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Andrea Lamprecht, Jane Sorbello, Christina Jang, David J Torpy and Warrick J Inder

Objective

To evaluate pituitary function, sexual function and quality of life (QoL) in patients on oral or transdermal opioids.

Design and methods

Cross-sectional study comparing pituitary function, QoL and sexual function in people on long-term opioid therapy (n = 40) vs an age- and sex-matched control group (n = 25). Baseline pituitary function was assessed on blood samples collected prior to 0900 h. Further testing with corticotropin (250 µg IV) and metyrapone (30 mg/kg) stimulation tests was undertaken on participants with serum cortisol <250 nmol/L. Validated questionnaires completed to assess QoL, fatigue and sexual function.

Results

Secondary adrenal insufficiency (SAI) was identified on the basis of a failed stimulation test in 22.5% of opioid users vs no controls (P = 0.01). Opioid users with SAI had a higher median morphine-equivalent daily dose (MEDD), P = 0.037 – 50% with MEDD >200 mg and 0% with MEDD <60 mg had SAI. Among male participants, testosterone was inversely associated with BMI (P = 0.001) but not opioid use. A non-significant trend to low testosterone <8 nmol/L in male opioid users (11/24 opioid users vs 2/14 control, P = 0.08) suggests a small subgroup with opioid-induced androgen deficiency. Opioid users had greater fatigue, reduced quality of life in all subsections of the SF-36 and impaired sexual function in both males and females (all scores P < 0.001 compared to controls).

Conclusion

Long-term opioid therapy was associated with dose-related SAI in over 20% of chronic pain patients and is associated with poor quality of life, fatigue and sexual dysfunction. Obesity confounds the interpretation of opioid-induced male androgen deficiency.

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F Maurice, A Dutour, C Vincentelli, I Abdesselam, M Bernard, H Dufour, Y Lefur, T Graillon, F Kober, P Cristofari, E Jouve, L Pini, R Fernandez, C Chagnaud, T Brue, F Castinetti and B Gaborit

Objective

Glucocorticoid excess is one of the most important causes of bone disorders. Bone marrow fat (BMF) has been identified as a new mediator of bone metabolism. Cushing syndrome (CS) is a main regulator of adipose tissue distribution but its impact on BMF is unknown. The objective of the study was to evaluate the effect of chronic hypercortisolism on BMF.

Design

This was a cross-sectional study. Seventeen active and 17 cured ACTH-dependent CS patients along with 17 controls (matched with the active group for age and sex) were included.

Methods

The BMF content of the femoral neck and L3 vertebrae were measured by 1H-MRS on a 3-Tesla wide-bore magnet. Bone mineral density (BMD) was evaluated in patients using dual-energy X-ray absorptiometry.

Results

Active CS patients had higher BMF content both in the femur (82.5 ± 2.6%) and vertebrae (70.1 ± 5.1%) compared to the controls (70.8 ± 3.6%, P = 0.013 and 49.0 ± 3.7% P = 0.005, respectively). In cured CS patients (average remission time of 43 months), BMF content was not different from controls at both sites (72.3 ± 2.9% (femur) and 46.7% ± 5.3% (L3)). BMF content was positively correlated with age, fasting plasma glucose, HbA1c, triglycerides and visceral adipose tissue in the whole cohort and negatively correlated with BMD values in the CS patients.

Conclusions

Accumulation of BMF is induced by hypercortisolism. In remission patients, BMF reached values of controls. Further studies are needed to determine whether this increase in marrow adiposity in CS is associated with bone loss.

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Henry B Burch and David S Cooper

The thionamide antithyroid drugs were discovered in large part following serendipitous observations by a number of investigators in the 1940s who found that sulfhydryl-containing compounds were goitrogenic in animals. This prompted Prof. Edwin B Astwood to pioneer the use of these compounds to treat hyperthyroidism in the early 1940s and to develop the more potent and less toxic drugs that are used today. Despite their simple molecular structure and ease of use, many uncertainties remain, including their mechanism(s) of action, clinical role, optimal use in pregnancy and the prediction and prevention of rare but potentially life-threatening adverse reactions. In this review, we summarize the history of the development of these drugs and outline their current role in the clinical management of patients with hyperthyroidism.

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Nicolas C Nicolaides and George P Chrousos

Glucocorticoids signal through their cognate, ubiquitously expressed glucocorticoid receptor (GR), which influences the transcription of a large number of target genes. Several genetic defects, including point mutations, deletions or insertions in the NR3C1 gene that encodes the GR, have been associated with familial or sporadic generalized glucocorticoid resistance or Chrousos syndrome. One of the clinical manifestations of this rare endocrine condition is bilateral adrenal hyperplasia due to compensatory elevations of plasma ACTH concentrations. In this commentary, we discuss the interesting findings of the recently published French MUTA-GR study and present our perspective on the evolving field of NR3C1 pathology.

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Ammar Muhammad, Eva C Coopmans, Patric J D Delhanty, Alof H G Dallenga, Iain K Haitsma, Joseph A M J L Janssen, Aart J van der Lely and Sebastian J C M M Neggers

Objective

To assess the efficacy and safety after 48 weeks of treatment with pasireotide long-acting-release (PAS-LAR) alone or in combination with pegvisomant in patients with acromegaly. In addition, we assessed the relation between insulin secretion and pasireotide-induced hyperglycemia.

Design

The PAPE extension study is a prospective follow-up study until 48 weeks after the core study of 24 weeks.

Methods

Fifty-nine out of 61 patients entered the extension study. Efficacy was defined as the percentage of patients achieving IGF-I normalization (≤1.2× the upper limit of normal (ULN)) at 48 weeks through protocol-based adjustment of pegvisomant and PAS-LAR doses. At baseline, insulin secretion was assessed by an oral glucose tolerance test (OGTT).

Results

At the end of the study, median IGF-I was 0.98× ULN, and 77% of patients achieved normal IGF-I levels with a mean pegvisomant dose of 64 mg/week, and an overall cumulative pegvisomant dose reduction of 52%. Frequency of diabetes mellitus increased from 68% at 24 weeks to 77% at 48 weeks, and nine patients discontinued PAS-LAR treatment, mainly because of severe hyperglycemia. Pasireotide-induced hyperglycemia was inversely correlated with baseline insulin secretion (r = −0.37, P < 0.005).

Conclusions

PAS-LAR normalizes IGF-I levels in most acromegaly patients, with a 50% pegvisomant-sparing effect. However, PAS-LAR treatment coincided with a high incidence of diabetes mellitus. The risk for developing diabetes during PAS-LAR treatment seems inversely related to insulin secretion at baseline.

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U Arshad, M Taubert, M Kurlbaum, S Frechen, S Herterich, F Megerle, S Hamacher, M Fassnacht, U Fuhr and M Kroiss

Objective

Mitotane is used for the treatment of adrenocortical carcinoma. High oral daily doses of typically 1–6 g are required to attain therapeutic concentrations. The drug has a narrow therapeutic index and patient management is difficult because of a high volume of distribution, very long elimination half-life and drug interaction through induction of metabolizing enzymes. The present evaluation aimed at the development of a population pharmacokinetic model of mitotane to facilitate therapeutic drug monitoring (TDM).

Methods

Appropriate dosing information, plasma concentrations (1137 data points) and covariates were available from TDM of 76 adrenocortical carcinoma patients treated with mitotane. Using nonlinear mixed-effects modeling, a simple structural model was first developed, with subsequent introduction of metabolic autoinduction. Covariate data were analyzed to improve overall model predictability. Simulations were performed to assess the attainment of therapeutic concentrations with clinical dosing schedules.

Results

A one-compartment pharmacokinetic model with first order absorption was found suitable to describe the data, with an estimated central volume of distribution of 6086 L related to a high interindividual variability of 81.5%. Increase in clearance of mitotane during treatment could be modeled by a linear enzyme autoinduction process. BMI was found to have an influence upon disposition kinetics of mitotane. Model simulations favor a high-dose regimen to rapidly attain therapeutic concentrations, with the first TDM suggested on day 16 of treatment to avoid systemic toxicity.

Conclusion

The proposed model describes mitotane pharmacokinetics and can be used to facilitate therapy by predicting plasma concentrations.

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Leo Niskanen, Timo Partonen, Anssi Auvinen and Jari Haukka

Aims

To characterize the burden of external causes of death attributable to alcohol-related causes, accidents and suicide among diabetic patients in a large national cohort.

Methods

The population included diabetic individuals who had purchased and received reimbursement for at least one insulin prescription and/or one oral antidiabetic drug prescription between January 1997 and December 2010, and a non-diabetic reference population matched by sex, age and area. All new insulin users in this period were included, as well as 50% of new oral drug (OAD) users as a random sample. The data were collected by means of linkage from national registries. We analyzed the cohort data using Poisson regression models separately for each end-point and by gender (mortality rate ratio (MRR)). We subjected the case-cohort data to conditional logistic regression analysis based on exposure information within 1 year of the end-point event. The follow-up started on the date of the first diabetes medication prescription and ended on 31 December 2012 or on the date of death.

Results

The study population comprised 434 629 individuals (226 372 men; diabetes population: 208 148 subjects, of whom 76% were treated only with OAD). The mean follow-up time was 7.1 years, during which there were 2832 deaths attributable to alcohol, 3187 to accidents and 853 to suicide. The diabetic subjects had higher mortality at almost all end-points, especially those treated with insulin: the adjusted MRRs for alcohol-related deaths were 1.71 for diabetic men treated with OAD and 6.92 for those on insulin; the respective MRRs for diabetic women were 2.10 and 10.60. There were more accident-related deaths among those treated with insulin (MRRs: 2.06 and 1.53 for men and women, respectively), and more suicides (MRR: 2.10 for men treated with insulin and 1.62 among women treated only with OAD). The results from the cohort study and the case-cohort study were rather similar. A time-dependent effect of diabetes was observed in alcohol-related mortality among men.

Conclusions

The findings from this large nationwide cohort indicate higher mortality attributable to suicide, alcohol-related causes and accidents among diabetic patients than among the non-diabetic population. The results emphasize the importance of effective psychosocial interventions among high-risk diabetic patients.

Free access

Monica Marazuela, Ana M Ramos-Leví, Patricia Borges de Souza and Maria Chiara Zatelli

Medical treatment of pituitary tumours may present important challenges in the presence of resistance to first-line therapy. In this setting, the availability of specific markers of responsiveness/resistance could be helpful to provide tailored patients’ treatment. Pituitary receptor profiling has emerged as a potentially useful tool for predicting the response to specific pituitary-directed medical therapy, mainly somatostatin analogues and dopamine agonists. However, its utility is not always straightforward. In fact, agonist-receptor coupling to the consequent biological response is complex and sometimes jeopardizes the understanding of the molecular basis of pharmacological resistance. Defective expression of pituitary receptors, genetic alterations, truncated variants, impaired signal transduction or involvement of other proteins, such as cytoskeleton proteins or the aryl hydrocarbon receptor-interacting protein amongst others, have been linked to differential tumour phenotype or treatment responsiveness with conflicting results, keeping the debate on the utility of pituitary receptor profiling open. Why does this occur? How can we overcome the difficulties? Is there a true role for pituitary receptor profiling in the near future? All authors of this debate article agree on the need of prospective studies using standardized methods in order to assess the efficacy of receptor profiling as a reliable clinical predictive factor.

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Svenja Boekhoff, Agnieszka Bogusz, Anthe S Sterkenburg, Maria Eveslage and Hermann L Müller

Objective

Quality of survival, prognosis and long-term outcome are often severely impaired in childhood-onset craniopharyngioma (CP) patients. Identification of risk factors for sequelae such as growth hormone (GH) deficiency is important for appropriate treatment and rehabilitation.

Design

In a cross-sectional study, 79 CP patients recruited in HIT-Endo before 2000 were analyzed according to GH substitution: (a) CP never GH treated (noGH); (b) CP GH treated only during childhood (pedGH); (c) CP under GH, initiated at adulthood (adultGH); (d) CP under GH during childhood and continued during adulthood (contGH).

Methods

Progression-free (PFS) and overall survival (OS), height, BMI, psychosocial and neuropsychological status (EORTC QLQ-C30, MFI-20).

Results

OS and PFS rates were similar in all subgroups. ContGH and pedGH CP presented with increases in height (P = 0.002; P = 0.0001) during long-term follow-up when compared with baseline. In all subgroups except for pedGH, increases in BMI were observed when compared with BMI at diagnosis. For emotional functionality and physical fatigue, adultGH CP showed worse (P = 0.037; P = 0.034) response (mean: 61.4%; 12.5%) when compared with pedGH CP (mean: 83.5%; 7.7%). Observed differences were not related to irradiation and hypothalamic involvement. In terms of psychosocial status, no differences were observed between subgroups.

Conclusions

We conclude that GH substitution was safe with regard to risk of tumor progression/relapse in CP. Growth was improved by GH, whereas the development of obesity was not influenced by GH substitution. However, early initiation of GH substitution after CP diagnosis might have beneficial effects on weight development and neuropsychological outcome.

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L Martinerie, A Condat, A Bargiacchi, C Bremont-Weill, M C de Vries and S E Hannema

Over the past 20 years, the care for transgender adolescents has developed throughout many countries following the ‘Dutch Approach’ initiated in the 90s in pioneer countries as the Netherlands, United States and Canada, with increasing numbers of children and adolescents seeking care in transgender clinics. This medical approach has considerable positive impacts on the psychological outcomes of these adolescents, and several studies have been recently published underlining the relative safety of such treatments. This paper reviews the current standards of care for transgender children and adolescents with particular emphasis on disparities among countries and short-to-medium-term outcomes. Finally, it highlights ethical considerations regarding categorization of gender dysphoria, timing of treatment initiation, infertility and how to deal with the long-term consequences.