Venous thromboembolism in Cushing syndrome: results from an EuRRECa and Endo-ERN survey.

Background: Patients with Cushing syndrome (CS) are at increased risk of venous thromboembolism (VTE). Objective: The aim was to evaluate the current management of new cases of CS with a focus on VTE and thromboprophylaxis. Design and methods: A survey was conducted within those that report in the electronic reporting tool (e-REC) of the European Registries for Rare Endocrine Conditions (EuRRECa) and the involved main thematic groups (MTG's) of the European Reference Networks for Rare Endocrine Disorders (Endo-ERN) on new patients with CS from January 2021 to July 2022. Results: Of 222 patients (mean age 44 years, 165 females), 141 patients had Cushing disease (64%), 69 adrenal CS (31%), and 12 patients with ectopic CS (5.4%). The mean follow-up period post-CS diagnosis was 15 months (range 3-30). Cortisol-lowering medications were initiated in 38% of patients. One hundred fifty-four patients (69%) received thromboprophylaxis (including patients on chronic anticoagulant treatment), of which low-molecular-weight heparins were used in 96% of cases. VTE was reported in six patients (2.7%), of which one was fatal: two long before CS diagnosis, two between diagnosis and surgery, and two postoperatively. Three patients were using thromboprophylaxis at time of the VTE diagnosis. The incidence rate of VTE in patients after Cushing syndrome diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Conclusion: Thirty percent of patients with CS did not receive preoperative thromboprophylaxis during their active disease stage, and half of the VTE cases even occurred during this stage despite thromboprophylaxis. Prospective trials to establish the optimal thromboprophylaxis strategy in CS patients are highly needed. Significance statement: The incidence rate of venous thromboembolism in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Notably, this survey showed that there is great heterogeneity regarding time of initiation and duration of thromboprophylaxis in expert centers throughout Europe.

Electronic reporting of rare endocrine conditions within a clinical network: results from the EuRRECa project.

Objective: The European Registries for Rare Endocrine Conditions (EuRRECa, eurreb.eu) includes an e-reporting registry (e-REC) used to perform surveillance of conditions within the European Reference Network (ERN) for rare endocrine conditions (Endo-ERN). The aim of this study was to report the experience of e-REC over the 3.5 years since its launch in 2018. Methods: Electronic reporting capturing new encounters of Endo-ERN conditions was performed monthly through a bespoke platform by clinicians registered to participate in e-REC from July 2018 to December 2021. Results: The number of centres reporting on e-REC increased to a total of 61 centres from 22 countries. A median of 29 (range 11, 45) paediatric and 32 (14, 51) adult centres had reported cases monthly. A total of 9715 and 4243 new cases were reported in adults (age ≥18 years) and children, respectively. In children, sex development conditions comprised 40% of all reported conditions and transgender cases were most frequently reported, comprising 58% of sex development conditions. The median number of sex development cases reported per centre per month was 0.6 (0, 38). Amongst adults, pituitary conditions comprised 44% of reported conditions and pituitary adenomas (69% of cases) were most commonly reported. The median number of pituitary cases reported per centre per month was 4 (0.4, 33). Conclusions: e-REC has gained increasing acceptability over the last 3.5 years for capturing brief information on new encounters of rare conditions and shows wide variations in the rate of presentation of these conditions to centres within a reference network. Significance statement Endocrinology includes a very wide range of rare conditions and their occurrence is often difficult to measure. By using an electronic platform that allowed monthly reporting of new clinical encounters of several rare endocrine conditions within a defined network that consisted of several reference centres in Europe, the EuRRECa project shows that a programme of e-surveillance is feasible and acceptable. The data that have been collected by the e-reporting of rare endocrine conditions (e-REC) can allow the continuous monitoring of rare conditions and may be used for clinical benchmarking, designing new studies or recruiting to clinical trials.

[Modified-release hydrocortisone for glucocorticoid deficiency]. / Modified-release-Hydrocortison bei Glukokortikoidmangel.

BACKGROUND: The central circadian pacemaker in the suprachiasmatic nucleus and interaction of clock genes with the hypothalamus pituitary adrenal axis are responsible for very distinct cortisol concentrations. Unphysiologically high doses of glucocorticoids that do not follow the circadian rhythm lead to increased rates of morbidity, mortality and reduced quality of life. OBJECTIVES: Does a switch to modified-release hydrocortisone in multimorbid elderly patients offer benefits compared to a conventional therapy regime? METHODS: Evaluation, analysis and discussion of statistics, recent research results and expert advice. RESULTS: Overdosage and unphysiological timing of cortisol administration result in higher incidences of obesity, hypertension, hyperglycemia, coronary heart disease and cardiac events. Body weight, body mass index and HbA1c decline with Plenadren® (Shire Pharmaceuticals Ireland Limited, Dublin, Ireland) treatment compared to conventional therapy. CD16+ natural killer cells and natural killer cytotoxycity are reduced, and the incidence of respiratory-tract infections is increased, with conventional therapy compared to Plenadren®. Cortisol influences sleep pattern and sleep quality by its circadian secretion. CONCLUSION: Novel modified-release hydrocortisone preparations offer diverse benefits with regard to their effect on metabolism, cardiovascular risk, immunity and sleep, which might be beneficial in particular in multimorbid elderly.

The current landscape of European registries for rare endocrine conditions.

Objective To identify cross-border international registries for rare endocrine conditions that are led from Europe and to understand the extent of engagement with these registries within a network of reference centres (RCs) for rare endocrine conditions. Methods Database search of international registries and a survey of RCs in the European Reference Network for rare endocrine conditions (Endo-ERN) with an overall response rate of 82%. Results Of the 42 conditions with orphacodes currently covered within Endo-ERN, international registries exist for 32 (76%). Of 27 registries identified in the Orphanet and RD-Connect databases, Endo-ERN RCs were aware of 11 (41%). Of 21 registries identified by the RC, RD-Connect and Orphanet did not have a record of 10 (48%). Of the 29 glucose RCs, the awareness and participation rate in an international registry was highest for rare diabetes at 75 and 56% respectively. Of the 37 sex development RCs, the corresponding rates were highest for disorders of sex development at 70 and 52%. Of the 33 adrenal RCs, the rates were highest for adrenocortical tumours at 68 and 43%. Of the 43 pituitary RCs, the rates were highest for pituitary adenomas at 43 and 29%. Of the 31 genetic tumour RCs, the rates were highest for MEN1 at 26 and 9%. For the remaining conditions, awareness and participation in registries was less than 25%. Conclusion Although there is a need to develop new registries for rare endocrine conditions, there is a more immediate need to improve the awareness and participation in existing registries.

[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.

Gonadal function in adult male patients with congenital adrenal hyperplasia.

CONTEXT: Current knowledge on gonadal function in congenital adrenal hyperplasia (CAH) is mostly limited to single-center/country studies enrolling small patient numbers. Overall data indicate that gonadal function can be compromised in men with CAH. OBJECTIVE: To determine gonadal function in men with CAH within the European 'dsd-LIFE' cohort. DESIGN: Cross-sectional clinical outcome study, including retrospective data from medical records. METHODS: Fourteen academic hospitals included 121 men with CAH aged 16-68 years. Main outcome measures were serum hormone concentrations, semen parameters and imaging data of the testes. RESULTS: At the time of assessment, 14/69 patients had a serum testosterone concentration below the reference range; 7 of those were hypogonadotropic, 6 normogonadotropic and 1 hypergonadotropic. In contrast, among the patients with normal serum testosterone (55/69), 4 were hypogonadotropic, 44 normogonadotropic and 7 hypergonadotropic. The association of decreased testosterone with reduced gonadotropin concentrations (odds ratio (OR) = 12.8 (2.9-57.3)) was weaker than the association between serum androstenedione/testosterone ratio ≥1 and reduced gonadotropin concentrations (OR = 39.3 (2.1-732.4)). Evaluation of sperm quality revealed decreased sperm concentrations (15/39), motility (13/37) and abnormal morphology (4/28). Testicular adrenal rest tumor (TART)s were present in 39/80 patients, with a higher prevalence in patients with the most severe genotype (14/18) and in patients with increased current 17-hydroxyprogesterone 20/35) or androstenedione (12/18) serum concentrations. Forty-three children were fathered by 26/113 patients. CONCLUSIONS: Men with CAH have a high risk of developing hypothalamic-pituitary-gonadal disturbances and spermatogenic abnormalities. Regular assessment of endocrine gonadal function and imaging for TART development are recommended, in addition to measures for fertility protection.

Experts' Opinion on the Prenatal Therapy of Congenital Adrenal Hyperplasia (CAH) Due to 21-Hydroxylase Deficiency - Guideline of DGKED in cooperation with DGGG (S1-Level, AWMF Registry No. 174/013, July 2015).

Purpose: This guideline of the German Society of Pediatric Endocrinology and Diabetology (DGKED) is designed to be experts' opinion on the current concept of prenatal therapy for congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH). Several scientific medical societies have also participated in the guideline. It aims to offer guidance to physicians when they counsel affected families about prenatal therapy. Methods: The experts commissioned by the medical societies developed a consensus in an informal process. The consensus was subsequently confirmed by the steering committees of the respective medical societies. Recommendations: Prenatal CAH therapy is an experimental therapy. We recommend designing and using standardized protocols for the prenatal diagnosis, therapy and long-term follow-up of women and children treated prenatally with dexamethasone. If long-term follow-up is not possible, then prenatal therapy should not be performed.

[Pheochromocytoma - still a challenge]. / Das Phäochromozytom - noch immer eine Herausforderung.

Pheochromocytomas are rare, mostly benign catecholamine-producing tumors arising from the chromaffin cells of the adrenal medulla or in the paraganglia. Clinical presentation is highly variable but typically with hypertension, severe headaches, palpitations and sweating. Biochemical testing by 24 h urinary fractioned metanephrines or catecholamines and plasma free metanephrines as the most sensitive screening approach, confirms the catecholamine excess. Computed tomography scan and magnetic resonance imaging of the adrenal glands and abdomen as well as functional imaging with (123)Iod-MIBG scintigraphy and (18)F-dopa positron emission tomography are used for tumor localization. Because approximately a quarter of tumors develop secondary to germ-line mutations, screening for genetic alterations is important. The therapy of choice is the endoscopic adrenal sparing surgery following preoperative alpha-blockade. Regular follow-up remains essential due to possible recurrence and malignancy.

Intracranial germinoma as a very rare cause of panhypopituitarism in a 23-year old man.

A 23 year-old patient was referred to the endocrine outpatient clinic with the suspicion of diabetes insipidus as he complained of nycturia and polydipsia since 2-3 months. Further he presented with nausea, vomiting, loss of appetite, rapid weight loss, diffuse body pain and fatigue. No headache, blurred vision, or fever were reported. The clinical examination showed sexual infantilism (poor beard, pubic and axillary hair growth, small testis). The patient's skin was strikingly pale as well as dry and scaly. Lymph node palpation was unremarkable. Endocrine evaluation revealed diabetes insipidus as well as complete anterior pituitary insufficiency. MR imaging demonstrated contrast-enhancing mass lesions at the pineal gland, hypothalamus, and anterior horn of lateral ventricles bilaterally. The localization pattern deemed to be highly suspicious for intracranial germinoma. As beta-HCG and AFP were negative in serum and cerebrospinal fluid the diagnosis of germinoma was confirmed histologically. After radiotherapy with cranio-spinal radiation therapy with 24 Gy followed by two weeks of local tumor boost with 16 Gy, the posttherapy MRI scan indicated complete tumor removal. This case demonstrates a very rare and potentially curable tumor as the cause of panhypopituitarism in adults.

[Testicular adrenal rest tumors (TART) in adult men with classic congenital adrenal hyperplasia (CAH)]. / Testikuläre adrenale Resttumoren (TART) bei erwachsenen Männern mit klassischem adrenogenitalen Syndrom (AGS).

BACKGROUND: Information about treatment of adult male patients with congenital adrenal hyperplasia (CAH) and testicular adrenal rest tumors (TART) is scarce. Diagnostic and therapeutic guidelines do not exist. The aim of this review is to evaluate the current state of therapeutic options in adult male patients with CAH. METHODS: We performed an extensive search of the literature of the last 10 years by using PubMed/MEDLINE. RESULTS: The aims of treatment in adult male patients with CAH are prevention of adrenal crisis and TART, improvement of general well-being, good quality of life and sexual well-being, fertility, and prevention of side effects of gluco- and mineralocorticoid therapy. However, fertility is impaired in these patients and correlates with TART. The current therapeutic concepts are discussed. CONCLUSIONS: A future system of regular follow-up visits and standards in therapeutic concepts is needed to guarantee an improved fertility and lifelong good quality of life in adult male patients with CAH.

[Treatment of adult men with congenital adrenal hyperplasia syndrome due to 21-hydroxylase deficiency]. / Behandlung des klassischen adrenogenitalen Syndroms mit 21-Hydroxylase-Defekt bei erwachsenen Männern.

Information about the treatment of males with congenital adrenal hyperplasia (CAH) is scarce and there are no therapeutical guidelines. The aim of this review is to provide a survey of the current data. An extensive literature research was performed in PubMed for relevant articles published in the last ten years. The aim in the treatment of adult male CAH patients is preservation of fertility, prevention of an addisonian crisis, blood pressure management, prevention of testicular adrenal rest tumors (TART), maintaining well-being and good quality of life, satisfactory sexual function and prevention of long-term side effects of gluco- and mineralocorticoid therapy. The change from paediatric to adult medicine should be handled in a transition outpatient clinic organized by paediatric and adult endocrinologists. Most studies have included only small numbers of patients. The steroid therapy is usually orientated on an individual basis; but, general guidelines are lacking. It is reported that fertility is often impaired and related to the occurrence of TART. Some of these tumors are responsive to altered glucocorticoid therapy. However, glucocorticoid-resistant TART have been described, and testis-sparing surgery seems to be a treatment option. A future system of regular follow-up visits and standardized therapy guidelines are essential to provide a better medical care and a higher quality of life for male patients with CAH.

[Hyponatraemic encephalopathy and rhabdomyolysis. Complications after preparation for colonoscopy with mannitol]. / Hyponatriämische Enzephalopathie und Rhabdomyolyse. Komplikationen nach Koloskopievorbereitung mit Mannit.

In the preparation for colonoscopy, it is necessary to drink a great deal of often hypo-osmotic fluid. Therefore, the electrolytes and intra- and extracellular water are disequilibrated. Most of the patients tolerate this without any subjective or objective symptoms. In our case, a young male patient suffered from a severe hyponatriaemia with encephalopathy for more than 48 h through the preparation for an elective ambulant colonoscopy with mannite. Furthermore, he developed a rhabdomyolysis (either through lying on the floor in coma for more than 9 h, through the hyponatriaemia itself or through compensation of the hyponatriaemia) that lasted for ca. 1 week.

Genetic testing for pheochromocytoma-associated syndromes.

Pheochromocytoma and paraganglioma are tumors of the autonomic nervous system. Various syndromes have been found to be associated with the development of pheochromocytomas and paragangliomas: multiple endocrine neoplasia type 2 (MEN 2, susceptibility gene: RET), von Hippel-Lindau disease (VHL, susceptibility gene: VHL), neurofibromatosis 1 (NF 1), and paraganglioma syndromes type 1, 3, and 4 (susceptibility genes: succinate dehydrogenase gene, SDH, subunits D, C and B, respectively). Prevalence and clinical features of pheochromocytomas and paragangliomas are different for each of these syndromes. Mutational analysis of the susceptibility genes of these syndromes in patients presenting with pheochromocytoma or paraganglioma may help to judge the risks of multifocality of the tumor as well as development of malignant pheochromocytoma or of other malignant tumors. Here we review the recent progress in clinical characterization and genetic testing for these syndromes. Based on tumor characteristics and prevalence data we give recommendations for an efficient genetic testing procedure in patients presenting with pheochromocytomas and paragangliomas.

[Hypoglycemia and transient diabetes mellitus in an insulin autoimmune syndrome]. / Hypoglykämien und transienter Diabetes mellitus bei einem Autoimmun-Insulinsyndrom.

HISTORY AND CLINICAL FINDINGS: A 53-year-old Caucasian woman presented with repeated episodes of hypoglycemia. Self-monitored blood glucose levels during the attacks were between 40 and 60 mg/dl (2.2-3.3 mmol/l). INVESTIGATIONS: An oral glucose tolerance test performed over 210 minutes showed normal baseline glucose levels, markedly elevated levels of serum insulin and slightly elevated C-peptide concentrations. During the test, a marked increase of insulin and a normal increment of C-peptide were observed. The tentative diagnosis of an insulinoma was raised and a 72 h fasting test performed, throughout which the insulin-glucose-ratio was pathologically elevated, whereas C-peptide levels were only slightly elevated. DIAGNOSIS: Strongly positive levels of insulin antibodies led to the diagnosis of an insulin autoimmune syndrome. TREATMENT AND COURSE: This syndrome is caused by IgG-insulin-complexes with prolonged plasma half-life in the presence of reduced insulin action. The therapy consisted of fractionated meals to avoid hyperinsulinism and following hypoglycemic episodes. After four months a spontaneous clinical remission was observed. CONCLUSION: The autoimmune insulin syndrome is a rare cause of recurrent, spontaneous hypoglycemia in Europe in non diabetic patients. Its prognosis is good as there is a high rate of spontaneous clinical remission in up to 80 % of patients.

Adrenocortical function of the domestic fowl: effects of orchiectomy and androgen replacement.

The effect of orchiectomy and androgen replacement on cockerel adrenocortical function was investigated. Orchiectomized cockerels (2 weeks old) were implanted with Silastic tubing containing various amounts of one of the following steroids: cholesterol, testosterone (T), androstenedione (A4), and 5 alpha-dihydrotestosterone (DHT). Birds were administered additional implants, containing doses of steroids equivalent to those of the initial implants, at 4 and 8 weeks of treatment (i.e., 6 and 10 weeks of age). Sham-operated cockerels administered empty implants served as intact controls for comparison of data. Animals were killed after 10 weeks of treatment (12 weeks old). Trunk plasma corticosterone (B) and plasma T, and B production by collagenase-isolated adrenocortical cells incubated briefly (2 hr) with or without steroidogenic agents were measured by radioimmunoassay. Orchiectomy with implantation of the inert sterol, cholesterol (hereafter referred to as orchiectomy), did not alter plasma B concentrations and did not affect basal cellular B production or cellular B production induced by a maximal steroidogenic concentration of ACTH or that maximally supported by 25-hydroxycholesterol. However, orchiectomy did lower maximal 8-bromo-cyclic AMP-induced B production by 30%. Low-implant doses of A4 (1-cm implant) and T (0.3-cm implant), that maintained comb growth, lowered plasma B concentrations by 24-42%, whereas a high-implant dose of T (3-cm implant) and all implant doses of DHT had no effect on plasma B concentrations. Thus, androgen replacement had different effects on plasma B depending on the type of androgen and the implant dose. In contrast, androgen replacement consistently suppressed basal and maximal ACTH-induced cellular B production regardless of the type of androgen. Furthermore, the degree of suppression was dose-dependent. These results suggest that the differential effect of androgen replacement on plasma B concentrations was due to differences in the clearance of circulating B and/or differences in blood volume. In addition, the present study suggests that in the absence of the testes, androgens are suppressants of adrenocortical cell function in the domestic fowl.