Estrone-3-Glucuronide (E1G) [BSA]

Changes in the disposition of estradiol 17 beta-D-glucuronide (E(2)17G), a substrate of the organic anion-transporting polypeptide family (Oatp) and multidrug resistance-associated protein 2 (Mrp2), were examined in livers of male Wag/Rij rats that were injected with CC531 cells intraportally to induce metastatic tumors (n = 5) or with phosphate-buffered saline for shamoperated controls (n = 4). Multiple indicator dilution, single-pass liver perfusions revealed extremely high influx clearances of [H-3]E(2)17G (> 190 ml/min) in both groups. In recirculating liver perfusions, [H-3]E(2)17G decayed monoexponentially in the reservoir perfusate, and the total (9.19 +/- 1.33 versus 8.18 +/- 0.94 ml/min) and biliary (4.94 +/- 1.07 versus 4.60 +/- 0.86 ml/min) clearances were similar in both groups (P > 0.05). The metabolic clearance of E(2)17G was higher in the tumor group (4.60 +/- 0.64 versus 3.23 +/- 0.23 ml/min, P < 0.05). E(2)3S17G, the 3-sulfate metabolite, whose identity was confirmed by mass spectrometry, appeared only in bile and not perfusate. Liver microsomal incubations of E(2)3(35)S17G and [H-3] estrone sulfate revealed similar sulfatase activities between the tumor and sham livers, albeit the activities were much lower for E(2)3(35)S17G. Oatp1a1 and Oatp1b2 protein expression in liver membrane fragments was reduced by 42% and 38%, respectively, whereas that of cytosolic estrogen sulfotransferase (Sult1e1) was significantly increased (41%) with tumor (P < 0.05). All of the observations were captured by modeling. From modeling, we showed that reduction of the high influx clearance (546 to 283 ml/min) failed to lower the total clearance of E(2)17G, whereas up-regulation of Sult1e1 increased the E(2)17G sulfation clearance (2.56 to 3.69 ml/min) in livers with metastatic tumors.

The effects of four low doses of synthetic steroids, administered orally and starting on day 8 (group I) or on day 10 of the menstrual cycle (group II), upon LH surge, ovarian steroidogenesis, follicular maturation and menstrual cycles were studied in 10 eumenorrheic women. The results revealed that the day before the LH surge, the highest level of estrone-3-glucuronide was observed in both groups. Twenty-four hours after the last dose, the maximum urinary LH levels were recorded in groups I (day 11), and II (day 13). Pregnanediol-3 alpha glucuronide remained low during the study in group I, whereas in group II a gradual rise of this hormone starting on day 13 was registered and the highest level was found at day 21 of the menstrual cycle. Follicular maturation and ovulation were observed only in women from group II. Short and normal length cycles were recorded in groups I and II, respectively. In summary, low doses of exogenous synthetic steroids administered on day 8, but not on day 10 of the cycle, inhibit follicular maturation and ovulation.