Standards of care for medical management of acromegaly in pituitary tumor centers of excellence (PTCOE).

PURPOSE: A series of consensus guidelines on medical treatment of acromegaly have been produced in the last two decades. However, little information is available on their application in clinical practice. Furthermore, international standards of acromegaly care have not been published. The aim of our study was to report current standards of care for medical therapy of acromegaly, using results collected through an audit performed to validate criteria for definition of Pituitary Tumor Centers of Excellence (PTCOE). METHODS: Details of medical treatment approaches to acromegaly were voluntarily provided by nine renowned international centers that participated in this audit. For the period 2018-2020, we assessed overall number of acromegaly patients under medical treatment, distribution of patients on different treatment modalities, overall biochemical control rate with medical therapy, and specific control rates for different medical treatment options. RESULTS: Median number of total patients and median number of new patients with acromegaly managed annually in the endocrinology units of the centers were 206 and 16.3, respectively. Median percentage of acromegaly patients on medical treatment was 48.9%. Among the patients on medical treatment, first-generation somatostatin receptor ligand (SRL) monotherapy was used with a median rate of 48.7%, followed by combination therapies with a median rate of 29.3%. Cabergoline monotherapy was used in 6.9% of patients. Pegvisomant monotherapy was used in 7 centers and pasireotide monotherapy in 5 centers, with median rates of 7.9% and 6.3%, respectively. CONCLUSIONS: Current standards of care in PTCOEs include use of first-generation SRLs as the first medical option in about 50% of patients, as recommended by consensus guidelines. However, some patients are kept on this treatment despite inadequate control suggesting that cost-effectiveness, availability, patient preference, side effects, and therapeutic inertia may play a possible role also in PTCOE. Moreover, at odds with consensus guidelines, other monotherapies for acromegaly appear to have a marginal role as compared to combination therapies as extrapolated from PTCOE practice data. Presence of uncontrolled patients in each treatment category suggest that further optimization of medical therapy, as well as use of other therapeutic tools such as radiosurgery may be needed.

Pilot study to define criteria for Pituitary Tumors Centers of Excellence (PTCOE): results of an audit of leading international centers.

PURPOSE: The Pituitary Society established the concept and mostly qualitative parameters for defining uniform criteria for Pituitary Tumor Centers of Excellence (PTCOEs) based on expert consensus. Aim of the study was to validate those previously proposed criteria through collection and evaluation of self-reported activity of several internationally-recognized tertiary pituitary centers, thereby transforming the qualitative 2017 definition into a validated quantitative one, which could serve as the basis for future objective PTCOE accreditation. METHODS: An ad hoc prepared database was distributed to nine Pituitary Centers chosen by the Project Scientific Committee and comprising Centers of worldwide repute, which agreed to provide activity information derived from registries related to the years 2018-2020 and completing the database within 60 days. The database, provided by each center and composed of Excel® spreadsheets with requested specific information on leading and supporting teams, was reviewed by two blinded referees and all 9 candidate centers satisfied the overall PTCOE definition, according to referees' evaluations. To obtain objective numerical criteria, median values for each activity/parameter were considered as the preferred PTCOE definition target, whereas the low limit of the range was selected as the acceptable target for each respective parameter. RESULTS: Three dedicated pituitary neurosurgeons are preferred, whereas one dedicated surgeon is acceptable. Moreover, 100 surgical procedures per center per year are preferred, while the results indicated that 50 surgeries per year are acceptable. Acute post-surgery complications, including mortality and readmission rates, should preferably be negligible or nonexistent, but acceptable criterion is a rate lower than 10% of patients with complications requiring readmission within 30 days after surgery. Four endocrinologists devoted to pituitary diseases are requested in a PTCOE and the total population of patients followed in a PTCOE should not be less than 850. It appears acceptable that at least one dedicated/expert in pituitary diseases is present in neuroradiology, pathology, and ophthalmology groups, whereas at least two expert radiation oncologists are needed. CONCLUSION: This is, to our knowledge, the first study to survey and evaluate the activity of a relevant number of high-volume centers in the pituitary field. This effort, internally validated by ad hoc reviewers, allowed for transformation of previously formulated theoretical criteria for the definition of a PTCOE to precise numerical definitions based on real-life evidence. The application of a derived synopsis of criteria could be used by independent bodies for accreditation of pituitary centers as PTCOEs.

One year of the pandemic - how European endocrinologists responded to the crisis: a statement from the European Society of Endocrinology.

Changes that COVID-19 induced in endocrine daily practice as well as the role of endocrine and metabolic comorbidities in COVID-19 outcomes were among the striking features of this last year. The aim of this statement is to illustrate the major characteristics of the response of European endocrinologists to the pandemic including the disclosure of the endocrine phenotype of COVID-19 with diabetes, obesity and hypovitaminosis D playing a key role in this clinical setting with its huge implication for the prevention and management of the disease. The role of the European Society of Endocrinology (ESE) as a reference point of the endocrine community during the pandemic will also be highlighted, including the refocusing of its educational and advocacy activities.

[Update on endocrine hypertension]. / Update endokrine Hypertonie.

Endocrine disorders are the most common causes of secondary hypertension. Early diagnosis and specific treatment are crucial for improvement of the prognosis. This article provides an overview on which clinical constellations point to an increased risk of secondary causes of hypertension. These include spontaneous hypokalemia, young age at onset of hypertension, adrenal incidentaloma and therapy refractive arterial hypertension. The basic diagnostics include determination of the aldosterone to renin ratio, measurement of free plasma metanephrines and a 1 mg dexamethasone suppression test. Borderline results require repeated control testing and/or confirmatory testing under standardized test conditions. In cases of repeatedly conspicuous results referral to a specialized clinic should be considered for further clarification and confirmation of the diagnosis. Imaging diagnostics may constitute an adjunct to laboratory testing after the diagnosis has been confirmed. Therapeutic algorithms vary depending on the underlying endocrine disease.

Radiation exposure of adrenal vein sampling: a German Multicenter Study

Objective: Adrenal vein sampling (AVS) represents the current diagnostic standard for subtype differentiation in primary aldosteronism (PA). However, AVS has its drawbacks. It is invasive, expensive, requires an experienced interventional radiologist and comes with radiation exposure. However, exact radiation exposure of patients undergoing AVS has never been examined. Design and Methods: We retrospectively analyzed radiation exposure of 656 AVS performed between 1999 and 2017 at four university hospitals. The primary outcomes were dose area product (DAP) and fluoroscopy time (FT). Consecutively the effective dose (ED) was approximately calculated. Results: Median DAP was found to be 32.5 Gy*cm2 (0.3­3181) and FT 18 min (0.3­184). The calculated ED was 6.4 mSv (0.1­636). Remarkably, values between participating centers highly varied: Median DAP ranged from 16 to 147 Gy*cm2, FT from 16 to 27 min, and ED from 3.2 to 29 mSv. As main reason for this variation, differences regarding AVS protocols between centers could be identified, such as number of sampling locations, frames per second and the use of digital subtraction angiographies. Conclusions: This first systematic assessment of radiation exposure in AVS not only shows fairly high values for patients, but also states notable differences among the centers. Thus, we not only recommend taking into account the risk of radiation exposure, when referring patients to undergo AVS, but also to establish improved standard operating procedures to prevent unnecessary radiation exposure.

[Hypothyroidism-when and how to treat?] / Hypothyreose ­ wann und wie behandeln?

The diagnosis of hypothyroidism is primarily based on clinical signs and symptoms as well as measurement of thyroid-stimulating hormone (TSH) concentration. Subclinical hypothyroidism is characterized by elevated TSH with normal serum free thyroxine (fT4) and triiodothyronine (fT3) levels, while in manifest hypothyroidism serum fT4 and fT3 levels are reduced. Common causes of primary hypothyroidism are autoimmune thyroiditis as well as therapeutic interventions, such as thyroid surgery or radioiodine therapy. Signs and symptoms of hypothyroidism include fatigue, bradycardia, constipation and cold intolerance. In subclinical hypothyroidism, symptoms may be absent. Initiation of levothyroxine (T4) therapy not only depends on the level of TSH elevation, but also on other factors, such as patient age, presence of pregnancy or comorbidities. Treatment of patients with subclinical hypothyroidism is still a controversial topic. In general, thyroid hormone replacement therapy in non-pregnant adults ≤ 70 years is clearly indicated if the TSH concentration is >10 mU/l. Standard of care for treatment of hypothyroidism is T4 monotherapy. The biochemical treatment goal for T4 replacement in primary hypothyroidism is a TSH level within the reference range (0.4-4.0 mU/l). In contrast, in secondary hypothyroidism, serum fT4 levels are the basis for adjusting thyroid hormone dosage. Inadequate replacement of T4 resulting in subclinical or even manifest hyperthyroidism should urgently be avoided. T4/liothyronine (T3) combination therapy is still a matter of debate and not recommended as standard therapy, but may be considered in patients with persistence of symptoms, despite optimal T4 treatment, based on expert opinion.

Physiological Aldosterone Concentrations Are Associated with Alterations of Lipid Metabolism: Observations from the General Population.

OBJECTIVE: Aldosterone and high-density lipoprotein cholesterol (HDL-C) are involved in many pathophysiological processes that contribute to the development of cardiovascular diseases. Previously, associations between the concentrations of aldosterone and certain components of the lipid metabolism in the peripheral circulation were suggested, but data from the general population is sparse. We therefore aimed to assess the associations between aldosterone and HDL-C, low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, or non-HDL-C in the general adult population. METHODS: Data from 793 men and 938 women aged 25-85 years who participated in the first follow-up of the Study of Health in Pomerania were obtained. The associations of aldosterone with serum lipid concentrations were assessed in multivariable linear regression models adjusted for sex, age, body mass index (BMI), estimated glomerular filtration rate (eGFR), and HbA1c. RESULTS: The linear regression models showed statistically significant positive associations of aldosterone with LDL-C (ß-coefficient = 0.022, standard error = 0.010, p = 0.03) and non-HDL-C (ß-coefficient = 0.023, standard error = 0.009, p = 0.01) as well as an inverse association of aldosterone with HDL-C (ß-coefficient = -0.022, standard error = 0.011, p = 0.04). CONCLUSIONS: The present data show that plasma aldosterone is positively associated with LDL-C and non-HDL-C and inversely associated with HDL-C in the general population. Our data thus suggests that aldosterone concentrations within the physiological range may be related to alterations of lipid metabolism.

[Endocrine paraneoplastic syndromes]. / Endokrine paraneoplastische Syndrome.

Endocrine paraneoplastic syndromes result from the production of bioactive substances from neoplastic cells, of endocrine or neuroendocrine origin. Typically these are located in the lungs, the gastrointestinal tract, pancreas, thyroid gland, adrenal medulla, skin, prostate or breast. In endocrine paraneoplastic syndromes the secretion of peptides, amines or other bioactive substances is always ectopic and not related to the anatomical source. The clinical presentation, however, is indistinguishable from a suspected eutopic endocrine tumor posing a diagnostic challenge. The most common endocrine paraneoplastic syndromes are based on the secretion of antidiuretic hormone (ADH) resulting in hyponatremia, secretion of adrenocorticotropic hormone (ACTH) or rarely corticotropin-releasing hormone (CRH) resulting in Cushing syndrome as well as secretion of growth hormone-releasing hormone resulting in acromegaly. Paraneoplastic endocrine syndromes mainly occur in highly malignant tumors; however, the development of these tumors does not necessarily correlate with tumor stage, malignant potential or prognosis. As endocrine paraneoplastic syndromes are a rare complication, there are hardly any evidence-based therapeutic recommendations. Treatment of the underlying tumor is the first choice and in a palliative setting symptomatic therapy is possible.

[Functional diagnostics in endocrinology]. / Funktionsdiagnostik in der Endokrinologie.

When investigating many endocrinological diseases, basal laboratory parameters are not sufficient to distinguish between physiological and pathological hormone secretion. Functional diagnostics plays a decisive role in this context. Stimulation and suppression tests are used depending on whether under- or over-function needs to be diagnosed. This review article discusses selected functional tests, each of which plays an important role in current guidelines. Indications and test principles, including their performance, reliability, and limitations, are discussed. Topics covered include the ACTH stimulation test for the diagnosis of adrenal cortex insufficiency and the dexamethasone inhibition test for suspected Cushing's syndrome, as well as functional tests for the diagnosis of primary hyperaldosteronism, pheochromocytoma, acromegaly, growth hormone deficiency, thyroid nodules and suspicion of medullary thyroid carcinoma, insulinoma, and Zollinger-Ellison syndrome. Functional tests that are explicitly not recommended are also addressed.

[Thyroid emergencies : Thyroid storm and myxedema coma]. / Schilddrüsennotfälle : Thyreotoxische Krise und Myxödemkoma.

Thyroid emergencies are rare life-threatening endocrine conditions resulting from either decompensated thyrotoxicosis (thyroid storm) or severe thyroid hormone deficiency (myxedema coma). Both conditions develop out of a long-standing undiagnosed or untreated hyper- or hypothyroidism, respectively, precipitated by an acute stress-associated event, such as infection, trauma, or surgery. Cardinal features of thyroid storm are myasthenia, cardiovascular symptoms, in particular tachycardia, as well as hyperthermia and central nervous system dysfunction. The diagnosis is made based on clinical criteria only as thyroid hormone measurements do not differentiate between thyroid storm and uncomplicated hyperthyroidism. In addition to critical care measures therapy focusses on inhibition of thyroid hormone synthesis and secretion (antithyroid drugs, perchlorate, Lugol's solution, cholestyramine, thyroidectomy) as well as inhibition of thyroid hormone effects in the periphery (ß-blocker, glucocorticoids).Cardinal symptoms of myxedema coma are hypothermia, decreased mental status, and hypoventilation with risk of pneumonia and hyponatremia. The diagnosis is also purely based on clinical criteria as measurements of thyroid hormone levels do not differ between uncomplicated severe hypothyroidism and myxedema coma. In addition to substitution of thyroid hormones and glucocorticoids, therapy focusses on critical care measures to treat hypoventilation and hypercapnia, correction of hyponatremia and hypothermia.Survival of both thyroid emergencies can only be optimized by early diagnosis based on clinical criteria and prompt initiation of multimodal therapy including supportive measures and treatment of the precipitating event.

Associations of aldosterone and renin concentrations with inflammation-the Study of Health in Pomerania and the German Conn's Registry.

PURPOSE: Chronic inflammation is an age-independent and body mass index-independent contributor to the development of multi-morbidity. Alterations of the renin-angiotensin-aldosterone system are observed within the context of proinflammatory states. We assessed circulating aldosterone, renin, and inflammatory biomarker concentrations in healthy, normotensive subjects and patients with primary aldosteronism. METHODS: We included 1177 normotensive individuals from the population-based Study of Health in Pomerania (first follow-up, Study of Health in Pomerania-1) and 103 primary aldosteronism patients from the German Conn's Registry. A 1:1 matching for sex, age, body mass index, smoking status, diabetes mellitus, and the estimated glomerular filtration rate was performed to determine whether primary aldosteronism patients exhibit higher inflammatory biomarker concentrations than normotensive controls. The associations of plasma aldosterone concentration or plasma renin concentration with circulating fibrinogen concentrations, white blood cell count, and high sensitive C-reactive protein concentrations in the normotensive sample were determined with multivariable linear and logistic regression analyses. RESULTS: 1:1 matched primary aldosteronism patients demonstrated significantly (p < 0.01) higher plasma aldosterone concentration (198 vs. 47 ng/l), lower plasma renin concentration (3.1 vs. 7.7 ng/l) and higher high sensitive C-reactive protein concentrations (1.5 vs. 1.0 mg/l) than normotensive controls. Within the normotensive cohort, plasma renin concentration but not plasma aldosterone concentration was positively associated with fibrinogen concentrations and white blood cell count. Further, a J-shaped association between plasma renin concentration and high sensitive C-reactive protein concentrations was detected. CONCLUSIONS: High plasma aldosterone concentration in a primary aldosteronism cohort and high plasma renin concentration in normotensive subjects are associated with increased concentrations of inflammatory biomarkers. This suggests a link between the renin-angiotensin-aldosterone system and inflammatory processes in patients with primary aldosteronism and even in normotensive subjects.

Genetic characterization of a mouse line with primary aldosteronism.

In an attempt to define novel genetic loci involved in the pathophysiology of primary aldosteronism, a mutagenesis screen after treatment with the alkylating agent N-ethyl-N-nitrosourea was established for the parameter aldosterone. One of the generated mouse lines with hyperaldosteronism was phenotypically and genetically characterized. This mouse line had high aldosterone levels but normal creatinine and urea values. The steroidogenic enzyme expression levels in the adrenal gland did not differ significantly among phenotypically affected and unaffected mice. Upon exome sequencing, point mutations were identified in seven candidate genes (Sspo, Dguok, Hoxaas2, Clstn3, Atm, Tipin and Mapk6). Subsequently, animals were stratified into wild-type and mutated groups according to their genotype for each of these candidate genes. A correlation of their genotypes with the respective aldosterone, aldosterone-to-renin ratio (ARR), urea and creatinine values as well as steroidogenic enzyme expression levels was performed. Aldosterone values were significantly higher in animals carrying mutations in four different genes (Sspo, Dguok, Hoxaas2 and Clstn3) and associated statistically significant adrenal Cyp11b2 overexpression as well as increased ARR was present only in mice with Sspo mutation. In contrast, mutations of the remaining candidate genes (Atm, Tipin and Mapk6) were associated with lower aldosterone values and lower Hsd3b6 expression levels. In summary, these data demonstrate association between the genes Sspo, Dguok, Hoxaas2 and Clstn3 and hyperaldosteronism. Final proofs for the causative nature of the mutations have to come from knock-out and knock-in experiments.