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Open access

Ashley Grossman, Gudmundur Johannsson, Marcus Quinkler and Pierre Zelissen

Background

Conventional glucocorticoid (GC) replacement for patients with adrenal insufficiency (AI) is inadequate. Patients with AI continue to have increased mortality and morbidity and compromised quality of life despite treatment and monitoring.

Objectives

i) To review current management of AI and the unmet medical need based on literature and treatment experience and ii) to offer practical advice for managing AI in specific clinical situations.

Methods

The review considers the most urgent questions endocrinologists face in managing AI and presents generalised patient cases with suggested strategies for treatment.

Results

Optimisation and individualisation of GC replacement remain a challenge because available therapies do not mimic physiological cortisol patterns. While increased mortality and morbidity appear related to inadequate GC replacement, there are no objective measures to guide dose selection and optimisation. Physicians must rely on experience to recognise the clinical signs, which are not unique to AI, of inadequate treatment. The increased demand for corticosteroids during periods of stress can result in a life-threatening adrenal crisis (AC) in a patient with AI. Education is paramount for patients and their caregivers to anticipate, recognise and provide proper early treatment to prevent or reduce the occurrence of ACs.

Conclusions

This review highlights and offers suggestions to address the challenges endocrinologists encounter in treating patients with AI. New preparations are being developed to better mimic normal physiological cortisol levels with convenient, once-daily dosing which may improve treatment outcomes.

Free access

Tina Kienitz, Marcus Quinkler, Christian J Strasburger and Manfred Ventz

Objective: TSH-secreting pituitary tumors (TSH-omas) are a rare cause of hyperthyroidism and account for <1% of all pituitary adenomas. Failure to recognize the presence of a TSH-oma may result in dramatic consequences such as thyroid ablation that may cause further growth in pituitary tumor. The primary goal of the treatment of TSH-omas is to remove the pituitary tumor. Medical treatment includes dopaminergic agonists or somatostatin analogs.

Methods and results: We report five cases of TSH-oma diagnosed between 1997 and 2006 and review the literature. All the patients are females with an age range from 54 to 65 years at diagnosis. Four of the five patients had at least one event of thyroid surgery due to goiter or nodule of unknown dignity. Three of the five patients had a stroke before the diagnosis of TSH-oma, probably due to hypertension, or smoking and contraceptive treatment. One patient with invasive tumor growth received stereotactic radiotherapy (and developed panhypopituitarism after operation), another patient received somatostatin analogs preoperatively and successfully underwent transsphenoidal operation. Three of the five patients received dopaminergic agonists (bromocriptine 5 mg daily or cabergoline 0.5–0.75 mg per week), because they refused surgical therapy or the tumor was stable under dopaminergic therapy. All patients have been followed-up for 2.5–8 years. A normalization of circulating thyroid hormone levels was achieved in all patients. The patient who underwent operation shows no recurrence of the disease. The other patients have a stable pituitary mass without signs of growth.

Conclusion: We report the successful long-term treatment of TSH-omas with different therapies.

Free access

Marcus Quinkler, Roy Miodini Nilsen, Kathrin Zopf, Manfred Ventz and Marianne Øksnes

Objective

Patients with adrenal insufficiency (AI) have impaired health-related quality of life (HRQoL), which is thought to be in part due to unphysiological glucocorticoid replacement therapy. The aim was to compare once-daily hydrocortisone (HC) dual-release tablet (modified-release) with conventional HC therapy regarding clinical data and HRQoL.

Design and methods

We conducted an open, prospective trial at one endocrine center. There were 15 of 26 patients with primary AI, nine of 18 patients with secondary AI, and six congenital adrenal hyperplasia patients switched to modified-release HC therapy by their own decision. We evaluated clinical outcome and disease-specific HRQoL by using AddiQoL questionnaire at baseline and at follow-up (median 202 days (85–498)).

Results

Patients on modified-release HC (n=30) showed significant decreases in BMI (26.0±0.75–25.6±0.71, P for change=0.006) and HbA1c (6.04±0.29–5.86±0.28, P for change=0.005), whereas patients remaining on conventional HC (n=20) showed no change in these parameters (P for interaction=0.029 and 0.017 respectively). No significant change in AddiQoL score were found in the modified-release HC group (83.8 baseline and 84.9 at follow-up; P for change=0.629). In the conventional HC group, there was a significant decrease in scores (84.0 baseline and 80.9 at follow-up; P for change=0.016), with a between-treatment P for interaction of 0.066. The fatigue subscore of AddiQoL showed the same pattern with a significant decrease (P for change=0.024) in patients on conventional HC therapy (P for interaction=0.116).

Conclusions

Modified-release HC decreases BMI and HbA1c compared with conventional HC treatment. In addition, it seems to stabilize HRQoL over time.

Free access

Julia Schulz, Kathrin R Frey, Mark S Cooper, Kathrin Zopf, Manfred Ventz, Sven Diederich and Marcus Quinkler

Objective

Individuals with primary adrenal insufficiency (PAI) or congenital adrenal hyperplasia (CAH) receive life-long glucocorticoid (GC) replacement therapy. Current daily GC doses are still higher than the reported adrenal cortisol production rate. This GC excess could result in long-term morbidities such as osteoporosis. No prospective trials have investigated the long-term effect of GC dose changes in PAI and CAH patients.

Methods

This is a prospective and longitudinal study including 57 subjects with PAI (42 women) and 33 with CAH (21 women). Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry at baseline and after 2 years. Subjects were divided into three groups (similar baseline characteristics) depending on changes in daily hydrocortisone equivalent dose (group 1: unchanged 25.2±8.2 mg (mean±s.d., n=50); group 2: increased 18.7±10.3 to 25.9±12.0 mg (n=13); group 3: decreased 30.8±8.5 to 21.4±7.2 mg (n=27)).

Results

Subjects in group 1 showed normal lumbar and femoral Z-scores which were unchanged over time. Group 2 subjects showed a significant decrease in femoral neck Z-scores over time (−0.15±1.1 to −0.37±1.0 (P<0.05)), whereas group 3 subjects showed a significant increase in lumbar spine and hip Z-scores (L1–L4: −0.93±1.2 to –0.65±1.5 (P<0.05); total hip: −0.40±1.0 to −0.28±1.0 (P<0.05)). No changes in BMI over time were seen within any group. Reduction in GC dose did not increase the risk of adrenal crisis.

Conclusion

This study demonstrates for the first time that cautious reduction in hydrocortisone equivalent doses leads to increases in BMD, whereas dose increments reduced BMD. These data emphasize the need for the lowest possible GC replacement dose in AI patients to maintain health and avoid long-term adverse effects.

Free access

Benjamin Bleicken, Stefanie Hahner, Melanie Loeffler, Manfred Ventz, Bruno Allolio and Marcus Quinkler

Context

Recent studies have suggested that current glucocorticoid replacement therapies fail to fully restore well-being in patients with adrenal insufficiency (AI).

Objective

To investigate the effect of different glucocorticoid preparations used for replacement therapy on subjective health status (SHS) in AI.

Design and patients

In a cross-sectional study, primary and secondary AI patients were contacted by mail. Individual glucocorticoid replacement regimens, underlying diagnoses and comorbidities were verified by questionnaires and review of medical records. Patients were asked to complete three validated self-assessment questionnaires (Short Form 36 (SF-36), Giessen Complaint List (GBB-24), and Hospital Anxiety and Depression Scale). Results were compared with sex- and age-matched controls drawn from the questionnaire-specific reference cohort.

Results

Of the 883 patients identified, 526 agreed to participate in the study. Completed questionnaire sets were available from 427 patients (primary AI n=232; secondary AI n=195). AI patients showed significantly impaired SHS compared with controls irrespective of the glucocorticoid used for replacement. The only difference in SHS between patients on prednisolone (PR) and hydrocortisone (all patients and sub-analysis for primary AI) was significant higher bodily pain (lower Z-score in SF-36) in patients on PR (P<0.05, P<0.01 respectively). In patients with secondary AI, the PR group showed significantly (P<0.05) less heart complaints (lower Z-score) in the GBB questionnaire compared with the cortisone acetate group.

Conclusions

Glucocorticoid replacement therapy with PR seems to be equivalent to hydrocortisone regarding SHS in patients with AI. However, SHS remains impaired in all patient groups suggesting a need for further improved glucocorticoid replacement strategies.

Free access

Sebastian Wortmann, Marcus Quinkler, Christian Ritter, Matthias Kroiss, Sarah Johanssen, Stefanie Hahner, Bruno Allolio and Martin Fassnacht

Objective

No standard therapy for advanced adrenocortical carcinoma (ACC) is established by any randomized trial but a consensus conference 2003 recommended mitotane as monotherapy or combined with etoposide, doxorubicin and cisplatin or with streptozotocin as first-line systemic therapy. However, there is no evidence for any therapy beneficial in patients failing these therapies. Therefore, we evaluated the effects of the anti-VEGF antibody bevacizumab plus capecitabine as salvage therapy in ACC.

Methods

Patients registered with the German ACC Registry with refractory ACC progressing after cytotoxic therapies were offered treatment with bevacizumab (5 mg/kg body weight i.v. every 21 days) and oral capecitabine (950 mg/m2 twice daily for 14 days followed by 7 days of rest) in 2006–2008. Evaluation of tumour response was performed by imaging according to response evaluation criteria in solid tumours every 12 weeks.

Results

Ten patients were treated with bevacizumab plus capecitabine. None of them experienced any objective response or stable disease. Two patients had to stop therapy after few weeks due to hand-foot syndrome, and three patients died on progressive disease within 12 weeks. Other adverse events were mild (grade I–II). Median survival after treatment initiation was 124 days.

Conclusions

Bevacizumab plus capecitabine has no activity in patients with very advanced ACC. Hence, this regimen cannot be recommended as a salvage therapy.

Free access

Nicole Reisch, Marina Willige, Denise Kohn, Hans-Peter Schwarz, Bruno Allolio, Martin Reincke, Marcus Quinkler, Stefanie Hahner and Felix Beuschlein

Objective

To study adrenal crisis (AC) in patients with congenital adrenal hyperplasia due to classical 21-hydroxylase deficiency (21-OHD). AC was defined as an acute state of health impairment requiring i.v. glucocorticoid administration and hospital admission.

Design and methods

In a cross-sectional study with detailed retrospective assessment, AC was studied following two approaches: i) questionnaire based: 122 adult 21-OHD patients (50 men, 72 women, median age 35 years, range 18–69 years) completed a disease-specific questionnaire; and ii) patient chart based: charts of 67 21-OHD patients (32 males, 35 females, median age 31 years, range 20–66 years) were analyzed from diagnosis to last follow-up with regard to frequency and causes of AC since diagnosis.

Results

Evaluation of questionnaires revealed 257 ACs in 4456 patient years (py; frequency 5.8 crises/100 py), while patient charts documented 106 ACs in 2181 py (4.9 crises/100 py). The chart-based evaluation showed that gastrointestinal infections (29%) and salt-wasting crisis (18%) were the main causes of AC. In 14%, the cause remained uncertain. There was no difference in the overall frequency of AC in males and females. AC mostly occurred during childhood, with more than 70% of AC in the first 10 years of life and one-third of AC in the first year of life. Still, 20% of cases of AC were observed in adults (>18 years).

Conclusion

Our data demonstrate a significant risk of AC in patients with 21-OHD over lifetime. Specific age-adapted and repeated crisis prevention training may help to reduce morbidity due to AC in 21-OHD.

Free access

Stefanie Hahner, Melanie Loeffler, Benjamin Bleicken, Christiane Drechsler, Danijela Milovanovic, Martin Fassnacht, Manfred Ventz, Marcus Quinkler and Bruno Allolio

Objective

Adrenal crisis (AC) is a life-threatening complication of adrenal insufficiency (AI). Here, we evaluated frequency, causes and risk factors of AC in patients with chronic AI.

Methods

In a cross-sectional study, 883 patients with AI were contacted by mail. Five-hundred and twenty-six patients agreed to participate and received a disease-specific questionnaire.

Results

Four-hundred and forty-four datasets were available for analysis (primary AI (PAI), n=254; secondary AI (SAI), n=190). Forty-two percent (PAI 47% and SAI 35%) reported at least one crisis. Three hundred and eighty-four AC in 6092 patient years were documented (frequency of 6.3 crises/100 patient years). Precipitating causes were mainly gastrointestinal infection and fever (45%) but also other stressful events (e.g. major pain, surgery, psychic distress, heat and pregnancy). Sudden onset of apparently unexplained AC was also reported (PAI 6.6% and SAI 12.7%). Patients with PAI reported more frequent emergency glucocorticoid administration (42.5 vs 28.4%, P=0.003). Crisis incidence was not influenced by educational status, body mass index, glucocorticoid dose, DHEA treatment, age at diagnosis, hypogonadism, hypothyroidism or GH deficiency. In PAI, patients with concomitant non-endocrine disease were at higher risk of crisis (odds ratio (OR)=2.02, 95% confidence interval (CI) 1.05–3.89, P=0.036). In SAI, female sex (OR=2.18, 95% CI 1.06–4.5, P=0.035) and diabetes insipidus (OR=2.71, 95% CI 1.22–5.99, P=0.014) were associated with higher crisis incidence.

Conclusion

AC occurs in a substantial proportion of patients with chronic AI, mainly triggered by infectious disease. Only a limited number of risk factors suitable for targeting prevention of AC were identified. These findings indicate the need for new concepts of crisis prevention in patients with AI.

Free access

Marcus Quinkler, Daniel Zehnder, Julia Lepenies, Massimiliano D Petrelli, Jasbir S Moore, Susan V Hughes, Paul Cockwell, Martin Hewison and Paul M Stewart

Objective: Renal 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enables selective access of aldosterone to the mineralocorticoid receptor (MR). Impaired 11β-HSD2 activity has been suggested in patients with hypertension as well as in patients with renal disease, where it may contribute to sodium retention, oedema and hypertension. To date, these studies have relied upon urinary cortisol (F) metabolite levels as surrogate markers of renal 11β-HSD2 activity.

Methods: We have directly analysed renal 11β-HSD2 mRNA expression in 95 patients undergoing kidney biopsy using TaqMan real-time PCR. Serum and 24-h urine samples were used to document underlying renal function and endocrine parameters. Urinary F and cortisone (E) metabolites were analysed using gas chromatography/mass spectrometry.

Results: Expression of 11β-HSD2 did not correlate with blood pressure or urinary Na/K ratio, but a significant positive correlation with creatinine clearance was observed (r = 0.284; P < 0.01). Immunofluorescence and confocal laser microscopy confirmed decreased 11β-HSD2 expression in patients with impaired renal function. For the first time, we showed that 11β-HSD2 mRNA expression correlated negatively with the urinary free (UF) F/E (UFF/UFE) ratio (r = 0.276; P < 0.05) as well as with the urinary tetrahydrocortisol + 5α-tetrahydrocortisol/tetrahydrocortisone ((THF + αTHF)/THE) ratio (r = 0.256; P < 0.05). No difference in 11β-HSD2 mRNA expression or in the UFF/UFE ratio was found between groups with no proteinuria, microalbuminuria, moderate or severe proteinuria. In contrast, the urinary (THF + αTHF)/THE ratio increased significantly (P < 0.05) in patients with severe albuminuria, suggesting increased hepatic 11β-HSD1 in those patients.

Conclusions: These data suggest that renal 11β-HSD2 expression may be represented only marginally better, if at all, by the UFF/UFE than by the (THF + αTHF)/THE ratio. Reduced renal 11β-HSD2 expression may lead to occupancy of the MR by glucocorticoids such as cortisol and may contribute to the increased sodium retention seen in patients with impaired renal function.

Free access

Marianne Weigel, Anna Riester, Gregor Hanslik, Katharina Lang, Holger S Willenberg, Stephan Endres, Bruno Allolio, Felix Beuschlein, Martin Reincke and Marcus Quinkler

Objective

The saline infusion test (SIT) is widely used as a confirmatory test for primary aldosteronism (PA). SIT results are judged as follows: post-test aldosterone levels <50 ng/l exclude PA, whereas levels >50 ng/l confirm PA. We hypothesized that post-SIT aldosterone concentrations indicate the severity of PA and might predict outcome.

Design

The study includes 256 PA patients of the German Conn's Registry who prospectively underwent SIT. The data of 126 patients with complete follow-up of 1.2±0.3 years after diagnosis were analyzed. The patients were divided into two groups with post-SIT aldosterone levels of 50–100 ng/l (group 1; n=38) and of >100 ng/l (group 2; n=88).

Results

Patients in group 2 had a significantly shorter duration of hypertension (7.5 vs 11.7 years (median), P=0.014), higher systolic blood pressure (BP; 151±16 vs 143±17 mmHg, P=0.036), lower serum potassium (3.3±0.6 vs 3.5±0.4 mmol/l, P=0.006), higher 24-h urine protein excretion (7.4 vs 5.4 mg/dl (median), P=0.012), and were more often female (P=0.038). They showed more often unilateral disease (P<0.005) with larger tumors (14±10 vs 7±10 mm, P=0.021), underwent more often adrenalectomy (75% vs 37%, P<0.005), required a lower number of antihypertensive drugs after adrenalectomy (1.2±1.2 vs 2.5±1.4, P=0.001), had a faster normalization of urinary protein excretion (with medical treatment P=0.049; with Adx P<0.005) at follow-up, and more frequently underlying well-characterized mutation (P=0.047).

Conclusions

PA patients with post-SIT aldosterone levels of >100 ng/l have a more rapid development of PA caused more frequently by unilateral disease with larger aldosterone-producing adenomas. However, this group of patients may have a significantly better outcome following specific treatment.