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Primary hyperparathyroidism has emerged as a prevalent endocrine disorder in clinical settings, necessitating in most cases, surgical intervention for the removal of the diseased gland. This condition is characterised by overactivity of the parathyroid glands, resulting in excessive parathyroid hormone production and subsequent disturbances in calcium homeostasis. The primary mode of management is surgical treatment, relying on the accurate localisation of the pathological parathyroid gland. Precise identification is paramount to ensuring that the surgical intervention effectively targets and removes the diseased gland, alleviating the hyperfunctioning state. However, localising the gland becomes challenging, as discrepancies between the clinical manifestation of active parathyroid and radiological identification are common. Based on our current knowledge, to date, no comprehensive review has been conducted that considers all factors collectively. This comprehensive review delves into the factors contributing to false-negative 99mTc-Sestamibi scans. Our research involved an exhaustive search in the PubMed database for hyperparathyroidism, with the identified literature meticulously filtered and reviewed by the authors. The results highlighted various factors, including multiple parathyroid diseases, nodular goitre, mild disease, or the presence of an ectopic gland that causes discordance. Hence, a thorough consideration of these factors is crucial during the diagnostic workup of hyperparathyroidism. Employing intraoperative PTH assays can significantly contribute to a successful cure of the disease, thereby providing a more comprehensive approach to managing this prevalent endocrine disorder.
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Centre for Cardiovascular Science, Queen’s Medical Research Unit, University of Edinburgh, Edinburgh, UK
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Objective
Primary hyperparathyroidism (PHPT) is a common reason for referral to endocrinology but the evidence base guiding assessment is limited. We evaluated the clinical presentation, assessment and subsequent management in PHPT.
Design
Retrospective cohort study.
Patients
PHPT assessed between 2006 and 2014 (n = 611) in a university hospital.
Measurements
Symptoms, clinical features, biochemistry, neck radiology and surgical outcomes.
Results
Fatigue (23.8%), polyuria (15.6%) and polydipsia (14.9%) were associated with PHPT biochemistry. Bone fracture was present in 16.4% but was not associated with biochemistry. A history of nephrolithiasis (10.0%) was associated only with younger age (P = 0.006) and male gender (P = 0.037). Thiazide diuretic discontinuation was not associated with any subsequent change in calcium (P = 0.514). Urine calcium creatinine clearance ratio (CCCR) was <0.01 in 18.2% of patients with confirmed PHPT. Older age (P < 0.001) and lower PTH (P = 0.043) were associated with failure to locate an adenoma on ultrasound (44.0% of scans). When an adenoma was identified on ultrasound the lateralisation was correct in 94.5%. Non-curative surgery occurred in 8.2% and was greater in those requiring more than one neck imaging modality (OR 2.42, P = 0.035).
Conclusions
Clinical features associated with PHPT are not strongly related to biochemistry. Thiazide cessation does not appear to attenuate hypercalcaemia. PHPT remains the likeliest diagnosis in the presence of low CCCR. Ultrasound is highly discriminant when an adenoma is identified but surgical failure is more likely when more than one imaging modality is required.
Faculté de Chirurgie Dentaire, Université de Toulouse III, Toulouse, France
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CHU de Toulouse, Laboratoire d’Hématologie, Toulouse, France
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Faculté de Chirurgie Dentaire, Université de Toulouse III, Toulouse, France
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Estrogen–progestin therapy was previously considered as the standard of care for managing bothersome symptoms associated with menopause, but it increases risks of breast cancer and of thromboembolism. The combination of conjugated estrogen (CE) with bazedoxifene (BZA) named tissue-selective estrogen complex (TSEC) was designed to minimize or even abrogate the undesirable effects on breast, while maintaining the beneficial effects such as prevention of osteoporosis and suppression of climacteric symptoms. The risk on thromboembolism associated with TSEC is unknown, although the clinical available data are reassuring. The aim of this study was to define the impact of a chronic administration of CE, BZA or CE + BZA on hemostasis and thrombosis in ovariectomized mice. As expected, CE, but not BZA neither CE + BZA, induced uterine and vagina hypertrophy. As previously demonstrated for 17β-estradiol (E2), we found that CE (i) increased tail-bleeding time, (ii) prevented occlusive thrombus formation in injured carotid artery and (iii) protected against collagen/epinephrine-induced thromboembolism. Thus, whereas BZA antagonized CE action on reproductive tissues, it had no impact on the effect of CE on hemostasis, thromboembolism and arterial thrombosis in mice. CE + BZA shared the anti-thrombotic actions of CE in these mouse models. If a similar process is at work in women, CE combined with BZA could contribute to minimize the risk of thrombosis associated with hormone replacement therapy.
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EHESP-School of Public Health, Rennes, France
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Inserm (Institut National de la Santé et de la Recherche Médicale), Irset – Inserm, UMR 1085, Rennes, France
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Concern has been raised over chemical-induced disruption of ovary development during fetal life resulting in long-lasting consequences only manifesting themselves much later during adulthood. A growing body of evidence suggests that prenatal exposure to the mild analgesic acetaminophen/paracetamol can cause such a scenario. Therefore, in this review, we discuss three recent reports that collectively indicate that prenatal exposure in a period of 13.5 days post coitum in both rats and mouse can result in reduced female reproductive health. The combined data show that the exposure results in the reduction of primordial follicles, irregular menstrual cycle, premature absence of corpus luteum, as well as reduced fertility, resembling premature ovarian insufficiency syndrome in humans that is linked to premature menopause. This could especially affect the Western parts of the world, where the age for childbirth is continuously being increased and acetaminophen is recommended during pregnancy for pain and fever. We therefore highlight an urgent need for more studies to verify these data including both experimental and epidemiological approaches.
Department of Clinical Science, Department of Medicine, Department of Medicine, Pediatric Department, University of Bergen, Bergen, Norway
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Department of Clinical Science, Department of Medicine, Department of Medicine, Pediatric Department, University of Bergen, Bergen, Norway
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Department of Clinical Science, Department of Medicine, Department of Medicine, Pediatric Department, University of Bergen, Bergen, Norway
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Primary hypomagnesemia with secondary hypocalcemia (HSH) is an autosomal recessive disorder characterized by neuromuscular symptoms in infancy due to extremely low levels of serum magnesium and moderate to severe hypocalcemia. Homozygous mutations in the magnesium transporter gene transient receptor potential cation channel member 6 (TRPM6) cause the disease. HSH can be misdiagnosed as primary hypoparathyroidism. The aim of this study was to describe the genetic, clinical and biochemical features of patients clinically diagnosed with HSH in a Norwegian cohort. Five patients in four families with clinical features of HSH were identified, including one during a national survey of hypoparathyroidism. The clinical history of the patients and their families were reviewed and gene analyses of TRPM6 performed. Four of five patients presented with generalized seizures in infancy and extremely low levels of serum magnesium accompanied by moderate hypocalcemia. Two of the patients had an older sibling who died in infancy. Four novel mutations and one large deletion in TRPM6 were identified. In one patient two linked homozygous mutations were located in exon 22 (p.F978L) and exon 23 (p.G1042V). Two families had an identical mutation in exon 25 (p.E1155X). The fourth patient had a missense mutation in exon 4 (p.H61N) combined with a large deletion in the C-terminal end of the gene. HSH is a potentially lethal condition that can be misdiagnosed as primary hypoparathyroidism. The diagnosis is easily made if serum magnesium is measured. When treated appropriately with high doses of oral magnesium supplementation, severe hypomagnesemia is uncommon and the long-term prognosis seems to be good.
Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
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Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
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Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
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Health Management Center, The Second Affiliated Hospital of Zhejiang Chinese Medicine University, Zhejiang, China
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Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
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Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
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Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
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Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
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The clinical presentation of primary hyperparathyroidism (PHPT) differs between patients from developed and developing countries. In China, the clinical pattern has changed over the past few decades. Our aim was to elucidate general changes in the clinical characteristics of PHPT from 2010 to 2021. We enrolled 343 patients with PHPT at the Qilu Hospital of Shandong University, Jinan, China, from January 2010 to May 2021, including both surgical and non-surgical patients. Patients were divided into two subgroups, 2010–2016 (group A, n = 152) and 2017–2021 (group B, n = 191), based on the time span. We compared clinical manifestations and laboratory result data between these two groups. The mean patient age was 52.59 ± 13.55 years, and the male-to-female ratio was 1:2.54. Of the 343 patients, 183 (53.35%) had symptomatic PHPT; bone pain, urolithiasis, and fatigue were the most common symptoms. Post-operative pathology showed that 96.20% of the patients had parathyroid adenoma, whereas 2.41% had parathyroid carcinoma. Great changes occurred between 2010 and 2021; the percentage of patients with asymptomatic PHPT (aPHPT) increased from 36.18% in group A to 54.97% in group B. Moreover, patients in group B showed significantly lower serum calcium, alkaline phosphatase, parathyroid hormone, and urinary phosphate levels but higher serum 25-hydroxyvitamin D levels than those in group A. Clinical presentations in group B were also milder. In conclusion, the clinical characteristics of Chinese PHPT patients changed dramatically from 2010 to 2021, with asymptomatic PHPT (aPHPT becoming the predominant type over the last 3 years.
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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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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.
Department of Clinical Science, Department of Medicine, University of Bergen, N-5021 Bergen, Norway
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Department of Clinical Science, Department of Medicine, University of Bergen, N-5021 Bergen, Norway
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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.
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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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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Departamento de Medicina, PUC-PR, Prado Velho, Curitiba, Parana, Brazil
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Departamento de Medicina, PUC-PR, Prado Velho, Curitiba, Parana, Brazil
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Departamento de Medicina, PUC-PR, Prado Velho, Curitiba, Parana, Brazil
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Departamento de Medicina, PUC-PR, Prado Velho, Curitiba, Parana, Brazil
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Faculdades Pequeno Príncipe, Rebouças, Curitiba, Parana, Brazil
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Departamento de Medicina, PUC-PR, Prado Velho, Curitiba, Parana, Brazil
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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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Laboratório Central de Análises Clínicas, Hospital de Clínicas, Universidade Federal do Paraná, Centro, Curitiba, Paraná, Brazil
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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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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.