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Old 03-26-18, 10:38 AM
The Science of Tren
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The Science of Tren



Introduction

Trenbolone is a hormone that has an almost mythical reputation within bodybuilding circles. Because there is very limited data on humans, we often must rely upon anecdotes when trying to form hypotheses. As can be seen on just about any bodybuilding board, experiences with trenbolone vary widely – with some absolutely worshipping the compound and others either advising extreme caution or telling folks to avoid it at all costs. Despite this large divide in opinion, there is no disputing its popularity as numerous surveys over the years have demonstrated it to be one of the most frequently used anabolic compounds, with anywhere between 20-25% of enhanced bodybuilders reporting they’ve used it within the last twelve months [1, 2, 3].

My goal with this article will be to use what information is available to try and form some more solid conclusions with regard to how the compound works. At the same time I hope to help dispel some myths that are still being propagated far too often.

As I mentioned, there are only one or two controlled human trials that I’m aware of so the vast majority of cited material is going to come from either animal studies or in vitro analysis. The question that must be asked is can we take this data and apply it to bodybuilders with any semblance of accuracy? Personally, I feel there are going to be some very concrete bits that are universally applicable to humans and then there are some that may require disclaimers. I will try and do my best to point these out as the article goes on.

Basics of Trenbolone

Trenbolone is a selective androgen receptor modulator (SARM) not designed for human use [4]. Despite this designation, it continues to be heavily used by bodybuilders for muscle growth, fat reduction, and body composition purposes [5–6]. SARMs are modified analogues of male sex hormones normally exhibiting favorable anabolic activity while simultaneously having moderate-to-minimal androgenic activity in vivo as compared to native androgens [7, 8, 9]. They are under development by many pharmaceutical firms in an attempt to create alternative means to treat conditions such as hypogonadism, as well as other muscle and bone wasting states. In essence, the goal is to recreate the positive aspects of supraphysiological doses of testosterone while simultaneously removing the risk for adverse events that tend to occur when using these high doses [10].

Most all SARMs start off life as a testosterone molecule. The chemical structure of the testosterone molecule is then traditionally modified in one of three ways [11–12]:

Esterification at the 17β-hydroxyl group which increases hydrophobicity or the likelihood of a molecule to be repelled from a mass of water
Alkylation at the 7α-position which reduces 5α-reductase binding affinity
Strategic modification of the C1, C2, C9, C11, or C19 carbons to achieve a wide range of therapeutic effects
Trenbolone is a C19 norandrogen (19-nor), derived from nandrolone (nortestosterone). Removal of the methyl group at position 19 of the steroid backbone significantly reduces the susceptibility of 19-nor androgens to aromatize as well as undergo 5α-reduction [4]. We’ll be getting deeper into the underlying mechanisms later but, for now, just understand that subtle modifications to the cholesterol backbone of the testosterone molecule can directly translate into significant changes to the behavior of the new SARM molecule. Some of these changes can include the SARM’s binding affinity for the androgen receptor as well as its binding affinity with numerous enzymes capable of converting SARMs to other steroids [13]. Trenbolone has SARM-like properties in that it has significant less affinity for testosterone’s downstream pathways. We’ll talk much more about this later.

History of Trenbolone

The enormous anabolic potential of trenbolone, as well as its analogs, was reported as far back as the 1960s. There was also an oral version created (methyl-trenbolone), however it has never been marketed as an anabolic agent due to its extreme liver toxicity – causing intrahepatic cholestasis at orally administered amounts as small as 1mg/day [14].

It has never been approved for human use and trenbolone is now primarily used as a growth promoting agent in livestock [15–16]. It is used natively as well as in combination with estradiol (E2) [17]. The use of implants containing the combination of androgenic and estrogenic steroids was approved by the FDA in 1992 [18] and now approximately 90% of beef cattle in the United States are being treated with a growth-promoting mix of estrogens, androgens, and/or progestins [19]. Implants are big business with up to 20 million cattle per year implanted with trenbolone and annual revenues likely exceeding a billion dollars [20].

Despite the FDA’s approval, there are still safety concerns as trenbolone acetate (TBA) and its metabolites have been identified as potential endocrine disrupting chemicals (EDCs). EDCs are exogenous molecules that can mimic or inhibit the action of sexual hormone receptors such as estrogen, androgen and thyroid hormone receptors. These EDCs can also disrupt the synthesis, movement, metabolism, and secretion of naturally occurring hormones which may lead to serious issues down the line including obesity, diabetes and even cancer [21–22].

Because of the potential severity of EDCs, the last two decades has seen higher international attention on environmental exposure, and the effects of EDCs in humans and wildlife [23–24]. As mentioned just a moment ago, TBA and its metabolites have been identified as EDCs through many studies, can be widespread in agricultural environments, and are associated with reproductive toxicity [25, 26, 27]. And it only takes exposure in very low concentrations to cause potential problems, as has been demonstrated in animals like fish with skewed sex ratios and decreased fertility [28].

It will also be important to be able to distinguish the various types of TBA implants, as many of the studies we’ll be reviewing later use different types on their subject animals. What follows is a list of common implant types used in the United States, along with their hormonal concentrations:

Revalor-XS (200mg TBA / 40mg E2)
Revalor-200 (200mg TBA / 20mg E2)
Revalor-H (140mg TBA / 14mg E2)
Revalor-S (120mg TBA / 24mg E2)
Revalor-IS (80mg TBA / 16mg E2)
Revalor-IH (80mg TBA / 8mg E2)
Revalor-G (40mg TBA / 8mg E2)
Synovex PLUS (200mg TBA / 28mg E2)
Synovex-C (100mg Progesterone / 10mg E2)
Synovex-ONE Grass (150mg TBA / 15mg E2)
Synovex-S (200mg Progesterone / 20mg E2)
Synovex-H (200mg Testosterone / 20mg E2)

Metabolism and Physiology

We made passing mentions to TBA’s metabolites, so let’s spend some time getting into the particulars. It is worth restating now that the vast majority of our knowledge on trenbolone’s in vivo metabolism comes from livestock and rodents [29, 30, 31]. It is also paramount to understand that there are marked differences in the amounts of various metabolites observed in rat and cow models, the two most heavily studied mammals [32]. We will circle back around to this in a moment after first going over some more of the basics.

The chemical alias of TBA is 17ß-hydroxy-estra-4,9,11-trien-3-one-17-acetate, sometimes shortened to 17β-TBOH-acetate. Following an intramuscular injection, it is rapidly hydrolyzed to the biologically active metabolite known as 17β-hydroxy-estra-4,9,11-trien-3-one, or 17β-TBOH [33]. From there it is further broken down into metabolites including glucuronides (e.g. trendione/TBO) and five other polar hydroxylated metabolites [34].

As mentioned earlier, there is some variation in the metabolism of 17β-TBOH among mammals as the primary metabolites are 17ß-hydroxy-estra-4,9,11-trien-3-one and Estra-4,9,11-triene-3,17-dione together with their 16α and 16ß-hydroxylated in the rat. In the cow, these metabolites were negligible and 17α-TBOH was the major product together with small amounts of 16α and 16ß-hydroxy-17α-TBOH [29–30].

Fortunately for us, there has been a human trial, which I affectionately refer to as the “human hamburger trial”, that helps elucidate how humans metabolize trenbolone – at least after being orally ingested [34]. The trial was designed to investigate the impacts of ingesting tainted food and therefore the research team injected 17β-TBOH into a 5g piece of fried hamburger, at a dose of 0.04 mg/kg of body weight. After a single oral consumption, 63% of the administered dose was excreted via urine by the 72 hour mark; at 24 hours 50% of the administered dose was seen in urine samples.

The results also revealed that, in humans, ingested 17β-TBOH is primarily excreted intact as 17β-TBOH, as epitrenbolone (17α-TBOH), or as trendione (TBO) – with the vast majority being in 17α-TBOH form. In this respect, the biotransformation of 17ß-TBOH in humans more closely resembles that of cows than rodents. In addition, several yet to be identified polar metabolites of 17β-TBOH have been detected in human urine, albeit in a much lower concentration than those metabolites previously mentioned above [39].

17β-TBOH has a low oral bioavailability because it is not methylated at the 17α position. Results from two Hershberger assays demonstrate that trenbolone was about 80–100 fold less effective via the oral route than via injection [25]. Despite this, TBA and 17β-TBOH have still been shown to disrupt the reproductive system of humans, pigs, mice, rats, and other mammalian species at relatively low dosage levels when administered orally.

In the next part of this article series, we’ll explore trenbolone’s impacts on various anabolic pathways as well as metabolic health markers. We’ll also look at how trenbolone impacts endogenous hormone production and potentially even begin our deep-dive into its effects on anabolism and hypertrophy.
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Old 03-26-18, 12:24 PM
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My 1st true love!
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Old 03-26-18, 03:54 PM
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"human hamburger trial" Awesome
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Old 03-27-18, 07:19 AM
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Originally Posted by rado View Post
My 1st true love!
your tren conversion thread was super popular. you should update that thread though because it seems like people that followed your original directions couldn't get it done. i wonder if the tren pellet makers added an extra step that fucked things up? i don't know shit about it so i'm asking you.
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Old 03-27-18, 08:32 AM
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your tren conversion thread was super popular. you should update that thread though because it seems like people that followed your original directions couldn't get it done. i wonder if the tren pellet makers added an extra step that fucked things up? i don't know shit about it so i'm asking you.
I will update, good point

The step that made it hard for basically everyone, was the drying and drip process...drying more so.

I still have cartridges lol...I should do a video
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Old 03-27-18, 04:46 PM
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Nothing makes me stronger than tren. It doesn’t take much. Even 25mg 3x/week does the job. I hate coming off tren though because my strength drops noticeably in days.
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Old 04-10-18, 05:33 PM
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THE SCIENCE OF TREN PART 2

VI. Effects on HPG Axis
In vertebrates, the hypothalamic-pituitary-gonadal (HPG) axis controls reproductive processes through a variety of hormones which act on target tissues either directly or indirectly. At a high level, in males, gonadotropin-releasing hormone (GnRH) released from the hypothalamus stimulates the pituitary to release luteinizing hormone (LH) and follicle stimulating hormone (FSH). These, in turn, stimulate the release of sex-hormones from the testes [1–2]. The strongly interwoven nature of the HPG axis means that no single component of the system operates in isolation. Upon entering circulation, both androgenic and estrogenic hormones are capable of crossing the blood-brain barrier and exerting negative feedback inhibition on the pituitary and hypothalamus, thereby downregulating GnRH release and suppressing the entire axis [3].

The administration of trenbolone is associated with numerous types of HPG axis disruptions, which is in line with what has been witnessed with various other androgen treatments over the years [4]. Some of the trenbolone-induced disruptions seen over the years include reduced levels of serum LH [5, 6, 7, 8, 9, 10], reduced serum FSH levels [11], reduced testosterone levels [5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16], reduced DHT levels [11], reduced estradiol levels [13,15], testicular atrophy [7,17–18], and a delayed onset of puberty [19]. These effects occur quite rapidly as, was demonstrated in one trial, within ten days of trenbolone enanthate administration, castrated rats had 80% suppression rates of serum testosterone and 70% suppression rates of DHT as compared to control animals [20]. It is worth noting, enanthate is a long ester variant of trenbolone (TBE) so the use of acetate (TBA) would have produced these effects even more rapidly.

It is not precisely understood what mechanisms are behind trenbolone’s suppressive effects on the HPG axis, however there have certainly been some trials over the years which provide clues. One popular hypothesis involves direct hypothalamic feedback inhibition, as evidenced by reduced GnRH transcription seen in the brains of fish models. This may be additive to its direct effects on testicular steroid biosynthesis, as supported by downregulated expression of testicular CYP17 [21]. CYP17 is a very important enzyme in steroid biosynthesis, and sequentially catalyzes two key reactions in the production of sex steroids in males.

It is also interesting to note that whatever the mechanism is, it does not appear to be androgen receptor (AR) dependent [22–23]. Further supporting this line of thought, in ovary tissue cultures from fish, non-aromatizable androgens such as trenbolone had direct and non-genomic, anti-androgen-insensitive inhibitory, effects on estrogen production [24]. It is highly likely that the underlying feedback mechanisms at work are similar to other androgens, resulting in inhibited GnRH levels and ultimately inhibited FSH and LH production [25].

One other potential gene candidate involved in decreased sex steroid concentrations, noted in fish trials in which they had been exposed to the strong exogenous androgen 17-trenbolone, is hydroxysteroid (17β) dehydrogenase 12a (hsd17b12a). Hsd17b12a catalyzes the conversion of androstenedione to testosterone which, in turn, is converted to 17β-estradiol by the aromatase enzymes. Thus, down-regulation of hsd17b12a, as seen in these trenbolone-exposed fish, is predictably expected to lead to declines in both testosterone and estradiol [14].

VII. Effects on Anabolic Pathways
As we’ve covered previously, trenbolone expresses SARM-like behaviors and I’d like to use this section to discuss them in more depth.

5α REDUCTASE
Despite a structural similarity to testosterone, trenbolone does not undergo 5α reduction due to the presence of a 3-oxotriene structure which prevents A ring reduction [26]. This is the pathway used for converting testosterone into its more potent form dihydrotestosterone (DHT). As trenbolone is not a substrate for 5α reductase, it has been shown to stimulate less pronounced androgenic effects than testosterone in androgen-sensitive tissues which express the 5α reductase enzyme, including the prostate and accessory sex organs [27, 28, 29. 30. 31, 32]. To put this statement into perspective, testosterone has an approximately three-fold higher potency in androgenic tissues that express 5α reductase despite having a significantly lower binding affinity to the AR than trenbolone [33]. We’ll discuss how this impacts hypertrophy potential in these tissues a bit later.

As you can already start to imagine, one particular reason trenbolone is beginning to pick up steam in scientific communities is due to its potential to lower the risks associated with prostate cancer in those patients being treated for hypogonadism. The current de facto treatment strategy for these individuals includes providing them with testosterone, in a manner designed to restore hormone levels to natural reference ranges. However, in adult males, benign and malignant growth of the glandular prostate tissue is largely regulated by sex hormones. And furthermore even moderate increases in circulating testosterone have been shown to directly translate into pronounced hyperplastic effects in prostate tissues, mediated via its 5α reduction into DHT [34–35]. Later in the article, we’ll dig deeper into the available literature to see if trenbolone’s potential to lower prostate cancer risk actually pans out.

AROMATASE ENZYME
Seemingly one of the more asked about questions is whether or not trenbolone has impacts on serum estrogen levels, as well as whether or not it can aromatize like testosterone. Popular opinion in the scientific community is that trenbolone and other 19-nor compounds are not substrates for the aromatase enzyme [36–37]. With that said, please understand this is not the same thing as saying they cannot convert to estrogen as C19 norandrogens can induce estrogenic effects [38–39].

Following this line of thought, trenbolone-itself is largely thought to be non-estrogenic [40–41] and there have been numerous animal trials that have demonstrated it reduces serum estradiol concentrations [13, 14, 15, 42, 43, 44]. Keep in mind that there have been a few trials that did not show this suppressive effect on estrogen levels [10,45–46] but, by and large, the body of literature as a whole does support the hypothesis that trenbolone possesses anti-estrogenic effects.

Based upon what we now know about the HPG axis, this would tend to make a lot of sense as the anti-estrogenic effects caused by trenbolone administration likely have to do with its negative feedback on the axis. This negative feedback would cause the inhibition of endogenous testosterone production, thereby leading to suppressed levels of aromatization via the aromatase enzyme, which is necessary for endogenous estrogen biosynthesis in males. This impact on the HPG axis would cause a more severe rate of estrogen inhibition as compared to any potential direct effects trenbolone would have on estrogen receptors and/or the aromatase enzyme [5–6, 8, 21, 47]. There may even be a secondary mechanism at work here which is related to trenbolone’s ability to downregulate expression in both the estrogen alpha and beta receptors [48].

There have been some other interesting discoveries with regard to the mechanisms behind trenbolone’s relationship with estrogen, as well as the compensatory responses associated with suppressed hormone levels. Trenbolone has been shown to reduce tissue concentrations, and gene expression, of VTG (vitellogenin) which is a protein positively associated with exposure to estrogenic compounds [13–14,21,41,47,49,50,51,52,53,54]. It has also been shown to downregulate brain CYP19B (aromatase B) and upregulate gonadal CYP19A (aromatase A) in female fish, but interestingly not in males [14,54].

Similar to what we’ve seen already in the HPG axis, the impacts of trenbolone on estrogen do not appear to be AR-dependent as trials have shown co-treatment with an AR antagonist (flutamide) resulted in the same anti-estrogenic activity in fish [13]. Interestingly, there has been another fish trial that reported trenbolone to have low-affinity with the estrogen receptor and can potentially even activate it [44]. Whether or not this is species-specific is a matter of debate, as I have not seen this occur in any other trials I’ve reviewed. However, cell culture experiments and bioassays do show that trenbolone and its metabolites have a very low binding affinity with estrogen receptors, roughly 20% of the efficacy of estradiol [40].

So can it aromatize? Although I have found nothing which definitively suggests it can, there has been a hypothesis thrown out there by Holland et al [55] which I find intriguing enough to include in its entirety:

“We previously reported that trenbolone enanthate potently reduced visceral fat mass in young and older ORX animals, indicating that fat loss occurs in response to androgen administration, even in the absence of an androgenic substrate for aromatase. However, our previous work did not account for the possibility that androstenedione (derived from dehydroepiandrosterone) can be aromatized to estrone and, subsequently, converted to E2 by actions of 17β-hydroxysteroid dehydrogenase in tissues, such as fat, expressing the required enzymes”

PROGESTERONE/SHBG
Trenbolone has been shown to have a high affinity for the bovine progestin receptor, and it is assumed that it has a similar affinity to the progesterone receptor as progesterone itself [56]. In vitro analysis has revealed that the relative binding affinity to the bovine progesterone receptor, as compared to progesterone, was 137.4% for 17β-TbOH and 2.1% for 17α-TbOH [57]. And finally, the relative binding affinity of trenbolone to human SHBG, as compared to DHT, is 29.4% for 17β-TbOH and 94.8% for 17α-TbOH.

VIII. Effects on Metabolic Health Markers
One of the primary reasons the anti-trenbolone crowd admonish against its use is related to how harsh the compound seemingly is on one’s health markers. I had hoped to have some actual reference blood work to add to this article, however unfortunately my crowdsourcing efforts were not successful as not many individuals run trenbolone by itself. So what I will do in this section is go over the available animal literature covering various health markers and trenbolone’s impacts upon them.

THYROIDAL AXIS
Arguably the most intriguing relationship to me is trenbolone and the thyroidal axis. Although the effects have been a bit inconsistent, there does seem to be a pattern which suggests trenbolone has an overall suppressive effect on the thyroidal axis. In one trial, trenbolone-alone decreased T4 in heifers while trenbolone plus estradiol decreased T4 in steers, while no impact was seen on T3 uptake [58]. In another trial, trenbolone plus estradiol actually increased T3 whereas trenbolone by itself decreased both T3 and T4 [59]. We must remember that estradiol stimulates the GH/IGF axis, which acutely increases the conversion of T4 to T3. This may help to explain why co-treatment with estradiol can result in higher T3 levels whereas trenbolone-only has the opposite effect, as estradiol levels are highly suppressed. Even in trials where thyroid levels are not significantly different, trenbolone decreased fasting metabolic rates, leading to less intake requirements for creating intake surplus [60].

Therefore, it may be reasonable to speculate the increased feed efficiency seen in numerous studies over the years could be related to trenbolone-mediated suppression of metabolic rate. Of course, it should be noted that leaner cattle just tend to grow faster, and use feed more efficiently, so it also may just be a byproduct of this [61]. Before I wrap this article series up, I’ll talk a bit more about the practical applications here and why these impacts may want to be considered when deciding how to use trenbolone for bodybuilding purposes.

CHOLESTEROL
Generally speaking, there is a strong correlation between fat loss and favorable changes in serum lipid levels, particularly in men [62–63]. Therefore, because trenbolone has been consistently shown to improve body composition, it is reasonable to speculate that it may have favorable impacts on lipid markers. So, let’s see what animal trials have shown us.

Studies on rats have shown that both testosterone and trenbolone elicit similar protections against elevated cholesterol despite trenbolone’s ability to elicit more visceral fat loss. This suggests that serum cholesterol levels may be governed primarily by overall body composition, independently of changes in visceral stores. In one trial, serum total cholesterol, HDL, and LDL were all significantly lower in trenbolone-treated intact rats than in control rats (- 62%, – 57%, and – 78% respectively). The byproduct of this was that treated rats had a greater HDL:LDL ratio. Serum triglycerides were also significantly decreased by 51% as compared to control rats [15]. In another trial, both testosterone and trenbolone reduced circulating cholesterol in rats fed a high fat and high sugar diet, but only trenbolone reduced circulating triglyceride levels [64].

It is strongly suggested to keep an eye on cholesterol levels when using supraphysiological doses of androgens, as they tend to have the ability to increase catecholamine-stimulated hormone-sensitive lipase (HSL) activity in both the liver and cardiac tissues [65–66]. This increased HSL activity tends to result in an increased rate of triglyceride breakdown and suppressed rates of HDL hydrolyzation. Having chronically suppressed levels of HDL seems to be an independent cardiovascular risk factor so prolonged use of androgens resulting in suppressed HDL levels should be done with extreme caution [67]

LIVER MARKERS
There are quite a few hepatic markers commonly used to assess overall liver functionality and health, as well as hepatic damage. Albumin is a marker indicative of overall liver function while AST, ALT, ALP are all general markers of hepatic damage.

Recent rodent trials have shown that trenbolone does not appear to induce significant damage to hepatic tissues. In one trial, hepatic tissue samples of trenbolone-treated rats showed a similar morphology to those of control rats. AST, ALT, ALP, and albumin were all at similar level in trenbolone-treated rats as compared to control [15]. In a follow-up trial, similar liver enzyme values were seen with rats fed high fat and high sugar diet in all treatment groups, including testosterone and trenbolone treatments [64].

INSULIN
This is another hormone that tends to have a direct correlation with body fat, and specifically visceral fat levels. Visceral fat accumulation and elevated circulating triglyceride levels are both associated with insulin resistance [68]. Conversely, calorie restriction and weight loss in viscerally obese non-diabetics induced significant improvements in insulin sensitivity [69]. In addition to obesity, there is also compelling evidence which shows that low androgen levels also promote insulin resistance [70]. It has been hypothesized that trenbolone treatment in animal models may promote insulin sensitizing effects through similar mechanisms to those achieved by calorie restriction in human males so let’s see what the trials have actually demonstrated.

One trial showed serum insulin to be significantly lower in trenbolone-treated rats (38% reduction) as compared to control rats which translated into a significantly lower HOMA-IR value, a metric used to measure insulin resistance [15]. Fascinatingly, rats being fed high fat and high sugar diets had significantly elevated serum insulin levels that were only partly restored with testosterone, yet trenbolone significantly reduced insulin levels [64]. In fact, trenbolone was also the only treatment group to reduce HOMA-IR values indicating increased beta-cell function and lowered insulin resistance. So albeit limited, the evidence does suggest that trenbolone has superior insulin sensitizing effects as compared to testosterone.

Adiponectin is a 30 kDa insulin sensitizing adipokine that is primarily secreted by visceral adipose tissues [71–72]. Generally speaking, serum adiponectin levels are inversely proportional to fat mass [73]. Testosterone and trenbolone tend to reduce total adiponectin levels to a similar degree in rats [74].

ERYTHROPOIESIS
Erythropoiesis is just a fancy term for the body’s production of red blood cells (RBCs). One of the most commonly reported side effects of TRT treatments tends to be elevated levels of hematocrit and hemoglobin. Specifically, androgen deprivation reduces both hematocrit and hemoglobin whereas testosterone administration results in a dose-dependent increase in both [75–76].

The mechanisms by which androgens augment RBC production may be directly related to stimulation of kidney erythropoietin secretion or even bone marrow [77]. And based upon existing evidence, it would appear as if androgens directly elevate erythropoiesis via AR-mediated mechanisms [11]. It does not appear as if the aromatization of testosterone is required for erythropoiesis as DHT administration also increases the process in male subjects [78]. Furthermore, it has also been demonstrated to occur in male subjects with aromatase-deficiencies [79]. Similarly, 5α reduction of testosterone does not appear to be required for erythropoiesis as the co-administration of testosterone and finasteride (5α reductase inhibitor) increased both hematocrit and hemoglobin to the same extent as testosterone alone despite 65% lower DHT concentrations in the finasteride group [80].

If trenbolone can reduce the elevations of hematocrit and hemoglobin seen with traditional TRT treatments, then this would be another potential reason it could be an interesting candidate for HRT. Let’s see what the trials indicate.

Preliminary evidence indicates that trenbolone increases hemoglobin in male rodents in a dose-dependent manner, and to a slightly greater extent than supraphysiological testosterone (8-10%), despite DHT being suppressed by over 70% following administration [20]. In another trial, at administered doses which were seven times higher than testosterone, trenbolone treated rats had nearly identical levels of hemoglobin, although both were significantly elevated as compared to controls [81].

Okay, I think this is a natural stopping point for part two. In part three, we’re going to begin to dive into the more exciting stuff as we cover anabolism and hypertrophy. Depending on how deeply we dive on the topic, it may be all we cover in part three. However, we also may cover lipolysis and some other fun topics if time permits. So, until next time…
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Old 04-10-18, 05:35 PM
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The Science of Trenbolone Part 3

IX. Anabolism
Before we get into the studies, it is important to point out that there are differences between humans and the animals most commonly used in trenbolone studies (e.g. sheep, mice, cows, etc). As we dive deeper into the studies, I’d like for us to all keep these differences in mind, as they can certainly impact the relevancy to humans.

Most rodent skeletal muscle possesses a very low percentage of AR positive nuclei. An example is the extensor digitorum longus, located near the front of the leg, with only 7% AR positive myonuclei [1]. This is not universally true, as the levator ani/bulbocavernosus (LABC) muscle complex (located near the pelvis) contains 70-75% AR-positive myonuclei and experiences robust myotropic response to androgen administration [2,3,4]. So, if you are comparing multiple rodent studies, and they used combinations of these muscles in the trial, then you can likely expect a wide disparity in results.

Conversely, cattle are generally highly sensitive to androgen-induced stimuli due to high concentrations of ARs in bovine skeletal muscle and satellite cells [5,6,7]. We’ll need to further understand that bulls are mature, and intact, males whereas steers are males that have been castrated before reaching sexual maturity. The vast majority of trials are going to be performed on steers as implantation of trenbolone does relatively nothing to intact bulls. They are likely already at their maximum growth potential with their elevated endogenous hormone levels, however combined TBA/E2 implants are necessary to produce maximum growth and feed efficiency in castrated steers [8]. Heifers are young females that have never calved; they are also used on occasion for implantation trials.

Intact bulls produce very high levels of testosterone. In addition to having a very poor response to implantation, they also generally have larger muscle fibers than steers [9]. Bulls also tend to have a higher percentage of fast-twitch oxidative-glycolytic fibers combined with a lower percentage of fast-twitch glycolytic fibers in the longissimus dorsi (LD) muscles than steers have [10]. It is for these reasons that bulls produce higher total carcass yields but they are generally lower quality grade. Castrated steers tend to have more external fat and marbling however they are offset by a decreased rate of weight gain and lower feed efficiency. So in the quest for higher yields with higher quality meat, researchers began to investigate anabolic implants to see if they can produce the best of both worlds.

Lastly, a quick little side-note – humans are quite similar to cows in that we also respond robustly to androgenic stimuli due to the high percentages of AR-positive myonuclei [11].

Androgen Receptor Affinity
Trenbolone has been shown to bind with both the human AR, as well as ARs of various other species, with approximately three times the affinity than testosterone, or approximately equal to that of DHT [12,13,14,15,16]. In human ARs, the active metabolite 17β-TbOH showed a 109% binding affinity as compared to DHT, with the inactive metabolite 17α-TbOH coming in at 4.5% [13]. With this said, receptor binding studies should be seen as a cheap and rapid tool for an initial evaluation of a ligand, not factoring in things such as subsequent initiation of gene transcription, etc. In other words, because trenbolone binds with a three times higher affinity than testosterone to the AR, this does not literally mean it will produce three times the hypertrophy.

Furthering this point, in comparison trials, trenbolone was shown to produce either equal or slightly greater growth in the LABC muscle complex as compared to testosterone [14,17,18,19,20,21,22]. The LABC is an androgen responsive tissue which lacks the 5α reductase enzymes. Whereas testosterone exerts enhanced effects in tissues expressing 5α reductase, trenbolone exerts equal effects in those tissues versus those that do not which produces a favorable anabolic:androgenic ratio compared to testosterone [23]. We’ll go more into this when we discuss prostate cancer risks later in the article series.

X. Hypertrophy
I had originally planned to do a very deep-dive into the mechanisms behind hypertrophy however I think that may be better done in its own article as it is a very complex topic. I will still need to cover the foundational elements of hypertrophy though, or else a lot of this topic may be more confusing than it needs to be. So therefore, I will not be diving too deeply in intracellular signaling pathways, as this would take this article and make it unnecessarily inflated. If there is enough interest, perhaps an article on that topic can be a future project.

Hypertrophy Fundamentals
Before we get into the studies, let’s talk a little about what hypertrophy is and how it occurs in mammals. Again, this is going to be more of a high-level pass at the topic but hopefully deep enough that the terms used later will be better understood.

The number of muscle fibers in mammals is essentially fixed at birth, so postnatal muscle growth must result from the hypertrophy of existing muscle fibers. This fiber hypertrophy requires an increase in the number of myonuclei present within these fibers; however the nuclei present in muscle fibers are unable to divide, so the nuclei must come from outside the fiber [24]. The source of the nuclei needed to support fiber hypertrophy happen to be a group of mononucleated myogenic cells (satellite cells) located between the basal lamina and the plasma membrane (sarcolemma) of muscle fibers [25]. There is a strong correlation between rates of postnatal growth and the rates at which satellite cells accumulate within muscle tissues. This would seemingly make sense as there will be more overall machinery available to fuel the hypertrophy process [26].

These muscle satellite cells play a crucial role in postnatal muscle growth by fusing with existing muscle fibers, providing the nuclei required for postnatal fiber growth. In newborn animals, a much higher percentage of muscle nuclei are satellite cells, but this percentage significantly decreases with age [27]. Not only is there a reduction in satellite cell numbers, but those cells still present withdraw from the proliferative state of the cell cycle and enter a state of quiescence, which consequently leads to a growth plateau. So finding ways to overcome these physiological limitations can hypothetically lead to superior postnatal growth rates.

To ensure there are adequate numbers of usable satellite cells, they first must be activated which will allow them to progress through the cell cycle and ultimately contribute DNA to the existing muscle fiber. After these dormant satellite cells have been activated, there is subsequently a need for growth factors capable of stimulating satellite cell proliferation and differentiation. Both IGF-1 and fibroblast growth factor-2 (FGF-2) are examples of potent stimulators of satellite cell proliferation [28–29]. IGF-I is unique in that it promotes muscle cell differentiation in skeletal muscle, whereas FGF-2 inhibits differentiation [30]. I’ll talk more about the relationship between trenbolone and IGF-1 a bit later in the article.

So taking a slight step backward, when a hypertrophy activation event occurs (e.g. exercise or muscle damage) it leads to satellite cell proliferation. This satellite cell proliferation causes them to fuse with existing muscle fibers, providing new nuclei for hypertrophy and repair, and to support ramped-up protein synthesis. An overly-simplified way to think about this – satellite cells can be activated to proliferate (divide) and donate their DNA (nuclei) to the existing muscle fiber (differentiation).

This donated DNA leads muscle fibers to form the fusion of myoblasts (proliferating cells) into multinucleated muscle fibers called myotubes. These myotubes may fuse to existing myofibers, or even each other, directly generating new muscle fibers. This is about as deeply as I want to take this topic for now.

Growth Promoting Effects
The growth promoting effects of trenbolone are well-known and have been studied by researchers for decades. The goal has always been to find ways to promote greater meat yields along with a higher quality finished product. We’ll focus primarily on the meat yields for now, as the quality of meat often tends to coincide with the amount of intramuscular fat content. This falls more into the realm of lipolysis, which we’ll be covering later in this article series.

Trenbolone has been shown to increase total body growth and skeletal muscle mass in various animal trials when administered alone [3, 14, 17, 19, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44], in combination with estradiol [45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66], in combination with testosterone and estradiol [67], as well as in combination with estradiol plus growth hormone [68]. This hypertrophy potential is pretty much universally observed, and crosses many different administration methods as well as species of animals.

Interestingly, numerous studies have shown that a combined TBA/E2 implant is more effective than either TBA or E2 alone in stimulating the growth of feedlot steers [8, 45, 52, 54–55, 69, 70, 71, 72, 73, 74]. The hypothesis that estradiol enhances the anabolic effects of trenbolone has been floating around as far back as the 1970s [75–76]. Potentially even more interesting is that the combined treatment increases hypertrophy potential despite the fact that it results in serum trenbolone levels which are actually lower, by roughly half [8].

One of the reasons I suspect this to be the case, particularly in steers, is that implantation with trenbolone suppresses endogenous estradiol levels due to its impacts on the HPG axis. Estrogen and, more specifically, aromatase activity is a potent stimulator of the GH/IGF axis. Supporting this hypothesis, implantation with trenbolone-only has been shown to lower, serum GH levels [8,68,69,70,71]. Conversely, steers implanted with E2 alone have been shown to have increased circulating concentrations of both GH and IGF-1 [77–78]. These combined TBA/E2 implants likely result in increased GH levels, and may even alter the number and/or affinity of GHRs in tissues such as the liver [79]. As we learned earlier, having adequate growth factors to stimulate satellite cell proliferation and differentiation is a crucial step in the hypertrophy process.

Optimal TBA / E2 Ratios
Since combined treatments seem to have enhanced anabolic characteristics, many trials over the years have attempted to answer the question what is the optimal TBA/E2 ratio for eliciting maximal growth ratio? There have been some that proclaim the answer lies somewhere between 5:1 and 8:1 [52,54] however results have varied quite a bit over the years. In fact, in one trial, average daily growth rates (ADG) were quite similar in steers implanted with either 25mg E2, 120mg TBA, or a combined 120mg TBA + 24mg E2 implant [80].

Another trial demonstrated that 120mg TBA + 24mg E2 increased average rates of gain by 20-25% and feed efficiency by 15-20% [55]. In fact, it has been shown that combined treatments lead to 50% more actively proliferating satellite cells from the semimembranosus muscle (hamstring) of control steers [81]. As you recall from earlier, the proliferation of satellite cells is a crucial step in the hypertrophy process. Other trials have similarly shown a trenbolone-induced increase in both satellite cell activation and proliferation [82–83]. It appears that trenbolone and testosterone increase satellite cell numbers per muscle fiber to a similar degree [22] so this is not a unique effect of trenbolone. Its effects on satellite cells may be, at least partially, mediated via the IGF-1 receptor as inhibition of several downstream targets of IGF-1 (e.g. MAPK, MEK/ERK, PI3K/Akt) suppressed trenbolone-induced satellite cell proliferation in cell cultures [7].

In 2007 the FDA approved Revalor-XS which is 200mg of TBA + 40mg of E2, designed to have a delayed release of hormones due to a specialized polymer coating on six of the ten pellets in the pack. This is beneficial as traditional implant methods require multiple implants having the potential to add stress which could negatively affect cattle performance. Much of the variation in trial results over the years could very well be related to this. Trials investigating Revalor-XS have found that the higher dose of TBA/E2 improved steer performance when steers are on feed for longer periods [65,140]. Despite the speculation that multiple implants can cause added stress to steers, the delayed release pattern of Revalor-XS did not actually provide any unique effects on steer performance, or quality grade, when compared with a reimplantation strategy of an equal TBA + E2 dose.

Effects of IGF-1
TBA/E2 implants have been shown to significantly increase IGF-1 levels. These combined treatments have resulted in increased serum IGF-1 levels [59,84,85,86], increased hepatic IGF-1 mRNA expression [56], and increased IGF-1 mRNA expression in skeletal muscle tissues [59,61,81].

TBA-only implants have also been shown to increase IGF-1 levels in various species, however not nearly to the degree of combined implants [87,88,89]. In fact, trenbolone does not significantly increase either autocrine or endocrine IGF-1 in a manner greater than testosterone. One trial even demonstrated that testosterone increases autocrine IGF-1 levels slightly higher than TBA [4]. Evidence seems to suggest that any effects on IGF-1 may be mediated via estradiol, and may even be stimulated via distinct androgen and estrogen receptor mechanisms, which include involvement of the G-protein-coupled receptor (GPR30) [90]. One trial in particular found that increased autocrine expression of IGF-1 in skeletal muscle requires estrogen, and TBA-only implants resulted in no increases in muscle IGF-1 mRNA levels [91]. It is certainly reasonable to speculate that there may be a threshold that must be met, which may not be realistic to see in animal trials. Let’s move along to cell studies to see if this hypothesis pans out.

In vitro studies using bovine satellite cells (BSCs) showed a dose-dependent relationship between trenbolone and IGF-1 mRNA levels. In the cells treated with 1nM or 10nM of trenbolone for 48 hours, IGF-1 mRNA levels were 1.7 times higher, however mRNA levels were not affected by treatments of 0.001, 0.01, or 0.1nM [92]. It also appeared that the effects were at least partially mediated via the AR as co-treatment with flutamide (AR inhibitor) completely negated the increased IGF-1 expression seen in these cultures [90].

It does not take much time at all to see increased levels of IGF-1 after an implantation. In one trial, lambs implanted with Revalor-S (120mg TBA / 24mg E2) showed increased serum IGF-1 levels by day 3 and day 10 of 43% and 62% respectively [56]. This increased IGF-1 was maintained for the entire 24 days of the study and steady state hepatic IGF-1 mRNA levels were 150% higher in implanted lambs than in controls, suggesting the liver is likely a primary source of the increased circulating IGF-1. Autocrine IGF-1 mRNA levels were also 68% higher in the longissimus muscles of implanted lambs than were seen in controls. The dosage of TBA and E2, per kilogram of body weight, was approximately three times higher than that approved for use in steers though. Because of the species and dosage differences, caution should be used when trying to take these results and apply them to steers.

Using this same dose in steers has been shown to produce higher serum IGF-1 levels as compared to non-implanted cattle, within 6-42 days of implantation [93]. Within only 48 hours, implanted steers had a 13.4% increase in serum IGF-1 concentrations [84]. On days 21 and 40, implanted steers had 16% and 22% higher IGF-1 levels as compared to controls. Now where it gets interesting is that IGF-1 levels peaked during this timeframe and subsequently began falling through day 115 of the study where they ended up similar to day 1 values. With that said, control steers still had lower IGF-1 levels than day one. So although the increases in IGF-1 levels appear transient, implants still seem to provide an overall additive effect, even with long-term use.

Other trials on cattle have shown muscle samples with higher IGF-1 mRNA within 30-40 days of implantation [56,61]. These implanted animals also showed more proliferating satellite cells than non-implanted steers suggesting TBA/E2-induced increases in muscle IGF-I may be at least partially responsible for the muscle growth observed in implanted steers. As we discussed earlier, it is well established that postnatal muscle growth depends on fusion of satellite cells with existing fibers to provide myonuclei necessary to support growth [24]. This increase is also important because only a small number of satellite cells are present at this time in yearling cattle, and many of the existing cells have become quiescent or left the cell cycle. It is also worth mentioning that IGF-1 overexpression extends the replicative lifespan of satellite cells, at least in cell cultures [94]. Therefore, it seems reasonable to hypothesize that increased muscle IGF-I expression plays a role in the AAS-induced increase in muscle satellite cell numbers.

In another trial, hepatic steady state IGF-1 mRNA levels were shown to be 69% higher in implanted steers, again suggesting that the liver may be a large contributing factor to increased circulating IGF-1 in implanted animals [61]. Please note that there has been at least one study, which I’m aware of, to show no differences in IGF-1 concentrations between implanted steers and control cattle [95]. This would tend to be the exception and not the rule, however.

An androgen response element (ARE) has been identified in the promoter region of the IGF-I gene, suggesting that the androgen receptor-ligand complex may interact with this ARE to stimulate transcription of the IGF-I gene. Androgens tend to act via multiple mechanisms on muscle though, and estrogen tends to act on the hypothalamus/anterior pituitary to stimulate GH/IGF axis [96]. The relationship between estrogen and the GH/IGF axis has been shown to be additive [97–98].

Estrogen Primer
Since we are kind of heading this direction anyway, let’s take a brief moment to focus our attention more on estrogen before moving forward.

In vitro studies have shown that treatment of bovine satellite cell cultures for 48 hours with E2 significantly increases IGF-1 mRNA expression [92]. This is in line with what we already know about E2, as it has been shown to stimulate expression of IGF-1 mRNA in a number of tissues [99–100]. Interestingly enough, co-treatment with ICI (estrogen receptor antagonist) did not suppress this E2-stimulated IGF-1 expression. This seems to suggest that the mechanism by which E2 stimulates IGF-I mRNA expression in BSCs may be different than the mechanism acting in other tissues which have been examined to date.

Even though the IGF-I gene does not contain a traditional estrogen response element (ERE) in its regulatory region, E2-stimulation of IGF-I mRNA expression can occur via a pathway involving the AP-1 enhancer [101]. As mentioned previously, in addition to the classical estrogen receptors, G-protein-coupled receptor 30 (GRP30) may play a role in mediating the actions of estrogen [102,103,104]. This is relevant to our interests as muscle tissue contains GPR30 mRNA and immunohistochemical studies have localized GPR30 receptor protein within skeletal muscle cells [105]. Furthermore, the effects of GPR agonist/antagonist strongly indicate the GPR30 receptor is involved in the E2-stimulated increase in IGF-1 mRNA observed in bovine satellite cell cultures [90].

Effects on Muscle Fibers
Implantation with TBA/E2 increases the cross-sectional area (CSA) of muscle fibers due to an initial increase in DNA transcription followed by an increase in nuclei within the muscle fiber which support hypertrophy [106]. TBA (either alone or in combination with E2) has traditionally been shown to increase the CSA of type I but not type II muscle fibers [9,107]. Combined implantation of feedlot steers has also been shown to increase type I and IIA CSA in LM muscles [110]. There have been exceptions, as one trial has been shown to increase type IIB fibers without any impact on the size or number of type I fibers [57]. These trials, when taken as a whole, seem to suggest that trenbolone induces a fiber switch from more glycolytic to more oxidative fibers, which indicates an increase in the oxidative capacity of the skeletal muscle fibers.

Getting back to the potential differences seen in species, despite the increase in muscle weight and muscle fiber size, the number of myonuclei per fiber was not enhanced with rats being administered either trenbolone or testosterone [22]. This contradicts the results from an earlier trial, however testosterone was administered beginning at the onset of puberty which is a rapid growth phase for the LABC muscle versus the more mature muscles in the previous study [108]. It is highly likely that androgen-induced hypertrophy in adult rats without exercise stimulus may not require myonuclear addition [109], which kind of goes against the grain of what we’ve been talking about the entire article. But these are also exactly the types of things to keep an eye out for when looking over animal trials and trying to establish patterns which may be potentially translated to humans.

Effects of Androgen Receptors
There have been multiple in vitro experiments that indicate trenbolone upregulates AR mRNA expression [111–112]. There does appear to be a ceiling effect though, where higher doses fail to alter mRNA levels to a degree relative to those present in untreated control cultures [92].

This has not universally been demonstrated in trials however, as some have shown no trenbolone-mediated effects upon AR mRNA expression [4,91]. This discrepancy may be because the elevated AR expression occurs at an earlier time point than data collection was taken in these trials, but that is speculative. In vitro evidence also indicates trenbolone induces translocation of human ARs to the cell nucleus in a dose-dependent manner, and it also stimulates gene transcription to at least the same degree as DHT [14].

XI. Atrophy / Anti-Catabolism
Trenbolone’s reputation as a muscle-preserving hormone is actually well deserved. I would like to briefly go over the basics of skeletal muscle atrophy before diving into the literature associated with trenbolone-specifically.

During various catabolic states, the ubiquitin-proteasome pathway increases protein breakdown leading to skeletal muscle atrophy. Specifically two ubiquitin ligases, MuRF1 and MAFbx (also called Atrogin-1) serve as markers of skeletal muscle atrophy under these various catabolic states such as fasting, cancer, renal failure, and diabetes [113,114,115]. Trenbolone has been shown to significantly decrease MuRF1 and atrogin-1 mRNA expression in the skeletal muscle tissues by a factor of 3 in castrated rats. Atrogin-1 rates were suppressed in these animals to an even greater degree than testosterone administration [4].

Glucocorticoids
Glucocorticoids are steroid hormones which help regulate whole-body metabolic homeostasis. They also exert their influence on skeletal muscle with elevated exposure to them potentially leading to atrophy of tissues. The major members of the glucocorticoid family are cortisol, corticosterone, and cortisone. They bind with the intracellular glucocorticoid receptor (GR) where they activate and exert their effects. It is worth mentioning that cortisol can bind to both the GR and mineralocorticoid receptor (MR), however a deep dive on this is beyond the scope of this article series.

Trenbolone has been shown to lower glucocorticoid binding capacity by causing a decreased number of GRs in skeletal muscle tissues [36,116]. In vitro studies have demonstrated trenbolone to act as a glucocorticoid receptor antagonist [14] despite 17β-TbOH possessing only a 9.4% relative binding affinity to the bovine glucocorticoid receptor as compared to cortisol [13]. Other studies have shown that trenbolone reduces the ability of cortisol to bind to skeletal muscle GRs as well as downregulating overall GR expression [117–118]. In fact, trenbolone suppresses GR expression 50% more than testosterone [4]. And its anti-glucocorticoid actions likely help it produce a significantly more robust inhibition of muscle protein breakdown (MPB) than testosterone, which only slightly reduces MPB while simultaneously increasing MPS [119].

Trenbolone has been shown to reduce circulating corticosterone concentrations in rodents [37,39,116,120] as well as cortisol in implanted cattle [50]. Evidence suggests that trenbolone works in the adrenals to suppress ACTH-stimulated cortisol synthesis as well as suppressing cortisol release [121].

We may now try and extrapolate a bit further on what these lowered glucocorticoid levels may do. For example, glucocorticoids inhibit glucose uptake and help stimulate glycogen breakdown in skeletal muscle by attenuating insulin-induced GLUT4 translocation to the cell membranes [122]. Insulin signaling in muscle tissues is essentially suppressed by glucocorticoids [123]. With this said, is it possible that trenbolone administration could create an environment of enhanced glucose utilization? We’ve already seen its ability to increase insulin sensitivity in rat models, what if one were to run it alongside exogenous insulin?

Glucocorticoids also tend to increase intramuscular triglyceride levels [124]. Is it thereby reasonable to speculate that the cosmetic effects traditionally attributed to trenbolone may have something to do with this? If trenbolone is reducing intramuscular triglyceride levels, then could this be a primary factor behind why many tend to have drier looking muscles? I’ll circle back to some of these questions in my closing remarks of the article series.

Effects on Protein Synthesis and Breakdown
One of the more amusing bits of information on trenbolone is that the rate of muscle protein synthesis (MPS) actually decreases with administration. This has been demonstrated in trials with either TBA implants or TBA+E2 implants [17,32,48]. Many folks hear this and wonder how trenbolone can be such a potent anabolic when it reduces MPS rates? The key here goes back to trenbolone’s impacts on MPB, as it is very adept at lowering rates of MPB to a greater degree than MPS, which results in a net-anabolic state.

In fact, despite lowering rates of MPS, trenbolone has been shown to increase whole body nitrogen retention in various species [32,125,126,127]. Again, this has a lot to do with trenbolone’s impacts on MPB rates. It has been shown to cause significantly decreased rates of total and myofibrillar MPB in various species [32,34,36,120,128].

It is worth noting that in vitro studies have actually shown trenbolone-induced concentration-dependent increases in MPS rates. They can be significant, with up to a 1.7-fold increase using the highest 10 nM dose in the study [129]. So, similar to what we saw earlier with IGF-1 expression, there may be a point where trenbolone stops suppressing MPS and begins increasing it. It is likely this point extends beyond realistic real-world use cases though, as in vivo studies in various animals do not show this same effect. In these cells, rates of protein degradation were also lowered, with the highest dose of TBA causing rate of degradation to be 70% of that shown in cultures with no TBA. This was, at least, a partially AR-mediated effect as flutamide suppresses trenbolone’s ability to stimulate protein synthesis as well as suppress protein degradation rates. Treatment of the cell cultures with JB1 (IGF-1 inhibitor) also impacts trenbolone’s effects on protein synthesis/degradation so it is highly likely these effects require both the AR and IGF-1 receptor to some degree.

Trenbolone has also been shown to suppress amino acid degradation within the liver [37,130]. This can also be a key factor to the overall effects on MPB, as the first step in amino acid degradation takes place there – the removal of nitrogen. In fact, the major site of amino acid degradation in mammals is the liver.

Effects on Bone
Age-related hypogonadism is a major factor contributing to the loss of bone in older men [131]. As we’ve discussed previously, the de facto treatment for hypogonadism is testosterone (TRT). The problem is that TRT only produces modest improvements on bone mineral density in treated subjects [132–133]. Conversely, supraphysiological doses of testosterone fully protects against bone loss, however it comes with a lot of unwanted side-effects [134,135,136]. So, we are back at the place we were at earlier, where we are looking for the protective effects of supraphysiological doses but without the unwanted sides.

Early indications are promising as rodent trials demonstrate trenbolone prevents hypogonadism-induced bone loss in castrated rats to a degree equal to that of supraphysiological testosterone, but without inducing prostate growth or elevations in hemoglobin which are frequently seen with testosterone treatments [3,20].

Trenbolone potentially exerts part of its influence on bone through reductions in circulating corticosterone, via its anti-glucocorticoid activity [14,39]. And, despite trenbolone suppressing estrogen, it still possesses bone-preserving characteristics similar to testosterone. This is similar to what was seen with DHT so it appears as if non-aromatizing androgens are capable of bone protection directly through AR mediated pathways [137–138]. There are still lines of thought out there that believe a small degree of skeletal-specific aromatization of testosterone to E2 is essential for bone protection in males [139]. So, before any conclusions can be drawn, long-term trials with TBA will have to be conducted.

We’ve covered a lot of ground, so I’m going to call this a good stopping point for now. In the next, and final, installment of this series we will cover lipolysis, potential risks, and finish with my concluding remarks and recommendations.
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