Does low estradiol cause joint pain in men because of inflammation?

I have Rheumatoid Arthritis, and I am on TRT, so several things to balance. Last month I noticed I was getting a slight amount of pitting edema along my lower (bilat) shins, could be missed by a lesser clinician. I wasn't sure if it was the Hcg or the Preg/DHEA, but I was certain it was higher E2. So I took some Arimidex for about 3 days, then got in for several tests. I continued the AI until I went on vacation, and decdied to skip a week of Hcg and AI. I got my labs back quickly, and it turned out my E2 was low when I tested,
E2 17.9pg/ml 8-35
TT 861 ng/dl 348 - 1197
FT 26.2 pg/ml 6.6 - 18.1
Prolactin 11.0 ng/dl 4 - 15.2
C Reactive protein (sensitive) 8.7 mg/l 0- 4.9
DHT 39 ng/dl
Other labs were all WNL and good
So, last CRP was low 0.9 mg/l, although this was when I was still on Prednisone, (and Enbrel and Methotrexate). The pain is resolving today after 2 or so weeks of knee pain, I am assuming the reason for the pain was the lower than 17.9 E2, and that this also was the reason for the higher CRP? Any thoughts?
My prolactin has usually been about this result, am I too low to attempt a trial of (liquid) Cabergoline? My libido still is not good, and I have delayed ejaculation, a long standing issue.
I understand that my RA is not a typical TRT component of many men in this forum, but RA is responsible for 60% of its male victims to have low T, so its a common issue in my disease community.

Great question!

Yes, low estradiol can cause joint/muscle aches due to increased inflammation (high CRP is a parameter)

Low testosterone also can increase CRP.
Association of sex hormones and C-reactive protein levels in men


"However, besides the well established positive effects of sex hormones in selected pathologies with a relevant inflammatory component, such as MS and osteoporosis, there is now a wealth of experimental models where the lack of endogenous estrogens facilitates the onset of inflammation that is antagonized by estrogen replacement. Examples of such models are: carrageenan-induced pleurisy, endotoxin-induced uveitis, experimental encephalomyelitis and adjuvant-induced arthritis and cutaneous wound healing.

In all of these models estradiol clearly opposes the inflammatory process." From: Estrogen and inflammation: hormone generous action spreads to the brain

I am tired of warning men to be careful with high anastrozole doses (over 1 mg per week), and use of anabolic steroids that are DHT derivatives that reduce estradiol to undetectable blood levels. We also have data on how low estradiol makes you fat and lowers your libido.

The question really is what is high estradiol? Does that number depend on how high or low your testosterone is? We can spend hours on that is Dr Saya and I get into it.

Testosterone is the precursor hormone for estradiol. Estradiol is a hormone more abundant in women than men that is produced by the aromatization of testosterone in liver, fat and other cells. Nature created it for a reason. It has been shown to be responsible for healthy bone density but its role in men's sex drive, body composition and other variables is source of great debate. One thing is certain: High estradiol blood levels can cause growth of breast tissue in men :https://www.excelmale.com/forum/threads/442...ight=man+boobs

When the HPT hormonal axis senses that testosterone or estradiol are high, it automatically decreases or shuts down testosterone production.

Many anti-aging or men's health clinics prescribe anastrozole, a blocker of estradiol production, to men who start testosterone replacement (TRT). Higher estradiol blood levels not only can cause breast tissue growth (gynecomastia) but also water retention (edema). Some people speculate that high estradiol can also lead to erectile dysfunction but no scientific papers have been published on this subject. Since higher testosterone blood levels can originate higher estradiol levels, the belief is that using anastrozole will prevent breast tissue growth and erectile dysfunction by lowering any potential increase in estradiol. However, we have no data on how high is too high when it comes to this hormone in men. Some even speculate that low testosterone-to-estradiol ratios may be more closely correlated to gynecomastia and erectile problems than estradiol alone.

The truth about these speculations is starting to emerge but we still do not have enough data to say what the upper value of the optimal range of estradiol really is. We have a lot of evidence about the lower side of the optimal range since it has been found that estradiol blood levels below 10-20 pg/ml can increase bone loss in men. A recently published study also nicely demonstrated that low estradiol can be associated with higher fat mass and lower sexual function in men. So, be very careful when a clinic wants to put you on this drug without first justifying its use.

Another concerning fact is that many clinics may be using the wrong estradiol test that may be over-estimating the levels of this hormone in men. An ultrasensitive estradiol test more accurately measures estradiol in men instead of the regular test that costs less.

Fortunately, most men on TRT do not develop gynecomastia even without using anastrozole (gynecomastia is common in bodybuilders who may use high doses of testosterone, however). Those that have gynecomastia at TRT doses (100-200 mg of injectable testosterone or 5-10 grams of testosterone gel per day) may be genetically predisposed to having more aromatase activity or have liver dysfunction. Treating all men who start TRT with anastrozole from the start may be counterproductive since this may lower estradiol to very low levels. Some physicians monitor estradiol blood levels after 6-8 weeks of having a man start TRT alone using the ultrasensitive estradiol test to determine if anastrozole use is warranted. Doses range from 0.25 mg per week to some clinics using excessive doses of 1 mg three times per week. After 4-6 weeks on anastrozole its dose can be adjusted to ensure than estradiol is not under 20 pg/ml. Fortunately, many men on TRT do not need anastrozole at all.

So we await for more studies that will clarify the role and optimal ranges of estradiol. Here are a few studies that we already have available based on the role investigated.

Role of Estradiol in Men and Its Management

Nelson Vergel said:

The question really is what is high estradiol? We can spend hours on that is Dr Saya and I get into it.

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Ok, now I'm curious! I assume this means that you and Dr. Saya have different opinions on this? Can you give us the Cliff Notes version of what you and Dr. Saya would consider high estradiol?

Saya and all doctors in the men's health network clinics believe that 40 pg/mL is the upper limit of estradiol no matter what type of men and T levels we are talking about.

I don't believe that. I believe that 0.2-0.3 % or so of T converts to estradiol for a reason and that means that a man with 1800 ng/dL can have 54 pg/mL with absolutely no need for an AI.

I also do not believe any man who is starting TRT should be given anastrozole until we see what it is at week 6 via sensitive analysis.

Nelson Vergel said:

Saya and all doctors in the men's health network clinics believe that 40 pg/mL is the upper limit of estradiol no matter what type of men and T levels we are talking about.

I don't believe that. I believe that 0.3 % or so of T converts to estradiol for a reason and that means that a man with 1800 ng/dL can have 54 pg/mL with absolutely no need for an AI.

I also do not believe any man who is starting TRT should be given anastrozole until we see what it is at week 6 via sensitive analysis.

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This makes a lot of sense... Probably no magic range as all men are different. I will says this, my E was over 60 and when I started taking the Adex it was crazy how I started feeling better during the "fall"... And it was quick too! The key is what is that zone to feel good and once we find it how do we stay there... Not get too low and not get too high...

Vergel, thank you for the post and the study. Having a disease that usually results in higher CRP (last year hit 69), I am always unsure if my problems are RA or TRT related. Because I continued with my very low dose AI use, including a few days after my lab test (with a 17.9 E2) I assume the RA drags out the joint pain, but maybe not the inflammation. Since I just got tested, and my E2 is heading back up, I will wait until I lose morning wood, and then resume Arimidex with my usual 0.025mg dose at each of my 3 x I take T Cyp.
I am meeting with my Urologist in late Sept, will have to discuss placing some HCTZ or similar diuretic once a week in place of my Lisinopril.(Unless he has a better idea)

Nelson Vergel said:

Saya and all doctors in the men's health network clinics believe that 40 pg/mL is the upper limit of estradiol no matter what type of men and T levels we are talking about.

I don't believe that. I believe that 0.2-0.3 % or so of T converts to estradiol for a reason and that means that a man with 1800 ng/dL can have 54 pg/mL with absolutely no need for an AI.

I also do not believe any man who is starting TRT should be given anastrozole until we see what it is at week 6 via sensitive analysis.

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Very interesting. Thanks! Is there an Estradiol number that you feel is the upper limit for a man with around 1100 total T (the "high end of natural")? Or do you feel that the numbers don't matter and we should only be watching symptoms, regardless of how high the Estradiol level gets?

Nelson Vergel said:

Saya and all doctors in the men's health network clinics believe that 40 pg/mL is the upper limit of estradiol no matter what type of men and T levels we are talking about.

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Not quite accurate. As I mentioned with your recent chart reference ranges, Neslon, I would generally stretch the E2 upper limit to ~45-50pg/mL....DEPENDING on symptoms or lack thereof for a specific patient.

interesting, last summer mt total T was 1300 and E2 was around 50pg/mL and feeling great and I was pretty lean, now my T is about 700 my estrogen around 25, not feeling good at all and I do have water retention more now that my estrogen are low

100 % of the data we have on estradiol in men comes from studies that followed men with total testosterone is the low to mid range. Not one followed LH suppressed men with total testosterone of over 1000 ng/dL. The lab ranges from Labcorp and Quest were derived from low to mid T range men.

No study has proven than giving anastrozole to healthy men on TRT improves anything. Not one study (except for two that contradict each other in men with epilepsy who tend to have high estradiol and prolactin.) This misconception has caused a lot of "chasing after the wrong rabbit" syndrome in many men.

Dr Morgentaler (one of the most respected TRT clinicians in the world with several videos on ExcelMale) wrote an excellent review paper on the subject that solidified my opinion (attached for download).

It doesn't help interpretation that virtually all of the (flawed) data we do have on estradiol is utilizing the inaccurate Roche ECLIA (standard) estradiol assay. Trying to glean ACCURATE clinical data and interpretations from a test that is, in itself, INACCURATE is a rabbit hole in it's own right.

Dr Justin Saya said:

It doesn't help interpretation that virtually all of the (flawed) data we do have on estradiol is utilizing the inaccurate Roche ECLIA (standard) estradiol assay. Trying to glean ACCURATE clinical data and interpretations from a test that is, in itself, INACCURATE is a rabbit hole in it's own right.

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Agreed. But using the wrong test across studies at least standardizes the error across them. Hopefully Baylor can eventually use the right E2 test and run some studies in men on TRT in the future!

Nelson Vergel said:

Agreed. But using the wrong test across studies at least standardizes the error across them. Hopefully Baylor can eventually use the right E2 test and run some studies in men on TRT in the future!

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Let's make that happen with Baylor...amongst other things we need to look at (HCG -> pregnenolone, DHEA, progesterone relationship...etc).

Unfortunately even using the RIA consistently in those studies won't do much to standardize the error across the studies as we know CRP levels (and thus cross-reactivity with the Roche ECLIA) vary drastically amongst individuals and even for the same individual from day-to-day...really makes the data relatively useless.

Estradiol Inhibits Certain Inflammatory Activation of C-Reactive Protein

https://www.excelmale.com/forum/sho...Inflammatory-Activation-of-C-Reactive-Protein