Pancreatic islets from pregnant rats develop a transitory increase in the pancreatic β-cell proliferation rate and mass. Increased apoptosis during early lactation contributes to the rapid reversal of those morphological changes. Exposure to synthetic glucocorticoids during pregnancy has been previously reported to impair insulin secretion, but its impacts on pancreatic islet morphological changes during pregnancy and lactation have not been described. To address this issue, we assessed the morphological and molecular characteristics of pancreatic islets from rats that underwent undisturbed pregnancy (CTL) or were treated with dexamethasone between the 14th and 19th days of pregnancy (DEX). Pancreatic islets were analyzed on the 20th day of pregnancy (P20) and on the 3rd, 8th, 14th and 21st days of lactation (L3, L8, L14 and L21, respectively). Pancreatic islets from CTL rats exhibited transitory increases in cellular proliferation and pancreatic β-cell mass at P20, which were reversed at L3, when a transitory increase in apoptosis was observed. This was followed by the appearance of morphological features of pancreatic islet neogenesis at L8. Islets from DEX rats did not demonstrate an increase in apoptosis at L3, which coincided with an increase in the expression of M2 macrophage markers relative to M1 macrophage and T lymphocyte markers. Islets from DEX rats also did not exhibit the morphological characteristics of pancreatic islet neogenesis at L8. Our data demonstrate that maternal pancreatic islets undergo a renewal process during lactation that is impaired by exposure to DEX during pregnancy.
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Caio Jordão Teixeira, Junia Carolina Santos-Silva, Dailson Nogueira de Souza, Alex Rafacho, Gabriel Forato Anhe and Silvana Bordin
Luca Persani, Biagio Cangiano and Marco Bonomi
Central hypothyrodism (CeH) is a hypothyroid state caused by an insufficient stimulation by thyrotropin (TSH) of an otherwise normal thyroid gland. Several advancements, including the recent publication of expert guidelines for CeH diagnosis and management, have been made in recent years thus increasing the clinical awareness on this condition. Here, we reviewed the recent advancements and give expert opinions on critical issues. Indeed, CeH can be the consequence of various disorders affecting either the pituitary gland or the hypothalamus. Recent data enlarged the list of candidate genes for heritable CeH and a genetic origin may be the underlying cause for CeH discovered in pediatric or even adult patients without apparent pituitary lesions. This raises the doubt that the frequency of CeH may be underestimated. CeH is most frequently diagnosed as a consequence of the biochemical assessments in patients with hypothalamic/pituitary lesions. In contrast with primary hypothyroidism, low FT4 with low/normal TSH levels are the biochemical hallmark of CeH, and adequate thyroid hormone replacement leads to the suppression of residual TSH secretion. Thus, CeH often represents a clinical challenge because physicians cannot rely on the use of the ‘reflex TSH strategy’ for screening or therapy monitoring. Nevertheless, in contrast with general assumption, the finding of normal TSH levels may indicate thyroxine under-replacement in CeH patients. The clinical management of CeH is further complicated by the combination with multiple pituitary deficiencies, as the introduction of sex steroids or GH replacements may uncover latent forms of CeH or increase the thyroxine requirements.
Mélanie Rouleau, Francis Lemire, Michel Déry, Benoît Thériault, Gabriel Dubois, Yves Fradet, Paul Toren, Chantal Guillemette, Louis Lacombe, Laurence Klotz, Fred Saad, Dominique Guérette and Frédéric Pouliot
Failure to suppress testosterone below 0.7 nM in castrated prostate cancer patients is associated with poor clinical outcomes. Testosterone levels in castrated patients are therefore routinely measured. Although mass spectrometry is the gold standard used to measure testosterone, most hospitals use an immunoassay method. In this study, we sought to evaluate the accuracy of an immunoassay method to measure castrate testosterone levels, with mass spectrometry as the reference standard. We retrospectively evaluated a cohort of 435 serum samples retrieved from castrated prostate cancer patients from April to September 2017. No follow-up of clinical outcomes was performed. Serum testosterone levels were measured in the same sample using liquid chromatography coupled with tandem mass spectrometry and electrochemiluminescent immunoassay methods. The mean testosterone levels were significantly higher with immunoassay than with mass spectrometry (0.672 ± 0.359 vs 0.461 ± 0.541 nM; P < 0.0001). Half of the samples with testosterone ≥0.7 nM assessed by immunoassay were measured <0.7 nM using mass spectrometry. However, we observed that only 2.95% of the samples with testosterone <0.7 nM measured by immunoassay were quantified ≥0.7 nM using mass spectrometry. The percentage of serum samples experiencing testosterone breakthrough at >0.7 nM was significantly higher with immunoassay (22.1%) than with mass spectrometry (13.1%; P < 0.0001). Quantitative measurement of serum testosterone levels >0.7 nM by immunoassay can result in an inaccurately identified castration status. Suboptimal testosterone levels in castrated patients should be confirmed by either mass spectrometry or an immunoassay method validated at low testosterone levels and interpreted with caution before any changes are made to treatment management.
Zeming Liu, Di Hu, Yihui Huang, Sichao Chen, Wen Zeng, Ling Zhou, Wei Zhou, Min Wang, Haifeng Feng, Wei Wei, Chao Zhang, Danyang Chen and Liang Guo
Controversies regarding factors associated with distant metastasis in pediatric thyroid cancer remain among the scientific community. The aim of this study was to investigate factors influencing distant metastasis in pediatric thyroid cancer.
We reviewed 1376 patients (aged 2 to 18 years) with thyroid cancer treated between 2003 and 2014. Data collected and analyzed included sex, race, age at diagnosis, year of diagnosis, pathological type, number of tumor foci, tumor extension, T-stage, N-stage, surgical procedure and radiation. Univariate and multivariate analyses were conducted to evaluate factors influencing distant metastasis of pediatric thyroid cancer.
In the univariate analysis, factors influencing distant metastasis of thyroid cancer were age at diagnosis (P < 0.001), N-stage (P < 0.001), number of tumor foci (P = 0.003), tumor extension (P < 0.001) and T-stage (T1 vs T2 (P = 0.803), T3 (P < 0.001) and T4 (P < 0.001)). In multivariate analysis, factors influencing distant metastasis of thyroid cancer were age at diagnosis (P = 0.001), N-stage (P < 0.001) and T-stage (T1 vs T3 (P = 0.036) and T4 (P < 0.001)). Sex, race, year of diagnosis, pathological type, number of tumor foci, tumor extension, surgical procedure and radiation had no significant influence on distant metastasis (all P > 0.05). Furthermore, according to chi-squared test, younger pediatric thyroid cancer patients with higher T- and N-stages are more likely to have distant metastasis.
Age at diagnosis, T-stage and N-stage influence distant metastasis of thyroid cancer patients aged 2 to 18 years; accordingly, more radical treatments may need to be used for patients with those risk elements.
Stefan Riedl, Friedrich-Wilhelm Röhl, Walter Bonfig, Jürgen Brämswig, Annette Richter-Unruh, Susanne Fricke-Otto, Markus Bettendorf, Felix Riepe, Gernot Kriegshäuser, Eckhard Schönau, Gertrud Even, Berthold Hauffa, Helmuth-Günther Dörr, Reinhard W Holl, Klaus Mohnike and the AQUAPE CAH Study Group
Congenital adrenal hyperplasia (CAH) due to CYP21A2 gene mutations is associated with a variety of clinical phenotypes (salt wasting, SW; simple virilizing, SV; nonclassical, NC) depending on residual 21-hydroxylase activity. Phenotypes and genotypes correlate well in 80–90% of cases. We set out to test the predictive value of CAH phenotype assignment based on genotype classification in a large multicenter cohort. A retrospective evaluation of genetic data from 538 CAH patients (195 screened) collected from 28 tertiary centers as part of a German quality control program was performed. Genotypes were classified according to residual 21-hydroxylase activity (null, A, B, C) and assigned clinical phenotypes correlated with predicted phenotypes, including analysis of Prader stages. Ultimately, concordance of genotypes with clinical phenotypes was compared in patients diagnosed before or after the introduction of nationwide CAH-newborn screening. Severe genotypes (null and A) correlated well with the expected phenotype (SW in 97 and 91%, respectively), whereas less severe genotypes (B and C) correlated poorly (SV in 45% and NC in 57%, respectively). This was underlined by a high degree of virilization in girls with C genotypes (Prader stage >1 in 28%). SW was diagnosed in 90% of screening-positive babies with classical CAH compared with 74% of prescreening patients. In our CAH series, assigned phenotypes were more severe than expected in milder genotypes and in screened vs prescreening patients. Diagnostic discrimination between phenotypes based on genotypes may prove overcome due to the overlap in their clinical presentations.
L A Hughes, K McKay-Bounford, E A Webb, P Dasani, S Clokie, H Chandran, L McCarthy, Z Mohamed, J M W Kirk, N P Krone, S Allen and T R P Cole
Disorders of sex development (DSDs) are a diverse group of conditions where the chromosomal, gonadal or anatomical sex can be atypical. The highly heterogeneous nature of this group of conditions often makes determining a genetic diagnosis challenging. Prior to next generation sequencing (NGS) technologies, genetic diagnostic tests were only available for a few of the many DSD-associated genes, which consequently had to be tested sequentially. Genetic testing is key in establishing the diagnosis, allowing for personalised management of these patients. Pinpointing the molecular cause of a patient’s DSD can significantly impact patient management by informing future development needs, altering management strategies and identifying correct inheritance pattern when counselling family members. We have developed a 30-gene NGS panel, designed to be used as a frontline test for all suspected cases of DSD (both 46,XX and 46,XY cases). We have confirmed a diagnosis in 25 of the 80 patients tested to date. Confirmed diagnoses were linked to mutations in AMH, AMHR2, AR, HSD17B3, HSD3B2, MAMLD1, NR5A1, SRD5A2 and WT1 which have resulted in changes to patient management. The minimum diagnostic yield for patients with 46,XY DSD is 25/73. In 34/80 patients, only benign or likely benign variants were identified, and in 21/80 patients only variants of uncertain significance (VOUS) were identified, resulting in a diagnosis not being confirmed in these individuals. Our data support previous studies that an NGS panel approach is a clinically useful and cost-effective frontline test for patients with DSDs.
Alexander Tacey, Lewan Parker, Bu B Yeap, John Joseph, Ee M Lim, Andrew Garnham, David L Hare, Tara Brennan-Speranza and Itamar Levinger
The aim of this study was to investigate the effect of a single dose of prednisolone on (A) high-intensity interval cycling performance and (B) post-exercise metabolic, hormonal and haematological responses. Nine young men participated in this double-blind, randomised, cross-over study. The participants completed exercise sessions (4 × 4 min cycling bouts at 90–95% of peak heart rate), 12 h after ingesting prednisolone (20 mg) or placebo. Work load was adjusted to maintain the same relative heart rate between the sessions. Exercise performance was measured as total work performed. Blood samples were taken at rest, immediately post exercise and up to 3 h post exercise. Prednisolone ingestion decreased total work performed by 5% (P < 0.05). Baseline blood glucose was elevated following prednisolone compared to placebo (P < 0.001). Three hours post exercise, blood glucose in the prednisolone trial was reduced to a level equivalent to the baseline concentration in the placebo trial (P > 0.05). Prednisolone suppressed the increase in blood lactate immediately post exercise (P < 0.05). Total white blood cell count was elevated at all time-points with prednisolone (P < 0.01). Androgens and sex hormone-binding globulin were elevated immediately after exercise, irrespective of prednisolone or placebo. In contrast, prednisolone significantly reduced the ratio of testosterone/luteinizing hormone (P < 0.01). Acute prednisolone treatment impairs high-intensity interval cycling performance and alters metabolic and haematological parameters in healthy young men. Exercise may be an effective tool to minimise the effect of prednisolone on blood glucose levels.
Ermina Bach, Niels Møller, Jens Otto L Jørgensen, Mads Buhl and Holger Jon Møller
The macrophage-specific glycoprotein sCD163 has emerged as a biomarker of low-grade inflammation in the metabolic syndrome and related disorders. High sCD163 levels are seen in acute sepsis as a result of direct lipopolysaccharide-mediated shedding of the protein from macrophage surfaces including Kupffer cells. The aim of this study was to investigate if low-grade endotoxinemia in human subjects results in increasing levels of sCD163 in a cortisol-dependent manner.
We studied eight male hypopituitary patients and eight age- and gender-matched healthy controls during intravenous low-dose LPS or placebo infusion administered continuously over 360 min. Furthermore, we studied eight healthy volunteers with bilateral femoral vein and artery catheters during a 360-min infusion with saline and low-dose LPS in each leg respectively.
Systemic low-grade endotoxinemia resulted in a gradual increase in sCD163 from 1.65 ± 0.51 mg/L (placebo) to 1.92 ± 0.46 mg/L (LPS) at 220 min, P = 0.005 and from 1.66 ± 0.42 mg/L (placebo) to 2.19 ± 0.56 mg/L (LPS) at 340 min, P = 0.006. A very similar response was observed in hypopituitary patients: from 1.59 ± 0.53 mg/L (placebo) to 1.83 ± 0.45 mg/L (LPS) at 220 min, P = 0.021 and from 1.52 ± 0.53 mg/L (placebo) to 2.03 ± 0.44 mg/L (LPS) at 340 min, P < 0.001. As opposed to systemic treatment, continuous femoral artery infusion did not result in increased sCD163.
Systemic low-grade endotoxinemia resulted in increased sCD163 to levels seen in the metabolic syndrome in both controls and hypopituitary patients. This suggests a direct and cortisol-independent effect of LPS on the shedding of sCD163. We observed no effect of local endotoxinemia on levels of serum sCD163.
Michael Ulm, Arvind V Ramesh, Keely M McNamara, Suriyan Ponnusamy, Hironobu Sasano and Ramesh Narayanan
Hormonal cancers affect over 400,000 men and women and contribute collectively to over 100,000 deaths in the United States alone. Thanks to advances in the understanding of these cancers at the molecular level and to the discovery of several disease-modifying therapeutics, the last decade has seen a plateauing or even a decreasing trend in the number of deaths from these cancers. These advanced therapeutics not only effectively slow the growth of hormonal cancers, but also provide an insight on how these cancers become refractory and evolve as an altogether distinct subset. This review summarizes the current therapeutic trends in hormonal cancers, with focus on prostate, breast and ovarian cancers. The review discusses the clinical drugs being used now, promising molecules that are going through various stages of development and makes some predictions on how the therapeutic landscape will shift in the next decade.
Stefan Pilz, Armin Zittermann, Christian Trummer, Verena Theiler-Schwetz, Elisabeth Lerchbaum, Martin H Keppel, Martin R Grübler, Winfried März and Marlene Pandis
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.