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There are some pitfalls of measuring testosterone levels in our patients. In this post I want to tackle the issue of which testosterone to actually measure (answer: Total Testosterone), which NOT to measure (Answer: Free testosterone), why it's better to calculate Free T from additional biomarkers (hint: Total Testosterone, Albumin, and SHBG), and why this provides a more accurate measurement of Free T as well as giving us a few more biomarkers: Bioavailable Testosterone, % Free testosterone, and % Bioavailable testosterone. I hope this post is useful for you and your practice!
What is Testosterone?
Testosterone is a powerful anabolic hormone. That means it stimulates the body's development of muscle, bone, skin, and sex organs, along with masculine physical features, such as hair growth. For both men and women, testosterone helps maintain libido.
In men, testosterone is produced in the testes, by a group of cells known as Leydig cells. In women, testosterone is produced primarily by the ovaries and adrenal glands.
Peak testosterone levels are reached in a man's early to mid- 20s. As a man ages, the Leydig cells that secrete testosterone begin to wear away. Because of this, between the ages of 40 and 70, the average man loses nearly 60% of the testosterone inside his body!
Low testosterone levels in men are associated with many adverse health conditions, including diminished libido, erectile dysfunction, loss of muscle tone, increased abdominal fat, low bone density, depression, Alzheimer’s disease, and heart disease.
This is why it is essential to measure testosterone in all male patients over the age of 40.
Which Testosterone to Measure?
So now we understand some of the diseases, disorders and dysfunctions associated with testosterone let’s look at of the ways we can evaluate testosterone levels in the serum. The first question I usually get is Why the serum?
Because it gives us a good static measurement of levels in the blood and levels that are bioavailable to the body.
Also because we are collecting a blood sample we might as well order these extra few tests that can tell us a lot about not only sexual function/ dysfunction but also are part of a thorough cardiovascular risk work up.
The 2 measurements I recommend we use for assessing testosterone levels are total and serum free testosterone:
Total testosterone consists of all the testosterone that is free and unbound and all the testosterone that is bound.
This is not dissimilar to total T3 and free T3 in thyroid hormone evaluation.
- Testosterone circulates in the blood non-specifically bound to albumin and specifically bound to sex hormone binding globulin (SHBG).
- Less than 2% of testosterone is typically found in the “free” (uncomplexed) state in the serum of both men and women and the remaining 98% is bound.
Measuring total testosterone is very accurate and I recommend that you add total testosterone to all of your panels because it’s such an important biomarker to measure in our adult patients.
As you’ll see in a few paragraphs, Free Testosterone measurement is not as cut and dry as Total Testosterone. You can measure it but the units vary from lab to lab depending on the method they use. My recommendation is to actually calculate Free T but I’m getting ahead of myself!
Why measure Total Testosterone? Because it can aid in the diagnosis of androgen decline and hypogonadism. In men, total testosterone (complexed and uncomplexed) is useful for assessing gonadal, adrenal, and pituitary function.
Testosterone is specifically bound to Sex Hormone Binding Globulin (SHBG) and non-specifically bound to albumin.
Roughly 54% of testosterone is bound to SHBG in men and 78% in women.
This leaves testosterone bound to albumin and free testosterone.
This has been called the bioavailable testosterone but really in order to get a sense of what’s going on with testosterone we need to measure free testosterone and here’s where it gets complicated because there are a number of different ways of measuring or getting this value.
The 2 ways to measure Free testosterone are either by direct measurement or via calculation.
The problem with direct measurement of Free testosterone is that it is not consistent because there are 2 methods that produce different results:
The first is via a process called Immunochemiluminometric Assay (ICMA) followed by LC/MS/MS (Liquid Chromatography/Tandem Mass Spectrometry) this is probably “the physiologically” most exact method for estimating free testosterone levels. It’s highly accurate if it is done correctly but it is time consuming, equipment intensive and cumbersome. Despite this, it’s the gold standard for direct free testosterone measurements. This is the method Quest uses to get us Free testosterone.
The second is a method used by LabCorp. They use a different methodology called Direct Analog Enzyme Immunoassay (EIA). It is often considered the easiest and fastest method for measuring free Testosterone but it’s not without its critic.
The problem of these direct measurements is the reference range for free testosterone according to LabCorp using EIA method is about 4 times lower than Quest using ICMA and LC/MS/MS.
This leaves us to our final method of determining free testosterone, which is by calculation rather than direct measurement, and this is my recommended method.
Calculating Free Testosterone - Preferred
Free testosterone can be calculate by using the following 3 biomarkers:
Total Testosterone (direct measurement by LC/MS/MS)
These 3 biomarkers are used in what has been known as the "Vermulein Method" of calculating Free testosterone. Without going into too much detail, the background validation of this method can be found in this article:
“J Clin Endocrinol Metab 84:3666-3672, 1999 – A critical evaluation of simple methods for the estimation of free testosterone in serum”
I mentioned above that “the physiologically” most exact method for estimating free testosterone levels was the method used by Quest and many other labs (with the exception of LabCorp). Interestingly, the Vermulein method of calculating Free Testosterone is as close as you can get to getting a result that is consistent with the method used by Quest. So much so that I prefer to use the calculated measurement of Free testosterone over the direct measurement from Quest!
ODX's Built-In Free Testosterone Calculator
Now, this isn't a simple calculation that you can do yourself so you'll have to use the ODX Free Testosterone calculator to do this for you.
Good News - The ODX Software Does This Calculation For You
The amazing developers over at ODX have built the Vermulein calculation into the ODX software. If you add in Albumin, SHBG, and the Total Testosterone the software will calculate the following:
- Free testosterone
- Bioavailable testosterone
- % Free testosterone
- % Bioavailable testosterone
By NOT measuring Free testosterone and simply substituting it with SHBG, you get 4 calculated biomarkers that will help you with your sex hormone assessments. A good trade-off I think!
BONUS - 5 Reasons Free testosterone May Be Low
- Too much testosterone being converted to estradiol
- Too much free testosterone bound to SHBG
- Low LH secretion from pituitary
- Low output from testes
- Inadequate amounts of DHEA