danmirage
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I have read the entire paper, available here:
http://www.jissn.com/content/4/1/13
I have come to the opinion that the subjects were not specifically on a program aimed at muscle hypertrophy wit the requisite specific diet/training protocol, and so no proper performance results could be determined. To properly judge the effectiveness of such an supplement, there must be a "dry" training period before supplementation to observe training advances and establish their optimal rate per individual. Then the supplemental period should be conducted with appropriate training and nutrition. Following should be the "wash out", another period of training to observe advances or lack of advances and establish their rate per individual.
Rather, here I would guess that these were college students who simply trained in the gym. All we can learn from this is the serum effects of the supplement. The applications to different training protocols must be derived.
I have left out the experimental portion of the paper and only included the discussions and references. follow the link to see the full paper in .pdf form.
Comments and questions welcome.
Effects of eight weeks of an alleged aromatase inhibiting nutritional supplement
6-OXO (androst-4-ene-3,6,17-trione) on serum hormone profiles and clinical
safety markers in resistance-trained, eugonadal males
Journal of the International Society of Sports Nutrition 2007, 4:13 doi:10.1186/1550-2783-4-13
Rohle, D. , Wilborn C., Taylor, L. , Mulligan, C., Kreider, R., Willoughby, D.
Abstract
The purpose of this study was to determine the effects of 6-OXO, a purported nutritional
aromatase inhibitor, in a dose dependent manner on body composition, serum hormone levels,
and clinical safety markers in resistance trained males. Sixteen males were supplemented with
either 300 mg or 600 mg of 6-OXO in a double-blind manner for eight weeks. Blood and urine
samples were obtained at weeks 0, 1, 3, 8, and 11 (after a 3-week washout period). Blood
samples were analyzed for total testosterone (TT), free testosterone (FT), dihydrotestosterone
(DHT), estradiol, estriol, estrone, SHBG, leutinizing hormone (LH), follicle stimulating hormone
(FSH), growth hormone (GH), cortisol, FT/estradiol (T/E). Blood and urine were also analyzed
for clinical chemistry markers. Data were analyzed with two-way MANOVA. For all of the
serum hormones, there were no significant differences between groups (p > 0.05). Compared to
baseline, free testosterone underwent overall increases of 90% for 300 mg 6-OXO and 84% for
600 mg, respectively (p < 0.05). DHT underwent significant overall increases (p < 0.05) of
192% and 265% with 300 mg and 600 mg, respectively. T/E increased 53% and 67% for 300
mg and 600 mg 6-OXO, respectively. For estrone, 300 mg produced an overall increase of 22%,
whereas 600 mg caused a 52% increase (p < 0.05). Body composition did not change with
supplementation (p > 0.05) and clinical safety markers were not adversely affected with
ingestion of either supplement dose (p > 0.05). While neither of the 6-OXO dosages appears to
have any negative effects on clinical chemistry markers, supplementation at a daily dosage of
300 mg and 600 mg for eight weeks did not completely inhibit aromatase activity, yet
significantly increased FT, DHT, and T/E.
Background
Athletes have long been looking for a way to gain an edge in competition, which has lead
many to turn to anabolic steroids. Anabolic steroids are defined as testosterone (TST) or
derivatives of TST that are used for their ability to create a state of nitrogen retention and
increase fat-free mass by stimulating protein synthesis and/or by decreasing protein breakdown.
It has been previously thought that anabolic steroids did not cause an increase in muscle size and
strength, but now more recent studies have shown the effect that supra-physiological levels of
TST and TST derivatives can increase muscle size and strength in males [1-7].
Once produced, TST does not circulate freely in the blood. Rather, total testosterone
(TT) is almost 100% bound in blood to proteins with 40% bound to albumin, 40% bound to a β-
globulin called sex hormone binding globulin (SHBG), and 17% is bound to other proteins. The
small fraction of TST that is not bound is considered the free testosterone (FT) and is the
bioactive component of the hormone. Once bound to its androgen receptor, TST can also be
converted to dihydrotestosterone (DHT) by the enzyme 5-_ reductase. Alternatively, TST can be
converted into estradiol through aromatization by the action of the enzyme aromatase.
There are pro-hormone nutritional supplements available, such as androstenedione, that
are precursors to TST, and designer androstenedione derivatives such as androstenediol that are
purported to support TST production. These compounds are alleged to increase TST, or to
increase the concentration of compounds that can act like TST. There are data in young men
demonstrating that the acute sublingual ingestion of androstenedione and androstenediol
increased FT and TT up to 180 min [8] and 240 min [9] after ingestion. However, these are
acute studies with a small window of TST elevation and do not relevantly reflect the manner in
which these types of supplements are typically utilized. More appropriately, there are studies
demonstrating that the daily oral ingestion of these compounds over the course of several weeks,
in conjunction with resistance training [10,11] and otherwise [12] to be ineffective at increasing
endogenous TST levels.
However, in the continued attempts to find supplements that elevate testosterone levels,
some companies are manufacturing compounds that have no apparent androgenic activity, but
are targeted at increasing the endogenous levels of TST by blunting aromatization and
subsequent estrogen synthesis. Aromatase inhibiting drugs are not new and have been used for
years as a method of preventing and treating various types of cancer. The drugs operate by
suppressing estrogen levels and subsequently increasing endogenous free testosterone levels
[increased free testosterone/estrogen (T/E) ratio] and the effects of various pharmacologic
aromatase inhibitors such as anastrozole and exemestane on the T/E in both young and old men
are well documented [13-15].
Nutritional supplements designed with the intent of inhibiting aromatase activity are
relatively new to the fitness community. Examples of these supplements are 6-OXO and
Novedex XT, and are alleged to act similar to such aromatase inhibiting drugs as formestane.
We have recently shown that eight weeks of supplementation with the aromatase inhibiting
nutritional supplement Novedex XT (hydroxyandrost-4-ene-6,17-dioxo-3-THP ether and 3,17-
diketo-androst-1,4,6-triene) was effective at increasing serum testosterone and DHT, while only
displaying slight increases in estrogen levels in young, eugonadal men [16]. Additionally,
compounds with the same (androst-4-ene-3,6,17-trione) and very similar (androst-5-ene-4,7,17-
trione) structure as 6-OXO have been shown to irreversibly bind to the aromatase enzyme
thereby causing a decrease in estradiol production [17,18]. Therefore, use of these aromatase
inhibiting compounds seem to decrease aromatization and subsequent estradiol synthesis, which
apparently increases both TST and T/E.
In view of our previous work [16], there is still little data available on the effects of the
various nutritional aromatase inhibiting supplements. Therefore, the purpose of the study was
threefold and was to determine the efficacy of an eight week oral supplementation period with
either 300 mg/day or 600 mg/day of 6-OXO on: 1) serum hormone levels, 2) serum and urinary
clinical safety markers and systemic hemodynamic effects, and 3) serum hormone, serum and
urinary clinical safety markers, and systemic hemodynamic effects after a 3-week washout
period following both supplementation protocols.
Discussion
In this study, we sought to determine the effects of 6-OXO supplementation provided at a
daily dosage of 300 mg and 600 mg for eight weeks on body composition, serum hormones, and
clinical safety markers. There were no adverse side effects reported from the participants and no
significant changes in hemodynamic measures and in clinical chemistry markers measured in
whole blood, serum, or urine during the course of the study suggesting that 6-OXO at the
dosages investigated for a period of eight weeks appears safe within the confines of the markers
assessed.
In regard to body composition, neither dose of 6-OXO demonstrated any significant
improvement in fat mass or fat-free mass over the course of the study. Even with significant
increases in FT and DHT, this furthers indicates that 6-OXO supplemented at these dosages for
eight weeks did not decrease fat mass or cause an anabolic response by increasing muscle mass.
Increased serum androgens levels have been shown to stimulate lipolysis due to increases in the
activity of hormone sensitive lipase [21]; however, relative to the dosage and/or the duration of
ingestion of 6-OXO on serum androgens in the present study, neither had any effect on body
composition. In our previous study, eight weeks of supplementation with 72 mg/day of the
nutritional aromatase inhibitor Novedex XT had no effect on fat-free mass, but was effective at
producing a modest, but significant 3.5% decrease in fat mass when compared to placebo [16].
For the serum hormones, the only significant changes that occurred over the course of the
study that were 6-OXO dependent were for FT, DHT, estrone, and T/E. FT and DHT underwent
overall increases of 90% and 192% for 300 mg 6-OXO and 84% and 265% for 600 mg,
respectively, while T/E increased 53% and 67% for 300 mg and 600 mg 6-OXO, respectively.
However, for FT, DHT, and T/E there were no significant differences between groups,
suggesting 300 mg and 600 mg of 6-OXO to be equally as effective in increasing androgen
levels. In addition, by the end of the three-week washout period, the levels of these hormones
(and all others) had returned to normal levels. The FT, DHT, and T/E data is in agreement with
previous research, which showed an increase in TT with ingestion of an aromatase inhibitor
[19,22,23], with 6-OXO (unpublished data) [24], and with our previous study with Novedex XT
where we showed average increases of 283%, 625%, and 566% for TT, FT, and DHT [16].
Relative to the ability of 6-OXO to inhibit aromatization by way of our serum hormone markers,
estrone underwent overall increases of 22% and 52% for 300 mg and 600 mg, respectively, and
estradiol underwent overall increases of 27% and 12% for 300 mg and 600 mg, respectively.
These data indicate that aromatase activity was not completely inhibited by 6-OXO throughout
the eight-week period.
It seems logical that DHT concentration would increase concomitantly with elevations in
TST because DHT is a TST metabolite. Relative to the change in FT and the significant
increases in DHT over the eight-week period, the present data suggest a role for 6-OXO
in upregulating the activity of the 5_-reductase enzyme. Unlike TST, DHT is a non-aromatizable
androgen [13]. Because 6-OXO is a type I steroidal aromatase inhibitor, it is assumed that this
supplement would completely inhibit aromatase activity, thereby leading to elevations in
endogenous TST. However, our results suggest the contrary; 6-OXO does elevate TST and DHT
levels without the complete inhibition of serum aromatase activity. As a result, it is conceivable
that the apparent TST aromatization occurring was in part responsible for the observed
elevations in estradiol and estrone. Aromatase catalyzes the conversion of TST to estradiol, of
androstenedione to estrone, and of 16α-hydroxylated dehydroepiandrosterone to estriol [25].
The purported mechanism for an increase in TST with aromatase inhibition has been reported as
a decrease in estradiol levels that leads to feedback to the hypothalamus to stimulate TSTinduced
increases in estradiol [26,27]. This would infer that in order for an increase in TST to
occur, a decrease in estradiol would have to be seen, and this is not what happened in this study.
Regarding SHBG, the levels did not change over the course of the study. This suggests
that the effects of 6-OXO on FT to be somewhat independent of the circulating levels of SHBG
since at least 95% of circulating testosterone is bound to SHBG at any one time. Interestingly,
however, the 600 mg group had lower SHBG concentrations at baseline and throughout the
course of the study suggesting this to be independent of the specific dose of 6-OXO.
The results of this study indicate that eight weeks of 6-OXO supplementation had no
effect on body composition or clinical safety markers, but incompletely inhibited aromatase
activity and significantly increased endogenous DHT levels that were attenuated after a threeweek
washout period. Therefore, while neither of the 6-OXO dosages appears to have any
negative effects on clinical chemistry markers, supplementation at a daily dosage of 300 mg and
600 mg for eight weeks did not completely inhibit aromatase activity, yet significantly increased
FT, DHT, and T/E.
References
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Casaburi R.Testosterone replacement increases fat-free mass and muscle size in
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