Laboratory assessment of low testosterone
Laboratory assessment of low testosterone or “Low T”
Understanding laboratory assessment of low testosterone (Low T)
One of the first things that is done when a clinician suspects “low t”, more formally in medicine termed “hypogonadism”, is check a testosterone level. (Side note for the word hypogonadism; “hypo” means under-active. And “gonads”, in this case, means testicles. Women have gonads too but they are termed “ovaries”)
Total testosterone testing in the morning
Moving forward. The first test that is often ordered in this case is a “total testosterone”. Unfortunately, in many cases, this may be the only test that is ordered when investigating symptoms of low testosterone.
The recommended time for testosterone testing is in the morning time, ideally before 10 or 11 am. This is due to the fact that testosterone has a diurnal pattern in the vast majority of adults. Testosterone production is stimulated by the pituitary hormone LH (luteinizing hormone). LH signals the leydig cells of the testicles to produce testosterone. The secretion of LH (and FSH as well) is pulsatile. Typically, in the younger adult male, testosterone levels are significantly higher in the morning (< 10am) than compared to the evening time. It would not be a rare occurrence to find a difference of 30-40 % in a testosterone level for a 21 year old male between 8am vs. 6pm. Certainly one may find discrepancies much less than the 30% but it's helpful for the clinician to be mindful of the possibility in a younger male.
Testosterone diurnal variation in aging male
On the flip side, an older male (65+) may see relatively little difference between a morning and evening testosterone lab value. (though, even in older men, it’s worth noting that significantly higher testosterone level is possible) The take home message is that for the vast majority of men our testosterone levels not only begin to lower as we age, but the difference between morning and evening also tends to diminish.
* One might be asking, “should it matter when the testosterone level is low?” We will come back to this question later.
What is free testosterone and SHBG
There are two tests that are commonly ordered when it comes to laboratory assessment of low t. The first is the total testosterone, which is the total amount of the hormone found in a given amount of blood. Often written in terms of ng/dl (nanograms per deciliter). Testosterone doesn’t mix well with water or water like substances such as blood. Due to this, it attaches to proteins in the blood like albumin and SHBG (sex hormone binding protein) that are more “water soluable”, i.e. able to mix well with water. Thus far it appears that testosterone molecules attached to proteins have no biological effect on cells (basically no effect on the body). The testosterone molecules not attached to carrier proteins do have biological effects. Typically 2-3 percent of the total testosterone. We call this portion “free testosterone”. Because it is not attached to other proteins and thus is able to make its way inside of cells and have an effect. Basically when we think about what effect testosterone has on the body we are talking about the free testosterone. There is also another testosterone test often termed “bioavailable testosterone” which is testosterone that is not attached to SHBG. Or, another way to put it, is that bioavailable testosterone is the total of the “free T” plus the T that is attached to albumin. Some clinicians like to use this test when assessing low t.
Each carrier protein (SHBG or albumin) have certain affinities (how strong they attach) to testosterone. SHBG is the major determinant of free testosterone because it holds on very tightly to testosterone (high affinity) and does not easily let go. Hence, when testosterone is attached to SHBG it is not available for use. Albumin also holds onto testosterone but is much less strong at holding (its affinity is considerably less). Subsequently, testosterone attached to albumin is considered biologically active and when added to the free testosterone level is considered the “bioavailable testosterone”.
In some cases a total testosterone will identify a man who is likely to be struggling with low t. Though in many men the total testosterone level can be deceiving. Because SHBG levels made by the body tend to increase as we age the free testosterone will drop faster than the total testosterone. This can mean a male with a relatively normal looking total testosterone (say 500ng/dl) could be very low on his free testosterone (maybe 3 or 4ng/dl), which is the test that really matters the most. [Side note- while 500ng/dl on total testosterone may be considered normal I certainly wouldn’t consider that optimal. More on that idea/concept in later post.]
Normal testosterone levels range per the laboratory
Each laboratory used will have its own reference range for “normal”. Reference ranges are typically derived from a given number (more the better) of certain people. Say in this case, the lab derived its “normal range” from 500 healthy, non obese men in the middle TN area. In some cases you might need to ask yourself where is the reference range derived from. What was meant by “healthy” and “non-obese”? Were some of the men overweight? Had other health conditions? A quality lab should have a pretty solid range but my point is that normal does not always equal optimal. Especially in this day and age in the United States or other first world, industrialized nations especially. In many senses we are likely of the poorest overall health we’ve seen in hundreds of years or more. Due to a multitude of factors (no shortage of food, excess of unhealthy foods or “food-like” substances, and stressors/environmental toxins).
For ease of reading, the typical normal range for total testosterone is often around 300 or 350ng/dl on the low end and about 900-1000 ng/dl on high end. Free testosterone normal ranges are often from 6-9 ng/dl on low end up to around 25 ng/dl on high end of normal. For insurance purposes (those patients who want to use their insurance for treatment) the patient must have a total testosterone ( in some cases free testosterone is allowed) below the “normal range”, i.e. “low”. In many cases this “low” reading must be on 2 different mornings. Many insurance companies already require this in order to consider the person eligible for treatment.
Two morning testosterone test rule
The “2 morning tests” rule is likely derived from the Endocrine Society Guidelines for men on TRT that states that testosterone levels can be “low” on one day but then “normal” the next day. It is true that testosterone levels can vary markedly from one day to the next. But I suppose the term “marked variation” needs more definition. My guess is that the authors of the TRT guidelines meant something along the lines of a patient testing within that 100 point (ng/dl) range around the cutoff for a “low testosterone test” – say 300ng/dl for ease of use? And that, when considering lab testing alone (not typically a great idea), that person may not need treatment for “low t” if normally his T levels are say “420” but this morning was an “off day” for whatever reason and his levels came back at “290”ng/dl. The next question that one should ask themselves is what is the risk vs. benefits of treating a person who may not have “low t” vs. not treating someone who may have “low t” and allowing them to suffer. Very similar to a Type 1 vs. Type 2 error in hypothesis testing ….. which is essentially what every clinician does when he/she evaluates a patient with a complaint and then considers a treatment. [see my blog video for a more in depth risks vs. benefits conversation]
Back on topic, in my experience with thousands of “low t” assessments this potential difference of testosterone levels is not the difference between healthy (total t of 600’s+ or better yet a free t >20ng/dl) and undoubtedly “low” (say 200ng/dl or less). Assuming the person was not ill on one of the test days or had a very abnormal night’s sleep (very poor and/or limited sleep) the night before, we can assume the testing will be consistent most of the time when compared to another day. When in doubt always test two or more times. In my experience when someone’s total testosterone is less than 200ng/dl then even if the level happens to be skewed “low” due to normal variation (I’m not talking about being ill or very hung over from the night before, etc.) then even if a repeat test is 20-30% better that difference is not going to be significant to the overall clinical picture IF the man in question also reports moderate-severe symptoms consistent with hypogonadism (or low T). Again, when in doubt or uncomfortable the provider or patient can request multiple tests. And of course, “rule outs” of other, maybe more likely, culprits should always be pursued.
To wrap it all up. In my opinion, if the free testosterone level is below 10ng/dl in the morning (or total testosterone below 350ng/dl, either one), the man has a good understanding of the potential risks of TRT and no major contraindications, has signs or symptoms consistent with “lot t” and those s/s are more than mild in severity, and other causes of his complaints have been investigated/ruled out, then this person deserves a serious conversation about TRT and what the regimen might entail ( topical vs. injection, pellet, etc.). I would very likely treat this male.
What if T levels are normal in morning but low in afternoon?
In cases were some of those “bullet points” were not met completely then TRT could still be on the table. More on those variations very soon in another post.