TY - JOUR
AU - Jaffe, Allan, S
AB - Abstract Background: Natriuretic peptide concentrations in adults require age- and sex-specific reference intervals for optimal interpretation. Females have higher natriuretic peptide concentrations, and hypotheses suggest that estrogen may be responsible. This study sought to determine the influence of hormone modulation on N-terminal probrain natriuretic peptide (NT-proBNP) by using a pediatric cohort. Children/adolescents typically have rapid hormone changes during puberty, making them an ideal group to study. Methods: We selected 759 specimens (303 male, 456 female; ages 2 months to 18 years, mean 13 years) obtained from the Mayo Clinic Pediatric Residual Specimen Bank. We measured NT-proBNP, sex hormone–binding globulin (SHBG), estradiol, and testosterone by immunoassays or LC-MS/MS and calculated free testosterone. We performed univariate and multivariate analyses to investigate the significance of NT-proBNP with each hormone. Results: Reference values demonstrated a sex difference and sequential age differences in females. Univariate modeling of the hormones with NT-proBNP revealed an independent inverse association of NT-proBNP with testosterone, a direct association with SHBG, and no significant association with estradiol. Multivariate modeling confirmed a strong association of testosterone and SHBG with NT-proBNP. Correlation of hormones with NT-proBNP retained greater significance than either age or sex. Conclusions: In pediatric patients, NT-proBNP is independently associated with both testosterone and SHBG hormone concentrations. Measurements of testosterone are inversely associated with NT-proBNP, and estrogens are marginally associated with NT-proBNP in males but not females, suggesting that androgens and not estrogens modulate sex differences notable in natriuretic peptides. Children and adolescents may require an objective assessment of hormones if optimal interpretation of natriuretic peptide concentrations is desired or the concentrations are confounded. . Measured concentrations of brain natriuretic peptide (BNP),1 or its amino-terminal cleavage profragment, NT-proBNP, are widely used in the diagnostic workup of patients with various cardiovascular disorders. In particular, BNP represents a pivotal laboratory marker to diagnose or to exclude the presence of congestive heart failure, and to a lesser extent, assist in the risk stratification of patients with acute ischemic heart disease. Concentrations of BNP and NT-proBNP are related to the severity of heart failure symptoms (1)(2), and several trials have investigated the use of BNP or NT-proBNP measurements to help assess treatment response and assist in the titration of therapy (3)(4)(5). BNP concentrations in healthy individuals are known to increase with age and are higher in females than males. There is uncertainty about the optimal reference intervals for clinical use because of these sex and age effects as well as the effects of associated noncardiac diseases on BNP (6)(7)(8)(9). These effects are likely due to the influence on BNP and NT-proBNP production, both directly and indirectly, of a variety of autocrine, paracrine, and hormonal factors, such as norepinephrine, angiotensin II, glucocorticoids, proinflammatory cytokines, and possibly sex-steroids. In addition, there is a relationship between natriuretic peptide concentrations and renal function. Recent data have suggested that some of the associations between sex, age, and BNP/NT-proBNP might be related to sex-hormone concentrations and their changes throughout life (10). Such changes might be even more significant in children, in whom androgen and estrogen concentrations fluctuate widely depending on the degree of sexual maturity. All of these issues must be taken into account to use natriuretic peptide values optimally in individual patients, and this variability could have profound effects on the ability to interpret BNP/NT-proBNP values in pediatric patients. To investigate these influences further, we analyzed the relationship between NT-proBNP, estradiol (E2), sex hormone–binding globulin (SHBG), testosterone, and calculated free testosterone in a large number (n = 759) of pediatric samples. In this population, hormonal changes occur variably but over a relatively short period of time (years vs decades), thus allowing direct observation of the modulation of natriuretic peptide concentrations. In addition, comorbidities that are known to affect NT-proBNP concentrations and confound interpretation are less likely to occur in children. Most importantly, this study cohort allowed us to explore how NT-proBNP concentrations in pediatric patients should potentially be interpreted. Materials and Methods specimen and data collection This study protocol was approved by the Mayo Clinic Institutional Review Board. We obtained archived pediatric samples from the Mayo Clinic Pediatric Specimen Bank, which contains residual sera from pediatric patients who have blood drawn for clinical purposes. Sera were collected in standard serum tubes (Becton Dickinson), centrifuged, and frozen at −20 °C until assayed. Samples were deidentified and archived with information denoting the patient’s age, sex, Tanner staging (when available), International Classification of Diseases, 9th Revision (ICD-9) diagnostic codes, laboratory test results, sample volume, appearance (hemolysis, lipemia, icterus), and list of medications (when available) at the time of blood draw. Using search criteria, we preselected specimens to exclude samples with ICD-9 codes indicative of known cardiac disease, renal dysfunction, hypo- or hypervolemia, salt overload or depletion, or endocrinopathies. We selected 759 specimens for inclusion in this study. assays We measured NT-proBNP using an electrochemiluminescent polyclonal immunoassay on the Roche Modular E170 (Roche Diagnostics). The intra- and interassay CVs for the NT-proBNP assay are 1.2% and 3.1%, respectively, at 192 ng/L and 2.2% and 3.6% at 6180 ng/L. The lower limit of quantification was 5 ng/L, with a CV of 5.9%. We quantified SHBG using an automated chemiluminometric assay on an Immulite 2000 instrument (Siemens Healthcare Diagnostics). The assay’s lowest reportable result is limited by the instrument software to 3 nmol/L, which appears to be well above the limit of quantification (interassay CV in patient samples of ≤20%), as the interassay CV at 3.7 nmol/L is only 3%. The nature of the preserved specimens precluded an evaluation of BNP. We measured estradiol by liquid chromatography–tandem mass spectrometry (LC-MS/MS) after dansyl chloride derivatization, as described (11). The assay’s limit of quantification is 23.2 pmol/L (6.3 pg/mL, CV 20%). We measured testosteroneby LC-MS/MS without prior derivatization, also as described (12)(13). The limit of quantification is 242.7 pmol/L (7 ng/dL, CV 18.8%). We calculated free testosterone from an equation that used values from total testosterone and SHBG measurements. The equation used for the calculation is based on 3 published calculations of free testosterone from total testosterone and SHBG, which were modified based on a comparison of the results of measurements of free testosterone in 205 patient samples by equilibrium dialysis (the gold standard) with those obtained for the same samples by calculation from SHBG and total testosterone measurements. The derived equation assumes a value of 4.3 g/dL for plasma albumin (14). statistical analyses Statistical analyses were performed by the Mayo Clinic Division of Biomedical Statistics and Informatics using SAS version 9.1 (SAS Institute). Relationships of the mid-95th percentiles (2.5th and 97.5th percentile) with age and sex were evaluated using quantile regression. In quantile regression, the conditional quantile functions are estimated by minimizing an asymmetrically weighted sum of absolute errors (15). Standard errors of the quantile regression parameters were estimated using a bootstrap resampling procedure with replacement with 10 000 replicates, and P values were determined. Because age can be a surrogate for maturity in children, relationships of NT-proBNP with hormones that change during puberty were assessed using general linear regression models with log NT-proBNP as the dependent variable and sex (0 = female, 1 = male), SHBG, estradiol, testosterone, and their significant 2- and 3-level interactions as independent variables. We defined statistical significance as a P value <0.05. Results Of the 759 pediatric serum specimens obtained from the Residual Specimen Bank, 303 (40%) samples were from male patients and 456 (60%) from female patients. The age range of sample donors was from 2 months to 18 years and was grouped into 3 distinct age ranges (0–10, 11–13, and 14–18 years). There were a larger number of specimens distributed throughout the preadolescent to adolescent period, as this is when rapid hormonal changes ensue. We excluded specimens with a creatinine concentration >88.4 μmol/L (1.0 mg/dL) in addition to those with predefined exclusion criteria. Tanner staging and medications were not available for all individuals and thus were not included in the analyses. We initially established surrogate pediatric reference intervals for NT-proBNP based solely on the age and sex of the subjects (Table 1 ). For males, the range was 5–742 ng/L (median 38.7 ng/L), and values did not vary with age. The reference intervals were significantly dependent on age in females. Female NT-proBNP reference intervals were 21–1122 ng/L (median 173.8 ng/L) at 0–10 years, 11–1122 ng/L (median 118.5 ng/L) at 11–13 years, and 6–1122 ng/L (median 61.1 ng/L) at 14–18 years. Differences across the 3 female age groups were statistically significant (P < 0.03). Regardless of age, females had higher concentrations of NT-proBNP than males. Overall, sex alone in pediatrics was significantly associated with NT-proBNP (P = 0.008) (Fig. 1 ) and retained significance throughout comparisons between males and separate female age groups (Table 1 ). Figure 1. Open in new tabDownload slide Association of NT-proBNP with sex. Data points represent the median (25th and 75th percentile) for males and females. All specimens (n = 759) are included. Figure 1. Open in new tabDownload slide Association of NT-proBNP with sex. Data points represent the median (25th and 75th percentile) for males and females. All specimens (n = 759) are included. Table 1. Pediatric surrogate reference intervals for NT-proBNP. . n . Median NT-proBNP, ng/L . 95% reference interval, ng/L . 95% CI on 2.5th percentile . 95% CI on 97.5th percentile . P1 . Males 303 38.7 5–742 (4.7–5.1) (131–1150) Females 456 70.8 0.008  Age 0–10 years 68 173.8 21–1122 (8.3–33.2) (739–1505) <0.001  Age 11–13 years 84 118.5 11–1122 (6.0–15.6) (739–1505) 0.005  Age 14–18 years 304 61.1 6–1122 (3.0–8.9) (739–1505) 0.01 . n . Median NT-proBNP, ng/L . 95% reference interval, ng/L . 95% CI on 2.5th percentile . 95% CI on 97.5th percentile . P1 . Males 303 38.7 5–742 (4.7–5.1) (131–1150) Females 456 70.8 0.008  Age 0–10 years 68 173.8 21–1122 (8.3–33.2) (739–1505) <0.001  Age 11–13 years 84 118.5 11–1122 (6.0–15.6) (739–1505) 0.005  Age 14–18 years 304 61.1 6–1122 (3.0–8.9) (739–1505) 0.01 1 Significance between males and females and males with each female age group. Open in new tab Table 1. Pediatric surrogate reference intervals for NT-proBNP. . n . Median NT-proBNP, ng/L . 95% reference interval, ng/L . 95% CI on 2.5th percentile . 95% CI on 97.5th percentile . P1 . Males 303 38.7 5–742 (4.7–5.1) (131–1150) Females 456 70.8 0.008  Age 0–10 years 68 173.8 21–1122 (8.3–33.2) (739–1505) <0.001  Age 11–13 years 84 118.5 11–1122 (6.0–15.6) (739–1505) 0.005  Age 14–18 years 304 61.1 6–1122 (3.0–8.9) (739–1505) 0.01 . n . Median NT-proBNP, ng/L . 95% reference interval, ng/L . 95% CI on 2.5th percentile . 95% CI on 97.5th percentile . P1 . Males 303 38.7 5–742 (4.7–5.1) (131–1150) Females 456 70.8 0.008  Age 0–10 years 68 173.8 21–1122 (8.3–33.2) (739–1505) <0.001  Age 11–13 years 84 118.5 11–1122 (6.0–15.6) (739–1505) 0.005  Age 14–18 years 304 61.1 6–1122 (3.0–8.9) (739–1505) 0.01 1 Significance between males and females and males with each female age group. Open in new tab We explored univariate associations with NT-proBNP and the individual hormones (estradiol, testosterone, SHBG, and calculated free testosterone) to evaluate if the hormones explained the age relationship (Table 2 ). Overall, when combining males and females together, NT-proBNP was not significantly associated with estradiol concentrations (P = 0.36) but was strongly associated with SHBG (P = 0.0009), total testosterone (P < 0.0001), and free testosterone (P = 0.001). In males, NT-proBNP was significantly associated with all hormones (SHBG, estradiol, testosterone, and free testosterone), whereas in females there was no significance with either SHBG (P = 0.23) or estradiol (P = 0.40), but a strong association with both total testosterone (P = 0.04) and free testosterone (P = 0.0007). Table 2. Univariate correlation and multivariable analysis between NT-proBNP and hormones. . β (SE) . P . Univariate correlation  Log(NT-proBNP), males/females   Model 1: Sex −0.157 (0.088) 0.008   Model 2: SHBG 0.0026 (0.0008) 0.0009   Model 3: Estradiol 0.00002 (0.00002) 0.36   Model 4: Testosterone −0.0012 (0.0002) <0.0001   Model 5: Free testosterone −0.0324 (0.005) 0.001  Log(NT-proBNP), Males   Model 1: SHBG 0.0094 (0.0020) <0.0001   Model 2: Estradiol −0.0563 (0.0109) <0.0001   Model 3: Testosterone −0.0014 (0.0002) <0.0001   Model 4: Free testosterone −0.0382 (0.0061) <0.0001  Log(NT-proBNP), females   Model 1: SHBG 0.0010 (0.0009) 0.23   Model 2: Estradiol 0.00002 (0.00002) 0.4   Model 3: Testosterone −0.0024 (0.0011) 0.04   Model 4: Free testosterone −0.1847 (0.0542) 0.0007 Multivariable analysis  Log(NT-proBNP), males   Intercept 5.3944 (0.4127) <0.0001   SHBG −0.0164 (0.0066) 0.01   Estradiol −0.1202 (0.0307) <0.0001   Testosterone −0.0024 (0.0015) 0.0016   SHBG × estradiol interaction 0.0018 (0.0005) 0.0009   Estradiol × testosterone interaction 0.00001 (0.000003) <0.0001  Log(NT-proBNP), females   Intercept 5.0251 (0.2171) <0.0001   Age −0.0662 (0.0152) <0.0001   SHBG −0.0004 (0.0011) 0.69   Testosterone −0.0055 (0.0016) 0.0006   SHBG × testosterone interaction 0.00003 (0.000008) 0.0008 . β (SE) . P . Univariate correlation  Log(NT-proBNP), males/females   Model 1: Sex −0.157 (0.088) 0.008   Model 2: SHBG 0.0026 (0.0008) 0.0009   Model 3: Estradiol 0.00002 (0.00002) 0.36   Model 4: Testosterone −0.0012 (0.0002) <0.0001   Model 5: Free testosterone −0.0324 (0.005) 0.001  Log(NT-proBNP), Males   Model 1: SHBG 0.0094 (0.0020) <0.0001   Model 2: Estradiol −0.0563 (0.0109) <0.0001   Model 3: Testosterone −0.0014 (0.0002) <0.0001   Model 4: Free testosterone −0.0382 (0.0061) <0.0001  Log(NT-proBNP), females   Model 1: SHBG 0.0010 (0.0009) 0.23   Model 2: Estradiol 0.00002 (0.00002) 0.4   Model 3: Testosterone −0.0024 (0.0011) 0.04   Model 4: Free testosterone −0.1847 (0.0542) 0.0007 Multivariable analysis  Log(NT-proBNP), males   Intercept 5.3944 (0.4127) <0.0001   SHBG −0.0164 (0.0066) 0.01   Estradiol −0.1202 (0.0307) <0.0001   Testosterone −0.0024 (0.0015) 0.0016   SHBG × estradiol interaction 0.0018 (0.0005) 0.0009   Estradiol × testosterone interaction 0.00001 (0.000003) <0.0001  Log(NT-proBNP), females   Intercept 5.0251 (0.2171) <0.0001   Age −0.0662 (0.0152) <0.0001   SHBG −0.0004 (0.0011) 0.69   Testosterone −0.0055 (0.0016) 0.0006   SHBG × testosterone interaction 0.00003 (0.000008) 0.0008 Open in new tab Table 2. Univariate correlation and multivariable analysis between NT-proBNP and hormones. . β (SE) . P . Univariate correlation  Log(NT-proBNP), males/females   Model 1: Sex −0.157 (0.088) 0.008   Model 2: SHBG 0.0026 (0.0008) 0.0009   Model 3: Estradiol 0.00002 (0.00002) 0.36   Model 4: Testosterone −0.0012 (0.0002) <0.0001   Model 5: Free testosterone −0.0324 (0.005) 0.001  Log(NT-proBNP), Males   Model 1: SHBG 0.0094 (0.0020) <0.0001   Model 2: Estradiol −0.0563 (0.0109) <0.0001   Model 3: Testosterone −0.0014 (0.0002) <0.0001   Model 4: Free testosterone −0.0382 (0.0061) <0.0001  Log(NT-proBNP), females   Model 1: SHBG 0.0010 (0.0009) 0.23   Model 2: Estradiol 0.00002 (0.00002) 0.4   Model 3: Testosterone −0.0024 (0.0011) 0.04   Model 4: Free testosterone −0.1847 (0.0542) 0.0007 Multivariable analysis  Log(NT-proBNP), males   Intercept 5.3944 (0.4127) <0.0001   SHBG −0.0164 (0.0066) 0.01   Estradiol −0.1202 (0.0307) <0.0001   Testosterone −0.0024 (0.0015) 0.0016   SHBG × estradiol interaction 0.0018 (0.0005) 0.0009   Estradiol × testosterone interaction 0.00001 (0.000003) <0.0001  Log(NT-proBNP), females   Intercept 5.0251 (0.2171) <0.0001   Age −0.0662 (0.0152) <0.0001   SHBG −0.0004 (0.0011) 0.69   Testosterone −0.0055 (0.0016) 0.0006   SHBG × testosterone interaction 0.00003 (0.000008) 0.0008 . β (SE) . P . Univariate correlation  Log(NT-proBNP), males/females   Model 1: Sex −0.157 (0.088) 0.008   Model 2: SHBG 0.0026 (0.0008) 0.0009   Model 3: Estradiol 0.00002 (0.00002) 0.36   Model 4: Testosterone −0.0012 (0.0002) <0.0001   Model 5: Free testosterone −0.0324 (0.005) 0.001  Log(NT-proBNP), Males   Model 1: SHBG 0.0094 (0.0020) <0.0001   Model 2: Estradiol −0.0563 (0.0109) <0.0001   Model 3: Testosterone −0.0014 (0.0002) <0.0001   Model 4: Free testosterone −0.0382 (0.0061) <0.0001  Log(NT-proBNP), females   Model 1: SHBG 0.0010 (0.0009) 0.23   Model 2: Estradiol 0.00002 (0.00002) 0.4   Model 3: Testosterone −0.0024 (0.0011) 0.04   Model 4: Free testosterone −0.1847 (0.0542) 0.0007 Multivariable analysis  Log(NT-proBNP), males   Intercept 5.3944 (0.4127) <0.0001   SHBG −0.0164 (0.0066) 0.01   Estradiol −0.1202 (0.0307) <0.0001   Testosterone −0.0024 (0.0015) 0.0016   SHBG × estradiol interaction 0.0018 (0.0005) 0.0009   Estradiol × testosterone interaction 0.00001 (0.000003) <0.0001  Log(NT-proBNP), females   Intercept 5.0251 (0.2171) <0.0001   Age −0.0662 (0.0152) <0.0001   SHBG −0.0004 (0.0011) 0.69   Testosterone −0.0055 (0.0016) 0.0006   SHBG × testosterone interaction 0.00003 (0.000008) 0.0008 Open in new tab Concentrations of NT-proBNP increased significantly across quartiles of SHBG and decreased across quartiles of total testosterone with both sexes combined (Figs. 2 and 3 ). Therefore, a higher testosterone concentration correlated with a decreased NT-proBNP concentration and higher SHBG correlated with higher NT-proBNP. The mean concentrations of NT-proBNP remained similar across quartiles of estradiol concentrations without taking sex into consideration (Fig. 4 ). When we analyzed males and females independently, we found prominent differences. In males, SHBG increased in quartiles in relationship to NT-proBNP concentration, whereas in females there was little correlation (Fig. 2 ). NT-proBNP in both males and females had a significant relationship with testosterone, such that higher testosterone was associated with lower NT-proBNP (Fig. 3 ). Estradiol appeared to demonstrate a greater relationship in males than females across all quartiles (Fig. 4 ). Figure 2. Open in new tabDownload slide Relationship between NT-proBNP and SHBG for both sexes (▪), males (•), and females (○). Data points represent the median (25th and 75th percentiles) for each quartile of SHBG. Figure 2. Open in new tabDownload slide Relationship between NT-proBNP and SHBG for both sexes (▪), males (•), and females (○). Data points represent the median (25th and 75th percentiles) for each quartile of SHBG. Figure 3. Open in new tabDownload slide Relationship between NT-proBNP and total testosterone for both sexes (▪), males (•), and females (○). Data points represent the median (25th and 75th percentiles) for each quartile of testosterone. Figure 3. Open in new tabDownload slide Relationship between NT-proBNP and total testosterone for both sexes (▪), males (•), and females (○). Data points represent the median (25th and 75th percentiles) for each quartile of testosterone. Figure 4. Open in new tabDownload slide Relationship between NT-proBNP and estradiol for both sexes (▪), males (•), and females (○). Data points represent the median (25th and 75th percentiles) for each quartile of estradiol. Figure 4. Open in new tabDownload slide Relationship between NT-proBNP and estradiol for both sexes (▪), males (•), and females (○). Data points represent the median (25th and 75th percentiles) for each quartile of estradiol. Figs. 2 , 3, and 4 were consonant with the univariate analyses (Table 2 ), which demonstrated a significant relationship between NT-proBNP and SHBG (in males) and total testosterone (in both males and females); this relationship was more significant than that between NT-proBNP and sex alone and suggests that hormones play a considerable role in modulating individual NT-proBNP concentrations. Estradiol, testosterone, and SHBG are so strongly associated with one another and highly dependent on an individual’s sex that we explored multivariable linear regression models associating NT-proBNP with sex, estradiol, testosterone, and SHBG (Table 2 ). Because the univariate relationship was slightly more significant with total testosterone than with free testosterone, and free testosterone is a calculation-based parameter, we performed multivariable regression analyses using only total testosterone to eliminate redundancy. Multiple linear regression models adjusting for confounders demonstrated the persistence of a significant relationship between sex, SHBG, and testosterone (Table 2 ). For males, NT-proBNP is significantly decreased by SHBG, estrogen, and testosterone. For females, estrogen does not play a role in NT-proBNP concentrations. However, the interaction between age, SHBG, and testosterone had a significantly decreasing association with female NT-proBNP concentrations. Discussion These data provide novel insights into the mechanism and modulation of natriuretic peptides and provide confirmatory evidence of the importance of testosterone and its binding proteins as a mechanism for the consistently higher concentrations of natriuretic peptides observed in females. Furthermore, these data suggest that the hormonal status and sexual maturity of an individual is an important aspect to consider when evaluating natriuretic concentrations in children and adolescents. In our data set, multivariate modeling that included testosterone and its binding protein was essential to define reference limits. Estradiol concentrations did not play an important role in females but appeared to attenuate NT-proBNP to some extent in males. Testosterone appears to be directly involved in the modulation of natriuretic peptides in both males and females, and thus the extent of testosterone expression in an individual appears to be more contributory than the age or sex of an individual. Although this study and data analysis was conducted with NT-proBNP, it is highly probable that these results can be extrapolated to BNP as well, since the 2 peptides show similar patterns of influence with sex and age (8)(9)(16)(17). Normative reference interval data in pediatric publications have included conflicting observations, some of which could be because BNP immunoassays are not standardized. Therefore reported concentrations in the literature vary widely depending on the assay used, in part because each assay’s antibody configuration may respond differently to various peptide degradation fragments of BNP in plasma. NT-proBNP assays are much more standardized, but the differences observed remain, suggesting that other factors such as glycosylation may play an important role (18). Some of the variability could also be related to the challenges encountered in obtaining pediatric samples for reference interval studies and the patients’ comorbidities and clinical history, which is imperative for proper interpretation and validation of BNP/NT-proBNP reference intervals. Multiple factors account for the lack of research of natriuretic peptides in pediatrics, including the intricacy of physiology in the developing and perinatal heart, the complexity of congenital and acquired cardiac disease in children, and the difficulties inherent to pediatric research in acquiring large sample banks from both diseased and truly normal populations. It is also likely that the marked variability seen in normal adults is present in children as well (19). Our data, taken together with the data of Chang et al. (10), suggest that androgen effects are another important source of variability in children and adolescents and may be taken into consideration when evaluating BNP/NT-proBNP concentrations, especially in female adolescents. That we did not observe an equivalent effect of testosterone on NT-proBNP in males could be because this influence may require relatively low testosterone concentrations, and that older male children may already manifest a maximal testosterone-mediated response and thus a BNP/NT-proBNP–suppressing effect. In addition, because of the significance of estrogen in males, it is likely that these hormones act harmoniously in tandem, such that testosterone or estrogen alone in males does not dictate natriuretic peptides. Although this study focused on the pediatric population, the mechanistic results we observed are likely relevant to an adult cohort and help explain why females have higher natriuretic peptide concentrations. Such extrapolations also provide correlations for the present study, since pediatric studies have not previously investigated this question. Our data are consonant with the study of Chang et al. (10), who reported no significant differences in BNP or NT-proBNP concentrations between pre- and postmenopausal women or within a subset of women who were on hormone replacement therapy. They also demonstrated a strong influence of testosterone on BNP/NT-proBNP concentrations in these women; however, these phenomena were not reported for men. Premenopausal women have low levels of testosterone and higher BNP levels than men. Aging men have physiologically declining concentrations of testosterone, and thus it appears that over time their BNP and NT-proBNP levels “catch up” with those of women. It is hypothesized that this lack of testosterone may contribute to cardiovascular protection for premenopausal women. Therefore, it has been suggested that adult men perhaps have suppressed concentrations of natriuretic peptides, similar to depressed concentrations seen in obese individuals, and that increased concentrations of BNP may lead to improved cardiovascular health in premenopausal females (10). A population-based study in Olmsted County, Minnesota, confirmed moderately higher BNP concentrations in females who were given oral estrogens vs the control group (7). Hormone replacement therapy also suppresses testosterone concentrations; therefore, it is plausible that estrogen (and therefore BNP) is indeed higher in those women. This inhibitory effect in men, if present, may have implications for the use of testosterone therapy. A study by Dockery et al. (20) examined the effects of suppression of sex hormones on NT-proBNP and found that upon blockage of androgen receptors, a notable increase in NT-proBNP occurred, supporting the hypothesis that testosterone is directly involved in attenuating natriuretic peptides. These data suggest that sex variations in natriuretic peptides may be the result of an inhibitory effect of testosterone in males rather than a stimulatory response of estrogen in females, and that the relationship between natriuretic peptides is stronger with androgens than sex. Strengths and Limitations In this study, we sought to determine pediatric reference intervals for NT-proBNP and explored the relationship of NT-proBNP with sex, estradiol, SHBG, and testosterone. Pediatric studies are inherently challenging due to the nature of the population in which specimens and data are collected. Because of the limited available volume of the pediatric specimens and the large number of tests performed in this study, serum was the preferred specimen of choice and limited analytical testing for natriuretic peptides to only NT-proBNP. Although specimens were screened using ICD-9 codes as described in “Materials and Methods,” there potentially were abnormal patients analyzed in this study. Traditionally, reference interval studies are performed using and analyzing age and sex as variables, but this approach may not always provide the most useful information. NT-proBNP reference intervals based solely on age show distinct differences between males and females and, within the female group, dependencies with age. Thus, the hormonal status of the pediatric patient must be considered for optimal interpretation of natriuretic peptide concentrations. Use of the Mayo Clinic Pediatric Residual Specimen Bank has facilitated both clinical and biological studies that provided important information concerning the regulation of natriuretic peptides by androgens and estrogens. Specifically, NT-proBNP concentrations are independently inversely associated with testosterone in both males and females, and estrogen had no significant relationship to NT-proBNP in females. Thus, it is androgens and not estrogens that strongly modulate the sex differences noted in natriuretic peptides. Author Contributions:All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article. Authors’ Disclosures of Potential Conflicts of Interest:Upon manuscript submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest: Employment or Leadership: None declared. Consultant or Advisory Role: A.S. Jaffe, Beckman Coulter, Siemens, Critical Diagnostics, Singulex, Nanosphere, Novartis, Inverness, GlaxoSmithKline, and Ortho Clinical Diagnostics. Stock Ownership: None declared. Honoraria: None declared. Research Funding: A.K. Saenger, Roche Diagnostics. Expert Testimony: None declared. 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TI - Pediatric Brain Natriuretic Peptide Concentrations Vary with Age and Sex and Appear to Be Modulated by Testosterone
JO - Clinical Chemistry
DO - 10.1373/clinchem.2009.123778
DA - 2009-10-01
UR - https://www.deepdyve.com/lp/oxford-university-press/pediatric-brain-natriuretic-peptide-concentrations-vary-with-age-and-nM6bbPfm0T
SP - 1869
VL - 55
IS - 10
DP - DeepDyve
ER -