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Ecdysterone: potential mechanisms of action

Type-IIx

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Ecdysterone: Potential mechanisms of action
by Type-IIx

Proposed Mechanism of Ecdysterone.png
Proposed mechanism of action from [3] Gorelick-Feldman, et al.

Basic pharmacology
Phytoecdysteroids (PEs), i.e., polyhydroxylated ketosteroids, are characterized as polyhydroxylated basic carbon ring structures of 27-29 carbon atoms. To date, approximately 250 variants of PEs have been identified, but the most widely invetigated and physiologically significant PE appears to be 20-hydroxyecdysone [2β,3β,14α,20β,22R,25-hexahydroxy-5β-cholest-7-en-6-one] (20E; 20-OHE; ecdysterone).

A vast amount of research (most of which full text versions are unavailable in English) suggests that PEs possess a broad spectrum of biological, pharmacological, and medicinal properties in mammals, with no known adverse side effects [1]. PEs elicit anabolic, hepatoprotective, immunoprotective, antioxidant, and hypoglycaemic effects [1]. Folklore describes Siberians consuming hardy plants (now identified as containing high levels of PEs) to enhance stamina and ward off fatigue [1].

With regard to elucidated effects, aside from its promotion of muscle anabolism with particular effect on type II fibers, pronounced enhancement of blood glucose homeostasis has been demonstrated, in mice mostly (Kizelsztein et al., 2009, described an anti-obesity and anti-diabetic effect of ecdysterone via reduced hepatic glucose production in association with increased Akt phosphorylation[7]).

The only (debated) contraindication for high-dose, chronic use in the literature is hypothetical: Parr, et al. proposes a plausible mechanism for HPA negative feedback/inhibition as a potential consequence of ecdysterone's (and similar PEs') ability to transactivate ERβ [2]. The observation that ecdysterone reduced E2 but not testosterone "may indicate that [ecdysterone] may influence gonadotropin secretion and activate negative feedback mechanisms on the hypothalamic-pituatary axis" [2]. This is based on the logical yet untested assocation between reduced serum E2 levels and gonadotropin administration - and whether it applies to ecdysterone.

Other classes of PEs include ecdysone and turkesterone2-3, ponasterone, ajugasterone, and muristerone, which are characterized by a dearth of research.

Potential mechanisms of action in hypertrophy

Despite a rudimentary chemical similarity to AAS, AAS exert their anabolic effects via the AR, whereas there is no significant interaction with the human AR with PEs. Rather, investigation into the possible mechanisms is presently ongoing.

- ER-β
- Partial antagonism of ecdysterone's effects was demonstrated with a selective ERβ antagonist demonstrating that some of ecdysterone's anabolic effects are mediated by ERβ activity [2].
- "A more specific molecular mechanism involved in the interaction of ERβ and ecdysterone may be the modulation of phosphorylation effects." [2].
- "mainly fibers of the subtype IIa and IIb were stimulated ("the diameter of type IIb fibers showed a significant increase, and for type IIa fibers a clear tendency..."). This is remarkably significant contrasted with AAS - as anabolic steroids such as testosterone affect mainly type I fibers [2]. Ecdysterone has been shown to significantly effect muscle force [2].
- Ecdyterone transactivates ERβ and directly binds to both ER [2].
- Reduced serum E2 (debated):
- The observation that ecdysterone reduced E2 but not testosterone "may indicate that [ecdysterone] may influence gonadotropin secretion and activate negative feedback mechanisms on the hypothalamic-pituatary axis" [2] (rodent study). Isenmann demonstrated a tendency (human study) for reduced E2 not reaching significance, yet made it a point to disentangle this particular finding from ecdysterone while using other non-significant tendencies to appeal to doping authorities for prohibition of this substance with dramatic flair [5].
- PI3K/Akt
- via a G protein-coupled receptor to activate the PI3K/Akt signaling pathway (GPCR-PLC-PI3K), resulting in protein synthesis via a different mechanism than IGF-1, discussed by Gorelick-Feldman et al [3]. Relative to IGF-1, ecdysterone demonstrates a much more gradual onset of protein synthesis: whereas IGF-1 phosphorylates Akt within minutes, significance in the increase with ecdysterone took 2h [3]. This suggests that ecdysterone, moreso with consideration of potential bioavailability questions raised by Parr et al., requires long-term intake for efficacy.
- intracellular Ca²⁺ spike, activated Akt (elevated phosphorylation from 2h to 24h) in a dose- and time-dependent manner ⇒ 16% increase in protein synthesis, in mammalian myotubes [3] "Although there is as of yet no direct evidence of its existence, a putative 20HE GPCR may activate the PLC-IP₃ pathway as well as open Ca²⁺ channels, leading to G-αᵢ protein-dependent activation of PI3K/Akt and increased protein synthesis [3] { see image above demonstrating putative mechanism }
- mTORC1:
- -mTORC1-mediated mechanism discused by McBride [1].
- Anthony, et al. weakened the plausibility of mTORC1's role in observed anabolism [7]; still, more research is needed.
- IGF-1 and insulin signaling
- Antagonism of training-induced decrease in serum IGF-1 discussed by Isenmann [5]
- An increase in serum IGF-1 and a decrease in serum corticosterone were observed [7]
- Potential mechanism may be augmentation of IGF-1/Insulin signaling with carbohydrate feeding [7]
- phospholipase C and cAMP/PKA ([3])
- reduced protein breakdown [7]
- altering vitamin D status or action in muscle [7]

Dosages in the literature vs. popular media
On the internet, anecdotal and marketing recommendation for human (adult) doses are typically 200mg/day (i.e., 2-3mg/kg/day): an important caveat is that this dosage is practically difficult, given the findings that with regard to commercially available supplements. Kraeim et al. demonstrated widespread, near-universal prevalence of severely underdosed and fraudulent product labeling and contents ("Of the 16 supplements tested, only five showed detectable levels of [ecdysterone], with concentrations ranging from undetectable up to 2.3mg per capsule [6] Doses below 5μg/kg are ineffective [5]. Isenmann found a significant, dose-dependent effect on upper body (bench press) strength, muscle mass, as well as a time- and dose-relationship with a "tendency for an increase in performance" in the back squat (participants, except the control group, followed a well-designed traditional periodization plan) by the supplementation of ecdysterone with 48mg daily (for the high dose group) of ecdysterone in 80kg participants (0.6mg/kg) [5]. Neither a dose-response curve nor mechanisms of action for PEs including ecdysterone have been established: i.e., there has not yet been elucidated a point of diminishing returns; and the LD50 in humans is impracticably high. There has been no demonstration of any toxicity and the potential health benefits are myriad. Pragmatically, however, ecdysterone is expensive, and if one were to weight its costs versus benefits and market availability of well-researched and widely available hormonal alternatives, it is not practical. That is not, however, to say it is ineffective.

Drug testing (WADA Monitoring List: Substance of concern as of 2021)
Parent compound and/or metabolites (14-deoxy-20-OHE) were detectable 96 hr after consumption of 4.6mg of ecdysterone using a GC/MS/MS method of analysis [6]. The prevalence of detected use in WADA urine samples was a mere 0.4% [6].

Miscellaneous; See Also
[Ecdysterone SportsWiki (Russian Translation)]
_____
References:
[1] M McBride, J. (2013). Phytoecdysteroids: A Novel, Non-Androgenic Alternative for Muscle Health and Performance. Journal of Steroids & Hormonal Science, s12(01). doi:10.4172/2157-7536.s12-e001
[2] Parr, M. K., Zhao, P., Haupt, O., Ngueu, S. T., Hengevoss, J., Fritzemeier, K. H., … Diel, P. (2014). Estrogen receptor beta is involved in skeletal muscle hypertrophy induced by the phytoecdysteroid ecdysterone. Molecular Nutrition & Food Research, 58(9), 1861–1872. doi:10.1002/mnfr.201300806
[3] Gorelick-Feldman, J., Cohick, W., & Raskin, I. (2010). Ecdysteroids elicit a rapid Ca2+ flux leading to Akt activation and increased protein synthesis in skeletal muscle cells. Steroids, 75(10), 632–637. doi:10.1016/j.steroids.2010.03.008
[4] Parr, M K et al. “Ecdysteroids: A novel class of anabolic agents?.” Biology of sport vol. 32,2 (2015): 169-73. doi:10.5604/20831862.1144420
[5] Isenmann, E., Ambrosio, G., Joseph, J. F., Mazzarino, M., de la Torre, X., Zimmer, P., … Parr, M. K. (2019). Ecdysteroids as non-conventional anabolic agent: performance enhancement by ecdysterone supplementation in humans. Archives of Toxicology, 93(7), 1807–1816. doi:10.1007/s00204-019-02490-x
[6] Kraiem, S, Al-Jaber, MY, Al-Mohammed, H, et al. Analytical strategy for the detection of ecdysterone and its metabolites in vivo in uPA(+/+)-SCID mice with humanized liver, human urine samples, and estimation of prevalence of its use in anti-doping samples. Drug Test Anal. 2021; 1– 13. https://doi.org/10.1002/dta.3032
[7] Anthony TG, Mirek ET, Bargoud AR, et al. Evaluating the effect of 20-hydroxyecdysone (20HE) on mechanistic target of rapamycin complex 1 (mTORC1) signaling in the skeletal muscle and liver of rats. Appl Physiol Nutr Metab. 2015;40(12):1324-1328. doi:10.1139/apnm-2015-0301
 

aphextwin

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I don't know the difference between this and true Turk. I will say there's some legit Turk products out there that do work. I have tried 2.
 

Type-IIx

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I don't know the difference between this and true Turk. I will say there's some legit Turk products out there that do work. I have tried 2.
Yes, it's been reported that turkesterone is strongly anabolic. The problem with these PEs is they are expensive, to the point where the classic hormones are just so much more cost-effective. As per usual, the research follows the anecdotes in the form of reports from users. It will take a while for the English-speaking world to catch up with the East's research on this class of compounds. To me, it is very interesting how/why a molting hormone/defense against insects in plants has a real effect in humans.

If you log your experience with turkesterone I'd be interested in following.
 

aphextwin

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I agree, but if I were to post my results on turk, most would either not care or think I'm being paid. Of course, if I don't think something is any good, I won't even comment. Let's face it, Tren is much sexier. I use to be that guy so I get it, but as you grow up you care about your health. Thanks brother.
 

aphextwin

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Very noticeable increases in strength and walking around with full muscle pumps all day. I believe it’s dose dependent too because at lower doses, I didn’t experience any noticeable benefits.
 

BigGame

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Very noticeable increases in strength and walking around with full muscle pumps all day. I believe it’s dose dependent too because at lower doses, I didn’t experience any noticeable benefits.

Thanks for the feedback.

I’m also wondering how much of your results are the result of the apigenin.
 

emeric delczeg

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I don't know the difference between this and true Turk. I will say there's some legit Turk products out there that do work. I have tried 2.
Extrapolating a human equivalent dose from the animal studies puts the dosage around 400mg of ajuga turkestanica extract standardized to 40% ecdysteroids, with the ecdysteroid content slanted heavily in the favor of 20-hydroxyecdysone (ecdysterone) NOT turkesterone.[14]
 

aphextwin

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Extrapolating a human equivalent dose from the animal studies puts the dosage around 400mg of ajuga turkestanica extract standardized to 40% ecdysteroids, with the ecdysteroid content slanted heavily in the favor of 20-hydroxyecdysone (ecdysterone) NOT turkesterone.[14]

Like I stated earlier I’m not an expert nor do I claim to be. I just know the brands I’ve used are solid. Abolic is the best.
 

Cerberus777

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Very noticeable increases in strength and walking around with full muscle pumps all day. I believe it’s dose dependent too because at lower doses, I didn’t experience any noticeable benefits.
Standard dose seems very mild I doubled it to see what it would be like. And it is impressive. Not a cost effective route compared to gear. But if you're older and just want some pop and feel good without effecting health it's pretty good.
 

Matsuo Munefusa

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Anybody try transdermal yet? Most interested in that, maybe 250mg day dosage split bilateral
 

Flex500

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I've tried abolic off and on and have generally positive feelings. At 5-6 pills a day it does seem to have slight, noticeable effects which to me is quite a compliment since many (most?) OTC items seem to basically do nothing lol. Basically I take 35 pills a week so a $60 bottle will last 24 days.

That's not a knock, Dante reduced the price (well I think he doubled the pills). I've also done 6 pills a day, 5 days a week which I think worked pretty well and then you get a clean four weeks from it. 8 weeks = $120...not too bad overall considering I'll doordash twice a week without a thought for $50 each lol.

The dosing for abolic is what confuses me the most. The bottle indicates two pills a day, most say 4 pills a day if you are over 200 and 6+ if you are over 250 so the actual effective dose is a bit confusing. It would be beneficial if there as a male/female weight chart on the bottle.

overall good product
 

micro2000

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Anybody try transdermal yet? Most interested in that, maybe 250mg day dosage split bilateral
If you can get a high purity ecdysterone powder(>95%), it goes dissolves pretty well in 50:50 PEG400:water. IIR I did 100mg/ml pretty easily. Thin and painless.

I never used it continuously, can't recall why, but it stayed in solution pretty long time then started recrystallizing out.
 

phoenix13

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The dosing for abolic is what confuses me the most. The bottle indicates two pills a day, most say 4 pills a day if you are over 200 and 6+ if you are over 250 so the actual effective dose is a bit confusing. It would be beneficial if there as a male/female weight chart on the bottle.

overall good product
I may be reading your post incorrectly, but the bottle says 1 serving (2 pills) twice a day (4/day). In the comments in a post on Dante's IG a while back, he says under guys under 200 3+3 (6/day), and over 200 4+4 (8/day); for females 2+2, and if no low blood pressure issues 3+3. (If this isn't allowed, I can delete.)
 

DOGGCRAPP

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I've tried abolic off and on and have generally positive feelings. At 5-6 pills a day it does seem to have slight, noticeable effects which to me is quite a compliment since many (most?) OTC items seem to basically do nothing lol. Basically I take 35 pills a week so a $60 bottle will last 24 days.

That's not a knock, Dante reduced the price (well I think he doubled the pills). I've also done 6 pills a day, 5 days a week which I think worked pretty well and then you get a clean four weeks from it. 8 weeks = $120...not too bad overall considering I'll doordash twice a week without a thought for $50 each lol.

The dosing for abolic is what confuses me the most. The bottle indicates two pills a day, most say 4 pills a day if you are over 200 and 6+ if you are over 250 so the actual effective dose is a bit confusing. It would be beneficial if there as a male/female weight chart on the bottle.

overall good product

I have to do that flex.
apigenin lowers blood pressure and blood sugar slightly. If i have a woman who is 105lbs using it (and this has happened) and she already has low blood sugar....they can run into problems. with bodybuilders its usually the exact opposite but i have to put a conservative dose on the label for FDA and other concerns. 3+3 or 4+4 is what i like most men to use. I am trying to get the price even lower trust me...but apigenin is expensive.

Apigenin = cancer fighter, reduces size of the heart, lowers blood pressure and blood sugar and also has a weird side effect of building muscle mass

Apigenin​

Apigenin is a 5,7,4′-trihydroxyflavone found in edible plants, such as parsley, celery, and grapefruit (Jang et al., 2017). Apigenin treatment inhibited LPS-induced atrogin-1 expression in C2C12 myotubes by reducing the phosphorylation of c-Jun N-terminal protein kinase (JNK), thereby increasing the myotube diameter; however, 5,7-dihydroxychromone showed no effect. Interestingly, 5,7-dihydroxychormone has the similar structure as apigenin, except that apigenin has a phenyl group at the 2-position (Shiota et al., 2015). These results indicate that the reduction in atrogin-1 expression in response to apigenin treatment is due to its phenyl group. In C2C12 cells, apigenin also increased the palmitic acid-reduced myotube diameter by downregulating MuRF1 and improving mitochondrial function through oxidative phosphorylation (OXPHOS)-involved markers (Choi et al., 2017). In the animal model for obesity-induced muscle atrophy, a high-fat diet containing apigenin increased muscle mass, the cross-sectional area of muscle fibers, and running distance by downregulating MuRF1 and atrogin-1 expression; furthermore, it reduced the levels of TNF-α and IL-6 in the serum and the gastrocnemius muscle tissue (Choi et al., 2017). Besides, apigenin reduced mitochondrial dysfunction by stimulating citrate synthases, complex I, and complex II activities and upregulating succinate dehydrogenase complex subunits (SDH) B, SDHD, and ubiquinol-cytochrome C reductase core protein 1 (UQCRC1). Apigenin also stimulated mitochondrial biogenesis through PGC-1α and Tfam mRNA expression. The denervation of the sciatic nerve decreased the area of the muscle fibers; however, a diet containing apigenin increased the muscle fiber area and the weight of the gastrocnemius and soleus muscles (Choi et al., 2018). At a molecular level, apigenin upregulated MHC, downregulated MuRF1, and decreased TNF-α expression in the gastrocnemius muscle tissue. In the soleus muscle, apigenin increased MHCIIa expression and reduced TNF-α and IL-6 expression. Apart from inhibiting muscle atrophy, apigenin induced muscle hypertrophy and myogenic differentiation by stimulating the Akt/p70S6K/4EBP-1 pathway and myoD protein expression, respectively (Jang et al., 2017). Apigenin treatment notably increased the thickness of C2C12 myotubes and running distance and the weight of quadriceps muscle in C57BL/6 mice. These results suggest that apigenin has the therapeutic potential for inhibiting muscle atrophy and inducing muscle hypertrophy.

Then its got an enzymatically changed Quercetin (which is 22 times more biovailable than regular and that has shown both metabolic (fat burning) properties and slight muscle mass increasing (and anti atrophying) properties. And then it has Turkesterone or (thinking about Rhaponticum Carthamoides in it instead) which increases protein synthesis by low end 15-30% high end.
 

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