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Objective
We aimed to evaluate whether thyroid hormones, autoimmune and thyroid homeostasis status were related to bone turnover in type 2 diabetes.
Methods
The data were obtained from a cross-sectional study, the METAL study. In this study, 4209 participants (2059 men and 2150 postmenopausal women) with type 2 diabetes were enrolled. Thyroid function, thyroid antibodies and three bone turnover markers (BTMs), including a large N-mid fragment of osteocalcin (N-MID osteocalcin), β-C-terminal cross-linked telopeptides of type I collagen (β-CTX) and procollagen type I N-terminal propeptide (P1NP), were measured. Thyroid homeostasis parameters, including the sum activity of step-up deiodinases (SPINA-GD), thyroid secretory capacity (SPINA-GT), Jostel’s TSH index (TSHI) and the thyrotroph thyroid hormone resistance index (TTSI), were calculated. The associations of thyroid parameters with BTMs were analyzed using linear regression.
Results
Free and total triiodothyronine were positively associated with N-MID osteocalcin and P1NP in both sexes and positively associated with β-CTX in postmenopausal women. Thyroid-stimulating hormone was negatively associated with β-CTX in postmenopausal women, and free thyroxine was negatively associated with N-MID osteocalcin and P1NP in men. SPINA-GD was positively associated with N-MID osteocalcin and P1NP in both sexes. There was a positive relationship of SPINA-GT with β-CTX, a negative relationship of TTSI with β-CTX, and a negative relationship of TSHI with β-CTX and P1NP in postmenopausal women.
Conclusions
Among men and postmenopausal women with type 2 diabetes, significant associations were observed between N-MID osteocalcin, β-CTX and P1NP with thyroid function and thyroid homeostasis. Further prospective studies are warranted to understand the causal relationship and underlying mechanism.
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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.
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Universidad La Salle, Posgrado de la Facultad de Ciencias Químicas, 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.
Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, People’s Republic of China
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Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, People’s Republic of China
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Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, People’s Republic of China
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Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, People’s Republic of China
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Diabetes-induced advanced glycation end products (AGEs) overproduction would result in compromised osseointegration of titanium implant and high rate of implantation failure. 1α,25-dihydroxyvitamin D3 (1,25VD3) plays a vital role in osteogenesis, whereas its effects on the osseointegration and the underlying mechanism are unclear. The purpose of this study was to investigate that 1,25VD3 might promote the defensive ability of osseointegration through suppressing AGEs/RAGE in type 2 diabetes mellitus. In animal study, streptozotocin-induced diabetic rats accepted implant surgery, with or without 1,25VD3 intervention for 12 weeks. After killing, the serum AGEs level, bone microarchitecture and biomechanical index of rats were measured systematically. In vitro study, osteoblasts differentiation capacity was analyzed by alizarin red staining, alkaline phosphatase assay and Western blotting, after treatment with BSA, AGEs, AGEs with RAGE inhibitor and AGEs with 1,25VD3. And the expression of RAGE protein was detected to explore the mechanism. Results showed that 1,25VD3 could reverse the impaired osseointegration and mechanical strength, which possibly resulted from the increased AGEs. Moreover, 1,25VD3 could ameliorate AGEs-induced damage of cell osteogenic differentiation, as well as downregulating the RAGE expression. These data may provide a theoretical basis that 1,25VD3 could work as an adjuvant treatment against poor osseointegration in patients with type 2 diabetes mellitus.
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Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, Ruperto-Carola University of Heidelberg, Heidelberg, Germany
Synlab Medical Center of Human Genetics Mannheim, Mannheim, Germany
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Vitamin D testing and treatment is a subject of controversial scientific discussions, and it is challenging to navigate through the expanding vitamin D literature with heterogeneous and partially opposed opinions and recommendations. In this narrative review, we aim to provide an update on vitamin D guidelines and the current evidence on the role of vitamin D for human health with its subsequent implications for patient care and public health issues. Vitamin D is critical for bone and mineral metabolism, and it is established that vitamin D deficiency can cause rickets and osteomalacia. While many guidelines recommend target serum 25-hydroxyvitamin D (25[OH]D) concentrations of ≥50 nmol/L (20 ng/mL), the minimum consensus in the scientific community is that serum 25(OH)D concentrations below 25–30 nmol/L (10–12 ng/mL) must be prevented and treated. Using this latter threshold of serum 25(OH)D concentrations, it has been documented that there is a high worldwide prevalence of vitamin D deficiency that may require public health actions such as vitamin D food fortification. On the other hand, there is also reason for concern that an exploding rate of vitamin D testing and supplementation increases costs and might potentially be harmful. In the scientific debate on vitamin D, we should consider that nutrient trials differ from drug trials and that apart from the opposed positions regarding indications for vitamin D treatment we still have to better characterize the precise role of vitamin D for human health.
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Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
Harvard Medical School, Boston, Massachusetts, USA
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Glucocorticoid use is the most common cause of secondary osteoporosis. Poor skeletal health related to glucocorticoid use is thought to involve inhibition of the Wnt/β-catenin signaling pathway, a key pathway in osteoblastogenesis. Sclerostin, a peptide produced primarily by osteocytes, is an antagonist of the Wnt/β-catenin signaling pathway, raising the possibility that sclerostin is involved in glucocorticoids’ adverse effects on bone. The aim of this study was to determine whether an acute infusion of cosyntropin (i.e. ACTH(1–24)), which increases endogenous cortisol, increases serum sclerostin levels as compared to a placebo infusion. This study was performed using blood samples obtained from a previously published, double-blind, placebo-controlled, randomized, cross-over study among healthy men and women who received infusions of placebo or cosyntropin after being supine and fasted overnight (ClinicalTrials.gov NCT02339506). A total of 17 participants were analyzed. There was a strong correlation (R2 = 0.65, P < 0.0001) between the two baseline sclerostin measurements measured at the start of each visit, and men had a significantly higher average baseline sclerostin compared to women. As anticipated, cosyntropin significantly increased serum cortisol levels, whereas cortisol levels fell during placebo infusion, consistent with the diurnal variation in cortisol. There was no significant effect of cosyntropin as compared to placebo infusions on serum sclerostin over 6–24 h (P = 0.10). In conclusion, this randomized, placebo-controlled study was unable to detect a significant effect of a cosyntropin infusion on serum sclerostin levels in healthy men and women.
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Objective
To evaluate the clinical features of Chinese women with idiopathic hypogonadotropic hypogonadism (IHH).
Methods
We retrospectively reviewed the clinical characteristics, laboratory and imaging findings, therapeutic management and fertility outcomes of 138 women with IHH. All patients had been treated and followed up at an academic medical centre during 1990–2016.
Results
Among the 138 patients, 82 patients (59.4%) were diagnosed with normosmic IHH and 56 patients (40.6%) were diagnosed with Kallmann syndrome (KS). The patients with IHH experienced occasional menses (4.3%), spontaneous thelarche (45.7%) or spontaneous pubarche (50.7%). Women with thelarche had a higher percentage of pubarche (P < 0.001) and higher gonadotropin concentrations (P < 0.01). Olfactory bulb/sulci abnormalities were found during the magnetic resonance imaging (MRI) of all patients with KS. Most patients with IHH had osteopenia and low bone age. Among the 16 women who received gonadotropin-releasing hormone treatment, ovulation induction or assisted reproductive technology, the clinical pregnancy rate was 81.3% and the live birth rate was 68.8%.
Conclusions
The present study revealed that the phenotypic spectrum of women with IHH is broader than typical primary amenorrhoea with no secondary sexual development, including occasional menses, spontaneous thelarche or pubarche. MRI of the olfactory system can facilitate the diagnosis of KS. Pregnancy can be achieved after receiving appropriate treatment.