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Title: Factors affecting oestrogen action in the human prostate : does 5α-reductase type 1 isozyme have a role?
Author: Ho, Clement Kam Man
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2002
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The hypothesis that 5αR1 plays a role in the regulation of aromatase activity by limiting substrate availability to the latter in the human prostate was tested in a co-transfection model and in primary cultures of prostatic cells. In COS-1 cells transiently co-transfected with plasmids encoding 5αR1 and aromatase, inhibition of 5αR1 led to an increase in aromatase activity but not vice versa. This pattern of interaction between the two enzymes was also shown to occur with endogenous enzymes expressed in primary cultures of prostatic fibroblasts. No aromatase activity was detectable in epithelial cells. By regulating aromatase activity, 5αR1 may therefore contribute to the local control of oestrogen concentration within the prostate gland. In this study, prostatic cells were revealed to be oestrogen target cells, not only expressing mRNAs of both subtypes of oestrogen receptor (ERα and ERβ) but also responding to oestradiol with increased proliferation rtes. This oestrogen stimulation of proliferation was antagonised by the antioestrogen ICI 182,780. Moreover, prostatic fibroblasts aromatised androgen substrates to oestrogens (oestrogens formation). Both fibroblast and epithelial cell cultures also converted oestradiol to oestrone (oestrogen catabolism) but not vice versa. Primary cultures of prostatic cells therefore responded to oestrogen stimulation and expressed major components for oestrogen action including oestrogen receptors and oestrogen-metabolising enzymes; they would serve as a useful model to further study oestrogen action, regulation and signalling pathways in the prostate. In addition to the above enzyme inhibitors, the effects of Permixon® (a phytotherapeutic agent for the management of prostatic hyperplasia) were investigated. The mechanism of action of Permixon® is not entirely clear; however, in previous studies in inhibited both 5α-reductase isozymes in prostatic cells. Permixon® was herein shown to have oestrogenic properties. It not only indirectly increased aromatase activity in fibroblasts by inhibiting 5αR1, but also inhibited the conversion of oestradiol to the weaker oestrogen oestrone. It is therefore conceivable that Permixon® exerts its therapeutic effects by affecting the metabolism of both androgens and oestrogens within the human prostate.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available