Publications by authors named "Martin Reincke"

321 Publications

Endocrine risk factors for COVID-19: Endogenous and exogenous glucocorticoid excess.

Rev Endocr Metab Disord 2021 Jul 9. Epub 2021 Jul 9.

Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany.

Patients with endogenous or exogenous glucocorticoid (GC) excess exhibit a range of side effects, including an increased risk of infections. Via both mechanism, immune impairments and cardiometabolic concomitant diseases, patients with GC excess could be at increased risk for COVID-19. The impact on incidence and outcome of a SARS-CoV-2 infection in this population are not yet completely clear. This review aims to compile the data available to date and to discuss the existing literature on this topic. Further we highlight potential effects of SARS-CoV-2 on the hypothalamic-pituitary-adrenal axis as well as the influence of endogenous or exogenous GC excess on SARS-CoV-2 mRNA vaccination. There is growing evidence suggesting an increased risk of infection and severe outcome in patients with high-dose GC therapy after contracting SARS-CoV-2. The few data and case reports on patients with endogenous GC excess and SARS-CoV-2 infection point in a similar direction: chronic GC excess seems to be associated with an unfavorable course of COVID-19. Whether this is mainly a primary immune-mediated effect, or also triggered by the many GC-associated comorbidities in this population, is not yet fully understood. Patients with endogenous or exogenous GC excess should be considered as a vulnerable group during the SARS-CoV-2 pandemic. Regardless of the cause, vaccination and consistent surveillance and control of associated comorbidities are recommended.
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http://dx.doi.org/10.1007/s11154-021-09670-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267234PMC
July 2021

Identification of Surgically Curable Primary Aldosteronism by Imaging in a Large Multiethnic International Study.

J Clin Endocrinol Metab 2021 Jul 2. Epub 2021 Jul 2.

3rd Department of Medicine, Charles University Prague, General Hospital, Czech Republic.

Context: Adrenal glands imaging is recommended by the current guidelines for the work-up of primary aldosteronism (PA). However, its diagnostic performance has not been established in large multi-ethnic cohorts of patients submitted to adrenal vein sampling (AVS) and adrenalectomy.

Objective: To assess the diagnostic accuracy of cross-sectional adrenal imaging.

Design: International multi-center study.

Setting: Tertiary referral centers.

Patients Or Other Participants: 1625 PA patients seeking surgical cure enrolled in an international study involving 19 centers in North America, Europe, Asia, and Australia. 1311 (81%) had imaging data available and 369 (23%), who received a final diagnosis of surgically cured unilateral PA, were examined.

Intervention(s): Patients underwent AVS and imaging by computed tomography (CT) and/or magnetic resonance (MR).

Main Outcome Measure(s): The accuracy of detection of unilateral PA at imaging was estimated by the area under the receiver operator characteristics (ROC) curve using cure (biochemical and/or full clinical success) as the reference at follow-up after unilateral adrenalectomy.

Results: In the cohort of 1311 patients with imaging data available, 34% and 7% of cases showed no detectable or bilateral nodules, respectively. Imaging did not detect the culprit adrenal in 28% of the surgically cured unilateral PA patients. Moreover, the clinical outcome did not differ significantly between the imaging-positive and imaging-negative patients.

Conclusions: Cross-sectional imaging did not identify a lateralized cause of disease in around 40% of PA patients and failed in identifying the culprit adrenal in more than one fourth of patients with unilateral PA.
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http://dx.doi.org/10.1210/clinem/dgab482DOI Listing
July 2021

Cushing Syndrome Associated Myopathy: It Is Time for a Change.

Authors:
Martin Reincke

Endocrinol Metab (Seoul) 2021 Jun 18;36(3):564-571. Epub 2021 Jun 18.

Medical Department IV, LMU-University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.

Cushing syndrome is the result of excessive levels of glucocorticoids. Endogenous Cushing syndrome is rare with an incidence of two to three cases per million per year. Clinically, the presentation consists of a characteristic phenotype including skin symptoms and metabolic manifestations. A frequent co-morbidity with high impact on quality of life is Cushing syndrome associated myopathy. It characteristically affects the proximal myopathy, impairing stair climbing and straightening up. The pathophysiology is complex and involves protein degradation via the forkhead box O3 (FOXO3) pathway, intramuscular fat accumulation, and inactivity-associated muscle atrophy. Surgical remission of Cushing syndrome is the most important step for recovery of muscle function. Restoration depends on age, co-morbidities and postoperative insulin-like growth factor concentrations. At average, functionality remains impaired during the long-term compared to age and sex matched control persons. Growth hormone therapy in individuals with impaired growth hormone secretion could be an option but has not been proved in a randomized trial.
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http://dx.doi.org/10.3803/EnM.2021.1069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258338PMC
June 2021

The role of regulated necrosis in endocrine diseases.

Nat Rev Endocrinol 2021 Aug 16;17(8):497-510. Epub 2021 Jun 16.

Clinic of Internal Medicine III, Division of Nephrology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.

The death of endocrine cells is involved in type 1 diabetes mellitus, autoimmunity, adrenopause and hypogonadotropism. Insights from research on basic cell death have revealed that most pathophysiologically important cell death is necrotic in nature, whereas regular metabolism is maintained by apoptosis programmes. Necrosis is defined as cell death by plasma membrane rupture, which allows the release of damage-associated molecular patterns that trigger an immune response referred to as necroinflammation. Regulated necrosis comes in different forms, such as necroptosis, pyroptosis and ferroptosis. In this Perspective, with a focus on the endocrine environment, we introduce these cell death pathways and discuss the specific consequences of regulated necrosis. Given that clinical trials of necrostatins for the treatment of autoimmune conditions have already been initiated, we highlight the therapeutic potential of such novel therapeutic approaches that, in our opinion, should be tested in endocrine disorders in the future.
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http://dx.doi.org/10.1038/s41574-021-00499-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207819PMC
August 2021

Characteristics of preoperative steroid profiles and glucose metabolism in patients with primary aldosteronism developing adrenal insufficiency after adrenalectomy.

Sci Rep 2021 May 27;11(1):11181. Epub 2021 May 27.

Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstraße 1, 80336, Munich, Germany.

Treatment of choice in patients with unilateral aldosterone producing adenoma (APA) is adrenalectomy. Following surgery, most patients retain normal adrenal function, while some develop adrenal insufficiency (AI). To facilitate early detection and treatment of AI, we aimed to identify variables measured pre-operatively that are associated with post-operative AI. Variables obtained from 66 patients before and after surgery included anthropometrical data, clinical chemistry, endocrine work-up. LC-MS/MS steroid hormone profiles from tests before surgery (ACTH-stimulation, saline infusion, dexamethasone suppression) were obtained. Based on 78 variables, machine-learning methods were used in model fitting for classification and regression to predict ACTH-stimulated cortisol after surgery. Among the 78 variables, insulin concentration during pre-operative oral glucose tolerance test (OGTT) correlated positively, and dexamethasone suppressed glucocorticoids correlated negatively with ACTH-stimulated cortisol after surgery. Inclusion of LC-MS/MS measurements allowed construction of better models associated with the occurrence of AI in the training data, but did not allow reliable prediction in cross-validation. Our results suggest that glucocorticoid co-secretion (low insulin during pre-operative OGTT and insufficient suppression of glucocorticoids following dexamethasone) are correlated with the development of post-operative AI. Addition of steroid profiles improved the accuracy of prediction, but cross validation revealed lack of reliability in the prediction of AI.
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http://dx.doi.org/10.1038/s41598-021-90901-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160266PMC
May 2021

Single-Center Prospective Cohort Study on the Histopathology, Genotype, and Postsurgical Outcomes of Patients With Primary Aldosteronism.

Hypertension 2021 May 24:HYPERTENSIONAHA12117348. Epub 2021 May 24.

Medizinische Klinik und Poliklinik IV, Klinikum der Universitaät Muünchen, Ludwig-Maximilians-Universität München, Germany. (L.S.M., L.H., I.K., M.B., M.R., T.A.W.).

Unilateral forms of primary aldosteronism are usually surgically treated to remove the source of aldosterone excess. After adrenalectomy, aldosteronism persists in some patients indicating abnormal aldosterone production from the unresected gland. Our objective was to investigate histopathology, genotype, and postsurgical outcomes in a 3-year prospective cohort of surgically treated patients for primary aldosteronism (from 2016 to 2018). The cohort comprised 60 consecutively operated patients categorized with classical or nonclassical histopathologic findings of unilateral primary aldosteronism. In the classical group were 45 solitary aldosterone-producing adenomas or dominant aldosterone-producing nodules; in the nonclassical group were 15 cases of multiple aldosterone-producing micronodules or nodules (12 cases) or aldosterone-producing diffuse hyperplasia (3 cases). The classical group displayed higher baseline plasma aldosterone concentrations (262 versus 155 pg/mL, =0.008) and an increased aldosterone-to-renin ratio (81 versus 42, =0.002). A high proportion of the classical group achieved complete biochemical success (97.6% versus 66.7% in the nonclassical group, =0.002). The nonclassical versus classical group displayed an increased ratio of absolute aldosterone concentration in the contralateral adrenal vein to peripheral vein at adrenal venous sampling (3.8 versus 2.0, =0.004). Variants in aldosterone-driver genes were identified in 85% of 41 aldosterone-producing adenomas and were excluded in the remaining 15% by CYP11B2 guided next-generation sequencing. There were no differences in clinical or biochemical outcomes in patients with a solitary aldosterone-producing adenoma categorized by mutation status. In conclusion, adrenals with a nonclassical histopathology of unilateral primary aldosteronism are associated with a higher incidence of postsurgical disease persistence and increased aldosterone production from the unresected adrenal.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.17348DOI Listing
May 2021

Mass spectrometry imaging identifies metabolic patterns associated with malignant potential in pheochromocytoma and paraganglioma.

Eur J Endocrinol 2021 Jun 5;185(1):179-191. Epub 2021 Jun 5.

Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany.

Objective: Within the past decade, important genetic drivers of pheochromocytoma and paraganglioma (PPGLs) development have been identified. The pathophysiological mechanism that translates these alterations into functional autonomy and potentially malignant behavior has not been elucidated in detail. Here we used MALDI-mass spectrometry imaging (MALDI-MSI) of formalin-fixed paraffin-embedded tissue specimens to comprehensively characterize the metabolic profiles of PPGLs.

Design And Methods: MALDI-MSI was conducted in 344 PPGLs and results correlated with genetic and phenotypic information. We experimentally silenced genetic drivers by siRNA in PC12 cells to confirm their metabolic impact in vitro.

Results: Tissue abundance of kynurenine pathway metabolites such as xanthurenic acid was significantly lower (P = 2.35E-09) in the pseudohypoxia pathway cluster 1 compared to PPGLs of the kinase-driven PPGLs cluster 2. Lower abundance of xanthurenic acid was associated with shorter metastasis-free survival (log-rank tests P = 7.96E-06) and identified as a risk factor for metastasis independent of the genetic status (hazard ratio, 32.6, P = 0.002). Knockdown of Sdhb and Vhl in an in vitro model demonstrated that inositol metabolism and sialic acids were similarly modulated as in tumors of the respective cluster.

Conclusions: The present study has identified distinct tissue metabolomic profiles of PPGLs in relation to tumor genotypes. In addition, we revealed significantly altered metabolites in the kynurenine pathway in metastatic PPGLs, which can aid in the prediction of its malignant potential. However, further validation studies will be required to confirm our findings.
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http://dx.doi.org/10.1530/EJE-20-1407DOI Listing
June 2021

[Osteology in the spotlight].

Internist (Berl) 2021 May 27;62(5):461-462. Epub 2021 Apr 27.

Paris Lodron Universität Salzburg, Kapitelgasse 4/I, 5020, Salzburg, Österreich.

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http://dx.doi.org/10.1007/s00108-021-01026-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077855PMC
May 2021

The Effect of Biochemical Remission on Bone Metabolism in Cushing's Syndrome: A 2-Year Follow-Up Study.

J Bone Miner Res 2021 Apr 26. Epub 2021 Apr 26.

Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany.

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http://dx.doi.org/10.1002/jbmr.4309DOI Listing
April 2021

Patients with low IGF-I after curative surgery for Cushing's syndrome have an adverse long-term outcome of hypercortisolism-induced myopathy.

Eur J Endocrinol 2021 May 4;184(6):813-821. Epub 2021 May 4.

Medizinische Klinik und Poliklinik IV, LMU Klinikum, Ludwig-Maximilians-Universität München, Munich, Bayern, Germany.

Background: Glucocorticoid excess leads to muscle atrophy and weakness in patients with endogenous Cushing's syndrome. Insulin-like growth factor I (IGF-I) is known to have protective effects on muscle loss. We hypothesized that individual serum IGF-I concentrations might be predictive for long-term myopathy outcome in Cushing's syndrome.

Patients And Methods: In a prospective longitudinal study of 31 patients with florid Cushing's syndrome, we analyzed IGF-I and IGF binding protein 3 (IGFBP 3) concentrations at the time of diagnosis and following surgical remission over a period of up to 3 years. We assessed muscle strength by grip strength measurements using a hand grip dynamometer and muscle mass by bio-impedance measurements.

Findings: Individual serum IGF-I concentrations in the postoperative phase were strongly predictive of long-term grip strength outcome (rs = 0.696, P ≤ 0.001). Also, lower IGF-I concentrations were associated with a lower muscle mass after 3 years (rs = 0.404, P = 0.033). While patients with high IGF-I s.d. scores (SDS; >1.4) showed an improvement in grip strength within the follow-up period (P = 0.009), patients with lower IGF-I SDS (≤-0.4) had a worse outcome with persisting muscle dysfunction. In contrast, preoperative IGF-I concentrations during the florid phase of Cushing's syndrome did not predict long-term muscle function outcome (rs = 0.285, P = 0.127).

Conclusion: Lower individual IGF-I concentrations 6 months after curative surgery for Cushing's syndrome are associated with adverse long-term myopathy outcome and IGF-I might be essential for muscle regeneration in the early phase after correction of hypercortisolism.
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http://dx.doi.org/10.1530/EJE-20-1285DOI Listing
May 2021

Chemosensory dysfunction in Cushing's syndrome.

Endocrine 2021 Sep 5;73(3):674-681. Epub 2021 Apr 5.

Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität, München, Germany.

Purpose: Cushing's syndrome (CS) can lead to structural changes in the brain and cognitive impairment, but chemosensory function has not been investigated yet. The aim was to analyze sense of smell and taste in patients with CS and explore the effect of therapy.

Methods: The study cohort comprised 20 patients with florid CS treated between 2018 and 2020 in the outpatient clinic of the LMU Munich. We compared these 20 patients with CS to 40 healthy subjects matched for age, sex, and smoking status. Patients' sense of smell and taste was examined at diagnosis and 3 months after successful therapeutic surgery leading to clinical and biochemical remission. Odor threshold, discrimination, and identification were measured with "Sniffin' Sticks", taste was measured with "Taste Strips". Perceived sense of smell and taste was retrieved via a questionnaire.

Results: Patients with florid CS had significantly reduced smell (total smell score 30.3 vs. 34.4, p < 0.0005) and taste scores (9.5 vs. 12.0, p < 0.0005) compared to controls and significantly more frequently hyposmia (55 vs. 2.5%, p < 0.0005), hypogeusia (40 vs. 0%, p < 0.0005), and self-reported chemosensory impairment (60 vs. 0%, p < 0.0005). Three months after successful surgery, CS patients showed significant improvement of odor threshold (8.1 vs. 7.0, p < 0.0005), odor discrimination (12.0 vs. 11.0, p = 0.003), total smell score (33.4 vs. 30.3, p < 0.0005), and taste (11.5 vs. 9.5, p = 0.003).

Conclusions: Chemosensory dysfunction is a novel and clinically relevant feature of CS.
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http://dx.doi.org/10.1007/s12020-021-02707-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325648PMC
September 2021

Differential effects of reduced mineralocorticoid receptor activation by unilateral adrenalectomy vs mineralocorticoid antagonist treatment in patients with primary aldosteronism - Implications for depression and anxiety.

J Psychiatr Res 2021 05 13;137:376-382. Epub 2021 Mar 13.

Medizinische Klinik und Poliklinik 4, LMU, München, Germany. Electronic address:

The mineralocorticoid receptor (MR) and its ligand aldosterone have been found to play a major role in the pathophysiology of depression. Both could be targets of therapeutic interventions. We analyzed laboratory data and questionnaires evaluating anxiety (using GAD-7 questionnaire) and depression (using PHQD questionnaire) of up to 210 patients with primary aldosteronism (PA) (82 females, 54.7 ± 12.0yrs; 128 males, 48.7 ± 12.8yrs) before and one year after initiation of specific treatment of PA by either adrenalectomy (ADX) or treatment with mineralocorticoid receptor antagonists (MRA). After ADX normalization of aldosterone excess was observed. This was associated with a significant reduction of depressive symptoms, but no significant change in GAD-7 score. MRA treatment was accompanied with persistent high aldosterone levels, but led to a significant improvement of anxiety, but no significant changes in PHQD scores. These data suggest different mechanistic pathways for depression and anxiety mediated via the MR. For treatment of depression a reduction of aldosterone levels might be relevant at CNS locations specific for aldosterone, whereas MRA targets MR more broadly, including areas, where cortisol is the main ligand. MRA may be useful in treatment of anxiety related behavior.
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http://dx.doi.org/10.1016/j.jpsychires.2021.02.064DOI Listing
May 2021

Is Differentially Expressed in Aldosterone-Producing Adenomas and Protects Human Adrenocortical Cells From Ferroptosis.

Hypertension 2021 May 22;77(5):1647-1658. Epub 2021 Mar 22.

Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU München, Germany (Y.Y., T.V., C.A., M.B., F.B., M.R., T.A.W.).

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16774DOI Listing
May 2021

Drug-resistant hypertension in primary aldosteronism patients undergoing adrenal vein sampling: the AVIS-2-RH study.

Eur J Prev Cardiol 2021 Mar 20. Epub 2021 Mar 20.

3rd Department of Medicine, Charles University Prague, General Hospital, Prague, Czech Republic.

Aims: We aimed at determining the rate of drug-resistant arterial hypertension in patients with an unambiguous diagnosis of primary aldosteronism (PA). Moreover, we sought for investigating the diagnostic performance of adrenal vein sampling (AVS), and the effect of adrenalectomy on blood pressure (BP) and prior treatment resistance in PA patients subtyped by AVS in major referral centres.

Methods And Results: The Adrenal Vein Sampling International Study-2 (AVIS-2) was a multicentre international study that recruited consecutive PA patients submitted to AVS, according to current guidelines, during 15 years. The patients were over 18 years old with arterial hypertension and had an unambiguous diagnosis of PA. The rate of resistant hypertension was assessed at baseline and after adrenalectomy using the American Heart Association (AHA) 2018 definition. Information on presence or absence of resistant hypertension was available in 89% of the 1625 enrolled PA patients. Based on the AHA 2018 criteria, resistant hypertension was found in 20% of patients, of which about two-thirds (14%) were men and one-third (6%) women (χ2 = 17.1, P < 1*10-4) with a higher rate of RH in men than in women (23% vs. 15% P < 1*10-4). Of the 292 patients with resistant hypertension, 98 (34%) underwent unilateral AVS-guided adrenalectomy, which resolved BP resistance to antihypertensive treatment in all.

Conclusions: (i) Resistant hypertension is a common presentation in patients seeking surgical cure of PA; (ii) AVS is key for the optimal management of patients with PA due to resistant hypertension; and (iii) AVS-guided adrenalectomy allowed resolution of treatment-resistant hypertension.
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http://dx.doi.org/10.1093/eurjpc/zwaa108DOI Listing
March 2021

Perspectives of the European Society of Endocrinology (ESE) and the European Society of Paediatric Endocrinology (ESPE) on rare endocrine disease.

Endocrine 2021 03 19;71(3):539-541. Epub 2021 Mar 19.

Secretary General, European Society for Paediatric Endocrinology (ESPE), Erasmus University Medical Center, Rotterdam, The Netherlands.

Purpose: Rare diseases affect <1 in 2000 people. Despite their rarity, they collectively affect ~30 million people across Europe. The aim of this article is to present the view of our European endocrine societies on the care of patients with rare endocrine conditions.

Methods: We evaluated the current situation of patients with rare endocrine disease and present the joint views of the European Society for Endocrinology (ESE) and the European Society for Pediatric Endocrinology (ESPE) on how the endocrine disciplines can support and contribute to a better health of patients with rare endocrine conditions in Europe.

Results: Rare diseases pose many challenges, including early diagnosis and innovative treatment options. Rare endocrine diseases can be found among inherited disorders, cancers, and conditions associated with metabolic disorders such as diabetes, calcium and bone metabolism, lipid metabolism, hypogonadism, and adrenal, pituitary, and thyroid dysfunction. According to the European Registries for Rare Endocrine conditions, there are over 440 distinct rare diseases that affect the endocrine system. Rare endocrine diseases are often chronic and life-threatening.

Conclusions: ESE and ESPE support a strategic plan to address unmet needs in the area of rare endocrine conditions. The EU should continue to evolve and expand its plans for funding European Reference Networks so that they can expand their activities.
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http://dx.doi.org/10.1007/s12020-021-02652-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976677PMC
March 2021

Circulating microRNA Expression in Cushing's Syndrome.

Front Endocrinol (Lausanne) 2021 22;12:620012. Epub 2021 Feb 22.

Department of Endocrinology, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University, Munich, Germany.

Context: Cushing's syndrome (CS) is a rare disease of endogenous hypercortisolism associated with high morbidity and mortality. Diagnosis and classification of CS is still challenging.

Objective: Circulating microRNAs (miRNAs) are minimally invasive diagnostic markers. Our aim was to characterize the circulating miRNA profiles of CS patients and to identify distinct profiles between the two major CS subtypes.

Methods: We included three groups of patients from the German Cushing's registry: ACTH-independent CS (Cortisol-Producing-Adenoma; CPA), ACTH-dependent pituitary CS (Cushing's Disease; CD), and patients in whom CS had been ruled out (controls). Profiling of miRNAs was performed by next-generation-sequencing (NGS) in serum samples of 15 CS patients (each before and after curative surgery) and 10 controls. Significant miRNAs were first validated by qPCR in the discovery cohort and then in an independent validation cohort of 20 CS patients and 11 controls.

Results: NGS identified 411 circulating miRNAs. Differential expression of 14 miRNAs were found in the pre- and postoperative groups. qPCR in the discovery cohort validated 5 of the significant miRNAs from the preoperative group analyses. Only, miR-182-5p was found to be significantly upregulated in the CD group of the validation cohort. Comparing all CS samples as a group with the controls did not reveal any significant differences in expression.

Outcome: In conclusion, our study identified miR-182-5p as a possible biomarker for CD, which has to be validated in a prospective cohort. Furthermore, our results suggest that presence or absence of ACTH might be at least as relevant for miRNA expression as hypercortisolism itself.
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http://dx.doi.org/10.3389/fendo.2021.620012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937959PMC
February 2021

First German Guideline on Diagnostics and Therapy of Clinically Non-Functioning Pituitary Tumors.

Exp Clin Endocrinol Diabetes 2021 Mar 9;129(3):250-264. Epub 2021 Mar 9.

Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg, University of Würzburg, Würzburg, Germany.

Although non-functioning pituitary tumors are frequent, diagnostic and therapeutic concepts are not well standardized. We here present the first German multidisciplinary guideline on this topic. The single most important message is to manage the patients by a multidisciplinary team (consisting at least of an endocrinologist, a neurosurgeon, and a (neuro-) radiologist). The initial diagnostic work-up comprises a detailed characterization of both biochemical (focusing on hormonal excess or deficiency states) and morphological aspects (with magnetic resonance imaging of the sellar region). An ophthalmological examination is only needed in presence of symptoms or large tumors affecting the visual system. Asymptomatic, hormonally inactive tumors allow for a 'wait and scan' strategy. In contrast, surgical treatment by an experienced pituitary surgeon is standard of care in case of (impending) visual impairment. Therapeutic options for incompletely resected or recurrent tumors include re-operation, radiotherapy, and observation; the individual treatment plan should be developed multidisciplinary. Irrespective of the therapeutic approach applied, patients require long-term follow-up. Patient with larger pituitary tumors or former surgery/radiotherapy should be regularly counseled regarding potential symptoms of hormonal deficiency states.
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http://dx.doi.org/10.1055/a-1373-4087DOI Listing
March 2021

Pituitary in the Spotlight.

Exp Clin Endocrinol Diabetes 2021 Mar 9;129(3):143-145. Epub 2021 Mar 9.

Department of Neurosurgery, University of Tuebingen, Tuebingen, Germany.

The German Society of Endocrinology (DGE) has a long-standing scientific and clinical focus on the pituitary. The pituitary working group ' is an interdisciplinary special interest group with a focus on advancing diagnosis and treatment of pituitary conditions. On the occasion of the English publication of the S2K clinical guideline , we present here a series of 12 articles from internationally renowned authors from inside and outside of Germany.
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http://dx.doi.org/10.1055/a-1369-8898DOI Listing
March 2021

Approach to the Patient Treated with Steroidogenesis Inhibitors.

J Clin Endocrinol Metab 2021 Jun;106(7):2114-2123

Department of Oncology and Metabolism, University of Sheffield, Sheffield, S10 2TN, UK.

Steroidogenesis inhibitors can be given to control the hypercortisolism of Cushing's syndrome in various situations: when surgery has been unsuccessful or not possible; in metastatic adrenocorticotropin hormone (ACTH) or cortisol-secreting tumors; when waiting for the maximal efficacy of radiation techniques; for rapid treatment of severe hypercortisolism in patients with occult ACTH-producing tumors; or as a presurgical treatment in patients with severe comorbidities. Whilst biochemical "control" can be achieved in more than 50% of cases, daily management of such drugs can be challenging. Indeed, with a "dose-titration" or a "block and replace" approach, defining eucortisolism is usually difficult, requiring the measurement of several biological markers. Moreover, each drug has its own side effects, which must be monitored closely. The aim of this "approach to the patient" is to shed light on the management of hypercortisolism with 4 steroidogenesis inhibitors (ketoconazole, levoketoconazole, metyrapone, osilodrostat) to help endocrinologists dealing with patients with Cushing's syndrome. Various points will be discussed, such as initial dose of treatment, dose schedule, monitoring of efficacy, and side effects of monotherapy. The combination of steroidogenesis inhibitors will also be discussed.
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http://dx.doi.org/10.1210/clinem/dgab122DOI Listing
June 2021

Altered Taste Perception for Sodium Chloride in Patients With Primary Aldosteronism: A Prospective Cohort Study.

Hypertension 2021 Apr 1;77(4):1332-1340. Epub 2021 Mar 1.

From the Medizinische Klinik und Poliklinik IV (C.A., V.G., D.A.H., H.S., L.H., H.K., L.S., F.B., M.R.), Klinikum der Universität München, LMU München, Munich, Germany.

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16440DOI Listing
April 2021

Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?

J Endocr Soc 2021 Mar 9;5(3):bvaa205. Epub 2021 Feb 9.

Royal Veterinary College, University of London, London, UK.

The designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.
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http://dx.doi.org/10.1210/jendso/bvaa205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874572PMC
March 2021

Autonomous Cortisol Secretion Influences Psychopathological Symptoms in Patients With Primary Aldosteronism.

J Clin Endocrinol Metab 2021 May;106(6):e2423-e2433

Endokrinologie in Charlottenburg, Endokrinologie Praxis am Stuttgarter Platz, Berlin, Germany.

Context: Primary aldosteronism (PA) is associated with impaired quality of life (QoL). Autonomous cortisol cosecretion (ACS) is a relevant phenotype of PA, which could contribute to depression and anxiety disorders. This has not been investigated so far.

Objective: To evaluate the prevalence of depression and anxiety in PA patients according to ACS.

Methods: We performed testing for hypercortisolism and evaluated anxiety, depression and QoL by self-rating questionnaires in newly diagnosed PA patients of the German Conn's Registry; 298 patients were reevaluated at follow-up.

Results: In the overall cohort, scores for anxiety (P < .001), depression (P < .001), and QoL (mental P = .021; physical P = .015) improved significantly at follow-up. This improvement was seen in both subgroups of patients with and without ACS, with the exception of the mental subscore in no-ACS patients. Analysis for sex differences showed that anxiety decreased significantly in females with ACS and no-ACS, whereas males with no-ACS failed to improve. Depression improved significantly in males and females with ACS (P = .004, P = 0.011 respectively), but not in those with no-ACS. Physical subscore of QoL improved significantly (P = .023) in females with ACS and mental subscore (P = .027) in males with ACS, whereas no differences were seen for the no-ACS groups.

Conclusion: Improvement in depression and anxiety scores in response to treatment of PA is more pronounced in patients with ACS in contrast to no-ACS suggesting a role of ACS in the psychopathological symptoms of patients with PA. Furthermore, we observed significant differences in depression and anxiety scores between the sexes.
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http://dx.doi.org/10.1210/clinem/dgab099DOI Listing
May 2021

Update on primary bilateral macronodular adrenal hyperplasia (PBMAH).

Endocrine 2021 03 15;71(3):595-603. Epub 2021 Feb 15.

Institut Cochin, Université de Paris, Inserm U1016, CNRS UMR8104, 24 rue du Faubourg Saint-Jacques, 75014, Paris, France.

Primary bilateral macronodular adrenal hyperplasia (PBMAH), characterized by bilateral benign adrenal macronodules (>1 cm) potentially responsible for variable levels of cortisol excess, is a rare and heterogeneous disease. However, its frequency increases due to incidentally diagnosed cases on abdominal imaging carried out for reasons other than suspected adrenal disease. Mostly isolated, it can also be associated with dominantly inherited genetic conditions in rare cases. Considering the bilateral nature of adrenal involvement and the description of familial cases, the search of a genetic predisposition has led to the identification of germline heterozygous inactivating mutations of the putative tumor suppressor gene ARMC5, causing around 25% of the apparent sporadic cases. Rigorous biochemical and imaging assessment are key elements in the management of this challenging disease in terms of diagnosis. Treatment is reserved for symptomatic patients with overt or subclinical Cushing syndrome, and was historically based on bilateral adrenalectomy, which nowadays tends to be replaced by unilateral adrenalectomy or lifelong treatment with cortisol synthesis inhibitors.
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http://dx.doi.org/10.1007/s12020-021-02645-wDOI Listing
March 2021

Single-cell molecular profiling of all three components of the HPA axis reveals adrenal ABCB1 as a regulator of stress adaptation.

Sci Adv 2021 Jan 27;7(5). Epub 2021 Jan 27.

Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Bavaria 80804, Germany.

Chronic activation and dysregulation of the neuroendocrine stress response have severe physiological and psychological consequences, including the development of metabolic and stress-related psychiatric disorders. We provide the first unbiased, cell type-specific, molecular characterization of all three components of the hypothalamic-pituitary-adrenal axis, under baseline and chronic stress conditions. Among others, we identified a previously unreported subpopulation of cells involved in stress adaptation in the adrenal gland. We validated our findings in a mouse stress model, adrenal tissues from patients with Cushing's syndrome, adrenocortical cell lines, and peripheral cortisol and genotyping data from depressed patients. This extensive dataset provides a valuable resource for researchers and clinicians interested in the organism's nervous and endocrine responses to stress and the interplay between these tissues. Our findings raise the possibility that modulating ABCB1 function may be important in the development of treatment strategies for patients suffering from metabolic and stress-related psychiatric disorders.
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http://dx.doi.org/10.1126/sciadv.abe4497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840126PMC
January 2021

Genomics in Cushing's Disease: The Dawn of a New Era.

J Clin Endocrinol Metab 2021 May;106(6):e2455-e2456

Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, München, Germany.

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http://dx.doi.org/10.1210/clinem/dgaa969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118357PMC
May 2021

Corticotroph tumor progression after bilateral adrenalectomy (Nelson's syndrome): systematic review and expert consensus recommendations.

Eur J Endocrinol 2021 Mar;184(3):P1-P16

Section on Genetics & Endocrinology Eunice Kennedy Shriver National Insitute of Child Health & Human Development (NICHD) National Institute of Health (NIH), NIH Clinical Research Center, Bethesda, Maryland, USA.

Background: Corticotroph tumor progression (CTP) leading to Nelson's syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing's disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing.

Methods: A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, cumulative incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28, 2018.

Results: Data covered definition and cumulative incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients).

Conclusions: We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2-4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension.
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http://dx.doi.org/10.1530/EJE-20-1088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060870PMC
March 2021

Atherosclerotic Burden and Arterial Stiffness are Not Increased in Patients with Milder Forms of Primary Aldosteronism Compared to Patients with Essential Hypertension.

Horm Metab Res 2021 Mar 13;53(3):178-184. Epub 2021 Jan 13.

Medizinische Klinik und Poliklinik IV, LMU München, Munich, Germany.

Patients with primary aldosteronism (PA) are at increased cardiovascular risk, compared to patients with essential hypertension (EH). Cardiovascular damage could depend on PA phenotype, potentially being lower in milder forms of PA. Our aim was to assess atherosclerotic burden and arterial stiffness in 88 prospectively recruited patients, including 44 patients with mild PA and EH respectively. All patients underwent a structured study program, including measurements of ankle-brachial index, oscillometric measurement of central pulse wave velocity (cPWV) and vascular ultrasound examination of the supraaortic arteries, the abdominal aorta, and the femoropopliteal arteries. A plaque score was calculated to estimate atherosclerotic burden for each patient. This is a prospective case-control study set at a tertiary care hospital. Patients with PA and EH matched well for age, gender, blood pressure, BMI, and cardiovascular risk factors such as diabetes mellitus and smoking status. Common carotid intima-media thickness (0.77 vs. 0.75 mm; p=0.997) and cPWV (7.2 vs. 7.1 m/s; p=0.372) were comparable between patients with PA and EH. The atherosclerotic burden, as expressed by the plaque score, did not differ between the two groups (p=0.159). However, after initiation of treatment cPWV was significantly decreased in patients with PA (p=0.017). This study shows that subclinical atherosclerotic burden and arterial stiffness in patients with milder forms of PA is comparable to patients with EH. Nevertheless, specific treatment for PA significantly improved cPWV, which argues for a more liberal use of mineralocorticoid receptor antagonists in patients with arterial hypertension.
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http://dx.doi.org/10.1055/a-1326-2164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924991PMC
March 2021

Targeted Metabolomics as a Tool in Discriminating Endocrine From Primary Hypertension.

J Clin Endocrinol Metab 2021 Mar;106(4):1111-1128

Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, UniversitätsSpital Zürich, Zurich, Switzerland.

Context: Identification of patients with endocrine forms of hypertension (EHT) (primary hyperaldosteronism [PA], pheochromocytoma/paraganglioma [PPGL], and Cushing syndrome [CS]) provides the basis to implement individualized therapeutic strategies. Targeted metabolomics (TM) have revealed promising results in profiling cardiovascular diseases and endocrine conditions associated with hypertension.

Objective: Use TM to identify distinct metabolic patterns between primary hypertension (PHT) and EHT and test its discriminating ability.

Methods: Retrospective analyses of PHT and EHT patients from a European multicenter study (ENSAT-HT). TM was performed on stored blood samples using liquid chromatography mass spectrometry. To identify discriminating metabolites a "classical approach" (CA) (performing a series of univariate and multivariate analyses) and a "machine learning approach" (MLA) (using random forest) were used.The study included 282 adult patients (52% female; mean age 49 years) with proven PHT (n = 59) and EHT (n = 223 with 40 CS, 107 PA, and 76 PPGL), respectively.

Results: From 155 metabolites eligible for statistical analyses, 31 were identified discriminating between PHT and EHT using the CA and 27 using the MLA, of which 16 metabolites (C9, C16, C16:1, C18:1, C18:2, arginine, aspartate, glutamate, ornithine, spermidine, lysoPCaC16:0, lysoPCaC20:4, lysoPCaC24:0, PCaeC42:0, SM C18:1, SM C20:2) were found by both approaches. The receiver operating characteristic curve built on the top 15 metabolites from the CA provided an area under the curve (AUC) of 0.86, which was similar to the performance of the 15 metabolites from MLA (AUC 0.83).

Conclusion: TM identifies distinct metabolic pattern between PHT and EHT providing promising discriminating performance.
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http://dx.doi.org/10.1210/clinem/dgaa954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993566PMC
March 2021

IGF-I/IGFBP3/ALS Deficiency in Sarcopenia: Low GHBP Suggests GH Resistance in a Subgroup of Geriatric Patients.

J Clin Endocrinol Metab 2021 Mar;106(4):e1698-e1707

Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany.

Context: Definition of etiological subgroups of sarcopenia may help to develop targeted treatments. insulin like growth factor-I (IGF-I), Insulinlike growth factor binding protein 3 (IGFBP3), and acid labile subunit (ALS) build a ternary complex that mediates growth hormone (GH) effects on peripheral organs, such as muscle. Low GH binding protein (GHBP) as a marker of GH receptor number would hint toward GH resistance.

Objective: We aimed to analyze the association of IGF-I, IGFBP3, and ALS with sarcopenia.

Study Participants And Setting: A total of 131 consecutively recruited patients of a geriatric ward were included in a single-center cross-sectional analysis; the nonsarcopenic patients served as controls.

Methods: Measures included sarcopenia status by hand-grip strength measurement and Skeletal Muscle Index (SMI); IGF-I, IGFBP3, ALS, GH, GHBP; body mass index (BMI); Activity of Daily Living (ADL); Mini-Mental State Examination (MMSE); routine laboratory parameters; and statistical regression modeling.

Results: Compared with controls, sarcopenic patients did not differ regarding age, sex, ADL, MMSE, C-reactive protein, glomerular filtration rate, and albumin serum concentrations. However, sarcopenic patients had significantly lower IGF-I, IGFBP3, and ALS. IGF-I and ALS associated significantly with sarcopenia and low hand-grip strength, even after adjustment for age, sex, BMI, and albumin, but not with low SMI. GHBP serum was low in sarcopenic patients, but normal in geriatric patients without sarcopenia. Over 60% of patients with IGF-I/ALS deficiency patients showed GH resistance.

Conclusions: Our data suggest that in geriatric patients, low IGF-I/IGFBP3/ALS could be evaluated for causative connection of the sarcopenia spectrum. Low GHBP points toward potential GH resistance as one possible explanation of this deficiency.
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http://dx.doi.org/10.1210/clinem/dgaa972DOI Listing
March 2021
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