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Open access

Jakob Skov, Daniel Eriksson, Ralf Kuja-Halkola, Jonas Höijer, Soffia Gudbjörnsdottir, Ann-Marie Svensson, Patrik K E Magnusson, Jonas F Ludvigsson, Olle Kämpe and Sophie Bensing

Objective

Co-aggregation of autoimmune diseases is common, suggesting partly shared etiologies. Genetic factors are believed to be important, but objective measures of environmental vs heritable influences on co-aggregation are absent. With a novel approach to twin studies, we aimed at estimating heritability and genetic overlap in seven organ-specific autoimmune diseases.

Design

Prospective twin cohort study.

Methods

We used a cohort of 110 814 twins to examine co-aggregation and heritability of Hashimoto’s thyroiditis, atrophic gastritis, celiac disease, Graves’ disease, type 1 diabetes, vitiligo and Addison’s disease. Hazard ratios (HR) were calculated for twins developing the same or different disease as compared to their co-twin. The differences between monozygotic and dizygotic twin pairs were used to estimate the genetic influence on co-aggregation. Heritability for individual disorders was calculated using structural equational modeling adjusting for censoring and truncation of data.

Results

Co-aggregation was more pronounced in monozygotic twins (median HR: 3.2, range: 2.2–9.2) than in dizygotic twins (median HR: 2.4, range: 1.1–10.0). Heritability was moderate for atrophic gastritis (0.38, 95% CI: 0.23–0.53) but high for all other diseases, ranging from 0.60 (95% CI: 0.49–0.71) for Graves’ disease to 0.97 (95% CI: 0.91–1.00) for Addison’s disease.

Conclusions

Overall, co-aggregation was more pronounced in monozygotic than in dizygotic twins, suggesting that disease overlap is largely attributable to genetic factors. Co-aggregation was common, and twins faced up to a ten-fold risk of developing diseases not present in their co-twin. Our results validate and refine previous heritability estimates based on smaller twin cohorts.

Free access

Luis F de Castro, Diana Ovejero and Alison M Boyce

Fibrous dysplasia/McCune–Albright Syndrome (FD/MAS), arising from gain-of-function mutations in Gαs, and cutaneous skeletal hypophosphatemia syndrome (CSHS), arising from gain-of-function mutations in the Ras/MAPK pathway, are strikingly complex, mosaic diseases with overlapping phenotypes. Both disorders are defined by mosaic skin and bone involvement, and both are complicated by increased FGF23 production. These similarities have frequently led to mis-diagnoses, primarily in patients with CSHS who are often assumed to have FD/MAS. The intriguing similarities in skeletal involvement in these genetically distinct disorders have led to novel insights into FGF23 physiology, making an understanding of FD/MAS and CSHS relevant to both clinicians and researchers interested in bone and endocrine disorders. This review will give an overview of FD/MAS and CSHS, focusing on the roles of mosaicism and FGF23 in the pathogenesis and clinical presentation of these disorders.

Restricted access

Marco Mezzullo, Guido Di Dalmazi, Alessia Fazzini, Margherita Baccini, Andrea Repaci, Alessandra Gambineri, Valentina Vicennati, Carla Pelusi, Uberto Pagotto and Flaminia Fanelli

Objective

To evaluate the independent impact of age, obesity and metabolic risk factors on 13 circulating steroid levels; to generate reference intervals for adult men.

Design

Cross-sectional study.

Methods

Three hundred and fifteen adults, drug-free and apparently healthy men underwent clinical and biochemical evaluation. Thirteen steroids were measured by LC-MS/MS and compared among men with increasing BMI. Moreover, the independent impact of age, BMI and metabolic parameters on steroid levels was estimated. Upper and lower reference limits were generated in steroid-specific reference sub-cohorts and compared with dysmetabolic sub-cohorts.

Results

We observed lower steroid precursors and testosterone and increase in estrone levels in men with higher BMI ranges. By multivariate analysis, 17-hydroxyprogesterone and dihydrotestosterone decreased with BMI, while cortisol decreased with waist circumference. Estrone increased with BMI and systolic blood pressure. Testosterone decreased with worsening insulin resistance. 17-hydroxypregnenolone and corticosterone decreased with increasing total/HDL-cholesterol ratio. Age-related reference intervals were estimated for 17-hydroxypregnenolone, DHEA, 17-hydroxyprogesterone, corticosterone, 11-deoxycortisol, cortisol and androstenedione, while age-independent reference intervals were estimated for progesterone, 11-deoxycorticosterone, testosterone, dihydrotestosterone, estrone and estradiol. Testosterone lower limit was 2.29 nmol/L lower (P = 0.007) in insulin resistant vs insulin sensitive men. Furthermore, the upper limits for dihydrotestosterone (−0.34 nmol/L, P = 0.045), cortisol (−87 nmol/L, P = 0.045–0.002) and corticosterone (−10.1 nmol/L, P = 0.048–0.016) were lower in overweight/obese, in abdominal obese and in dyslipidaemic subjects compared to reference sub-cohorts, respectively.

Conclusions

Obesity and mild unmedicated metabolic risk factors alter the circulating steroid profile and bias the estimation of reference limits for testosterone, dihydrotestosterone, cortisol and corticosterone. Applying age-dependent reference intervals is mandatory for steroid precursors and corticosteroids.

Free access

Nèle F Lenders, Ann I McCormack and Ken K Y Ho

Gonadal steroids modulate the effects of GH, with oestrogens attenuating and androgens augmenting GH action. Whether these divergent effects influence the clinical manifestation, management and prognosis of acromegaly have not been carefully reviewed. This review examines whether there is a gender difference in epidemiology, presentation, quality of life (QoL), morbidity, treatments and mortality of acromegaly. Acromegaly is more common in women who present at an older age with longer diagnostic delay. At presentation, women have a higher GH relative to IGF-1 level than men. QoL is more adversely affected in women both before and after treatment. Prevalence of hypertension and diabetes are greater in women than in men with acromegaly. Treatment outcomes with SSAs are comparable between sexes, but women may require a higher dose of pegvisomant for equivalent response. Mortality in untreated acromegaly is more profoundly affected in women; however, improved treatments in recent decades have resulted in normalisation of standard mortality ratios in both sexes. We conclude that gender does matter in the management of acromegaly, with women presenting later in life, with greater diagnostic delay, higher prevalence of comorbidities and experiencing worse QoL.

Restricted access

Rolf H H Groenwold and Olaf M Dekkers

The results of observational studies of causal effects are potentially biased due to confounding. Various methods have been proposed to control for confounding in observational studies. Eight basic aspects of confounding adjustment are described, with a focus on correction for confounding through covariate adjustment using regression analysis. These aspects should be considered when planning an observational study of causal effects or when assessing the validity of the results of such a study.

Restricted access

Connor Wright, Patrick O’Day, Mohammed Alyamani, Nima Sharifi and Richard J Auchus

Context

The human adrenal is the dominant source of androgens in castration-resistant prostate cancer (CRPC) and classic 21-hydroxylase deficiency (21OHD). Abiraterone, derived from the prodrug abiraterone acetate (AA), inhibits the activity of cytochrome P450 17-hydroxylase/17,20-lyase (CYP17A1), the enzyme required for all androgen biosynthesis. AA treatment effectively lowers testosterone and androstenedione in 21OHD and CRPC patients. The 11-oxygenated androgens are major adrenal-derived androgens, yet little is known regarding the effects of AA administration on 11-oxygenated androgens.

Objective

To test the hypothesis that AA therapy decreases 11-oxygenated androgens.

Design

Samples were obtained from 21OHD or CRPC participants in AA or AA plus prednisone (AAP)-treatment studies, respectively.

Methods

We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the 11-oxygenated androgens, 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone, in plasma or serum samples from six 21OHD and six CRPC patients before and after treatment with AA or AAP, respectively.

Results

In CRPC patients, administration of AAP (1000 mg/day AA with prednisone and medical castration) lowered all four 11-oxygenated androgens to below the lower limits of quantitation (<0.1–0.3 nmol/L), equivalent to 64–94% reductions from baseline. In 21OHD patients, administration of AA (100–250 mg/day for 6 days) reduced all 11-oxygenated androgens by on average 56–77% from baseline.

Conclusions

We conclude that AA and AAP therapies markedly reduce the production of the adrenal-derived 11-oxygenated androgens, both in patients with high (21OHD) or normal (CRPC) 11-oxygenated androgens at baseline, respectively. Reduction of 11-oxygenated androgens is an important aspect of AA and AAP pharmacology.

Open access

A Veltroni, E Cosaro, F Spada, N Fazio, A Faggiano, A Colao, S Pusceddu, M C Zatelli, D Campana, A Piovesan, A Pia, E M Grossrubatscher, A Filice, A Bianchi, P Razzore, M Toaiari, S Cingarlini, L Landoni, R Micciolo and M V Davì

Introduction

Management of malignant insulinomas is challenging due to the need to control both hypoglycaemic syndrome and tumor growth. Literature data is limited to small series.

Aim of the study

To analyze clinico-pathological characteristics, treatments and prognosis of patients with malignant insulinoma.

Materials and methods

Multicenter retrospective study on 31 patients (male: 61.3%) diagnosed between 1988 and 2017.

Results

The mean age at diagnosis was 48 years. The mean NET diameter was 41 ± 31 mm, and 70.8% of NETs were G2. Metastases were widespread in 38.7%, hepatic in 41.9% and only lymph nodal in 19.4%. In 16.1% of the cases, the hypoglycaemic syndrome occurred after 46 ± 35 months from the diagnosis of originally non-functioning NET, whereas in 83.9% of the cases it led to the diagnosis of NET, of which 42.3% with a mean diagnostic delay of 32.7 ± 39.8 months. Surgical treatment was performed in 67.7% of the cases. The 5-year survival rate was 62%. Overall survival was significantly higher in patients with Ki-67 ≤10% (P = 0.03), insulin level <60 µU/mL (P = 0.015) and in patients who underwent surgery (P = 0.006). Peptide Receptor Radionuclide Therapy (PRRT) was performed in 45.1%, with syndrome control in 93% of patients.

Conclusions

Our study includes the largest series of patients with malignant insulinoma reported to date. The hypoglycaemic syndrome may occur after years in initially non-functioning NETs or be misunderstood with delayed diagnosis of NETs. Surgical treatment and Ki67 ≤10% are prognostic factors associated with better survival. PPRT proved to be effective in the control of hypoglycaemia in majority of cases.

Restricted access

S H Donze, L Damen, E F Mahabier and A C S Hokken-Koelega

Objective

Children with Prader–Willi syndrome (PWS) have mild to moderate cognitive impairment. Short-term studies showed positive effects of growth hormone (GH) on cognitive development. This study investigated the effects of 8 years of GH on cognitive development in children with PWS. We also investigated whether starting GH during infancy results in higher cognitive functioning after 8 years of GH.

Design

Longitudinal study in 43 children with PWS during 8 years of GH (median age at GH start 8.1 years). Cognitive functioning after 8 years was compared to another group of 22 children with PWS (median age at GH start 1.4 years).

Methods

Cognitive functioning was measured by Wechsler Intelligence Scale for Children. Vocabulary, Similarities and Block Design subtests were expressed as standard deviation scores (SDS) and total IQ (TIQ) calculated.

Results

Estimated mean (95%CI) Block Design SDS changed from −2.2 (−2.6; −1.8) at GH start to −1.8 (−2.2; −1.4) after 8 years of GH (P = 0.18), similarly SDS from −1.5 (−2.1; −0.9) to −1.3 (−1.9; −0.7, P = 0.66) and TIQ from 66 (60; 72) to 69 (63; 75, P = 0.57). Vocabulary SDS remained similar, being −1.9 (−2.3; −1.4) at GH start and −1.9 (−2.4; −1.5) after 8 years (P = 0.85). After 8 years of GH Vocabulary, SDS and TIQ were higher in the children who started GH during infancy, compared to those who started GH later in childhood (P < 0.01, P = 0.04, respectively).

Conclusions

Cognitive functioning in children with PWS remains similar during long-term GH and develops at the same pace as healthy peers.

Restricted access

Dimitra Argyro Vassiliadi and Stylianos Tsagarakis

Trans-sphenoidal surgery (TSS) is the treatment of choice in Cushing’s disease. However, recurrence rates are substantial and currently there are no robust predictors of late prognosis. As accumulating evidence challenge the accuracy of the traditionally used early postoperative cortisol values, alternative tests are required. The study of Cambos et al, published in this issue of European Journal of Endocrinology, adds to the existing data that support a role of the desmopressin test as an early and reliable predictive marker in successfully TSS-treated patients. However, despite these promising data, the use of this test is hampered by the fact that it can be applied only in patients with a documented pre-operative positive test. Moreover, the lack of robust criteria to define positive post-operative responses represents another major limitation.

Open access

Andreas Stomby, Julia Otten, Mats Ryberg, Ruth Andrew, Brian R Walker and Tommy Olsson

Context

Altered tissue-specific glucocorticoid metabolism has been described in uncomplicated obesity and type 2 diabetes. We hypothesized that weight loss induced by diet and exercise, which has previously been shown to reverse abnormal cortisol metabolism in uncomplicated obesity, also normalizes cortisol metabolism in patients with type 2 diabetes.

Objective

Test the effects of a diet intervention with added exercise on glucocorticoid metabolism.

Design

Two groups followed a Paleolithic diet (PD) for 12 weeks with added 180 min of structured aerobic and resistance exercise per week in one randomized group (PDEX).

Setting

Umeå University Hospital.

Participants

Men and women with type 2 diabetes treated with lifestyle modification ± metformin were included. Twenty-eight participants (PD, n = 15; PDEX, n = 13) completed measurements of glucocorticoid metabolism.

Main outcome measures

Changes in glucocorticoid metabolite levels in 24-h urine samples, expression of HSD11B1 mRNA in s.c. adipose tissue and conversion of orally administered cortisone to cortisol measured in plasma. Body composition and insulin sensitivity were measured using a hyperinsulinemic-euglycemic clamp, and liver fat was measured by magnetic resonance spectroscopy.

Results

Both groups lost weight and improved insulin sensitivity. Conversion of orally taken cortisone to plasma cortisol and the ratio of 5α-THF + 5β-THF/THE in urine increased in both groups.

Conclusions

These interventions caused weight loss and improved insulin sensitivity with concomitant increases in the conversion of cortisone to cortisol, which is an estimate of hepatic HSD11B1 activity. This suggests that dysregulation of liver glucocorticoid metabolism in these patients is a consequence rather than a cause of metabolic dysfunction.