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Open access

Wafa Kallali, Ewan Gray, Muhammad Zain Mehdi, Robert Lindsay, Louise A Metherell, Federica Buonocore, Jenifer P Suntharalingham, John C Achermann and Malcolm Donaldson


CYP11A1 mutations cause P450 side-chain cleavage (scc) deficiency, a rare form of congenital adrenal hyperplasia with a wide clinical spectrum. We detail the phenotype and evolution in a male sibship identified by HaloPlex targeted capture array.

Family study

The youngest of three brothers from a non-consanguineous Scottish family presented with hyperpigmentation at 3.7 years. Investigation showed grossly impaired glucocorticoid function with ACTH elevation, moderately impaired mineralocorticoid function, and normal external genitalia. The older brothers were found to be pigmented also, with glucocorticoid impairment but normal electrolytes. Linkage studies in 2002 showed that all three brothers had inherited the same critical regions of the maternal X chromosome suggesting an X-linked disorder, but analysis of NR0B1 (DAX-1, adrenal hypoplasia) and ABCD1 (adrenoleukodystrophy) were negative.

In 2016, next-generation sequencing revealed compound heterozygosity for the rs6161 variant in CYP11A1 (c.940G>A, p.Glu314Lys), together with a severely disruptive frameshift mutation (c.790_802del, K264Lfs*5). The brothers were stable on hydrocortisone and fludrocortisone replacement, testicular volumes (15–20 mL), and serum testosterone levels (24.7, 33.3, and 27.2 nmol/L) were normal, but FSH (41.2 µ/L) was elevated in the proband. The latter had undergone left orchidectomy for suspected malignancy at the age of 25 years and was attending a fertility clinic for oligospermia. Initial histology was reported as showing nodular Leydig cell hyperplasia. However, histological review using CD56 staining confirmed testicular adrenal rest cell tumour (TART).


This kinship with partial P450scc deficiency demonstrates the importance of precise diagnosis in primary adrenal insufficiency to ensure appropriate counselling and management, particularly of TART.

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Roberta Ricotti, Arianna Solito, Elena Mariotti Zani, Marina Caputo, Giulia Genoni, Francesco Barone-Adesi, Valentina Mancioppi, Emanuela Agosti, Gianluca Aimaretti, Simonetta Bellone and Flavia Prodam


Data on metabolic impairments in Cushing’s syndrome and GH deficiency all suggest that the relationship between cortisol and GH/IGF-I axis in obesity may have a role in the related diseases. However, studies focusing only on one of these hormones are often controversial in paediatrics. We aimed to explore the simultaneous relationship between cortisol and IGF-I with the metabolic alterations in paediatric obesity.


Retrospective cross-sectional study in a tertiary care center. We recruited 876 (441 males and 435 females) overweight and obese children and adolescents. A complete clinical and biochemical evaluation including OGTT was performed. Cortisol and IGF-I SDS were divided in quartiles and then crossed to explore the reciprocal influence of high/high, low/low, and high/low levels of each one on the metabolic alterations of obesity.


Subjects in the higher quartiles of IGF-I-SDS and cortisol had an increased risk of hypertension, hypercholesterolemia, high levels of triglycerides, and reduced HDL cholesterol. Diversely, lower IGF-I-SDS quartiles were associated with higher blood glucose, insulin, insulin resistance, and reduced insulin sensitivity levels with the rise of cortisol quartiles.


We observed that apart from glucose metabolism that is associated with low IGF-I and high cortisol levels, the other parameters known to be associated with increased cardiovascular risk were related to high levels of both IGF-I and cortisol, even if within normal range. Cortisol and IGF-I play a complex role in the comorbidities of obesity, and the evaluation of both variables could clarify some of the discordant results.

Open access

Blerim Mujaj, Daniel Bos, Maryam Kavousi, Aad van der Lugt, Jan A Staessen, Oscar H Franco and Meike W Vernooij


To investigate the association between fasting serum insulin and glucose levels with atherosclerotic plaque composition in the carotid artery. Impaired insulin and glucose levels are implicated in the etiology of cardiovascular disease; however, their influence on the formation and composition of atherosclerotic plaque remains unclear.


In 1740 participants (mean age 72.9 years, 46% women, 14.4% diabetes mellitus) from the population-based Rotterdam Study, we performed carotid MRI to evaluate the presence of calcification, lipid core, and intraplaque hemorrhage in carotid atherosclerosis. All participants also underwent blood sampling to obtain information on serum insulin and glucose levels. Using logistic regression models, we assessed the association of serum insulin and glucose levels (per s.d. and in tertiles) with the different plaque components, while adjusting for sex, age, intima-media thickness, and cardiovascular risk factors.


Serum insulin levels were associated with the presence of intraplaque hemorrhage (adjusted odds ratio (OR): 1.42 (95% CI: 1.12–1.7)) We found no association with the presence of calcification or lipid core. Sensitivity analyses restricted to individuals without diabetes mellitus yielded similar results. No associations were found between serum glucose levels and any of the plaque components.


Serum insulin levels are associated with the presence of vulnerable components of carotid plaque, specifically with intraplaque hemorrhage. These findings suggest a complex role for serum insulin in the pathophysiology of carotid atherosclerosis and in plaque vulnerability.

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Connor Wright, Patrick O'Day, Mohammad Alyamani, Nima Sharifi and Richard 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/d 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/d 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.

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Rolf H.h. Groenwold and Olaf M Dekkers

Observational studies of causal effects potentially suffer from confounding. Various methods have been proposed to control for confounding in observational studies. Eight basic principles of confounding adjustment are described, which should be considered when planning or reading about an observational study of causal effects.

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Alessio Veltroni, Elisa Cosaro, Francesca Spada, Nicola Fazio, Antongiulio Faggiano, Annamaria Colao, Sara Pusceddu, Maria Chiara Zatelli, Davide Campana, Alessandro Piovesan, Anna Pia, Erika Maria Grossrubatscher, Angelina Filice, Antonio Bianchi, Paola Razzore, Marco Toaiari, Sara Cingarlini, Luca Landoni, Rocco Micciolo and Maria Vittoria Davi'

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 (M 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%, only lymph nodal in 19.4%. In 16.1% the hypoglycaemic syndrome occurred after 46 ±35 months from the diagnosis of originally non-functioning NET, whereas in 83.9% of 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%. 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 up to now reported. 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 the majority of cases.

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Luigi Maione, Giovanna Pala, Claire Bouvattier, Séverine Trabado, Georgios Papadakis, Philippe Chanson, Jérôme Bouligand, Nelly Pitteloud, Andrew A Dwyer, Mohamad Maghnie and Jacques Young


Congenital hypogonadotropic hypogonadism/Kallmann syndrome (CHH/KS) is a rare condition characterized by gonadotropin deficiency and pubertal failure. Adult height (AH) in patients with CHH/KS has not been well studied.


To assess AH in a large cohort of patients with CHH/KS.


A total of 219 patients (165 males, 54 females). Parents and siblings were included.


AH was assessed in patients and family members. AH was compared to the general French population, mid parental target height (TH) and between patients and same-sex siblings. Delta height (∆H) was considered as the difference between AH and parental TH. ∆H was compared between patients and siblings, normosmic CHH and KS (CHH with anosmia/hyposmia), and according to underlying genetic defect. We examined the correlations between ∆H and age at diagnosis and therapeutically induced individual statural gain.


Mean AH in men and women with CHH/KS was greater than that in the French general population. Patients of both sexes had AH > TH. Males with CHH/KS were significantly, albeit moderately, taller than their brothers. ∆H was higher in CHH/KS compared to unaffected siblings (+6.2 ± 7.2 cm vs +3.4 ± 5.2 cm, P < 0.0001). ∆H was positively correlated with age at diagnosis. Neither olfactory function (normosmic CHH vs KS) nor specific genetic cause impacted ∆H. Individual growth during replacement therapy inversely correlated with the age at initiation of hormonal treatment (P < 0.0001).


CHH/KS is associated with higher AH compared to the general population and mid-parental TH. Greater height in CHH/KS than siblings indicates that those differences are in part independent of an intergenerational effect.

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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 has 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.

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 minutes 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-hour urine samples, expression of 11HSD1 mRNA in subcutaneous adipose tissue and conversion of orally administered cortisone to cortisol measured in plasma. Body composition, insulin sensitivity measured using a hyperinsulinemic-euglycemic clamp and liver fat 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 (5-THF+5-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 11HSD1 activity. This suggests that dysregulation of liver glucocorticoid metabolism in these patients is a consequence rather than a cause of metabolic dysfunction.

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M D Aydemirli, E Kapiteijn, K R M Ferrier, P B Ottevanger, T P Links, A N A van der Horst-Schrivers, K E Broekman, R H H Groenwold and J Zwaveling


The SELECT trial showed progression-free survival (PFS) benefit for lenvatinib for advanced radioiodine-refractory differentiated thyroid cancer (RAI-refractory or RR-DTC) patients, on which current clinical practice is based. We assessed whether the effectiveness and toxicity of lenvatinib in real-life clinical practice in the Netherlands were comparable to the pivotal SELECT trial.


From three Dutch centres Electronic Health Records (EHRs) of patients treated in the lenvatinib compassionate use program or as standard of care were reviewed and checked for SELECT eligibility criteria. Baseline characteristics, safety, and efficacy measures were compared and PFS and overall survival (OS) were calculated. Furthermore, PFS was compared to estimates of PFS reported in other studies.


A total of 39 DTC patients with a median age of 62 years were analysed. Of these, 27 patients (69%) did not fulfil the SELECT eligibility criteria. The most common grade ≥3 toxicities were hypertension (n = 11, 28%), diarrhoea (n = 7, 18%), vomiting (n = 4, 10%), and gallbladder disease (n = 3, 8%). Median PFS and median OS were 9.7 (95% confidence interval (CI): 4.0–15.5) and 18.3 (95% CI: 4.9–31.7) months, respectively, response rate was 38% (95% CI: 23–54%). PFS in the Dutch real-life situation was comparable to previous real-life studies, but inferior to PFS as shown in the SELECT trial (P = 0.04).


PFS in our non-trial population was significantly shorter than in the SELECT trial population. In the interpretation of results, differences in the real-life population and the SELECT study population regarding patient characteristics should be taken into account.