants, 75 (29%) were diagnosed with sleep apnea before the study start. In 43 (57%) of these patients, sleep apnea had been diagnosed before the diagnosis of acromegaly. After clinical assessment and sleep studies, sleep apnea was diagnosed in an additional 20 patients, yielding a total sleep apnea prevalence of 37%. Higher sleep apnea risk was associated with higher BMI, waist circumference, and index finger circumference. Sleep apnea was more frequent among patients with S-IGF-1 levels in the highest quartile.

Conclusion: Sleep apnea is common among patients with acromegaly, and is often diagnosed prior to their acromegaly diagnosis. These results support early screening for sleep apnea in patients with acromegaly and awareness for acromegaly in patients with sleep apnea.
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http://dx.doi.org/10.1007/s12020-018-1694-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208862PMC
November 2018

The effect of time on cognitive impairments after non-traumatic subarachnoid haemorrhage and after traumatic brain injury.

Brain Inj 2018 16;32(12):1465-1476. Epub 2018 Jul 16.

a Dep. of Clinical Sciences, Danderyd Hospital , Karolinska Institutet , Stockholm , Sweden.

Objectives: To compare the effect of time on cognitive impairments after Subarachnoid Haemorrhage and Traumatic Brain Injury and explore associations with baseline variables and global function.

Methods: Patients with a Glasgow Coma Scale score of 3-13, were assessed at 3, 6 and 12 months post injury by use of BNIS for cognitive impairment, RLAS-R to categorise cognitive and behavioural function, Barthel Index to assess performance of daily living, HADS to screen for depression and anxiety, and EuroQoL-5D, LiSat-11 and Glasgow Outcome Scale Extended to assess global function.

Results: BNIS T-scores did not differ significantly between groups and the proportion of patients with cognitive impairments was not significantly different at any time point. Cognition improved significantly between all time points in both groups except from 6 to 12 months after TBI. Generalised estimating equation showed non-significant signs of slower recovery of BNIS T-scores over time after SAH. Acute GCS scores were associated with BNIS T-scores after TBI but not after SAH. At 12 months, similar proportions of patients with SAH and TBI had good outcome.

Conclusions: Cognitive improvements after SAH and TBI exhibit similarities and correlate with global function. GCS scores are associated with outcome after TBI but not after SAH.
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http://dx.doi.org/10.1080/02699052.2018.1497203DOI Listing
August 2019