Two decades after the discovery of the hormone FGF23, we know more about phosphate homeostasis as it turned out that FGF23 is the central hormone that regulates this. Hereditary hypophosphatemic ...rickets and tumor-induced osteomalacia could by then be explained, by autonomous FGF23 production, and the nephrology field was excited by this new marker as it turned out to be independently associated with mortality in people treated by hemodialysis. This led to the development of several immunoassays to be able to measure FGF23 in blood. In the past years we learned that FGF23 is a rather stable peptide, the precision of the assays is acceptable but assays are not standardized and therefore not comparable. This means that reference values and cutoff values need to be assay specific. For several assays reference values have been established and gender and age did not seem of high importance. The phosphate content of the diet, which can be culturally dependent, however, should be taken into account when interpreting results, but to what extent is not totally clear. Currently, clinical application of the immunoassays is established in the diagnosis of hereditary hypophosphatemic rickets and diagnosis and follow-up of tumor-induced osteomalacia. Definite conclusions on the usefulness of the FGF23 measurement in people with CKD either as a marker for risk prediction or a as target for treatment remains to be determined. The latter applications would require dedicated prospective clinical trials, which may take years, before providing answers. To improve the standardization of the FGF23 assays and to shed light on the biological functions that fragments might have we might aim for an LC–MS/MS-based method to quantify both intact and fragmented FGF23. In this literature review we will summarize the current knowledge on the physiological role of FGF23, its quantification, and the clinical usefulness of its determination.
The First International Conference on Controversies in Vitamin D was held in Pisa, Italy, 14–16 June 2017. The meeting's purpose was to address controversies in vitamin D research, review the data ...available, to help resolve them, and suggest a research agenda to clarify areas of uncertainty. The serum 25‐hydroxyvitamin D 25(OH)D concentration i.e. the sum of 25(OH)D3 and 25(OH)D2 remains the critical measurement for defining vitamin D status. Assay variation for 25(OH)D has contributed to the current chaos surrounding efforts to define hypovitaminosis D. An essential requirement to develop a consensus on vitamin D status is that measurement of 25(OH)D and, in the future, other potential vitamin D biomarkers e.g. 1α,25(OH)2D3, 3‐epi‐25(OH)D, 24,25(OH)2D3, vitamin D‐binding protein, free/bioavailable 25(OH)D and parathyroid hormone be standardized/harmonized, to allow pooling of research data. Vitamin D Standardization Program tools are described and recommended for standardizing 25(OH)D measurement in research. In the future, similar methodology, based on National Institute for Standards and Technology standard reference materials, must be developed for other candidate markers of vitamin D status. Failure to standardize/harmonize vitamin D metabolite measurements is destined to promulgate continued chaos. At this time, 25(OH)D values below 12 ng ml–1 (30 nmol l–1) should be considered to be associated with an increased risk of rickets/osteomalacia, whereas 25(OH)D concentrations between 20 ng ml–1 and 50 ng ml–1 (50–125 nmol l–1) appear to be safe and sufficient in the general population for skeletal health. In an effort to bridge knowledge gaps in defining hypovitaminosis D, an international study on rickets as a multifactorial disease is proposed.
Recent recognition of its broad pathophysiological importance has triggered an increased interest in 25-hydroxyvitamin D 25(OH)D. By consequence, throughput in 25(OH)D testing has become an issue for ...clinical laboratories, and several automated assays for measurement of 25(OH)D are now available. The aim of this study was to test the accuracy and robustness of these assays by comparing their results to those of an isotope dilution/online solid-phase extraction liquid chromatography/tandem mass spectrometry (ID-XLC-MS/MS) method. We put specific focus on the influence of vitamin D-binding protein (DBP) by using samples with various concentrations of DBP.
We used 5 automated assays (Architect, Centaur, iSYS, Liaison, and Elecsys), 1 RIA (Diasorin) preceded by extraction, and an ID-XLC-MS/MS method to measure 25(OH)D concentrations in plasma samples of 51 healthy individuals, 52 pregnant women, 50 hemodialysis patients, and 50 intensive care patients. Using ELISA, we also measured DBP concentrations in these samples.
Most of the examined 25(OH)D assays showed significant deviations in 25(OH)D concentrations from those of the ID-XLC-MS/MS method. As expected, DBP concentrations were higher in samples of pregnant women and lower in samples of IC patients compared to healthy controls. In 4 of the 5 fully automated 25(OH)D assays, we observed an inverse relationship between DBP concentrations and deviations from the ID-XLC-MS/MS results.
25(OH)D measurements performed with most immunoassays suffer from inaccuracies that are DBP concentration dependent. Therefore, when interpreting results of 25(OH)D measurements, careful consideration of the measurement method is necessary.
Vitamin D, acknowledged since the 1930s for its role in preventing rickets, gained additional prominence in relation to fragility fracture prevention in the late 1980s. From the early 2000s, ...connections between vitamin D deficiency and extra-skeletal pathologies emerged, alongside increased awareness of widespread deficits. This prompted crucial debates on optimal serum concentrations, expected to conclude when the outcomes of high-dose supplementation randomized controlled trials were available. Skepticism arose with inconclusive results from these trials.
This review begins with an exploration of vitamin D metabolism, followed by a detailed description of the measurement of vitamin D metabolites and the crucial role of standardization. Subsequent sections focus on the association of vitamin D with bone health and explore the extra-skeletal effects. The review concludes with a comprehensive discussion on the definition of vitamin D status and its implications for supplementation.
Despite standardization efforts, assay variations and challenges still exist, especially in specific patient groups. Vitamin D supplementation has a significant impact on bone metabolism and optimal vitamin D status improves the efficacy of antiresorptive drugs such as bisphosphonates. The extra-skeletal effects of vitamin D remain debated, but may include potential benefits in conditions such as respiratory infections and cancer mortality, particularly in deficient individuals. The definition of vitamin D sufficiency is nuanced, especially when variations in population groups and analytical methods are taken into account. Despite ongoing debates and recent mega-trials tempering enthusiasm, vitamin D remains a complex and essential element in human health. Further research is needed to clarify its role in various health outcomes and guide supplementation strategies.
Androgens are synthesized from cholesterol through sequential conversions by enzymes in the adrenal glands and gonads. Serum levels of androgens change during the different phases of life and ...regulate important developmental and maturational processes. Androgen excess or deficiency can therefore present at various ages in various ways.
The diagnostic approach for atypical genitalia, premature pubarche, delayed pubertal onset or progression, and hirsutism or virilization, including measurement of androgens (testosterone, androstenedione, 17-OHprogesterone, dehydroepiandrosterone, and dihydrotestosterone) is discussed in the current review. Androgens can be measured in serum, saliva, urine, or dried blood spots. Techniques to measure androgens, including immunoassays and LC-MS, have their own advantages and pitfalls. In addition, pre- and postanalytical issues are important when measuring androgens.
During clinical interpretation of androgen measurements, it is important to take preanalytical circumstances, such as time of blood withdrawal, into account. As immunoassays have major drawbacks, especially in samples from women and neonates, concentrations measured using these assays should be interpreted with care. Reference intervals can only be used in relation to the measurement technique and the standardization of the assay. In the near future, new androgens will probably be added to the current repertoire to further improve the diagnosis and follow-up of androgen excess or deficiency.
Currently, thyroid hormone status is predominantly determined by the measurement of serum thyroid-stimulating hormone and free thyroxine. Although it is assumed that serum thyroid hormone (TH) ...concentrations within the reference range represent euthyroidism, it is unknown whether this reflects euthyroidism in all tissues (e.g. brain, muscle, bone and liver). To date, no serum marker has been established for clinical use that represents TH status within tissues accurately. However, several biomarkers have been investigated and innovative techniques have been used to unravel new biomarkers. This review provides an overview of proposed serum biomarkers that reflect tissue TH status in humans. Furthermore, we discuss the feasibility of these serum markers in clinical practice.
Cryoactivation is known to occur in whole blood and plasma samples when kept between +4 and -5 °C, leading to falsely high renin concentrations. In 2022 it has been clearly shown that cryoactivation ...can also occur in samples stored at -20 °C. Based on these new findings, here we discuss how this can influence the clinical diagnosis of patients. First, we show that storage of renin plasma samples can affect the renin measurements and thereby the aldosterone to renin ratio (ARR) calculation, which might explain the high intraindividual variability in ARR also recently demonstrated. Second, we discuss the existing studies on the establishment of renin reference intervals and note the lack of attention given to this recently revealed preanalytical condition. Our literature review of the reference intervals for renin suggest that cryoactivation might have influenced the published data.
Abstract
Context
Available evidence shows an association of vitamin D with androgen levels in men. However, results from preliminary randomized controlled trials (RCTs) are conflicting.
Objective
To ...evaluate whether vitamin D supplementation increases total testosterone (TT) levels in healthy men.
Design
The Graz Vitamin D&TT-RCT is a single-center, double-blind, randomized, placebo-controlled trial conducted between December 2012 and January 2017.
Setting
Endocrine outpatient clinic at the Medical University of Graz, Austria.
Participants
Ninety-eight healthy men with TT levels ≥10.4 nmol/L and 25-hydroxyvitamin D 25(OH)D levels <75 nmol/L completed the study.
Intervention
Subjects were randomly assigned to receive 20,000 IU/wk of vitamin D3 (n = 50) or placebo (n = 50) for 12 weeks.
Main Outcome Measures
Primary outcome was TT measured using mass spectrometry. Secondary outcomes were free testosterone, sex hormone-binding globulin, estradiol, follicle-stimulating hormone, and luteinizing hormone levels; free androgen index; metabolic characteristics; and body composition.
Results
In healthy men mean values ± standard deviation: age, 39 years (±13 years); 25(OH)D level, 53.3 nmol/L (±18.3 nmol/L); TT, 19.1 nmol/L (±5.6 nmol/l), no significant treatment effect on TT was found; however, there were significant effects on quantitative insulin sensitivity check index (QUICKI) and a trend toward decreased Matsuda index. In the treatment group, median (interquartile range) changes for TT, QUICKI, and Matsuda index were 0.5 nmol/L (−0.63 to 0.63 nmol/L; P = 0.497), −0.02 (−0.04 to 0.01; P = 0.034), and −0.9 (−3.2 to 0.8; P = 0.051), respectively.
Conclusion
Vitamin D treatment had no effect on TT levels in middle-aged healthy men with normal baseline TT, but it significantly decreased QUICKI. Additional studies investigating vitamin D effects on TT and insulin sensitivity in healthy men are required.
In this 12-week RCT, we studied the effect of vitamin D on TT levels in 100 eugonadal men with 25(OH)D <;75 nmol/L. We found no effect of vitamin D treatment on TT but a significant decrease in the QUICKI.
Abstract Puberty is highly important for the accumulation of bone mass. Bone turnover and bone mineral density (BMD) can be affected in transgender adolescents when puberty is suppressed by ...gonadotropin-releasing hormone analogues (GnRHa), followed by treatment with cross-sex hormone therapy (CSHT). We aimed to investigate the effect of GnRHa and CSHT on bone turnover markers (BTMs) and bone mineral apparent density (BMAD) in transgender adolescents. Gender dysphoria was diagnosed based on diagnostic criteria according to the DSM-IV (TR). Thirty four
female-to-male persons (transmen) and 22
male-to-female persons (transwomen)were included. Patients were allocated to a young (bone age of < 15 years in transwomen or < 14 in transmen) or old group (bone age of ≥ 15 years in transwomen or ≥ 14 years in transmen). All were treated with GnRHa triptorelin and CSHT was added in incremental doses from the age of 16 years. Transmen received testosterone esters (Sustanon, MSD) and transwomen received 17-β estradiol. P1NP, osteocalcin, ICTP and BMD of lumbar spine (LS) and femoral neck (FN) were measured at three time points. In addition, BMAD and Z-scores were calculated. We found a decrease of P1NP and 1CTP during GnRHa treatment, indicating decreased bone turnover (young transmen 95% CI
− 74 to
− 50%
, p = 0.02, young transwomen 95% CI
− 73 to
− 43, p = 0.008). The decrease in bone turnover upon GnRHa treatment was accompanied by an unchanged BMAD of FN and LS, whereas BMAD Z-scores of predominantly the LS decreased especially in the young transwomen. Twenty-four months after CSHT the BTMs P1NP and ICTP were even more decreased in all groups except for the old transmen.
During CSHT BMAD increased and Z-scores returned towards normal, especially of the LS (young transwomen CI 95% 0.1 to 0.6, p = 0.01, old transwomen 95% CI 0.3 to 0.8, p = 0.04). To conclude, suppressing puberty by GnRHa leads to a decrease of BTMs in both transwomen and transmen transgender adolescents. The increase of BMAD and BMAD Z-scores predominantly in the LS as a result of treatment with CSHT is accompanied by decreasing BTM concentrations after 24 months of CSHT. Therefore, the added value of evaluating BTMs seems to be limited and DXA-scans remain important in follow-up of bone health of transgender adolescents.
•Dried blood spot size is linearly related to hematocrit.•Hematocrit and spotted volume do not have a significant impact on steroid hormone measurements in dried blood spots.•Measurements in dried ...blood spots can be recalculated into plasma concentrations.
Dried blood spot (DBS) sampling has many advantages over conventionally used blood samples, but is thought to suffer from hematocrit related issues. The aim of our research was to investigate whether reliable results can be obtained without bothering about hematocrit effects in DBS analysis of analytes that are mainly present in the plasma compartment.
Venous blood samples with variation in hematocrit and spotted volume were prepared. Spot diameter and 25-OH Vitamin D3 and testosterone concentrations were measured. Moreover, DBS and plasma concentrations of 25-OH Vitamin D3, testosterone and hematocrit were determined in random patient samples.
DBS spot size was linearly related to hematocrit. Measured DBS concentrations of 25-OH Vitamin D3 and testosterone were independent of hematocrit and spotted volume. Determining the relation between plasma and DBS concentration resulted in a factor that can be used to convert DBS concentrations to standardized plasma concentrations.
Addressing the hematocrit issue is not necessary for hormones that are mainly present in the plasma compartment. The relation between plasma and DBS concentration can be used to convert DBS concentrations to standardized plasma concentrations which makes interpretation of DBS concentrations easier.
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