Updated Research and Knowledge - Cutting Edge

[Chemical]

I find the bit about estrogen receptors to be particularly interesting. I'm currently taking a SERM to reduce the effects of gyno I got after taking RU for several months. It's 30 mg of Raloxifene, said to be stronger than tamoxifen, that I am taking now every other day. It's not topical but I'll certainly try to keep my eye on any noticeable results, as unlikely as they are.

You probably wont notice any hair growth since any agonistic activity of raloxifene on ERa will be negated by DKK1 that is strongly induced by DHT. I'm more interested in seeing you use oleuropein with raloxifene since that'll address both ends of spectrum, and I plan to mix tamoxifen with a separate minox bottle to test out this theory in the next two weeks or so.

This guy knows what he is talking about,won't be surprised if he got a cure for baldness!

Why thank you baldybald, but I believe a cure can be found if we work together, combining our knowledge and trying novel approaches instead of just waiting for these big drug companies to give us false hope. These companies are just people motivated by money, with their time and resources they should be trying to figure out how the complex biomechanics work (like DKK1 and how it' actually induced or that there are might be other factors like 3Beta-Diol inhibiting hair follicle blood vessel formation) instead of blindly trying to create single compounds that will miraculously cure baldness in a vaccuum. The human body isn't black and white, its not just a few simple interactions either, its ridiculously complex with feedback loops designed to adapt and requires an approach that will tackle all the factors. "Igf-1 increases hair growth - lets spend millions trying to create compound that can deliver igf-1 to hair follicles, it worked in-vivo and in-vitro, so it will definitely work if we put in the necessary R&D". Its a system that can be exploited if you're brave enough to take calculated risks. Just my 2 cents that I'd wanted to share.

Do you think that it's possible to mix the oleuropein capsules into castor oil instead of minox?

I tried that, it did not go well. You end up with oleuropein still in its powder form and when the oil dries up it leaves a hard residue of oleuropein that is a nightmare, especially since I recommend applying the solution as often as possible to keep tissue concentrations high. You want the oleuropein to dissolve as much as possible so it can be carried through the skin layers by emu oil. Emu oil also helps with imflammation allowing you to use keto/mico and minox without irritation. I also dissolved saw palmetto, not sure if that actually did anything.

And here are some more recent pictures of my hairline. I've noticed alot less stubble since I stopped using it everyday (I'm just waiting for minoxidil to come through to make a new 3 month batch).

2 weeks ago:



You can see my most recent pictures here: http://imgur.com/a/g6TdQ

[Medium]

Great,
Thanks for the response.
My only concern is that I don't want to get on minox, so would dissolving the oleuropein capsules in emu oil still be effective?

[tiktok]

I plan on trying to use http://www.nowfoods.com/Olive-Leaf-G...tarian-2oz.htm with emu oil.

[Swooping]

Chemical thanks . I’ll get in on this discussion on a later point (busy atm). But here is what I think about androgenetic alopecia (AGA) as a whole. Hopefully it can help you.

First of all AGA is androgen and AR dependent right (Androgens > AR)? This begs the question; Why does AR activation lead to hair loss?
Well we don’t know, but to simplify it I would just like to call that AR activation causes cellular stress in AGA.

We can already maintain hair simply by castration. So we know that castration removes the “stress” right? So is it really beneficial for us to search for other “stress” factors beside the AR? One could argue it is because of possible better therapies that could give someone maintenance of their hair state. For instance let’s assume hypothetically that pathway “X” is implicated after AR activation in AGA. This would make the pathway chain; Androgens > AR > X. So if that was the case we could modulate X too and provide someone with maintenance of hair just like removing the AR would provide or castration does. Perhaps modulation of X would be something better because of a better side effect profile. This is exactly what Kythera (Cotsarelis) their hypothesis is made of. Instead of X however they argue that PGD2 functions highly upstream after AR activation and this leads to hair loss. So in their hypothesis modulation of PGD2 should work too (I don't think that is even the case but we will see.).

However will that bring back our hair? No right? I mean castration doesn't do it either. That is why I think in terms of reversal of AGA it’s less important to understand what causes the damage but rather what happens because of the damage. So let’s assume it is Androgens > AR > X. That causes the damage or “stress”. But what happens in response to that ? I have showed you the studies that points out to rather major pathways that seem to be implicated in AGA. And the thing is they seem to be implicated in stress responses like ROS and DNA damage. In this sense we can perhaps broaden the damage factor to DNA damage or ROS. So because of what happens in AGA these pathways react to the damage and this can be for example DNA damage or ROS. To make a example one might argue that Androgens > AR causes DNA damage and because of the DNA damage pathways come into action that react to this cellular stress.

Really I believe it all originates from the dermal papilla cells too. They are the master cells of the hair follicle. Dermal papilla numbers correlate with hair follicle size. A decline of dermal papilla is seen in AGA as the hair follicle continues to miniaturize. Several studies have pointed this out. Not only that we know that in bald scalp we lack progenitor cells. Well guess what? The dermal papilla regulates these progenitor cells. So if the dermal papilla cells get stressed and altered it could easily lead to a lack of progenitors. Studies have pointed out that the dermal papilla regulates progenitors as recently confirmed again by a abstract on the hair congress;

Getting It Right: Coordinating Progenitors and Their Niche to Specify Hair Size and Structure

ABSTRACT: The size and shape of the hair shaft is dependent on the number and activity of hair progenitor cells, which is in turn dependent on the number and activity of the dermal papilla cells that comprise their niche

Anyway back to the original point again. I have shown you the papers that point out the evidence of the pathways that seem to be implicated in AGA . And as you can see it is these pathways, exactly these pathways that react to cellular stress. I would like to simply call AGA cellular stress. Then they decide what action to take with a cell. Is it apoptosis? Is it senescence? Is it cell cycle arrest? Is it repair? What action is taken in AGA that leads to a miniaturized hair follicle? It might be even a combination for instance there might be a wave of apoptosis first before cell cycle arrest or senescence. For instance as seen here in a animal model;

http://s22.postimg.org/iojfxcpu9/senescne6.jpg

“Activation of P14, but not of P16, also caused a rapid but transient wave of apoptosis prior to the generation of senescent cells”.

As you can see it displays the multi-facetted role these pathways can take upon this stress and the several actions they can take."

What sort of stress or damage is it furthermore in AGA? Is it ROS or DNA damage? Maybe something else. I guess we don’t understand the specifics details yet. In my opinion the picture is becoming clear though. To no wonder, more and more researchers and studies are starting to point out in the same direction.

Finally here are some related pictures that go with this all.

Senescence (note how they mention that it causes SASP (inflammatory response, would explain the inflammation in AGA and also how they mention that it may not only affect differentiated cells but also stem and progenitor and limit the regenerative capacity of tissues):




Cell cycle (arrest):

[Swooping]

Forgot this one. Shows some pathways that are implicated in senescence due to different stress causes (DNA damage, ROS etc.);

[Chemical]

Great,
Thanks for the response.
My only concern is that I don't want to get on minox, so would dissolving the oleuropein capsules in emu oil still be effective?

I'm terribly sorry, I had a feeling you wanted to avoid minoxidil altogether, in which case you can make vehicle to dissolve the oleuropein with the following:

50% (v/v) ethanol, 30% water, and 20% propylene glycol.

You really need to dissolve the oleuropein so that it gets absorbed effectively.

I plan on trying to use http://www.nowfoods.com/Olive-Leaf-G...tarian-2oz.htm with emu oil.

The oleuropein extract would be ideal, and I wouldnt encourage anything else. You need the extract, not the leaf. Theres not a whole lot of brands out there that make oleuropein in extract form. Its a pain but it's worth it imo.

You probably wont notice any hair growth since any agonistic activity of raloxifene on ERa will be negated by DKK1 that is strongly induced by DHT. I'm more interested in seeing you use oleuropein with raloxifene since that'll address both ends of spectrum, and I plan to mix tamoxifen with a separate minox bottle to test out this theory in the next two weeks or so.

I'd also like to add that SERMs are especially useful for increasing testosterone by negating the negative feedback loop of estrogen on the pituitary, thus increasing LH and subsequently testosterone. More testosterone = more DHT and more DKK1. This is why its also important to have a serm that acts locally vith little systematic absorbtion, and raloxifene is very very potent stuff, along with tamox.

@Swooping

It seems you're a better researcher than me. This community needs more people like yourself.

Those diagrams are excellent. And I like your philosophy of targeting the root cause instead of damage control.

I'll keep this brief and to the point but I'll expand later.

Like you've pointed out, the DPC control the Mesenchymal stem cells, possibly by HGF/c-met, WNTs, and IGF1 which acts as a pro-survival cytokine. In short, if the DPC need to grow hair, they will signal to the progenitor cells to maintain their pluripotency. They stop growing, the progenitor no longer needs to be kept pluripotent and they may start to differentiate. This could explain why its hard for nw5s to grow back hair without aggressive treatment. However, these stem cells can be reactivated with consistent agonist activity and stimulation from IGF-1, EGF, or HGF/KGF. The AR is the cause of all of this. But I've given on this avenue because its notoriously difficult to inhibit AR locally and feasibly.

The pathways that induce senescence are not exactly a switch, they're actually on all the time. Its when they start winning the tug of war that bad stuff happens, like aging and hair loss. I'm also aware that ROS activates P53 and from the diagram it appears p16 and p21 too. I posted a study on my first post about L-threonate an Ascorbic Acid derivative abolishing the inhibitory effect of DHT-induced DKK1, where L-threonate completely prevented the growth inhibition. DHT is known to increase P53, and this study I found after a quick search does confirm the hypothesis that Androgens do increase reactive oxygen species generation (mitochondria dependant pathway in that study). ROS is a clear mediator of cellular apoptosis and senescence.

In aerobic organisms the energy needed to fuel biological functions is produced in the mitochondria via the electron transport chain. In addition to energy, reactive oxygen species (ROS) with the potential to cause cellular damage are produced. ROS can damage DNA, RNA, and proteins, which, in theory, contributes to the physiology of ageing.

ROS are produced as a normal product of cellular metabolism. In particular, one major contributor to oxidative damage is hydrogen peroxide (H2O2), which is converted from superoxide that leaks from the mitochondria. Catalase and superoxide dismutase ameliorate the damaging effects of hydrogen peroxide and superoxide, respectively, by converting these compounds into oxygen and hydrogen peroxide (which is later converted to water), resulting in the production of benign molecules. However, this conversion is not 100% efficient, and residual peroxides persist in the cell. While ROS are produced as a product of normal cellular functioning, excessive amounts can cause deleterious effects.[14] Memory capabilities decline with age, evident in human degenerative diseases such as Alzheimer's disease, which is accompanied by an accumulation of oxidative damage. Current studies demonstrate that the accumulation of ROS can decrease an organism's fitness because oxidative damage is a contributor to senescence.

And guess what, Ascorbic Acid and its derivates are known to be powerful ROS scavengers. So perhaps we need an effective ROS scavenger. The other tumor suppressor proteins could be ignored since we cannot and shouldnt trying to eliminate them, but preventing ROS generation will most definitely reduce the amount of DNA damage cause by androgens.

I'd like to hear your thoughts on this too.

[Trouse5858]

@ Chemical you're obviously very well informed on a lot of these topics. I was wondering if I could get your opinion on taking Raloxifene. I read somewhere that it can have a detrimental effect on libido, even though at the same time it is raising testosterone production. I was wondering if you could shed any light on this whatsoever. I may be feeling this side effect right now but it could also be a placebo..any insight on safe dosages or long term implications for men? Thanks

[Chemical]

@ Chemical you're obviously very well informed on a lot of these topics. I was wondering if I could get your opinion on taking Raloxifene. I read somewhere that it can have a detrimental effect on libido, even though at the same time it is raising testosterone production. I was wondering if you could shed any light on this whatsoever. I may be feeling this side effect right now but it could also be a placebo..any insight on safe dosages or long term implications for men? Thanks

Libido actually heavily depends on estrogen converted from testosterone via aromatase. The brain is quite sensitive to estrogen receptor changes, and among the steroid users who use ralox or tamox or even letro like I did, some notice a sharp decline in libido/sex drive, and a select few not so much. Its not a placebo effect if you're feeling it, but its short term so as soon as you stop you'll be fine. It also reduces sperm count temporarily. As for dosages, Ralox has a 27 hr half life, you're better off taking it everyday to reduce the gyno quicker, and you'll be able to come off it sooner. Its good for your HDL levels and unlike letro it wont **** up your bone mineral density so you dont have to be extra cautious when using it for more than 2 months, and I'd say its the best SERM out there to treat gyno.

[TheKingofFighters]

Libido actually heavily depends on estrogen converted from testosterone via aromatase. The brain is quite sensitive to estrogen receptor changes, and among the steroid users who use ralox or tamox or even letro like I did, some notice a sharp decline in libido/sex drive, and a select few not so much. Its not a placebo effect if you're feeling it, but its short term so as soon as you stop you'll be fine. It also reduces sperm count temporarily. As for dosages, Ralox has a 27 hr half life, you're better off taking it everyday to reduce the gyno quicker, and you'll be able to come off it sooner. Its good for your HDL levels and unlike letro it wont **** up your bone mineral density so you dont have to be extra cautious when using it for more than 2 months, and I'd say its the best SERM out there to treat gyno.

Wow thx for ur hard work! Can u check profile? Would oleupein help me in activating stem cells? Im using minoxidil but it has only grown some tiny baby hairs thst nv seem to terminal. Would oleupein turn them terminal?

[Trouse5858]

Yeah that was an even more in depth answer than I was anticipating, I appreciate the information.