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

kofi kofi at anon.un
Sat Oct 11 02:57:42 EST 2003

> In article <kofi-C3FEF6.14043508102003 at news03.west.earthlink.net>,
>  kofi <kofi at anon.un> wrote:
> > If someone with some form of TMJ, attention deficit or glutamate 
> > excitotoxicity experienced a severe worsening of symptoms when taking a 
> > 5AR inhibitor, would you attribute that then to some neurological 
> > function performed by 5AR itself?
> It's not a 5AR inhibitor - it's a competitive inert substrate.  That is 
> to say it attenuates the 5-alpha-reduction process needed to convert the 
> inactive to the neurologically active steroid.  So I would attribute 
> that to changes in active steroid levels, but I think they would need to 
> be gross before it would be allowed to produce enough disruption to 
> seize.

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?  I've 
consulted with two practicing neurologists and was underwhelmed at their 
lack of knowledge.

Isn't progesterone itself classifiable as a "neurologically active 

> I'm not at all sure what you mean by grouping "TMJ, attention deficit or 
> glutamate excitotoxicity" there - I don't know what TMJ is, aside from 
> the temporo-mandibular joint; I know of no link between ADD and 
> glutamate or GABA modulation; and "glutamate excitotoxicity" refers to 
> cell death triggered during brain ischaemia as far as I know.  Why do 
> you specifically refer to these as if they were at particular risk for 
> finasteride side effects?

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.  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.  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.  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 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 

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 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.  I posted a question about progesterone replacement on 
a candidiasis list and got some interesting feedback.  Some of the women 
even had TMJ problems.  Of course, it's all a lot more complex than just 
inhibition.  (Blame GABA.  Sounds like a new _Southpark_ song poking fun 
at '70s supergroups, doesn't it?)

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.

The whole thing confuses me and I'm simply trying to sort it out.

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.  It 
comes with a generic warning not to use it if you have ringing in your 
ears (glutamate, perhaps?).  Of particular worry for sufferers of TMJ, 
minoxidil upregulates VEGF - arguably the worst angiogenic factor you 
can use to replace ephrin (baldness is a form of osteoporosis which 
occurs when an overactivated androgen receptor produces too much TGF-B 
and somehow knocks out ephrin and BMP-7 expression).  As a form of 
arthritis, TMJ pain is sustained, in part, by VEGF overexpression.  The 
joint pain disturbs sleep and nearby nerves, etc., etc.

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.

>> I have communicated with people who took even low dose finasteride 
> > experienced, consistently, very palpable differences in the way they 
> > felt while drinking.
> I can certainly believe this - both substances act at the GABA-A 
> receptor, and the phenomenon of being drunk shows just how little the 
> system needs to be perturbed in order to feel very weird indeed.  If 
> you're simultaneously altering the levels of another substance acting at 
> the same receptor, I would expect strong subjective differences in the 
> experience.  Alcohol and allopregnanolone would interact differentially 
> depending on the subunit composition of the receptor itself (i.e. the 
> different variants of the elements forming the channel).  In that case, 
> changing both factors simultaneously would have different effects in 
> different parts of the brain (e.g. synergistic inhibition in one region, 
> partial antagonism in others) and would alter the sensation hugely I 
> think.

Can you explain how finasteride acts at GABA(A)?  I thought it merely 
affected it through allopregnanolone/thDOC synthesis?  I'm also curious 
how alcohol affects GABA.  Does ethanol bind directly?  It's always 
given me headaches.  The only research I've been able to find indicates 
it lowers the threshold of Substance P release from vanilloid receptors 
- another substance not to mix with TMJ.  I had thought it acted through 
this avenue to aggravate neuralgia.  (Also had some strange ups and 
downs on DHEA, but I won't go into it.)

> An interesting conversation - why are your posts anonymous, by the way?

I post in less friendly places on the internet sometimes frequented by 
your more irritable, obsessive-compulsive personalities - hence my 
interest in inhibition.

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.

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