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[tryingnottoworry]

Ok there's a serious lot to it. I'm not prepared to steal all his stuff, here is an extract from a study:...

...There is MUCH more but it's not my place to take it, guys.

Honestly I don't mind at all if you tell other people about it, my only goal is to help people who are suffering from this. Now keep in mind that this is still a work in progress so to speak, and proper research still has to be performed before we can begin to draw conclusions. I'll be keeping the propeciahelp.com thread updated regularly, with the most relevant data on the first post of the Dolichol Deprivation Theory. If possible, please try to follow it there (I'll be adding a FAQ soon). Here's what I currently have there now:

The Dolichol Deprivation Theory

What is the dolichol deprivation theory? It is the theory that our syndrome is caused by the inhibition of SRD5A3 (in addition to SRD5A2) by finasteride, dutasteride, and/or saw palmetto.

5 alpha reductase type 3 (SRD5A3) and its function was recently discovered, and it was also discovered only last year that finasteride inhibits SRD5A3 about the same as 5 alpha reductase type 2. SRD5A3's primary function is to synthesize a special sort of alcohol called "dolichol" which is used in protein folding within the endoplasmic reticulum of cells for the very beginning stages of glycosylation, and also has a role in DHT production. Glycosylation is an extremely important cellular process which is both upstream and the precursor to proper function of the higher functions of the body (including thyroid function, liver function, hormone function, and many more). Disruption of the glycosylation process can affect almost every system in the body, and can cause a cascade reaction causing a multitude of system-wide dysfunctions, including endocrinopathies (dysfunctional endocrine system), secondary hypogonadism, small testicles, muscle weakness, muscle atrophy, poor motor skills, stroke-like episodes (e.g. brain fog), cognitive impairment, speech difficulties, vitamin D deficiency, and many more.

Until we have a proper laboratory study performed, we won't know exactly how SRD5A3 inhibition by finasteride ultimately affects us, but based off of research currently available, it may potentially happen like this: Finasteride inhibits 5 alpha reductase type 3 > Inhibited SRD5A3 inhibits dolichol production > Endoplasmic Reticulum becomes stressed due to incompetent protein folding due to dolichol deprivation > ER initiates the Unfolded Protein Response due to overwhelming stress caused by too many unfolded proteins > UPR causes upregulation of gene expressions associated in dolichol production (such as the GlcNAc-1-P transferase (GPT) gene) > overexpressed GPT gene hinders Lec35 gene product (Lec35p) > hindered Lec35p causes inefficient utilization of dolichol (yet dolichol and Lec35p levels remain normal) > inefficient utilization of dolichol stresses the ER and continues the loop > this causes a psuedo-congenital disorder of glycosylation.

5 alpha reductase type 2 has been, for the longest time, the focal point of our research and understanding of PFS, but it isn't until now that we can see the effects of inhibiting 5 alpha reductase type 3. Unlike what most other theories suggest, a glycosylation disorder would be our "root" cause, as it is upstream of basically every higher function in the body, including cortisol production, thyroid function, liver function, hormone function, and nearly everything else. Every other theory may address the cause of our symptoms, but what's causing the cause? Understanding the effects of the inhibition of SRD5A3 through the actions of finasteride may be the key to understanding the scope of the post finasteride syndrome.


Relevant Scientific Research

Human type 3 5?-reductase is expressed in peripheral tissues at higher levels than types 1 and 2 and its activity is potently inhibited by finasteride and dutasteride

We found that SRD5a-3 is highly sensitive to finasteride and dutasteride and shows similar sensitivity as SRD5a-2 for finasteride, while it is much more sensitive to dutasteride. The enzyme is highly expressed in the human skin, brain, mammary gland and breast cancer cells. Our data strongly suggest that SRD5a-3 could be the main enzyme responsible for 5areductase activity, previously believed to be associated with SRD5a-1, in many tissues and cell lines.

SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder.

We found that SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols, required for synthesis of dolichol-linked monosaccharides, and the oligosaccharide precursor used for N-glycosylation. The presence of residual dolichol in cells depleted for this enzyme suggests the existence of an unexpected alternative pathway for dolichol de novo biosynthesis. Our results thus suggest that SRD5A3 is likely to be the long-sought polyprenol reductase and reveal the genetic basis of one of the earliest steps in protein N-linked glycosylation...

Dolichol Inhibition

Dolichols are isoprenoids synthesised from mevalonate. They are vital to the process of Glycoprotein formation in the endoplasmic reticulum of cells. In this capacity it is critical to the formation of the Glycoproteins involved in neuropeptides, cell identification, cell messaging and Immunodefence. Reduced bioavailability of dolichols can affect every cellular process in the body.
Potential side effects from altered glycoprotein synthesis include impairment of DNA error correction, dysfunction of almost any cellular process, altered cell identification, altered cell messaging, and altered immunodefense.

Unexpected Basis for Impaired Glc3Man9GlcNAc2-P-P-Dolichol Biosynthesis by Elevated Expression of GlcNAc-1-P Transferase

By compensatory overexpression of Lec35p, G3M9Gn2-P-P-Dol synthesis in GPT overexpressers could be restored. However, GPT overexpression did not affect the levels of Lec35 mRNA or protein. These results suggest that GPT may impair Lec35p function, and imply that upper as well as lower limits on GPT expression exist in normal cells. Since the mammalian GPT gene can undergo spontaneous amplification, the data also indicate a potential basis for forms of pseudo-CDG-If...

...In humans, this might be predicted to cause a nonheritable pseudo-CDG-If mosaic phenotype. These would escape detection by standard sequence-based screening of blood cells of unclassified CDG-I patients because the phenotype would not necessarily be expressed in blood cells, and sequences of GPT DNA and RNA would appear normal.

Inherited Glycosylation Disorder: Researchers Find Cause of Metabolic Disease -- And Possible Cure

Writing in the July 15 online edition of the journal Cell, Joseph G. Gleeson, MD, professor of neurosciences and pediatrics at UC San Diego, with Lihadh Al-Gazali, a professor of pediatrics and pathology at United Arab Emirates University, and colleagues discovered that the gene SRD5A3 is responsible for the synthesis of a lipid used by cells as a sugar carrier for protein glycosylation -- a complicated, multi-part process in which proteins are modified by the addition of a sugar or sugar chain. Without the added sugars, proteins do not fold or fold incorrectly, resulting in dysfunction and disease...

..."The key was identifying the enzyme's role in producing dolichol. This is the basic step that is blocked in our patients, and the disease is the result. Our idea is that if you feed these patients dolichol, that might just treat the condition. It would be similar to giving insulin to diabetics. It's a simple solution, but one nobody had thought of."...

...Currently, artificially produced dolichol is very expensive, mostly because there hasn't been much demand for it, but the researchers note that the compound is naturally abundant in some plants, such as the gingko or maidenhair tree and spinach. "Ginkgo is already the source of a lot of compounds, so getting dolichol might just mean another step in the extraction process. After that, you could develop a pill that patients could take as a supplement to their diet."

Glossary:

SRD5A1- Steroid 5-alpha-reductase type 1, also known as 5AR1. This enzyme converts testosterone into dihydrotestosterone (DHT), and is weakly inhibited by Finasteride.

SRD5A2 - Steroid 5-alpha-reductase type 2, also known as 5AR2. This enzyme converts testosterone into dihydrotestosterone (DHT), and is potently inhibited by Finasteride.

SRD5A3 - Steroid 5-alpha-reductase type 3, also known as 5AR3. This enzyme converts polyprenol into dolichol for use in N-Glycosylation, and also has a role in DHT production. SRD5A3 is potently inhibited by Finasteride.

Finasteride - Designed to be a SRD5A2 inhibitor, it was recently discovered to also potently inhibit SRD5A3.

Dutasteride - Designed to be an SRD5A1 and SRD5A2 inhibitor, it was recently discovered to inhibit SRD5A3 with extreme potency, roughly 50 times more than finasteride.

Saw Palmetto - A natural SRD5A1 and SRD5A2 inhibitor. Due to a lack of research it is unknown to what extent saw palmetto has on SRD5A3, but due to it's similarity to the actions of dutasteride (though much weaker), it is likely to inhibit SRD5A3 at least as much as finasteride, if not more.

Ropren - An experimental Polyprenol/Dolichol supplement.

Polyprenol - A type of alcohol, and the precursor to dolichol. Polyprenol is converted into dolichol by SRD5A3.

Dolichol - A type of alcohol, and a necessary component of N-Glycosylation. Dolichol synthesis is dependent on the functionality of SRD5A3, and the depletion of dolichol leads to the disruption of glycosylation and subsequent diseases.

Glycosylation - is the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules. This enzymatic process produces one of the fundamental biopolymers found in cells (along with DNA, RNA, and proteins). Glycosylation is performed in several stages, such as N-linked and O-linked glycosylation. Disruption of glycosylation leads to congenital disorders of glycosylation (CDG), and near or complete shut down of glycosylation is lethal.

N-linked Glycosylation: Also known as N-Glycosylation, and is the beginning step in glycosylation, and is involved with folding eukaryotic proteins. N-Glycosylation occurs within the endoplasmic reticulum (ER) of cells.

O-linked Glycosylation: Also known as O-Glycosylation, and is the next phase of glycosylation, after N-Glycosylation. O-Glycosylation occurs within the golgi apparatus.

Glycoproteins - The product of glycosylation, glycoproteins are proteins that contain oligosaccharide chains (glycans) covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification.

Endoplasmic Reticulum (ER) - The ER is a eukaryotic organelle that forms an interconnected network of tubules, vesicles, and cisternae within cells. Rough endoplasmic reticula synthesize proteins, while smooth endoplasmic reticula synthesize lipids and steroids, metabolize carbohydrates and steroids (but not lipids), and regulate calcium concentration, drug detoxification, and attachment of receptors on cell membrane proteins.

Golgi Apparatus - The Golgi Apparatus (also Golgi body or the Golgi complex) is an organelle found in most eukaryotic cells. It processes and packages macromolecules, such as proteins and lipids, after their synthesis and before they make their way to their destination; it is particularly important in the processing of proteins for secretion. The Golgi apparatus forms a part of the cellular endomembrane system.

Congenital Disorders of Glycosylation (CDG) - A CDG is one of several rare inborn errors of metabolism in which glycosylation of a variety of tissue proteins and/or lipids is deficient or defective. The majority of CDGs are caused by a disruption in the dolichol pathway.

Pseudo CDG - An non-inheritable acquired version of a CDG. While not a true CDG, it may share many of the same characteristics.

The Unfolded Protein Response (UPR) - The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum. It is a stress response that has been found to be conserved between all mammalian species, as well as yeast and worm organisms. The UPR is activated in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum. In this scenario, the UPR has two primary aims: initially to restore normal function of the cell by halting protein translation and activate the signaling pathways that lead to increasing the production of molecular chaperones involved in protein folding. If these objectives are not achieved within a certain time lapse or the disruption is prolonged, the UPR aims to initiate programmed cell death (apoptosis).

GlcNAc-1-P transferase gene (GPT) - GPT catalyzes the first and committed step in the dolichol cycle, thus playing a fundamental role in the pathway for protein N-glycosylation. It also has upper and lower limits of expression, and if overexpressed, has the potential to hinder Lec35p.

Lec35 gene product (Lec35p) - Lec35p required for utilization of the mannose donor mannose-P-dolichol (MPD) in synthesis of both lipid-linked oligosaccharides (LLOs) and glycosylphosphatidylinositols, which are important for functions such as protein folding and membrane anchoring, respectively. Hinderance of Lec35p can cause a psuedo-CDG which is undetectable by conventional CDG blood screening.

Spinach - A delicious dark green leafy vegetable rich in dolichol.


The Spinach Diet

This is the first treatment based off of the dolichol deprivation theory. If the inhibition of SRD5A3 (and subsequent dolichol deprivation) was indeed what caused our syndrome, then by increasing our dolichol levels the point of overcompensating, we could theoretically lessen the stress on the ER. If the stress on the ER caused a UPR to induce a persistent overexpression of the GPT gene, then by lessening the stress on the ER, it could potentially convince the ER to cause a persistent normal expression of the GPT gene, which could potentially lead to the resolution of our syndrome. Unfortunately the only dolichol supplement currently available "Ropren" is extremely expensive and not readily available, so we would have to seek an alternative source. Spinach is one of the few natural sources of dolichol, so the spinach diet treatment was formed.

If you would like to try the spinach diet, here's what you'll need to do: Eat a bag (about 170g) of raw uncooked spinach a day, every day. If possible, get organic spinach. Continue eating your spinach once a day for at least a month. When you decide to start weening off, eat about 3/4th of a bag for about 4 days, then 1/2 a bag for 4 days, then 1/4th for 4 days, and finally 1/8th for 4 days.

Keep in mind that everyone's body is different, so don't go into this expecting a miracle. To put it in perspective, it's trying to treat a supposed glycosylation disorder with food. There is evidence that it has the potential to help, but it all comes down to how your body was broken, and what it needs to be fixed.

If you have any questions I'd be happy to answer them to the best of my ability, but I'd prefer it if you asked them on the propeciahelp.com site, as I'd really like to keep things consolidated (but I'll do my best regardless).

Praying for you all,
-TNTW

 

[Mens Rea]

BTW is the supplement called Ropren? Apparently that's a new medication coming out of Russia that supplements Dolichol, and is used to treat some mental disorders and liver problems. One website said Dolichol is found in high quantities in the testicles... The dude on propeciahelp that figured all this out is one smart cookie. I didn't even know a 5AR Type-3 existed.

Yes, i believe that is the drug. It's very expensive.




TNTW: Thanks for that post man I'm sure this readers on this forum really appreciates you chimeing in. unk:

 

[Wuffer]

Thanks for posting TNTW.

Even as the resident antagonistic PFS critic, your theories are very intriguing to me. Do you have a medical/scientific background?

Just a suggestion, if a larger amount of Dolichol is desired, it might be effective to boil several bags of it, strain and discard the spinach, then drink the broth. The broth could be reduced by further boiling, and the liquid could be consumed throughout the day which would make it more convenient than eating that much spinach. However, I’m not sure how effective boiling would be to extract the desired Dolichol, but I know this method works for extracting DIM from Brocolli.

Do you know why your thread blocked from being viewed by non-propeciahelp members? I think what you have posted there is very important and shouldn’t be blocked from non members. I’m not personally registered there because I’m not a PFS sufferer, but I’m still very interested in following your thread.

 

[tryingnottoworry]

Thanks for posting TNTW.
Even as the resident antagonistic PFS critic, your theories are very intriguing to me. Do you have a medical/scientific background?

No medical background, just very dedicated. Everything is based on laboratory research studies. A human cellular biologist would be the most relevant medical profession for understanding the effects of SRD5A3 inhibition.

Just a suggestion, if a larger amount of Dolichol is desired, it might be effective to boil several bags of it, strain and discard the spinach, then drink the broth. The broth could be reduced by further boiling, and the liquid could be consumed throughout the day which would make it more convenient than eating that much spinach. However, I’m not sure how effective boiling would be to extract the desired Dolichol, but I know this method works for extracting DIM from Brocolli.

That probably wouldn't work. Dolichol is a type of alcohol, and if you cook foods containing alcohol, you will remove the alcohol from them. It's not an easy substance to extract.

Do you know why your thread blocked from being viewed by non-propeciahelp members? I think what you have posted there is very important and shouldn’t be blocked from non members. I’m not personally registered there because I’m not a PFS sufferer, but I’m still very interested in following your thread.

I'm not in charge of the forum or its settings, so I can't answer that. I doubt it would be a problem if you just wanted to register an account to lurk, but it's not my forum.

 

[Ende]

It's always nice to see other dedicated PFS sufferers working with something they believe in, even if it turns out to be a blind alley in the end, it's a very important contribution - whatever it is. I can't stand those who do nothing but whine, and come up with excuses instead of solutions. I think this approach deserves its own thread. Did you recover with a spinach diet?

 

[Prop]

there isn't a Ropren equivalent drug?
i ate lot of spinach but only cooked