Acute Effects of Testosterone on Whole-Body Protein Metabolism in Hypogonadal and Eugonadal Conditions: A Randomized, Placebo-Controlled, Crossover Study.

Chronic testosterone (T) substitution and short-term T administration positively affect protein metabolism, however, data on acute effects in humans are sparse. This study aimed to investigate T's acute effects on whole-body protein metabolism in hypogonadal and eugonadal conditions. We designed a randomized, double-blind, placebo-controlled, crossover study, including twelve healthy young males. Whole-body protein metabolism was evaluated during 1) eugonadism, and after medically-induced hypogonadism, with application of a gel on each trial day containing either 2) placebo, 3) T 50 mg, or 4) T 150 mg; under basal (5h basal period) and insulin-stimulated conditions (3h clamp). The main outcome measure was change in net protein balance. The net protein loss was 62% larger in the placebo-treated hypogonadal state compared with the eugonadal state during the basal period (-5.5 ±3.5 µmol/kg/h versus -3.4 ± 1.2 µmol/kg/h, p=0.038), but not during the clamp (p=0.06). Also, hypogonadism resulted in a 25% increase in whole-body urea flux (p=0.006). However, T did not result in any significant changes in protein breakdown, synthesis, or net balance during either the basal period or clamp (all p > 0.05). Protein breakdown was reduced during clamp compared to the basal period regardless of gonadal status or T exposure (all p≤0.001). In conclusion, the application of transdermal T did not counteract the negative effects of hypogonadism with no effects on protein metabolism within five hours of administration. Insulin (during clamp) mitigated the effects of hypogonadism. This study is the first to investigate acute protein-metabolic effects of T in hypogonadal men.

School Well-Being and Academic Performance of Children With Juvenile Idiopathic Arthritis: A National Register-Based Study.

OBJECTIVE: We aimed to investigate how school well-being (SWB) and academic performance of children with juvenile idiopathic arthritis (JIA) compare to their peers on a national level using the Danish national registers. Further, we investigated the potential influence of socioeconomic status (SES). METHODS: A population-wide, register-based, cross-sectional study was performed. We compared the results of children with and without JIA in the Danish National Well-Being Questionnaire (DNWQ), the National Danish School Testing (NDST), and their ninth grade (aged approximately 16 yrs) final school marks in Danish and mathematics. The results were analyzed using adjusted ordinal logistic regression (SWB) and linear regression (tests and marks). RESULTS: In separate cohorts, we included a total of 505,340 children answering the DNWQ, 812,461 children with NDST results, and the ninth-grade final marks of 581,804 children. Of these children, 1042, 1541, and 1410, respectively, fulfilled the criteria of JIA. Children with JIA reported SWB comparable to their peers, except for the question "Do you perform well in school?" (odds ratio 0.89, 95% CI 0.81-0.99). In the NDST, the children with JIA in general did just as well as their peers. We found no differences in the ninth-grade final marks in either Danish or mathematics. Stratifying the analyses on SES showed no significant differences in the associations. CONCLUSION: Overall, children with JIA report SWB comparable to that of children without JIA and perform equally well in school as children without JIA.

Psychiatric Morbidity Is Common Among Children With Juvenile Idiopathic Arthritis: A National Matched Cohort Study.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a chronic rheumatic disease that causes joint inflammation and pain. Previous studies have indicated affected mental health and increased risk of psychiatric conditions among patients with JIA. We aimed to explore differences in psychiatric morbidity between children with JIA and their peers. We further studied if parental socioeconomic status (SES) influences the association between JIA and the risk of psychiatric morbidity. METHODS: We used a matched cohort design to estimate the association between JIA and psychiatric disease. Children with JIA, born between 1995 and 2014, were identified in Danish national registers. Based on birth registers, we randomly selected 100 age- and sex-matched children per index child. Index date was the date of the fifth JIA diagnosis code or the date of matching for reference children. End of follow-up was the date of psychiatric diagnosis, death, emigration, or December 31, 2018, whatever came first. Data were analyzed using a Cox proportional hazard model. RESULTS: We identified 2086 children with JIA with a mean age at diagnosis of 8.1 years. Children with JIA had a 17% higher instantaneous risk of a psychiatric diagnosis when compared with the reference group, with an adjusted hazard ratio of 1.17 (95% CI 1.02-1.34). Relevant associations were found only for depression and adjustment disorders. Stratifying our analysis for SES showed no modifying effect of SES. CONCLUSION: Children with JIA had a higher risk of psychiatric diagnoses compared to their peers, especially diagnoses of depression and adjustment disorders. The association between JIA and psychiatric disease did not depend on parental SES.

Evaluation of Macrophage Activation Syndrome in Patients with Systemic Juvenile Idiopathic Arthritis: A Single Center Experience.

Objectives: Macrophage activation syndrome (MAS) is a severe complication of systemic juvenile arthritis (sJIA), and early diagnosis is critical for survival. The objective of this study was to evaluate the 2016 MAS classification criteria in a Danish sJIA cohort and to compare different sets of criteria for the early identification of MAS including the HLH-2004 diagnostic guidelines, MS score, and the ferritin/ESR ratio. Methods: Data was extracted from medical charts of 32 patients with sJIA from a single Danish paediatric rheumatology center diagnosed between January 2014 and June 2021. Patients who met the 2016 MAS classification criteria were classified as having MAS. From a receiver operating characteristic (ROC) plot, the area under the curve (AUC) was calculated for the prediction of patients with MAS according to the 2016 MAS classification criteria using either MS score or the ferritin/ESR ratio. Results: Of the cohort, eight (25%) patients were classified as having MAS according to the 2016 MAS classification criteria compared to only three (9.4%) patients fulfilling the HLH-2004 diagnostic guidelines, all of which had recurrent MAS. The ferritin/ESR ratio showed the highest sensitivity (100%) but the lowest specificity (72.2%). In comparison, the MS score had a higher specificity (90.9%) for the identification of MAS according to the 2016 classification criteria. In our cohort, the most optimal cut-off point for the ferritin/ESR ratio was ≥19.4 (sensitivity: 100%, specificity: 72.2%) and ≥ -1.5 for the MS score (sensitivity: 71.4%, specificity: 91.7%), respectively. Conclusion: The 2016 MAS classification criteria were a valuable tool in the discrimination of sJIA with and without MAS. The HLH-2004 diagnostic guidelines showed the lowest sensitivity, ferritin/ESR ratio, and the lowest specificity compared to the MS score where an acceptable high sensitivity and specificity was found.

Idiopathic hypereosinophilic syndrome: A rare diagnosis in children.

Idiopathic hypereosinophilic syndrome (IHES) is one of numerous hypereosinophilic syndromes. The incidence of IHES among children is unknown, but it is considered a rare disease. We report a pediatric case of IHES and the challenges to finding an effective treatment. The patient described here was responsive to prednisolone and thalidomide.

Systemic juvenile idiopathic arthritis and recurrent macrophage activation syndrome due to a CASP1 variant causing inflammasome hyperactivation.

OBJECTIVES: We investigated a patient with systemic juvenile idiopathic arthritis (sJIA) and recurrent macrophage activation syndrome (MAS) to discover genetic and immunological contributing factors. METHODS: Severe recurrent MAS motivated whole exome sequencing (WES) to identify genetic variants potentially involved in disease pathogenesis. In vitro peripheral blood mononuclear cell (PBMC) stimulations for cytokine expression and caspase-1 activity assays as well as NF-κB reporter luciferase assays were performed to functionally characterize variants. RESULTS: WES revealed an extremely rare heterozygous missense variant, c.482G>A, p.R161H in the CASP1 gene encoding pro-caspase-1. Lipopolysaccharide (LPS) stimulation of patient PBMCs induced high levels of IL-6 compared to controls, and activation of the NLRP3 inflammasome resulted in increased production of IL-1ß and IL-18 as well as significantly elevated caspase-1 activity. Constitutive and inducible levels of IL-18 and IFNγ in whole blood were markedly elevated. Expression of the CASP1 variant in an NF-κB reporter luciferase assay induced increased NF-κB activation in a RIP2-dependent manner. The disease course of the patient was complicated by severe recurrent MAS. However, dual IL-1 and IL-6 blockade caused disease remission. CONCLUSION: For the first time, we demonstrate the involvement of a CASP1 variant in sJIA and recurrent MAS. This variant is gain-of-function for both inflammasome and NF-κB activation leading to increased production of IL-6, IL-1ß and IL-18. Although dual IL-1 and IL-6 blockade may be beneficial in patients, in whom single treatment is not sufficient to control MAS, caution should be practiced, since interstitial lung disease may progress despite apparent clinical and biochemical remission.

Autoinflammatory disease with corneal and mucosal dyskeratosis caused by a novel NLRP1 variant.

OBJECTIVES: Here we investigated a patient with inflammatory corneal intraepithelial dyskeratosis, mucosal inflammation, tooth abnormalities and, eczema to uncover the genetic and immunological basis of the disease. METHODS: On suspicion of an autoinflammatory condition, Sanger sequencing of nucleotide-binding oligomerization domain-like, leucine-rich repeat pyrin domain containing 1 (NLRP1) was performed and combined with an in vitro inflammasome reconstitution assay to measure caspase-1-mediated IL-1ß cleavage, stimulation of patient peripheral blood mononuclear cells (PBMCs) and whole blood to measure IL-1ß, IL-18 production and quantification of apoptosis-associated speck-like protein containing CARD (ASC) speck formation as a measure of inflammasome activation by flow cytometry. RESULTS: Sanger sequencing revealed a novel mutation (c.175G>C, p.A59P; NM_33004.4) in the inflammasome molecule NLRP1 segregating with disease, although with incomplete penetrance, in three generations. We found that patient PBMCs produced increased IL-1ß in response to inflammatory stimuli, as well as increased constitutive levels of IL-18. Moreover, we demonstrate that expression of the identified NLRP1 A59P variant caused spontaneous IL-1ß cleavage to mature IL-1ß. In addition, patient PBMCs responded to NLRP1 stimulation with increased ASC speck formation as a reflection of elevated inflammasome activity. CONCLUSION: We demonstrate that this novel NLRP1 A59P variant caused increased activation of the NLRP1 inflammasome, resulting in constitutively and inducibly elevated IL-1ß and IL-18 synthesis. We suggest the NLRP1 mutation underlies the pathogenesis of this rare autoinflammatory dyskeratotic disease inherited in an autosomal dominant manner with incomplete penetrance in the patient and within the family for several generations.

A placebo-controlled randomized study with testosterone in Klinefelter syndrome: beneficial effects on body composition.

CONTEXT AND OBJECTIVE: Males with Klinefelter syndrome (KS) are typically hypogonadal with a high incidence of metabolic disease, increased body fat and mortality. Testosterone treatment of hypogonadal patients decrease fat mass, increase lean body mass and improve insulin sensitivity, but whether this extends to patients with KS is presently unknown. RESEARCH DESIGN AND METHODS: In a randomized, double-blind, placebo-controlled, BMI-matched cross-over study, 13 males with KS (age: 34.8 years; BMI: 26.7 kg/m2) received testosterone (Andriol®) 160 mg per day (testosterone) or placebo treatment for 6 months. Thirteen age- and BMI-matched healthy controls were recruited. DEXA scan, abdominal computed tomography (CT) scan and a hyperinsulinemic-euglycemic clamp, muscle strength and maximal oxygen uptake measurement were performed. RESULTS: Total lean body mass and body fat mass were comparable between testosterone-naïve KS and controls using DEXA, whereas visceral fat mass, total abdominal and intra-abdominal fat by CT was increased (P < 0.05). Testosterone decreased total body fat (P = 0.01) and abdominal fat by CT (P = 0.04). Glucose disposal was similar between testosterone-naïve KS and controls (P = 0.3) and unchanged during testosterone (P = 0.8). Free fatty acid suppression during the clamp was impaired in KS and maximal oxygen uptake was markedly lower in KS, but both were unaffected by treatment. Testosterone increased hemoglobin and IGF-I. CONCLUSION: Testosterone treatment in adult males with KS for 6 months leads to favorable changes in body composition with reductions in fat mass, including abdominal fat mass, but does not change measures of glucose homeostasis.

Response to Early-onset Pamidronate Treatment in Chronic Nonbacterial Osteomyelitis: A Retrospective Single-center Study.

OBJECTIVES: Chronic nonbacterial osteomyelitis (CNO) is a sterile inflammatory bone disorder with an unpredictable disease course. The objective was to assess clinical and radiological disease activity in children with CNO including response to early-onset pamidronate treatment. METHODS: A single-center retrospective study was conducted of children fulfilling the Bristol Criteria for CNO. At the time of diagnosis, whole-body magnetic resonance imaging (WB-MRI) or local MRI was performed to assess radiological disease activity. Children with multifocal or spinal bone inflammation and clinical disease activity not responding to nonsteroidal antiinflammatory drugs were categorized as having extended CNO. Clinical disease activity was assessed annually. RESULTS: Fifty-one children were included. Median followup time was 4 years (interquartile range 3-7). Children categorized with extended CNO (n = 32) were treated in an early-onset 2-year pamidronate regimen. In extended CNO, WB-MRI was performed at time of diagnosis, and at years 1 and 2 in 88%, 84%, and 91% of cases, respectively. During the first year, the total number of radiologically active lesions and number of spinal lesions per patient declined (p = 0.01). Clinically inactive disease was recorded in 12/32 children (38%). However, 8/12 children (67%) experienced clinical relapse. In limited CNO (n = 19), 10/19 children (53%) presented with clinically inactive disease after 1 year and did not experience clinical relapse. CONCLUSION: Pamidronate might contribute to improvement in clinical and radiological disease activity in extended CNO, especially after 1 year of treatment. However, children with continuously active disease after 2 years of pamidronate treatment were seen.

Activating calcium-sensing receptor gene variants in children: a case study of infant hypocalcaemia and literature review.

UNLABELLED: Autosomal dominant hypocalcaemia (ADH) is caused by activating variants in the calcium-sensing receptor (CASR) gene, but detailed information on the paediatric phenotype is limited. The current paper presents a case of severe ADH and systematically reviews the literature on ADH in children. CONCLUSION: We found that the severity of clinical neurological symptoms was inversely related to serum calcium levels and a high prevalence of renal calcifications and/or basal ganglia calcifications in children with ADH.

Acute and short-term chronic testosterone fluctuation effects on glucose homeostasis, insulin sensitivity, and adiponectin: a randomized, double-blind, placebo-controlled, crossover study.

CONTEXT: Low levels of adiponectin and T in men have been shown to predict development of the metabolic syndrome, but the effects of T on glucose metabolism are incompletely understood and may be influenced either directly or indirectly through changes in body composition or in levels of adiponectin. OBJECTIVE: The aim of the study was to test whether T exerts its effects on glucose metabolism directly or indirectly. DESIGN, SETTING, AND PARTICIPANTS: In a randomized, double-blind, placebo-controlled, crossover study, 12 healthy young males were studied on four separate occasions. They received GnRH agonist treatment 1 month before 3 of 4 trial days to induce castrate levels of T. On trial days, T gel containing either high or low physiological T dose or placebo was applied to the body. On a fourth trial day, participants constituted their own eugonadal controls. INTERVENTION: Each study comprised a 5-hour basal period and a 3-hour hyperinsulinemic euglycemic clamp. MAIN OUTCOME MEASURES: We measured the effect of acute T on peripheral glucose disposal, total adiponectin and subforms, and other indices of glucose metabolism. RESULTS: Short-term hypogonadism was associated with increased high molecular weight adiponectin levels (P < .03) and increased oxidative glucose disposal (P = .03) but not total glucose disposal (P = .07). Acute T treatment was an independent suppressor of high molecular weight adiponectin levels (P = .04) but did not affect total glucose disposal (P = .17). CONCLUSIONS: These data show that T can act through putative fast nongenomic pathways to affect adiponectin levels in humans. The early hypogonadal state is characterized by a marked shift in fuel oxidation from lipids toward glucose, which may rely partly on buffering capabilities of adiponectin.

The role of hypogonadism in Klinefelter syndrome.

Klinefelter syndrome (KS) (47, XXY) is the most abundant sex-chromosome disorder, and is a common cause of infertility and hypogonadism in men. Most men with KS go through life without knowing the diagnosis, as only 25% are diagnosed and only a few of these before puberty. Apart from hypogonadism and azoospermia, most men with KS suffer from some degree of learning disability and may have various kinds of psychiatric problems. The effects of long-term hypogonadism may be diffi cult to discern from the gene dose effect of the extra X-chromosome. Whatever the cause, alterations in body composition, with more fat and less muscle mass and diminished bone mineral mass, as well as increased risk of metabolic consequences, such as type 2 diabetes and the metabolic syndrome are all common in KS. These findings should be a concern as they are not simply laboratory findings; epidemiological studies in KS populations show an increased risk of both hospitalization and death from various diseases. Testosterone treatment should be offered to KS patients from early puberty, to secure a proper masculine development, nonetheless the evidence is weak or nonexisting, since no randomized controlled trials have ever been published. Here, we will review the current knowledge of hypogonadism in KS and the rationale for testosterone treatment and try to give our best recommendations for surveillance of this rather common, but often ignored, syndrome.

The macrophage low-grade inflammation marker sCD163 is modulated by exogenous sex steroids.

Soluble CD163 (sCD163) is a novel marker linked to states of low-grade inflammation such as diabetes, obesity, liver disease, and atherosclerosis, all prevalent in subjects with Turner syndrome (TS) and Klinefelter syndrome (KS). We aimed to assess the levels of sCD163 and the regulation of sCD163 in regards to treatment with sex hormone therapy in males with and without KS and females with and without TS. Males with KS (n=70) and age-matched controls (n=71) participating in a cross-sectional study and 12 healthy males from an experimental hypogonadism study. Females with TS (n=8) and healthy age-matched controls (n=8) participating in a randomized crossover trial. The intervention comprised of treatment with sex steroids. Males with KS had higher levels of sCD163 compared with controls (1.75 (0.47-6.90) and 1.36 (0.77-3.11) respectively, P<0.001) and the levels correlated to plasma testosterone (r=-0.31, P<0.01), BMI (r=0.42, P<0.001), and homeostasis model of assessment insulin resistance (r=0.46, P<0.001). Treatment with testosterone did not significantly lower sCD163. Females with TS not receiving hormone replacement therapy (HRT) had higher levels of sCD163 than those of their age-matched healthy controls (1.38±0.44 vs 0.91±0.40, P=0.04). HRT and oral contraceptive therapy decreased sCD163 in TS by 22% (1.07±0.30) and in controls by 39% (0.55±0.36), with significance in both groups (P=0.01 and P=0.04). We conclude that levels of sCD163 correlate with endogenous testosterone in KS and are higher in KS subjects compared with controls, but treatment did not significantly lower levels. Both endogenous and exogenous estradiol in TS was associated with lower levels of sCD163.

Clinical review: Klinefelter syndrome--a clinical update.

CONTEXT: Recently, new clinically important information regarding Klinefelter syndrome (KS) has been published. We review aspects of epidemiology, endocrinology, metabolism, body composition, and neuropsychology with reference to recent genetic discoveries. EVIDENCE ACQUISITION: PubMed was searched for "Klinefelter," "Klinefelter's," and "XXY" in titles and abstracts. Relevant papers were obtained and reviewed, as well as other articles selected by the authors. EVIDENCE SYNTHESIS: KS is the most common sex chromosome disorder in males, affecting one in 660 men. The genetic background is the extra X-chromosome, which may be inherited from either parent. Most genes from the extra X undergo inactivation, but some escape and serve as the putative genetic cause of the syndrome. KS is severely underdiagnosed or is diagnosed late in life, roughly 25% are diagnosed, and the mean age of diagnosis is in the mid-30s. KS is associated with an increased morbidity resulting in loss of approximately 2 yr in life span with an increased mortality from many different diseases. The key findings in KS are small testes, hypergonadotropic hypogonadism, and cognitive impairment. The hypogonadism may lead to changes in body composition and a risk of developing metabolic syndrome and type 2 diabetes. The cognitive impairment is mainly in the area of language processing. Boys with KS are often in need of speech therapy, and many suffer from learning disability and may benefit from special education. Medical treatment is mainly testosterone replacement therapy to alleviate acute and long-term consequences of hypogonadism as well as treating or preventing the frequent comorbidity. CONCLUSIONS: More emphasis should be placed on increasing the rate of diagnosis and generating evidence for timing and dose of testosterone replacement. Treatment of KS should be a multidisciplinary task including pediatricians, speech therapists, general practitioners, psychologists, infertility specialists, urologists, and endocrinologists.

Independent effects of testosterone on lipid oxidation and VLDL-TG production: a randomized, double-blind, placebo-controlled, crossover study.

Low testosterone (T) levels in men have been shown to predict development of the metabolic syndrome, but the effects of T on lipid metabolism are incompletely understood. In a randomized, double-blind, placebo-controlled, crossover study, 12 healthy, young males received gonadotropin-releasing hormone agonist treatment 1 month prior to 3 of 4 trial days to induce castrate levels of T. On trial days, T gel was applied to the body containing either high or low physiological T dose or placebo. On the 4th trial day, participants constituted their own eugonadal controls. Each study comprised a 5-h basal period and a 3-h hyperinsulinemic-euglycemic clamp. Short-term hypogonadism did not affect VLDL triglyceride (TG) secretion, nor did it affect VLDL-TG concentrations. It was, however, characterized by lower total lipid oxidation. In addition, acute rescue with high physiological T increased VLDL-TG secretion during both basal and clamp conditions. These data show that T can act through fast nongenomic pathways in the liver. In addition, the early hypogonadal state is characterized by decreased total lipid oxidation, but whether these changes represent early hypogonadal metabolic dysfunction warrants further investigations. T is not a major determinant of resting VLDL-TG kinetics in men.

Estradiol acutely inhibits whole body lipid oxidation and attenuates lipolysis in subcutaneous adipose tissue: a randomized, placebo-controlled study in postmenopausal women.

CONTEXT: Estradiol (E(2)) promotes and maintains the female phenotype characterized by subcutaneous fat accumulation. There is evidence to suggest that this effect is due to increased anti-lipolytic α2A-adrenergic receptors, but whether this requires long-term exposure to E(2) or is an immediate effect is not clear. OBJECTIVE: To study acute effects of a single dose (4 mg) of 17ß-E(2) on regional and systemic lipolysis. METHODS: Sixteen postmenopausal women (age, 595 years; weight, 6710 kg; and BMI, 24.82.9) were studied in a crossover design: i) placebo and ii) 4 mg E(2). Basal and adrenaline-stimulated regional lipolysis was assessed by microdialysis and substrate oxidation rates by indirect calorimetry. Tissue biopsies were obtained to assess lipoprotein lipase activity and mRNA expression of adrenergic, estrogen, cytokine, and vascular reactivity receptors. RESULTS: Acute E(2) stimulation significantly attenuated catecholamine-stimulated lipolysis in femoral subcutaneous adipose tissue (interstitial glycerol concentration (micromole/liter) ANOVA time vs treatment interaction, P=0.01) and lipolysis in general in abdominal adipose tissue (ANOVA treatment alone, P<0.05). E(2) also reduced basal lipid oxidation ((mg/kg per min) placebo, 0.58 ± 0.06 vs E(2), 0.45 ± 0.03; P=0.03) and induced a significantly higher expression of anti-lipolytic α2A-adrenergic receptor mRNA (P=0.02) in skeletal muscle tissue as well as an upregulation of eNOS (NOS3) mRNA (P=0.02). CONCLUSION: E(2) acutely attenuates the lipolytic response to catecholamines in subcutaneous adipose tissue, shifts muscular adrenergic receptor mRNA toward anti-lipolytic α2A-receptors, decreases whole body lipid oxidation, and enhances expression of markers of vascular reactivity.

Body composition, metabolic syndrome and type 2 diabetes in Klinefelter syndrome.

UNLABELLED: Klinefelter syndrome (KS) affects 1:660 men, making it the most common sex-chromosome disorder in man, and is a common cause of infertility, hypogonadism and learning disability. Men with KS are described as tall, slim, narrow shouldered, broad hipped, with hypergonadotropic hypogonadism and small testes, and recently the description has been expanded to include increased risk of the metabolic syndrome, type 2 diabetes and an unfavourable change in body composition, with accumulation of body fat and decreased muscle mass and a concomitant decrease in insulin sensitivity, muscle strength and oxygen consumption capacity. Here, we review the data on body composition, bone turnover, liver function, insulin resistance and metabolic syndrome in relation to testosterone in both patients with KS and normal men. Treatment with testosterone in hypogonadal men (other than KS) improves body composition in both clinical and experimental studies. Despite the lack of such studies in KS, we recommend testosterone treatment to patients with KS with low serum testosterone or increased LH and change in body composition and thus possibly prevent common diseases like type 2 diabetes, osteoporosis and heart disease. CONCLUSION: Preventable causes of the increased morbidity and mortality, such as osteoporosis, chronic obstructive airway disease or type 2 diabetes, should be screened for. Despite the lack of randomized controlled studies, we recommend testosterone treatment in case of increased LH or low serum testosterone, and weight reduction programmes if overweight.

Acute estrogen exposure does not affect basal very low-density lipoprotein-triglyceride production or oxidation in postmenopausal women.

CONTEXT: Long-term hormone replacement therapy (HRT) with estradiol (E(2)) is associated with an altered lipid profile including unfavorable increases in triglyceride (TG) concentrations and augmented hepatic very low-density lipoprotein (VLDL)-TG production. There are indications that this effect of estrogens may be immediate. OBJECTIVE: To study the in vivo effect of a single dose of E(2) on VLDL-TG kinetics and oxidation in humans. METHODS: Eight healthy, postmenopausal women were given a single dose of either placebo or E(2) (4 mg) orally. VLDL-TG kinetics was assessed by a 240-min primed-continuous infusion of ex vivo labeled [1-(14)C]triolein-labeled VLDL. Fractional and absolute VLDL-TG oxidation was determined by hyamin trapping of exhaled (14)C label. Indirect calorimetry provided measurements of lipid oxidation. RESULTS: Administration of 4 mg of E(2) orally rapidly increased plasma E(2) concentrations from below detection threshold to premenopausal levels. Free fatty acids (FFA) and TG concentrations were unaltered. No immediate effect was observed on either VLDL-TG production (placebo versus E(2)): 20.0+/-12.4 vs 24.1+/-10.7 micromol/min, P=0.33; VLDL-TG oxidation: 12.3+/-10.9 vs 12.6+/-5.6 micromol/min, P=0.93); or VLDL-TG clearance rates: 51.4+/-16.8 vs 64.9+/-28.8 ml/min, P=0.34). CONCLUSIONS: Short-term E(2) elevation does not affect VLDL-TG production, oxidation, or clearance in humans. We therefore propose that HRT-associated dyslipidemia has a gradual rather than immediate onset.

Klinefelter's syndrome, type 2 diabetes and the metabolic syndrome: the impact of body composition.

Klinefelter's syndrome (KS) is the most common sex-chromosome disorder in men, affecting approximately 1:660 men, and is a rather common cause of infertility, hypogonadism and learning disability. Traditionally, men with KS have been described as tall, slim, narrow shouldered, broad hipped, with hypergonadotrophic hypogonadism and small testes. Recent studies showed an increased risk of diabetes and an unfavourable change in body composition; with accumulation of body fat and decreased muscle mass and a concomitant decrease in insulin sensitivity, muscle strength and oxygen consumption capacity. Here, we review the data on body composition, insulin resistance and metabolic syndrome in relation to testosterone in both KS patients and normal men. Treatment with testosterone in hypogonadal states (other than KS) seems to improve body composition in both clinical and experimental studies. Despite the lack of such studies in KS, we recommend testosterone treatment to KS patients with low serum testosterone or increased LH and change in body composition.

Idiopathic neuralgic amyotrophy in children. Case report, 4 year follow up and review of the literature.

BACKGROUND: Idiopathic neuralgic amyotrophy (INA) is a neurological disorder with a suspected autoimmune cause, and is characterized by a sudden onset of pain and subsequent atrophies of the arm and shoulder muscles. It has rarely been documented in children, but it has been suggested that the prognostic outcome is worse in children compared with adults. AIM AND METHODS: We present a case and 4 year follow up of severe INA in a 12-year-old boy along with a thorough review of reported cases in children, to provide an overview of the paediatric phenotype and prognosis. RESULTS: The patient presented with severe pain and a subsequent paresis around the right shoulder girdle. Blood tests, MRI and X-ray of the shoulder were all normal. Electromyography revealed patchy denervation of individual nerves of the brachial plexus. At 5 months he started recovering, but full recovery was only achieved after 3-4 years. We then reviewed the literature and identified 58 paediatric cases of INA. In total, 63% made a full recovery, 25% made a partial, and 13% made no recovery. Overall, recovery was quick with a mean recovery time of 11.1 months. Specific preceding events such as osteomyelitis, viral- and upper airway infections were frequently associated with INA, but with an age dependent pattern. CONCLUSION: INA is a rare neurological disorder, especially in children. When compared with adults, pain and bilateral affection seems less common, and recovery is quick. Although limited by its retrospective nature, this review suggests that the paediatric phenotype is different and milder from that of adults. It also indicates a better prognosis in children than previously anticipated.