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

Matthew Kirkcaldie Matthew.Kirkcaldie at deletethis.newcastle.edu.au
Mon Oct 13 00:51:08 EST 2003

In article <kofi-68E974.02583311102003 at news04.west.earthlink.net>,
 kofi <kofi at anon.un> wrote:

> I thank you for your reply, but it's left me with still more questions.
> What exactly is going on with drugs like dutasteride and finasteride?  I 
> thought they blocked one or more isoforms of 5AR from converting 
> testosterone to DHT and progesterone to allopregnanolone?  Can you 
> describe their method of action more into layman's terms?

Yep, it's an artificial steroid with structural similarity to the 
substrate of 5-alpha-reductase, such that 5-alpha-reductase binds to it 
as if it was going to do a 5-alpha reduction on it, but is unable to.  
Hence it keeps the usual substrate from being activated by the enzyme.

> Isn't progesterone itself classifiable as a "neurologically active 
> steroid?"

I don't know of direct interactions between progesterone and CNS 
transmitter systems, but that may be ignorance on my part.  I guess it 
has strong trophic actions on the nervous system but that's not the 
usual definition of "neurologically active".

> Not everything that's vulnerable to seizure lies is in the brain.  TMJ 
> pain/myofascial pain is, frankly, not well understood.  Many doctors 
> don't even know it exists and a definition of it wasn't agreed upon 
> until quite recently.  It's common in women and seems to relate to 
> progesterone swings, quite possibly as much due to its effects on joints 
> and collagen than on GABAergic function; I don't know.

The former sounds much more likely to me.

>  It seems to 
> create trigger points - loci of anatomical stress involving bundles of 
> nerve, tendon, muscular and vascular tissue which knot up painfully (and 
> can create some ischemia).  Lidocaine injections - which can bind to 
> GABA receptors - are used as treatments.

Lidocaine is primarily a sodium channel blocker - it prevents sensory 
neurons from making action potentials.  As far as GABA effects go, it 
seems that lidocaine *blocks* GABA receptors and hence *reduces* 
inhibition.  Anyway, it's not that relevant - GABA isn't even present in 
peripheral nerves as far as I know.

>  Glutamate injections into rat 
> masseters can induce TMJ pain.  Trigger points have been experimentally 
> induced with intramuscular injections of bradykinin, histamine, 5-HT, 
> PGE2 and ATP. 

Maybe injections are painful! (sorry)  Point is that all these chemicals 
are known, potent algogens, and activate nociceptors directly, so it's 
hardly surprising that they elicit pain.

> TMJ is known to advance into Parkinson's in severe cases 
> and GABAergic drugs have had limited recent success treating Parkinson's 
> and have long been used in TMJ - although since the associated nerves 
> lie outside the blood-brain barrier, it doesn't seem to have occurred to 
> anyone that GABA per se or a combination of precursor amino acids might 
> serve the same purpose.  

Since GABAergic transmission doesn't occur outside the blood-brain 
barrier, and the trafficking of precursors is tightly regulated, it 
sounds unlikely.  When you say GABAergic drugs, what do you mean?  
Barbiturates?  Benzodiazepines?

The assertion that TMJ pain progresses into Parkinson's is extraordinary 
- what evidence do you base it on?  I can't see how on earth it could 

> Since no one knows what causes myofascial pain, 
> I can't explain the exact role GABA transmission plays or what problem 
> 5AR blockers might pose.  From my own experience, I can say they are a 
> problem.

Well - GABA modulators aren't usually considered to be analgesics, they 
tend to have effects on consciousness (which may reduce the perception 
of pain by dulling the mind) but they don't modulate pain or nociception 
per se, as far as I'm aware.  That system depends on interactions 
between glutamate and substance P transmission, and opioid modulation.

> Mercury poisoning increases glutamate in certain nerves.  Mercury 
> poisoning and autism have overlapping symptoms (see 
> <http://www.autism.org/ari/mercurylong.html>).  I can't draw a direct 
> link between autism, ADHD and glutamate excitotoxicity except to note 
> that many clinicians find GABAergic supplements like glutamine and 
> L-Theanine helpful (see <http://www.dietsexercise.com>).  Many people 
> with TMJ pain complain of symptoms similar to ADHD and benefit from some 
> of the same guidelines.

I think the arguments here are pretty tenuous - if you put your mind to 
it, you can link any phenomena in the nervous system together, because 
by its nature it's integrated across all scales.

> I can even link intestinal candidiasis/leaky gut syndrome too; it 
> impairs glutamine absorption.  Both LGS sufferers and TMJ patients seem 
> prone to frequent sinus infections whose underlying cause is candida 
> albicans, not bacteria.  Administering antibiotics makes the short term 
> problem better and the long term problem worse - especially when more 
> gut colonies of lactobacillus die off.  Both LGS and TMJ can feature 
> sleep disturbances/insomnia, impaired memory, emotional control problems 
> and other issues. 

This is a very very long bow to draw, without any real justification.  
Thing is, if you modulate the intake of the raw material you don't 
necessarily change the rates of synthesis or usage, any more than 
filling the tank of a car with petrol would make it run faster (except 
in the limiting case of running out of fuel).  These systems are tightly 
regulated - the tiniest deviation makes you feel drunk, or go into 
seizure, or whatever.  Dietary supplements are likely to be placebo as 
much as anything, especially when you consider the tight regulation of 
traffic across the blood brain barrier.

Finasteride is not subject to these rules because (a) it interferes with 
last-stage synthesis, not raw materials, and (b) being a steroid, its 
lipid solubility allows it to cross the BBB easily.

> I have no doubt you would not expect to see side effects from low-dose 
> 5AR inhibitors on most people.  However, there are these disorders 
> involving GABAergic signaling - sometimes only in small areas outside 
> the brain - which can be affected (from my own experience it takes a few 
> days or weeks to build).  Who knows?  All of these disorders involve 
> disturbed sleep patterns.  Testosterone supplementation can create sleep 
> disturbances.  5AR inhibition can increase testosterone levels by 20-30% 
> although you would expect general androgen-related stimulation to drop 
> since DHT has a greater affinity for the androgen receptor.  Maybe 
> there's something funny going on there?  My first suspicion is with GABA 
> function, although maybe THDOC is the culprit.  There are plenty of 5AR 
> deficient males.  While they don't get prostate cancer or go bald, I'm 
> not aware of any deficiencies in GABAergic signaling.  Maybe they've got 
> another pathway to take up the slack (3alpha-HSD?).  Maybe there's some 
> other direct function of 5ARs in the nervous system people have missed.

This is more endocrinology and I don't have any useful comment to make - 
it's outside my knowledge.  The term "5AR deficient" doesn't really make 
any sense to me - and how would you characterise "deficiencies in 
GABAergic signaling"?  Continuous seizure?

> It's of particular interest because the other baldness drug, minoxidil, 
> can have effects on GABA too.  It increases intracellular calcium which 
> can induce NMDA-type glutamate receptors to suppress GABA function. 

This is a very odd-sounding effect - if you increased intracellular 
calcium I can't see how NMDARs would suppress GABA receptors - they're 
not even in the same physical location usually.  Neurons maintain an 
amazingly tight control of calcium levels too.

> It 
> comes with a generic warning not to use it if you have ringing in your 
> ears (glutamate, perhaps?). 

Probably hair cells in the cochlea - I would guess upsetting calcium 
balance too much would induce abnormal signalling there.
> While I have you here, can you comment on the impact of insulin 
> resistance and/or proteasome inhibition on GABA receptor function?  
> Insulin resistance increases with age and certain forms of TMJ are more 
> common among diabetics.  I'm looking at proteasome inhibition to pump up 
> some bone morphogenic proteins but I'm concerned about secondary effects.

No idea sorry - why do you want the BMPs to increase?  I would have 
thought it would make the nervous system more plastic, which might make 
it more likely to produce neuropathic pain!

It sounds like you have absorbed a large amount of information and 
cross-linked it, but some of the things you're considering need a little 
more critical thinking.  In many cases the correlation between phenomena 
doesn't imply causation.  The truth is that nobody really knows how pain 
works at the cellular level, or how individual transmitters and 
receptors contribute to behaviour, and anyone who tells you otherwise is 
either ignorant, deluded or operating from an ulterior motive.

> Can you explain how finasteride acts at GABA(A)?  I thought it merely 
> affected it through allopregnanolone/thDOC synthesis?

Yes it does - I was short-cutting to mean that it would affect GABA by 
those means.

>  I'm also curious 
> how alcohol affects GABA.  Does ethanol bind directly?  It's always 
> given me headaches.  

As far as I know ethanol is thought to act at the GABA-A receptor (as 
well as large scale modulatory effects on membranes) but I don't know 
how its activity is achieved.  Try this paper:


> What's the weather like in Newcastle this time of year?  Warming up, I'd 
> imagine?  I had a roommate from there when I was studying at Sydney Uni.

Mixed - I swam in the ocean last weekend but it's been raining off and 
on all week!

Hope this helps.



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