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.

[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.

[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.

[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.

Left-Sided Living Kidney Donation Leads to Transiently Reduced Adrenocortical Responsiveness.

Living kidney donation is safe and established, but can lead to long-term complications such as chronic fatigue. Since the adrenal vein is usually transected during left-sided donor nephrectomy-which is not necessary on the right-we hypothesized that venous congestion might lead to an impairment of adrenal function, offering a possible explanation. In this prospective open label, monocentric cohort study, adrenal function was compared in left- and right-sided living kidney donors. The primary endpoint was plasma cortisol response to low-dose adrenocorticotropic hormone (ACTH) stimulation. Secondary endpoints included plasma renin and ACTH concentration as well as adrenal volume in response to donor nephrectomy. A total of 30 healthy donors-20 left- and 10 right-sided donations-were included. On postoperative day 1, response to low-dose ACTH stimulation was intact, but significantly lower after left-sided donor nephrectomy. After 28 days, adrenal responsiveness to ACTH stimulation did not differ any longer. Magnetic resonance imaging volumetry showed no significant adrenal volume change over 4 weeks, neither after left- nor after right-sided nephrectomy. In conclusion, left-sided living kidney donation entails a transiently reduced adrenocortical responsiveness, which returns to baseline after 28 days.

[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.

The Clinical Value of Salivary Aldosterone in Diagnosis and Follow-Up of Primary Aldosteronism.

Primary aldosteronism (PA), the most common form of secondary hypertension, causes relevant morbidity. The value of salivary measurements of aldosterone in clinical routine in PA so far has not been assessed. First, we analyzed salivary and plasma aldosterone concentrations of 42 patients with PA and 37 hypertensive controls (HC) during a sodium infusion test prospectively. Second, morning salivary and plasma aldosterone concentrations as well as diurnal saliva aldosterone profiles were analyzed in 115 patients treated for PA (46 adrenalectomy, 56 spironolactone, 13 eplerenone). Salivary aldosterone was substantially elevated in PA patients compared to HC at baseline (106±119 vs. 40±21 ng/l, p=0.01), and after 4-h sodium infusion test (60±36 vs. 23±14, p=0.01). Positive correlation between salivary and plasma aldosterone levels was evident, with exception of concentrations in or below the lower normal range. Applying a salivary aldosterone cutoff of 51.2 ng/l, found by ROC curve analysis, rendered a sensitivity of 81% and a specificity of 73% for PA. The diurnal rhythm of aldosterone was preserved in untreated PA patients, but concentrations were higher in the context of PA, and normalized after surgery (118±57 vs. 31±18 ng/l, p<0.01). Taken together, salivary aldosterone measurements correlate with plasma levels, allowing simple and cost effective assessments of aldosterone secretion in an outpatient setting. Nevertheless, as this method alone cannot replace other plasma parameters, and as aldosterone profiling would not alter diagnostic or treatment strategies, salivary aldosterone measurements in routine practice are of limited clinical value.

Genetics of Cushing's disease: an update.

INTRODUCTION: Cushing's disease (CD) results from uncontrolled hypercortisolism induced by ACTH-secreting corticotroph adenomas; accordingly, patients diagnosed with CD usually present several comorbidities and an increased risk of mortality. Hypothesis-driven screenings have led to identification of rare alterations in a low number of patients, although the genetic basis underlying CD has remained unclear until recently. Using whole-exome sequencing, recurrent mutations have been reported in the gene coding for the ubiquitin-specific protease 8 (USP8), a protein with deubiquitinase (DUB) activity that modulates the lysosomal turnover of the EGF receptor (EGFR) and other membrane proteins. METHODS: In this review, we summarize the recent genetic findings and discuss the clinical and pathological implications of USP8 deregulation in corticotroph adenomas. CONCLUSIONS: Mutations in USP8 have been identified in 35-62 % of functional sporadic corticotroph adenomas causing Cushing's disease, but not in any other type of pituitary tumor. These mutations are found mostly in adult female patients and lead to an aberrant DUB activation by impairing the regulation of USP8 by members of the 14-3-3 family of proteins. The consequence of this hyperactivation is a longer retention of EGFR at the plasma membrane which promotes an enhanced production of ACTH.

[The Choosing Wisely Initiative of the German Society of Internal Medicine : Recommendations of the German Society for Endocrinology and the German Society for Geriatrics]. / Die Klug-entscheiden-Initiative der Deutschen Gesellschaft für Innere Medizin : Empfehlungen der Deutschen Gesellschaft für Endokrinologie und der Deutschen Gesellschaft für Geriatrie.

POSITIVE RECOMMENDATIONS: A. After osteoporotic fractures in the elderly, as a rule specific antiosteoporotic therapy should be initiated. a. Osteoporosis as a disease of the elderly should be diagnosed and treated (recommendation of the German Society for Geriatrics). B. All patients with diabetes mellitus should complete a specific diabetes training program when antidiabetic drug medication is initiated. C. In Germany, all pregnant women should be advised to undertake iodine supplementation. D. Endocrine causes of hypertension should be ruled out in younger patients and in patients on multiple antihypertensive drugs. E. All unclear cases of hypercalcemia should be clarified. NEGATIVE RECOMMENDATIONS: A. Testosterone substitution therapy should not be initiated on the basis of only one measurement of a reduced testosterone level without clinical signs and clarification of the underlying cause. B. Imaging procedures should only be used after the existence of hormonal disease has been confirmed. C. Sonographic screening for thyroid disease is not advised in the elderly. D. Long-term therapy with levothyroxine for nodular goiter should be avoided. E. In relevant stress situations hydrocortisone replacement therapy should not be continued without dose adjustment in patients with adrenal or pituitary insufficiency.

Progress in Primary Aldosteronism: Translation on the Move.

Hypertension is a major cardiovascular risk factor that affects between 10-40% of the general population in an age dependent manner. The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure, fluid volume, and the vascular response to injury and inflammation 1. Chronic RAAS activation in the presence of sufficient sodium consumption leads to persistent hypertension, setting off a cascade of inflammatory, thrombotic, and atherogenic effects eventually leading to end-organ damage 2 3. Accordingly, numerous studies have demonstrated that elevated renin and/or aldosterone levels are predictors of adverse outcome in hypertension 4, heart failure 5 6, myocardial infarction 7, and renal insufficiency 8 and influence insulin resistance 9. Primary aldosteronism (PA) is the most common secondary form of hypertension with an estimated prevalence between 4 and 12% of hypertensives 10 11 12 and 11-20% in patients that are resistant to combined antihypertensive medication 13 14. Given the severe cardiovascular adverse effects of aldosterone excess that are independent of high blood pressure levels 15 16 17 18 detection and treatment of PA has important impact on clinical outcome and survival.

Parathyroid Gland Function in Primary Aldosteronism.

Primary aldosteronism (PA) is the most frequent cause of secondary arterial hypertension. Beyond its effects on intravascular volume and blood pressure, PA causes metabolic alterations and a higher cardiovascular morbidity, which is reduced by PA-directed therapy. Experimental studies demonstrated that mineralocorticoid excess may also influence mineral homeostasis. A role in cardiovascular disease has also been attributed to parathyroid hormone (PTH). Increasing evidence supports a bidirectional interaction between aldosterone and PTH.Primary hyperparathyroidism is associated with arterial hypertension and an increased cardiovascular morbidity and mortality, which might be associated to higher aldosterone values; parathyreoidectomy results in lowered aldosterone and blood pressure levels. PA leads to secondary hyperparathyroidism, which is reversible by PA-directed therapy. A lower bone mineral density and a higher fracture rate were also shown to be reversible by PA-directed therapy. There is a suspicion of a bidirectional interaction between aldosterone and PTH, which might lead to a higher cardiovascular risk. There are more and more reports about coincident PA and primary hyperparathyroidism. From a pathophysiologic point of view this constellation is best characterized as tertiary hyperparathyroidism. Future aspects should further clarify the extent of these endocrine interactions and analyze the influence of this interplay on cardiovascular morbidity and mortality and bone health.

KCNJ5 Mutations: Sex, Salt and Selection.

Somatic mutations have been identified in the KCNJ5 gene (encoding the potassium channel GIRK4) in aldosterone-producing adenomas (APA). Most of these mutations are located in or near the selectivity filter of the GIRK4 channel pore and several have been shown to lead to the constitutive overproduction of aldosterone. KCNJ5 mutations in APA are more frequent in women; however, this gender dimorphism is a reported phenomenon of Western but not East Asian populations. In this review we discuss some of the issues that could potentially underlie this observation.

Steroid Hormone Production in Patients with Aldosterone Producing Adenomas.

Primary aldosteronism encompasses 2 major underlying causes: (1) aldosterone producing adenoma and (2) bilateral adrenal hyperplasia. In addition to the aldosterone excess, increased production of other compounds of the steroidogenic pathways may be involved. Until recently, most studies examined the production of steroids other than aldosterone in tumor tissue, urine, or peripheral plasma samples, but several new studies have also addressed steroid levels in adrenal venous blood samples using liquid chromatography tandem mass spectrometry. Plasma and tissue levels of several precursors of aldosterone with mineralocorticoid activity are higher in patients with aldosterone producing adenomas than in those with bilateral hyperplasia. These include corticosterone, deoxycorticosterone, and their 18-hydroxylated metabolites. Similarly, urinary, peripheral, and adrenal venous concentrations of the hybrid steroids 18-oxocortisol and 18-hydroxycortisol are higher in patients with aldosterone producing adenomas than in bilateral hyperplasia. Differences in the pathophysiology and in clinical and biochemical phenotypes caused by aldosterone producing adenomas and bilateral adrenal hyperplasia may be related to the differential expression of steroidogenic enzymes, and associated to specific underlying somatic mutations. Correct appreciation of differences in steroid profiling between aldosterone producing adenomas and bilateral adrenal hyperplasia may not only contribute to a better understanding of the pathogenesis of primary aldosteronism but may also be helpful for future subtyping of primary aldosteronism.

Assay characteristics influence the aldosterone to renin ratio as a screening tool for primary aldosteronism: results of the German Conn's registry.

Primary aldosteronism (PA) is the most frequent cause of secondary arterial hypertension. The aldosterone to renin ratio (ARR) is the gold standard for screening, but variability between biochemical methods used remains of concern. The aim of the study was to analyze center-specific features of biochemical diagnostic strategies prior to the 2008 consensus within the German Conn's Registry. The study was designed as a retrospective study in 5 tertiary care hospitals. Patients analyzed for PA between 1990 and 2006 were studied. Characteristics of the assays used to determine ARR during establishing the diagnosis of PA were analyzed in the retrospective part of the German Conn's Registry. Eighty-six out of 484 documented ARR values had to be excluded from further evaluations because the laboratory or the assays were unknown. In the remaining 398 patients ARR was determined using 10 different assay combinations in the centers (aldosterone plus plasma renin activity or concentration). Considerable differences were seen between the mean concentrations for aldosterone (p<0.0001), renin concentration (p<0.001), and renin activity (p=0.009) for the different assays. The differences between the absolute concentrations measured by the different assays also had significant impact upon the resulting mean ratios. If published cutoff values are applied, the use of different commercial assays to determine the ARR in clinical routine results in major differences in positive screening rates. This heterogeneity affects sensitivity and specificity of screening for PA. Our data emphasize the importance of standardized screening procedures, which must include standardization of biochemical methods.

Characterization of NCI-H295R cells as an in vitro model of hyperaldosteronism.

In depth analysis of key molecular mechanisms involved in functional autonomy of aldosterone secretion is hampered by the lack of tumor cell lines that reflect functional characteristics of aldosterone producing adenomas. Herein, we describe the characteristics of the adrenocortical carcinoma cell line NCI-H295R and its suitability as a model of hyperaldosteronism in relation to different culture conditions. Steroid profiling revealed that NCI-H295R cells predominantly secrete cortisol, while aldosterone and other steroids are released at much lower concentrations. However, aldosterone output specifically increased in response to different stimuli such as ACTH and angiotensin II, and in particular to potassium in a dose dependent manner. NCI-H295R cells readily formed spheroids under specific culture conditions, a method widely used for the enrichment of progenitor cells. Unexpectedly, spheroid cells excelled with higher aldosterone concentration and higher expression levels of the steroidogenic enzymes StAR, 3ßHSD, CYP17, SF-1, and the MC2-receptor. Further investigations revealed that this phenomenon is mainly attributed to epithelial growth factor (EGF) and particularly fibroblast growth factor (FGF), which are both essential ingredients in the spheroid culture medium. Aldosterone release under the combinatory influence of EGF and FGF was not higher than the effect of FGF alone. Spheroid growth per se, therefore, does not ensure an enrichment of less differentiated cell types in this cell line.

[Endocrine disease symptoms]. / Endokrine Krankheitsbilder.

Diseases of the endocrine system can be classified according to the prevalence into two categories: very frequent endocrinopathies, which affect a population of several millions in Germany and include diabetes mellitus, endemic goiter, osteoporosis and obesity. On the other hand there are a large number of rare endocrine diseases which share the paradox of other rare diseases: they are also often falsely suspected in patients who are not affected but at the same time there are sometimes long delays in diagnosis in those who do have the disease. In cases of adrenal insufficiency, absolute glucocorticoid deficiency can progress to an adrenal crisis which is fatal if not treated. Patients with de Quervain thyroiditis often suffer from prolonged episodes of fever with tender, diffuse goiter and neck pain. Pheochromocytomas should be recognized early in the course of disease because of life-threatening cardiovascular complications. This article highlights the essential characteristics in order to increase awareness.