Type-IIx
Well-known Member
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. Perhaps @PeterBond @PeterBond will weigh in here.
- 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)]
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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
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