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Diminished Effect with Long Term Use of Letrozole?


Morepain posted this study in InTheZone's thread on Letrozole.


I had read the abstract some time ago, but failed to look any further until he posted it.

Does anyone who looked at this study have a hypothesis on why Total Estradiol increased 33% and Free Estradiol increased 39% from the six week to the six month mark?


Could the body be increasing production of the aromatase enzyme? Why?

Could the drug become less competitive with the aromatase enzyme over time?

I'm far too tired to attempt to come up with any other possible reasons. I'm curious about this because I use Letrozole for extended periods of time. I imagine those who use it or Arimidex for TRT purposes would also be interested to know. I don't currently have much knowledge of human physiology, so I'm SWAGing it at best. What do you guys think?


Im afraid I dont see the statistic you quoted, could you tell me what part exactly you read that?

EDIT: just kidding, I was on the wrong webpage!


Well, up-regulation of the ER is noted both with SERMS and aromatase inhibitors, which is attributed with most of the diminished long term response of treatment. This, I believe, is implying something else. I dont believe there is much belief that estrogen management drugs up-regulate the aromatase enzyme specifically, or if there is, I haven't seen it. What I would suggest is that the large increase in FT and TT, over time caused an increase in activity of the aromatase enzyme. The FT/TT levels increased by a substantial amount, ina very short time, which IMO, would be the cause of the increase E levels in the long term. There is plenty of other factors that modulate Aroma activity as well, which could also contribute to the increased E levels.

For the compound to become "less competitive" would mean a significant and wide spread conformational change in the enzyme, which I doubt.


Thank you Justayoungen!

I have seen plenty of people make claims that SERMs cause up-regulation of the ER, but I have never seen anyone substantiate those claims with any science based evidence. As I recall- from my short lived exploration of the topic- there are no studies using men that show up-regulation of the ER. It's difficult for me personally to assume certain actions will take place in the bodies of men as they do in women. I'm not saying the information doesn't exist and I could certainly be wrong about all of this. If you have any information to pass on, please post of PM me.

If estrogen acts like testosterone- in the fact that an abundance of it will up-regulate the the receptor- then I could see SERM's being responsible for up-regulation of the ER, as they would most likely cause a higher circulating level of estrogen in the absence of an aromatase inhibitor. I have, however, never seen anything about aromatase inhibitors causing an up-regulation of the ER. I will definitely have to take a look at that. That however would not explain the higher level of circulating estrogen- indicated by the data table posted above.

Perhaps- instead of the increased FT/TT causing an increase in aromatase activity- the subjects involved in the study- who were indicated as being obese- had lost a substantial amount of body-fat over the course of treatment. This loss of body-fat caused an increase in circulating estrogen levels due to freed estrogen once stored in the fat. Far fetched? Can the aromatase enzyme also be stored in body-fat?


You are probably correct that there are no long studies examining possible ER up-regulation in men due to SERMS or AIs. That is more because there are very few studies involving SERMS and men in general. Clinically, I have never seen a SERM recommended to a man, other than once case of male breast cancer (now I am not a clinician, so my case-load is limited).

Keep in mind, this up-regulation came after long term administration, which I doubt is significant for men who are using SERMS in the fashion you do. Perhaps look up Raloxifene and men, I still have not seen much of it, but you are much more likely to find something than with Tamoxifen (still probably wont though).

The aromatase enzyme is active in body fat, but as far as being "stored" in body fat, no, that is not the case. A loss of bodyfat, would if anything, lower estrogen levels more. The problem is even after the increase in E, the levels are still well within the mid to lower normal range. I think this could easily be explained by homeostatis-the act of the body to regulate its internal atmosphere to a certain range. Now, if you found studies showing diminished effect of aromatase inhibitors, in men, with estrogen going back to the high range, that would, IMO be much more significant.


I have never been all that concerned about ER up-regulation or hepatotoxicity due to SERMs. That is why I never spent much time researching the subject. The four to six week period of use does not lead me to believe much if any damage can be done.

I understand that a loss of body-fat would- in the long term- likely reduce estrogen levels. I was unsure if- in the short term- a substantial amount of fat loss would temporarily increase estrogen levels.

These are "obese" individuals- obviously they have a substantial amount of body-fat and possibly a substantial amount of stored estrogen. I originally had the thought when I noticed the testosterone levels had also risen slightly.

I thought the same idea could be true for testosterone stored in body-fat- or that maybe a combination of freed estrogen and testosterone together could be responsible for the rise in estrogen levels.

Anyway, I was just throwing another idea out there. I know my thoughts here are a bit crazy and do not adhere to Occam's razor. I'm satisfied with the fact that I will probably never know. The only solution is see is to get E2 levels tested every six months and adjust from there.

Thank you for your comments, Justayoungen. This is the first thread I've ever made here. I'm glad someone commented and didn't let it drift into obscurity. I hope you stick around- you're one of the better posters I've seen in here in a long time.


much respect bro...nice to have another good brain on hand around here


I find it funny that out of all the boards I posted on here, I have only gotten such a warm welcom in this forum. Despite the fact that I am young, as well as the more important fact that I dont even take steroids. Really says something about the stereotype of typical steroid users, IMO.


you have two types of steroid users...teh guys that get their info from "biggunzifbbproguy" or some shit....and the guys that get their info from scintific journals, years of education, years of real world experience, and the help of a few educated epople such as yourself...welcome