Surgery is the treatment of choice for non-functioning pituitary macroadenomas (NFPAs). In cases of postoperative remnant growth or tumor recurrence, radiotherapy (RT) can be considered. The role of RT in the postoperative management of NFPAs is still debated. The main arguments against routine use of RT are the lack of randomized controlled trials, the use of clinically irrelevant endpoints in most studies on RT, the benign character of the condition, the potential for side effects of RT, and the option to apply RT at a later stage. However, because of its excellent efficacy in inhibiting tumor growth, reducing tumor volume and improving any existing visual defects, and as its side effects seem to be limited compared to the benefits provided, RT keeps a place in the management of NFPAs when a tumor remnant persists, particularly if it is invasive and displays high proliferation markers, if surveillance shows a relevant increase in tumor volume or if the tumor is close to the optic chiasm. The size of the remnant, its vicinity with the optic pathways, and the potential risk to healthy surrounding tissues need to be considered when deciding on an RT procedure.
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Philippe Chanson, Alexandre Dormoy and Olaf M Dekkers
A Calabrese, V Basile, S Puglisi, P Perotti, A Pia, L Saba, P Berchialla, F Porpiglia, A Veltri, M Volante, G Reimondo, A Berruti and M Terzolo
Many patients with adrenocortical carcinoma (ACC) suffer from tumor recurrence despite radical surgery. Evidence on the post-operative use of mitotane is controversial and no predictors of response are available. We aimed to assess whether adjuvant mitotane treatment may prolong survival in patients with non-metastatic ACC following complete resection and whether ACC patients at high risk of recurrence may benefit from treatment.
Design and methods
We retrospectively reviewed data from 152 non-metastatic ACC patients followed at the San Luigi Gonzaga Hospital: 100 patients were treated with adjuvant mitotane and 52 patients were left untreated following surgery. We assessed a number of potential predictive factors of recurrence and death. Mitotane effect was explored stratifying patients by staging (stage I–II vs stage III), hormone secretion (yes vs no) and Ki67 index.
The non-treated group had a higher risk of recurrence (HR: 2.79, 95%CI: 1.58–4.91; P < 0.001) than mitotane-treated group, while overall survival was not significantly different between groups. Hormone secretion, elevated Weiss score and elevated Ki67 index confer a higher risk of both recurrence and death and stage III ACC of death. Adjuvant mitotane treatment reduced significantly the risk of death in patients with elevated Ki67 index (P = 0.005) and in patients with stage III ACC (P = 0.02).
Adjuvant mitotane may prolong recurrence-free survival in radically resected ACC patients with acceptable toxicity and may also prolong overall survival in a subgroup of ACC patients at high risk of recurrence.
Jaap Deinum, Hans Groenewoud, Gert Jan Van Der Wilt, GianPaolo Rossi and Livia Lenzini
Notwithstanding the high prevalence of primary aldosteronism (PA), probably the most common form of secondary hypertension, the diagnosis of PA is often neglected, or delayed, thus precluding target treatment, which is curative in many cases. For selection of the most appropriate treatment a fundamental step is the distinction between a lateralized form, mainly aldosterone-producing adenoma (APA), and bilateral adrenocortical hyperplasia (BAH), also known as idiopathic hyperaldosteronism (IHA). To this aim all current guidelines recommend adrenal vein sampling (AVS), a technically challenging procedure that often fails, particularly in non-experienced hands. Cosyntropin (synthetic ACTH) is administered in the attempt to maximize adrenal cortisol secretion and avoid pulsatile adrenocortical hormone secretion in about 40% of the referral centres around the world. However, the Endocrine Society guidelines do not advise about the use or not of cosyntropin as stimulus during AVS, as there are arguments in favour and against its use. These arguments are presented in this debate article reflecting the views of groups that currently use and do not use cosyntropin.
Julie Refardt, Clara O. Odilia Sailer, Irina Chifu, Bettina Winzeler, Ingeborg Schnyder, Martin Fassnacht, Wiebke Kristin Fenske and Mirjam Christ-Crain
Background: Diagnosis and treatment of dysnatremia is challenging and further complicated by the pitfalls of different sodium measurement methods. Routinely used sodium measurements are the indirect (plasma/serum) and direct (whole blood) ion selective electrode (ISE) method, showing discrepant results especially in the setting of acute illness. Few clinicians are aware of differences between the methods in clinically stable patients or healthy volunteers.
Methods: Data of 140 patients and 91 healthy volunteers undergoing osmotic stimulation with hypertonic saline infusion were analyzed. Sodium levels were measured simultaneously by indirect and direct ISE method before and at different time points during osmotic stimulation up to a sodium threshold of ≥150 mmol/l. The primary outcome was the difference in sodium levels between the indirect and the direct ISE method.
Results: 878 sodium measurements were analyzed. Mean (SD) sodium levels ranged from 141mmol/l (2.9) to 151mmol/ (2.1) by the indirect ISE compared to 140mmol/l (3) to 149mmol/l (2.8) by the direct ISE method. The interclass correlation coefficient between the two methods was 0.844 (95%-CI 0.823, 0.863). On average, measurements by the indirect ISE were 1.9mmol/l (95%-CI limits -3.2; 6.9) higher than by the direct ISE method (p<0.001). The tendency of the indirect ISE method resulting in higher levels increased with increasing sodium levels.
Conclusion: Intra-individual sodium levels differ significantly between the indirect and direct ISE method also in the absence of acute illness. It is therefore crucial to adhere to the same method in critical situations to avoid false decisions due to measurement differences.
Laura Dauben, Marie-Christine Simon, Klaus Strassburger, Volker Burkart, Katharina S Weber, Sven Schinner, Michael Roden and Karsten Müssig
Insulinomas are rare pancreatic endocrine tumors characterized by hypoglycemia. Guidelines by the Endocrine Society (ES), the European (ENETS) and the North American (NANETS) Neuroendocrine Tumor Societies provide divergent diagnostic criteria. This study compared the diagnostic accuracy of these different criteria during the 72-h fasting test.
Retrospective cohort study.
From 2000 to 2014, 64 patients with a suspected insulinoma underwent a 72-h fasting test and were included in the analysis. This study assessed the diagnostic sensitivity, specificity and accuracy based on venous blood glucose and corresponding insulin levels measured by electrochemiluminescence immunoassay (ECLIA).
Based on 64 individuals (18 with, 46 without insulinoma), the ES criteria provided a diagnostic sensitivity of 0.94 (0.73–1.00), specificity of 0.89 (0.76–0.96) and accuracy of 0.91 (0.81–0.96). ENETS/NANETS criteria reached a diagnostic sensitivity of 0.78 (0.52–0.94), specificity of 1.00 (0.92–1.00) and accuracy of 0.94 (0.85–0.98).
These results point to a higher diagnostic sensitivity with less specificity for diagnosing insulinoma using ES criteria and a higher specificity at lower sensitivity by using ENETS/NANETS criteria. Before considering these results when applying the different criteria in clinical practice, the results should be confirmed in further studies comprising larger cohorts.
Iulia Potorac, Ashutosh Trehan, Kamila Szymanska, Julie Fudvoye, Albert Thiry, Ilpo T Huhtaniemi, Adrian F Daly, Albert Beckers, Anne-Simone Parent and Adolfo Rivero-Müller
Testosterone production by the fetal testis depends on a functional relationship between hCG and the LH/chorionic gonadotrophin receptor (LHCGR). Failure of the receptor to correctly respond to its ligand leads to impaired sexual differentiation in males.
A phenotypically-female patient with pubertal delay, had a 46,XY karyotype and was diagnosed with 46X,Y disorder of sex development (DSD). Novel compound heterozygous LHCGR mutations were found in the signal peptide: a duplication p.L10_Q17dup of maternal origin, and a deletion (p.K12_L15del) and a p.L16Q missense mutation of paternal origin.
cAMP production was very low for both the deletion and duplication mutations and was halved for the missense mutant. The duplication and missense mutations were both expressed intracellularly, but at very low levels at the cell membrane; they were most likely retained in the endoplasmic reticulum. The deletion mutant had a very limited intracellular expression, indicating impaired biosynthesis. There was reduced expression of all three mutants, which was most marked for the deletion mutation. There was also decreased protein expression of all three mutant receptors. In the deletion mutation, the presence of a lower molecular weight band corresponding to LHCGR monomer, probably due to lack of glycosylation, and a lack of bands corresponding to dimers/oligomers suggests absent ER entry.
This novel case of 46X,Y DSD illustrates how three different LHCGR signal peptide mutations led to complete receptor inactivation by separate mechanisms. The study underlines the importance of specific regions of signal peptides and expands the spectrum of LHCGR mutations.
Selveta Sanne van Santen, Daniel S Olsson, Casper Hammarstrand, Mark Wijnen, Marry M. van den Heuvel - Eibrink, A J Van der Lely, Gudmundur Johannsson, Joseph A.m.j.l. Janssen and Sebastian J. C. M. M. Neggers
Objective: Craniopharyngioma patients often have poor metabolic profiles due to hypothalamic-pituitary damage. Previously, using body mass index (BMI) as obesity marker, the occurrence of the metabolic syndrome in these patients was estimated at 46%. Our aim was to determine if Dual X-ray Absorptiometry (DXA-) scan in evaluation of obesity and metabolic syndrome would be superior.
Design: Retrospective study of craniopharyngioma patients for whom DXA-scan results were available.
Methods: BMI, fat percentage and fat mass index were used to evaluate obesity and as components for obesity in metabolic syndrome.
Results: Ninety-five craniopharyngioma patients were included (51% female, 49% childhood-onset disease). Metabolic syndrome occurred in 34-53 (45-51%) subjects (depending on the definition of obesity, although all definitions occurred in higher frequency than in the general population). Metabolic syndrome frequency was higher if obesity was defined by fat percentage (52% vs. 42%) or fat mass index (51% vs. 43%) compared to BMI. Misclassification appeared in 9% (fat percentage vs. BMI) and 7% (fat mass index vs. BMI) for metabolic syndrome and 29% and 13% for obesity itself, respectively. For metabolic syndrome, almost perfect agreement was found for BMI compared with fat percentage or fat mass index. For obesity, agreement was fair to moderate (BMI vs. fat percentage).
Conclusion: Using BMI to evaluate obesity underestimates the true prevalence of metabolic syndrome in patients with craniopharyngioma. Furthermore, fat percentage contributes to a better evaluation of obesity than BMI. The contribution of DXA-scan might be limited for identification of the metabolic syndrome.
Cristina Eller-Vainicher, Alberto Falchetti, Luigi Gennari, Elisa Cairoli, Francesco Bertoldo, Fabio Vescini, Alfredo Scillitani and Iacopo Chiodini
An underlying disease affecting bone health is present in up to 40 and 60% of osteoporotic postmenopausal women and men respectively. Among the disorders leading to a secondary form of osteoporosis, the endocrine diseases are highly represented. A frequent finding in patients affected with an endocrine-related forms of bone disease is that the skeletal fragility is partially independent of the bone density, since the fracture risk in these patients is related more to a reduction of bone quality than to a decrease of bone mass. As a consequence, bone mineral density evaluation by dual-X-ray absorptiometry may be inadequate for establishing the risk of fracture in the setting of the endocrine-related forms of osteoporosis. In the recent years, several attempts to non-invasively estimating bone quality have been done. Nowadays, some new tools are available in the clinical practice for optimising the fracture risk estimation in patients with endocrine disorders. The aim of this review is to summarise the evidence regarding the role of the different imaging tools for evaluating bone density and bone quality in the most frequent forms of endocrine-related osteoporosis, such as obesity, diabetes, acromegaly, thyrotoxicosis, primary hyperparathyroidism, hypercortisolism and hypogonadism. For each of these disorders, data regarding both the current available tools and the future possible new techniques for assessing bone fragility in patients with endocrine diseases are reported.
Katrine Hygum, Jakob Kau Starup-Linde, Torben Harsløf, Niklas Rye Joergensen, Bolette Hartmann, Jens Juul Holst and Bente Langdahl
Objective: Bone turnover has a diurnal variation influenced by food intake, incretin hormones, the sympathetic nervous system, and osteocyte function. The aim of the study was to compare diurnal variation in bone turnover in patients with diabetes and controls.
Design: A clinical 24-hour study with patients with type 1 diabetes (n=5), patients with type 2 diabetes (n=5), and controls (n=5).
Methods: Inclusion criterion: age >50 years. Exclusion criteria: diseases/medication that affect bone metabolism or recent use of incretin-based drugs. We drew blood samples hourly during the day and every three hours during the night. We served an identical diet on all study days. We used repeated measures one-way analysis of variance to compare the levels of the investigated markers, and we quantified the effect of time by comparing group mean standard deviations.
Results: The bone formation marker procollagen type 1 N-terminal propeptide showed significant interaction between time and group (p=0.01), and the mean standard deviation was lower in patients with type 2 diabetes compared with controls (p=0.04) and patients with type 1 diabetes (p=0.02). Other markers of bone formation and resorption showed significant effect of time. Levels of glucagon-like peptide-2, glucose-dependent insulinotropic peptide, and sclerostin only showed significant effect of time (all p-values 0.01), but levels of sclerostin tended to being highest in type 2 diabetes and lowest in controls.
Conclusions: The diurnal variation in bone formation is attenuated in patients with type 2 diabetes. This is not explained by changes in incretin hormone levels, but possibly mediated by sclerostin.
Mads Lillevang-Johansen, Bo Abrahamsen, Henrik Løvendahl Jørgensen, Thomas Heiberg Brix and Laszlo Hegedüs
To investigate the association between hypothyroidism and cardiovascular disease (CVD) in both treated and untreated hypothyroid patients, and the consequences of over- and under-treatment with respect to cardiovascular risk.
A registry-based case–control study nested within a population-based cohort of 275 467 individuals with at least one serum thyroid stimulating hormone (TSH) measurement in the period of 1995–2011.
Incident cases of CVD were matched with controls according to gender, age and year of birth. Conditional logistic regression analyses were performed to calculate CVD risks associated with exposure to hypothyroidism, with adjustment for 19 pre-existing comorbidities, including cardiovascular disease and diabetes, using the Charlson Comorbidity Index.
Overall, 20 487 individuals experienced CVD (9.4%, incidence rate 13.1 per 1000 person-years, 95% confidence interval (CI), 13.0–13.3). Risk of CVD was increased in untreated hypothyroidism compared to euthyroidism (odds ratio (OR): 1.83 (95% CI: 1.43–2.35; P < 0.001)). Cardiovascular risk was increased in both treated and untreated hypothyroid individuals per half year of elevated TSH (OR: 1.11 (95% CI: 1.06–1.16; P < 0.001) and OR: 1.15 (95% CI: 1.09–1.23; P = 0.001), respectively). In patients treated with levothyroxine, OR for CVD was 1.12 (95% CI: 1.06–1.18; P < 0.001) for each 6 months of decreased TSH.
Cardiovascular risk is increased in untreated, but not in treated hypothyroid patients. Among those with treated hypothyroidism, duration of decreased TSH (overtreatment) had a similar impact on cardiovascular risk as duration of elevated TSH (under-treatment), highlighting the importance of initiating treatment and maintaining biochemical euthyroidism in hypothyroid patients in order to reduce the risk of CVD and death.