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Could a male fertility pill adversely affect inhibition via allopregnanolone levels?

Matthew Kirkcaldie Matthew.Kirkcaldie at deletethis.newcastle.edu.au
Tue Oct 7 21:40:44 EST 2003

Just a comment - our lab works with allopregnanolone and we 
pharmacologically inhibit its synthesis by administering the competetive 
substrate finasteride (it outcompetes 5-alpha-dihydroprogesterone, the 
natural substrate of 5-alpha-reductase, which is the final synthetic 
step in making allopregnanolone).

At physiologically effective doses the finasteride is capable of 
inducing seizures by upsetting the GABA-glutamate balance in the cortex.  
However, you have to push the system hard to do this.

My impression is that the synthesis and activity regulation of 
allopregnanolone is of sufficient potency with regard to balancing 
inhibition and excitation, that it is likely to be controlled very 
tightly.  Although it hasn't been shown directly for allopregnanolone, 
the processes of sulfation and desulfation are able to regulate 
neurosteroid actions in a manner directly comparable to phosphorylation 
for proteins, and I would suspect that there is a large pool of 
deactivated allopregnanolone sulfate in the cell body, of which a minute 
proportion is activated at any given time.  In fact I presented this 
hypothesis with some preliminary immunohistochemical data at the 
Australian Neuroscience Society meeting in January this year (in 
conjunction with Yuri Saalman who did the initial assays).

So I don't think it's of immediate concern - finasteride has been used 
clinically for baldness for some time without reports of side effects, 
and it's a direct blocker of allopregnanolone synthesis at high levels.  
A competitor for progesterone is one synthesis step further up the chain 
and hence one order of magnitude less likely to interfere with 
allopregnanolone synthesis on demand, especially if the active pool is 
determined by a sulfation / desulfation equilibrium.

Hope that's a useful comment.



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