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Background: Non-prescribed anabolic androgenic steroid (AAS) use is associated with AAS-induced hypogonadism (ASIH), and metabolic, cardiovascular, and mental health risks. Symptoms of ASIH (fatigue, depression, anxiety, sexual dysfunction) are hard to endure following cessation, but there is no consensus on whether endocrine treatment should be used to treat ASIH. This proof-of-concept study aims to explore safety of off-label clomiphene citrate therapy, whether the treatment will reduce the symptoms of androgen deficiency, and to study changes in health risks after cessation., Methods: In this open-labeled non-randomized off-label hormone intervention pilot study, we shall include males with AAS dependence intending to cease use. The 16-week intervention included clomiphene citrate, transdermal testosterone gel for the first four weeks and optional human chorionic gonadotropin (hCG) from week 4 if low treatment response. Measures of physical and mental health will be examined from ongoing AAS use, during the intervention, and at 6- and 12 months post cessation. Change in self-reported symptoms of hypogonadism and other withdrawal symptoms will be compared with data from a group of men who ended AAS use temporarily without the medical intervention. The study may provide valuable clinical insights and may be used to inform the design of future intervention studies., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Immune tolerance fails in autoimmune polyendocrine syndrome type 1 (APS-1) because of AIRE mutations. We have used single cell transcriptomics to characterize regulatory T cells (Tregs) sorted directly from blood and from in vitro expanded Tregs in APS-1 patients compared to healthy controls. We revealed only CD52 and LTB (down) and TXNIP (up) as consistently differentially expressed genes in the datasets. There were furthermore no large differences of the TCR-repertoire of expanded Tregs between the cohorts, but unique patients showed a more restricted use of specific clonotypes. We also found that in vitro expanded Tregs from APS-1 patients had similar suppressive capacity as controls in co-culture assays, despite expanding faster and having more exhausted cells. Our results suggest that APS-1 patients do not have intrinsic defects in their Treg functionality, and that their Tregs can be expanded ex vivo for potential therapeutic applications., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Individuals born with very low birth weight (VLBW; < 1500 g) have a higher risk of reduced visual function and brain alterations. In a longitudinal cohort study, we assessed differences in visual outcomes and diffusion metrics from diffusion tensor imaging (DTI) at 3 tesla in the visual white matter pathway and primary visual cortex at age 26 in VLBW adults versus controls and explored whether DTI metrics at 26 years was associated with visual outcomes at 32 years. Thirty-three VLBW adults and 50 term-born controls was included in the study. Visual outcomes included best corrected visual acuity, contrast sensitivity, P100 latency, and retinal nerve fibre layer thickness. Mean diffusivity, axial diffusivity, radial diffusivity, and fractional anisotropy was extracted from seven regions of interest in the visual pathway: splenium, genu, and body of corpus callosum, optic radiations, lateral geniculate nucleus, inferior-fronto occipital fasciculus, and primary visual cortex. On average the VLBW group had lower contrast sensitivity, a thicker retinal nerve fibre layer and higher axial diffusivity and radial diffusivity in genu of corpus callosum and higher radial diffusivity in optic radiations than the control group. Higher fractional anisotropy in corpus callosum areas were associated with better visual function in the VLBW group but not the control group., (© 2024. The Author(s).)

Objective: Increased prevalence of cardiovascular disease has been reported in autoimmune Addison's disease (AAD), but pathomechanisms are poorly understood., Design: Cross-sectional study., Methods: We compared serum levels of 177 cardiovascular and inflammatory biomarkers in 43 patients with AAD at >18-h glucocorticoid withdrawal and 43 matched controls, overall and stratified for sex. Biomarker levels were correlated with the frequency of adrenal crises and quality of life (QoL) by AddiQoL-30. Finally, we investigated changes in biomarker levels following 250 µg tetracosactide injection in patients without residual adrenocortical function (RAF) to explore glucocorticoid-independent effects of high ACTH., Results: Nineteen biomarkers significantly differed between patients with AAD and controls; all but 1 (ST1A1) were higher in AAD. Eight biomarkers were significantly higher in female patients compared with controls (IL6, MCP1, GAL9, SPON2, DR4, RAGE, TNFRSF9, and PGF), but none differed between male patients and controls. Levels of RAGE correlated with the frequency of adrenal crises (r = 0.415, P = .006) and AddiQoL-30 scores (r = -0.347, P = .028) but not after correction for multiple testing. PDL2 and leptin significantly declined 60 min after injection of ACTH in AAD without RAF (-0.15 normalized protein expression [NPX], P = .0001, and -0.25 NPX, P = .0003, respectively)., Conclusions: We show that cardiovascular and inflammatory biomarkers are altered in AAD compared with controls, particularly in women. RAGE might be a marker of disease severity in AAD, associated with more adrenal crises and reduced QoL. High ACTH reduced PDL2 and leptin levels in a glucocorticoid-independent manner but the overall effect on biomarker profiles was small., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)

A hallmark of patients with autoimmune polyendocrine syndrome type 1 (APS-1) is serological neutralizing autoantibodies against type 1 interferons (IFN-I). The presence of these antibodies has been associated with severe course of COVID-19. The aims of this study were to investigate SARS-CoV-2 vaccine tolerability and immune responses in a large cohort of patients with APS-1 (N = 33) and how these vaccinated patients coped with subsequent infections. We report that adult patients with APS-1 were able to mount adequate SARS-CoV-2 spike-specific antibody responses after vaccination and observed no signs of decreased tolerability. Compared with age- and gender-matched healthy controls, patients with APS-1 had considerably lower peak antibody responses resembling elderly persons, but antibody decline was more rapid in the elderly. We demonstrate that vaccination protected patients with APS-1 from severe illness when infected with SARS-CoV-2 virus, overriding the systemic danger of IFN-I autoantibodies observed in previous studies., Competing Interests: We confirm that we do not have any financial or other interest related to the submitted work that could affect or have the perception of affecting the authors objectively or could influence or have the perception of influencing the content of the article., (© 2023 The Author(s).)

Background: Autoimmune Addison's disease (AAD) is the most common cause of primary adrenal insufficiency (PAI). Despite its exceptionally high heritability, tools to estimate disease susceptibility in individual patients are lacking. We hypothesized that polygenic risk score (PRS) for AAD could help investigate PAI pathogenesis in pediatric patients., Methods: We here constructed and evaluated a PRS for AAD in 1223 seropositive cases and 4097 controls. To test its clinical utility, we reevaluated 18 pediatric patients, whose whole genome we also sequenced. We next explored the individual PRS in more than 120 seronegative patients with idiopathic PAI., Results: The genetic susceptibility to AAD-quantified using PRS-was on average 1.5 standard deviations (SD) higher in patients compared with healthy controls (p < 2e - 16), and 1.2 SD higher in the young patients compared with the old (p = 3e - 4). Using the novel PRS, we searched for pediatric patients with strikingly low AAD susceptibility and identified cases of monogenic PAI, previously misdiagnosed as AAD. By stratifying seronegative adult patients by autoimmune comorbidities and disease duration we could delineate subgroups of PRS suggesting various disease etiologies., Conclusions: The PRS performed well for case-control differentiation and susceptibility estimation in individual patients. Remarkably, a PRS for AAD holds promise as a means to detect disease etiologies other than autoimmunity., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Purpose: Residual adrenocortical function, RAF, has recently been demonstrated in one-third of patients with autoimmune Addison's disease (AAD). Here, we set out to explore any influence of RAF on the levels of plasma metanephrines and any changes following stimulation with cosyntropin., Methods: We included 50 patients with verified RAF and 20 patients without RAF who served as controls upon cosyntropin stimulation testing. The patients had abstained from glucocorticoid and fludrocortisone replacement > 18 and 24 h, respectively, prior to morning blood sampling. The samples were obtained before and 30 and 60 min after cosyntropin stimulation and analyzed for serum cortisol, plasma metanephrine (MN), and normetanephrine (NMN) by liquid-chromatography tandem-mass pectrometry (LC-MS/MS)., Results: Among the 70 patients with AAD, MN was detectable in 33%, 25%, and 26% at baseline, 30 min, and 60 min after cosyntropin stimulation, respectively. Patients with RAF were more likely to have detectable MN at baseline (p = 0.035) and at the time of 60 min ( p = 0.048) compared to patients without RAF. There was a positive correlation between detectable MN and the level of cortisol at all time points ( p = 0.02, p = 0.04, p < 0.001). No difference was noted for NMN levels, which remained within the normal reference ranges., Conclusion: Even very small amounts of endogenous cortisol production affect MN levels in patients with AAD.

Purpose: Transforming growth factor-beta receptor 3-like (TGFBR3L) is a pituitary enriched membrane protein selectively detected in gonadotroph cells. TGFBR3L is named after transforming growth factor-beta receptor 3 (TGFBR3), an inhibin A co-receptor in mice, due to sequence identity to the C-terminal region. We aimed to characterize TGFBR3L detection in a well-characterized, prospectively collected cohort of non-functioning pituitary neuroendocrine tumours (NF-PitNETs) and correlate it to clinical data., Methods: 144 patients operated for clinically NF-PitNETs were included. Clinical, radiological and biochemical data were recorded. Immunohistochemical (IHC) staining for FSHβ and LHβ was scored using the immunoreactive score (IRS), TGFBR3L and TGFBR3 were scored by the percentage of positive stained cells., Results: TGFBR3L staining was selectively present in 52% of gonadotroph tumours. TGFBR3L was associated to IRS of LHβ (median 2 [IQR 0-3] in TGFBR3L negative and median 6 [IQR 3-9] in TGFBR3L positive tumours, p < 0.001), but not to the IRS of FSHβ (p = 0.32). The presence of TGFBR3L was negatively associated with plasma gonadotropin concentrations in males (P-FSH median 5.5 IU/L [IQR 2.9-9.6] and median 3.0 [IQR 1.8-5.6] in TGFBR3L negative and positive tumours respectively, p = 0.008) and P-LH (median 2.8 IU/L [IQR 1.9-3.7] and median 1.8 [IQR 1.1-3.0] in TGFBR3L negative and positive tumours respectively, p = 0.03). TGFBR3 stained positive in 22% (n = 25) of gonadotroph tumours with no correlation to TGFBR3L., Conclusion: TGFBR3L was selectively detected in half (52%) of gonadotroph NF-PitNETs. The association to LHβ staining and plasma gonadotropins suggests that TGFBR3L may be involved in hormone production in gonadotroph NF-PitNETs., (© 2023. The Author(s).)

Context: Autoimmune thyroid disease is the most common endocrine comorbidity in autoimmune Addison disease (AAD), but detailed investigations of prevalence and clinical course are lacking., Objective: This work aimed to provide comprehensive epidemiological and clinical data on autoimmune thyroid disorders in AAD., Methods: A nationwide registry-based study including 442 patients with AAD and autoimmune thyroid disease were identified through the Norwegian National Registry of Autoimmune Diseases., Results: Of 912 registered AAD patients, 442 (48%) were diagnosed with autoimmune thyroid disease. A total of 380 (42%) had autoimmune hypothyroidism. Of the 203 with available thyroid function tests at time of diagnosis, 20% had overt hypothyroidism, 73% had subclinical hypothyroidism, and 7% had thyroid levels in the normal range. Negative thyroid peroxidase antibodies was found in 32%. Ninety-eight percent were treated with levothyroxine, 5% with combination therapy with liothyronine or thyroid extracts, and 1% were observed without treatment. Seventy-eight patients (9%) were diagnosed with Graves disease (GD), of whom 16 (21%) were diagnosed with autoimmune hypothyroidism either before onset or after remission of GD. At the end of follow-up, 33% had normal thyroid hormone levels without antithyroid-drugs or levothyroxine treatment. The remaining had either active disease (5%), had undergone ablative treatment (41%), or had developed autoimmune hypothyroidism (21%)., Conclusion: The true prevalence of hypothyroidism in AAD is lower than reported in the current literature. Careful consideration of the indication to start thyroxin therapy is warranted. Long-term remission rates in GD patients with AAD are comparable to recent reports on long-term follow-up of patients without AAD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Prader-Willi syndrome (PWS) is a rare, genetic, multisymptom, neurodevelopmental disease due to lack of the expression of the paternal genes in the q11 to 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., Objective: Here we present the effect of GH treatment on polysomnographic measurements., Methods: Thirty-seven adults, 15 men and 22 women, with confirmed PWS were randomly assigned to 1 year of GH treatment (n = 19) or placebo (n = 18) followed by 2 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 that received GH for 3 years., Results: At baseline median age was 29.5 years, body mass index 27.1, insulin-like growth factor 115 µg/L, apnea-hypopnea index (AHI) 1.4 (range, 0.0-13.9), and sleep efficiency (SE) 89.0% (range, 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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Autoimmune Addison's disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10 -8 ). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7-4.3), P = 9.0 × 10 -25 ) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35-41% of heritability (h 2 ).

Here, we report the investigation of transforming growth factor beta-receptor 3 like (TGFBR3L), an uncharacterised pituitary specific membrane protein, in non-neoplastic anterior pituitary gland and pituitary neuroendocrine tumours. A polyclonal antibody produced within the Human Protein Atlas project (HPA074356) was used for TGFBR3L staining and combined with SF1 and FSH for a 3-plex fluorescent protocol, providing more details about the cell lineage specificity of TGFBR3L expression. A cohort of 230 pituitary neuroendocrine tumours were analysed. In a subgroup of previously characterised gonadotroph tumours, correlation with expression of FSH/LH, E-cadherin, oestrogen (ER) and somatostatin receptors (SSTR) was explored. TGFBR3L showed membranous immunolabeling and was found to be gonadotroph cell lineage-specific, verified by co-expression with SF1 and FSH/LH staining in both tumour and non-neoplastic anterior pituitary tissues. TGFBR3L immunoreactivity was observed in gonadotroph tumours only and demonstrated intra-tumour heterogeneity with a perivascular location. TGFBR3L immunostaining correlated positively to both FSH ( R = 0.290) and LH ( R = 0.390) immunostaining, and SSTR3 ( R = 0.315). TGFBR3L correlated inversely to membranous E-cadherin staining ( R = -0.351) and oestrogen receptor β mRNA ( R = -0.274). In conclusion, TGFBR3L is a novel pituitary gland specific protein, located in the membrane of gonadotroph cells in non-neoplastic anterior pituitary gland and in a subset of gonadotroph pituitary tumours.

Context: Gonadotroph pituitary neuroendocrine tumors (PitNETs) can express follicle-stimulating hormone (FSH) and luteinizing hormone (LH) or be hormone negative, but they rarely secrete hormones. During tumor development, epithelial cells develop a mesenchymal phenotype. This process is characterized by decreased membranous E-cadherin and translocation of E-cadherin to the nucleus. Estrogen receptors (ERs) regulate both E-cadherin and FSH expression and secretion. Whether the hormone status of patients with gonadotroph PitNETs is regulated by epithelial-to-mesenchymal transition (EMT) and ERs is unknown., Objectives: To study the effect of EMT on hormone expression in gonadotroph nonfunctioning (NF)-PitNETs., Design: Molecular and clinical analyses of 105 gonadotroph PitNETs. Immunohistochemical studies and real-time quantitative polymerase chain reaction were performed for FSH, LH, E-cadherin, and ERα. Further analyses included blood samples, clinical data, and radiological images., Setting: All patients were operated on in the same tertiary referral center., Results: NF-PitNET with high FSH expression had decreased immunohistochemical staining for membranous E-cadherin (P < .0001) and increased staining for nuclear E-cadherin (P < .0001). Furthermore, high FSH expression was associated with increased ERα staining (P = .0002) and ERα mRNA (P = .0039). Circulating levels of plasma-FSH (P-FSH) correlated with FSH staining in gonadotroph NF-PitNET (P = .0025). Tumor size and invasiveness was not related to FSH staining, E-cadherin, or ERα. LH expression was not associated with E-cadherin or ERα., Conclusion: In gonadotroph PitNETs, FSH staining is related to E-cadherin, ERα expression, and circulating levels of P-FSH. There was no association between FSH staining and invasiveness. The clinical significance of these findings will be investigated in ongoing prospective studies., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© Endocrine Society 2020.)

Objective: The aim was to study the prevalence of secondary adrenal insufficiency before and after surgery for non-functioning pituitary adenomas, as well as determine risk factors for developing secondary adrenal insufficiency. A secondary aim was to determine adequate p-cortisol response to a 1-μg Short Synacthen Test after surgery., Design: Longitudinal cohort study., Methods: One hundred seventeen patients (52/65 females/males, age 59 years) undergoing primary surgery for clinically non-functioning pituitary adenomas were included. P-cortisol was measured in morning blood samples. Three months after surgery, a Short Synacthen Test was performed., Results: All tumours were macroadenomas (mean size 26.9 mm, range 13-61 mm). The surgical indications were visual impairment (93), tumour growth (16), pituitary apoplexy (6) and headache (2). Before surgery, 17% of the patients had secondary adrenal insufficiency (SAI), decreasing to 15% 3 months postoperatively. Risk of SAI was increased in patients operated for pituitary apoplexy (p < 0.001), while age, sex, tumour size and complication rate were not different from the remaining cohort. Three months after surgery, all patients with baseline p-cortisol ≥ 172 nmol/l (6.2 μg/dl) and peak p-cortisol during Short Synacthen Test ≥ 320 nmol/l (11.6 μg/dl) tapered cortisone unproblematically. In patients with intact hypothalamic-pituitary-adrenal axis, p-cortisol peaked < 500 nmol/l (18.1 μg/dl) during Short Synacthen Test in 48% of patient., Conclusion: Pituitary surgery is safe and transsphenoidal surgery rarely causes new SAI. Relying solely on morning p-cortisol for diagnosing secondary adrenal insufficiency gives false positives and the Short Synacthen Test remains useful. A peak p-cortisol ≥ 320 during (11.6 μg/dl) Short Synacthen Test indicates a sufficient response, while < 309 nmol/l (11.2 μg/dl) indicates secondary adrenal insufficiency.

Background: Early detection of autoimmune Addison's disease (AAD) is important as delay in diagnosis may result in a life-threatening adrenal crisis and death. The classical clinical picture of untreated AAD is well-described, but methodical investigations are scarce., Objective: Perform a retrospective audit of patient records with the aim of identifying biochemical markers for early diagnosis of AAD., Material and Methods: A multicentre retrospective study including 272 patients diagnosed with AAD at hospitals in Norway and Sweden during 1978-2016. Scrutiny of medical records provided patient data and laboratory values., Results: Low sodium occurred in 207 of 247 (84%), but only one-third had elevated potassium. Other common nonendocrine tests were largely normal. TSH was elevated in 79 of 153 patients, and hypoglycaemia was found in 10%. Thirty-three per cent were diagnosed subsequent to adrenal crisis, in whom electrolyte disturbances were significantly more pronounced (P < 0.001). Serum cortisol was consistently decreased (median 62 nmol L -1 [1-668]) and significantly lower in individuals with adrenal crisis (38 nmol L -1 [2-442]) than in those without (81 nmol L -1 [1-668], P < 0.001)., Conclusion: The most consistent biochemical finding of untreated AAD was low sodium independent of the degree of glucocorticoid deficiency. Half of the patients had elevated TSH levels. Only a minority presented with marked hyperkalaemia or other nonhormonal abnormalities. Thus, unexplained low sodium and/or elevated TSH should prompt consideration of an undiagnosed AAD, and on clinical suspicion bring about assay of cortisol and ACTH. Presence of 21-hydroxylase autoantibodies confirms autoimmune aetiology. Anticipating additional abnormalities in routine blood tests may delay diagnosis., (© 2017 The Association for the Publication of the Journal of Internal Medicine.)

Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disease defined by the presence of two of the three major components: hypoparathyroidism, primary adrenocortical insufficiency, and chronic mucocutaneous candidiasis (CMC). Information on longitudinal follow-up of APS1 is sparse., Objective: To describe the phenotypes of APS1 and correlate the clinical features with autoantibody profiles and autoimmune regulator (AIRE) mutations during extended follow-up (1996-2016)., Patients: All known Norwegian patients with APS1., Results: Fifty-two patients from 34 families were identified. The majority presented with one of the major disease components during childhood. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. With age, most patients presented three to five disease manifestations, although some had milder phenotypes diagnosed in adulthood. Fifteen of the patients died during follow-up (median age at death, 34 years) or were deceased siblings with a high probability of undisclosed APS1. All except three had interferon-ω) autoantibodies, and all had organ-specific autoantibodies. The most common AIRE mutation was c.967&#95;979del13, found in homozygosity in 15 patients. A mild phenotype was associated with the splice mutation c.879+1G>A. Primary adrenocortical insufficiency and type 1 diabetes were associated with protective human leucocyte antigen genotypes., Conclusions: Multiple presumable autoimmune manifestations, in particular hypoparathyroidism, CMC, and enamel hypoplasia, should prompt further diagnostic workup using autoantibody analyses (eg, interferon-ω) and AIRE sequencing to reveal APS1, even in adults. Treatment is complicated, and mortality is high. Structured follow-up should be performed in a specialized center.

Context: Growth hormone (GH) substitution of adult-onset growth hormone deficiency (aoGHD) patients partially reverses unfavorable body composition profile. Wnt signaling pathway has being acknowledged as an important modulator of bone mass and of energy metabolism in adipose tissue and in β-cells., Objective: To assess the role of selected Wnt antagonists in bone and glucose metabolism before and after GH replacement in aoGHD., Patients and Methods: Patients from two randomized placebo-controlled studies of GH replacement in aoGHD were used. In study 1, 39 patients received GH or placebo for 9 months with 4 months wash-out. In study 2, iliac bone biopsies were obtained before and after GH or placebo (n = 10 each) for 12 months. Body composition and serum (study 1) and bone matrix (study 2) levels of Wnt antagonists (DKK-1, sFRP-3, WIF-1, and SOST) were quantified before and after GH. In vitro effect of GH and IGF-1 on DKK-1 secretion and expression of Wnt signaling modulators was assessed in human osteoblasts and mature adipocytes., Results: GH replacement increased circulating and bone matrix levels of DKK-1, but not sFRP-3, WIF-1, and SOST. Furthermore, DKK-1 secretion increased in human osteoblasts stimulated by GH in vitro, with no effects on other cells. At baseline and after treatment, circulating DKK-1 was negatively associated with bone mass, but not fat mass or measures of insulin resistance, in aoGHD patients., Conclusions: An increase in DKK-1 may limit the effects of GH on bone mass, but does not seem to impact the increase in insulin resistance following GH substitution.

Context: Visceral adipose tissue (VAT) is established as a risk factor for type 2 diabetes and cardiovascular disease, but the radiation exposure and cost of computed tomography (CT) measurements limits its daily clinical use., Objective: The main objective of this study was to compare the degree of agreement between VAT measurements by a new dual-energy X-ray absorptiometry (DXA) application and one of the standard methods, CT, in a population of patients with Prader-Willi syndrome (PWS) before and after GH treatment. Furthermore, we tested whether VAT estimations by these two methods are equivalent in assessing the metabolic risk in this population., Design and Patients: Data from the Norwegian population of a multicenter study in adults with genetically proven PWS were used. Subjects with complete anthropometry, biochemical, and imagistic measurements at all study visits (baseline and after 12 and 24 months of GH treatment) (n = 14, six men) were included. VAT was quantified both using CT scans (GE Lightspeed 16 Pro) of the abdomen at L2-L3 level and a total body DXA scan (GE Healthcare Lunar Prodigy)., Results: VAT DXA was strongly associated with VAT CT at baseline (r = 0.97) and after 12 (r = 0.90) and 24 months (r = 0.89) of GH treatment (all P < .001). We found moderate to strong positive correlations between VAT by both methods, and blood pressure, weight, body mass index, waist circumference, glucose metabolism, and other fat depots (arms, legs, android, trunk, total body) but no association with age, gender, blood lipids, and IGF-I. Adiponectin was negatively associated with the amount of VAT. At baseline, the highest correlation with homeostasis model assessment of insulin resistance (HOMA-IR) was found for VAT DXA (r = 0.76, P = .001) and VAT CT (r = 0.75, P = .002), respectively., Conclusion: VAT can be accurately estimated by DXA, in patients with PWS, and might contribute to the assessment of the metabolic risk.

Objectives: To investigate glucose homeostasis in relation to body mass index (BMI) in adults with PWS before and after GH therapy., Design: We prospectively investigated the effects of a 12-month GH treatment on body composition and glucose homeostasis in relation to BMI in 39 adults, mean (±SD) age=28.6 (6.5) years with genetically verified PWS. We compared the results for different BMI categories (<25 kg/m²; 25-30 kg/m²; >30 kg/m²) and performed a regression analysis to detect predictors for homeostasis model of assessment-insulin resistance (HOMA-IR)., Results: The baseline HOMA-IR was higher, with BMI of >30 kg/m². Our main findings were as follows: i) GH treatment (mean final dose, 0.6 (0.25) mg) was associated with small increases in fasting p-glucose, 2-h p-glucose by oral glucose load tolerance test, HOMA-IR and lean mass, and a reduction in fat mass. ii) Whereas the baseline HOMA-IR was associated with increased BMI (>30 kg/m²), we found no differences in HOMA-IR among the BMI categories after 12 months of GH. iii) Stepwise linear regression identified the triglyceride level as the strongest predictor of HOMA-IR at baseline, whereas an increase in VAT was the strongest predictor of the increase in HOMA-IR after therapy., Conclusions: GH treatment for 12 months in adults with PWS resulted in an increase in HOMA-IR, irrespective of BMI, confirming that control of HbA1c is essential during GH treatment in PWS., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Bone mineral density (BMD) in adult patients with Prader-Willi syndrome (PWS) might be low due to high bone turnover., Objectives: The objective of the study was to investigate bone mass in a group of adult PWS subjects and study the effects of GH treatment on BMD and markers of bone turnover., Design: Forty-six adults with genetically verified PWS were randomized to GH or placebo for 12 months, followed by open prospective GH for 24 additional months. BMD at the lumbar spine (LS) L1-4, the total hip, and the total body was assessed by dual-energy x-ray absorptiometry at baseline and every 12th month thereafter. Markers of bone turnover were measured at baseline and at the end of the controlled study., Results: In this cohort of adult subjects with PWS, baseline BMD was reduced in all compartments compared with the reference (Z-scores). Men had lower Z-scores BMD than women in LS and total body (P < .05). With 12 months of GH, LS-BMD was significantly reduced compared with placebo. No changes in BMD were observed with continuous GH treatment for 24 months. The bone formation markers increased with GH therapy compared with placebo, whereas the resorption marker did not change., Conclusions: Adult PWS subjects, especially the men, have low bone mass that was not improved with GH treatment for 2 years. Because PWS subjects are short, BMD might be underestimated and should be adjusted for. Further studies, with adequate GH and sex hormone replacement throughout puberty and early adult life, are needed to better characterize PWS.

Objective: Patients with adult onset GH deficiency (aoGHD) have secondary osteoporosis, which is reversed by long-term GH substitution. Transforming growth factor β1 (TGFβ1 or TGFB1) is abundant in bone tissue and could mediate some effects of GH/IGFs on bone. We investigated its regulation by GH/IGF1 in vivo and in vitro., Design and Methods: The effects of GH substitution (9-12 months, placebo controlled) on circulating and cortical bone matrix contents of TGFβ1 were investigated in patients with aoGHD. The effects of GH/IGF1 on TGFβ1 secretion in osteoblasts (hFOB), adipocytes, and THP-1 macrophages as well as the effects on release from platelets were investigated in vitro., Results: In vivo GH substitution increased TGFβ1 protein levels in cortical bone and serum. In vitro, GH/IGF1 stimulation induced a significant increase in TGFβ1 secretion in hFOB. In contrast, no major effect of GH/IGF1 on TGFβ1 was found in adipocytes and THP-1 macrophages. Finally, a minor modifying effect on SFLLRN-stimulated platelet release of TGFβ1 was observed in the presence of IGF1., Conclusion: GH substitution increases TGFβ1 in vivo and in vitro, and this effect could contribute to improved bone metabolism during such therapy, potentially reflecting direct effect of GH/IGF1 on bone cells.

Objective: The goal of growth hormone (GH) replacement is to improve quality of life (QoL) and prevent the long-term complications of GH deficiency (GHD). Thirty-nine patients with adult-onset GH deficiency (AOGHD) who had originally participated in a randomized placebo-controlled crossover study involving treatment with either GH or placebo for nine months were enrolled in an open, 33-month follow-up study of the effects on QoL as well as bone and metabolic parameters., Methods: GH replacement was dosed individually to obtain IGF-I concentrations that were within the upper part of the normal range for age (mean+1SD). The variables were assessed on five occasions during the study., Results: QoL, as assessed by the sum scores of HSCL-58, AGHDA, physical activity (KIMS question 11) and the dimension vitality in SF-36, improved. Markers of bone formation and resorption remained increased throughout the study period. Bone mineral area (BMA), bone mineral content (BMC) and bone mineral density (BMD) increased in both the lumbar (L2-L4) spine and total body. BMC and BMD increased in the femur. Hypogonadal women however, showed reduced bone mass during the study period. The changes in body fat mass (BFM) and lean body mass (LBM) were sustained throughout the long-term treatment (BFM -2.18 (+/-4.87) kg LBM by 2.01(+/-3.25) kg). Low-density lipoprotein cholesterol (LDL-C) levels were reduced by 0.6 (+/-1.1) mmol/l, and high-density lipoprotein cholesterol (HDL-C) levels increased by 0.2 (+/-0.3) mmol/l. No changes were observed in body weight, fasting total cholesterol, triglycerides, HbA1c and plasma glucose. Mean fasting insulin levels increased significantly from 110 pmol/l to 159 pmol/l, p<0.02., Conclusion: Long-term replacement of growth hormone in patients with AOGHD induces favorable effects on QoL as well as bone and metabolic parameters. An increase in insulin levels is also noteworthy., (Copyright © 2011 Growth Hormone Research Society. Published by Elsevier Ltd. All rights reserved.)

Objective: We examined the effect of GH substitution on adipose tissue-derived hormones and cytokines and sought to identify predictors for changes in body composition during therapy. Long-standing adult-onset GH deficiency (AO-GHD) is associated with increased body fat mass (FM) which, through production of hormones and inflammatory cytokines from adipose tissue, may contribute to different manifestations of the metabolic syndrome., Design, Patients and Measurements: Fifty-five patients with AO-GHD (24 women, 31 men, mean age 49 years) were enrolled in a placebo-controlled, double-blind crossover study. GH therapy was individually dosed to obtain an IGF-I concentration within the normal range for age and sex. GH and placebo were administered for 9 months each, separated by a 4-month washout period. Adipose tissue-derived cytokines were measured by enzyme immunoassay., Results: GH treatment was associated with a significant decrease in IL-1 receptor antagonist (IL-1Ra) compared to placebo, which correlated with declining body FM (truncal and total) after GH substitution. The change in IL-1Ra was the strongest predictor of the variation in BFM in regression models. No changes were observed for leptin, adiponectin, soluble TNF receptor 1 or interleukin (IL)-8., Conclusion: The data indicate a possible unrecognized association between IL-1Ra and changes in body composition during GH substitution and suggest further research on the interaction between the GH-IGF axis and the IL-1 system., (© 2010 Blackwell Publishing Ltd.)

Background: Diabetic foot ulcers (DFUs) are common complications of diabetes mellitus (DM), with a complex pathogenesis. Treatment is difficult and no single treatment with measurable clinical impact is available. In the present clinical pilot trial, we investigated whether statins could be of use against some of the pathogenic factors in DFUs., Methods: Thirteen diabetic patients (10 men; 11 with Type 2 DM; mean age 64 years; mean duration of DM 18 years) with neuropathic DFUs <4 months were randomized to treatment with either 10 mg (six patients; six ulcers) or 80 mg (seven patients; nine ulcers) atorvastatin for 6 months in addition to conventional DFU care (i.e. prompt debridement, DFU pressure relief, and management of any underlying infection)., Results: There were no significant differences in background factors (i.e. HbA1c 8.9%, micro- and macrovascular complications, concomitant medications) or DFU characteristics (duration, surface area, grading) between the two groups. All ulcers in the group receiving 10 mg atorvastatin healed, compared with six of nine ulcers in the group receiving 80 mg atorvastatin (NS). However, two previously healed DFUs recurred and six new DFUs developed in the low-dose group compared with none and one, respectively, in the high-dose group (P = 0.048). There was a significant decrease in C-reactive protein (-1.5 mg/L; P = 0.044) and a non-significant trend towards beneficial effects on lipids and the ankle-arm blood pressure index in the high-dose compared with the low-dose group., Conclusions:   We observed a possible beneficial effect of 6-months high-dose atorvastatin on DFUs, which should be tested in appropriately sized prospective studies., (© 2009 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.)

Background: Glitazones (thiazolidinediones) represent a new class of hypoglycaemic medication. We hereby report the clinical effects we have observed of such treatment., Material and Methods: Medical records of 33 patients (24 men) with type 2 diabetes (mean age 53 years, mean HbA1c 9.0%, mean BMI 32.4 kg/m2) were reviewed. The patients were followed regularly at a diabetic out-patient clinic between 2001 and 2005. They had been treated with either pioglitazone 15-45 mg (19 patients) or rosiglitazone 4-8 mg (14 patients) for > or = 6 months. Body weight, HbA1c, fasting plasma glucose, lipids, liver transaminases, haemoglobin and creatinine were recorded every 6 months., Results: Glitazone treatment was associated with significant reductions in HbA1c and fasting plasma glucose. HbA1c was reduced with 1.2% after 6 months, 1.3% after 12, 2.3 after 18 and 1.5% after 24 months. Fasting plasma glucose was reduced with 2.8 mmol/L after 12 months, 4.5 mmol/L after 18 and 3.8 mmol/L after 24 months. There was a significant increase in HDL-cholesterol (0.1 mmol/L after 6 months). A statistically significant increase in weight (2.0 +/- 3.6 kg at 6 months and 3.6 +/-4.6 kg at 12 months) was found with a statistically significant negative correlation between the increase in weight and the reduction in HbA1c after 6 months of treatment (r = -0.625, n = 29, p < 0.001). Three patients developed peripheral oedema and three patients were withdrawn from treatment., Interpretation: Glitazone-treatment in overweight patients with poorly controlled type 2 diabetes mellitus significantly lowered HbA1c and fasting plasma glucose and raised HDL-cholesterol, but was associated with significant weight gain.

Objective: GH deficiency is associated with an increased cardiovascular mortality. Fifty-five patients with adult-onset GH deficiency (AO-GHD) (24 female, 31 male, mean age 49 years) were enrolled in a placebo-controlled double-blind crossover study to investigate the effects of GH therapy on a variety of cardiovascular risk factors representing different aspects of atherogenesis, including apolipo-proteins (Apo A-1, Apo B), markers of subclinical inflammation (high-sensitivity C-reactive protein (CRP) and interleukin-6) and markers of endothelial function (intercellular adhesion molecule-1, von Willebrand factor and sCD40L (a pro-atherogenic factor and marker for plaque destabilization))., Methods: GH therapy was individually dosed to obtain an IGF-I concentration within the normal range for age and sex. GH and placebo were administered for 9 months each, separated by a 4 month washout period., Results: The final mean dose of GH was 50% higher for women and IGF-I increased to the same level in both sexes. Compared with placebo, substitution with GH showed a significant effect on Apo B (mean change -0.15 (-0.22 to -0.08) mg/l) and CRP (-1.8 (-3.3 to -0.3) mg/l). The baseline level of and change in IGF-I during treatment with GH contributed significantly to the improvement in both markers. No effects were found on interleukin-6 or Apo A-1, or on markers of endothelial function. No gender differences were observed for any of the markers at baseline or following intervention., Conclusions: GH substitution to naïve patients with AO-GHD at a low, individually titrated dose aiming at normalizing IGF-I was followed by significant reductions in Apo B and CRP, indicating a positive effect of GH on cardiovascular risk.

Fifty-five patients with adult-onset GH deficiency (mean age, 49 years) were enrolled in a placebo-controlled, crossover study to investigate the effects of GH therapy on exercise capacity, body composition, and quality of life (QOL). GH and placebo were administered for 9 months each, separated by a 4-month washout period. GH therapy was individually dosed to obtain an IGF-I concentration within the normal range for age and sex. The final mean daily dose of GH was 1.2 IU/day for men and 1.8 IU/day for women. Mean IGF-I concentration at baseline was higher in men than in women (95+/-33 vs 68+/-41 microg/l respectively; P < 0.04) and increased to a similar level on GH therapy. Body fat mass was reduced by 1.9+/-2.9 kg and lean body mass was increased by 1.8+/-2.8 kg (P = 0.0001 for each) with GH treatment. Total and low-density cholesterol levels decreased. Absolute maximal oxygen uptake increased by 6% (P = 0.01), relative to body weight by 9% (P = 0.004), and there was a trend toward increased endurance performance by 7% (P = 0.07). There were no significant effects on QOL. In conclusion, treatment with a low, physiologic dose of GH produced positive effects on body composition and lipids and improved exercise capacity, likely to be of clinical relevance. No changes in QOL were seen, possibly because of a good QOL at baseline.

Clinical handbooks and procedure descriptions have been suggested as a way to improve the practical part of the medical education in Norway, but experience with books of this type is scarce, and the applicability of the model has been questioned. This paper reports a questionnaire survey among Norwegian medical students who have had hands-on experience with such a book throughout their student practice. The book apparently has been used, and no serious criticism has been put forward. It is an obvious sine qua non that such a book is used with proper care, and that the cooperation with senior doctors on duty is maintained.