Estradiol replacement inhibits increased expression of Cyp17a1 mRNA in residual ovarian tissue of VCD‐treated follicle‐depleted mice

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Cyp17a1 encodes the protein responsible for production of androstenedione (A) and it has been proposed to be negatively regulated at the mRNA level by estradiol (E2) via estrogen receptor alpha in a local negative feedback loop. Enriched expression of Cyp17a1 mRNA has been observed in residual ovarian tissue of an ovary‐intact mouse model of menopause (VCD‐treated mouse) when compared to cycling controls. This study was designed to test the hypothesis that increased expression of Cyp17a1 in VCD‐treated follicle‐depleted ovaries can be reversed by replacement with E2. Female B6C3F1 mice (age d28) were dosed daily (17d; i.p.) with sesame oil (n=5) or VCD (160mg/kg; n=5). On day 19 after the onset of dosing a group of VCD‐treated mice received subcutaneous E2 implants (VCD/E2 mice; 180 μg/ml; silastic) which were replaced on d47, 75, 103 and 131. Ovaries and blood were collected on d188 and processed for analysis by real‐time PCR and measurement of circulating E2, A and E1 (estrone). Relative to VCD‐treated mice, ovarian Cyp17a1 mRNA was lower (VCD/E2: 2.44±0.35/control; VCD: 8.97±0.14/control; P<0.05) in VCD/E2 mice but remained higher (P<0.05) than in controls. Circulating A and E1 were decreased (P<0.05) in VCD/E2 mice when compared to VCD‐treated and cycling controls, whereas, levels of E2 did not differ between groups (P>0.05). These results provide evidence that E2 replacement decreases expression of Cyp17a1 mRNA in residual ovarian tissue of VCD‐treated mice which results in a decrease in levels of circulating A and E1. (AG021948)