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Relation of sex and estrogen therapy to serum fibroblast growth factor 23, serum phosphorus, and urine phosphorus: the Heart and Soul Study.

ABSTRACT: Menopause is associated with urine phosphorus retention, which is mitigated by estrogen therapy. Fibroblast growth factor 23 (FGF-23) is a hormone originating from bone that regulates urine phosphorus excretion. Whether sex or estrogen therapy is associated with different FGF-23 levels is unknown.Cross-sectional study of ambulatory individuals with prevalent cardiovascular disease.Sex and, in women, use or nonuse of estrogen.Serum phosphorus, tubular maximum reabsorption of phosphorus indexed to glomerular filtration rate (TMP/GFR), and plasma FGF-23 concentrations.For 987 participants, mean age was 67 ± 11 years, 182 (18%) were women, and 46 (25%) were using estrogen. Mean estimated GFR was 71 ± 23 (SD) mL/min/1.73 m(2). Compared with women who were not using estrogen, both women on estrogen therapy and men had significantly lower serum phosphorus concentrations, lower TMP/GFR values (indicating higher urine phosphorus excretion), and lower FGF-23 concentrations with adjustment for age, demographics, and kidney function (P < 0.001 for each). Mean FGF-23 levels were 68.7 (95% CI, 59.7-79.0) relative units (RU)/mL in non-estrogen-using women, 43.8 (95% CI, 41.2-46.5) RU/mL in men, and 45.1 (95% CI, 35.2-57.4) RU/mL in women using estrogen in adjusted analysis (P < 0.001).Most participants were men. Estrogen therapy was not randomly assigned.Older women who are not using estrogen have higher FGF-23 levels than either men or women using estrogen. In the context of prior literature, these data suggest that postmenopausal phosphorus retention may stimulate higher FGF-23 concentrations after menopause.

SUBMITTER: Ix JH

PROVIDER: S-EPMC3199317 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Relation of sex and estrogen therapy to serum fibroblast growth factor 23, serum phosphorus, and urine phosphorus: the Heart and Soul Study.

Ix Joachim H JH Chonchol Michel M Laughlin Gail A GA Shlipak Michael G MG Whooley Mary A MA

American journal of kidney diseases : the official journal of the National Kidney Foundation 20110819 5

<h4>Background</h4>Menopause is associated with urine phosphorus retention, which is mitigated by estrogen therapy. Fibroblast growth factor 23 (FGF-23) is a hormone originating from bone that regulates urine phosphorus excretion. Whether sex or estrogen therapy is associated with different FGF-23 levels is unknown.<h4>Study design & setting</h4>Cross-sectional study of ambulatory individuals with prevalent cardiovascular disease.<h4>Predictors</h4>Sex and, in women, use or nonuse of estrogen.<h ...[more]

PMID: 21855188

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Project description:AimsThis study aimed to assess plasma fibroblast growth factor 23 (FGF23) in patients with heart failure with preserved ejection fraction (HFpEF) and its relation to inflammation, renal function, clinical and imaging characteristics, exercise capacity, and prognosis.Methods and resultsWe performed a prospective, observational study of 172 age-matched and sex-matched subjects (HFpEF n = 130; controls n = 42, age 73 ± 9, female 50%) who underwent plasma biomarker sampling, echocardiography, cardiac magnetic resonance imaging, and 6 min walk testing (6MWT). The primary endpoint was the composite of all-cause death or HF hospitalization. FGF23 was higher in HFpEF compared with controls (62 [42-105] vs. 34 [22-41] pg/mL, P < 0.0001). In HFpEF, FGF23 correlated with greater symptom burden (New York Heart Association class: r = 0.308), poorer exercise capacity (6MWT distance: r = -0.345), and plasma biomarkers reflecting inflammation (highly sensitive C-reactive protein: r = 0.207, myeloperoxidase: r = 0.311), bone metabolism (osteoprotegerin: r = 0.446), renal dysfunction (urea: r = 0.267, creatinine: r = 0.351, estimated glomerular filtration rate: r = -0.367), and echocardiographic E/e' (r = 0.298); P < 0.05. Following multivariable linear regression modelling, FGF23 remained independently associated with shorter 6MWT distance (P = 0.012) in addition to age, body mass index, and lower haemoglobin. During follow-up (median 1428 days), there were 61 composite events (21 deaths, 40 HF hospitalizations) in patients with HFpEF. In multivariable Cox regression analysis, FGF23 [adjusted hazard ratio (HR) 1.665; 95% confidence interval (CI) (1.284-2.160; P < 0.0001)], B-type natriuretic peptide (HR 1.433; CI 1.053-1.951; P = 0.022), and prior HF hospitalization (HR 2.058; CI 1.074-3.942; P = 0.030) were independent predictors of the composite endpoint.ConclusionsPlasma FGF23 is higher in HFpEF compared with age-matched and sex-matched controls and is strongly associated with exercise incapacity and prognosis. FGF23 correlates with plasma markers of inflammation and renal impairment.

Project description:ObjectiveIn chronic kidney disease (CKD), both anemia and deregulated phosphate metabolism are common and predictive of adverse outcome. Previous studies suggest that iron status influences phosphate metabolism by modulating proteolytic cleavage of FGF23 into C-terminal fragments. Red cell distribution width (RDW) was recently identified as a strong prognostic determinant for cardiovascular morbidity and mortality, independently of iron status. We assessed whether RDW is associated with FGF23 cleaving in CKD patients with heart failure.Materials and methodsThe associations between RDW and either intact FGF23 (iFGF23), C-terminal FGF23 (cFGF23, reflecting iFGF23 and C-terminal fragments together) and the iFGF23/cFGF23 ratio were analyzed in 52 patients with CKD (eGFR 34,9 ± 13.9 ml/min/1.73m2) and chronic heart failure (CHF). Associations between RDW and FGF23 forms were studied by linear regression analysis adjusted for parameters of renal function, iron metabolism, phosphate metabolism and inflammation.ResultsMedian cFGF23 levels were 197.5 [110-408.5] RU/ml, median iFGF23 levels were 107.3 [65.1-162.2] pg/ml and median FGF23 ratio was 0.80 [0.37-0.86]. Mean RDW was 14.1 ± 1.2%. cFGF23 and RDW were associated (? = 1.63 x 10(-3), P < 0.001), whereas iFGF23 and RDW were not (? = -1.38 x 10(-3), P = 0.336). The iFGF23/cFGF23 ratio was inversely associated with RDW. The difference between cFGF23 and iFGF23 (cFGF23- iFGF23) was positively associated with RDW (? = 1.74 x 10(-3), P < 0.001). The association between cFGF23 and RDW persisted upon multivariable linear regression analysis, adjusted for parameters of renal function, phosphate metabolism, iron metabolism and inflammation (? = 0.97 x 10(-3), P = 0.047).ConclusionRDW is associated with cFGF23 but not with iFGF23 levels in patients with CKD and CHF. This suggests a connection between RDW and FGF23 catabolism, independent of iron status and inflammation. Future studies are needed to unravel underlying mechanisms and whether these pertain to the link between RDW and outcome.

Project description:Fibroblast growth factor 23 (FGF23) circulates as active protein and inactive fragments. Low iron status increases FGF23 gene expression, and iron deficiency is common. We hypothesized that in healthy premenopausal women, serum iron influences C-terminal and intact FGF23 concentrations, and that iron and FGF23 associate with bone mineral density (BMD). Serum iron, iron binding capacity, percent iron saturation, phosphorus, and other biochemistries were measured in stored fasting samples from healthy premenopausal white (n=1898) and black women (n=994), age 20-55years. Serum C-terminal and intact FGF23 were measured in a subset (1631 white and 296 black women). BMD was measured at the lumbar spine and femur neck. Serum phosphorus, calcium, alkaline phosphatase and creatinine were lower in white women than black women (p<0.001). Serum iron (p<0.0001) and intact FGF23 (p<0.01) were higher in white women. C-terminal FGF23 did not differ between races. Phosphorus correlated with intact FGF23 (white women, r=0.120, p<0.0001; black women r=0.163, p<0.01). However, phosphorus correlated with C-terminal FGF23 only in black women (r=0.157, p<0.01). Intact FGF23 did not correlate with iron. C-terminal FGF23 correlated inversely with iron (white women r=-0.134, p<0.0001; black women r=-0.188, p<0.01), having a steeper slope at iron <50mcg/dl than ?50mcg/dl. Longitudinal changes in iron predicted changes in C-terminal FGF23. Spine BMD correlated with iron negatively (r=-0.076, p<0.01) in white women; femur neck BMD correlated with iron negatively (r=-0.119, p<0.0001) in black women. Both relationships were eliminated in weight-adjusted models. BMD did not correlate with FGF23. Serum iron did not relate to intact FGF23, but was inversely related to C-terminal FGF23. Intact FGF23 correlated with serum phosphorus. In weight-adjusted models, BMD was not related to intact FGF23, C-terminal FGF23 or iron. The influence of iron on FGF23 gene expression is not important in determining bone density in healthy premenopausal women.

Project description:Dietary phosphorus oversupply wastes non-renewable natural resources and raises environmental concerns in animal agriculture. We hypothesized that laying hens do not need large safety margins for dietary phosphorus because of the existence of fibroblast growth factor 23 (FGF23). In experiment 1, a total of 504 Hy-Line Brown laying hens (40-week-old) were randomly assigned to seven diets (for each diet, six replicates of 12 hens), containing 0.12, 0.17, 0.22, 0.27, 0.32, 0.37, and 0.42% non-phytate phosphorus, respectively, for 15 weeks. In experiment 2, a total of 14 Hy-Line Brown laying hens (40-week-old) were randomly assigned to two diets: (1) phosphorus restricted (n = 7) diet containing 0.14% non-phytate phosphorus, and (2) regular phosphorus (n = 7) diet containing 0.32% non-phytate phosphorus, for 21 days. Laying performance and egg quality were investigated in experiments 1 and 2. Phosphorus excretion and physiological changes were determined in experiment 2. It was found that dietary non-phytate phosphorus levels had no effects (P > 0.05) on laying performance and egg quality in either experiment. In experiment 2, laying hens fed 0.14% non-phytate phosphorus had decreased phosphorus excretion (by 52.6%, P < 0.001) when compared to those fed 0.32% non-phytate phosphorus. In response to the 0.14% non-phytate phosphorus diet, laying hens in experiment 2 exhibited: (1) suppressed calvaria mRNA expressions of FGF23 (by 57.8%, P < 0.001) and fibroblast growth factor receptor 1 (FGFR1, by 52.8%, P = 0.012), (2) decreased serum levels of FGF23 (by 41.7%, P = 0.011) and phosphorus (by 40.3%, P < 0.001), (3) decreased kidney mRNA expressions of FGFR1 (by 66.0%, P = 0.040) and FGFR4 (by 63.3%, P = 0.012) and decreased kidney protein expression of type 2a sodium-phosphorus co-transporter (NPt2a, by 51%, P = 0.025), (4) increased duodenum protein expression of NPt2b (by 45%, P = 0.032), and (5) increased excretion of calcium (by 22.9%, P ? 0.024). Collectively, decreasing dietary non-phytate phosphorus by up to 0.12% had no negative effects on egg-production performance but significantly decreased phosphorus excretion in laying hens. The laying hens adjusted to low-phosphorus diets by increasing intestinal NPt2b protein production, which was associated with decreased serum FGF23 concentration. Decreasing dietary non-phytate phosphorus is suggested to laying-hen nutritionists.

Dataset Information

Relation of sex and estrogen therapy to serum fibroblast growth factor 23, serum phosphorus, and urine phosphorus: the Heart and Soul Study.

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Relation of sex and estrogen therapy to serum fibroblast growth factor 23, serum phosphorus, and urine phosphorus: the Heart and Soul Study.

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