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Bruno Allolio

Adrenal crisis is a life-threatening emergency contributing to the excess mortality of patients with adrenal insufficiency. Studies in patients on chronic replacement therapy for adrenal insufficiency have revealed an incidence of 5–10 adrenal crises/100 patient years and suggested a mortality rate from adrenal crisis of 0.5/100 patient years. Patients with adrenal crisis typically present with profoundly impaired well-being, hypotension, nausea and vomiting, and fever responding well to parenteral hydrocortisone administration. Infections are the major precipitating causes of adrenal crisis. Lack of increased cortisol concentrations during infection enhances pro-inflammatory cytokine release and sensitivity to the toxic effects of these cytokines (e.g. tumour necrosis factor alpha). Furthermore, pro-inflammatory cytokines may impair glucocorticoid receptor function aggravating glucocorticoid deficiency. Treatment of adrenal crisis is simple and highly effective consisting of i.v. hydrocortisone (initial bolus of 100 mg followed by 200 mg over 24 h as continuous infusion) and 0.9% saline (1000 ml within the first hour). Prevention of adrenal crisis requires appropriate hydrocortisone dose adjustments to stressful medical procedures (e.g. major surgery) and other stressful events (e.g. infection). Patient education is a key for such dose adjustments but current education concepts are not sufficiently effective. Thus, improved education strategies are needed. Every patient should carry an emergency card and should be provided with an emergency kit for parenteral hydrocortisone self-administration. A hydrocortisone pen would hold a great potential to lower the current barriers to hydrocortisone self-injection. Improved patient education and measures to facilitate parenteral hydrocortisone self-administration in impending crisis are expected to significantly reduce morbidity and mortality from adrenal crisis.

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Sarah Johanssen and Bruno Allolio

Abstract

Context

Mifepristone (RU 486) blocks the action of cortisol by binding to the glucocorticoid receptor and, therefore, is of potential therapeutic value in Cushing's syndrome. However, research in endogenous hypercortisolism has been hampered by the controversy related to the use of mifepristone for inducing abortion. Currently, new studies are planned to better define the role of RU 486 in Cushing's syndrome. This paper reviews the available evidence concerning the therapeutic effects and adverse events of RU 486 in Cushing's syndrome.

Evidence acquisition

Original articles and reviews were identified using a PubMed search strategy covering the time period until February 2007.

Evidence synthesis

Treatment of Cushing's syndrome with mifepristone has been reported in a total of 18 patients, with daily doses ranging from 5 to 30 mg/kg. Case reports indicate that the mifepristone-induced receptor blockade may lead to significant clinical improvement in patients with Cushing's syndrome in whom surgery and inhibitors of adrenal steroidogenesis fail to control hypercortisolism. Due to its rapid onset of action, mifepristone may be particularly useful in acute crises, e.g. in cortisol-induced psychosis. Side effects include adrenal insufficiency and, as a result of its antiprogestin action, endometrial hyperplasia in long-term treatment. Adrenal insufficiency can be assessed only by careful clinical evaluation, as the hormonal parameters are not reliable during receptor blockade, and is rapidly reversed by exogenous dexamethasone. Well-designed larger clinical trials are needed to better assess the value of this interesting drug in the treatment of Cushing's syndrome.

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Heinrich M. Schulte and Bruno Allolio

Abstract.

The existence of a short-loop feedback inhibition of pituitary ACTH release by administration of β-endorphin was postulated. However, data on the effect of peripherally administered β-endorphin in humans are highly controversial. We infused human synthetic β-endorphin at a constant rate of 1 μg · kg−1 · min−1 or normal saline to 7 normal volunteers for 90 min. Thirty min after starting the β-endorphin or placebo infusion, releasing hormones were injected as a bolus iv (oCRH and GHRH 1 μg/kg, GnRH 100 μg, TRH 200 μg) and blood was drawn for measurements of β-endorphin immunoreactivity, all other pituitary hormones, and cortisol. Infusion of β-endorphin resulted in high β-endorphin plasma levels with a rapid decrease after the infusion was stopped. During the control infusion, β-endorphin plasma levels rose in response to CRH. Plasma ACTH and serum cortisol levels in response to the releasing hormone were not different in subjects infused with β-endorphin or placebo. The PRL response to TRH was significantly higher after β-endorphin than after placebo (area under the stimulation curve 1209±183 vs 834±104 μg · 1−1 · h). There was no difference in the response of all other hormones measured. Our data on ACTH and cortisol secretion do not support the concept of a shortloop negative feedback of β-endorphin acting at the site of the pituitary.

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Ulf Elbelt, Stefanie Hahner and Bruno Allolio

Objective

Current glucocorticoid replacement regimens fail to fully mimic physiologic cortisol secretion in patients with primary adrenal insufficiency. This may lead to changes in insulin requirement in patients with primary adrenal insufficiency and type 1 diabetes. Therefore, we assessed insulin requirement in patients with autoimmune polyendocrine syndrome type 2 (APS-2).

Design and subjects

Ten females with primary adrenal insufficiency and type 1 diabetes (mean duration of type 1 diabetes 13±11 years and of primary adrenal insufficiency 11±9 years) were retrospectively assessed regarding insulin regimen and insulin dose adjustment. Data were compared with control patients matched for age, sex and duration of diabetes drawn from all patients with type 1 diabetes attending the diabetes outpatient clinics at the University Hospital Wuerzburg for a scheduled consultation.

Results

Glycaemia was well controlled in both groups (mean HbA1c 6.99±0.81% in APS-2 patients versus 6.69±1.03% in control patients). The mean weight-adjusted daily dose of insulin was non-significantly higher in patients with APS-2 compared with control patients (0.69±0.35 IU/kg body weight versus 0.51±0.17 respectively). The mean insulin (IU)/carbohydrate-ratio for 10 g of carbohydrate in the morning was 1.9±1.0 and 1.4±0.5 respectively. However, the insulin/carbohydrate-ratios were significantly higher in the APS-2 patients both at noon (mean ratio 2.0±0.9 vs 1.1±0.5 in control patients) and in the evening (mean ratio 2.1±1.1 vs 1.3±0.5 respectively; P<0.05).

Conclusions

Glucocorticoid replacement therapy in patients with primary adrenal insufficiency and type 1 diabetes leads to significant changes in insulin requirement compared with patients with type 1 diabetes only.

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Stefanie Hahner, Stephanie Burger-Stritt and Bruno Allolio

Objective

Evaluation of the pharmacokinetics and safety of s.c. hydrocortisone injection for use in adrenal emergency.

Design

Single-center, open-label, sequence-randomized, crossover study in a tertiary care center.

Patients and methods

Twelve patients with chronic Addison's disease. Comparison of hydrocortisone pharmacokinetics after s.c. and i.m. injection (100 mg) and after s.c. administration of sodium chloride (0.9%) respectively at three different visits.

Main outcome measure: maximum serum cortisol (C max), time to C max (t max), and time to serum cortisol >36 μg/dl (t serum cortisol >36 μg/dl) after s.c. administration compared with i.m. administration, safety, and patient preference.

Results

Serum cortisol increased rapidly and substantially after both i.m. and s.c. injections (C max: 110±29 vs 97±28 μg/dl, P=0.27, t max: 66±51 vs 91±34 min, P=0.17, and t serum cortisol >36 μg/dl: 11±5 vs 22±11 min, P=0.004 respectively). Both i.m. and s.c. injections were well tolerated. Eleven (91.7%) patients preferred s.c. injection, whereas one patient did not have any preference.

Conclusions

S.c. administration of 100 mg hydrocortisone shows excellent pharmacokinetics for emergency use with only a short delay in cortisol increase compared with i.m. injection. It has a good safety profile and is preferred by patients over i.m. injection.

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Martin Reincke, Michael Peter, Wolfgang G Sippell and Bruno Allolio

Abstract

Recent reports have shown an exaggerated response of 17-hydroxyprogesterone in up to 70% of patients with incidentally detected adrenal adenomas ('incidentalomas'). This has been explained by pre-existing 21-hydroxylase deficiency which may be a pathogenetic factor in the development of adrenal tumours. However, other defects in steroidogenesis, such as mild 11β-hydroxylase deficiency, could also result in increased 17-hydroxyprogesterone secretion. We therefore studied the glucocorticoid and mineralocorticoid pathways in patients with adrenal 'incidentalomas' by measuring multiple adrenal steroids before and after 1–24 ACTH stimulation. Twenty patients with adrenal 'incidentalomas' (14 females, 6 males) and 27 healthy controls (14 females, 13 males) were studied. All subjects underwent a 1–24 ACTH stimulation test (250 μg i.v.) with determination of progesterone, 11-deoxycorticosterone, corticosterone, 17-hydroxyprogesterone, 11-deoxycortisol and cortisol at O and 60 min. All steroids were measured by RIA after extraction and HPLC. Patients with 'incidentalomas' had higher stimulated concentrations of 17-hydroxyprogesterone (21·6 ± 8·4 vs 4·2 ± 0·3 nmol/l; P ≤ 0·001), 11-deoxycortisol (8·1 ± 1·2 vs 3·6 ± 0·3 nmol/l; P ≤ 0·001), progesterone (8·28 ± 2·82 vs 1·08 ± 0·15 nmol/l; P ≤ 0·001), and 11-deoxycorticosterone (2·1 ± 0·39 vs 0·78 ± 0·12 nmol/l; P = 0·002) compared with controls. In contrast, cortisol and corticosterone concentrations were not different. There was evidence for impairment of 11β-hydroxylase activity by an increased 11-deoxycortisol/cortisol ratio (0·012 ± 0·003 vs 0·005 ± 0·001 in controls; P = 0·002) and 11-deoxycorticosterone/corticosterone ratio (0·04 ± 0·003 vs 0·015 ± 0·003; P = 0·003). The conclusions reached were that patients with adrenal 'incidentalomas' have increased responses of precursors of the mineralocorticoid and glucocorticoid pathway including 17-hydroxyprogesterone after stimulation with ACTH. This seems to be caused by impairment of 11β-hydroxylase activity rather than by impaired 21-hydroxylase activity in these tumours.

European Journal of Endocrinology 136 196–200

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Bruno Allolio, Martin Oremus, Martin Reincke, Hans-Jörg Schaeffer, Werner Winkelmann, Georg Heck and Heinrich M Schulte

Allolio B, Oremus M, Reincke M, Schaeffer H-J, Winkelmann W, Heck G, Schulte HM. High-dose progesterone infusion in healthy males: evidence against antiglucocorticoid activity of progesterone. Eur J Endocrinol 1995;133:696–700. ISSN 0804–4643

High concentrations of unbound cortisol in late pregnancy have been explained by the antiglucocorticoid activity of high progesterone levels. To further test this hypothesis we studied the effect of high-dose progesterone on baseline and corticotrophin-releasing hormone (CRH)-induced hormone secretion in humans. In a double-blind crossover study eight healthy male volunteers received either progesterone (0.714 mg · kg−1 · h−1 for 60 min followed by a dose of 0.45 mg · kg−1 · h−1 over a total infusion time of 315 min) or vehicle as a continuous intravenous infusion. At 210 min a CRH test (0.1 μg/kg body weight as bolus iv) was performed. Within 30 min after the start of progesterone administration the serum progesterone level increased to 454 ± 31 nmol/l and remained in the range of third trimester pregnancy concentrations throughout the infusion period. During vehicle infusion the progesterone level remained in the normal range for healthy males and demonstrated a small but significant increase after CRH (1.52 ± 0.23 vs 0.74 ± 0.14 nmol/l; p < 0.01). However, baseline and CRH-stimulated serum cortisol and plasma adrenocorticotrophic hormone remained unaffected by high-dose progesterone. Moreover, unbound salivary cortisol also was not affected by progesterone, suggesting that there is no significant competition for transcortin binding sites. In conclusion, no antiglucorticoid activity was found after short-term administration of progesterone in males. These findings cast doubts on the concept that the alterations of the pituitary–adrenal axis in late pregnancy are induced by the antiglucocorticoid activity of high progesterone concentrations.

Bruno Allolio, Medizinische Universitätsklinik Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany

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.

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Stefanie Hahner, Martin Fassnacht, Fabian Hammer, Markus Schammann, Dirk Weismann, Immo Alex Hansen and Bruno Allolio

Objective: A serine protease from rat adrenal cortex was recently characterized and named adrenal secretory protease (AsP). AsP is expressed in the adrenal cortex and is capable of cleaving pro-γ-melanocyte-stimulating hormone (1-76 N-terminus of pro-opiomelanocortin) into fragments that act as adrenal mitogens. AsP may therefore play a crucial role in adrenal growth and tumourigenesis. The aim of this study was to further characterize the human homologue of AsP and its possible role in adrenal tumourigenesis.

Methods and results: Starting with the rat cDNA sequence of AsP we detected high homology to the catalytic C-terminus of the human airway trypsin-like protease (HAT). Further analysis revealed that the HAT gene is the human homologue of a long splice variant of AsP, which we recently described as rat airway trypsin-like serine protease 1. In contrast to rodents, no short isoform of HAT was found in humans due to a stop codon in exon 6 which prevents the expression of a short isoform. While high expression of HAT mRNA was found in the trachea and in the gastrointestinal tract, expression in the adrenal was only very weak. RT-PCR and real-time PCR analysis revealed a complex tissue expression pattern of HAT, indicating a role for this protease in multiple tissues. We further investigated HAT expression in five normal adrenal glands, 15 adrenocortical adenomas (five hormonally inactive adenomas, five aldosterone-producing adenomas and five cortisol-producing adenomas), nine adrenocortical carcinomas, five phaeochromocytomas and two adrenal hyperplasias. Weak HAT expression was detectable in only two out of five normal adrenal glands, in one out of twenty-four adrenocortical tumours and four out of five phaeochromocytomas. However, the expression in the adrenal tissue was several orders of magnitude lower than in the trachea. In addition, we could not detect any HAT transcripts in a sample of fetal adrenal.

Conclusion: Gene structure and tissue distribution of HAT, the human homologue of the rat adrenal secretory protease AsP, reveal major interspecies differences. The observation of very low expression levels in normal adrenal tissue and adrenocortical tumours casts doubt about a role for HAT in the physiological and pathological growth of adrenocortical cells.