Wednesday, September 18, 2013

T-Gel with or Without an Aromatase Inhibitor? If You Are Healthy & Lean and Want to Stay This Way, There is Only One Answer: T-Gel Without Aromatase Inhibitor!

Don't let her talk you into participating in studies that risk your manliness ;-)
Would you be willing to participate in a study, where you could end up without testosterone? No? Well me neither... strangely Joel S. Finkelstein et al. were able to find 198 healthy men between 20 and 50 years who were stupid enough to participate in an experiment, where they were randomized to placebo, or testosterone gel (1.25, 2.5, 5, or 10g per day) while being on gosererelin acetate, which did suppress their natural testosterone production.

With additional 202 subjects receiving an identical "treatment", but in this case alongside a whoppy dose of the aromatase inhibitor anastrazol as a bonus, the study design leaves us with plenty of groups and tons of subjects. To "determine the relative degree of testosterone deficiency, estradiol defi­ciency, or both at which undesirable changes in body composition, strength, and sexual function begin to occur." (Finkelstein 2013)

Yep, that is the study you don't not want to be part of, but....

I bet you will still be interested in the results. Am I right? Ok, let's see then. In men receiving goserelin acetate (kills the natural testosterone production) and 0 g (pla­cebo), 1.25 g, 2.5 g, 5 g, or 10 g of testosterone gel daily (cohort 1), the mean testosterone levels were
  • 0g testosterone: 44±13 ng per deciliter, 
  • 1.25g testosterone: 191±78 ng per deci­liter
  • 2.5g testosterone: 337±173 ng per deciliter, 
  • 5g testosterone 470±201 ng per, and
  • 10g testosterone 805±355 ng per deciliter
With 1.4 pg per milliliter, 7.9±2.9 pg per mil­liliter, 11.9±5.7 pg per milliliter, 18.2±10.2 pg per milliliter, and 33.3±15.3 pg per milliliter the estrogen levels of all participants were all well within the normal range (<55pg/ml).
Update: As Dr. Crisler (www.allthingsmale.com) just told me the accuracy of the information about estrogen may be questionable, because the essay the scientists used is not reliable in adult men. Instead, he suggest you use a "sensitive" essay like LabCorp (#500108), which uses the "cutting edge" LC/MS technology, Mayo Clinic's "Enhanced Estradiol" (#81816) or LabCorp's "Sensitive Estradiol (#140244), which is less expensive and thus probably a good choice for those without insurance. Dr. Crisler also pointed out that the wide variations you see in T-levels are actually a "very good thing, since this more closely mimics the serum profile of young healthy men". I do not deny that, but I still thought that it was wise to point out that the difference between 805ng/dl and 924ng/dl is absolutely non-significant when you have a range of ±521ng/dl.
Now the latter was obviously true for the guys on the aromatase inhibitor as well, with 1-2pg/ml their levels were however pathologically low and considering the high standard deviations, their T-levels were not that much higher:
Figure 1: Testosterone (ng/dl) and estrogen (pg/ml x10) in healthy men on 0, 1.25, 2.5, 5 and 10g (T0-T10) of testosterone gel with and without an additional aromatase inhibitor (Finkelstein. 2013)
"In men who also received anastrozole (cohort 2), the corresponding mean testosterone levels were 41±13 ng per deciliter, 231±171 ng per deciliter, 367±248 ng per deciliter, 485±240 ng per deci­liter, and 924±521 ng per deciliter and the corresponding mean estradiol levels were 1.0±0.4 pg per milliliter, 1.2±0.4 pg per milliliter, 2.0±2.3 pg per milliliter, 2.1±1.9 pg per millili­ter, and 2.8±1.8 pg per milliliter." (Finkelstein 2003)
[*please note the high (up to 50%!) standard deviations which tell you that the response to transdermal testosterone may vary profoundly from one men to another]
If you take a closer look at the data in Figure 1 and keep in mind that I had to multiply the estrogen levels by x10 in order to fit them into the same graph, it becomes all the more evident that the men in the non-AI group all had normal (<55pg/ml) estrogen levels. Their peers in the anastrazole group, on the other hand, had basically no estrogen at all and correspondingly high testosterone to estrogen ratios. In the worst case (yep, that is something bad!), namely 10g of t-gel + A,I the latter was as high as 335, which is almost 12x higher than in the 2.5g testosterone group without anastrazole (cohort 1).

No T, but tons of body fat

Apropos, cohort 1, in this group of men those who received the anti-androgen goserelin alongside a low(ish) doses of T-gel, i.e. either 0 g, 1.25 g, or 2.5 g of testosterone, daily, had significantly higher body fat levels and those in the 0 and 1.25g of T-gel significantly lower levels of lean mass compared to their peers in the 5g T-gel per day group.

Just a reminder: The testosterone level of the guys in the 5g group was only 470ng/dl and thus still rock bottom - the age adjusted normal levels for men are after all (I highlighted the group, where most of the subjects were in):
  • Effects of high and low testosterone on body composition (learn more)
    14-15 yr: 33-585 ng/dL
  • 16-17 yr: 185-886 ng/dL
  • 18-39 yr: 400-1080 ng/dL
  • 40-59 yr: 350-890 ng/dL
  • > 60 yr: 350-720 ng/dL
Those on the highest dose of T-gel (10g) ended up at the top (remember the standard deviations) of the normal range for testosterone and right in the happy medium for estrogen (normal range is 14-55pg/ml). These guys  experienced a significant decrease in body fat and increases in tigh muscle area and leg press strength.

Interestingly, both the decrease and increase in body in response to high and low testosterone levels occurred almost exclusively in the "benign" subcutaneous adipose tissue. The intra-abdominal­ fat area, on the other hand did not change significantly in any group. If we follow the standard interpretation of the health effects of the different body fat stores, the conclusion would thus be that low T is not so much of a problem, after all it's all "healthy fat" that you will gain... to bad that too much of that "healthy fat" will make you just as insulin resistance as the visceral fat - it just takes longer for the negative effects to occur.

Now what did the AI do?

Suggested read explaining why the annihilation of E2 has negative effects on your body comp: "Estrogen, Friend or Foe of Muscle Hypertrophy? Plus: Are You 'SERMing' Away Your Satellite Cells?" | more
I know, the most intriguing question has not been answered yet: What was the role of anastrazole in all this? And how did the subjects in cohort 2 fare compared to their "high" (remember even the 10g guys had normal estrogen levels) estrogen counterparts. Well,...
"In cohort 2, the percentage of body fat increased in all groups when the aromatization of testosterone to estradiol was inhibited. The magni­tudes of these increases were similar with doses of 0 g, 1.25 g, 2.5 g, and 5 g of testosterone daily, a finding that suggests a predominantly estro­genic effect" (Finkelstein. 2013)
Yep, I deliberately quoted this, because I know that you've been brain-washed to believe the opposite would happen. The big bad estrogen is what keeps you lean... good that you have been taking natural AIs for years, right? Well, no obviously not. Probably rather the reason that you still don't have the cover-model look you are aspiring.

Did you know that (a) the endogenous production of estrogens has significant protective effects on your heard cardiovascular health (Sudhir. 1999) and that (b) aromatase is neuroprotective and low levels of it have been associated with the occurance + progression of neurological diseases such as dementia, Alzheimer's and Parkinsons as well as an inability to recover from mechanic (trauma) or chemical (intlammation) damage to the brain (Azcoitia. 2001)? No? Well, let's hope that this is because you've never heard it and not because you've been abusing AIs for the past decade ;-)
So, to use an AI or not - is that even a question? A direct comparison of all the data from cohort 1 (no aromatase inhibitor) and cohort 2 (using anastrazole), informs us that
"The cohort–testosterone dose interaction was significant for the percentage of body fat (P = 0.001), intraabdominal­fat area (P = 0.021), subcutaneous ­fat area (P = 0.029), sexual desire (P = 0.045), and erectile function (P = 0.032)" (Finkelstein. 2013)
Or, to put it another way: The study shows us that estradiol exerts an inde­pendent effect on body fat, sexual desire and erectile function. So you better don't ignore the real world implications you are about to suffer, when you put too much faith in hearsay instead of looking at your actual blood levels:
"In the groups that received testosterone, inhibi­tion of estrogen synthesis (cohort 2), as com­pared with intact estrogen synthesis (cohort 1), was associated with significant increases in the percentage of body fat (P<0.001), subcutaneous­ fat area (P<0.001), and intraabdominal­fat area (P = 0.002) and with significant decreases in sexual desire (P<0.001) and erectile function (P = 0.022)" (Finkelstein. 2013)
Yes, you heard the scientists right. Suppressing your estrogen levels is going to make you fat, rob you of your sexual desire and render you unable to perform the deed.

At the same time it had no beneficial effect on the increases in lean body mass or strength or any other positive outcome the subjects got from using T-gel. On the contrary, the low estrogen levels on in the 10g T-gel group did actually blunt reduce the lean mass gains and the fat loss the men in cohort 1 (no anastrozole) experienced, when they used 10g of T-gel per day was effectively reversed by the AI.

Figure 2: Fat gain, lower lean mass gain, less sexual desire & lower sexual function (not shown) and the list goes on... there really is nothing remotely beneficial about low estrogen (figures from Finkelstein. 2013).
It should thus be absolutely obvious that the only reason you should use an aromatase inhibitor with your testosterone replacement therapy is blood work that indicates that you have serious issues with over-aromatization. In many cases those can be reduced if not solved by (a) reducing inflammation and (b) getting rid of your belly.

To deliberately annihilate your estrogen levels, on the other hand, is simply stupid - irrespective of whether you are on TRT or not and even if you don't care about the negative long-term effects on your brain and heart health.

References:
  • Azcoitia I, Sierra A, Veiga S, Honda S, Harada N, Garcia-Segura LM. Brain aromatase is neuroprotective. J Neurobiol. 2001 Jun 15;47(4):318-29.
  • Sudhir K, Komesaroff PA. Clinical review 110: Cardiovascular actions of estrogens in men. J Clin Endocrinol Metab. 1999 Oct;84(10):3411-5. Review.