Sensitive E2 in the 100’s

[TRTARNP]

Was looking for input from some of the moderators/experienced users. I work in hormone optimization/peptides/ED management/primary care. First, huge thanks to this forum, Nelson and others who have been instrumental in advancing my understanding of TRT and how to engage in optimization versus cookie cutter protocols.

I have a few guys whose E2 is running in the low 100’s for their LC/MS, no side effects though. These are guys I know well, and have engaged in close follow up with in regards to how they feel/SE profile. Mid to low SHBG levels. TT in the 900-1000 range. Is it crazy to not give concern to these E2 findings, in the absence of SEs? By not give concern I mean not start them on AIs.

I just don’t see any primary literature that suggests elevated E2 is concerning, in the context of the situations I am dealing with. In my experience, and from what I have learned, if you have the gyno gene you are likely to have issues on TRT, and if you don’t, elevated E2 shouldn’t be concerning in regards to breast tissue. Just looking for some input, as I know some of the moderators on here have been involved in this field much longer than myself, and this is as challenging, much debated issue....

 

[Cataceous]

It's uncharted territory. Healthy young men might average around 30 pg/mL for estradiol. The standard deviation is something like 6 or 8 pg/mL. The odds of naturally being even seven standard deviations above average approach one in a trillion. Do the guys really want to participate in this experiment?

Ideally high estradiol is addressed by a reduction in the testosterone, and the cited levels are arguably unnecessarily high, especially for the low-SHBG individuals. But the aromatization rate of one percent is double what's typical. Any ideas on why? Is there hCG use and/or obesity?

 

[TRTARNP]

Thanks for the response! Yes HcG use in both men. One is young, and desiring fertility. So he needs HcG, and is using 500 IUs three times weekly. The other also is using HcG, 500 IUs twice weekly. I have routinely started men on both test cyp and HcG, and maybe in the non fertility crowd, I would be better off holding off on HcG use, and only using it if they develop testicular pain or are bothered by the mild atrophy.

I think you are right, reducing dose is a great first step. The uncharted territory you elude makes me nervous, but at the same time, I really don’t like to use AIs to manage numbers, versus adding them to manage specific issues in the context of elevated LC/MS lab assessments. But the 100 range feels uncomfortable, and there isn’t a playbook or base of primary literature to fall back on with this issue. I know the Scott Howells, Kieth Nichols, Jordan Grants of the world, all individuals I highly respect, favor not using AIs... But with levels that elevated I get somewhat uncertain.

Any other thoughts or ideas are appreciated. Again, I reallly appreicate this forum as a means to learn things in areas that are not covered well or at all through traditional sources of medical information.

 

[Cataceous]

HCG is a nuisance for some of us due to the added aromatization. On average using it increases my aromatization rate from 0.5% to 0.7%. So it's at least conceivable that more extreme cases would push 1%, especially in individuals starting with above-average rates. At present I don't think we can say with any certainty whether long-term high estradiol is better or worse than long-term AI use.

The LC/MS estradiol tests are not entirely trustworthy, so I would have repeat measurements before doing anything other than reducing the testosterone doses. Ideally an immunoassay test would be included in repeat testing. If it comes back lower than the sensitive method then you might suspect something's wrong.

 

[Sean Mosher]

What were the corresponding healthy young male TotalT and Free T levels associated with that 30pg/ml level?
Just for curiosity sake.

That definitely seems like unchartered territory.
In the 50's and 60's I've seen no problems personally at all.
Same with many others.

But then you have the whole Rouzier crowd who has claimed to see no problems in the low 100's for a portion of their patient population as well.
Thanks for posting and please keep us updated.
I'm totally in your camp in not wanting to suppress estradiol with AI use.
I would think those patients would be way outside the bell curve and statistical anomalies but none the less you want to offer them the best care possible and safest as well.

Please keep us posted!

 

[JimGainz]

I’ve done it both ways - micromanaging E2 with AIs and then letting it rise to whatever level (based on all the latest “theories” and doctors like Rouzier. My levels rose to 78- 90 when unchecked. While I didn’t have direct symptoms, I felt it was unnatural and does not exist in nature (no normal young healthy male has estradiol that high). I take only 0.125 mg Arimidex per week because I am so sensitive to it and that puts me in the mid to high 40s. I leave it at that. Whenever I take two pills of Ai in a week, my joints creak.

 

[Cataceous]

What were the corresponding healthy young male TotalT and Free T levels associated with that 30pg/ml level?
...

Total testosterone is probably around 600-700 ng/dL. SHBG is around 30 nMol/L. These put Tru-T free T at about 23 ng/dL (16-31). Vermeulen free T is about 15 ng/dL. I'd put the healthy reference range for this method at (10-20).

 

[TRTARNP]

HCG is a nuisance for some of us due to the added aromatization. On average using it increases my aromatization rate from 0.5% to 0.7%. So it's at least conceivable that more extreme cases would push 1%, especially in individuals starting with above-average rates. At present I don't think we can say with any certainty whether long-term high estradiol is better or worse than long-term AI use.

The LC/MS estradiol tests are not entirely trustworthy, so I would have repeat measurements before doing anything other than reducing the testosterone doses. Ideally an immunoassay test would be included in repeat testing. If it comes back lower than the sensitive method then you might suspect something's wrong.

Do you generally favor not using HcG when starting TRT, in the context of a non-fertility desiring patient? I am starting to think perhaps this is more desirable in this patient base.

The E2 issue continues to be challenging, it is good to at least get some input that perhaps, it is not crazy to consider letting patients ride in the 60-120 range, assuming they are tolerating that well, therapy is going well and achieving the identified goals of therapy, etc. As you eluded to, there is lacking justification that AI use is a better long-term solution, especially if the use is strictly to control a number versus side effect management.

Interestingly, the clinic's standard E2 assessment is the immunoassay. I don't use this for Ai considerations, and always assess LC/MS if there are issues. I would estimate 25% of the time the LC/MS has read higher than the immunoassay. And in both of these individuals, the LC/MS read between 20-30 point higher than the immunoassay. These were run by Quest.

I have also seen many immunoassay levels measure anywhere from 8-120 points lower than the LC/MS. So the levels are all over the place. Lab assessment of these hormone values can be maddeningly frustrating at times.

 

[TRTARNP]

I’ve done it both ways - micromanaging E2 with AIs and then letting it rise to whatever level (based on all the latest “theories” and doctors like Rouzier. My levels rose to 78- 90 when unchecked. While I didn’t have direct symptoms, I felt it was unnatural and does not exist in nature (no normal young healthy male has estradiol that high). I take only 0.125 mg Arimidex per week because I am so sensitive to it and that puts me in the mid to high 40s. I leave it at that. Whenever I take two pills of Ai in a week, my joints creak.

Playing devil's advocate, FYI I'm not totally against AI use, and certainly, your use is responsible, and a protocol I would approve of with my patients, if they were strongly in favor of lower their E2.

Couldn't I argue that inhibiting aromatase through use of a medication is also "not existent in nature."

This is the crux of something I am wrestling with, obviously, are we better off managing numbers, in the absence of symptoms, through use of AIs, or, ONLY managing based on symptoms and numbers. It seems the jury is out... I will say I have been surprised how well various patients have fared with relatively higher E2 values.

 

[Cataceous]

Do you generally favor not using HcG when starting TRT, in the context of a non-fertility desiring patient? I am starting to think perhaps this is more desirable in this patient base.
...

I'd consider it ideal to start all TRT patients with frequent injections—qd/qod—and no hCG. The reason why is to develop a dose-response relationship uncontaminated by endogenous testosterone production. After this hCG use could be encouraged, along with less demanding dosing schedules. In spite of the problems with hCG, many guys will still find using it to be preferable to not using it, and not just because of fertility.

...
Interestingly, the clinic's standard E2 assessment is the immunoassay. I don't use this for Ai considerations, and always assess LC/MS if there are issues. I would estimate 25% of the time the LC/MS has read higher than the immunoassay. And in both of these individuals, the LC/MS read between 20-30 point higher than the immunoassay. These were run by Quest.

I have also seen many immunoassay levels measure anywhere from 8-120 points lower than the LC/MS. So the levels are all over the place. Lab assessment of these hormone values can be maddeningly frustrating at times.

My experience with LabCorp's standard immunoassay estradiol test has been good. It is very consistent, in stark contrast to the "sensitive" LC/MS test, which seems to throw out non sequiturs at an alarmingly high rate. When the sensitive test isn't botched the immunoassay result is generally a few percent higher. The shortcomings of the immunoassay tests are their cross-reactivity to things like C-reactive protein and their lack of sensitivity at low hormone levels. On the other hand, the immunoassay tests are pretty idiot-proof, while the LC/MS tests are complex and may require a fair bit of fiddling to work correctly. I'd consider it a red flag for the LC/MS test result to be significantly higher than that of the immunoassay test.

 

[TorontoTRT]

Young men also don’t run test in the 1000’s. So yeah 30 E2 is ok if you’re in the 600-800 test range. But these ranges don’t apply to people on trt. If your test is 1200-1500 then you’d want your E2 in proper ratio. Definitely over 60.

 

[Systemlord]

Young men also don’t run test in the 1000’s.

That and testosterone levels are higher over the course of the day on TRT versus naturally.

 

[Cataceous]

Young men also don’t run test in the 1000’s. So yeah 30 E2 is ok if you’re in the 600-800 test range. But these ranges don’t apply to people on trt. ...

The ranges apply to people on TRT. They serve to remind that supraphysiological dosing is no longer TRT.

... If your test is 1200-1500 then you’d want your E2 in proper ratio. Definitely over 60.

What's your supporting evidence for this statement?

 

[JA Battle]

The ranges apply to people on TRT. They serve to remind that supraphysiological dosing is no longer TRT.

What's your supporting evidence for this statement?

I would tend to agree that if one exceeds Supra-physiological amounts of testosterone, that there should be be a concurrent amount of estradiol to balance competitive activation of various receptors. As to the ratios we’ve widely used on this forum including all posted versions is 14-30 (tt/se2 in their respective different lab units). This puts e2 at 107 pg/ml max for a 1500ng/dl t level.

The question is not about the e2 level exclusively. But rather, the testosterone dosage as it is the cause of the high e2.

Many men experience varied metabolism of testosterone into its respective metabolites. And this I believe is the cause of men using more t than what we believe would be necessary.

The larger issue you elude to being TT (testosterone therapy) vs TRT (testosterone replacement therapy). They are certainly two things and we are both in the same camp with respect to this matter. Replacement constitutes maintaining reference range testosterone at all times.

The issue arises when normal testosterone levels do not create the proper ratio of metabolites usually due to deeper metabolic issues.

For example I have a daily peak of around 1000ng/dl testosterone as you know; however, my estradiol sits at around 17pg/ml. I also have around 48ng/dl dht level. So I under convert. In order to achieve robust levels of metabolites I directly supplement dht and estradiol while Many men just up their dose of testosterone.

The issue is that the ratios are already bad so upping the dose makes them worse possibly until maybe at certain point at which enzymes are maxed out with one metabolite and then the ratio begins to improve with further testosterone administration.

I look too muscular to only be on 6.25mg of pure testosterone daily and this would partially explain it.

I’m becoming a pretty firm believer in dht:e2 ratio being the most important ratio for overall function. They are much more directly tied to neurosteroid and nervous system function than testosterone. We often conflate many of dht and testosterone’s effects.

We need more control of the metabolites as that is the reason the people unknowingly are needing higher amounts of testosterone. Not ar sensitivity issues.

 

[Match]

T 637 ng/dl
E 32 pg/ml
SHBG 62 nomol / l
Queria saber qual a relação de Estradiol no calculo de TLivre, pois só se usa SHBG.
Significa que SHBG é sinomino de Estradiol ??
Meu SHBG parece alto, entao deveria reduzir pelo Estradiol, nesse caso?
OU de que forma?

 

[Cataceous]

I would tend to agree that if one exceeds Supra-physiological amounts of testosterone, that there should be be a concurrent amount of estradiol to balance competitive activation of various receptors. As to the ratios we’ve widely used on this forum including all posted versions is 14-30 (tt/se2 in their respective different lab units). This puts e2 at 107 pg/ml max for a 1500ng/dl t level.
...

We tend to accept the hypothesis that a skewed E2:T ratio is worse than excessive absolute levels, but do we have hard evidence to support that? Maybe there is some work showing that low testosterone in the presence of somewhat high estradiol is problematic... But that doesn't help us evaluate the possible risks of extremely high absolute levels of estradiol. It seems questionable that having similarly high testosterone is going to be protective in all circumstances. I previously touched on some specific concerns here. One of them is the potential for testicular damage:

A paradoxical decline in semen parameters in men treated with clomiphene citrate​

...​

Elevated estradiol levels result in vacuolization and increased glycoprotein production impairing Sertoli cell function. It also disturbs communication with germ cells, increases collagen synthesis and fatty degeneration in the testicular connective tissue. All these actions collectively result in the induction of germ cell death (Leavy et al., 2017). Oestradiol also plays a critical role in round spermatid chromatin reorganization during spermiogenesis through its action on Estrogen Receptor Alpha (ERα) present on Sertoli cells (Cacciola et al., 2013). Overexposure to estrogens reduces the expression of ERα on Sertoli cells, impacting this critical action. Moreover, it has been recognized that supraphysiological concentrations of estrogen act as powerful apoptotic triggers that induce germ cell apoptosis (Correia et al., 2015).​

...​

Among men who had a decline in semen parameters, 17% of them may not recover following discontinuation of therapy.​

[R]

 

[JA Battle]

We tend to accept the hypothesis that a skewed E2:T ratio is worse than excessive absolute levels, but do we have hard evidence to support that? Maybe there is some work showing that low testosterone in the presence of somewhat high estradiol is problematic... But that doesn't help us evaluate the possible risks of extremely high absolute levels of estradiol. It seems questionable that having similarly high testosterone is going to be protective in all circumstances. I previously touched on some specific concerns here. One of them is the potential for testicular damage:

A paradoxical decline in semen parameters in men treated with clomiphene citrate​

...​

Elevated estradiol levels result in vacuolization and increased glycoprotein production impairing Sertoli cell function. It also disturbs communication with germ cells, increases collagen synthesis and fatty degeneration in the testicular connective tissue. All these actions collectively result in the induction of germ cell death (Leavy et al., 2017). Oestradiol also plays a critical role in round spermatid chromatin reorganization during spermiogenesis through its action on Estrogen Receptor Alpha (ERα) present on Sertoli cells (Cacciola et al., 2013). Overexposure to estrogens reduces the expression of ERα on Sertoli cells, impacting this critical action. Moreover, it has been recognized that supraphysiological concentrations of estrogen act as powerful apoptotic triggers that induce germ cell apoptosis (Correia et al., 2015).​

...​

Among men who had a decline in semen parameters, 17% of them may not recover following discontinuation of therapy.​

[R]

Yes, the protective nature the respective steroids provide against one another is very useful. I’m in complete agreement that there is not enough data on the absolute e2 level.

I tend to believe it can only cause issues but it would seem as though a low e2 in the presence of high androgens is certainly toxic. The ratio issue does hold true. This however is not a license to run supraphysiological amounts of testosterone because absolute levels may still prove detrimental in a dose dependent manner. We simply do not know yet. But the neurosteroid enhancement of the androgenic metabolites is what men are chasing with their increasing doses of testosterone. E2 is just a consequence.

Androgens, especially the metabolites of testosterone, can be another reason people opt to run higher testosterone levels. Androgen metabolites increase t4 to t3 conversion. And healthy thyroid numbers also equal more metabolites. Which comes first? I believe either can effect the other.

People have lower metabolic function especially cellular thyroid function and lower creation of metabolites. They take supraphysiological amounts of testosterone to improve their load of androgenic metabolites that they are just under converting.

That’s why we need to just begin also supplementing metabolites and keeping everything physiological.

I also have my doubts to the anticipated conversion rates we have for estradiol and dht. We will see with my bloodwork. I believe that there may be much more conversion peripherally than what we see in serum. The serum measurement is what our ratio’s currently speak to. Not the cellular load.

I’d be hesitant to think that systemic estradiol makes its way back into organs such as testes. For example exogenous Dht does not raise intra prostatic dht levels. Maybe clomiphene elevates lh too high causing higher intra testicular e2 or some other direct action of clomiphene. While I cannot dispute the correlations, I’m nervous to accept a clomiphene study on its own because it is indeed a different animal than testosterone therapy.

There are many men with low testosterone that feel like super hero’s because they have robust conversion of dht and e2. Some men have high testosterone but deficiency or less than ideal 5ar activity. They are muscular but have sexual dysfunction or small genitalia in more extreme cases micropenis.