Abstract


Background: Adipose tissue (AT) is the most important organ in peripheral estrogen synthesis and metabolism in postmenopausal women, and obesity is a risk factor for the development of estrogen-dependent cancers. Enzymes in AT produce biologically active estrogens from circulating precursor steroids. Key enzymes include steroid sulfatase (STS), which hydrolyzes estrone sulfate (E1S) to free estrone (E1), and aromatase, which converts androstenedione to E1, as well as testosterone to estradiol (E2). view more

Background: Adipose tissue (AT) is the most important organ in peripheral estrogen synthesis and metabolism in postmenopausal women, and obesity is a risk factor for the development of estrogen-dependent cancers. Enzymes in AT produce biologically active estrogens from circulating precursor steroids. Key enzymes include steroid sulfatase (STS), which hydrolyzes estrone sulfate (E1S) to free estrone (E1), and aromatase, which converts androstenedione to E1, as well as testosterone to estradiol (E2). STS protein and mRNA have been detected in human adipose tissue, but the activity of STS in the conversion of E1S to E1 in human AT has not been reported previously.
Objectives: We studied the activity of STS in the hydrolysis of E1S to E1 in AT in postmenopausal women, and determined STS and aromatase-encoding CYP19A1 gene mRNA expression levels. We also measured concentrations of E1 in serum and AT.
Subjects and methods: Subcutaneous and visceral AT samples were obtained from postmenopausal women undergoing surgery for non-malignant gynecological reasons at the Helsinki University Hospital (n=30, age 46-80 years, no hormone replacement therapy). We incubated whole AT homogenates with [3H]-E1S, and separated reaction products by hydrophobic column chromatography. [3H]-E1 liberated was determined by liquid-scintillation counting. STS and CYP19A1 mRNA expression levels were quantified by real-time qPCR. Liquid chromatography-tandem mass spectrometry was used to measure E1 concentrations in serum and AT.
Results: We found similar STS activity in subcutaneous (n=24) and visceral (n=21) AT, 4.7 (4.0-6.4) vs. 5.1 (4.2-6.1) nmol/kg adipose tissue/h (median, range). The relative mRNA expression levels of STS and CYP19A1 were higher in subcutaneous (n=16) than in visceral (n=17) AT, 0.30 (0.29-0,47) vs. 0.16 (0.11-0.40), P=0.001 for STS, and 0.23 (0.11-0.49) vs. 0.08 (0.03-0.44), P=0.008 for CYP19A1. E1 concentration was higher in visceral (960 pmol/kg) than in subcutaneous AT (734 pmol/kg, P=0.02) and serum (88 pmol/l, P<0.001). Serum concentration of E1 correlated with both subcutaneous (r=0.67, P<0.001, n=24) and visceral (r=0.69, P<0.001, n=29) AT E1 concentrations. STS mRNA expression correlated positively with E1 concentration in visceral AT (r=0.53, P=0.03, n=17), which in turn correlated with body mass index (BMI) (r=0.40, P=0.03, n=29). Visceral AT STS mRNA expression also correlated positively with serum E1 (r=0.59, P=0.01, n=17).
Conclusions: We show that STS is active in converting E1S to E1 in AT of postmenopausal women. mRNA expression levels of genes coding for key E1-producing enzymes, STS and CYP19A1, were higher in subcutaneous than in visceral AT, but E1 concentration was higher in visceral AT and showed a positive correlation with BMI and also serum E1. This suggests an important role of visceral AT in peripheral estrogen synthesis and metabolism in postmenopausal women.

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