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Open access

Marcus Quinkler, Robert D Murray, Pinggao Zhang, Claudio Marelli, Robert Petermann, Andrea M. Isidori, and Bertil Ekman

Objective: This study aimed to characterize the clinical and biochemical features of patients with primary (PAI) and secondary (SAI) adrenal insufficiency who developed adrenal crises (ACs) and estimate the incidence of ACs in these patients.

Design: Retrospective case-control analysis of the European Adrenal Insufficiency Registry (EU-AIR; NCT01661387).

Methods: 2694 patients with AI (1054 PAI; 1640 SAI) enrolled in EU-AIR. Patients who developed ≥1 AC were matched 1:3 with patients without ACs for age, sex and AI type. Data were collected at baseline and follow-up (mean±SD: PAI 3.2±1.7 years; SAI 2.9±1.7 years).

Results: 148/2694 patients (5.5%; n=84 PAI; n=64 SAI) had an AC during the study: 6.53 (PAI) and 3.17 (SAI) ACs/100 patient-years. Of patients who experienced an AC, 16% (PAI) and 9.4% (SAI) experienced ≥1 AC/year. The incidence of adverse events, infectious intercurrent illnesses and infectious serious adverse events were higher in patients with ACs than without ACs.

No differences were observed in BMI, HbA1c, blood pressure and frequencies of diabetes mellitus or hypertension between subgroups (PAI and SAI, with and without ACs). At baseline, PAI patients with AC had higher serum potassium (4.3±0.5 vs 4.2±0.4mmol/L; P=0.03) and lower sodium (138.5±3.4 vs 139.7±2.9mmol/L; P=0.004) than patients without AC. At last observation, SAI patients with AC had higher hydrocortisone doses than patients without AC (11.9±5.1 vs 10.1±2.9mg/m2; P<0.001).

Conclusions: These results demonstrate that concomitant diseases and cardiovascular risk factors do not feature in the risk profile of AC; however, patients with AC had a higher incidence of infectious events.

Free access

Helene Holmer, Bertil Ekman, Jonas Björk, Carl-Henrik Nordstöm, Vera Popovic, AnnBritt Siversson, and Eva-Marie Erfurth

Context

Craniopharyngioma patients without GH therapy are at an increased cardiovascular disease (CVD) risk and particularly concerning women. No previous study on long-term GH therapy in adults with childhood onset (CO) craniopharyngioma was identified.

Objective

To investigate CVD risk in adults with CO craniopharyngioma on complete hormone replacement, including long-term GH therapy, and to investigate the impact of disease-related factors on CVD risk.

Design and participants

In a cross-sectional study of operated CO craniopharyngiomas (1958–2000) from a defined area of Sweden (2.5 million), we enrolled 42 patients (20 women) with a median age of 28 years (range 17–57) and assessed CVD risk of 20 (4–40) years after first operation. Comparisons were made with matched controls and between patients with tumor growth into the third ventricle (TGTV) versus non-TGTV. GH therapy was 10–12 years in women and men.

Results

In comparison with controls, both male and female patients had increased body mass index, fat mass, insulin, and leptin levels. Overall, while not significantly increased in male patients, 55–60% of female patients had a medium–high CVD risk, compared with 10–20% in controls. An increased CVD risk (all P<0.05) and higher levels of fat mass and insulin were recorded in the TGTV group versus the non-TGTV group. Late puberty induction and lack of androgens were shown in female patients.

Conclusions

Adult patients with CO craniopharyngioma, especially those with TGTV, have persistently increased CVD risk. Conventional hormone substitution, including GH, is insufficient to normalize CVD risk, suggesting an important role for irreversible hypothalamic dysfunction.

Free access

Helene Holmer, Vera Popovic, Bertil Ekman, Cecilia Follin, Ann Britt Siversson, and Eva Marie Erfurth

Context

Data on bone mineral density (BMD) are lacking in adults with childhood onset (CO)–craniopharyngioma (CP) with hypothalamic damage from the tumor. In patients with CO GH deficiency, BMD increases during GH treatment.

Objective

The aims were to evaluate BMD in adults with CO–CPs on complete hormone replacement, including long-term GH and to evaluate the impact of hypothalamic damage on these measures.

Design and participants

BMD (dual-energy X-ray absorptiometry), markers of bone turn over, physical activity and calcium intake were assessed in 39 CO–CP adults (20 women), with a median age of 28 (17–57) years, in comparison with matched population controls.

Results

Late puberty induction was recorded in both genders, but reduced androgen levels in females only. Only CP women had lower BMD (P=0.03) at L2–L4, and reduced Z-scores at femoral neck (P=0.004) and L2–L4 (P=0.004). Both genders had increased serum leptin levels (P=0.001), which significantly correlated negatively with BMD at L2–L4 (P=0.003; r=−0.5) and 45% of CP women had Z-score levels ≤−2.0 s.d. Furthermore, 75% of those with a Z-score ≤−2.0 s.d. had hypothalamic involvement by the tumor. Calcium intake (P=0.008) and physical activity (P=0.007) levels were reduced in CP men only. Levels of ostecalcin and crossLaps were increased in CP men only.

Conclusions

Despite continuous GH therapy, low BMD was recorded in CO–CP females. Insufficient estrogen and androgen supplementation during adolescence was the main cause, but hypothalamic involvement with consequent leptin resistance was also strongly associated with low BMD in both genders.

Free access

Pia Burman, Britt Edén-Engström, Bertil Ekman, F Anders Karlsson, Erik Schwarcz, and Jeanette Wahlberg

Context and objective

The role of cabergoline in Cushing's disease (CD) remains controversial. The experience is limited to case reports and few open studies that report the effects determined after ≥1 month of treatment. In prolactinomas and dopamine-responsive GH-secreting tumours, effects of cabergoline are seen within days or weeks. Here, we searched for short-term effects of cabergoline in CD.

Design

Twenty patients (19 naïve and one recurrent) were included in a prospective study. Cabergoline was administered in increasing doses of 0.5–5 mg/week over 6 weeks.

Methods

Urinary free cortisol (UFC) 24 h, morning cortisol and ACTH, and salivary cortisol at 0800, 1600 and 2300 h were determined once weekly throughout. Diurnal curves (six samples) of serum cortisol were measured at start and end.

Results

At study end, the median cabergoline dose was 5 mg, range 2.5–5 mg/week. The prolactin levels, markers of compliance, were suppressed in all patients. During the treatment, hypercortisolism varied, gradual and dose-dependent reductions were not seen. Five patients had a >50% decrease of UFC, three had a >50% rise of UFC. Salivary cortisol at 2300 h showed a congruent >50% change with UFC in two of the five cases with decreased UFC, and in one of the three cases with increased UFC. One patient with decreases in both UFC and 2300 h salivary cortisol also had a reduction in diurnal serum cortisol during the course of the study.

Conclusions

Cabergoline seems to be of little value in the management of CD. Only one patient had a response-like pattern. Given the known variability of disease activity in CD, this might represent a chance finding.

Restricted access

Fredrik H Nyström, Peter K Öhman, Bertil Å Ekman, Maria K Österlund, Bengt E Karlberg, and Hans J Arnqvist

Abstract

Population-based reference values for IGF-I and IGF-binding protein-1 (IGFBP-1) have been established. One hundred and one women and the same number of men, 20–70 years old, were randomly selected from the population registry in the community of Linköping. Participation rate was 67%. Venous blood was drawn in the fasting state. Serum IGF-I was measured by RIA after acid-ethanol extraction and IGFBP-1 was determined by ELISA. IGF-I levels did not differ between genders and the decline with age was similar in men and women (men: Y=366–3·28×age (years), r =−0·61, P<0·0001; women: Y=386–3·49×age, r =−0·57, P<0·0001, P=0·4 for difference in slope). There were negative correlations between IGF-I and plasma lipids and blood pressure in both genders, but none was independent of age. Serum angiotensin-converting enzyme activity correlated positively with IGF-I in men independently from age (r =0·21, P=0·01). The distribution of IGFBP-1 was positively skewed and it was higher in women than in men (5·9±4·8 μg/l and 4·0±3·3 μg/l respectively; Mann–Whitney, P=0·002). In men and in the women not taking oestrogen, IGFBP-1 correlated positively with age (Spearman rank correlation (Spearman): men: r=0·32, P=0·002; women: r=0·24, P=0·03). C-peptide correlated negatively (Spearman: men: r =−0·38, P=0·002; women: r =−0·49, P<0·000) and sex hormone binding globulin positively with IGFBP-1 (Spearman: men: r=0·50, P<0·0001; women: r =0·55, P<0·0001).

IGF-I declined with age while IGFBP-1, which is considered to modulate the free bioactive fraction of IGF-I, increased. This suggests that IGF-I activity might be even lower in elderly subjects than is accounted for by the low total IGF-I.

European Journal of Endocrinology 136 165–172

Free access

Philippe Touraine, Gwyn A D'Souza, Ione Kourides, Roger Abs, Paul Barclay, Rujia Xie, Antonio Pico, Elena Torres-Vela, and Bertil Ekman

Objective

Changes observed during adult GH deficiency (GHD) are most often reversed with the administration of recombinant human GH (rhGH). To avoid daily injections, a long-acting GH molecule has been obtained by covalent binding of polyethylene glycol (PEG) with rhGH (PEG–GH), allowing weekly s.c. injections. This study was designed to assess its efficacy and safety, in adult GHD subjects.

Design and methods

This was a randomized, double-blind, placebo-controlled, multiple-dose, parallel group study. Subjects were recruited from 34 centers. A total of 105 subjects with GHD were assigned a treatment. They received 6 weekly injections of either PEG–GH or placebo. Subjects were randomized into one out of four treatment groups (Groups A–D) or placebo (Group E). Groups A, B, and C received 1, 3, and 4 mg PEG–GH respectively, for the first 3 weeks followed by 2, 6, and 8 mg PEG–GH respectively, for the remaining 3 weeks. Group D received 4 mg PEG–GH for 6 weeks. Group E received placebo. The study was suspended because of the development of lipoatrophy in certain subjects and restarted with an injection rotation plan, before being terminated due to further subjects developing lipoatrophy.

Results

A total of 13 cases of injection-site lipoatrophy were reported, of which ten were in females and three occurred after the first injection; all cases were independent of PEG–GH dose or IGF1 levels, either basal or under treatment.

Conclusion

The unpredictable occurrence of injection-site lipoatrophy with weekly long-acting pegylated GH molecules may be a limiting factor for their development.

Open access

Anna G Nilsson, Ragnhildur Bergthorsdottir, Pia Burman, Per Dahlqvist, Bertil Ekman, Britt Edén Engström, Oskar Ragnarsson, Stanko Skrtic, Jeanette Wahlberg, Heinrich Achenbach, Sharif Uddin, Claudio Marelli, and Gudmundur Johannsson

Objective

To investigate the long-term safety and tolerability of a once-daily, dual-release hydrocortisone (DR-HC) tablet as oral glucocorticoid replacement therapy in patients with primary adrenal insufficiency (AI).

Design

Prospective, open-label, multicenter, 5-year extension study of DR-HC conducted at five university clinics in Sweden.

Methods

Seventy-one adult patients diagnosed with primary AI who were receiving stable glucocorticoid replacement therapy were recruited. Safety and tolerability outcomes included adverse events (AEs), intercurrent illness episodes, laboratory parameters and vital signs. Quality of life (QoL) was evaluated using generic questionnaires.

Results

Total DR-HC exposure was 328 patient-treatment years. Seventy patients reported 1060 AEs (323 per 100 patient-years); 85% were considered unrelated to DR-HC by the investigator. The most common AEs were nasopharyngitis (70%), fatigue (52%) and gastroenteritis (48%). Of 65 serious AEs reported by 32 patients (20 per 100 patient-years), four were considered to be possibly related to DR-HC: acute AI (n = 2), gastritis (n = 1) and syncope (n = 1). Two deaths were reported (fall from height and subarachnoid hemorrhage), both considered to be unrelated to DR-HC. From baseline to 5 years, intercurrent illness episodes remained relatively stable (mean 2.6–5.4 episodes per patient per year), fasting plasma glucose (0.7 mmol/L; P < 0.0001) and HDL cholesterol (0.2 mmol/L; P < 0.0001) increased and patient-/investigator-assessed tolerability improved. QoL total scores were unchanged but worsening physical functioning was recorded (P = 0.008).

Conclusions

In the first prospective study evaluating the long-term safety of glucocorticoid replacement therapy in patients with primary AI, DR-HC was well tolerated with no safety concerns observed during 5-year treatment.