Testosterone and Cardiovascular Disease

You are referring to the publication of Travis et al, 2017 in which they established the new reference range taking into consideration the testosterone assay calibration efforts by the CDC.

Let me try to explain

The previous ref range that eg LabCorp used was 348 - 1197 ng/dl. Thats based on an LC-MS method using the data from the Framingham study (Bhasin et al, 2011).

The new reference range is 264 - 916 ng/dl. And thats based on the study from Travis et al., 2017 which used data from 1185 healthy nonobese young men. It also used LC-MS technology and used samples from 4 different cohorts the Framingham samples was one cohort).

Now where does the difference come from?
In short, about 90% of the difference comes from the fact that a newly established calibrant was used to calibrate the results from the different studies to the CDC standard.
About 10% comes from the fact that non obese (BMI <30) young males were studied in the Travis study whereas lean young men were used in the Bhasin study.

In more detail. Different testosterone assays have different responses. They give you different results when measuring the same sample. The assays need to be calibrated if one wants to compare different samples from different labs. Thats why the CDC came up with a testosterone assay standardization program. The study by Travis et al is the first study which made use of the newly established CDC calibrant.
Take a look at figure 1 of Travis 2017, second row. The exact same samples from the Framingham study (FHS) were re measured again using the new calibrant and compared to the original results. You can see that an average of difference of 144 ng/dl nwas found.
In other words. If you had your blood analyzed at LabCorp before 2017 and the result was 600 ng/dl and you had the blood froozen and reanalyzed now the result would be around 450 ng/dl (again Figure 1, 2nd row right shows the correlation between the old (FSH) data and the new data).
The reference range changed predominantly due to the calibration of the T assay to the CDC standars and not because the population testosterone declined.

Again i am not saying that the population T is not declining, in fact I personally believe they did, but the data is ambiguous.

I hope this ensures you that nobody is intentionally falsifying any T measurements to neglect treatment for low T.

Figure 1 from Travis et, 2017

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@NH_Watts

There is what?

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@johann77 - That was a great explanation of why ranges are different now than before. It seems like the examination method/technique, etc is just becoming more accurate. I enjoy reading your posts.

What do you think about men whose symptoms go away with levels higher than the ranges?

Facts are cool

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Like @bcostigan41 said, “That was a great explanation of why ranges are different now than before. It seems like the examination method/technique, etc is just becoming more accurate.”

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Most people feel pretty good on a cycle too. Just sayin…

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If you feel better at TT 2000 ng/dl and potentially also have high SHBG perfectly fine. In your 20s, 30s or 40s ok, you may want to reduce later in life though. Long term risks? - no idea.
Some data suggest that at levels above 4000 to 6000 one is at risk for developing heart related side effects even when used short term.

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I’ve never done a cycle. I have enough test stocked up to do one if I wanted to try it, but I’ve just come to a place this year where I’m starting to feel pretty good.

My numbers are a bit over the ranges, but I don’t think too crazy. For some reason, quest used the old ranges for free T in my last blood test, but here they are -

Screenshot_20190629-122339

I had follow up bloods about a month later at my Dr and my TT was 1080 and my HTC was 47.

This is on about 42-46mg EOD (dose hasn’t always been precise, if there was an accidental over draw, I just injected it)

Just wanted to say your posts are very refreshing.

As someone who began very seriously investigating TRT a few months ago, I quickly realized the amount of bro-science, complete BS, or total lack of understanding out there is absolutely mind boggling (w/ various conspiracy theories thrown in for good measure, or to help sell books, podcasts, or forum advertising, etc).

Sadly the information you provide will likely get washed out, and countless people will jump into a lifelong commitment of TRT without having the knowledge to make a truly informed decision. Nonetheless, again thanks for your posts.

That doesn’t make sense. A value is transferable from one institution to another. If you are 6ft in 2017 you are still 6ft in 2019.

If This is true then my previous results should be lower by 20% or whatever he’s saying. Meaning if you take 200mg and get 25 free t, then 20g free t in 2019 from 200 mg or whatever. That’s not how it supposed to work.

I’ll get some studies posted once I get home and find time between work and kids

Actually I think that is the study. But go look at his previous study where he states hormones are lower in men today than they’re have been in the past.

How do we say that and then base the new ranges on that study. Now we have this assay calibration that’s supposably the cause?

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This is what I’m trying to understand. We essentially agree on this. This is why I get frustrated with the industry, lab companies and etc

I have to look into the assay you discuss, but my doc and his partner is a research expert and he did not mention this when shared this study.

If this is true which I’m not doubting, the acurrancy improved and so the ranges are more accurate than they were prior. This makes more sense than some conspiracy trying to keep people off TRT.

I still think we have a long way to go to be able to definitively say whether or not someone is experiencing a testosterone deficiency not by simply looking at the numbers without seeing at what’s going on at the cellular level because everyone processes androgens a little differently.

Some guys are blessed with very sensitive receptors only needing a few milligrams daily and other guys needing a lot more androgens to have the same effect.

I don’t think it’s a conspiracy outright, but I question it. I just can’t wrap my head around how they can say ng/dL measurement in 2016 is now different in 2019 if tested again. I will read the study again that he referenced tomorrow and try to understand it further. If he’s right I’ll bow and agree.

But the other issues is that There are more lab companies out there and the ranges vary quite a bit. Everyone does not go to labcorp.

The fact remains that the same author reported that the hormones have dropped considerably over the years. Fact as he reported it. The study I have also has this author with the 900 new total where I believe this precious “men with lower hormones” study was cited. So it’s a double whammy. Yes we have less hormones and now we have more accuracy and it’s even lower than originally thought.

The fact that we have less hormones today and more and more men are having low t symptoms is obvious. Now we are trying to say that the test is just more accurate? By 30%. 1250 to 900. This is also not something that any doctor in the trt world has ever recognized as the reason why. Yet here we are.

If in 2017 my dose raised my levels to 1300 and now it is 900 I’ll believe it. Until then i am going to remain very skeptical. Has anyone here stayed on the same dose and noticed a drop with their lab Corp results! All of a sudden levels are lower?

FYI I just tried to pull the studies my doc sent to me but they are archived in my exchange email and I’ll have to dig through my email at the office tomorrow.

Google this study I can’t link to it from Facebook. Spot on.

https://www.jsm.jsexmed.org/article/S1743-6095(15)31411-9/fulltext

RESULTS: All of the academic and eight of the community centers performed total testosterone testing. Free testosterone was performed in-house by six of the 12 academic and one community center. Testing for bioavailable testosterone, free androgen index, and percent free testosterone was performed in-house by no more than two centers. There were eight and four different assays used for total and free testosterone, respectively. One national laboratory offered equilibrium dialysis measurement of free testosterone. Of the 25 labs, there were 17 and 13 different sets of reference values for total and free testosterone, respectively. The low reference value for total testosterone ranged from 130 to 450 ng/dL (350% difference), and the upper value ranged from 486 to 1,593 ng/dL (325% difference). Age-adjusted reference values were applied in four centers for total testosterone and in seven labs for free testosterone. All reference values were based on a standard statistical model without regard for clinical aspects of hypogonadism. Twenty-three of the 25 lab directors responded that clinically relevant testosterone reference ranges would be preferable to current standards.

I said numerous. I meant I have had many studies that point me to these thoughts, but only one that shows the new ref range.

Here is what I found. A new study that discusses assays and ranges.

I can’t seem to download and upload from
Phone so I have left you some screenshots.

One of the most remarkable findings in this study was that there were 17 different sets of TT reference ranges among 25 laboratories. Not only did reference ranges differ between different manufacturers of TT assays, but they even dif- fered for labs using the same kits. In addition, the reference value used to categorize individual test results as low varied by approximately 350%, meaning that the TT results for one man might be low at one laboratory, and well within the nor- mal range according to another. For instance, a TT value of 251 ng/dL would be categorized as hypogonadal by 14 of the labs we surveyed, and normal by the other 11 labs. Similar results were noted for FT.
Variability of the upper reference values given for TT and FT presents a slightly different prob- lem. This upper value is frequently used to monitor treatment levels for men undergoing testosterone supplementation. When upper refer- ence ranges are inappropriately low, clinicians may become unnecessarily concerned that therapeutic doses of testosterone treatment are excessive if TT or FT results are higher than the reference values.
However, in our opinion, the largest problem is that none of the institutions offered reference values linked to clinical considerations regarding hypogonadism. All the manufacturers represented in this study used a standard statistical model for reference values that categorizes only the lowest and highest 2.5% of values as abnormal. If the prevalence of hypogonadism affects 15–35% for men over the age of 50 years [19] and if only 2.5% of values are categorized as “low,” this means that a large majority of affected men will fail to be properly identified as hypogonadal.
The use of age-adjusted reference values com- pounds this problem by downshifting the lower and upper ends of reference ranges by as much as 50%. Because TT and FT values decline with age, this means that older men must have exceedingly low test results in order to be categorized as hypogonadal when age-adjusted values are
applied. The use of age-adjusted values may make sense for a statistical representation of a popula- tion, but has no clinical justification for the diag- nosis of hypogonadism. As stated by Ooi et al., which forms the basis for the reference values pro- vided with the DPC assay, age-adjusted reference values “decrease the test sensitivity for detecting androgen deficiency in aging males” [16].
When clinicians obtain a blood test to deter- mine whether hypogonadism is present, they expect that reference ranges provided by the lab- oratory report will help guide them to a proper diagnosis. As demonstrated herein, currently used reference ranges are inadequate in this regard, and may contribute to the underdiagnosis of hypogo- nadism. A more useful approach may well be the application of a clinically relevant threshold, or target levels, for TT and FT, as has been used in numerous clinical trials. This approach is univer- sally used for several tests, such as serum choles- terol, glucose, and prostate-specific antigen, in which a clinically determined threshold value pro- vides greater guidance than identification of values that fall within the lowest or highest 2.5% of the population.
Our survey of laboratory directors indicated that a strong majority (92%) favored clinically relevant threshold values for testosterone testing rather than the reference ranges used in current practice. Although national and international spe- cialty organizations have suggested thresholds for the laboratory diagnosis of hypogonadism, none of the 25 labs participating in this study referred to such values. Recommended values also lack consensus as evidenced by TT thresholds values ranging from 231 to 400 ng/dL [20,21].
In summary, these results indicate that the cur- rent use of testosterone reference values is confus- ing and inadequate. There is a clear need for greater standardization and more clinically rele- vant reference values to guide clinicians in the diagnosis and treatment of hypogonadism.
Corresponding Author: Abraham Morgentaler, MD, One Brookline Place, Suite 624, Brookline, MA 02445, USA. Tel: +1-617-277-5000; Fax: +1-617-277-5444; E-mail: amorgent@yahoo.com

Exactly. This publication is from 2006 and was one of the most important reasons why FDAs CDC initiated the hormone standardization program in 2007 (it took until 2010 before the first actions took place!). I completely understand that the existence of different ref ranges can be quite confusing.

From the AAAC homepage regarding the improvements made since then:

WHAT PROGRESS HAS CDC MADE WITH STANDARDIZING TOTAL TESTOSTERONE AND ESTRADIOL TESTS?

Since HoSt began in 2010, CDC has had more than 350 participants in 15 countries. Participants have shown measureable improvements for both total testosterone (TT) and estradiol (E2). Specifically, the among-laboratory bias has decreased from 16.5% in 2007 to 2.8% in 2017 for TT and from 54.8% in 2012 to 13.9% in 2017 for E2. Not only has bias improved, but data from proficiency testing programs also show that standardized testosterone assays are more accurate and consistent compared to non-standardized assays.

Recently, CDC CSP also collaborated with the Endocrine Society and PATH to develop reference ranges for testosterone in non-obese men ages 19-39 years old. These reference ranges are now part of an Endocrine Society clinical practice guideline and according to this guideline can be used by laboratory tests standardized to CDC’s criteria.

I agree that for most clinicians this is confusing (and I know many of MDs from my workplace) and some may only refer to the reference range to make a diagnosis. However, according to the literature and from my knowledge (i am not a clinician) it’s really difficult to tell apart the patient that suffers from androgen deficiency and benefits from TRT from the patient that has other conditions which lead to very similar symptoms. The best lab value that correlates with the symptoms of androgen deficiency is freeT but even at the lower ref value, about 50% of men have no symptoms of adr def if a random number of men are tested and questioned for symptoms.

In my personal opinion nobody should get TRT refused on the basis of a single TT measurement that shows TT just slightly within the reference range and when symptoms of androgen deficiency are present and other causes can be excluded.

I also had a frustrating experience with one urologist about 8 years ago. But at least in the country I life in the EU I did not encounter any problems in getting TRT fully paid by my insurance even though I was slightly above the ref range in most measurements. The urologist did a questioner called ‚aging male symptoms score‘ and we had a discussion about what to realistically expect from TRT and what potential risks TRT may pose. I found that very professional and still think this is the way to do it. But maybe I was just very lucky with my urologist and things are indeed different in the US.

https://www.cdc.gov/labstandards/hs_standardization.html

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@prouser
@NH_Watts
@charlie12
@systemlord

This information comes from an research expert In the androgen field dr. Howell. I spoke to him and took notes and here is our response. Pretty much what I thought. How the hell can one test vary from one to another.

  1. What’s different and if it is a quantitative, not qualitative difference, what about the reliability statistics for the ‘difference’?

“The harmonized references ranges by Travison in 2017 do not counter his previous work from 2007 which is an extremely interesting and insightful example of T declines.”

@johann77 You should be reading this by the same author.

When you read the study above you will see a massive decline in men serum levels.

Next paragraph is Important and exactly my point. How can a rest vary so much when you have the same measurement value. If I measure something it should be similar in 20 years. That is the point of a measurement “

“What he mentioned seems to be quantitative. A serum value of 1200 is a value of 1200 and I know of no lab test that would have that high of a coefficient of variation to really be 900. I could see + or - 50 but dropping 300 because the test is different is not based in reality. If the error was that high, we would all be FUCKED.”

“The 2017 study was to develop new reference ranges was from four large cohort studies and then average the ranges to make them harmonized. This has nothing to do with sensitivity and specificity of tests used 10 years ago and those used today. A value is a value regardless of the reference range used to compare it. “

This is coming from someone who has spent
Their life reading studies. Currently spends his days reading and extrapolating data referencing androgens and anything hormone related for men and women. The goal is to legitimize and standardize the approach to Hormone therapy for men like us. allowing men to get the proper health care without doctors fearing heart attacks and higher normal values. Prostate cancer and whatever other nonsense is believed.

Let’s hope this comes to light in the coming years and men no longer have to beg for trt.

Let’s now pull all of This together.

The same author clarified that there was a big drop in T serum across the board within the study. They specifically state this is Obvious and we definitely have less T.

Now fast forward and another study is made to
Harmonize reference ranges. They don’t mention the previous evidence mentioned above and mention they tested non obese men and all men and the results were shockingly similar.

Meaning a person that looks healthy has similar levels as someone who is obviously not healthy.

How many of us , before we got low t, thought we were healthy? And then we woke up one day and realized we were no longer healthy?

If this decline is noted in a study; another study that creates the new reference ranges should
Clarify this . We should all be up in arms … our population of mostly white Caucasian American and European males are not healthy. They did not test Africans,
South Americans, and other areas where technology and pollutants aren’t as extreme.

Who in their right mind would be comfortable saying “these so called healthy men have much lower levels than our last study. Yet we will use these ranges anyways. Because they are today’s healthy man”.

What the fk? No it has nothing to do with the Assays. They might deviate by a small
Percentage but not 1200 To 900.

Would you a man on trt be able to make these the new lab ranges jf you had created all these studies? Ofcourse not.

How csn anyone sit there and tell us this is healthy. Yet tell us in another study this is not healthy.

If anything they should say this is alarming and a big reason why so many men need trt today than 50 years ago.

———
Although the cohorts included in these analyses were diverse in morbidity, age, and geographic location, they were largely composed of men who identify as white within a US or European social context. Significant geographic and racial differences in sex-steroid levels, which have been reported in some studies (34, 35) but not in other studies (36), might have important implications for clinical decision making. It might therefore be important to develop larger investigations of multiracial, multiethnic, and more geographically diverse cohorts to confirm applicability of reference ranges to broader populations.

Several important conceptual issues remain unresolved. Should the reference range be based on a sample of healthy young men (the so-called T-score approach) or should the reference range be age adjusted (the Z-score approach)? We have provided reference ranges in a young healthy reference sample as well as by decades of age. The rationale for generating the reference range in healthy young men is similar to the use of bone mineral density T-scores for the diagnosis of osteoporosis. For analytes that exhibit substantial age-related change, such as testosterone and estradiol, it might arguably be more appropriate to derive the reference ranges in a healthy young population. Notably, results obtained in this study show a lesser age trend than that reported previously in cross-sectional analyses of men of different ages, underscoring the need for longitudinal studies of the effects of aging on sex steroid concentrations.