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Paal Methlie Department of Clinical Science, Department of Medicine, University of Bergen, N-5021 Bergen, Norway
Department of Clinical Science, Department of Medicine, University of Bergen, N-5021 Bergen, Norway

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Steinar Hustad Department of Clinical Science, Department of Medicine, University of Bergen, N-5021 Bergen, Norway

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Ralf Kellman Department of Clinical Science, Department of Medicine, University of Bergen, N-5021 Bergen, Norway

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Bjørg Almås Department of Clinical Science, Department of Medicine, University of Bergen, N-5021 Bergen, Norway

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Martina M Erichsen Department of Clinical Science, Department of Medicine, University of Bergen, N-5021 Bergen, Norway

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Eystein S Husebye Department of Clinical Science, Department of Medicine, University of Bergen, N-5021 Bergen, Norway
Department of Clinical Science, Department of Medicine, University of Bergen, N-5021 Bergen, Norway

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Kristian Løvås Department of Clinical Science, Department of Medicine, University of Bergen, N-5021 Bergen, Norway
Department of Clinical Science, Department of Medicine, University of Bergen, N-5021 Bergen, Norway

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Objective

Liquid chromatography–tandem mass spectrometry (LC–MS/MS) offers superior analytical specificity compared with immunoassays, but it is not available in many regions and hospitals due to expensive instrumentation and tedious sample preparation. Thus, we developed an automated, high-throughput LC–MS/MS assay for simultaneous quantification of ten endogenous and synthetic steroids targeting diseases of the hypothalamic–pituitary–adrenal axis and gonads.

Methods

Deuterated internal standards were added to 85 μl serum and processed by liquid–liquid extraction. Cortisol, cortisone, prednisolone, prednisone, 11-deoxycortisol, dexamethasone, testosterone, androstenedione and progesterone were resolved by ultra-high-pressure chromatography on a reversed-phase column in 6.1 min and detected by triple-quadrupole mass spectrometry. The method was used to assess steroid profiles in women with Addison's disease (AD, n=156) and blood donors (BDs, n=102).

Results

Precisions ranged from 4.5 to 10.1% relative standard deviations (RSD), accuracies from 95 to 108% and extraction recoveries from 60 to 84%. The method was practically free of matrix effects and robust to individual differences in serum composition. Most postmenopausal AD women had extremely low androstenedione concentrations, below 0.14 nmol/l, and median testosterone concentrations of 0.15 nmol/l (interquartile range 0.00–0.41), considerably lower than those of postmenopausal BDs (1.28 nmol/l (0.96–1.64) and 0.65 nmol/l (0.56–1.10) respectively). AD women in fertile years had androstenedione concentrations of 1.18 nmol/l (0.71–1.76) and testosterone concentrations of 0.44 nmol/l (0.22–0.63), approximately half of those found in BDs of corresponding age.

Conclusion

This LC–MS/MS assay provides highly sensitive and specific assessments of glucocorticoids and androgens with low sample volumes and is suitable for endocrine laboratories and research. Its utility has been demonstrated in a large cohort of women with AD, and the data suggest that women with AD are particularly androgen deficient after menopause.

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Emanuelle Nunes-Souza Pelé Pequeno Príncipe Research Institute, Água Verde, Curitiba, Parana, Brazil
Faculdades Pequeno Príncipe, Rebouças, Curitiba, Parana, Brazil
Centro de Genética Molecular e Pesquisa do Câncer em Crianças (CEGEMPAC) at Universidade Federal do Paraná, Agostinho Leão Jr., Glória, Curitiba, Parana, Brazil

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Mônica Evelise Silveira Laboratório Central de Análises Clínicas, Hospital de Clínicas, Universidade Federal do Paraná, Centro, Curitiba, Paraná, Brazil

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Monalisa Castilho Mendes Pelé Pequeno Príncipe Research Institute, Água Verde, Curitiba, Parana, Brazil
Faculdades Pequeno Príncipe, Rebouças, Curitiba, Parana, Brazil
Centro de Genética Molecular e Pesquisa do Câncer em Crianças (CEGEMPAC) at Universidade Federal do Paraná, Agostinho Leão Jr., Glória, Curitiba, Parana, Brazil

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Seigo Nagashima Serviço de Anatomia Patológica, Hospital de Clínicas, Universidade Federal do Paraná, General Carneiro, Alto da Glória, Curitiba, Parana, Brazil
Departamento de Medicina, PUC-PR, Prado Velho, Curitiba, Parana, Brazil

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Caroline Busatta Vaz de Paula Serviço de Anatomia Patológica, Hospital de Clínicas, Universidade Federal do Paraná, General Carneiro, Alto da Glória, Curitiba, Parana, Brazil
Departamento de Medicina, PUC-PR, Prado Velho, Curitiba, Parana, Brazil

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Guilherme Guilherme Vieira Cavalcante da Silva Serviço de Anatomia Patológica, Hospital de Clínicas, Universidade Federal do Paraná, General Carneiro, Alto da Glória, Curitiba, Parana, Brazil
Departamento de Medicina, PUC-PR, Prado Velho, Curitiba, Parana, Brazil

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Giovanna Silva Barbosa Serviço de Anatomia Patológica, Hospital de Clínicas, Universidade Federal do Paraná, General Carneiro, Alto da Glória, Curitiba, Parana, Brazil
Departamento de Medicina, PUC-PR, Prado Velho, Curitiba, Parana, Brazil

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Julia Belgrowicz Martins Pelé Pequeno Príncipe Research Institute, Água Verde, Curitiba, Parana, Brazil
Faculdades Pequeno Príncipe, Rebouças, Curitiba, Parana, Brazil

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Lúcia de Noronha Serviço de Anatomia Patológica, Hospital de Clínicas, Universidade Federal do Paraná, General Carneiro, Alto da Glória, Curitiba, Parana, Brazil
Departamento de Medicina, PUC-PR, Prado Velho, Curitiba, Parana, Brazil

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Luana Lenzi Departamento de Análises Clínicas, Universidade Federal do Paraná, Curitiba, Paraná, Brazil

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José Renato Sales Barbosa Pelé Pequeno Príncipe Research Institute, Água Verde, Curitiba, Parana, Brazil
Centro de Genética Molecular e Pesquisa do Câncer em Crianças (CEGEMPAC) at Universidade Federal do Paraná, Agostinho Leão Jr., Glória, Curitiba, Parana, Brazil

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Rayssa Danilow Fachin Donin Centro de Genética Molecular e Pesquisa do Câncer em Crianças (CEGEMPAC) at Universidade Federal do Paraná, Agostinho Leão Jr., Glória, Curitiba, Parana, Brazil

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Juliana Ferreira de Moura Pós Graduação em Microbiologia, Parasitologia e Patologia, Departamento de Patologia Básica – UFPR, Curitiba, Brazil

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Gislaine Custódio Faculdades Pequeno Príncipe, Rebouças, Curitiba, Parana, Brazil
Laboratório Central de Análises Clínicas, Hospital de Clínicas, Universidade Federal do Paraná, Centro, Curitiba, Paraná, Brazil

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Cleber Machado-Souza Pelé Pequeno Príncipe Research Institute, Água Verde, Curitiba, Parana, Brazil
Faculdades Pequeno Príncipe, Rebouças, Curitiba, Parana, Brazil
Centro de Genética Molecular e Pesquisa do Câncer em Crianças (CEGEMPAC) at Universidade Federal do Paraná, Agostinho Leão Jr., Glória, Curitiba, Parana, Brazil

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Enzo Lalli Institut de Pharmacologie Moléculaire et Cellulaire CNRS, Sophia Antipolis, Valbonne, France

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Bonald Cavalcante de Figueiredo Pelé Pequeno Príncipe Research Institute, Água Verde, Curitiba, Parana, Brazil
Faculdades Pequeno Príncipe, Rebouças, Curitiba, Parana, Brazil
Centro de Genética Molecular e Pesquisa do Câncer em Crianças (CEGEMPAC) at Universidade Federal do Paraná, Agostinho Leão Jr., Glória, Curitiba, Parana, Brazil
Departamento de Saúde Coletiva, Universidade Federal do Paraná, Curitiba, Paraná, Brazil

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Objective

Adaptive changes in DHEA and sulfated-DHEA (DHEAS) production from adrenal zona reticularis (ZR) have been observed in normal and pathological conditions. Here we used three different cohorts to assess timing differences in DHEAS blood level changes and characterize the relationship between early blood DHEAS reduction and cell number changes in women ZR.

Materials and methods

DHEAS plasma samples (n = 463) were analyzed in 166 healthy prepubertal girls before pubarche (<9 years) and 324 serum samples from 268 adult females (31.9–83.8 years) without conditions affecting steroidogenesis. Guided by DHEAS blood levels reduction rate, we selected the age range for ZR cell counting using DHEA/DHEAS and phosphatase and tensin homolog (PTEN), tumor suppressor and cell stress marker, immunostaining, and hematoxylin stained nuclei of 14 post-mortem adrenal glands.

Results

We confirmed that overweight girls exhibited higher and earlier DHEAS levels and no difference was found compared with the average European and South American girls with a similar body mass index (BMI). Adrenopause onset threshold (AOT) defined as DHEAS blood levels <2040 nmol/L was identified in >35% of the females >40 years old and associated with significantly reduced ZR cell number (based on PTEN and hematoxylin signals). ZR cell loss may in part account for lower DHEA/DHEAS expression, but most cells remain alive with lower DHEA/DHEAS biosynthesis.

Conclusion

The timely relation between significant reduction of blood DHEAS levels and decreased ZR cell number at the beginning of the 40s suggests that adrenopause is an additional burden for a significant number of middle-aged women, and may become an emergent problem associated with further sex steroids reduction during the menopausal transition.

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Enrique Pedernera Universidad Nacional Autónoma de México, Facultad de Medicina, Departamento de Embriología y Genética, Ciudad de México, México

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Flavia Morales-Vásquez Instituto Nacional de Cancerología, Ciudad de México, México

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María J Gómora Universidad Nacional Autónoma de México, Facultad de Medicina, Departamento de Embriología y Genética, Ciudad de México, México

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Miguel A Almaraz Universidad Nacional Autónoma de México, Facultad de Medicina, Departamento de Embriología y Genética, Ciudad de México, México

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Esteban Mena Universidad Nacional Autónoma de México, Facultad de Medicina, Secretaría General, Ciudad de México, México
Universidad La Salle, Posgrado de la Facultad de Ciencias Químicas, Ciudad de México, México

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Delia Pérez-Montiel Instituto Nacional de Cancerología, Ciudad de México, México

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Elizabeth Rendon Hospital Militar de Especialidades de la Mujer y Neonatología. Ciudad de México, México

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Horacio López-Basave Instituto Nacional de Cancerología, Ciudad de México, México

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Juan Maldonado-Cubas Universidad La Salle, Posgrado de la Facultad de Ciencias Químicas, Ciudad de México, México

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Carmen Méndez Universidad Nacional Autónoma de México, Facultad de Medicina, Departamento de Embriología y Genética, Ciudad de México, México

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The incidence of ovarian cancer has been epidemiologically related to female reproductive events and hormone replacement therapy after menopause. This highlights the importance of evaluating the role of sexual steroid hormones in ovarian cancer by the expression of enzymes related to steroid hormone biosynthesis in the tumor cells. This study was aimed to evaluate the presence of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), aromatase and estrogen receptor alpha (ERα) in the tumor cells and their association with the overall survival in 111 patients diagnosed with primary ovarian tumors. Positive immunoreactivity for 17β-HSD1 was observed in 74% of the tumors. In the same samples, aromatase and ERα revealed 66% and 47% positivity, respectively. No association was observed of 17β-HSD1 expression with the histological subtypes and clinical stages of the tumor. The overall survival of patients was improved in 17β-HSD1-positive group in Kaplan–Meier analysis (P = 0.028), and 17β-HSD1 expression had a protective effect from multivariate proportional regression evaluation (HR = 0.44; 95% CI 0.24–0.9; P = 0.040). The improved survival was observed in serous epithelial tumors but not in nonserous ovarian tumors. The expression of 17β-HSD1 in the cells of the serous epithelial ovarian tumors was associated with an improved overall survival, whereas aromatase and ERα were not related to a better survival. The evaluation of hazard risk factors demonstrated that age and clinical stage showed worse prognosis, and 17β-HSD1 expression displayed a protective effect with a better survival outcome in patients of epithelial ovarian tumors.

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Daniel Bell Department of Pharmacy, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK

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Julia Hale Department of Endocrinology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK

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Cara Go Department of Endocrinology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK

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Ben G Challis Department of Endocrinology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK

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Tilak Das Department of Radiology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK

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Brian Fish Department of Head and Neck Surgery, Cambridge University NHS Foundation Trust, Cambridge, UK

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Ruth T Casey Department of Endocrinology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
Department of Medical Genetics, Cambridge University, Cambridge, UK

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Primary hyperparathyroidism (pHPT) is a common endocrine disorder that can be cured by parathyroidectomy; patients unsuitable for surgery can be treated with cinacalcet. Availability of surgery may be reduced during COVID-19, and cinacalcet can be used as bridging therapy. In this single-centre retrospective analysis, we investigated the utility and safety of cinacalcet in patients with pHPT receiving cinacalcet between March 2019 and July 2020, including pre-parathyroidectomy bridging. We reviewed and summarised the published literature. Cinacalcet dosages were adjusted by endocrinologists to achieve target calcium < 2.70 mmol/L. Eighty-six patients were identified, with the most achieving target calcium (79.1%) with a mean dose of 39.4 mg/day (±17.1 mg/day) for a median duration of 35 weeks (1–178 weeks). Calcium was normalised in a median time of 5 weeks. The majority of patients commenced cinacalcet of 30 mg/day (78 patients) with the remainder at 60 mg/day (8 patients). Forty-seven patients commencing lower dose cinacalcet (30 mg/day) achieved target calcium without requiring 60 mg/day. Baseline PTH was significantly higher in patients requiring higher doses of cinacalcet. 18.6% of patients reported adverse reactions and 4.7% discontinued cinacalcet. Patients treated with cinacalcet pre-parathyroidectomy required a higher dose and fewer achieved target calcium compared to medical treatment with cinacalcet alone. Post-operative calcium was similar to patients who were not given pre-parathyroidectomy cinacalcet. In summary, cinacalcet at an initial dose of 30 mg/day is safe and useful for achieving target calcium in patients with symptomatic or severe hypercalcaemia in pHPT, including those treated for pre-parathyroidectomy. We propose a PTH threshold of >30 pmol/L to initiate at a higher dose of 60 mg/day.

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Marília D’Elboux Guimarães Brescia Endocrine Genetics Unit (LIM-25), Endocrinology Division, University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Hospital das Clinicas (HCFMUSP), São Paulo, São Paulo, Brazil
Parathyroid Unit – LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Division of Head and Neck Surgery, Department of Surgery, Hospital das Clinicas (HCFMUSP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil

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Karine Candido Rodrigues Endocrine Genetics Unit (LIM-25), Endocrinology Division, University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Hospital das Clinicas (HCFMUSP), São Paulo, São Paulo, Brazil
Endocrine Oncology Division, Institute of Cancer of the State of São Paulo (ICESP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, São Paulo, Brazil

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André Fernandes d’Alessandro Parathyroid Unit – LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Division of Head and Neck Surgery, Department of Surgery, Hospital das Clinicas (HCFMUSP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil

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Wellington Alves Filho Department of Surgery, Walter Cantidio University Hospital, Federal University of Ceara School of Medicine (FAMED-UFC), Fortaleza, Brazil

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Willemijn Y van der Plas Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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Schelto Kruijff Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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Sergio Samir Arap Parathyroid Unit – LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Division of Head and Neck Surgery, Department of Surgery, Hospital das Clinicas (HCFMUSP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil

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Sergio Pereira de Almeida Toledo Endocrine Genetics Unit (LIM-25), Endocrinology Division, University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Hospital das Clinicas (HCFMUSP), São Paulo, São Paulo, Brazil

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Fábio Luiz de Menezes Montenegro Parathyroid Unit – LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Division of Head and Neck Surgery, Department of Surgery, Hospital das Clinicas (HCFMUSP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil

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Delmar Muniz Lourenço Jr Endocrine Genetics Unit (LIM-25), Endocrinology Division, University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Hospital das Clinicas (HCFMUSP), São Paulo, São Paulo, Brazil
Endocrine Oncology Division, Institute of Cancer of the State of São Paulo (ICESP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, São Paulo, Brazil

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Background

Potential influences of parathyroidectomy (PTx) on the quality of life (QoL) in multiple endocrine neoplasia type 1-related primary hyperparathyroidism (HPT/MEN1) are unknown.

Method

Short Form 36 Health Survey Questionnaire was prospectively applied to 30 HPT/MEN1 patients submitted to PTx (20, subtotal; 10, total with autograft) before, 6 and 12 months after surgery. Parameters that were analyzed included QoL, age, HPT-related symptoms, general pain, comorbidities, biochemical/hormonal response, PTx type and parathyroid volume.

Results

Asymptomatic patients were younger (30 vs 38 years; P = 0.04) and presented higher QoL scores than symptomatic ones: Physical Component Summary score (PCS) 92.5 vs 61.2, P = 0.0051; Mental Component Summary score (MCS) 82.0 vs 56.0, P = 0.04. In both groups, QoL remained stable 1 year after PTx, independently of the number of comorbidities. Preoperative general pain was negatively correlated with PCS (r = −0.60, P = 0.0004) and MCS (r = −0.57, P = 0.0009). Also, moderate/intense pain was progressively (6/12 months) more frequent in cases developing hypoparathyroidism. The PTx type and hypoparathyroidism did not affect the QoL at 12 months although remnant parathyroid tissue volume did have a positive correlation (P = 0.0490; r = 0.3625) to PCS 12 months after surgery. Patients with one to two comorbidities had as pre-PTx PCS (P = 0.0015) as 12 months and post-PTx PCS (P = 0.0031) and MCS (P = 0.0365) better than patients with three to four comorbidities.

Conclusion

A variable QoL profile was underscored in HPT/MEN1 reflecting multiple factors associated with this complex disorder as comorbidities, advanced age at PTx and presence of preoperative symptoms or of general pain perception. Our data encourage the early indication of PTx in HPT/MEN1 by providing known metabolic benefits to target organs and avoiding potential negative impact on QoL.

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Sondra O’Callaghan Endocrinology, Diabetes & Metabolism, Orlando VA Healthcare System, Orlando, Florida, USA

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Hanford Yau Endocrinology, Diabetes & Metabolism, Orlando VA Healthcare System, Orlando, Florida, USA

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Palliation of symptoms related to malignancy-associated hypercalcemia (MAH) is essential and clinically meaningful for patients, given the continued poor prognosis, with high morbidity and mortality associated with this disease process. Historically, agents have been temporizing, having no impact on patient morbidity nor survival. We suggest that cinacalcet can be an efficacious agent to be taken orally, reducing patients’ time in the hospital/clinic settings. It is well-tolerated and maintains serum calcium levels in the normal range, while targeted cancer treatments can be employed. This has a direct, major impact on morbidity. Maintaining eucalcemia can increase quality of life, while allowing targeted therapies time to improve survival. Given that our case (and others) showed calcium reduction in MAH, there is promising evidence that cinacalcet can be more widely employed in this setting. Future consideration should be given to studies addressing the efficacy of cinacalcet in calcium normalization, improvement of quality of life, and impact on survival in patients with MAH. Though the exact mechanism of action for cinacalcet’s reduction in calcium in this setting is not currently known, we can still afford patients the possible benefit from it.

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Anna Eremkina Endocrinology Research Center, Russian Federation, Moscow, Russia

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Julia Krupinova Endocrinology Research Center, Russian Federation, Moscow, Russia

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Ekaterina Dobreva Endocrinology Research Center, Russian Federation, Moscow, Russia

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Anna Gorbacheva Endocrinology Research Center, Russian Federation, Moscow, Russia

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Ekaterina Bibik Endocrinology Research Center, Russian Federation, Moscow, Russia

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Margarita Samsonova Faculty of Fundamental Medicine, ederal State Budget Educational Institution of Higher Education M.V. Lomonosov Moscow State University, Moscow, Russia

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Alina Ajnetdinova Endocrinology Research Center, Russian Federation, Moscow, Russia

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Natalya Mokrysheva Endocrinology Research Center, Russian Federation, Moscow, Russia

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Hypercalcemic crisis is a severe but rare complication of primary hyperparathyroidism (PHPT), and data on denosumab treatment of patients with this disease is still very limited. The aim of this paper is to investigate the hypocalcemic effect of denosumab in PHPT patients with severe hypercalcemia when surgery should be delayed or is impossible for some reasons. We performed a retrospective study of 10 patients. The analysis included the use of biochemical markers of calcium-phosphorus metabolism, which were followed after the administration of 60 mg of denosumab. The trend to calcium reduction was already determined on the 3rd day after denosumab administration. In most cases the decrease in serum calcium level to the range of 2.8 mmol/L on average or lower was observed on the 7th day (P = 0.002). In addition to a significant increase in calcium levels we confirmed a significant increase in the estimated glomerular filtration rate on 7th day (P = 0.012). After that, seven patients underwent successful parathyroidectomy and achieved eucalcemia or hypocalcemia, one patient developed the recurrence of parathyroid cancer after initial surgery, while two patients with severe cardiovascular pathology refused surgery. Our study shows that denosumab is a useful tool in PHPT-associated hypercalcemia before surgery or if surgery is contraindicated.

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Maria Stelmachowska-Banaś Department of Endocrinology, The Centre of Postgraduate Medical Education, Warsaw, Polska, Poland

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Izabella Czajka-Oraniec Department of Endocrinology, The Centre of Postgraduate Medical Education, Warsaw, Polska, Poland

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Immune checkpoint inhibitors (ICIs) belong to a new group of anticancer drugs targeting T-cell proteins involved in the activation of immune response toward malignancies. Their introduction into clinical practice was a milestone in modern cancer treatment. However, the significant advantage of ICIs over conventional chemotherapy in terms of therapeutic efficacy is accompanied by new challenges related to specific side effects. ICI-induced immune system activation could lead to the loss of self-tolerance, presenting as autoimmune inflammation and dysfunction of various tissues and organs. Thus, the typical side effects of ICIs include immune-related adverse events (irAEs), among which endocrine irAEs, affecting numerous endocrine glands, have been commonly recognized. This review aimed to outline the current knowledge regarding ICI-induced endocrine disorders from a clinical perspective. We present updated information on the incidence and clinical development of ICI-induced endocrinopathies, including the most frequent thyroiditis and hypophysitis, the rarely observed insulin-dependent diabetes mellitus and primary adrenal insufficiency, and the recently described cases of hypoparathyroidism and lipodystrophy. Practical guidelines for monitoring, diagnosis, and treatment of ICI-related endocrine toxicities are also offered. Rising awareness of endocrine irAEs among oncologists, endocrinologists, and other health professionals caring for patients receiving ICIs could contribute to better safety and efficacy. As immunotherapy becomes widespread and approved for new types of malignancies, increased incidences of endocrine irAEs are expected in the future.

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Ursula M M Costa Division of Cardiology, Division of Endocrinology, Division of Endocrinology, Federal University of Sergipe, Aracaju, SE 49060-100, Brazil

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Carla R P Oliveira Division of Cardiology, Division of Endocrinology, Division of Endocrinology, Federal University of Sergipe, Aracaju, SE 49060-100, Brazil

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Roberto Salvatori Division of Cardiology, Division of Endocrinology, Division of Endocrinology, Federal University of Sergipe, Aracaju, SE 49060-100, Brazil

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José A S Barreto-Filho Division of Cardiology, Division of Endocrinology, Division of Endocrinology, Federal University of Sergipe, Aracaju, SE 49060-100, Brazil

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Viviane C Campos Division of Cardiology, Division of Endocrinology, Division of Endocrinology, Federal University of Sergipe, Aracaju, SE 49060-100, Brazil

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Francielle T Oliveira Division of Cardiology, Division of Endocrinology, Division of Endocrinology, Federal University of Sergipe, Aracaju, SE 49060-100, Brazil

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Ivina E S Rocha Division of Cardiology, Division of Endocrinology, Division of Endocrinology, Federal University of Sergipe, Aracaju, SE 49060-100, Brazil

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Joselina L M Oliveira Division of Cardiology, Division of Endocrinology, Division of Endocrinology, Federal University of Sergipe, Aracaju, SE 49060-100, Brazil

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Wersley A Silva Division of Cardiology, Division of Endocrinology, Division of Endocrinology, Federal University of Sergipe, Aracaju, SE 49060-100, Brazil

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Manuel H Aguiar-Oliveira Division of Cardiology, Division of Endocrinology, Division of Endocrinology, Federal University of Sergipe, Aracaju, SE 49060-100, Brazil

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Abstract

GH and its principal mediator IGF1 have important effects on metabolic and cardiovascular (CV) status. While acquired GH deficiency (GHD) is often associated with increased CV risk, the consequences of congenital GHD are not known. We have described a large group of patients with isolated GHD (IGHD) due to a homozygous mutation (c.57+1G>A) in the GH releasing hormone receptor gene, and shown that adult GH-naïve individuals have no evidence of clinically evident premature atherosclerosis. To test whether subclinical atherosclerosis is anticipated in untreated IGHD, we performed a cross-sectional study of 25 IGHD and 27 adult controls matched for age and gender. A comprehensive clinical and biochemical panel and coronary artery calcium scores were evaluated by multi-detector tomography. Height, weight, IGF1, homeostasis model assessment of insulin resistance, creatinine and creatininekinase were lower in the IGHD group. Median and interquartile range of calcium scores distribution was similar in the two groups: IGHD 0(0) and control 0(4.9). The vast majority of the calcium scores (20 of 25 IGHD (80%) and 18 of 27 controls (66.6%)) were equal to zero (difference not significant). There was no difference in the calcium scores classification. None of IGHD subjects had minimal calcification, which were present in four controls. Three IGHD and four controls had mild calcification. There were two IGHD individuals with moderate calcification and one control with severe calcification. Our study provides evidence that subjects with congenital isolated lifetime and untreated severe IGHD do not have accelerated subclinical coronary atherosclerosis.

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Tomás P Griffin Centre for Endocrinology, Diabetes and Metabolism, Saolta University Health Care Group (SUHCG), Galway University Hospitals (GUH), Galway, Ireland
Regenerative Medicine Institute at CÚRAM SFI Research Centre, School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland

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Caroline M Joyce Department of Clinical Biochemistry, Cork University Hospital, Cork, Ireland

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Sumaya Alkanderi Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

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Liam M Blake Department of Clinical Biochemistry, SUHCG, GUH, Galway, Ireland

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Derek T O’Keeffe Centre for Endocrinology, Diabetes and Metabolism, Saolta University Health Care Group (SUHCG), Galway University Hospitals (GUH), Galway, Ireland

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Delia Bogdanet Centre for Endocrinology, Diabetes and Metabolism, Saolta University Health Care Group (SUHCG), Galway University Hospitals (GUH), Galway, Ireland

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Md Nahidul Islam Regenerative Medicine Institute at CÚRAM SFI Research Centre, School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland
Department of Clinical Biochemistry, SUHCG, GUH, Galway, Ireland

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Michael C Dennedy Centre for Endocrinology, Diabetes and Metabolism, Saolta University Health Care Group (SUHCG), Galway University Hospitals (GUH), Galway, Ireland
Lambe Institute for Translational Research, School of Medicine, NUIG, Galway, Ireland

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John E Gillan Department of Histopathology, SUHCG, GUH, Galway, Ireland

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John J Morrison Department of Obstetrics and Gynaecology, SUHCG, GUH, Galway, Ireland

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Timothy O’Brien Centre for Endocrinology, Diabetes and Metabolism, Saolta University Health Care Group (SUHCG), Galway University Hospitals (GUH), Galway, Ireland
Regenerative Medicine Institute at CÚRAM SFI Research Centre, School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland

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John A Sayer Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
Newcastle upon Tyne NHS Hospitals Foundation Trust, Newcastle upon Tyne, UK
NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne, UK

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Marcia Bell Centre for Endocrinology, Diabetes and Metabolism, Saolta University Health Care Group (SUHCG), Galway University Hospitals (GUH), Galway, Ireland

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Paula M O’Shea Department of Clinical Biochemistry, SUHCG, GUH, Galway, Ireland

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Introduction

Inactivating mutations in CYP24A1, encoding vitamin D-24-hydroxylase, can lead to an accumulation of active vitamin D metabolites and consequent hypercalcaemia. Patient (infantile and adult) presentation is varied and includes mild-severe hypercalcaemia, hypercalciuria, nephrocalcinosis and nephrolithiasis. This study aimed to characterize the clinical and biochemical phenotypes of a family with two CYP24A1 missense variants.

Methods

The proband and seven family members underwent detailed clinical and biochemical evaluation. Laboratory measurements included serum calcium, intact parathyroid hormone (iPTH), vitamin D metabolites and urine calcium and creatinine.

Results

The proband presented during the second trimester of a planned pregnancy with flu-like symptoms. Laboratory tests showed elevated adjusted calcium of 3.27 (upper reference limit (URL: 2.30) mmol/L), suppressed iPTH (<6 ng/L), elevated 25(OH)D (264 (URL: 55) nmol/L) and elevated 1,25(OH)D (293 (URL: <280) pmol/L). Ionized calcium was 1.55 (URL: 1.28) mmol/L. Sanger sequencing revealed two heterozygous missense variants in the CYP24A1: p.(Arg439Cys), R439C and p.(Trp275Arg), W275R. The proband’s brother and sister had the same genotype. The brother had intermittent hypercalcaemia and hypervitaminosis D. Only the sister had a history of nephrolithiasis. The proband’s daughter and two nephews were heterozygous for the R439C variant. The proband and her brother frequently had elevated 25(OH)D:24,25(OH)2D ratios (>50) during follow-up.

Conclusions

W275R is a new pathogenic CYP24A1 mutation in compound heterozygotic form with R439C in this family.

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