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- Abstract: Calcium x
- Abstract: Menopause x
- Abstract: Osteo* x
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.
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Objective
Chronic hypoparathyroidism (HP) is associated with acute and chronic complications, especially those related to hypocalcemia. We aimed to analyze details on hospital admissions and the reported deaths in affected patients.
Design and methods
In a retrospective analysis, we reviewed the medical history of 198 patients diagnosed with chronic HP over a continuous period of up to 17 years at the Medical University Graz.
Results
The mean age in our mostly female cohort (70.2%) was 62.6 ± 18.7 years. The etiology was predominantly postsurgical (84.8%). About 87.4% of patients received standard medication (oral calcium/vitamin D), 15 patients (7.6%) used rhPTH1–84/Natpar® and 10 patients (4.5%) had no/unknown medication. Two hundred and nineteen emergency room (ER) visits and 627 hospitalizations were documented among 149 patients, and 49 patients (24.7%) did not record any hospital admissions. According to symptoms and decreased serum calcium levels, 12% of ER (n = 26) visits and 7% of hospitalizations (n = 44) were likely attributable to HP. A subgroup of 13 patients (6.5%) received kidney transplants prior to the HP diagnosis. In eight of these patients, parathyroidectomy for tertiary renal hyperparathyroidism was the cause of permanent HP. The mortality was 7.8% (n = 12), and the causes of death appeared to be unrelated to HP. Although the awareness for HP was low, calcium levels were documented in 71% (n = 447) of hospitalizations.
Conclusions
Acute symptoms directly related to HP did not represent the primary cause of ER visits. However, comorbidities (e.g. renal/cardiovascular diseases) associated with HP played a key role in hospitalizations and deaths.
Significance statement
Hypoparathyroidism (HP) is the most common complication after anterior neck surgery. Yet, it remains underdiagnosed as well as undertreated, and the burden of disease and long-term complications are usually underestimated. There are few detailed data on emergency room (ER) visits hospitalizations and death in patients with chronic HP, although acute symptoms due to hypo-/hypercalcemia are easily detectable. We show that HP is not the primary cause for presentation but that hypocalcemia is a typical laboratory finding (when ordered) and thus may contribute to subjective symptoms. Patients often present with renal/cardiovascular/oncologic illness for which HP is known to be a contributing factor. A small but very special group (n = 13, 6.5%) are patients after kidney transplantations who showed a high ER hospitalization rate. Surprisingly, HP was never the cause for their frequent hospitalizations but rather the result of chronic kidney disease. The most frequent cause for HP in these patients was parathyroidectomy due to tertiary hyperparathyroidism. The causes of death in 12 patients appeared to be unrelated to HP, but we found a high prevalence of chronic organ damages/comorbidities related to it in this group. Less than 25% documented HP correctly in the discharge letters, which indicates a high potential for improvement.
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Endocrinology, Department of Public Health, Group Administration, Helsinki University Hospital, University of Eastern Finland, Abdominal Center, University of Helsinki and Helsinki University Hospital, Post Box 340, FI-00290 Helsinki, Finland
Endocrinology, Department of Public Health, Group Administration, Helsinki University Hospital, University of Eastern Finland, Abdominal Center, University of Helsinki and Helsinki University Hospital, Post Box 340, FI-00290 Helsinki, Finland
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Health-related quality of life (HRQoL) is frequently impaired in primary hyperparathyroidism (PHPT) but it is unclear if surgery is beneficial. The objective was to prospectively assess HRQoL in PHPT (n=124) with the 15D instrument before and after surgery, to compare it with that of a comparable sample of the general population (n=4295), and search for predictors of HRQoL and its change. HRQoL, and clinical and laboratory parameters were measured before and at 6 and 12 months after surgery. Regression techniques were used to search for predictors of HRQoL and gains from treatment. Before surgery, PHPT patients had significantly lower mean 15D score compared to controls (0.813 vs 0.904, P<0.001). Excretion, mental function, discomfort and symptoms, distress, depression, vitality, and sexual activity were most impaired (all P<0.001). Number of medications (P=0.001) and subjective symptoms (P<0.05) but not calcium or parathyroid hormone (PTH) predicted impaired HRQoL. Serum 25-hydroxyvitamin D (25OHD) was of borderline significance (P=0.051). Compared to baseline, mean 15D score improved significantly 6 months after surgery (0.813 vs 0.865, P<0.001) and the effect sustained at 1 year (0.878, P<0.001). The improvement was clinically important in 77.4% of patients (P<0.001). Educational level independently predicted improvement (P<0.005). HRQoL is severely impaired in PHPT but improves significantly after surgery. The 15D is a sensitive tool for assessing HRQoL and recognizing patients likely to benefit from surgery.
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Chromogranin A (CgA (CHGA)) is the major soluble protein co-stored and co-released with catecholamines and can function as a pro-hormone by giving rise to several bioactive peptides. This review summarizes the physiological functions, the pathogenic implications, and the recent use of these molecules as biomarkers in several pathological conditions. A thorough literature review of the electronic healthcare databases MEDLINE, from January 1985 to September 2013, was conducted to identify articles and studies concerned with CgA and its processing. The search strategies utilized keywords such as chromogranin A, vasostatins 1 and 2, chromofungin, chromacin, pancreastatin, catestatin, WE14, chromostatin, GE25, parastatin, and serpinin and was supplemented by the screening of references from included papers and review articles. A total of 209 English-language, peer-reviewed original articles or reviews were examined. The analysis of the retrospective literature suggested that CgA and its several bioactive fragments exert a broad spectrum of regulatory activities by influencing the endocrine, the cardiovascular, and the immune systems and by affecting the glucose or calcium homeostasis. As some peptides exert similar effects, but others elicit opposite responses, the regulation of the CgA processing is critical to maintain homeostasis, whereas an unbalanced production of peptides that exert opposing effects can have a pathogenic role in several diseases. These clinical implications entail that CgA and its derived peptides are now used as diagnostic and prognostic markers or to monitor the response to pharmacological intervention not only in endocrine tumors, but also in cardiovascular, inflammatory, and neuropsychiatric diseases.
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Both in the United States and Europe, the number of minors who present at transgender healthcare services before the onset of puberty is rapidly expanding. Many of those who will have persistent gender dysphoria at the onset of puberty will pursue long-term puberty suppression before reaching the appropriate age to start using gender-affirming hormones. Exposure to pubertal sex steroids is thus significantly deferred in these individuals. Puberty is a critical period for bone development: increasing concentrations of estrogens and androgens (directly or after aromatization to estrogens) promote progressive bone growth and mineralization and induce sexually dimorphic skeletal changes. As a consequence, safety concerns regarding bone development and increased future fracture risk in transgender youth have been raised. We here review published data on bone development in transgender adolescents, focusing in particular on differences in age and pubertal stage at the start of puberty suppression, chosen strategy to block puberty progression, duration of puberty suppression, and the timing of re-evaluation after estradiol or testosterone administration. Results consistently indicate a negative impact of long-term puberty suppression on bone mineral density, especially at the lumbar spine, which is only partially restored after sex steroid administration. Trans girls are more vulnerable than trans boys for compromised bone health. Behavioral health measures that can promote bone mineralization, such as weight-bearing exercise and calcium and vitamin D supplementation, are strongly recommended in transgender youth, during the phase of puberty suppression and thereafter.
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Nineteen cases of parathyroid carcinoma in patients with multiple endocrine neoplasia type 1 have been reported in the literature, of which 11 carry an inactivating germline mutation in the MEN1 gene. Somatic genetic abnormalities in these parathyroid carcinomas have never been detected. In this paper, we aimed to describe the clinical and molecular characterization of a parathyroid carcinoma identified in a patient with MEN1. A 60-year-old man was diagnosed with primary hyperparathyroidism during the postoperative period of lung carcinoid surgery. Serum calcium and parathyroid hormone levels were 15.0 mg/dL (8.4–10.2) and 472 pg/mL (12–65), respectively. The patient underwent parathyroid surgery, and histological findings were consistent with parathyroid carcinoma. Analysis of the MEN1 gene by next-generation sequencing (NGS) identified a novel germline heterozygous nonsense pathogenic variant (c.978C>A; p.(Tyr326*)), predicted to encode a truncated protein. Genetic analysis of the parathyroid carcinoma revealed a c.307del, p.(Leu103Cysfs*16) frameshift truncating somatic MEN1 variant in the MEN1 gene, which is consistent with MEN1 tumor-suppressor role, confirming its involvement in parathyroid carcinoma etiology. Genetic analysis of CDC73, GCM2, TP53, RB1, AKT1, MTOR, PIK3CA and CCND1 genes in the parathyroid carcinoma DNA did not detect any somatic mutations. To our knowledge, this is the first report of a PC case presenting both germline (first-hit) and somatic (second-hit) inactivation of the MEN1 gene.
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Primary aldosteronism (PA) is associated with urolithiasis as it causes hypercalciuria and hypocitraturia. However, the influence of different subtypes of PA on urinary stone formation remains unclear. This study aimed to evaluate the association between aldosterone-producing adenoma (APA) and the burden of urolithiasis in patients with PA. In the present study, we enrolled 312 patients with PA from a prospectively maintained database, of whom 179 had APA. Clinical, biochemical, and imaging data (including the presence, volume, and density of urinary stones on abdominal computed tomography) were compared between groups, with employment of propensity score matching (PSM) analysis to balance possible confounding factors. Kaplan–Meier analysis was used to estimate the acute renal colic event during follow-up. After PSM for age, sex, serum calcium, phosphate, blood urea nitrogen, creatinine, and uric acid, the APA and non-APA groups had 106 patients each. Patients with APA had higher serum intact parathyroid hormone (iPTH) (79.1 ± 45.0 vs 56.1 ± 30.3, P < 0.001) and a higher prevalence of urolithiasis (27.4% vs 12.3%, P = 0.006) than non-APA patients. During follow-up, a higher incidence of acute renal colic events was noted in the APA group than the non-APA group (P = 0.011); this association remained significant (P = 0.038) after adjustment for age and sex in Cox-regression analysis. Our data suggest that APA is associated with a heavier burden of urolithiasis and higher incidence of renal colic events compared to the non-APA subtype of PA.
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Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
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Besides age, estrogen exposure plays a crucial role in changes in bone density (BD) in women. Premature ovarian insufficiency (POI) and polycystic ovary syndrome (PCOS) are conditions in reproductive-aged women in which the exposure to estrogen is substantially different. Women with a history of preeclampsia (PE) are expected to have normal estrogen exposure. Within the CREw-IMAGO study, we investigated if trabecular BD is different in these women because of differences in the duration of estrogen exposure. Trabecular BD was measured in thoracic vertebrae on coronary CT scans. Women with a reduced estrogen exposure (POI) have a lower BD compared to women with an intermediate exposure (PE) (mean difference (MD) −26.8, 95% CI −37.2 to −16.3). Women with a prolonged estrogen exposure (PCOS) have the highest BD (MD 15.0, 95% CI 4.3–25.7). These results support the hypothesis that the duration of estrogen exposure in these women is associated with trabecular BD.
Significance statement
Our results suggest that middle-aged women with PCOS have a higher BD and women with POI have a lower BD. We hypothesized that this is due to either a prolonged estrogen exposure, as seen in women with PCOS, or a reduced estrogen exposure, as in women with POI. In the counseling of women with reproductive disorders on long-term health issues, coronary CT provides a unique opportunity to assess both coronary artery calcium score for cardiovascular screening as well as trabecular BD.
