TGFBR3L is associated with gonadotropin production in non-functioning gonadotroph pituitary neuroendocrine tumours.

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 FSHß and LHß 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 LHß (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 FSHß (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 LHß staining and plasma gonadotropins suggests that TGFBR3L may be involved in hormone production in gonadotroph NF-PitNETs.

Cut-off values for sufficient cortisol response to low dose Short Synacthen Test after surgery for non-functioning pituitary adenoma.

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.

Off-label use of clomiphene citrate to treat anabolic androgenic steroid induced hypogonadism upon cessation among men (CloTASH) - A pilot study protocol.

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.

Plasma-Metanephrines in Patients with Autoimmune Addison's Disease with and without Residual Adrenocortical Function.

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.

Altered biomarkers for cardiovascular disease and inflammation in autoimmune Addison's disease - a cross-sectional study.

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.

Effects of Growth Hormone Treatment on Sleep-Related Parameters in Adults With Prader-Willi Syndrome.

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.

GWAS for autoimmune Addison's disease identifies multiple risk loci and highlights AIRE in disease susceptibility.

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 (h2).

Residual Corticosteroid Production in Autoimmune Addison Disease.

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.

[Glitazone treatment of type 2 diabetes mellitus]. / Glitazonbehandling ved type 2-diabetes.

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.

Low-dose GH improves exercise capacity in adults with GH deficiency: effects of a 22-month placebo-controlled, crossover trial.

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.

Dual-energy X-ray absorptiometry is a valid method to estimate visceral adipose tissue in adult patients with Prader-Willi syndrome during treatment with growth hormone.

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.