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Introduction: Prolactinomas are the most frequent type of pituitary adenoma encountered in clinical practice. Dopamine agonists (DA) like cabergoline typically provide sign/ symptom control, normalize prolactin levels and decrease tumor size in most patients. DA-resistant prolactinomas are infrequent and can occur in association with some genetic causes like MEN1 and pathogenic germline variants in the AIP gene (AIPvar)., Methods: We compared the clinical, radiological, and therapeutic characteristics of AIPvar-related prolactinomas (n=13) with unselected hospital-treated prolactinomas ("unselected", n=41) and genetically-negative, DA-resistant prolactinomas (DA-resistant, n=39)., Results: AIPvar-related prolactinomas occurred at a significantly younger age than the unselected or DA-resistant prolactinomas (p<0.01). Males were more common in the AIPvar (75.0%) and DA- resistant (49.7%) versus unselected prolactinomas (9.8%; p<0.001). AIPvar prolactinomas exhibited significantly more frequent invasion than the other groups (p<0.001) and exhibited a trend to larger tumor diameter. The DA-resistant group had significantly higher prolactin levels at diagnosis than the AIPvar group (p<0.001). Maximum DA doses were significantly higher in the AIPvar and DA-resistant groups versus unselected. DA-induced macroadenoma shrinkage (>50%) occurred in 58.3% in the AIPvar group versus 4.2% in the DA-resistant group (p<0.01). Surgery was more frequent in the AIPvar and DA- resistant groups (43.8% and 61.5%, respectively) versus unselected (19.5%: p<0.01). Radiotherapy was used only in AIPvar (18.8%) and DA-resistant (25.6%) groups., Discussion: AIPvar confer an aggressive phenotype in prolactinomas, with invasive tumors occurring at a younger age. These characteristics can help differentiate rare AIPvar related prolactinomas from DA-resistant, genetically-negative tumors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Vroonen, Beckers, Camby, Cuny, Beckers, Jaffrain-Rea, Cogne, Naves, Ferriere, Romanet, Elenkova, Karhu, Brue, Barlier, Pétrossians and Daly.)

Case Presentation: A 34-year-old woman presented to the emergency department for arterial hypertension. Blood analysis requested by the endocrinologist showed very high level of aldosterone (1805 ng/L, normal values: <264 ng/L) and high level of renin activity (2.8 ng/mL/h, normal values: 0.1-2.0 ng/mL/h). The patient reported the use of Yasmin® (ethinylestradiol 30 µg/drospirenone 3 mg) continuously (without hormone-free week between cycles) as oral contraception. Medical imaging examinations revealed no anomaly in the kidneys and the adrenal glands. On the endocrinologist advice, patient stopped the intake of Yasmin®. Aldosterone and renin levels were measured several times after the discontinuation of the oral contraception and a diminution of these levels was observed with a complete normalization of both levels 26 days after the synthetic hormones discontinuation., Discussion: The literature shows that ethynilestradiol/drospirenone association can interfere with the renin-angiotensin-aldosterone system and increase the levels of aldosterone and/or renin. We reported here a clinical case illustrating the significant impact of this medication on the renin-angiotensin-aldosterone axis of a young woman. However, this association is not listed among the drugs interfering with the aldosterone and renin-level measurements., Conclusion: Considering the data in the literature and our clinical case, we suggest adding drospirenone and the ethinylestradiol/drospirenone association in the list of drugs interfering with aldosterone and renin level determination.

Objective: Primary adrenal insufficiency (PAI) is a rare disease with an increasing prevalence, which may be complicated by life-threatening adrenal crisis (AC). Good quality epidemiological data remain scarce. We performed a Belgian survey to describe the aetiology, clinical characteristics, treatment regimens, comorbidities and frequency of AC in PAI., Methods: A nationwide multicentre study involving 10 major university hospitals in Belgium collected data from adult patients with known PAI., Results: Two hundred patients were included in this survey. The median age at diagnosis was 38 years (IQR 25-48) with a higher female prevalence (F/M sex ratio = 1.53). The median disease duration was 13 years (IQR 7-25). Autoimmune disease was the most common aetiology (62.5%) followed by bilateral adrenalectomy (23.5%) and genetic variations (8.5%). The majority (96%) of patients were treated with hydrocortisone at a mean daily dose of 24.5 ± 7.0 mg, whereas 87.5% of patients also received fludrocortisone. About one-third of patients experienced one or more AC over the follow-up period, giving an incidence of 3.2 crises per 100 patient-years. There was no association between the incidence of AC and the maintenance dose of hydrocortisone. As high as 27.5% of patients were hypertensive, 17.5% had diabetes and 17.5% had a diagnosis of osteoporosis., Conclusion: This study provides the first information on the management of PAI in large clinical centres in Belgium, showing an increased frequency of postsurgical PAI, a nearly normal prevalence of several comorbidities and an overall good quality of care with a low incidence of adrenal crises, compared with data from other registries.

Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

The breakthrough of the secrets of hypertension and the renin-angiotensin-aldosterone system (RAAS) is one of the legends of medicine. The first chapter is the one of Tigerstedt's experiments about renin, and Loesch and Gollblatt's model of renal hypertension. The race to elucidate the mechanisms of angiotensin, angiotensinogen and the angiotensin conversion enzyme cascade, by Braun Menéndez and Page teams, is a second chapter. The puzzle of this elegant cascade is completed by aldosterone isolation by the collaboration of Tait spouses and Tadeus Rechstein. As a corollary of these findings, Conn made the first description of primary hyperaldosteronism. The elucidation of RAAS pathophysiology naturally led to the synthesis of the antihypertensive captopril by Ondetti and Cushman, thereby opening the modern era of ACE inhibitors and ARII blockers. In March 2020, a viral pandemic caused by SARS-Cov-2 ignites the entire planet. This new coronavirus uses the RAAS angiotensin conversion enzyme type 2 (ACE-2) as a gateway. The SARS-CoV-2/ACE-2 signalling pathway and its pathological effects on the cardio-respiratory and renal system of these patients initiate a new chapter. The interaction of SARS-Cov-2/ACE-2 axis with anti-hypertensive agents, as well as with ACE-2 activators and ACE-2 homologs, takes a part of an active international study searching for therapeutic targets. This modern research, summarized in this article, will further develop our knowledge of RAAS and, hopefully, will improve the management of COVID-19 patients.

Background: Up to 7% of all adrenal incidentalomas (AIs) are pheochromocytomas (PCCs). In the evaluation of AI, it is generally recommended that PCC be excluded by measurement of plasma-free or 24-hour urinary fractionated metanephrines. However, recent studies suggest that biochemical exclusion of PCC not be performed for lesions with CT characteristics of an adrenocortical adenoma (ACA)., Aim: To determine the proportion of PCCs with ACA-like attenuation or contrast washout on CT., Methods: For this multicenter retrospective study, two central investigators independently analyzed the CT reports of 533 patients with 548 histologically confirmed PCCs. Data on tumor size, unenhanced Hounsfield units (HU), absolute percentage washout (APW), and relative percentage washout (RPW) were collected in addition to clinical parameters., Results: Among the 376 PCCs for which unenhanced attenuation data were available, 374 had an attenuation of >10 HU (99.5%). In the two exceptions (0.5%), unenhanced attenuation was exactly 10 HU, which lies just within the range of ≤10 HU that would suggest a diagnosis of ACA. Of 76 PCCs with unenhanced HU > 10 and available washout data, 22 (28.9%) had a high APW and/or RPW, suggestive of ACA., Conclusion: Based on the lack of PCCs with an unenhanced attenuation of <10 HU and the low proportion (0.5%) of PCCs with an attenuation of 10 HU, it seems reasonable to abstain from biochemical testing for PCC in AIs with an unenhanced attenuation of ≤10 HU. The assessment of contrast washout, however, is unreliable for ruling out PCC.

Clinically relevant pituitary adenomas are present in about 1 per 1,000 of the general population and prolactinomas are by far the most common clinical subtype of pituitary adenomas. Usually prolactinomas affect premenopausal women and present with typical symptoms of menstrual disturbance and/or galactorrhea. They are generally managed with dopamine agonists to restore fertility and to control symptoms and tumor size. In a subset of prolactinomas, however, management remains challenging. Studies in recent years have identified the factors related to dopamine agonist resistance, such as male sex, genetic features, and aggressive tumor behavior. Certain other patient groups represent particular challenges for management, such as pediatric patients and pregnant women. Treatment with dopamine agonists is usually safe and effective, and adverse effects such as clinically relevant cardiac valvular complications and impulse control disorders may occur in isolated instances. A number of important disease characteristics of prolactinomas remain to be explained, such as the difference in sex prevalence before and after menopause, the higher prevalence of macroadenomas in older males, and the biochemical mechanisms of resistance to dopaminergic agonists., (© 2019 S. Karger AG, Basel.)

Purpose: MDH2 (malate dehydrogenase 2) has recently been proposed as a novel potential pheochromocytoma/paraganglioma (PPGL) susceptibility gene, but its role in the disease has not been addressed. This study aimed to determine the prevalence of MDH2 pathogenic variants among PPGL patients and determine the associated phenotype., Methods: Eight hundred thirty patients with PPGLs, negative for the main PPGL driver genes, were included in the study. Interpretation of variants of unknown significance (VUS) was performed using an algorithm based on 20 computational predictions, by implementing cell-based enzymatic and immunofluorescence assays, and/or by using a molecular dynamics simulation approach., Results: Five variants with potential involvement in pathogenicity were identified: three missense (p.Arg104Gly, p.Val160Met and p.Ala256Thr), one in-frame deletion (p.Lys314del), and a splice-site variant (c.429+1G>T). All were germline and those with available biochemical data, corresponded to noradrenergic PPGL., Conclusion: This study suggests that MDH2 pathogenic variants may play a role in PPGL susceptibility and that they might be responsible for less than 1% of PPGLs in patients without pathogenic variants in other major PPGL driver genes, a prevalence similar to the one recently described for other PPGL genes. However, more epidemiological data are needed to recommend MDH2 testing in patients negative for other major PPGL genes.

Background: Aldosterone measurement is critical for diagnosis of primary aldosteronism and disorders of the renin-angiotensin system. We developed an LC-MS/MS method for plasma and urinary aldosterone and compared it to our RIA method. We present a reference interval study for a Belgian population., Methods: 68 plasma and 23 urine samples were assayed for as part of a method comparison. For the reference interval study, we enrolled 282 healthy Caucasian volunteers (114 Male: mean age 35 ± 11 y and 168 Female: mean age 42 ± 13 y). A subset of 139 healthy volunteers agreed to a 24-h urine collection. For the method validation, 5 plasma and 8 urine pools were run in triplicate and quadruplicate, respectively, on 3 different days., Results: Between-run imprecision (CV) was 2.8-5.1% for plasma and 4.5-8.6% for urine, except at the low urine concentration of 2.99 nmol/L where a CV of 15.4% was observed. The limit of quantitation was 0.04 nmol/L for plasma and 6.65 nmol/L for urine. Recoveries, based on spiking experiments into natural matrix, did not differ significantly from 100%. Regression comparisons showed that, on average, RIA generated results were 59% and 11% higher than LC-MS/MS for plasma and urine, respectively. The MS reference interval we propose for plasma aldosterone is 0.07 nmol/L-0.73 nmol/L for women and 0.04 nmol/L-0.41 nmol/L for men. No gender difference was observed for urine aldosterone. The reference interval was determined to be <60.94 nmol/day., Conclusions: The LC-MS/MS method was validated and reference intervals for plasma and urine were established. A significant bias between RIA and LC-MS/MS was noted., (© 2018 Published by Elsevier B.V. on behalf of The Association for Mass Spectrometry: Applications to the Clinical Lab (MSACL).)