Cholecalciferol (vitamin D3) must not be considered as an endocrine disruptor / Le cholécalciférol (la vitamine D3) ne doit pas être inclus dans la liste des perturbateurs endocriniens

A French ministerial decree planning to include cholecalciferol, i.e. vitamin D3 (VD3), in the endocrine disruptors (ED) list has generated a lot of concerns in French physicians and scientists. The aim of the present article was to discuss the scientific rationale that may support or not this decision, which seems to be due to the use of VD3 overdose as a rodenticide in some European countries. First, it is noticeable that cholecalciferol is not an "exogenous substance", a term used in all the definitions of ED, as it is largely synthesized in the skin after UVB rays exposure. Second, we did not find any published article that may support the inclusion of VD3 in the ED list. The request "vitamin D AND endocrine disruptor" reported 33 references in the PubMed database on March, 10, 2022, most of them discussing disturbances of vitamin D metabolism by EDs. Third, a large amount of studies conclude that VD3 has or may have beneficial effects on many functions that are known to be altered by EDs. In addition, we warn that learning that VD3 could be legally considered as a PE may cause the general public to mistrust vitamin D supplementation, which is not desirable in terms of public health as it may increase the already too high prevalence of vitamin D deficient individuals. We consider the aberrant decision of including cholecalciferol in the ED list should be rapidly invalidated before being effective in France and possibly disseminated in the European Union.

Un projet d'arrêté ministériel inscrivant le cholécalciférol, c'est-à-dire la vitamine D3 (VD3), dans la liste des perturbateurs endocriniens (PE) est à l'origine de débats en France. L'objectif de notre article était de préciser les arguments scientifiques pour et contre l'inscription de la VD3 dans la liste des PE, qui semble être initialement due à son utilisation à très forte dose comme raticide/rodenticide dans certains pays. Premièrement, le cholécalciférol ne peut être défini comme une substance exogène, terme utilisé dans les différentes définitions des PE, car il est largement synthétisé dans la peau suite à l'exposition aux UVB. Deuxièmement, il n'existe aucune publication dans la base de données PubMed en faveur d'une inscription de la VD3 dans la liste des PE. La requête « vitamin D AND endocrine disruptor ¼ retrouvait 33 références au 10 mars 2022, la plupart évoquant des perturbations du métabolisme de la vitamine D par les PE. Troisièmement, un grand nombre d'études concluent, au contraire, que la VD3 a des effets bénéfiques sur de nombreuses fonctions altérées par les PE. Plus largement, nous alertons sur le fait qu'apprendre que la VD3 pourrait être règlementairement considérée comme un PE pourrait occasionner, auprès du grand public, une défiance vis-à-vis de la supplémentation en vitamine D, ce qui n'est pas souhaitable en termes de santé publique car de nature à aggraver la prévalence déjà trop élevée des individus carencés en vitamine D. Il est encore temps d'éviter cette décision aberrante et non fondée.

Acromégalie : améliorer la prise en charge: Acromegaly: improving care.

Acromegaly is characterized by increased release of growth hormone (GH) and, consequently, Insulin-Like Growth Factor I (IGF-I), most often by a pituitary adenoma. Prolonged exposure to excess hormone leads to progressive somatic disfigurement and a wide range of systemic manifestations that are associated with increased mortality. Transsphenoidal adenomectomy is the treatment of choice of GH-secreting pituitary tumors but surgical cure is not achieved in around 50% of patients, then adjuvant treatment is necessary. Mortality in acromegaly is normalized with biochemical control and has decreased in the last decade with the increased use of adjuvant therapy. Both GH and IGF-I are currently biomarkers for assessing disease activity in patients with acromegaly. However, discordance between GH and IGF-I results is encountered in a quarter of treated patients. The impacts of such a discrepancy over mortality and morbidity and the risk of biochemical and/or clinical recurrence are unclear. Moreover, despite a good biochemical control, some symptoms persist, leading to a decreased quality of life. Back pain due to vertebral fractures seem to be frequent in these patients and underdiagnosed. In patients with acromegaly, bone mineral density is not a reliable predictor of fracture risk. A more accurate evaluation of bone microstructural alterations associated with GH hypersecretion and vertebral fractures may be provided by new radiological devices analyzing alteration of trabecular microarchitecture, leading to a better prevention. © 2019 Published by Elsevier Masson SAS. All rights reserved. Cet article fait partie du numéro supplément Les Must de l'Endocrinologie 2019 réalisé avec le soutien institutionnel de Ipsen-Pharma.

A Somewhat Bizarre Case of Graves Disease Due to Vitamin Treatment.

CONTEXT: Accurate measurements of circulating hormones is essential for the practice of endocrinology. Immunometric assays employing the streptavidin-biotin system are widely used to measure hormones. However, these assays are susceptible to interference in patients taking biotin supplementations. This interference could mimic a coherent hormone profile, leading to misdiagnosis and unnecessary treatment. CASE DESCRIPTION: The patient, a 32-year-old man with X-linked adrenomyeloneuropathy recently diagnosed with Graves disease, was referred to our department to evaluate his response to antithyroid drugs. His thyroid function tests were still consistent with hyperthyroidism while he had been receiving carbimazole 40 mg/d for 6 weeks. We found no signs of thyrotoxicosis on physical examination despite the "frank and severe" biochemical hyperthyroidism. Noticing that all the patient's assays had been done at the same laboratory, we suspected assay interference. We therefore repeated the thyroid function tests at our hospital laboratory, which uses a different assay platform. Surprisingly, all the results were normal, confirming assay interference. The patient was taking an investigational "vitamin" therapy, which turned out to be biotin, prescribed at a dose of 100 mg tid as part of a trial of high-dose biotin in X-linked adrenomyeloneuropathy. CONCLUSIONS: This case should encourage physicians to ask their patients about possible biotin intake, especially when laboratory results are not compatible with clinical findings. If biotin interference is suspected, we propose either using a different assay not based on the streptavidin-biotin system or repeating the analyses after stopping biotin supplementation for one week.

High-dose biotin therapy leading to false biochemical endocrine profiles: validation of a simple method to overcome biotin interference.

BACKGROUND: High-dose biotin therapy is beneficial in progressive multiple sclerosis (MS) and is expected to be adopted by a large number of patients. Biotin therapy leads to analytical interference in many immunoassays that utilize streptavidin-biotin capture techniques, yielding skewed results that can mimic various endocrine disorders. We aimed at exploring this interference, to be able to remove biotin and avoid misleading results. METHODS: We measured free triiodothyronine (fT3), free thyroxine (fT4), thyroid-stimulating hormone (TSH), parathyroid homrone (PTH), 25-hydroxyvitamin D (25OHD), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, C-peptide, cortisol (Roche Diagnostics assays), biotin and its main metabolites (liquid chromatography tandem mass spectrometry) in 23 plasmas from MS patients and healthy volunteers receiving high-dose biotin, and in 39 biotin-unsupplemented patients, before and after a simple procedure (designated N5) designed to remove biotin by means of streptavidin-coated microparticles. We also assayed fT4, TSH and PTH in the 23 high-biotin plasmas using assays not employing streptavidin-biotin binding. RESULTS: The biotin concentration ranged from 31.7 to 1160 µg/L in the 23 high-biotin plasmas samples. After the N5 protocol, the biotin concentration was below the detection limit in all but two samples (8.3 and 27.6 µg/L). Most hormones results were abnormal, but normalized after N5. All results with the alternative methods were normal except two slight PTH elevations. In the 39 biotin-unsupplemented patients, the N5 protocol did not affect the results for any of the hormones, apart from an 8.4% decrease in PTH. CONCLUSIONS: We confirm that most streptavidin-biotin hormone immunoassays are affected by high biotin concentrations, leading to a risk of misdiagnosis. Our simple neutralization method efficiently suppresses biotin interference.

Serum calcitriol concentrations measured with a new direct automated assay in a large population of adult healthy subjects and in various clinical situations.

The measurement of calcitriol [1,25(OH2)D], is important for the differential diagnosis of several disorders of calcium/phosphorus metabolism but is time-consuming and tricky. We measured serum calcitriol with a new automated direct assay on the Liaison XL platform in 888 healthy French Caucasian subjects aged 18-89 years, 32 patients with a surgically-proven PHPT, 32 pregnant women at the end of the first and at the end of the third trimester, and 24 dialysis patients before and after one year of supplementation with vitamin D3 or placebo. The mean calcitriol concentration (±SD) in the healthy population was 52.9±14.5 ng/L with a 95% CI interval of 29-83.6 ng/L. In PHPT patients, calcitriol concentration was 81.6±29.0 ng/L, 15 of them (46.9%) having a concentration >83.6 ng/L. In pregnant women, calcitriol was 80.4±26.4 ng/L at the end of the first trimester, and 113.1±33.0 ng/L at the end of the third trimester, 12 (37.5%) and 26 (81.3%) of them having a calcitriol concentration >83.6 ng/L at the first and third trimesters respectively. In 14 dialysis patients, calcitriol was 9.5±7.7 ng/L and rose to 19.3 ng/L after one year of supplementation with 50,000 IU vitamin D3/month. In 10 other dialysis patients, calcitriol was 9.9±2.9 ng/L and remained stable (12.4±3.7 ng/L) after one year of placebo. In conclusion, this new automated calcitriol assay, in addition to presenting excellent analytical performances, gives the expected variations in patients compared to "normal" values obtained in an extensive reference population.

Primary hyperparathyroidism in pregnancy.

Primary hyperparathyroidism (PHPT) is rarely diagnosed during pregnancy but is associated with significant maternal and fetal morbidity and mortality. Information on appropriate management is limited. We reviewed the medical literature through December 2012 for key articles on PHPT during pregnancy, focusing on large series. Clinical knowledge in this area is restricted to isolated case reports and a few retrospective studies. Diagnosis can be difficult, owing to the non-specific nature of signs and symptoms of hypercalcemia during pregnancy. Pregnant women with a calcium level over 2.85 mmol/L (11.4 mg/dL) and prior pregnancy loss are at a particularly high risk of maternal complications (hypercalcemic crisis, nephrolithiasis, pancreatitis, etc.) and fetal loss. Around one-half of neonates born to mothers with untreated PHPT have hypocalcemia and tetany. Algorithms proposed for the management of the pregnant woman with PHPT are not evidence based, reflecting the paucity of data. Treatment should thus be individually tailored. Gestational age and the severity of hypercalcemia should be taken into account when assessing the risk-benefit balance of a conservative approach (hyperhydration and vitamin D supplementation) versus parathyroid surgery. Current evidence supports parathyroidectomy as the main treatment, performed preferably during the second trimester, when the serum calcium is above 2.75 mmol/L (11 mg/dL). In the patients with mild forms of PHPT, which are nowadays the most frequent, a conservative management is generally preferred.

Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing's syndrome.

CONTEXT: Mitotane is highly effective in the long-term management of Cushing's syndrome but has a slow onset of action. Mitotane combined with fast-acting steroidogenesis inhibitors might avoid the need for emergency bilateral adrenalectomy in patients with severe hypercortisolism. OBJECTIVE: Our objective was to assess the efficacy and safety of combination therapy with mitotane, metyrapone, and ketoconazole in severe ACTH-dependent Cushing's syndrome. PATIENTS, DESIGN, AND SETTING: Eleven patients with severe Cushing's syndrome participated in this follow-up study in a tertiary referral hospital. INTERVENTIONS: High-dose therapy combining mitotane (3.0-5.0 g/24 h), metyrapone (3.0-4.5 g/24 h), and ketoconazole (400-1200 mg/24 h) was initiated concomitantly. Twenty-four-hour urinary free cortisol (UFC) excretion (normal values 10-65 µg/24 h) was monitored. RESULTS: Data are reported as medians (range). All 11 patients experienced a marked clinical improvement. UFC excretion fell rapidly from 2737 µg/24 h (range 853-22,605) at baseline to 50 µg/24 h (range 18-298) (P = 0.001) within 24-48 h of treatment initiation and remained low to normal on the combination therapy. In seven patients, metyrapone and ketoconazole were discontinued after 3.5 months (range 3.0-6.0) of combination therapy, and UFC excretion remained controlled by mitotane monotherapy (UFC 17 µg/24 h, range 5-85; P = 0.016). Five patients became able to undergo etiological surgery and are presently in remission. Four of them recovered normal adrenal function after mitotane discontinuation. Adverse effects were tolerable, consisting mainly of gastrointestinal discomfort and a significant rise in total cholesterol and γ-glutamyl transferase levels (P = 0.012 and P = 0.002, respectively). CONCLUSIONS: When surgical treatment for severe ACTH-dependent Cushing's syndrome is not feasible, combination therapy with mitotane, metyrapone, and ketoconazole is an effective alternative to bilateral adrenalectomy, a procedure associated with significant morbidity and permanent hypoadrenalism.

Endocrine aspects of obstructive sleep apnea.

CONTEXT: Some endocrine and metabolic disorders are associated with a high frequency of obstructive sleep apnea (OSA), and treatment of the underlying endocrine disorder can improve and occasionally cure OSA. On the other hand, epidemiological and interventional studies suggest that OSA increases the cardiovascular risk, and a link between OSA and glucose metabolism has been suggested, via reduced sleep duration and/or quality. EVIDENCE ACQUISITION: We reviewed the medical literature for key articles through June 2009. EVIDENCE SYNTHESIS: Some endocrine and metabolic conditions (obesity, acromegaly, hypothyroidism, polycystic ovary disease, etc.) can be associated with OSA. The pathophysiological mechanisms of OSA in these cases are reviewed. In rare instances, OSA may be improved or even cured by treatment of underlying endocrine disorders: this is the case of hypothyroidism and acromegaly, situations in which OSA is mainly related to upper airways narrowing due to reversible thickening of the pharyngeal walls. However, when irreversible skeletal defects and/or obesity are present, OSA may persist despite treatment of endocrine disorders and may thus require complementary therapy. This is also frequently the case in patients with obesity, even after substantial weight reduction. CONCLUSIONS: Given the potential neurocognitive consequences and increased cardiovascular risk associated with OSA, specific therapy such as continuous positive airway pressure is recommended if OSA persists despite effective treatment of its potential endocrine and metabolic causes. "Apropos of sleep, that sinister adventure of all our nights, we might say that men go to bed daily with an audacity that would be incomprehensible if we did not know that it is the result of ignorance of the danger." Charles Baudelaire, in "Fusées, IX"

McCune-Albright syndrome and acromegaly: effects of hypothalamopituitary radiotherapy and/or pegvisomant in somatostatin analog-resistant patients.

BACKGROUND: Acromegaly, which may be present in patients with McCune-Albright syndrome (MCAS), in association with café-au-lait spots, precocious puberty, and fibrous dysplasia, is often difficult to treat surgically because skull base bone dysplasia prevents the removal of the pituitary adenoma. Somatostatin analogs (SAs) generally give only partial responses. The use of radiotherapy (RT) is controversial because of a possible risk of bone sarcomatous transformation. AIM: This study was a retrospective analysis of the efficacy and adverse effects of different treatment modalities in six patients with both MCAS and acromegaly. PATIENTS AND METHODS: Because surgery was impossible and SA failed to normalize GH/IGF-I hypersecretion, five of the six patients received fractionated RT (45-55 Grays). Three patients (two with previous RT) were also prescribed pegvisomant. We analyzed the clinical features of acromegaly, GH, and IGF-I concentrations and bone radiological features. RESULTS: GH and IGF-I concentrations fell after RT (median follow-up, 5 yr; range, 0.5-9 yr). Symptoms of acromegaly improved in parallel. Bone sarcomatous transformation was only noted in one patient in a region (the mandible) outside the radiation field. RT alone and/or combined with SA failed to normalize GH/IGF-I levels in the five patients concerned. In contrast, IGF-I levels normalized very rapidly (5-9 months) in the three patients receiving pegvisomant (10-20 mg/d). CONCLUSION: RT may be an option for the treatment of acromegaly in patients with MCAS when surgery is impossible and SA therapy is ineffective. However, although no bone sarcomatous transformation was observed within the radiation field in this series, this risk cannot be ruled out. As shown in this small series of severely affected patients, pegvisomant therapy may thus be useful to normalize IGF-I levels rapidly.