High Total T, High SHBG, Low Free T (natural)

[highshbg]

28M, active - lift weights and do cardio, 13% body fat, natural

I've been experiencing low libido (lack of sexual thoughts, no morning erections) and a general tiredness where I feel like I can't get enough sleep for a few years now.

I asked my Dr for a testosterone test a few years back and came back in the 800s, so I dismissed the testosterone idea as a cause until recently when I paid out of pocket for a test.

Supplements
Vitamin D 10mcg, magnesium 270mg, zinc 30mg. Prior to the first test I was taking these several times per week, but after I started taking everything but vitamin d daily.

Diet
High protein (chicken, red meat, whey), moderate carb, moderate fat
No drugs, no alcohol


Questions

Do you think the high shbg and potentially low free t could be the issue?

I see people say free t below 10 or under 2% of total is not ideal. But the reference ranges on these tests make me wonder if it's possible to compare the test values.

I got the equilibrium dialysis test from discountedlabs after seeing @Nelson Vergel recommend it. I'm happy to have this new result, but now I am wondering how their range is so much lower than everyone else's.

I will be talking with a Dr in about 10 days from a clinic mentioned on this forum, so I would appreciate any advice or thoughts this group has so I can go in informed.

 

[Systemlord]

Do you think the high shbg and potentially low free t could be the issue?

SHBG doesn’t lower Free T, the stimulating hormone LH and the testicles response to stimulation is what’s responsible for testosterone production.

SHBG has no influence on testosterone production. Androgens, testosterone lowers SHBG and so someone with low free testosterone might see SHBG increases result.

Starvation, cutting to get that super lean look will lower testosterone and increase SHBG by way of improvements in insulin sensitivity, similar to a type 2 diabetic reversing diabetes, and increasing SHBG.

 

[Systemlord]

I'm happy to have this new result, but now I am wondering how their range is so much lower than everyone else's.

I wouldn’t even bother trying to compare lab results with other lab companies, it’s pointless! Choose a company and stick with it.

If you go to Quest Diagnostics and check your free testosterone and it’s high normal range, and go to LabCorp with the same blood sample and now your mid range.

Dr. Abraham Morgenthaler found 27 different reference ranges for testosterone in the USA alone!

It’s a real sh** show!

 

[Cataceous]

Because your free testosterone looks to be adequate I do not think conventional TRT passes the risk-reward test. Be skeptical if anyone pushes this on you. That said, there are some suggestions in the literature that high SHBG can impair androgen signaling. A relatively safe way to test this proposition is to run a trial with testosterone nasal gel, e.g. Natesto. If you don't see any improvements in a few months then you will need to consider other potential causes for your symptoms.

 

[Vince]

Supplement with magnesium. It will increase your free T

Does magnesium decrease SHBG?

Does magnesium decrease SHBG? Magnesium binds SHBG in a nonspecific mode, leading to an uncompetitive inhibition with T in binding SHBG and to a subsequent enhancement of Bio-T availability. The binding is accompanied by a magnesium release (or uptake) with a corresponding heat effect around...

www.excelmale.com

 

[highshbg]

Supplement with magnesium. It will increase your free T

Does magnesium decrease SHBG?

Does magnesium decrease SHBG? Magnesium binds SHBG in a nonspecific mode, leading to an uncompetitive inhibition with T in binding SHBG and to a subsequent enhancement of Bio-T availability. The binding is accompanied by a magnesium release (or uptake) with a corresponding heat effect around...

www.excelmale.com

Thanks. After I got the results from the first test, I started taking 270mg daily, along with 30mg of zinc

 

[Cataceous]

Supplement with magnesium. It will increase your free T

Does magnesium decrease SHBG?

Does magnesium decrease SHBG? Magnesium binds SHBG in a nonspecific mode, leading to an uncompetitive inhibition with T in binding SHBG and to a subsequent enhancement of Bio-T availability. The binding is accompanied by a magnesium release (or uptake) with a corresponding heat effect around...

www.excelmale.com

Vince, you've been around long enough to know that lowering SHBG activity is not going to raise free testosterone. However, in a case like this, if high SHBG is causing problems directly then effectively lowering it could help, at least in theory.

 

[madman]

28M, active - lift weights and do cardio, 13% body fat, natural

I've been experiencing low libido (lack of sexual thoughts, no morning erections) and a general tiredness where I feel like I can't get enough sleep for a few years now.

I asked my Dr for a testosterone test a few years back and came back in the 800s, so I dismissed the testosterone idea as a cause until recently when I paid out of pocket for a test.

Supplements
Vitamin D 10mcg, magnesium 270mg, zinc 30mg. Prior to the first test I was taking these several times per week, but after I started taking everything but vitamin d daily.

Diet
High protein (chicken, red meat, whey), moderate carb, moderate fat
No drugs, no alcohol

Test Date	Time	Total Testosterone (ng/dL)	Free Testosterone (ng/dL)	Free T ref range	SHBG (nmol/L)	E2 (sensitive)	Method
5/28/24	Afternoon fasted	813	8.8	4 - 25	88	not measured	Standard immunoassay
6/14/24	Morning fasted	1188	8.1	9.3 - 26.5	85	33	Standard immunoassay
6/27/24	Morning fasted	921	8.9	3.5 - 15.5	not measured	not measured	LC/MS Equilibrium Dialysis

Questions









Do you think the high shbg and potentially low free t could be the issue?

I see people say free t below 10 or under 2% of total is not ideal. But the reference ranges on these tests make me wonder if it's possible to compare the test values.

I got the equilibrium dialysis test from discountedlabs after seeing @Nelson Vergel recommend it. I'm happy to have this new result, but now I am wondering how their range is so much lower than everyone else's.

I will be talking with a Dr in about 10 days from a clinic mentioned on this forum, so I would appreciate any advice or thoughts this group has so I can go in informed.

Just to be clear here the only way to know where your FT level truly sits is to have it tested using what would be considered the most accurate assay the gold standard Equilibrium Dialysis especially in cases of altered SHBG!

If you do not have access to such (highly doubtful) if you live in the US then you would need to use/rely upon the linear law-of-mass action cFTV.

Keep in mind as of now cFTV tends to slightly overestimate when compared against a standardized ED assay.

Just to put this in perspective most healthy young males would be hitting a FT 10-12 ng/dL tested using the gold standard Equilibrium Dialysis assay (most accurate) or a cFTV 13-15 ng/dL and this is a short-lived peak to boot!

Trough would be 20-25% lower.

More importantly a FT in the low-mid 20s whether cFTV or standardized ED assay would be very high!

As I have stated numerous times on the forum although TT is important to know FT is what truly matters as it is the active unbound fraction of T responsible for the positive effect.

The shitkicker here is when it comes to measuring FT it's complex.

Some critical points here that need to be kept in mind when it comes to free testosterone, testing methods used (assays/cFT), labs/reference ranges!

Top it off that there is no standardization/harmonized FT yet!

This will be coming to an end soon enough!


*Measurement of free hormone (FH) concentrations in biological samples presents a challenge to the clinical laboratory. FH concentrations are generally very low, requiring use of sensitive and specific techniques. Furthermore, special attention must be placed on the equilibrium between free and protein-bound hormone when separating and analyzing in vitro.

*Because FHs are present in biological samples in trace concentrations, highly sensitive and specific methods are required for accurate measurement of FH concentrations

* Limitations of using free testosterone by equilibrium dialysis and calculated free testosterone concentrations in practice are the lack of assay standardization, an accuracy-based quality control program, and a harmonized reference range. Until these limitations are addressed, free testosterone by equilibrium dialysis and calculated free testosterone should use reference ranges established by individual laboratories or their specific assay method

*Assays that are standardized are designed to provide accurate results, traceable to “true” value-assigned certified reference materials and gold-standard reference methods. Results obtained using standardized methods can be compared across assays, institutions, populations, and past and future test results, thereby improving diagnosis, treatment, and outcomes of patients




My reply from a previous thread:

Regarding labs, FT assays/reference ranges.

For the time being, if you have access to such then stick to testing your FT using what would be considered the most accurate assays such as the gold standard Equilibrium Dialysis or Equilibrium Ultrafiltration (next best), especially in cases of ALTERED SHBG!

Forget getting caught up in the different reference ranges for the same assays (ED, UF) used by different labs.

Let alone trying to compare the results of ED vs UF, or ED/UF vs the cFT methods.

Test using the same lab/same assay (most accurate).

Compare your blood work using the same lab/same assay (most accurate).

Top it all off that the calculated methods even have flaws!

We need accurate and standardized free testosterone assays with harmonized reference ranges!

Direct Measurements of Free Hormones Using Mass Spectrometry-Based Methods

Only at Excel, are we gonna take you deep! Clinical Utility and Analytical Aspects of Direct Measurements of Free Hormones Using Mass Spectrometry-Based Methods (2022) Mark M. Kushnir, Heather A. Nelson, and Kelly Doyle Background The free hormone (FH) hypothesis states that hormone...

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Take home points:

*Because FHs are present in biological samples in trace concentrations, highly sensitive and specific methods are required for accurate measurement of FH concentrations

*A limitation of calculation-based methods is in the assumption of uniform hormone affinity to binding proteins among individuals. However, binding protein variants, posttranslational modifications, and other factors may alter binding affinity, causing erroneous results and biases (10). Direct immunoassay methods show discrepancy among methods of different manufacturers and often perform poorly when binding protein concentrations are very elevated or decreased, with some methods suffering from biotin interference (9)

*When a binding protein abnormality is suspected (15). Equilibrium dialysis (ED) followed by LC–MS/MS is considered the gold standard methodology, with a number of LC–MS/ MS methods developed and introduced in routine patient testing (12, 16–22)

*FH concentrations measured by UF-based methods often do not agree with ED-based methods because of UF conditions (temperature, time, centrifugation speed), the type of the UF device (MWC membrane material, material of the of the housing, seal around the membrane, etc.), and inconsistencies in the filtration rate. Therefore, reference intervals are typically not interchangeable across methods for measurement of the same FH




CDC STANDARDIZED TOTAL T AND ESTRADIOL TESTS and soon-to-be FREE TESTOSTERONE!

Key Points:

* Limitations of using free testosterone by equilibrium dialysis and calculated free testosterone concentrations in practice are the lack of assay standardization, an accuracy-based quality control program, and a harmonized reference range. Until these limitations are addressed, free testosterone by equilibrium dialysis and calculated free testosterone should use reference ranges established by individual laboratories or their specific assay method

*Currently, the CDC is developing a harmonized method for free T based on calculated free T using REVISED FORMULAE. This may bring the measurement of free T to a referable standard in clinical laboratories and common reference intervals that all clinicians can use

*Assays that are standardized are designed to provide accurate results, traceable to “true” value-assigned certified reference materials and gold-standard reference methods. Results obtained using standardized methods can be compared across assays, institutions, populations, and past and future test results, thereby improving diagnosis, treatment, and outcomes of patients




The Need to Harmonize Clinical Laboratory Test Results-----

Laboratory test results are a critical component of patient care. These values help physicians diagnose disease and are critical to developing clinical guidelines that direct treatment options and are instrumental in ongoing efforts to improve and measure the quality of patient care. Most tests report a numeric value for healthcare providers to interpret and the range of numbers reported for a test for a certain condition may vary depending on the method used

Different test methods, however, may report different numeric values for the same condition. Although these test results may be accurate within the context of its own method, this variation can create confusion for physicians and patients. Clinical laboratory test results need to be harmonized so that healthcare providers and the public receive the same numeric result regardless of the method or instrument used or the setting where it was performed




Even though you fasted forget the 1st set of lab results (5/8/24) as not only did you use a known to be inaccurate assay but you also tested in the afternoon.

Anytime one is testing for TT/FT/BAT it has to be done in the early am (6-9) in a fasted state as we want to test at the peak let alone you need to be using the most accurate assays.

Even then take a week off from the gym if you are training intensely and make sure you are well rested otherwise your results can be skewed.

This is critical.

Natural endogenous testosterone secretion is pulsatile and diurnal.

During the natural 24-hour circadian rhythm of a healthy young male T levels will start rising gradually overnight reaching a peak (highest point) in the early AM followed by lower levels in the late afternoon and reaching trough (lowest point) in the evening.

Fluctuations from peak--->trough would be around 20-25%

One daily peak/trough.

Many fail to realize that T levels gradually rise overnight reaching a peak in the early AM.

*elevated and near peak TT level during nighttime sleep, peak TT level around the time of morning awakening

*T production occurs in the greatest amount during sleep as recurring pulses at approximately 90 min intervals in healthy young males and approximately 140 min in healthy middle-aged males (91).

Testosterone Blood Test Results - Time of Day?

I have taken two blood tests over the last two weeks with very different results. I appreciate levels fluctuate all the time from day, week, month and clearly hourly, so getting a consistent results is almost impossible. I was very surprised at the difference in levels! Test 1 - taken at...

www.excelmale.com

Understanding the Variations of LH, FSH, and Testosterone: Implications for Diagnostic Accuracy

Understanding the Variations of Reproductive Hormones: Implications for Diagnostic Accuracy Reproductive hormones play a crucial role in the functioning of the human body, influencing various physiological processes and reproductive health. Recent studies have shed light on the complex nature of...

www.excelmale.com

Forget the second set of lab results (6/14/24) even though you tested in the early am in a fasted state you still had your FT tested using a known to be inaccurate assay.

6/14/24

Morning fasted

1188

8.1

9.3 - 26.5

85

33

Standard immunoassay

Even if we calculate your FT using the cFTV with a very high TT 1188 ng/dL, high SHBG 85 nmoL/L and Albumin 4.3 g/dL (default) than your FT 15.1 ng/dL would considered healthy and far from low.

Remember I stated previously cFTV tends to overestimate slightly so if you had your FT tested using the most accurate assay (ED) then your FT would most likely still be around 13 ng/dL which is healthy and far from low.

Luckily on your final set of labs you tested in the early am in a fasted state using what would be considered the most accurate assay the gold standard Equilibrium Dialysis.

6/27/24

Morning fasted

921

8.9

3.5 - 15.5

not measured

not measured

LC/MS Equilibrium Dialysis

The lab was Quest and the reference range for that specific method/assay is 35-155 pg/mL (3.5-15.5 ng/dL).



A FT 15.5 ng/dL would be considered top-end and anything above would be high!

You are hitting a FT 8.9 ng/dL which is not low seeing as 9.5 ng/dl (mean).

Most healthy young males would be around 10-12 ng/dL and you are hovering just below that.

Could it cause issues for some sure but you also need to keep in mind that any dysfunction thyroid/adrenals can easily mimic low T symptoms.

Even then poor diet, lack of exercise, lack of quality sleep and excess stress (physical/mental) can easily hammer down your T!

Would be wise to make sure that when testing FT not only should it be done in the early am in a fasted state but also make sure you take a week off from the gym if you are training intensely and make sure you are well rested otherwise your results will be skewed.

If anything I would look into testing your thyroid/adrenals before jumping to any conclusions.

You stated.....I've been experiencing low libido (lack of sexual thoughts, no morning erections) and a general tiredness where I feel like I can't get enough sleep for a few years now.

Not trying to deter you in any way but just want you to understand where your levels truly sit let alone ruling out other causes (thyroid/adrenals) before jumping to any conclusions.

Age-stratified reference ranges for directly measured (ED LC-MS/MS) serum free testosterone in healthy men

Just to be clear up any confusion this is Fiers camps data for mFT reference ranges not the harmonized reference range being worked on by the CDC. *Serum samples were analyzed from healthy men participating in the SIBLOS/SIBEX and EMAS studies, both population-based cohort studies * mFT...

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*We established mFT reference ranges for healthy men aged 18 to 69 years




We present 95% mFT age-stratified reference ranges

Age category (years)	Median mFT (ng/dl)	95% mFT reference range (ng/dl)
18-29 (n=140) 30-39 (n=252)	12.0 9.8	6.7-25.3 4.9-18.5
40-49 (n=207)	8.1	4.3.14.2
50-59 (n=146)	7.1	3.8-12.8
60-69 (n=126)	6.4	3.4-11.7
70-79 (n=125)	5.6	2.7-8.7

*The gold-standard for the determination of FT levels is considered to be directly measured free testosterone (mFT) using equilibrium dialysis followed by mass spectrometry (ED LC-MS/MS). However, no widely accepted reference ranges are available for this clinical parameter. We established mFT reference ranges for healthy men aged 18 to 69 years






*Serum samples were analyzed from healthy men participating in the SIBLOS/SIBEX and EMAS studies, both population-based cohort studies


* mFT levels were measured in 867 men using ED LC-MS/MS as previously reported (1).


Reference: 1. Fiers T, Wu F, Moghetti P, Vanderschueren D, Lapauw B, Kaufman JM. Reassessing Free-Testosterone Calculation by Liquid Chromatography–Tandem Mass Spectrometry Direct Equilibrium Dialysis. J Clin Endocrinol Metab. 2018;103(6). doi:10.1210/jc.2017-02360

In the current study, we used a state-of-the-art direct ED method to reassess FT in sets of representative serum samples. This method takes advantage of the ability of a highly sensitive and accurate measurement of T by liquid chromatography–tandem mass spectrometry (LC-MS/MS) to reliably measure the low FT concentration directly in the dialysate after ED. This more straightforward method avoids potential sources of inaccuracy in indirect ED, such as those resulting from tracer impurities or from measures to limit their impact (e.g., sample dilution). We then used the measured FT results to re-evaluate some characteristics of two more established and a more recently proposed calculations for estimation of FT.

 

[madman]

I wouldn’t even bother trying to compare lab results with other lab companies, it’s pointless! Choose a company and stick with it.

If you go to Quest Diagnostics and check your free testosterone and it’s high normal range, and go to LabCorp with the same blood sample and now your mid range.

Dr. Abraham Morgenthaler found 27 different reference ranges for testosterone in the USA alone!

It’s a real sh** show!

Need to more specific here!

It's not just about choosing the same lab every time but more importantly choosing the same lab using the same assay (most accurate) which would be the gold standard Equilibrium Dialysis when testing free testosterone!

 

[Vince]

Vince, you've been around long enough to know that lowering SHBG activity is not going to raise free testosterone. However, in a case like this, if high SHBG is causing problems directly then effectively lowering it could help, at least in theory.

Remember my from October
Labs are from LabCorp. High shpg and high FT

Testosterone, Serum 1417 ng/dL range 264-916
Free Testosterone 47.8 ng/dL range 5.00-21.00
DHT 60 ng/dL (no range on results)
DHEA-Sulfate 523.0 H ug/dL range 30.9-295.6 (age adjusted)
Estradiol, Sensitive 23.0 pg/mL range 8.0-35.0
Sex Horm Binding Glob, Serum 47.9 nmol/L range 19.3-76.4
Hematocrit 45.9 % range 37.5-51.0
Hemoglobin 16.1 g/dL range 13.0-17.7
Albumin 4.3 g/dL range 3.8

 

[Vince]

I know 85 (nmol/L) shbg is super high.

It's also normal for SHBG levels to decrease with older age as the production of sex hormones also decreases. If your SHBG levels are too high, it likely means that less of your total testosterone is free testosterone that's available for your tissues to use. So, your tissues may not be getting enough testosterone.Dec 14, 2022

MedlinePlus - Health Information from the National Library of Medicine › lab-tests

SHBG Blood Test: MedlinePlus Medical Test​

 

[madman]

Comparability of Free Testosterone Measurements- Results of the Interlaboratory Study

https://academic.oup.com/clinchem/article/70/Supplement_1/hvae106.074/7760719 Assessment of free testosterone (FT) has been recommended as a biomarker for diagnosis and management of hypogonadism and female hyperandrogenism. Reliable laboratory measurements are essential for correctly...

www.excelmale.com

 

[Cataceous]

Remember my from October
Labs are from LabCorp. High shpg and high FT
...

And? Free testosterone is driven by dose. Your dose is very high, therefore your free T is very high.

...
It's also normal for SHBG levels to decrease with older age as the production of sex hormones also decreases. If your SHBG levels are too high, it likely means that less of your total testosterone is free testosterone that's available for your tissues to use. So, your tissues may not be getting enough testosterone.Dec 14, 2022
View attachment 45977
MedlinePlus - Health Information from the National Library of Medicine › lab-tests

SHBG Blood Test: MedlinePlus Medical Test​

They are wrong about SHBG, as it tends to increase with age. And they are flat-out wrong about free testosterone, repeating a myth that won't die. Don't make the same mistake. I challenge you to find evidence in the literature that changes in the binding protein affect free hormone levels. In contrast:

However, as discussed in Chapter 5, unbound drug concentrations will not be affected by decreases in the protein binding of restrictively metabolized drugs. Therefore, no dosage alterations are required for these drugs when protein binding is the only parameter that is changed.[R]​

​

--------------​

​

However, steady-state concentrations of unbound drug will be unchanged as long as there is no change in CLint.[R]​

 

[Vince]

And? Free testosterone is driven by dose. Your dose is very high, therefore your free T is very high.


They are wrong about SHBG, as it tends to increase with age. And they are flat-out wrong about free testosterone, repeating a myth that won't die. Don't make the same mistake. I challenge you to find evidence in the literature that changes in the binding protein affect free hormone levels. In contrast:

However, as discussed in Chapter 5, unbound drug concentrations will not be affected by decreases in the protein binding of restrictively metabolized drugs. Therefore, no dosage alterations are required for these drugs when protein binding is the only parameter that is changed.[R]​

​

--------------​

​

However, steady-state concentrations of unbound drug will be unchanged as long as there is no change in CLint.[R]​

View attachment 45989

I know all the struggle you had with trt. Thankfully for me, trt has been easy.

I would love for you to post your protocol and labs.
If you already have please post a link for me. I would love to see it.