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- Eriksson, Anna-Lena, 1971, et al.
(author)
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Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men.
- 2018
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In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 103:3, s. 991-1004
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Journal article (peer-reviewed)abstract
- Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability.To investigate the genetic regulation of serum E2 and E1 in men.Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts.Genetic determinants of serum E2 and E1 levels.Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance.Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1.
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| 2. |
- Orwoll, Eric S., et al.
(author)
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The Limited Clinical Utility of Testosterone, Estradiol, and Sex Hormone Binding Globulin Measurements in the Prediction of Fracture Risk and Bone Loss in Older Men
- 2017
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In: Journal of Bone and Mineral Research. - : WILEY. - 0884-0431 .- 1523-4681. ; 32:3, s. 633-640
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Journal article (peer-reviewed)abstract
- Measurement of serum testosterone (T) levels is recommended in the evaluation of osteoporosis in older men and estradiol (E2) and sex hormone binding globulin (SHBG) levels are associated with the rate of bone loss and fractures, but the clinical utility of sex steroid and SHBG measurements for the evaluation of osteoporosis in men has not been examined. To evaluate whether measurements of T, E2, and/or SHBG are useful for the prediction of fracture risk or the rate of bone loss in older men, we analyzed longitudinal data from 5487 community-based men participating in the Osteoporotic Fractures in Men (MrOS) study in the United States, Sweden, and Hong Kong. Serum T, E2, and SHBG levels were assessed at baseline; incident fractures were self-reported at 4-month intervals with radiographic verification (US), or ascertained via national health records (Sweden, Hong Kong). Rate of bone loss was assessed by serial measures of hip bone mineral density (BMD). We used receiver operating characteristic (ROC) curves, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) to assess improvement in prediction. Mean age at baseline was 72 to 75 years and the prevalence of low T levels (<300 ng/dL) was 7.6% to 21.3% in the three cohorts. There were 619 incident major osteoporotic and 266 hip fractures during follow-up of approximately 10 years. Based on ROC curves, there were no improvements in fracture risk discrimination for any biochemical measure when added to models, including the Fracture Risk Assessment Tool (FRAX) with BMD. Although minor improvements in NRI were observed for the dichotomous parameters low bioavailable E2 (BioE2) (<11.4 pg/mL) and high SHBG(>59.1 nM), neither sex steroids nor SHBG provided clinically useful improvement in fracture risk discrimination. Similarly, they did not contribute to the prediction of BMD change. In conclusion, there is limited clinical utility of serum E2, T, and SHBG measures for the evaluation of osteoporosis risk in elderly men.
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