Should We Be Managing Estradiol and Hematocrit in Men on Testosterone Replacement?

[Will Brink]

Polycythemia Vera is a blood disorder with a increase in all components. Most importantly platelets. Erythrocytosis is a increase in H/H not platelets. Platelets clot not H/H. I have to repeat. In over 50 years of TRT there has been no increase in heart attacks, strokes, orDVTs. We can't ignore these decades of studies. Recent flawed studies (we can discuss) dont undo 50 years of research with TRT being safe. The reason you believe H/H causes issues is because of the false interchangeable wording. In these studies where there was a increase in cardiac events with high H/H they actually had polycythemia Vera but use the words erythrocytosis and polycythemia Vera as if they are the same which does nothing but confuse us. instead of disecting the words and missing the bigger point such as with the sherpas (although if we are making it point that high H/H causes heart attacks, strokes, or DVT then adaptation has nothing to do with it. A sherpas H/H is elevated and if that caused heart attacks then that would be occurring "thick blood is thick blood" right?) the mechanism that causes a increase in H/H at altitude is the same as with TRT. I guess I could just have easily said measure all the people living in Denver and compare their H/H to the people living in Panama City Florida. Also, look at patients with COPD. They have significantly elevated H/H and we don't bleed them. Why, because it is a physiologic erythrocytosis not polycythemia Vera. I will say over and over again the confusion lies in physicians using these words interchangeably

I made no such claims nor statements, I simply pointed out some of the comments RE regarding cyclists, etc are factually incorrect and it might strengthen your position to modify those examples, or not use them. Simply trying to help you clarify your message.

In terms of the larger picture, I have not done enough research on high H/H vs polycythemia Vera to comment, but per comments by Nelson about Dr C et al, it seems some other docs agree with your assessment.

I have no opinion at this time.

 

[J. Keith Nichols MD]

We have not had any issues with loss of effectiveness, and as I have said before not one has gone back to injections. I will gladly provide them with injections if they desire. One issue I should address is the compounding pharmacies. I can tell you will absolute truth that there are unfortunately pharmacies that do not have the concentration prescribed. I only use one compunding pharmacy and they utilize independent testing in order to ensure the concentration is what it should be. I have had new patients come in with compounded creams from other pharmacies that were watered down (we sent samples out for testing). Med quest is a reputable national compunding pharmacy. if I could not find a reputable compounding pharmacy that independently tested their products I would also just use injectables.

 

[J. Keith Nichols MD]

I made no such claims nor statements, I simply pointed out some of the comments RE regarding cyclists, etc are factually incorrect and it might strengthen your position to modify those examples, or not use them. Simply trying to help you clarify your message.

In terms of the larger picture, I have not done enough research on high H/H vs polycythemia Vera to comment, but per comments by Nelson about Dr C et al, it seems some other docs agree with your assessment.

I have no opinion at this time.

I will do my best to provide you with the evidence you will find helpful in the coming weeks. Have two children graduating in 2 weeks somplate a little full at present , but I will try to dispel the myth for everyone

 

[Nelson Vergel]

The max hematocrit increase at high altitudes is about 4 percent. Most men at high altitudes have hematocrits that do not reach levels over 52. Extrapolating high altitude conditions to men on testosterone replacement whose hematocrit can climb to values over 60 is not justified at all.

High and Low Hematocrit Increase Cardiovascular Risks


Altitude adaptation through hematocrit changes.

 

[J. Keith Nichols MD]

The mechanism of increase in H/H is the same. You are presenting baseline values and prospective studies. To know if a increase in heart attacks, strokes, or DVTs occurs with the increase in H/H seen with TRT, then one must perform a interventional study and see what happens when you actually give testosterone and increase H/H. Baseline observations don't mean causation. How do we discount over 50 years of interventional studies without a increase in cardiac events or DVTs wirh T administration. These are associations which do not prove causation. No different than the studies where men with high estrogen levels died of heart attacks and strokes. Makes perfect sense. These men were obese with high visceral body fat and therefore high E2. The E2 didn't cause their heart attacks it was all the increased risk factors for MIs that goes along with being obese. The E2 was just a passive bystander. As I have described, give a man E2 that Is undergoing ADT and you protect them. So the studies you have provided say nothing about what happens when a man is actually given testosterone and his H/H increases. 50 years of TRT research prove otherwise.
You are extrapolating the effects seen with people with high Hct of unknown origin to that of patients increasing Hct on TRT which has not been shown. Don't extrapolate.
Morgentaler et al. "Testosterone therapy and cardiovascular risk: advances and controversies" Mayo cling proceedings 2015

 

[Will Brink]

I will do my best to provide you with the evidence you will find helpful in the coming weeks. Have two children graduating in 2 weeks somplate a little full at present , but I will try to dispel the myth for everyone

I look forward to reading it.

 

[Nelson Vergel]

If I had a medical license, I would definitely do something about a hematocrit of 60 with the non-TRT CDV data we have.

We have all watched Morgentaler's lecture and he never says to let go of hematocrit monitoring. In fact, four medical guidelines include hematocrit as part of their recommended monitoring recommendations. Enough data for attorneys hungry for medical malpractice lawsuits?

Dr Morgentaler Clarifies Misperceptions of Testosterone and Heart Disease Risk

Most men using doses under 150 mg per week of testosterone may not have significant hematocrit increases that persist over 1 year. However, there are a few (no data on the prevalence) whose hematocrit increase does not stabilize under 54. You are right when you say we have no data from a TRT study that plots hematocrit with cardiovascular disease incidence. We will probably never have one of those since most of the studies presented in the past few years do not seem to report hematocrit and do not include phlebotomies. Most studies show average total T of under 600 ng/dL anyway. Many men on ExcelMale have TT over 600 ng/dL.

I have only had one phlebotomy in 27 years. But some are not as lucky. I have seen guys with increased blood pressure and fatigue walking around with hematocrit of over 60 unmanaged by their doctors. Should we not address this issue?



Let's assume that no heart attacks or stroke occur with higher hematocrit in men on testosterone. There are other issues like blood pressure that come into play.

"It has been hypothesized that an increased hemoglobin level elevates blood pressure. The present study investigated the association between hemoglobin level and systolic blood pressure and diastolic blood pressure in healthy persons. The study population was composed of 101 377 whole blood and plasma donors, who made 691 107 visits to the blood bank. At each visit, hemoglobin level and blood pressure were measured as part of the standard procedure before a blood donation. We used repeated measurement analysis to analyze the data. We used generalized estimating equation models to assess the between-person effect and linear mixed models to assess the within-person effect. All of the analyses were done separately for men and women. In the study population, 50% were men. The mean age in men was 49.3 years (±12.5 years), and in women it was 42.4 years (±13.7 years). Hemoglobin level was positively associated with both systolic and diastolic blood pressures. With respect to the between-person effect, regression coefficients for systolic blood pressure were 1.3 mm Hg per millimole per liter increase in hemoglobin level for men and 1.8 mm Hg per millimole per liter increase in hemoglobin level for women. With respect to the within-person effect, regression coefficients for systolic blood pressure were 0.7 mm Hg and 0.9 mm Hg per millimole per liter increase in hemoglobin level, for men and women, respectively. For diastolic blood pressure, results were comparable. The results show that hemoglobin level is positively associated with both systolic and diastolic blood pressures in healthy individuals. We observed consistent effects between persons but also within persons."http://hyper.ahajournals.org/content/60/4/936

I am looking forward to the evidence you mentioned that you will get in the next few weeks. I am eager to learn new things that may change my opinion!

 

[Dr Justin Saya MD]

There are valid points on both sides of this.

Fact: polycythemia vera and erythrocytosis are COMPLETELY different phenomena and should not be confused (though the terms are often erroneously used interchangeably). Polycythemia vera is without a doubt MORE risky, but that doesn't mean erythrocytosis comes without (longterm) risk.

Fact: though the physiology is similar, erythrocytosis from TRT is NOT a physiologic erythrocytosis, but is IATROGENIC. Though physiologically similar, the ethics and medico-legal considerations are certainly much different.

Fact: there is no solid data of increased risk of MI, DVT, etc that is attributable directly to appropriate TRT (I know we all agree on this one).

My take: as I've said before, it is not concern for MI, DVT that presents itself to me with TRT-induced erythrocytosis, but more the LONGTERM vascular consequences. To be clear, I'm generally referring to HCT >53 which is about where I draw the line LONGTERM. Most folks at high altitude DO in fact have higher H/H than their counterparts at sea level, however most are NOT HCT > 53 unless they have multiple exacerbating factors contributing (smoker, high iron levels/intake, OSA - this is a BIG one, COPD, + TRT). We all agree higher HCT = more viscous blood. If we look at simple fluid dynamics and the laws of physics, thicker fluid (blood) inside of a pipe (vessel) = higher pressure (blood pressure). I've seen this countless times in patients requiring blood donation or therapeutic phlebotomy -- BP drops, sometimes dramatically, afterwards and generally remains at the lower levels until (if/when) HCT rises again.

Now of course we also have the other end of the equation with enhanced nitric oxide production - which helps as it dilates the pipe (vessel) - consequently counterbalancing the increase in pressure. The problem is that this vasodilation from nitric oxide is VARIABLE over time, whereas the increased HCT is more constant...meaning that this teeter-totter of "thicker blood" counterbalanced by nitric oxide vasodilation, will certainly present times when the viscosity side of the equation is at a distinct advantage. Thinking of it another way, the body is able to adapt REMARKABLY to many differing situations (one of which noted above with the vasodilation), but nonetheless has it's functional limits. Think of it as an airplane that flies at 60-70% of its functional engine capacity (just estimates as I'm not a pilot!) - this piece of machinery has the capacity to utilize a higher percentage of its capacity, but keeping the "normal operating capacity" of the plain at 60-70% gives that added safety margin. The plain can then "throw it into overdrive" and utilize a higher percentage (temporarily) of its capacity when the situation calls for it. This is a crude analogy, but hopefully will make some sense. For the human side - the human body has a capacity to TOLERATE (probably the best term) HCT levels very high under certain situations as an adaptive mechanism, but the higher the HCT goes you are eating into that safety margin for the max capacity of the cardiovascular system and thus reduce the ability of the cardiovascular to remain plastic and adaptable to other changing conditions or insults. For instance, all may be well when the "teeter-totter" of viscosity/nitric oxide is all balanced, but what about when the patient experiences times of reduced nitric oxide production (or other reasons that the pipe won't dilate...like atherosclerosis as they age)...well then the equation is shifted squarely in favor of the higher viscosity = higher BP --> increased shear forces on arterial walls --> increased risk of macro and microvascular pathology, etc.

We don't have longterm data (and likely will not for a long time to come) for MANY of the interesting and debatable talking points related to TRT and other hormonal treatments. We can just weigh the current data we have, use our own clinical judgment and understanding of the physiology of the human body, and sprinkle in a little common sense from time to time to make the decisions we feel are in the best interest of our patients longterm.

I personally would not feel forthright in telling one of my 30-40-50 year old patients that sustaining an iatrogenic erythrocytosis with HCT >53 for the next two, three, or four decades of their life will not present any longterm risk...but it's a debatable topic and one for which each provider (and patient) must determine where they stand and approach it accordingly.

 

[Pranayama]

When my Hematocrit goes above 53 my BP gets higher. After I donate blood my BP lowers. What's not to like aside from the iron issues with too frequent donations?

 

[Nelson Vergel]

Dr Nichols sent me this. He also sent me a paper that I will review tomorrow on the plane (attached)

Look at these averages of Hct. People living at high altitudes can have a very high Hct just as men on TRT. Same mechanism. No harm seen in any study to date. With PV you do have high viscosity because you have high H/H, WBCs, and platelets. Not seen with erythrocytosis from TRT. I'll go to the forum soon and post a lot of data that will hopefully change your mind
Sincerely
Keith




Look at the Hct levels of these individuals living at 14,000 feet. If you were a physician and they walked into your office and you measured their Hct would you send them for a phlebotomy?
http://circ.ahajournals.org/content/circulationaha/12/3/383.full.pdf

 

[Dr Justin Saya MD]

Dr Nichols sent me this. He also sent me a paper that I will review tomorrow on the plane (attached)

Look at these averages of Hct. People living at high altitudes can have a very high Hct just as men on TRT. Same mechanism. No harm seen in any study to date. With PV you do have high viscosity because you have high H/H, WBCs, and platelets. Not seen with erythrocytosis from TRT. I'll go to the forum soon and post a lot of data that will hopefully change your mind
Sincerely
Keith

View attachment 3630


Look at the Hct levels of these individuals living at 14,000 feet. If you were a physician and they walked into your office and you measured their Hct would you send them for a phlebotomy?
http://circ.ahajournals.org/content/circulationaha/12/3/383.full.pdf

If you look at the comments section of the article link, it states that "the data suggest that for a COMPARABLE AMOUNT of external work the heart of the native at altitude responds with a GREATER EFFORT than the heart of a sea level dweller at sea level."

Thus, the heart WORKS HARDER to pump the thicker blood...makes sense right? That's exactly one of the ways I explain this to patients. Looking at it from the angle I described above, the heart of a person with higher HCT is digging deeper into the max capacity of cardiac ability/function..."red lining" it as it were and leaving less further adaptive capacity to any other cardiac challenges or insults, as the heart is already working harder.

More work for left ventricle (especially over years...decades) and you will ultimately have increased risk of LVH (left ventricular hypertrophy), as we see expectedly with hypertension patients.

 

[MikeXL]

What would you say is an E2? The reason I ask this is because, and please don't take this the wrong way, many doctors have a bias. If your patient says doc I have itchy nips or I am bloated or cry at the drop of a hat. Do you say - oh no that is not from E2?

 

[johndoesmith]

I could fill several pages on the negative effects of ADT which totally wipes out both T and E2 (google it). It is used in the treatment of prostate cancer. These men then develop osteoporosis, sexual dysfunction, obesity, insulin resistance, diabetes, metabolic syndrome, cognitive dysfunction, dyslipidemia, and a significantly increased risk of cardiovascular mortality. If they don't die of prostate cancer we kill them in another way and believe me these men want to die because their quality of life is zero. When these men are treated with E2 it dramatically improves their quality of life. They don't become osteoporotic, their lipid profiles remain good, the have improved cognition, and they maintain the cardioprotective effects of estradiol. Also, E2 is apoptotic and anti angiogenic to prostate cancer cells. E2 has just as many important functions in men as it does women...we just don't need as much.

You're making this a kinda black and white thing, when it ordinarily is not. To say that "blocking"(I think you're referring to blocking aromatase not the ER?) by adding a small dose of AI is analogous to ADT is rather drastic.

A patient taking an AI to reduce E2 to 30 is vastly different than <5 or undetectable.

Many men just have high aromatization rates, and maintaining a total testosterone level of 1500 will cause them to have estradiol levels nearing what many menstruating women have. I simply cannot see how that does not cause massive side effects, plus you're discounting free estradiol, which is arguably more important than total.

I am absolutely convinced of estradiols importance, as I suffered from seriously low E2 due to primary hypogonadism, it was a miserable experience, therefore I am by no means advocating aggressive aromatase inhibition. Rather, I am stating that some men will need an AI, at a dose that is expertly titrated to symptoms and labs.

 

[Gianluca]

I realized that beside ferritin, we loose nutrients that are hard to replenish like Magnesium RBC, I donated a few times, and personally after all it weaken me, I already had adrenal fatigue and donating really made it worse, depleting nutrients adrenals and thyroid need, I would say if we need to often donate, I would encourage everyone to do right after an IV bag with minerals and vitamins,

When my Hematocrit goes above 53 my BP gets higher. After I donate blood my BP lowers. What's not to like aside from the iron issues with too frequent donations?

 

[J. Keith Nichols MD]

You're making this a kinda black and white thing, when it ordinarily is not. To say that "blocking"(I think you're referring to blocking aromatase not the ER?) by adding a small dose of AI is analogous to ADT is rather drastic.

A patient taking an AI to reduce E2 to 30 is vastly different than <5 or undetectable.

Many men just have high aromatization rates, and maintaining a total testosterone level of 1500 will cause them to have estradiol levels nearing what many menstruating women have. I simply cannot see how that does not cause massive side effects, plus you're discounting free estradiol, which is arguably more important than total.

I am absolutely convinced of estradiols importance, as I suffered from seriously low E2 due to primary hypogonadism, it was a miserable experience, therefore I am by no means advocating aggressive aromatase inhibition. Rather, I am stating that some men will need an AI, at a dose that is expertly titrated to symptoms and labs.

I have not seen what you are referring to in hundreds and hundreds of patients. With the method of delivery I have outlined I have NEVER had E2 levels that of "Premenstal women". I have not to date had to prescribe AIs for E2 excess. You have been programed inappropriately to worry and focus on your E2 levels. An expert doesn't titrate to labs, he titrates and adjust to symptoms. I have never myself or in ANY of my patients experienced "massive side effects". Focus on optimizing your free T, free T3, DHEA, Vit D3, appropriate diet, exercise, and supplements, and don't block your E2. The reason this is so foreign to you is it is just not how you have read it should be done on various websites and forums that continue to propagate false information.

 

[J. Keith Nichols MD]

I would of course provide them with a AI for a few weeks until symptoms resolve and then discontinue. I have not to date had a man complain of those symptoms. Not that it can't occur, but I have not see it happen in my patient population as of yet and we are talking of hundreds and hundreds of patients. I'm sure at some time it will occur and it will be adressed. I am sure that the mechanism of delivery plans a role in the absence of excess E2 symptoms.

 

[user_joe]

I tend to agree with the part regarding reasonable e2 control. I've personally seen my lipid panels respond favorably to controlled e2 in range and unfavorably to low e2.

I believe the Dr. is saying that at 1500-2000 TT his patients aren't seeing high e2. That would be because of the 12 hour half life of the cream. More of it is converting to dht compared to longer half life injectables. Also that 1500-2000 TT is 5 hours after application. That doesn't really compare to 1500 TT on test cypiomate imo. I'd imagine on the cream you are well down to physiological levels once you go to sleep. This is just what I've gathered. Someone correct me if I'm wrong.

You're making this a kinda black and white thing, when it ordinarily is not. To say that "blocking"(I think you're referring to blocking aromatase not the ER?) by adding a small dose of AI is analogous to ADT is rather drastic.

A patient taking an AI to reduce E2 to 30 is vastly different than <5 or undetectable.

Many men just have high aromatization rates, and maintaining a total testosterone level of 1500 will cause them to have estradiol levels nearing what many menstruating women have. I simply cannot see how that does not cause massive side effects, plus you're discounting free estradiol, which is arguably more important than total.

I am absolutely convinced of estradiols importance, as I suffered from seriously low E2 due to primary hypogonadism, it was a miserable experience, therefore I am by no means advocating aggressive aromatase inhibition. Rather, I am stating that some men will need an AI, at a dose that is expertly titrated to symptoms and labs.

 

[J. Keith Nichols MD]

What would you say is an E2? The reason I ask this is because, and please don't take this the wrong way, many doctors have a bias. If your patient says doc I have itchy nips or I am bloated or cry at the drop of a hat. Do you say - oh no that is not from E2?

Your answer is reply 36. Sorry I didn't put it under your post. I'm trying to work and reply at same time. Apologies

 

[sportsfan8724]

This thread is very informative. Love hearing feedback from different doctors. Dr. Nichols is there a cutoff that you feel is too high of a dose or free t levels that are too high or do you just believe in increasing until all symptoms are gone? Also looking forward to hearing what you have to say about shbg. I know you said you have things to share on that as well.

 

[J. Keith Nichols MD]

You are wrong. It is applied bid and levelsare still optimal "by the time you go to sleep". If I measured you 10 hours after application your free T will still be 30-50. Once again, if you are having a consistent morning erection your T is going to be in a optimal range. You are making a total assumption not based on actual medical data. How does that "not compare to a level of 1500 TT on test cypionate "? These opinions are which are not based on medical facts or what is seen in medical practice is what confuses those looking for information on HRT. I am in no way trying to be offensive but I think we should all focus on how we communicate by considering a quote by Hippocrates the father of medicine. "There are in effect two things, science and opinion: the former begets knowledge, the later ignorance" We should focus on what the medical literature supports. What study shows that increasing E2 with T is harmful? What study shows that decreasing E2 is beneficial?