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Free access

Matthias J Betz, Christoph Degenhart, Evelyn Fischer, Anna Pallauf, Volker Brand, Ulrich Linsenmaier, Felix Beuschlein, Martin Bidlingmaier, and Martin Reincke

Objective

Adrenal vein sampling (AVS) is considered the gold standard in the differential diagnosis of primary aldosteronism (PA), but success rates vary between centers. We hypothesized that rapid (intraprocedure) cortisol measurement can improve performance in a center with initially low AVS success rate.

Design

We analyzed 46 patients with confirmed PA studied between 2008 and 2010. Forty-seven PA patients studied between 2004 and 2008 identified by retrospective chart review served as controls. All patients were treated at a single tertiary care university hospital.

Methods

Starting in 2008, rapid cortisol assays (RCA) were performed in all patients during the AVS procedure. A cortisol gradient of ≥2.0 between adrenal vein and a femoral vein sample was used as success criterion. Up to two repeat samples were drawn if adrenal vein cortisol was below this threshold.

Results

During the control period 26 of 47 AVS were successful (55%). After introduction of RCA, 39 out of 46 AVS (85%) were successful (P=0.003). In 21 of the 46 cases (46%) a resampling was necessary. The increase in overall success was due to an increase in successful right AVS (85 vs 62% before introduction of RCA; P=0.02) and a training effect (P=0.024 for trend).

Conclusion

RCA during AVS are useful in centers with an initially low AVS success rate.

Free access

Oliver Zwermann, Felix Beuschlein, Enzo Lalli, Albrecht Klink, Paolo Sassone-Corsi, and Martin Reincke

Background: The ACTH receptor (ACTH-R) is a member of the seven transmembrane domain receptor super-family. In non-functional adrenal adenomas and adrenocortical carcinomas, ACTH-R expression is low. However, no inhibitory factor for ACTH-R expression has been defined to date. DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene-1) is a general repressor of steroid production, inhibiting steroidogenic factor-1 (SF-1)-dependent expression of multiple steroidogenic enzymes. The aim of this study was to investigate whether ACTH-R gene transcription is affected by DAX-1 and whether this mechanism is involved in down-regulation of ACTH-R expression in adrenocortical tumors.

Methods: We screened 22 adrenocortical tumors for ACTH-R and DAX-1 mRNA expression by Northern blot. For in vitro analyses we co-transfected mouse Y1 adrenocortical carcinoma cells with the luciferase reporter gene vector pGL3 containing full-length constructs of human (h) or mouse (m) ACTH-R promoter together with a DAX-1 expression plasmid. These experiments were also performed using ACTH-R promoter 5′-deletion constructs and constructs mutated at the SF-1-binding sites.

Results: We found a negative correlation between DAX-1 and ACTH-R mRNA expression (R = −0.47, P < 0.02). Accordingly, in vitro expression of DAX-1 significantly reduced hACTH-R and mACTH-R promoter activity by 89 and 55% respectively. DAX-1 inhibition was also present in the shortest construct of a series of 5′-deletion constructs of the human promoter extending from −64 to +40 bp relative to the transcription start site. Mutation of the SF-1-binding sites within the hACTH-R promoter resulted in reduced or abolished DAX-1 inhibition, arguing for a mechanism that involves SF-1 for DAX-1 inhibition.

Conclusions: These data support the concept that DAX-1 is a major repressor of ACTH-R gene expression in vitro and in vivo.

Open access

John Newell-Price, Lynnette K Nieman, Martin Reincke, and Antoine Tabarin

Clinical evaluation should guide those needing immediate investigation. Strict adherence to COVID-19 protection measures is necessary. Alternative ways of consultations (telephone, video) should be used. Early discussion with regional/national experts about investigation and management of potential and existing patients is strongly encouraged. Patients with moderate or severe clinical features need urgent investigation and management. Patients with active Cushing’s syndrome, especially when severe, are immunocompromised and vigorous adherence to the principles of social isolation is recommended. In patients with mild features or in whom a diagnosis is less likely, clinical re-evaluation should be repeated at 3 and 6 months or deferred until the prevalence of SARS-CoV-2 has significantly decreased; however, those individuals should be encouraged to maintain social distancing. Diagnostic pathways may need to be very different from usual recommendations in order to reduce possible exposure to SARS-CoV-2. When extensive differential diagnostic testing and/or surgery is not feasible, it should be deferred and medical treatment should be initiated. Transsphenoidal pituitary surgery should be delayed during high SARS-CoV-2 viral prevalence. Medical management rather than surgery will be the used for most patients, since the short- to mid-term prognosis depends in most cases on hypercortisolism rather than its cause; it should be initiated promptly to minimize the risk of infection in these immunosuppressed patients. The risk/benefit ratio of these recommendations will need re-evaluation every 2–3 months from April 2020 in each country (and possibly local areas) and will depend on the local health care structure and phase of pandemic.

Free access

Jacques W M Lenders, Tracy Ann Williams, Martin Reincke, and Celso E Gomez-Sanchez

Since the early 1980s 18-hydroxycortisol and 18-oxocortisol have attracted attention when it was shown that the urinary excretion of these hybrid steroids was increased in primary aldosteronism. The development and more widespread use of specific assays has improved the understanding of their role in the (patho)physiology of adrenal disorders. The adrenal site of synthesis is not fully understood although it is clear that for the synthesis of 18-hydroxycortisol and 18-oxocortisol the action of both aldosterone synthase (zona glomerulosa) and 17α-hydroxylase (zona fasciculata) is required with cortisol as main substrate. The major physiological regulator is ACTH and the biological activity of both steroids is very low and therefore only very high concentrations might be effective in vivo. In healthy subjects, the secretion of both steroids is low with 18-hydroxycortisol being substantially higher than that of 18-oxocortisol. The highest secretion of both steroids has been found in familial hyperaldosteronism type 1 (glucocorticoid-remediable aldosteronism) and in familial hyperaldosteronism type 3. Lower but yet substantially increased secretion is found in patients with aldosterone-producing adenomas in contrast to bilateral hyperplasia in whom the levels are similar to patients with hypertension. Several studies have attempted to show that these steroids, in particular, peripheral venous plasma 18-oxocortisol, might be a useful discriminatory biomarker for subtyping PA patients. The current available limited evidence precludes the use of these steroids for subtyping. We review the biosynthesis, regulation and function of 18-hydroxycortisol and 18-oxocortisol and their potential utility for the diagnosis and differential diagnosis of patients with primary aldosteronism.

Free access

Juergen Honegger, Sanna Zimmermann, Tsambika Psaras, Manfred Petrick, Michel Mittelbronn, Ulrike Ernemann, Martin Reincke, and Klaus Dietz

Objective

Recent observational studies have established progression and recurrence rates of pituitary adenomas. However, it is still unknown how individual pituitary adenomas grow over years and whether growth kinetics follow a distinct growth model. The objective of this study was to define a growth model for non-functioning pituitary adenomas.

Methods

Fifteen patients who had five or more serial high-quality examinations with magnetic resonance images or computerized tomography scans were identified among 216 patients with non-functioning pituitary adenomas. Tumour volumes were assessed using a stereological method based on the Cavalieri principle. Tumour growth during the observation period was analysed and different growth models were fitted to the data.

Results

Fifteen pituitary adenomas (12 recurrent tumours and 3 newly diagnosed tumours) were longitudinally observed during a median observation period of 7.4 years (range: 2.3–11.9 years). Growth kinetics could be described either by an exponential growth model (nine patients) or by a logistic model (five patients) with initial exponential growth followed by deceleration of growth. One tumour remained unchanged in size during the observation period. None of the adenomas showed accelerated growth during the observation period. Overall, the linear growth model was not suitable to describe the growth kinetics of non-functioning pituitary adenomas.

Conclusions

Our study shows that growth of pituitary adenomas can be described by distinct growth models. Knowledge of growth dynamics has implications for clinical practice and helps to adjust scanning protocols for follow-up investigations.

Free access

Caroline Schirpenbach, Lysann Seiler, Christiane Maser-Gluth, Frank Rüdiger, Christian Nickel, Felix Beuschlein, and Martin Reincke

Objective: Primary aldosteronism has recently been recognized as the most frequent cause of secondary hypertension. Since most patients are normokalaemic, differentiation to essential hypertension is challenging. As differentiation by baseline aldosterone/renin ratio may be insufficient, diagnosis should be confirmed by additional tests. However, as most confirmatory tests have been evaluated in hypokalaemic primary aldosteronism only, we reassessed the value of the saline infusion test and 24 h urinary aldosterone metabolites as confirmatory tests for both normo- and hypokalaemic primary aldosteronism under current antihypertensive medication.

Patients and methods: 25 patients with primary aldosteronism (11 hypokalaemic, 14 normokalaemic), 29 patients with essential hypertension and 47 normotensive subjects were studied. The hypertensives received their usual medication with the exception of spironolactone. All subjects underwent a standard saline infusion test (determination of plasma aldosterone before and after 2.0 liters of isotonic saline for 4 hours i.v.) and collected a 24 h urine sample for examination of urinary tetrahydroaldosterone and aldosterone-18-glucuronide.

Results: In hypokalaemic primary aldosteronism the saline infusion test showed a reasonable sensitivity (91%) and specificity (90%). However, the test failed to differentiate sufficiently between essential hypertension and normokalaemic primary aldosteronism (sensitivity 57%, specificity 90%). Similarly, urinary tetrahydroaldosterone had higher sensitivity in hypokalaemic than in normokalaemic primary aldosteronism (sensitivity 64% vs 36%, specificity 100%), whereas for aldosterone-18-glucuronide, no differences in hypo- and normokalaemic primary aldosteronism were found (sensitivity 45% and 43%, specificity 100%).

Conclusions: These data show that the saline infusion test as an established test in classical hypokalaemic primary aldosteronism is not a reliable test in the normokalaemic variant of the disease. Due to its low accuracy, determination of urinary aldosterone metabolites did not prove useful in confirming either normo- or hypokalaemic patients. We conclude from our data that these tests should not be used as confirmatory testing in the normokalaemic variant of primary aldosteronism.

Free access

Heinrich Kahles, Elizabeth Ramos-Lopez, Britta Lange, Oliver Zwermann, Martin Reincke, and Klaus Badenhoop

Background: Endocrine autoimmune disorders share genetic susceptibility loci, causing a disordered T-cell activation and homeostasis (HLA class II genes, CTLA-4). Recent studies showed a genetic variation within the PTPN22 gene to be an additional risk factor.

Materials and Methods: Patients with type 1 diabetes (n = 220), Hashimoto’s thyroiditis (n = 94), Addison’s disease (n = 121) and healthy controls (n = 239) were genotyped for the gene polymorphism PTPN22 1858 C/T.

Results: Our study confirms a significant association between allelic variation of the PTPN22 1858 C/T polymorphism and type 1 diabetes mellitus (T1D). 1858T was observed more frequently in T1D patients (19.3% vs 11.3%, P = 0.0009; odds ratio for allele T = 1.88, 95% confidence interval [1.3–2.7]). Furthermore, we found a strong association in female patients with T1D (P = 0.0003), whereas there was no significant difference between male patients with type 1 diabetes and male controls. No significant difference was observed between the distribution of PTPN22 C/T in patients with Hashimoto’s thyroiditis or Addison’s disease and healthy controls.

Conclusion: The PTPN22 polymorphism 1858 C/T may be involved in the pathogenesis of type 1 diabetes mellitus by a sex-specific mechanism that contributes to susceptibility in females.

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

Martin Reincke, Katrin Ritzel, Andrea Oßwald, Christina Berr, Günter Stalla, Klaus Hallfeldt, Nicole Reisch, Jochen Schopohl, and Felix Beuschlein

Objective

Our aim was to review short- and long-term outcomes of patients treated with bilateral adrenalectomy (BADx) in ACTH-dependent Cushing's syndrome.

Methods

We reviewed the literature and analysed our experience with 53 patients treated with BADx since 1990 in our institution.

Results

BADx is considered if ACTH-dependent Cushing's syndrome is refractory to other treatment modalities. In Cushing's disease (CD), BADx is mainly used as an ultima ratio after transsphenoidal surgery and medical therapies have failed. In these cases, the time span between the first diagnosis of CD and treatment with BADx is relatively long (median 44 months). In ectopic Cushing's syndrome, the time from diagnosis to BADx is shorter (median 2 months), and BADx is often performed as an emergency procedure because of life-threatening complications of severe hypercortisolism. In both situations, BADx is relatively safe (median surgical morbidity 15%; median surgical mortality 3%) and provides excellent control of hypercortisolism; Cushing's-associated signs and symptoms are rapidly corrected, and co-morbidities are stabilised. In CD, the quality of life following BADx is rapidly improving, and long-term mortality is low. Specific long-term complications include the development of adrenal crisis and Nelson's syndrome. In ectopic Cushing's syndrome, long-term mortality is high but is mostly dependent on the prognosis of the underlying malignant neuroendocrine tumour.

Conclusion

BADx is a relatively safe and highly effective treatment, and it provides adequate control of long-term co-morbidities associated with hypercortisolism.

Free access

Robert Kopetschke, Mario Slisko, Aylin Kilisli, Ulrich Tuschy, Henri Wallaschofski, Martin Fassnacht, Manfred Ventz, Felix Beuschlein, Martin Reincke, Nicole Reisch, and Marcus Quinkler

Context

Adrenal and extra-adrenal phaeochromocytoma are chromaffin cell-derived tumours that are discovered due to classical symptom triad with headache, sweating and palpitations combined with persistent or paroxysmal hypertension. However, an increasing proportion of phaeochromocytoma seems to be discovered incidentally upon abdominal imaging.

Objective

To specify the exact circumstances of discovery of adrenal and extra-adrenal phaeochromocytoma.

Design and patients

Four German endocrine centres participated in this retrospective study. Medical records of 201 patients with adrenal and extra-adrenal phaeochromocytoma who were diagnosed between 1973 and 2007 were analyzed.

Results

The typical triad of symptoms was found only in 10% of cases. Ten percent of patients presented were without clinical symptoms and 6.1% were normotensive. Documented blood pressure peaks occurred in 44.1% of cases. In 24 patients (12.2%), phaeochromocytoma was malignant. Before 1985, <10% of cases were incidentally discovered, whereas thereafter the frequency was >25% (29.4% of the total study population). Patients with incidentally detected phaeochromocytoma were significantly older (53.1±1.9 vs 47.0±1.3 years; P<0.05) and often had less blood pressure peaks (37.0 vs 70.7%; P<0.001) than patients in whom the diagnosis was suspected on clinical grounds. Of phaeochromocytomas 94.4% were intra-adrenal tumours, of which 12.9% were bilateral. Bilateral tumours were significantly smaller than unilateral tumours (36.6±14.7 vs 52.5±34.3 mm; P<0.05), whereas extra-adrenal tumours had a mean diameter of 52.6±28.7 mm.

Conclusions

Owing to better availability and accessibility of imaging procedures, the number of incidentally discovered phaeochromocytoma is increasing and reaches nearly 30% in our study population. Every adrenal incidentaloma should be investigated for the presence of phaeochromocytoma.