T Nation

Bill Roberts: Exemestane Toxicity?


#1

Exemestane has only been investigated as a treament for cancer. The terminal methylene group doesn't look good.

Exemestane has afftinity for AR and ER receptors I'm sure. It may be low affinity with no agonism but I'm sure it binds. Could the terminal methylene group be toxic by reacting with things other than the aromatase enzyme?


#2

A terminal methylene group doesn’t mean a compound will necessarily have a toxicity problem. So in and of itself this feature doesn’t have to rule out exemestane. For example, limonene, present in citrus, has this functionality but is safe in reasonable concentrations. Vitamin D also comes to mind.

But though not toxic for people in dietary amounts, or from exposure to common products containing it, limonene can react with SH groups for the same reason you say and at some concentrations can be toxic to some organisms. So limonene is an example not only of how a compound with this functionality can be safe in practice, but how toxicity might be found in some instances at some concentrations.

As for reaction with steroid receptors, these receptors are transient. Here today, gone perhaps not tomorrow but quite likely in days, constantly being renewed. I wouldn’t be concerned about losing androgen receptors via reaction with exemestane, not that you said specifically that.

It can exhibit some liver toxicity.

I’ve never found a reason to prefer it over anastrozole or letrozole.


#3

Thanks Bill! I’ve read that exemestane has a positive effect on IGF production while non-steroidal inhibitors decrease IGF. Testosterone is boosted with aromasin. IME exemestane is also easier to adjust than arimidex. Erectile dysfunction is the main side effect of aromatase inhibitors. If someone does B+C with UGL steroids, estrogen levels can be very hard to control. But, maybe I will reassess this idea…

Steroidal AIs seem superior to nonsteroidal inhibitors for male use. But, maybe the differences are not really significant. I actually think formastane and “Arimistane” (androsta-3,5-diene-7,17-dione) could be great for TRT and cycling. The only problem is absorption. An esterified, injectable version of formestane I think would be useful. It could be directly added to testosterone preparations at ~10-25mg/mL

From another thread on T-Nation:

[quote]conservativedog wrote:
Mr. Walkaway’s finding again gives us incentive to update our knowledge base and not feel our initial indoctrinating is all encompassing. I didn’t just read an hour for nothing so I’ll post some of what I found:

…study which showed an increase in the absorption of exemestane of 40% when taken with fats.

…it takes time for the body to produce new aromatase- so its effective time is much longer than the half life indicates.

…it seems to be forgiving in the area of eliminating all estrogen - even at 50mg/day with no exogenous test - the e levels were low but still in reference range. (we need some estrogen)

…no changes in circulating serum triglycerides, cholesterol, or LDL or HDL cholesterol concentrations with either a 25mg or 50mg daily dose of exemestane.

Exemestane (Aromasin) is a potent and selective irreversible aromatase inhibitor. To characterize its suppression of estrogen and its pharmacokinetic (PK) properties in males, healthy eugonadal subjects (14-26 yr of age) were recruited. In a cross-over study, 12 were randomly assigned to 25 and 50 mg exemestane daily, orally, for 10 d with a 14-d washout period. Blood was withdrawn before and 24 h after the last dose of each treatment period. A PK study was performed (n = 10) using a 25-mg dose. Exemestane suppressed plasma estradiol comparably with either dose [25 mg, 38% (P 0.002); 50 mg, 32% (P 0.008)], with a reciprocal increase in testosterone concentrations (60% and 56%; P 0.003 for both). Plasma lipids and IGF-I concentrations were unaffected by treatment. The PK properties of the 25-mg dose showed the highest exemestane concentrations 1 h after administration, indicating rapid absorption. The terminal half-life was 8.9 h. Maximal estradiol suppression of 62 14% was observed at 12 h. The drug was well tolerated. In conclusion, exemestane is a potent aromatase inhibitor in men and an alternative to the choice of available inhibitors.

… also BIG difference between aromasin / exemestane and arimidex / anastrozol:

There was an increase in circulating testosterone concentrations after both 25 mg (60 + 58%; P = 0.001) and 50 mg (56 48%; P = 0.003) exemestane. Androstenedione concentrations were increased as well after 25 mg (32 �?�± 36%; P = 0.004) and 50 mg (47 59%; P = 0.052) exemestane, respectively (Fig. 1Go and Table 2Go).

SHBG concentrations were decreased by 217% (P = 0.0003) and 19 39% (P = 0.18) at 25 and 50 mg exemestane, respectively.

Free testosterone concentrations were increased by 117 74% (P = 0.0001) and 154 95% (P < 0.0001) at both doses, due to the decrease in SHBG and the increase in total testosterone.
[/quote]


#4

[quote]Bill Roberts wrote:
A terminal methylene group doesn’t mean a compound will necessarily have a toxicity problem. So in and of itself this feature doesn’t have to rule out exemestane. For example, limonene, present in citrus, has this functionality but is safe in reasonable concentrations. Vitamin D also comes to mind.
[/quote]

O ya :() Youre right

However, vitamin D is natural, and quickly undergoes an annulation reaction. Undecylenic acid is another example. The methylene of exemestane just hanging out on C6 looks nasty…