[Tiuri]

Hier wel een aardig verhaal over de mogelijke bijwerkingen van fina en duta zoals hier eerder besproken. Het aardige is dat dit verhaal is onderbouwd met onderzoekjes die zijn terug te vinden op PubMed.

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 animal's 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 (DOC) 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.

While dietary factors like fat and sugar consumption are important, the major actor on DHT throughout our evolutionary history has been a substance called equol. Equol is a derivative of the soy metabolite daidzein produced by bifidus bacteria in the gut. It directly binds to dihydrotestosterone and deactivates it [PMID 14681200]. Most male mammals produce ample amounts of equol to regulate excessive DHT production. High levels of equol in men lowers the risk for prostate cancer [PMID 14681200, 14720329] and improves blood cholesterol [PMID 14679315].

By taking antibiotics, you usually increase your risk for chronic inflammatory disorders. In this case, killing your gut bacteria leaves abnormally high levels of free DHT floating around in your blood stimulating your androgen receptors beyond what your body is used to. Over a lifetime, this brings out your genetic risk for androgen-driven disorders like the ones I keep mentioning. Destroying your gut bacteria with antibiotics probably also increases the risk for allergies, asthma, arthritis and other inflammatory disorders (see <http://www.sciencedaily.com/releases/2004/07/040723091648.htm>, <http://www.newscientist.com/news/news.jsp?id=ns99995047>, PMID 15120189) - not to mention it can give you a bad yeast infection like you see in chronic sinusitis.

How can you obtain equol if you no longer make your own?

That's the problem. You can't. The only versions manufactured and sold today are racemic - meaning both the left and right isomers of the molecule are produced in a mixture. Only one form is naturally made and used in the human body. The other is not well studied. Another limiting factor is that finasteride and dutasteride are patented while equol can't be - it's a natural product which has been around too long. Contact manufacturers and let them know there is a market for this therapeutic substance and that it's worth conducting clinical trials.

If 5AR inhibitors do pose long term risks and you absolutely have to take them, it may be possible to lessen the neurological damage with things like acetyl-l-carnitine, minocycline, l-theanine, taurine, curcumin, green tea (EGCG), CoQ10, nicotinamide/niacinamide, creatine, ketogenic diets, so on and so forth (each of which carries with it its own complicating factors).

If this information has in any way improved your medical care, please consider voting for John Kerry.

- Your amazing one and only crime-fighting/medical-spelunking UN secretary general Kofi Anon

Bron: http://www.hairlosstalk.com/discussi...ic.php?t=15103