Background: Specific gravity (SG) may perform as well as creatinine (CR) correction for adjusting urinary hormone concentrations, as well as offer some advantages. We compared the two methods and applied them to US and Bangladeshi specimens to evaluate their use in different populations. Methods: Pearson correlations between serum concentrations and SG, CR, and uncorrected urinary concentrations were compared using paired daily urine and serum specimens from one menstrual cycle from 30 US women. Corrected urinary estrone conjugate and pregnanediol glucuronide concentrations were compared with serum estradiol and progesterone. Urine specimens across one menstrual cycle from 13 Bangladeshi women were used to evaluate the applicability of both methods to a nonindustrialized population. Linear mixed-effects models were used to compare CR and SG values in the Bangladeshi vs US specimens. Results: There was no significant difference between SG-corrected vs serum and CR-corrected vs serum correlations for either assay. Usable CR results were obtained for all US specimens, but 37% of the Bangladeshi specimens were below the CR assay limit of detection. The Bangladeshi sample had significantly lower CR and higher inter-and intrasubject CR variability than the US sample. Conclusions: SG is a potentially useful alternative to CR correction for normalizing urinary steroid hormone
C-reactive protein (CRP) is used as a biomarker of morbidity and mortality risk in studies of population health, and is essential to interpretation of several micronutrient biomarkers. There is thus need for a robust high sensitivity CRP (hsCRP) measurement method for large-scale, nonclinical studies. We developed an efficient, inexpensive assay suitable for quantifying CRP across the physiological range using any blood specimen type. The ELISA uses readily available monoclonal antibodies to measure CRP in serum, plasma, or dried blood spots (DBS) made from venous or capillary blood. Assay performance was evaluated by standard methods, including comparison with a previously described assay. Effects of specimen type were tested by measuring CRP in 52 matched serum, plasma, and venous and capillary dried blood spot specimens. Longand short-term CRP stability were evaluated. Assessments of assay limits of detection, linearity, recovery, imprecision, and concordance with an established method (Pearson correlation = 0.988, n = 20) demonstrated the validity of the new assay. CRP measurements in serum, plasma, and DBS had Pearson correlations from 0.974 to 0.995, n = 52, but CRP in serum was on average 1.6 times (SD 0.37) higher than in DBS. CRP was stable in frozen serum for up to 34 months, but DBS CRP declined quickly with exposure to ambient temperatures, and across long-term storage at −20°C. This hsCRP assay is a robust and inexpensive tool designed for use in large-scale population health research. Our results indicate that DBS CRP is less stable than previously reported.
Background:Monitoring of reproductive steroid hormones at the population level requires frequent measurements, hormones or metabolites that remain stable under less than ideal collection and storage conditions, a long-term supply of antibodies, and assays useful for a range of populations. We developed enzyme immunoassays for urinary pregnanediol 3-glucuronide (PDG) and estrone conjugates (E1Cs) that meet these criteria. Methods: Enzyme immunoassays based on monoclonal antibodies were evaluated for specificity, detection limit, parallelism, recovery, and imprecision. Paired urine and serum specimens were analyzed throughout menstrual cycles of 30 US women. Assay application in different populations was examined with 23 US and 42 Bangladeshi specimens. Metabolite stability in urine was evaluated for 0 -8 days at room temperature and for 0 -10 freeze-thaw cycles. Results: Recoveries were 108% for the PDG assay and 105% for the E1C assay. Serially diluted specimens exhibited parallelism with calibration curves in both assays. Inter-and intraassay CVs were <11%. Urinary and serum concentrations were highly correlated: r ؍ 0.93 for E1C-estradiol; r ؍ 0.98 for PDG-progesterone.
C-reactive protein (CRP) is a widely used, sensitive biomarker of inflammation. Studies conducted among users of exogenous hormones suggest that estrogen increases CRP, whereas progesterone decreases CRP. Examinations of CRP in normally cycling women suggest the opposite: CRP is negatively associated with endogenous estrogen and positively associated with endogenous progesterone. This work evaluates the association between menstrual cycle-related hormone changes and events (menstruation and ovulation) and CRP. Eight female subjects gave urine and blood samples from twelve days across the menstrual cycle, for a total of eleven cycles. Blood samples were assayed for CRP; urine samples for beta-follicle stimulating hormone (betaFSH), pregnanediol 3-glucuronide (PDG), and estrone glucuronide (E1G). Ovulation day was estimated using hormone levels. Presence or absence of menses was reported by subjects. Analyses were conducted with random-effects linear regression. All cycles were ovulatory; day of ovulation was identified for nine cycles. A ten-fold increase in progesterone was associated with a 23% increase in CRP (P = 0.01), a ten-fold increase in estrogen was associated with a 29% decrease in CRP (P = 0.05), and menses was associated with a 17% increase in CRP (P = 0.18); no association between ovulation or FSH and CRP was found. Hormone changes across the menstrual cycle should be controlled for in future studies of inflammation in reproductive-age women.
Aggregate-level analyses show general changes in steroid hormones and cycle length but cannot show variation within and across women. Individuals' cycle lengths were too variable to predict hormone levels. Clinicians should obtain more data on individual women's hormonal patterns when determining fertility or menopause treatments.
Deficiencies of vitamin A, iron, and iodine are major public health concerns in many low- and middle-income countries, but information on their status in populations is often lacking due to high costs and logistical challenges associated with assessing micronutrient status. Accurate, user-friendly, and low-cost analytical tools are needed to allow large-scale population surveys on micronutrient status. We present the expansion of a 7-plex protein microarray tool for the simultaneous measurement of up to seven biomarkers with relevance to the assessment of the key micronutrients iron, iodine, and vitamin A, and inflammation and malaria biomarkers: α-1-acid glycoprotein, C-reactive protein, ferritin, retinol binding protein 4, soluble transferrin receptor, thyroglobulin, and histidine-rich protein II. Assay performance was assessed using international reference standards and then verified by comparing the multiplexed and conventional immunoassay results on a training panel of plasma samples collected from US adults. These data were used to assign nominal concentrations to the calibrators of the assay to further improve performance which was then assessed by interrogating plasma samples from a cohort of pregnant women from Niger. The correlation between assays for each biomarker measured from this cohort was typically good, with the exception of thyroglobulin, and the sensitivity ranged from 74% to 93%, and specificity from 81% to 98%. The 7-Plex micronutrient assay has the potential for use as an affordable tool for population surveillance of vitamin A, iron, and iodine deficiencies as well as falciparum malarial parasitemia infectivity and inflammation. The assay is easy-to-use, requires minimal sample volume, and is scalable, rapid, and accurate—needing only a low-cost reader and basic equipment present in most reference laboratory settings and so may be employed by low and middle income countries for micronutrient surveillance to inform on status in key populations. Micronutrient deficiencies including iron, iodine, and vitamin A affect a significant portion of the world’s population. Efforts to assess the prevalence of these deficiencies in vulnerable populations are challenging, partly due to measurement tools that are inadequate for assessing multiple micronutrients in large-scale population surveys. We have developed a 7-plex immunoassay for the simultaneous measurement of seven biomarkers relevant to assessing iodine, iron, and vitamin A status, inflammation and Plasmodium falciparum parasitemia by measuring levels of thyroglobulin, ferritin, soluble transferrin receptor, retinol binding protein 4, α-1-acid glycoprotein, C-reactive protein, and histidine-rich protein II. This 7-plex immunoassay technique has potential as a rapid and effective tool for use in large-scale surveys and assessments of nutrition intervention programs in low- and middle-income countries.
A combined hierarchical algorithm using precise and accurate markers allows maximal use of available data for efficient and objective identification of ovulation using daily specimens. In intermittent sampling designs, the presence and the timing of ovulation can be estimated with good sensitivity, specificity and accuracy.
Objective-Detailed characterization of progesterone and ovulation across the menopausal transition provides insight into conception risk and mechanisms of reproductive aging.Design-Participants (N=108, aged 25-58 years) collected daily urine specimens for six month intervals in each of five consecutive years. Specimens were assayed for pregnanediol-glucuronide (PDG), LH, FSH and estrone-glucuronide (E1G). Reproductive stage was determined using cycle length variance. A hierarchical algorithm was used to identify ovulation. Linear mixed-effects models estimated: 1) the frequency and day of ovulation by age and stage; 2) differences in FSH, LH, and E1G levels between ovulatory (O) and anovulatory (AO) cycles; and 3) total PDG levels and PDG levels in ovulatory cycles by age and stage.Results-The probability of AO cycles increased across the perimenopause (p<.0001); reproductive stage was a stronger predictor than age of the probability of anovulation. Most cycles in late perimenopause were anovulatory (>60%), but one quarter of cycles longer than 60 days were ovulatory. Average day of ovulation was later in the late perimenopause (mean (SD) cycle day 27 (25)) compared to the premenopause. FSH and LH levels were higher, and E1G levels lower, in AO than O cycles (p<.0001 for each). Total PDG decreased in the late perimenopause, but 95 th percentile PDG in ovulatory cycles declined steadily across the transition.Conclusions-Exposure to the risk of conception in women experiencing cycles long enough to classify them as late perimenopausal is far from negligible. Reproductive stage is more informative than age about PDG levels and the likelihood of anovulation.
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