RESUMEN
Epitestosterone is a stereoisomer of the active androgen testosterone and its circulating concentrations are similar to those of testosterone in women and children. However, its biological function and pathways of metabolism remain unknown. The structural similarity to testosterone suggests a potential function in the modulation of androgen receptor signalling. It is well established that the conversion of testosterone to 5α-dihydrotestosterone enhances local androgen receptor signalling. In this study, we show that epitestosterone is metabolized to 5α-dihydroepitestosterone by both human steroid 5α-reductase isoforms, SRD5A1 and SRD5A2. Using two different variations of a reporter assay for transactivation of the human androgen receptor, we show that epitestosterone is a partial AR agonist and that the 5α-reduction of epitestosterone increases its androgenic activity. In line with this, we show that 5α-reduction of epitestosterone reduces its ability to antagonize 5α-dihydrotestosterone-induced androgen receptor transactivation. In conclusion, we provide evidence that steroid 5α-reductases regulate the modulatory effect of epitestosterone on androgen receptor signalling.
Asunto(s)
3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa , Epitestosterona , Proteínas de la Membrana , Receptores Androgénicos , Activación Transcripcional , Humanos , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/genética , Receptores Androgénicos/metabolismo , Receptores Androgénicos/genética , Activación Transcripcional/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Epitestosterona/metabolismo , Dihidrotestosterona/metabolismo , Andrógenos/metabolismo , Oxidación-ReducciónRESUMEN
BACKGROUND: Polycystic ovary syndrome (PCOS) is a common infertility disorder which affects reproductive-aged women. However, metabolic change profiles of follicular fluid (FF) in lean and obese women diagnosed with and without PCOS remains unclear. METHODS: 95 infertile women were divided into four subgroups: LC (lean control), OC (overweight control), LP (lean PCOS), and OP (overweight PCOS). The FF samples were collected during oocyte retrieval and assayed by ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS) metabolomics. RESULTS: A total of 236 metabolites were identified by metabolic analysis. The pathway enrichment analysis revealed that the glycerophospholipid metabolism (impact = 0.11182), ether lipid metabolism (impact = 0.14458), and primary bile acid biosynthesis (impact = 0.03267) were related to metabolic pathway between PCOS and control. Correlation analyses showed that epitestosterone sulfate was found positively correlated with fertilization rate in PCOS, while falcarindione, lucidone C. and notoginsenoside I was found to be negatively correlated. The combined four biomarkers including lucidone C, epitestosterone sulfate, falcarindione, and notoginsenoside I was better in predicting live birth rate, with AUC of 0.779. CONCLUSION: The follicular fluid of women with PCOS showed unique metabolic characteristics. Our study provides better identification of PCOS follicular fluid metabolic dynamics, which may serve as potential biomarkers of live birth.
Asunto(s)
Ciclopentanos , Infertilidad Femenina , Síndrome del Ovario Poliquístico , Embarazo , Femenino , Humanos , Adulto , Líquido Folicular/metabolismo , Nacimiento Vivo , Síndrome del Ovario Poliquístico/diagnóstico , Síndrome del Ovario Poliquístico/metabolismo , Infertilidad Femenina/diagnóstico , Cromatografía Líquida con Espectrometría de Masas , Sobrepeso , Epitestosterona/análisis , Epitestosterona/metabolismo , Cromatografía Liquida , Espectrometría de Masas en Tándem , Fertilización In Vitro , Biomarcadores/análisis , Sulfatos/análisis , Sulfatos/metabolismoRESUMEN
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Previous studies with different results have suggested that total and bioavailable testosterone levels are modified by physical exercise. Such changes may be related to modifications in cortisol levels and could be reflected in some urine androgens. To determine how weight lifting training may affect serum and urinary androgens, we measured total serum testosterone (T), cortisol, sex hormonebinding globulin (SHBG) and urinary testosterone, epitestosterone, androsterone, and etiocholanolone, in a group of 19 elite weight lifters after 20 weeks of training. SHBG increased (from 27.5 ± 9.5 to 34.7 ± 8.1 nM, p < 0.05) whereas T/SHBG decreased significantly (from 1.10 ± 0.4 to 0.85 ± 0.3, p < 0.05). Serum total testosterone and cortisol did not change significantly. In urine, androsterone and etiocholanolone decreased significantly, whereas testosterone and epitestosterone remained unchanged. Changes in T/SHBG were related positively with changes in urinary androgens (r = 0.680, p < 0.01), and changes in SHBG were negatively related with changes in urinary androgens (r = −0.578, p < 0.01). These results suggest that intense physical activity may have an influence on the elimination of androgenic hormones due mainly to changes in their transporting protein SHBG (AU)