Allopregnenolone (synthesized from 5AR) may prevent neurodegeneration
Kofi kofi at anon.un
Wed Aug 11 19:26:31 EST 2004
The latest research in mice raises a disturbing question about the
safety of FDA approved 5AR inhibitors like finasteride
(Proscar/Propecia) and especially dutasteride (Avodart) when it comes to
managing long-term risk for neurodegenerative diseases like Alzheimer's.
This is because these drugs not only reduce levels of DHT but also wound
allopregnanolone production in the process.
To summarize the new findings on allopregnanolone (see attached below),
Niemann-Pick type C is a rare lysosomal storage disorder/childhood
neurodegenerative disease in which brain cells accumulate fat and die
due in part to severely disrupted neurosteroidogenesis. A mutant gene
for lysosomal acid sphingomyelinase disturbs cholesterol synthesis
throughout the body and results in the accumulation of sphingomyelin.
Progressive loss of neurosteroid synthesis may contribute to
neurodegeneration. Replacing lost allopregnanolone substantially
increases the survival of mice with this type of disease by mitigating
the damage and delaying the onset of symptoms. Results were best when
administered as early as possible in the animal¹s life.
Allopregnanolone may be effective with managing other neurodegenerative
disorders. Other important neurosteroids like pregnenolone are also
diminished in Niemann-Pick type C but what's interesting here is how
valuable allopregnanolone is by itself.
<http://www.sciencedaily.com/releases/2004/07/040713082347.htm>. NPC
model mice may have amyloid-beta accumulations similar to those in
Alzheimer's [PMID 14982851, 14982829] and may represent a good model for
studying general aspects of neurodegeneration.
5 alpha reductase (5AR) is an enzyme which comes in two forms, type I
and type II. It not only converts testosterone (T) to
dihydrotestosterone (DHT, a ketone), it also converts progesterone to
allopregnanolone and deoxycorticosterone (Doctor) to tetrahydroDOC (THDOC),
both allosteric enhancers of the GABA(a) receptor (e.g., they increase
the effectiveness of inhibition signals relayed along GABA channels in
nerves). The second stage of this conversion is performed by
3alpha-hydroxysteroid oxidoreductase.
This pathway has widespread influence in the body. Progesterone is the
precursor to allopregnanolone. Monthly drops in women¹s progesterone
prior to their periods is a factor in PMS and epileptic seizure.
Progesterone lozenges ameliorate seizures. Both estrogen and
progesterone are important for TMJ remodeling [PMID 10670598]. Men with
epilepsy can benefit from aromatase inhibitors which block the
conversion of testosterone to estrogen via aromatase [PMID 15123030].
Allopregnanolone can block cocaine induced seizures [PMID 12921865].
Complete 5AR inhibition shortens inhibitory currents in GABA(A) channels
both via allopregnanolone [PMID 12559121] and
5alpha-dihydrocoticosterone (THDOC) [PMID 11978855].
SSRIs (antidepressants like Zoloft) have been shown to upregulate levels
of progesterone and allopregnanolone (THP) [PMID 12957330] as well as
neurogenesis [PMID 14872203, 15001810, 14512209]. In animal models it¹s
the hippocampal neurogenesis that accounts for the behavioral effects of
SSRIs [PMID 12907793]. Conversely, inescapable stress which reduces
hippocampal neurogenesis also causes depression [PMID 12838272].
Levels of allopregnanolone can also be regulated by 3alpha-HSDs
(3alpha-hydroxysteroid dehydrogenase) - enzymes which are identical in
function to 5AR, except they convert T back from DHT instead of the
other way around. 3alpha-HSDs are responsible for downregulating levels
of DHT in the prostate and unusual inhibition of 3alpha-HSD would
increase DHT levels, decrease allopregnanolone and incline a male toward
impaired GABA functioning, acne, baldness, BHP and prostate cancer.
Stimulating 3alpha-HSD might be more effective than 5AR inhibition for
treating androgen disorders (although elevated exposure to either
progesterone or allopregnanolone can become anxiety-provoking instead of
calming; there are gender differences to this effect [PMID 12606703]).
Certain synthetic progesterones may interfere with allopregnanolone
synthesis. Medroxyprogesterone acetate (MPA), an ingredient in some
birth control pills and hormone replacement therapies, doesn¹t convert
into allopregnanolone and causes anxiety, aggression and depressed sex
drive in mice compared to combinations of natural hormones
<http://www.sciencedaily.com/releases/2004/06/040608065645.htm>.
This overview should drive home just how important allopregnanolone may
be to human health. Finasteride is a 5AR type II inhibitor which
reduces DHT levels by up to 70%. Dutasteride inhibits both type I and
type II 5AR achieving a reduction of up to 94% of DHT. Type I is the
only 5AR expressed in the brain. Its long term inhibition was never
studied when dutasteride was approved by the FDA. Blocking DHT
synthesis in the brain like this also blocks allopregnanolone production
there. While other tissues like bone also express 5AR, finasteride has
been specifically studied on bone growth and has had no effect. Will
this also be true for neurodegenerative disorders which take decades to
develop? Will 5AR inhibitors be safe for individuals with epilepsy,
TMJ, neuropathy, alcoholism, tinnitus, metals poisoning or other
GABAergic illnesses?
If it's true that dramatic 5AR inhibition contributes to long term
neurodegeneration then what other therapeutic agents are available for
dealing with excessive DHT?
Understanding why male hormonal disorders like BHP, prostate cancer and
baldness have become common in "advanced" economies is important to
answering this question. One contributing factor is the bad mix of fats
consumed in the American diet (high in trans-fats, hydrogenated oils,
bad omega-6 and -9's and low in omega-3). Another factor is high
glycemic index diets which contribute to insulin resistance and androgen
signaling disorders like polycystic ovarian syndrome. High levels of
insulin lower levels of sex hormone-binding globulin, a substance which
binds to testosterone and lowers the amount of "free" androgens
available to bind to the receptor (see [PMID 14527633],
<
http://www.thepaleodiet.com/articles/acne vulgaris.pdf> ). These
androgen driven disorders are all complex genetic disorders which can
develop from many different angles. For instance, in a small study,
prematurely balding men could be divided into two groups: the first
group (about a third of the men) had a hormonal/insulin profile similar
to women with polycycstic ovarian syndrome (low SHBG, hyperinsulemia,
high free androgens and insulin resistance) whereas the second group had
no similarities or only lower SHBG [PMID 15209536]. How you react to
pathologically elevated levels of DHT is determined by your genetic risk
and your environment.
------------------------------------------------------------------
This sh*t is real ? were going dumb on fina or duta
