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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.

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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.

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P R Ebeling, R A Adler, G Jones, U A Liberman, G Mazziotti, S Minisola, C F Munns, N Napoli, A G Pittas, A Giustina, J P Bilezikian and R Rizzoli

Objective

The central role of vitamin D in bone health is well recognized. However, controversies regarding its clinical application remain. We therefore aimed to review the definition of hypovitaminosis D, the skeletal and extra-skeletal effects of vitamin D and the available therapeutic modalities.

Design

Narrative and systematic literature review.

Methods

An international working group that reviewed the current evidence linking bone and extra-skeletal health and vitamin D therapy to identify knowledge gaps for future research.

Results

Findings from observational studies and randomized controlled trials (RCTs) in vitamin D deficiency are discordant, with findings of RCTs being largely negative. This may be due to reverse causality with the illness itself contributing to low vitamin D levels. The results of many RCTs have also been inconsistent. However, overall evidence from RCTs shows vitamin D reduces fractures (when administered with calcium) in the institutionalized elderly. Although controversial, vitamin D reduces acute respiratory tract infections (if not given as bolus monthly or annual doses) and may reduce falls in those with the lowest serum 25-hydroxyvitamin D (25OHD) levels. However, despite large ongoing RCTs with 21 000–26 000 participants not recruiting based on baseline 25OHD levels, they will contain a large subset of participants with vitamin D deficiency and are adequately powered to meet their primary end-points.

Conclusions

The effects of long-term vitamin D supplementation on non-skeletal outcomes, such as type 2 diabetes mellitus (T2DM), cancer and cardiovascular disease (CVD) and the optimal dose and serum 25OHD level that balances extra-skeletal benefits (T2DM) vs risks (e.g. CVD), may soon be determined by data from large RCTs.

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A German, M Shmoish, J Belsky and Z Hochberg

Background

The relationship between pubertal onset and tempo and pubertal growth is controversial. We hypothesized that the age at onset of girls’ puberty predicts pubertal tempo and the rate of pubertal progression.

Methods

We analyzed the data of 380 girls from the prospective Study of Early Child Care and Youth Development (SECCYD) who were recruited in the USA from 1991 to 2006 and followed from birth to age 15.5 years. We used the following indicators: thelarche age (Tanner stage B2), pubarche age (P2), menarche age (M), the age when breast (B5) and pubic hair (P5) became fully mature, pubertal growth, pubertal duration (time from B2 to B5) and pubertal progression (time from B2 to M). We clustered the girls according to B2 age into early onset (EO; <9.4 years), intermediate (IO; 9.4–10.5 years), late onset (LO; >10.5 years).

Results

All indicators of pubertal onset and conclusion occurred earlier in the EOs than in the LOs; yet, the differences in the age at main pubertal milestones lessened as puberty progressed: 2 years for B2; −1.4 years for M; −1 year for B5. In EOs, puberty was 1 year (average) longer than in LOs. Although EOs grew 7 cm (average) more than LOs, their heights at B5 were comparable. There was a significant relationship between the thelarche age and puberty tempo (r = 0.23, P < 0.0001).

Conclusions

The study highlights the predictive nature of variation in the onset age of puberty on its progression and duration. These results are reassuring in this context and will add to clinicians’ and parental understanding of the expected milestones of puberty.

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Michelle Henry, Ian Louis Ross and Kevin Garth Flusk Thomas

Objectives

Cortisol plays a key role in initiating and maintaining different sleep stages. Patients with Addison’s disease (AD) frequently report disrupted sleep, and their hydrocortisone medication regimes do not restore the natural diurnal rhythm of cortisol. However, few studies have investigated relations between sleep quality, especially as measured by polysomnographic equipment, and night-time cortisol concentrations in patients with AD.

Methods

We used sleep-adapted EEG to monitor a full night of sleep in seven patients with AD and seven healthy controls. We sampled salivary cortisol before bedtime, at midnight, upon awakening and at 30 min post waking.

Results

Controls had lower cortisol concentrations than patients before bedtime and at midnight. During the second half of the night, patient cortisol concentrations declined steeply, while control concentrations increased steadily. Whereas most controls experienced a positive cortisol awakening response, all patients experienced a decrease in cortisol concentrations from waking to 30 min post waking (P = 0.003). Patients experienced significantly lower proportions of slow-wave sleep (SWS; P = 0.001), which was associated with elevated night-time cortisol concentrations.

Conclusion

Overall, these results suggest that patients with AD demonstrate different patterns of night-time cortisol concentrations to healthy controls and that relatively elevated concentrations are associated with a reduction of SWS. These hormonal and sleep architectural aberrations may disrupt the routine sleep-dependent processes of memory consolidation, and hence, may explain, at least partially, the memory impairments often experienced by patients with AD.

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Marine Ollivier, Magalie Haissaguerre, Amandine Ferriere and Antoine Tabarin