Beta Ecdysterone

[matalo]

E' notificato? quali sono le sue proprietà ed eventuali usi?

[Guru]

Puoi leggere quì Beta-Ecdysterone

Non è notificato.

[matalo]

Grazie guru scemo io che non ho fatto la ricerca

[greatescape]

io invece mi riservo il diritto di giudicare dato che avevo letto studi recenti con feed positivi anche sull'uomo
sicuramente i risultati non sono come quelli vociferati ed acclamati nel passato cioe avere risultati e guadagni da aas senza sballare l'asse
pero sembrerebbero funzionare

il problema è che questa sostanza viene data sempre con il contagocce negli integratori dove è presente tipo e-bol
pero sia con animal m-stack che con e-bol in america hanno ottenuto buoni risultati

poi a confermare anche la cosa sembra sia nato un allenamento da abbinare insieme a questi prodotti

un buon banco di prova sarebbe quello di usare uno di questi prodotti mantenendo la stessa alimentazione magari stando in ipercalorica con un buon numero di proteine cosi da vedere se effettivamente svolgono il loro lavoro

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J Int Soc Sports Nutr. 2006 Dec 13;3:19-27.

Effects of methoxyisoflavone, ecdysterone, and sulfo-polysaccharide supplementation on training adaptations in resistance-trained males.
Wilborn CD, Taylor LW, Campbell BI, Kerksick C, Rasmussen CJ, Greenwood M, Kreider RB.

Human Performance Lab, University of Mary Hardin Baylor, Belton, TX.

Abstract
ABSTRACT : PURPOSE : Methoxyisoflavone (M), 20-hydroxyecdysone (E), and sulfo-polysaccharide (CSP3) have been marketed to athletes as dietary supplements that can increase strength and muscle mass during resistance-training. However, little is known about their potential ergogenic value. The purpose of this study was to determine whether these supplements affect training adaptations and/or markers of muscle anabolism/catabolism in resistance-trained athletes. METHODS : Forty-five resistance-trained males (20.5 +/- 3 yrs; 179 +/- 7 cm, 84 +/- 16 kg, 17.3 +/- 9% body fat) were matched according to FFM and randomly assigned to ingest in a double blind manner supplements containing either a placebo (P); 800 mg/day of M; 200 mg of E; or, 1,000 mg/day of CSP3 for 8-weeks during training. At 0, 4, and 8-weeks, subjects donated fasting blood samples and completed comprehensive muscular strength, muscular endurance, anaerobic capacity, and body composition analysis. Data were analyzed by repeated measures ANOVA. RESULTS : No significant differences (p > 0.05) were observed in training adaptations among groups in the variables FFM, percent body fat, bench press 1 RM, leg press 1 RM or sprint peak power. Anabolic/catabolic analysis revealed no significant differences among groups in active testosterone (AT), free testosterone (FT), cortisol, the AT to cortisol ratio, urea nitrogen, creatinine, the blood urea nitrogen to creatinine ratio. In addition, no significant differences were seen from pre to post supplementation and/or training in AT, FT, or cortisol. CONCLUSION : Results indicate that M, E, and CSP3 supplementation do not affect body composition or training adaptations nor do they influence the anabolic/catabolic hormone status or general markers of catabolism in resistance-trained males.

PMID: 18500969 [PubMed - in process]PMCID: PMC2129166Free PMC Article



C'è da dire che il dosaggio dell'ecdysterone usato dallo studio
era più basso del dosaggio minimo solitamente usato (300mg).

[greatescape]

io ne ho trovati 2 positivi
1 sui topi, con aumento della massa magra e muscolare
anche se noi non siamo topi pero siamo sempre mammiferi
il 2 invece se non ricordo male era sull'uomo ma iniettandolo

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REVIEW

Effects and applications of arthropod steroid hormones (ecdysteroids) in mammals

Laurence Dinan and René Lafont1
Department of Biological Sciences, University of Exeter, Exeter, Devon EX4 4PS, UK
1 Laboratoire Protéines: Biochimie Structurale et Fonctionnelle, Université Pierre et Marie Curie, 7 Quai St. Bernard, F-75252 Paris 05, France
(Requests for offprints should be addressed to L Dinan who is now at 30 Hederman Close, Silverton, Nr. Exeter, Devon EX5 4HW, UK; Email: laurie@dinan.wanadoo.co.uk)

ABSTRACT

Zooecdysteroids (arthropod steroid hormones) regulate the development of arthropods and probably many other invertebrates. Phytoecdysteroids are analogues occurring in a wide range of plant species, where they contribute to the deterrence of phytophagous invertebrates. The purpose of this short review is to summarise findings on the occurrence, metabolism and pharmacological effects of ecdysteroids in mammalian systems and to draw attention to their potential applications, particularly in gene-switch technology, where ecdysteroid analogues (steroidal and non-steroidal) can be used as effective and potent elicitors.

INTRODUCTION

Ecdysteroids are the steroid hormones of arthropods, where they regulate moulting, metamorphosis, reproduction and diapause (Koolman 1989). They probably fulfil similar roles in many other invertebrate phyla, but these have not been so extensively investigated (Lafont 1997). Ecdysteroids are also present in 5–6% of plant species (Dinan 1995a), generally at far higher concentrations than those typically found in arthropods, where they are regarded as contributing to the deterrence of invertebrate predators (Lafont et al. 1991, Dinan 2001). The archetypal ecdysteroid in both arthropods and plants is 20-hydroxyecdysone (20E; Fig. 1), since it is the most commonly occurring and the most abundant, but a very wide range of structural analogues has been elucidated, especially from plant sources (Lafont et al. 2002). The first ecdysteroid (ecdysone; Fig. 2) was isolated in 1954 (Butenandt & Karlson 1954) and its structure was unambiguously identified only in 1965 (Huber & Hoppe 1965), with the result that research on ecdysteroids has generally lagged far behind that on the various classes of vertebrate steroid hormones, in spite of the fact that development in more than 90% of all animal species is dependent upon ecdysteroids. However, since the early reports of the occurrence of ecdysteroids in insects and plants, researchers have posed questions about the occurrence (from the diet), metabolism and possible effects of ecdysteroids in mammals. In the intervening period, a substantial body of evidence relevant to these questions has been obtained, suggesting that ecdysteroids may have significantly positive pharmacological properties. This is consistent with the use of several ecdysteroid-containing plant species in traditional medicines. The ready availability of large amounts of 20E from certain plant sources has led to a boom in recent years in its inclusion in many commercial anabolic preparations for body-builders and sportsmen. Further, since ecdysteroids are not endogenous products of mammalian metabolism and are non-toxic to mammals, they are also finding application as elicitors of novel gene-switch systems. With the intention of bringing this area to a wider audience of endocrinologists, we shall summarise the most significant findings. Also, we shall focus on the developments in this area since our previous review (Lafont & Dinan 2003), but the reader is referred to that review for a more extensive treatment of the relevant literature and the concepts.

Occurrence of ecdysteroids in mammals

Ecdysteroids are not regarded as products of mammalian metabolism. However, they can be detected in mammalian tissues and fluids as a consequence of dietary intake of ecdysteroid-containing plants (or insects in certain population groups) or infection by invertebrate parasites. Most crop plant species do not contain phytoecdysteroids, although both spinach (Spinacia oleracea) and quinoa (Chenopodium quinoa) do contain significant levels, especially in the seeds and younger leaves (Dinan 1995b). Ecdysteroids differ markedly from vertebrate steroid hormones in their polarity (polyhydroxylated), bulk (C27–C29) and shape (A/B-cis-ring junction), thus one would expect there to be little interaction with the steroid-hormone receptors or steroid-metabolising enzymes in mammals. Unfortunately, this has not been systematically verified. The mechanisms, by which any pharmacological effects of ecdysteroids in mammals are mediated, are presently unknown (but see below).

Metabolism of ecdysteroids in mammals

Injected or ingested ecdysteroids are rapidly cleared from the blood. In mice, ecdysone (Fig. 2) undergoes a complex array of metabolic reactions, including dehydroxylation (removal of the 14-OH) most probably by gut bacteria (cf. dehydroxylation of bile acids), reduction in the B-ring and epimerisation at C-3 (Lafont et al. 1988). In addition, when a 20,22-diol is present (as in 20E), side-chain cleavage can take place between C-20 and C-22 and the pattern of metabolites becomes very complex (Kumpun, Girault, Blais, Maria, Dauphin-Villemant, Yingyongnarongkul, Suksamrarn and Lafont, unpublished data). 14-Dehydroxylation also takes place in humans (Brandt 2003). Methods aimed at analysing 20E and its metabolites in human urine are presently being developed as anti-doping controls for humans and cattle (Tsitsimpikou et al. 2001, Le Bizec et al. 2002).


Pharmacological effects of ecdysteroids on mammals

Pharmacological tests were first performed on mammals (mice, rats) in the late 1960s to detect any harmful effects of ecdysteroids on vertebrate organisms, which could have precluded their use as insecticides. This was the starting point for many experiments, which reported a wide array of pharmacological effects of ecdysteroids on mammals (Sláma & Lafont 1995, Syrov 2000, Kholodova 2001, Báthori 2002, Lafont & Dinan 2003, Klein 2004, Báthori & Pongrácz 2005).

Early pharmacological experiments

First of all, it must be emphasised that the acute toxicity of ecdysteroids in mammals is very low: the LD50 for 20E is above 6 g/kg. The first reported effect of ecdysteroids on mammals was a stimulation of protein synthesis (translation) in vitro by liver polysomes prepared from rats having received 20E (or any of the other then available ecdysteroids). This effect was even used as a convenient bioassay for the presence of phytoecdysteroids in plant extracts during large-scale screening programmes (Otaka et al. 1969). At the same time, other authors analysed the distribution and metabolic fate of injected [3H]ecdysone (Hikino et al. 1972).

These pioneering studies were followed by extensive studies on possible anabolic effects of ecdysteroids in rats (and humans). The general strategy was to compare the physical performance or biochemical parameters of animals having received 20E (or another ecdysteroid) over 1–3 weeks to controls or animals treated with a ‘classical’ anabolic steroid (testosterone or dianabol), and these experiments indicated a significant anabolic effect of ecdysteroids. Several ecdysteroid preparations have been designed for sportsmen (e.g. ‘Ekdisten’ or ‘Retibol’) containing quite small amounts of 20E (5 mg/tablet). Since those early times, the market for ecdysteroid-containing preparations has developed considerably, and is now especially aimed at bodybuilders; presently, ca. 300 ecdysteroid-containing products are available on the market, some of which contain large amounts of 20E, with formulations recommending up to 1 g daily intake, usually in combination with other known anabolic chemicals and/or included in a high-protein diet. The basis for all the Internet claims about the effects of ecdysteroids is not clear. However, the scientific literature shows that a significant body of experiments has indeed been performed, which describe various effects of ecdysteroids on mammals/humans, and have resulted in more than 50 patents for both internal and external use. The main findings are summarised below (for more details, see Lafont & Dinan 2003).

Protein metabolism  General stimulatory effects on protein synthesis have been shown for various ecdysteroids, including rubrosterone, a C-19 ecdysteroid lacking the whole side-chain (Fig. 2). These effects have been observed in mice injected with 5 mg ecdysteroid/kg and they seem to result from increased mRNA translation efficiency and not from increased mRNA synthesis (transcription) (Otaka et al. 1968, Syrov et al. 1978, Khimiko et al. 2000).

Lipid metabolism  Ecdysteroids have hypocholesterolamic effects (Mironova et al. 1982, Syrov et al. 1983), best explained by increased conversion of cholesterol into bile acids, reminiscent of the effect of oxysterols (Schroepfer 2000). In rats, low doses (10–50 µg/kg) of injected 20E do not affect cholesterolaemia, but reduce hepatic cholesterol levels (Lupien et al. 1969). In addition, dietary 20E (0.1 mg/kg per day) administered over 30 days reduces lipid peroxidation in membranes (Kuzmenko et al. 1997).

Carbohydrate metabolism  Pretreatment with ecdysteroids (i.p. injections of 0.5 mg/kg) may reduce hyperglycaemia induced by administration of glucagon or destruction (by alloxan treatment) of pancreatic islet ß-cells in mice and rats (Yoshida et al. 1971). Antidiabetic effects are also known for ecdysteroid-containing plants used in traditional medicine (e.g. Ajuga iva; Wessner et al. 1992) and ecdysteroid-containing preparations have been proposed for use against diabetes (Takahashi & Nishimoto 1992, Yang et al. 2001). Recent experiments in vitro with human hepatocytes have established that ecdysteroids (10–6–10–4 M) increase glucose consumption in an insulin-independent fashion (Chen et al. 2006).

Effects on specific organs/systems

The beneficial effects of ecdysteroids on the function of many organs have been reported. We will give a few examples.

Muscle  Ecdysteroids increase muscle mass by enhancing protein synthesis and decreasing protein catabolism. It has been suggested that the latter effect operates indirectly through a reduction of glucocorticoid levels (i.e. a reduction of stress), but this assumption has not been directly documented.

Liver  Ecdysteroids stimulate bile secretion in rats (Syrov et al. 1986), and they improve liver regeneration after chemically induced damage (Badal’yants et al. 1996).

Kidney  Dietary 20E (5 mg/kg) can restore normal glomerular filtration rate and suppress albuminuria in rats treated with a nephrotoxic mixture (Syrov & Khushbaktova 2001).

Skin  Ecdysteroid-containing liposomes improve skin quality by accelerating the healing of small wounds or burns (Meybeck & Bonté 1990) and have been marketed by Louis Vuitton-Möet Hennessy Company in several commercial cosmetics. 20E (2 x 10–4 M) promotes differentiation of human keratinocytes in vitro (Detmar et al. 1994) and this might explain its psoriasis-inhibiting activity (Inaoka et al. 1997).

Brain  Several actions of ecdysteroids on the central nervous system have been described; induction of enzymes related to neurotransmitter synthesis (glutamic decarboxylase; Chaudhary et al. 1969) or degradation (acetylcholinesterase; Catalán et al. 1984) and protection of neurons against the deleterious effects of various drugs (Aikake et al. 1996, Xu et al. 1999). Neuromodulatory effects of 20E (100 µM) on the GABAA receptor have also been reported (Tsujiyama et al. 1995, Okada et al. 1998).

General comments

Many more (beneficial) effects have, in fact, been described for injected or ingested ecdysteroids in mammals (see Lafont & Dinan 2003, Báthori & Pongrácz 2005). The weight of the accumulated evidence leaves little doubt that ecdysteroids do have effects on mammals. However, in many individual studies, the published data need to be further substantiated by more experimental evidence to be fully convincing. When crude or semi-purified plant extracts have been used, they do not demonstrate that the observed effects result (only) from ecdysteroids themselves. Whenever pure ecdysteroids have been used, the results are not always as spectacular as claimed in publicity promoting the use of these molecules for humans (but in this case, ecdysteroids are usually part of complex cocktails). Also, the statistical significance of results is questionable when small effects are observed with a low number of replicates and, in many instances, there is no clear-cut dose–response effect. Finally, we may consider as most convincing the unexpected data obtained by users of ecdysteroid-inducible gene systems (see below), which demonstrate ecdysteroid effects in control experiments, which means that exogenous insect ecdysteroid receptors are not required for some ecdysteroid effects to occur in mammalian/human cells (Constantino et al. 2001, Oehme et al. 2006).

Possible mechanisms of action

Besides their neuromodulatory effects on the GABAA receptor, which can easily be explained, the other numerous effects cannot be due to a single target. Moreover, some could be due to specific metabolites rather than the administered compound. Some transcriptional effects (perhaps caused by side-chain cleavage metabolites of ecdysteroids) can be expected to take place through binding to nuclear receptors (pregnane X receptor (PXR), constitutive androgen receptor (CAR) and liver X receptor (LXR)), which can bind a wide array of ligands, including various xenobiotics (Blumberg et al. 1998, d’Ursi et al. 2005, Handschin & Meyer 2005), but to our knowledge, as yet, there is no direct evidence for such binding. Recent data (Constantino et al. 2001, Oehme et al. 2006) provide convincing evidence that ecdysteroids evoke significant changes of gene expression in mammalian cells, resulting in the activation of the phosphatidylinositol-3-kinase/protein kinase B signal transduction (PI3K/Akt) pathway responsible for anti-apoptotic effects. We may also expect some rapid actions via membrane receptors: high affinity-binding sites have already been described using 20E bound to magnetic nanoparticles (Mykhaylyk et al. 2001), together with rapid effects on, e.g. prostaglandin synthesis (Kotsyuruba et al. 1995).

Ecdysteroid receptors in arthropods

Most actions of ecdysteroids are mediated by intracellular receptor complexes, although it should not be forgotten that some rapid actions are mediated by other mechanisms (Tomaschko 1999, Schlattner et al. 2006). The intracellular receptors from a range of arthropod species have been characterised and the active complex consists of two proteins: the ecdysteroid-receptor (EcR) protein and an ultraspiracle (USP) or retinoid X receptor (RXR) protein (Henrich 2005). All the above are members of the nuclear receptor superfamily, and USP and RXR are homologues (Laudet & Bonneton 2005). Members of this superfamily are characterised by a domain structure, consisting of an N-terminal A/B-domain involved in transcriptional activation, a DNA-binding C-domain, a hinge D-domain, the ligand-binding E-domain and an F-domain of unknown function (which is not present in all members of the superfamily). The C-domains of EcR/USP complexes interact with specific ecdysteroid-responsive elements (EcREs) in the promoter regions of ecdysteroid-responsive genes to alter gene transcriptional activity. X-ray crystallographic structures for lepidopteran (Billas & Moras 2005) and hemipteran (Carmichael et al. 2005) EcR E-domains, dipteran (Clayton et al. 2001) and lepidopteran (Billas et al. 2001) USP E-domains and dipteran EcR/USP C-domains (Devarakonda et al. 2003) have been elucidated. The ligand-binding domain (LBD) is specific for ecdysteroids and other classes of ecdysteroid agonists and antagonists (Dinan 2003, Dinan & Hormann 2005), such that the EcR/USP complex is not activated by vertebrate steroid, retinoid or thyroid hormones. USP is regarded as an orphan receptor, for which there is no definite ligand, but it has been suggested that juvenile hormones may interact with its LBD (Jones & Jones 2000, Fang et al. 2005). Further, when USP is replaced by RXR as EcRs partner, retinoids potentiate the activity of ecdysteroids (Saez et al. 2000). Since neither ecdysteroids nor EcR proteins are endogenous components of mammalian cells, this system can be used as the basis for the regulation of transfected genes possessing appropriate hormone responsive elements (HREs), by ecdysteroid receptors (also expressed from transfected genes) and the use of appropriate ecdysteroid (ant)agonists as elicitors, to generate an ‘ecdysteroid-inducible gene-switch system’. While, in theory, the native arthropod components (20E, EcR and EcRE; RXR is a constitutive component of many mammalian cell types) could be used, in practice, it is necessary to modify each of the exogenous components to optimise the properties and performance of the system to improve the sensitivity, specificity and strict temporal regulation of the transfected gene (see section ‘Ecdysteroid-inducible gene-expression systems’).

Ecdysteroid-inducible gene expression systems

The spatial and temporal control of heterologous gene expression is an area of major current interest with application to basic and applied biological and medical research, including gene therapy and functional genomics. Such ‘gene-switch’ systems should provide rapid, precise and reversible induction (or suppression) of the target gene(s), but not interfere with the complex endogenous regulatory networks of the host cells/tissues. Thus, the key characteristics of the system should be (Fussenegger 2001):

The introduced regulatory machinery (transcription factor, elicitor) should be specific for the target gene(s) and not interfere with endogenous regulatory networks.
The system should be inducible by low concentrations of elicitor in a dose-dependent manner, have a very low baseline expression in the absence of elicitor and a high induction ratio.
The elicitor should be bio-available and readily penetrate to the target tissues.
The action of the inducer should be reversible, either through metabolism or excretion, so as to permit switching-off of the effect and repeated cycles of induction.
The components of the gene-switch system should not be immunogenic in the host.
The design of the gene-switch system should be flexible enough to allow for different tissue applications and circumstances.
Early ecdysteroid-related gene-switch systems (Christopherson et al. 1992, Yao et al. 1993) were based on the Drosophila melanogaster EcR (DmEcR), in conjunction with co-transfected USP or by using endogenous RXR as the heterologous partner. Thereafter, the activation potential and specificity for specific HREs were enhanced by modifying the activation and DNA-binding domains (No et al. 1996). A parallel system based on the Bombyx mori EcR (BmEcR) has been developed, and this has the advantage that BmEcR more readily partners with RXR than does DmEcR (Swevers et al. 1996, Suhr et al. 1998). Since then several Dm/Bm EcRs have been generated (Suhr et al. 1998), including one (DB-EcR; Hoppe et al. 2000), which is independent of recombinant RXR. A lentiviral vector system has been developed for the effective delivery of ecdysteroid-regulated genes into cells or animals (Galimi et al. 2005). Tight transcriptional regulation of foreign gene expression in insect cells has been obtained using a further system (Dai et al. 2005), consisting of (i) the DEF domains of the Choristoneura fumiferana EcR fused to the Saccharomyces cerevisiae GAL4 DNA-binding domain, (ii) the EF domains of mouse RXR fused to the acidic activation domains of baculovirus transactivators IE1 and IE0 and (iii) exogenously applied GS-E (RG-102240; Fig. 2). This system shows considerable promise for the controlled expression of toxic proteins, since any expression in the absence of inducer would result in cytotoxicity of the host cells.

Most researchers’ interest in ecdysteroid-inducible gene expression systems is in the functional analysis of cloned genes, which can be put under the control of ecdysteroid-regulated promoters and transfected into mammalian cells. To this end, several commercial gene-switch kits have been developed, notably those produced by Invitrogen (Invitrogen by Life Technologies) and Rheogene (Intrexon). As elicitors, these systems use either the steroidal analogues muristerone A or ponasterone A, or a non-steroidal ecdysteroid agonist of the diacylhydrazine class (Nakagawa 2005), such as GS-E (Fig. 2). In the longer term, the intention is to generate systems capable of the independent and coordinated regulation of multiple genes in a tissue and, hence, gene therapy of disease states.

Ecdysteroids and diacylhydrazines possess many properties that make them suitable as gene-switch elicitors. However, EcR LBDs, when expressed in mammalian cells, do not possess the same specificity or affinity as the same LBD in an insect system. Thus, much higher concentrations of active ecdysteroids are required and only certain analogues show significant activity. Thus, the endogenous hormone in insects, 20E, is hardly active in mammalian cells, and muristerone A and ponasterone A are required at concentrations of 1–10 µM to bring about a response when the effective concentrations in insect systems are much lower (e.g. EC50 values in the D. melanogaster BII bioassay are 2.2 x 10–8 and 3.1 x 10–10 M respectively; Dinan 2003). Identification of elicitors showing the same potency as these ecdysteroids in insect systems would considerably enhance the sensitivity and reduce the possibility of side-effects during gene therapy. This is being achieved by modifying LBDs of transgenic EcRs by site-directed mutagenesis to enhance the affinity for existing ligands (Palli et al. 2005a), modifying the partner RXR/USP (Palli et al. 2005b) or by comparative quantitative structure-activity relationship (QSAR) studies on the ligand specificities of ecdysteroid receptors expressed in insect and mammalian systems to identify the differences and to design more potent ligands (Dinan & Hormann 2005).

Conclusions and prospects

Most Internet claims for ‘spectacular’ effects of ecdysteroids on humans and other mammals are unsubstantiated or apocryphal. However, most reports in the scientific literature have demonstrated that the pharmacological effects of ecdysteroids in mammals are positive, and it is clear that ecdysteroids may influence/improve many physiological functions. Unfortunately, no extensive, systematic trials on any mammalian species have been published. Dietary intake of ecdysteroids is possible but limited for most humans, since the crop species which contain phytoecdysteroids are not extensively eaten. Thus, there may be a future for ecdysteroids as dietary supplements to contribute to human well-being (as ‘adaptogenic’ substances). However, more study is required to elucidate the metabolism of exogenous ecdysteroids in mammals and the biochemical modes of action of the parent ecdysteroids and their metabolites. Such studies are also important to underpin the use of ecdysteroid-induced gene switches. These systems possess considerable potential for basic biological studies of gene function and in gene therapy.

Funding

Research in the authors’ own research groups has been funded by BBSRC, CNRS, INTAS, Leverhulme Trust, MENESR and Rheogene LLC. There are no conflicts of interest which affect the impartiality of this review.

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[matalo]

Grazie ragazzi per gli interventi comunque immagino che degli effetti collaterali si debbano avere o no?

[Nettun]

no io non credo che prendendo dosi come quelle dell' m-stack avrai effetti collaterali anzi avrai solo effetti placebo dato che secondo me le dosi negli integratori sono basse e insignificanti per un soggetto giovane

[matalo]

Premetto che non lo chiedevo perchè devo usarlo semplicemente avevo curiosità dato che solitamente quando in mezzo si mettono meccanismi anche ormonali effetti negativi ci sono

[Nettun]

co ste dosi non succede niente purtroppo llol

[-Luci-]

Non si è neppure sicuri se funziona,
se pure da problemi... allora è proprio un integratore ottimo


ma a conti fatti qualcuno lo ha mai provato?

[Nettun]

io ho provato l'm-stack e sinceramente l'm-stack di effett isu di me ne ha fatti ben pochi lol