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Purpose The upper tolerable intake level for vitamin D in the general population has been set at 4000 international units (IU) daily, but considerable uncertainty remains. We summarized reported harmful effects of a daily vitamin D supplement of 3200–4000 IU in trials lasting ≥ 6 months. Methods We performed a systematic review and meta-analysis of randomized controlled trials in several databases and identified 22 trials reporting safety data. Parameters of calcium metabolism, falls, hospitalization, and mortality were assessed. Results The selected trials comprised a total number of 12,952 participants. All trials used supplemental vitamin D3. The relative risk (RR) of hypercalcemia in the vitamin D vs. control arm was 2.21 (95%CI: 1.26–3.87; 10 studies), with a vitamin D-induced frequency of hypercalcemia of 4 cases per 1000 individuals. Subgroup analysis in trials with > 100 and ≤ 100 study participants revealed an RR of 2.63 (95%CI: 1.30–5.30; 7 studies) and 0.80 (95%CI: 0.24–2.62; 3 studies), respectively (Pinteraction = 0.06). Risks of falls and hospitalization were also significantly increased in the vitamin D arm with an RR of 1.25 (95%CI: 1.01–1.55; 4 studies) and 1.16 (95%CI: 1.01–1.33; 7 studies), respectively. Risks of hypercalciuria, kidney stones, and mortality did not differ significantly between study arms. Quality assessment revealed high risk of incomplete reporting of safety-related outcome data. Conclusion Supplemental vitamin D doses of 3200–4000 IU/d appear to increase the risk of hypercalcemia and some other adverse events in a small proportion of individuals, indicating that this dose is not completely safe. In future studies, rigorous reporting of safety-related outcomes is needed when using moderately high doses of vitamin D.

Hypothyroidism is a condition where the patient’s thyroid gland cannot produce sufficient thyroid hormones (mainly triiodothyronine and thyroxine). The primary cause of hypothyroidism is autoimmune-mediated destruction of the thyroid gland, referred to as Hashimoto’s thyroiditis. A patient’s desired thyroid hormone concentration is achieved by oral administration of thyroid hormone, usually levothyroxine. Establishing individual levothyroxine doses to achieve desired thyroid hormone concentrations requires several patient visits. Additionally, clear guidance for the dosing regimen is lacking, and significant inter-individual differences exist. This study aims to design a digital automatic dosing algorithm for patients suffering from Hashimoto’s thyroiditis. The dynamic behaviour of the relevant thyroid function is mathematically modelled. Methods of automatic control are exploited for the design of the proposed robust model-based levothyroxine dosing algorithm. Numerical simulations are performed to evaluate the mathematical model and the dosing algorithm. With the help of the developed controller thyroid hormone concentrations of patients, emulated using Thyrosim, have been regulated under the euthyroid state. The proposed concept demonstrates reliable responses amidst varying patient parameters. Our developed model provides a useful basis for the design of automatic levothyroxine dosing algorithms. The proposed robust feedback loop contributes to the first results for computer-assisted thyroid dosing algorithms.

ZusammenfassungEin wichtiges Ziel bei der Behandlung der Nebenniereninsuffizienz ist die Prävention der Nebennierenkrise (auch akute Nebenniereninsuffizienz oder Addison-Krise genannt). Um in Österreich eine bessere Implementierung sowie Harmonisierung der Maßnahmen zur Prävention und Therapie der Nebennierenkrise zu erreichen, wurde dieses Konsensusdokument erarbeitet. Folgende Maßnahmen werden grundsätzlich für alle Patient*innen mit Nebenniereninsuffizienz empfohlen und in diesem Manuskript ausführlich erörtert: 1. Versorgung mit einer Notfallkarte („steroid emergency card“) sowie evtl. auch mit einem Armband oder einer Halskette (oder Ähnlichem) mit medizinischem Alarmhinweis „Nebenniereninsuffizienz, benötigt Glukokortikoide“. 2. Versorgung mit einem Hydrocortison-Notfallkit zur Injektion (alternativ auch Suppositorien/Zäpfchen zur Notfallapplikation) sowie ausreichenden oralen Glukokortikoiddosen für Stresssituationen/Erkrankungen. 3. Schulung von Patient*innen und Angehörigen zur Steigerung der Glukokortikoidtherapie in Stresssituationen bzw. bei Erkrankungen („sick day rules“) und zur Selbstinjektion von Hydrocortison. 4. Versorgung mit einer Behandlungsleitlinie (Informationszettel) zur Prävention und Therapie der Nebennierenkrise, welche bei Bedarf auch dem Gesundheitspersonal gezeigt werden soll. 5. Versorgung mit einer Notfall-Telefonnummer des behandelnden endokrinologischen Teams und/oder medizinisch geschulter Betreuungspersonen bzw. Angehöriger. 6. Regelmäßige (vorzugsweise jährliche) Wiederholung der Schulungsmaßnahmen. Dieses Konsensusdokument beinhaltet auch ausführliche Empfehlungen für die perioperative Glukokortikoidtherapie sowie für diverse andere Stresssituationen.

ZusammenfassungUm in der Therapie der kortikotropen Insuffizienz das physiologische Cortisolprofil besser nachahmen zu können, wurden in den letzten Jahren zwei Hydrocortisonpräparate mit verzögerter Wirkstofffreisetzung entwickelt. Plenadren®, ein Hydrocortisonpräparat mit zweistufiger Wirkstofffreisetzung für den Morbus Addison, kann den frühmorgendlichen Cortisolanstieg nicht imitieren, aber möglicherweise Lebensqualität und einige metabolische Parameter verbessern. Chronocort (Efmody®), ein Hydrocortisonpräparat mit veränderter Wirkstofffreisetzung mit abendlicher und morgendlicher Einnahme („toothbrush regimen“), kann ein nahezu physiologisches Cortisolprofil nachahmen und ist in der Therapie des adrenogenitalen Syndroms zugelassen, noch nicht aber für den Morbus Addison.

Resting heart rate (RHR) is associated with increased risk of cardiovascular morbidity and mortality. Thyroid hormones exert several effects on the cardiovascular system, but the relation between thyroid function and RHR remains to be further established. We evaluated whether measures of thyroid hormone status are associated with RHR in patients referred to coronary angiography. Thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxin (FT4), and RHR were determined in 2795 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study. Median (25th to 75th percentile) serum concentrations were 1.25 (0.76–1.92) mU/l for TSH, 4.8 (4.2–5.3) pmol/l for FT3 and 17.1 (15.4-19.0) pmol/l for FT4, and mean (±standard deviation) RHR was 68.8 (±11.7) beats/min. Comparing the highest versus the lowest quartile, RHR (beats/min) was significantly higher in the fourth FT4 quartile [3.48, 95% confidence interval (CI): 2.23–4.73; p

ZusammenfassungDie subakute Thyreoiditis (SAT) und die akute suppurative Thyreoiditis (AST) sind Schilddrüsenerkrankungen, bei welchen es durch Zerstörung von Schilddrüsengewebe zum Auftreten einer Hyperthyreose kommen kann. Die SAT ist vermutlich (post-)viraler Genese. Typischerweise folgt einer initial hyperthyreoten Phase oft eine zumeist transiente Hypothyreose, klinisch sind Halsschmerzen, Fieber oder Abgeschlagenheit charakteristisch. Laborchemisch werden oft erhöhte Entzündungsparameter gefunden, hilfreich für die Diagnosestellung sind außerdem ein erhöhtes Thyreoglobulin sowie hohe Leberparameter. Sonographisch zeigen sich häufig fokale, schlecht abgrenzbare hypoechogene Areale bei verminderter Schilddrüsendurchblutung, in szintigraphischen Untersuchungen ist der Tracer-Uptake reduziert. Therapeutisch kommen Betablocker zur Linderung hyperthyreoter Beschwerden zum Einsatz, zur analgetischen Therapie werden nichtsteroidale Antirheumatika (NSAR) und Glukokortikoide eingesetzt. In schweren Fällen kann auch eine Thyreoidektomie notwendig sein, bei unklaren Fällen sollte die Indikation zu einer Feinnadelpunktion großzügig gestellt werden, um eine Abgrenzung zu malignen Prozessen oder einer AST zu ermöglichen. Im Gegensatz zur SAT handelt es sich bei der AST um eine bakterielle Infektion der Schilddrüse, die oft auf dem Boden von anatomisch-strukturellen Veränderungen entsteht. Typische Symptome umfassten eine Schwellung des Halses verbunden mit Schmerzen, Fieber, Heiserkeit, Dysphagie sowie einem lokalen Erythem. Laborchemisch zeigen sich auch hier erhöhte Entzündungsparameter, während eine Hyperthyreose seltener ist. In der akuten Entzündungsphase kann eine Abszessformation und ihre Ausdehnung mittels Ultraschall oder CT dargestellt werden. Hinsichtlich der Therapie sind eine rasche antibiotische Therapie und eine Drainage des Abszesses von großer Bedeutung, teilweise kann auch eine operative Entfernung von Schilddrüsengewebe notwendig werden.

ZusammenfassungAmiodaron ist ein Klasse III-Antiarrhythmikum mit einem breiten Spektrum von Wirkungen auf die Schilddrüse, wodurch sowohl eine Schilddrüsenunterfunktion als auch eine Schilddrüsenüberfunktion entstehen kann. Dies ist zum einen durch den sehr hohen Jodgehalt von Amiodaron und zum anderen durch das mögliche Auslösen einer destruktiven Thyreoiditis zu erklären. Eine Amiodaron-induzierte Hypothyreose (AIH) wird wie auch sonst üblich mit Levothyroxin behandelt, ein Absetzen von Amiodaron ist deshalb nicht notwendig. Bei der Amiodaron-induzierten Thyreotoxikose (AIT) werden zwei Formen unterschieden: Die AIT 1 entsteht durch den Jodexzess bei Amiodarontherapie auf dem Boden eines Morbus Basedow oder einer Schilddrüsenautonomie, die AIT 2 stellt eine destruktive Thyreoiditis dar. Diese Unterscheidung ist bei der Diagnostik von großer Bedeutung, da je nach Subtyp eine unterschiedliche Erstlinientherapie begonnen wird. Die AIT 1 wird zunächst mit Thionamiden (± Natriumperchlorat) behandelt, PatientInnen mit AIT 2 erhalten zu Beginn Glukokortikoide. Falls eine genaue Einteilung in einen der beiden Subtypen nicht möglich ist (Mischtypen/undefinierte Typen), kann zunächst das Ansprechen auf Thionamide getestet werden oder von Beginn an eine Kombinationstherapie mit Glukokortikoiden erfolgen. Amiodaron muss insbesondere bei milden Fällen einer AIT 2 nicht abgesetzt werden, bei AIT 1 sollte ein Absetzen erwogen werden. In Notfällen sowie bei kritisch kranken PatientInnen kann auch eine Thyreoidektomie erfolgen.

ZusammenfassungDie häufigsten Ursachen für die Entstehung einer Hyperthyreose sind die Immunthyreopathie Basedow sowie die Schilddrüsenautonomie. Für die Diagnosestellung sind die Bestimmung der TSH-Rezeptor-Antikörper (TRAK) nebst Thyroidea-stimulierendem Hormon (TSH), freiem Thyroxin (fT4) und freiem Trijodthyronin (fT3) wichtig. Die Bestimmung der T3/T4-Ratio kann in der Abgrenzeng einer Immunthyreopathie Basedow zu einer destruktiven Thyreoiditis hilfreich sein. Bei der Immunthyreopathie Basedow sind das typische sonographische Bild einer hypoechogenen Schilddrüse mit erhöhter Vaskularisation und zunehmend auch die quantitative Bestimmung der Durchblutung in Form der „peak systolic velocity“ (PSV) weitere diagnostische Hilfsmittel. Die Szintigraphie hat bei der Diagnosestellung der Schilddrüsenautonomie nach wie vor ihren Stellenwert.Therapeutisch steht bei der Immunthyreopathie Basedow die medikamentöse, thyreostatische Therapie vorrangig mit Thiamazol in Form des Titrationsschemas im Vordergrund, die für 12–18 Monate durchgeführt wird. Liegen die TRAK dann im Normbereich, kann ein Absetzversuch unternommen werden. Wenn nicht, oder wenn es zum Auftreten eines Rezidivs kommt, sollte eine definitive Therapie mittels Radiojodtherapie oder Thyreoidektomie erwogen werden. Zur symptomatischen Behandlung können Betablocker wie Propranolol eingesetzt werden. Es gibt Hinweise, dass die lange praktizierte Jodrestriktion im Management der Immunthyreopathie Basedow vermieden werden sollte. Zum Einsatz von Selen liegen positive, aber noch großteils inkonsistente Daten vor, sodass eine Therapieempfehlung derzeit nicht ausgesprochen werden kann. In der Therapie der Schilddrüsenautonomie stehen Radiojodtherapie und die Operation im Vordergrund. Die Diagnose einer thyreotoxischen Krise ist eine klinische und wird anhand des Burch-Wartofsky-Scores gestellt – das Management erfordert meist intensivmedizinische Betreuung.

ZusammenfassungEine Hypothyreose (Schilddrüsenunterfunktion) findet sich bei ca. 5 % der Bevölkerung, wobei man bei der primären Hypothyreose eine manifeste Hypothyreose mit erhöhtem Thyreoidea-stimulierendem Hormon (TSH) und reduziertem freiem Thyroxin (fT4) von einer latenten (subklinischen) Hypothyreose mit zwar erhöhtem TSH, aber im Normbereich gelegenem fT4 unterscheidet. Die Indikationen für eine TSH-Testung sind nicht klar festgelegt, wobei aber von den meisten Fachgesellschaften kein generelles Screening empfohlen wird, es jedoch in der klinischen Routine häufig eine Überdiagnostik gibt. Während eine manifeste Hypothyreose eine klare Therapieindikation für eine Schilddrüsenhormonsubstitution darstellt, wird die Therapieindikation bei der latenten Hypothyreose zunehmend infrage gestellt, da sich häufig mit Hypothyreose in Verbindung gebrachte Beschwerden wie reduzierte Lebensqualität, Müdigkeit oder Übergewicht durch eine Therapie der latenten Hypothyreose nicht verbessern. Andererseits legen neue Erkenntnisse zur Homöostase und Allostase nahe, dass eine differenzierte Betrachtung der Schilddrüsenfunktion inklusive Berücksichtigung individueller Setpoints und adaptiver Mechanismen die Diagnostik und Therapie der Hypothyreose verbessert und die lineare, TSH-zentrierte Vorgehensweise verdrängen könnte. In diesem kurzen Übersichtsartikel gehen wir auf die aktuellen Richtlinien in Bezug auf Diagnostik und Therapie der Hypothyreose ein, wobei wir diese im Hinblick auf rezente Erkenntnisse auf diesem Gebiet beleuchten und großen Wert auf praktische Handlungsempfehlungen für die tägliche Routine legen.

ZusammenfassungSchilddrüsenfunktionsstörungen gehören zu den häufigsten endokrinen Nebenwirkungen, die unter einer Immuncheckpoint-Inhibitor-Therapie auftreten können. Sie sind unter Anti-PD-1- („Anti-programmed cell death 1“) häufiger als unter Anti-CTLA-4-Antikörpern („Anti-Cytotoxic-T-lymphocyte-antigen-4“), und die Inzidenz steigt mit einer Kombinationstherapie an. Pathophysiologisch scheint eine destruktive Thyreoiditis ähnlich einer Postpartum-Thyreoiditis vorzuliegen, im Rahmen derer es meistens zu einer kurzen Hyperthyreosephase kommt, gefolgt von einer Hypo- oder Euthyreose. Auch die Entwicklung einer alleinigen Hypothyreose ist möglich.Therapeutisch steht Observanz der Hyperthyreose im Vordergrund mit Einsatz einer Betablocker-Therapie, wenn eine symptomatische Therapie erforderlich ist. Der Einsatz von Glukokortikoiden oder Thyreostatika ist nicht sinnvoll. Bei Entwicklung einer symptomatischen Hypothyreose mit einem TSH (Thyroidea-stimulierendes Hormon) von 5–10 μU/ml oder einem TSH > 10 μU/ml sollte unabhängig von der Symptomatik eine Levothyroxin-Therapie eingeleitet werden.Aufgrund der häufig oligo- oder asymptomatischen klinischen Präsentation sollte ein regelmäßiges Screening auf Schilddrüsenfunktionsstörungen und Hypophysitis, beginnend vor Immuntherapieeinleitung und hiernach monatlich in den ersten 6 Monaten, durchgeführt werden inkl. TSH, freiem Trijodthyronin (fT3), freiem Thyroxin (fT4), Cortisol und adrenokortikotropem Hormon (ACTH). Nach den ersten 6 Monaten können die Kontrollintervalle ausgeweitet werden. Die Entwicklung von Schilddrüsenfunktionsstörungen sollte in der Regel nicht zu einer Unterbrechung der Immuntherapie führen, da diese häufig transient, mild und einfach behandelbar sind.

ZusammenfassungSchilddrüsenhormone und Schilddrüsenerkrankungen spielen eine wichtige Rolle bei Fertilität, Schwangerschaft und Laktation. Die diversen Richtlinien und Expertenempfehlungen zur Diagnostik und Therapie von Schilddrüsenerkrankungen bei Kinderwunsch und Schwangerschaft sind teils heterogen und oftmals ohne klare Handlungsanweisung für oder gegen eine bestimmte Maßnahme, was eine gewisse Verunsicherung hervorruft. In diesem Übersichtsartikel möchten wir daher die derzeitige Evidenz auf diesem Gebiet in Bezug auf praktische Handlungsanweisungen darlegen, um dem Leser für die Praxis eine nützliche Entscheidungshilfe an die Hand zu geben. Wir werden besonders auf die aktuelle Evidenzlage bzgl. der Behandlung der latenten Hypothyreose präkonzeptionell, bei Infertilität und in der Schwangerschaft eingehen, sowie auf die Wichtigkeit der Beratung und gemeinsamen Therapieentscheidung bei Hyperthyreose und Kinderwunsch bzw. Schwangerschaft. Wir möchten auch besonders betonen, dass diverse wichtige Studien erst nach Publikation der aktuellen Richtlinien auf diesem Gebiet veröffentlicht wurden, was in der Routinebehandlung unserer Patientinnen natürlich berücksichtigt werden sollte. Da manifeste Schilddrüsenerkrankungen präkonzeptionell und in der Schwangerschaft häufig und in der Regel therapiebedürftig sind, plädieren wir für ein generelles Screening auf Schilddrüsenfunktionsstörungen bei allen Frauen mit Kinderwunsch sowie bei allen mit positivem Schwangerschaftstest.

A central goal of the adrenal insufficiency management is the prevention of acute adrenal insufficiency (also known as adrenal crisis or Addison crisis). This consensus document was generated in order to achieve better implementation and harmonization of measures for the prevention and treatment of acute adrenal insufficiency in Austria. The following measures are generally recommended for all patients with adrenal insufficiency and are outlined in this manuscript: (1) Provision of a "steroid emergency card" and possibly also a medical alert bracelet or necklace (or similar identification). (2) Provision of a hydrocortisone injection kit (or alternative glucocorticoid preparations) for emergency use plus sufficient oral glucocorticoid doses for stress situations/illness. (3) Education of patients and relatives on glucocorticoid stress dosing and "sick day rules" as well as on self-injection of hydrocortisone. (4) Provision of a treatment guideline (information leaflet) for the prevention and therapy of the adrenal crisis, which should also be shown to healthcare staff if necessary. (5) Provision of an emergency phone number (contact details) of the responsible endocrine specialist team or other trained staff. (6) Reinforcement of patient education on a regular basis (preferably yearly). This consensus document also includes recommendations for glucocorticoid dosing in the perioperative setting as well as in various other stress situations.

Hashimoto’s thyroiditis (HT) is the most prevalent autoimmune disorder of the thyroid (AITD) and characterized by the presence of circulating autoantibodies evoked by a, to date, not fully understood dysregulation of the immune system. Autoreactive lymphocytes and inflammatory processes in the thyroid gland can impair or enhance thyroid hormone secretion. MicroRNAs (miRNAs) are small noncoding RNAs, which can play a pivotal role in immune functions and the development of autoimmunity. The aim of the present study was to evaluate whether the expression of 9 selected miRNAs related to immunological functions differ in patients with HT compared to healthy controls. MiRNA profiles were analysed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 24 patients with HT and 17 healthy controls. Systemic expressions of miR-21-5p, miR-22-3p, miR-22-5p, miR-142-3p, miR-146a-5p, miR-301-3p and miR-451 were significantly upregulated in patients with HT (p ≤ 0.01) and were suitable to discriminate between HT and healthy controls in AUC analysis. Altered expressions of miR-22-5p and miR-142-3p were associated with higher levels of thyroid antibodies, suggesting their contribution to the pathogenesis of HT.

As a consequence of epidemiological studies showing significant associations of vitamin D deficiency with a variety of adverse extra-skeletal clinical outcomes including cardiovascular diseases, cancer, and mortality, large vitamin D randomized controlled trials (RCTs) have been designed and conducted over the last few years. The vast majority of these trials did not restrict their study populations to individuals with vitamin D deficiency, and some even allowed moderate vitamin D supplementation in the placebo groups. In these RCTs, there were no significant effects on the primary outcomes, including cancer, cardiovascular events, and mortality, but explorative outcome analyses and meta-analyses revealed indications for potential benefits such as reductions in cancer mortality or acute respiratory infections. Importantly, data from RCTs with relatively high doses of vitamin D supplementation did, by the vast majority, not show significant safety issues, except for trials in critically or severely ill patients or in those using very high intermittent vitamin D doses. The recent large vitamin D RCTs did not challenge the beneficial effects of vitamin D regarding rickets and osteomalacia, that therefore continue to provide the scientific basis for nutritional vitamin D guidelines and recommendations. There remains a great need to evaluate the effects of vitamin D treatment in populations with vitamin D deficiency or certain characteristics suggesting a high sensitivity to treatment. Outcomes and limitations of recently published large vitamin D RCTs must inform the design of future vitamin D or nutrition trials that should use more personalized approaches.

Background and aims Animal and cell models indicated that vitamin D modulates inflammatory activity, which is considered relevant in the pathogenesis of arterial hypertension and cardiovascular diseases. We therefore aimed to investigate the effect of vitamin D supplementation on systemic markers of inflammation in a cohort of hypertensive patients. Methods and results The Styrian Vitamin D Hypertension Trial is a single-centre, double-blind, placebo-controlled study conducted from 2011 to 2014 in Austria. We enrolled 200 study participants with arterial hypertension and 25-hydroxy-vitamin-D (25(OH)D) concentration below 30 ng/mL. Study participants were randomized to receive either 2800 IU of vitamin D3 per day or placebo for 8 weeks. The present investigation is a post-hoc analysis using analysis of co-variance (ANCOVA). Outcome measures were biomarkers of inflammation including CRP, leukocytes including subtypes and leukocyte-to-lymphocyte ratio, leucine and kynurenic acid. A total of 187 participants (mean age 60.1 ± 11.3years; 47% women; mean baseline 25(OH)D 21.1 ± 5.6 ng/mL) completed the trial. ANCOVA revealed a mean treatment effect for none of the respective outcomes and no significant results were detected in various subgroup analyses. Conclusion Vitamin D3 supplementation in hypertensive patients with insufficient 25(OH)D concentrations has no significant effect on lowering markers of systemic inflammation. Further studies investigating the effect of vitamin D on other inflammatory pathways and in populations with severe vitamin D deficiency and a significant inflammatory burden are required. Registration ClinicalTrials.gov Identifier: NCT02136771; EudraCT No. 2009-018,125-70. Start Date: 2011-04-06.

Zusammenfassung Die chronische Nebenniereninsuffizienz ist trotz adäquater Hormonersatzstrategien nach wie vor mit einer erhöhten Mortalität assoziiert. Der Grund hierfür liegt im Auftreten von Addison-Krisen, hervorgerufen durch einen Zustand eines akuten Cortisolmangels in erster Linie durch erhöhten Bedarf (beispielsweise bei Gastroenteritis, Infektionskrankheiten, inadäquater Medikamenteneinnahme etc.). Eine pragmatische Definition der Addison-Krise ist eine Verschlechterung des Allgemeinzustands mit absoluter (systolischer Blutdruck

Context The aldosterone–to–active renin ratio (AARR) is the recommended screening test for primary aldosteronism (PA), but prospective study data on its sensitivity and specificity are sparse. Objective To investigate the diagnostic accuracy of the AARR for detecting PA. Design Prospective diagnostic accuracy study. Setting This study was conducted from February 2009 to August 2015 at the outpatient clinic of the Department of Endocrinology and Diabetology of the Medical University of Graz, Austria. Participants Four hundred patients with arterial hypertension who were referred to a tertiary care center for screening for endocrine hypertension. Intervention Participants had a determination of the AARR (index test) and a second AARR determination followed by a saline infusion test (SIT) after 2 to 6 weeks. PA was diagnosed in individuals with any AARR ≥3.7 ng/dL/µU/mL [including a plasma aldosterone concentration (PAC) of ≥9 ng/dL] who had a PAC ≥10 ng/dL after the SIT. We did not substantially alter antihypertensive drug intake. Main Outcome Measures Primary outcome was the receiver-operating characteristic (ROC) curve of the AARR in diagnosing PA. Results A total of 382 participants were eligible for analyses; PA was diagnosed in 18 (4.7%) patients. The area under the ROC curve of the AARR in detecting PA was 0.973 (95% CI, 0.956 to 0.990). Sensitivity and specificity for a positive AARR in diagnosing PA were 100% (95% CI, 81.5% to 100.0%) and 89.6% (95% CI, 86.0% to 92.5%), respectively. Conclusions The AARR has good diagnostic accuracy for detecting PA.

Vitamin D testing and treatment is a subject of controversial scientific discussions, and it is challenging to navigate through the expanding vitamin D literature with heterogeneous and partially opposed opinions and recommendations. In this narrative review, we aim to provide an update on vitamin D guidelines and the current evidence on the role of vitamin D for human health with its subsequent implications for patient care and public health issues. Vitamin D is critical for bone and mineral metabolism, and it is established that vitamin D deficiency can cause rickets and osteomalacia. While many guidelines recommend target serum 25-hydroxyvitamin D (25[OH]D) concentrations of ≥50 nmol/L (20 ng/mL), the minimum consensus in the scientific community is that serum 25(OH)D concentrations below 25–30 nmol/L (10–12 ng/mL) must be prevented and treated. Using this latter threshold of serum 25(OH)D concentrations, it has been documented that there is a high worldwide prevalence of vitamin D deficiency that may require public health actions such as vitamin D food fortification. On the other hand, there is also reason for concern that an exploding rate of vitamin D testing and supplementation increases costs and might potentially be harmful. In the scientific debate on vitamin D, we should consider that nutrient trials differ from drug trials and that apart from the opposed positions regarding indications for vitamin D treatment we still have to better characterize the precise role of vitamin D for human health.

Background and Aims Bile acids are now accepted as central signalling molecules for the regulation of glucose, amino acid and lipid metabolism. Adrenal gland cortex cells express the bile acid receptors farnesoid X receptor (FXR), the G protein‐coupled bile acid receptor (TGR5) and the sphingosine‐1‐phosphate receptor 2 (S1PR2). We aimed to determine the effects of cholestasis and more specifically of bile acids on cortisol production. Methods FXR and TGR5 knockout mice and controls were subjected to common bile duct ligation (CBDL) or chenodeoxycholic acid (CDCA) feeding to model cholestasis. Human adrenocortical H295R cells were challenged with bile acids for mechanistic studies. Results We found that CBDL and CDCA feeding increased the levels of corticosterone, the rodent equivalent to human cortisol and mRNA and protein levels of steroidogenesis‐related enzymes in adrenals independent of FXR and TGR5. Taurine‐conjugated CDCA (TCDCA) significantly stimulated cortisol secretion, phosphorylation of extracellular signal‐regulated kinase (ERK) and expression of steroidogenesis‐related genes in human adrenocortical H295R cells. FXR and TGR5 agonists failed to induce cortisol secretion in H295R cells. S1PR2 inhibition significantly abolished TCDCA‐induced cortisol secretion, lowered phosphorylation of ERK and abrogated enhanced transcription of steroidogenesis‐related genes in H295R cells. Likewise, siRNA S1PR2 treatment reduced the phosphorylation of ERK and cortisol secretion. Steroidogenic factor‐1 (SF‐1) transactivation activity was increased upon TCDCA treatment suggesting that bile acid signalling is linked to SF‐1. Treatment with SF‐1 inverse agonist AC45594 also reduced TCDCA‐induced steroidogenesis. Conclusions Our findings indicate that supraphysiological bile acid levels as observed in cholestasis stimulate steroidogenesis via an S1PR2‐ERK‐SF‐1 signalling pathway.

Background A key question concerning coronavirus disease 2019 (COVID‐19) is how effective and long lasting immunity against this disease is in individuals who were previously infected with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). We aimed to evaluate the risk of SARS‐CoV‐2 re‐infections in the general population in Austria. Methods This is a retrospective observational study using national SARS‐CoV‐2 infection data from the Austrian epidemiological reporting system. As the primary outcome, we aim to compare the odds of SARS‐CoV‐2 re‐infections of COVID‐19 survivors of the first wave (February to April 30, 2020) versus the odds of first infections in the remainder general population by tracking polymerase chain reaction (PCR)‐confirmed infections of both groups during the second wave from September 1 to November 30, 2020. Re‐infection counts are tentative, since it cannot be excluded that the positive PCR in the first and/or second wave might have been a false positive. Results We recorded 40 tentative re‐infections in 14 840 COVID‐19 survivors of the first wave (0.27%) and 253 581 infections in 8 885 640 individuals of the remaining general population (2.85%) translating into an odds ratio (95% confidence interval) of 0.09 (0.07 to 0.13). Conclusions We observed a relatively low re‐infection rate of SARS‐CoV‐2 in Austria. Protection against SARS‐CoV‐2 after natural infection is comparable with the highest available estimates on vaccine efficacies. Further well‐designed research on this issue is urgently needed for improving evidence‐based decisions on public health measures and vaccination strategies.

BackgroundA key question concerning coronavirus disease 2019 (COVID-19) is how effective and long lasting immunity against this disease is in individuals who were previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to evaluate the risk of SARS-CoV-2 re-infections in the general population in Austria.MethodsThis is a retrospective observational study using national SARS-CoV-2 infection data from the Austrian epidemiological reporting system. As the primary outcome, we aim to compare the odds of SARS-CoV-2 re-infections of COVID-19 survivors of the first wave (February to April 30, 2020) versus the odds of first infections in the remainder general population by tracking polymerase chain reaction (PCR)-confirmed infections of both groups during the second wave from September 1 to November 30, 2020. Re-infection counts are tentative, since it cannot be excluded that the positive PCR in the first and/or second wave might have been a false positive.ResultsWe recorded 40 tentative re-infections in 14,840 COVID-19 survivors of the first wave (0.27%) and 253,581 infections in 8,885,640 individuals of the remaining general population (2.85%) translating into an odds ratio (95% confidence interval) of 0.09 (0.07 to 0.13).ConclusionsWe observed a relatively low re-infection rate of SARS-CoV-2 in Austria. Protection against SARS-CoV-2 after natural infection is comparable to the highest available estimates on vaccine efficacies. Further well-designed research on this issue is urgently needed for improving evidence-based decisions on public health measures and vaccination strategies.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in premeno-pausal women, with a wide spectrum of possible phenotypes, symptoms and sequelae according to the current clinical definition. However, there are women who do not fulfill at least two out of the three commonly used “Rotterdam criteria” and their risk of developing type 2 diabetes or obesity later in life is not defined. Therefore, we addressed this important gap by conducting a retrospective analysis based on 750 women with and without PCOS. We compared four different PCOS pheno-types according to the Rotterdam criteria with women who exhibit only one Rotterdam criterion and with healthy controls. Hormone and metabolic differences were assessed by analysis of vari-ance (ANOVA) as well as logistic regression analysis. We found that hyperandrogenic women have per se a higher risk of developing insulin resistance compared to phenotypes without hyperandro-genism and healthy controls. In addition, hyperandrogenemia is associated with developing insulin resistance also in women with no other Rotterdam criterion. Our study encourages further diagnostic and therapeutic approaches for PCOS phenotypes in order to account for varying risks of developing metabolic diseases. Finally, women with hyperandrogenism as the only symptom should also be screened for insulin resistance to avoid later metabolic risks.

Context Serum cortisol may be associated with cardiovascular risk factors and mortality in patients undergoing coronary angiography, but previous data on this topic are limited and controversial. Objective We evaluated whether morning serum cortisol is associated with cardiovascular risk factors, lymphocyte subtypes, and mortality. Methods This is a prospective cohort study performed at a tertiary care centre in south-west Germany between 1997 and 2000. We included 3052 study participants who underwent coronary angiography. The primary outcome measures were cardiovascular risk factors, lymphocyte subtypes, and all-cause and cardiovascular mortality. Results Serum cortisol was associated with an adverse cardiovascular risk profile, but there was no significant association with coronary artery disease or acute coronary syndrome. In a subsample of 2107 participants, serum cortisol was positively associated with certain lymphocyte subsets, including CD16+CD56+ (natural killer) cells (P Conclusions Despite significant associations with classic cardiovascular risk factors and natural killer cells, serum cortisol was not a significant and independent predictor of mortality in patients referred to coronary angiography. These findings might reflect that adverse cardiovascular effects of cortisol could be counterbalanced by some cardiovascular protective actions.

Nitric oxide (NO) synthesis markers, comprising L-homoarginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), are significantly associated with cardiovascular events and mortality. Being involved in NO pathways, they may be of high importance regulating vascular tone and arterial hypertension, but data on this topic are sparse and controversial. In this study, we evaluated whether these NO synthesis markers are associated with blood pressure values and pulse wave velocity (PWV). This analysis was based on the data of the Styrian Vitamin D Hypertension Trial, which included adults with arterial hypertension. We analyzed correlations of NO synthesis markers with 24 h ambulatory blood pressure values and PWV (primary outcomes), as well as with anthropometric and laboratory data. A total of 509 patients were included in the present analysis. The mean age was 61.2 &plusmn, 10.5 years, mean PWV was 8.6 &plusmn, 2.4 m/s, mean 24 h systolic blood pressure was 127.5 &plusmn, 13.8 mmHg and mean 24 h diastolic blood pressure was 76.4 &plusmn, 9.5 mmHg. In bivariate analyses, there was a significant positive correlation between homoarginine and 24 h diastolic blood pressure (r = 0.1, p = 0.02), which was revealed to be no longer significant after adjustment for age, gender and glomerular filtration rate (GFR) in multivariate regression analysis. No other significant correlations of any NO synthesis markers with blood pressure or PWV were observed. In line with previous studies, there were inverse associations between homoarginine and age and between ADMA or SDMA and GFR (p &lt, 0.05 for all). This study did not reveal a significant association between homoarginine, ADMA or SDMA and blood pressure or PWV in hypertensive adults. These results suggested that the associations of these parameters with adverse outcome may not be mediated by hypertension and/or endothelial dysfunction.

Summary Background Psychosocial factors significantly influence patient care in many fields of medicine, among these in the field of endocrinology. Easily applicable validated assessment tools for such psychosocial factors are lacking. Visual instruments may facilitate doctor-patient communication. This study describes the development and validation of a multidimensional visual tool for the self-assessment of health. Methods An expert panel performed the multistep development of the psychosomatic assessment health disc (PAHD). Assessment of face validity was performed by means of a focus group of medical doctors (n = 6) and patient interviews (n = 24). For determining test-retest reliability, internal consistency and construct validity, patients of an endocrine outpatient clinic in Graz, Austria, completed the PAHD and the following questionnaires: short-form 36 health survey, work ability index, Pittsburgh sleep quality index and the social life scales of the life satisfaction questionnaire. Results A numeric six-item analogue scale was developed in the form of a disc. It addresses the following aspects of health: physical well-being, social life, sexuality, mental well-being, sleep, working ability/performance. For the validation process, 177 patients (57.1% females) participated in the study. Correlation coefficients of the six items with other questionnaires ranged between r = 0.51 (social life) and r = 0.72 (sleep). Test-retest reliability was assessed among 98 patients and was ≥ 0.74 for all 6 items, while Cronbach’s alpha was 0.78. Conclusion The psychometric properties of the PAHD support its use in clinical encounters with patients suffering from endocrine disorders. Further validation studies may be required to extend its application to other fields of medicine.

Background & aims: Vitamin D supplementation may affect glycemic as well as hormonal regulation. Thus, the aim of the current study was to investigate whether vitamin D supplementation has any significant effects on metabolic and endocrine parameters in healthy premenopausal women. Primary outcome measure was the plasma glucose area under the curve (AUCgluc). Methods: The current study was a single-center, double-blind, randomized placebo-controlled trial that was conducted at the Medical University of Graz, Austria, between March 2013 and October 2017. One-hundred and fifty healthy premenopausal women with 25-hydroxyvitamin D [25(OH)D] concentrations 2; baseline 25(OH)D 55.8 ± 19.7 nmol/L] completed the study. Vitamin D supplementation had no significant effect on AUCgluc (mean treatment effect 11.70; p = 0.069), while it had a significant treatment effect on homeostatic model assessment-insulin resistance (HOMA-IR; mean treatment effect 0.31; p = 0.019) and quantitative insulin-sensitivity check index (QUICKI; mean treatment effect −0.019; p = 0.013). There was no significant effect on the remaining secondary outcome parameters. Conclusions: In this randomized-controlled trial in healthy premenopausal women, there was a significant treatment effect of vitamin D supplementation on HOMA-IR and QUICKI, while there was no significant treatment effect on AUCgluc.

The 25-Hydroxyvitamin D (25[OH)D) serum concentration depends on vitamin D intake, endogenous vitamin D production and genetic factors. The latter have been demonstrated in large genome-wide association studies indicating that single nucleotide polymorphisms (SNPs) in genes related to the vitamin D metabolism are as important for serum 25(OH)D levels as the influence of season. The mechanism on how these SNPs influence serum 25(OH)D levels are still unclear. The aim of the present study was to investigate the genetic effects of ten selected SNPs related to vitamin D metabolism on 25-hydroxyvitamin D increase (∆25(OH)D) after vitamin D supplementation in three randomized controlled trials. Genotypes of SNPs related to vitamin D metabolism were determined in 411 participants with 25(OH)D concentrations &lt, 75 nmol/l receiving 20,000 IU cholecalciferol per week for 8 or 12 weeks after study inclusion. For the vitamin D receptor (VDR) rs10783219 polymorphism, the minor A-allele was associated with lower ∆25(OH)D values in the entire study population (p = 0.022), which was not consistent in all three cohorts when analysed separately. VDR rs10783219 might therefore be a genetic modulator of increasing 25-hydroxyvitamin D concentrations. Considering the wide-spread use of vitamin D supplementation, future large and well-designed randomized controlled trials (RCTs) should investigate the clinical impact of this polymorphism.

Introduction: The main differential diagnoses of secondary hyperthyroidism include thyrotropin-secreting neuroendocrine pituitary tumors (TSH-PitNETs) and resistance to thyroid hormone. As a rare cause of secondary hyperthyroidism, ectopic thyrotropin-producing neuroendocrine pituitary tumors must also be considered. Case Presentation: A 48-year-old female patient with overt hyperthyroidism and elevated thyrotropin was admitted to the endocrine outpatient clinic of a secondary care hospital in March 2018. The patient had an inconspicuous pituitary MRI and F18-F-DOPA PET-CT, but showed a tumor mass located at the pharyngeal roof. Most biochemical tests and an increased tracer uptake of the pharyngeal mass in a Ga68-DOTANOC PET-CT argued for the presence of an ectopic TSH-PitNET. After treatment with octreotide over 5 days and a consecutive normalization of free thyroxine and free triiodothyronine, the tumor was endoscopically resected. Histologically, the mass consisted of small partially spindle, partially polygonal monomorphic to mildly pleomorphic cells with immunoreactivity for thyrotropin and luteinizing hormone. Postoperatively, the patient required intermittent levothyroxine therapy. Discussion and Conclusions: Ectopic TSH-PitNETs represent an extremely rare cause for secondary hyperthyroidism. While the diagnostic process may be complicated by negative imaging studies of the pituitary gland, family history, biochemical tests, and functional imaging using gallium-labelled somatostatin analogues may be helpful in establishing the diagnosis.

Purpose: It has been hypothesized that vitamin D is associated with androgen levels in men. We, therefore, aimed to evaluate whether vitamin D supplementation increases serum total testosterone (TT) levels in men with low TT levels at baseline. Methods: The Graz Vitamin D&TT-RCT is a single-center, double-blind, randomized placebo-controlled trial conducted between March 2013 and November 2017 at the endocrine outpatient clinic at the Medical University of Graz, Austria. One-hundred healthy men with serum TT levels < 10.4 nmol/l and 25-hydroxyvitamin D [25(OH)D] levels < 75 nmol/l participated in the trial. Subjects were randomized to receive 20,000 IU of vitamin D3/week (n = 50) or placebo (n = 50) for 12 weeks. Primary outcome was TT measured using mass spectrometry. Secondary outcomes were free testosterone, free androgen index, sex hormone-binding globulin, estradiol, follicle-stimulating hormone, luteinizing hormone, metabolic characteristics, and body composition. Results: Ninety-four men [mean age and 25(OH)D: 47 (± 12) years and 56.3 (± 18.3) nmol/l, respectively] completed the study. We found no significant treatment effect on serum TT or on the remaining secondary outcome variables. Conclusion: Vitamin D treatment had no effect on serum TT levels in middle-aged healthy men with low TT levels.