Men's Lab Panels 101 (Part 3)

By Dan Covert

(If you missed Part 1 and Part 2, you’re missing out)

Hormones

Here’s where things get fun, and typically go the most awry when being called for by providers…

Sex Hormones

Testosterone (Total, LC-MS/MS & Free, Dialysis)

I’m assuming the first hormone on the list needs no introduction, as most men these days are (hopefully) aware that having their testosterone levels checked routinely is of the utmost importance. That being said, not all testosterone panels are created equal. The majority of the time, providers will only check your total testosterone level, and they’ll do so via an ECLIA test, which is an acronym for an incredibly long and unimportant name to remember (electrochemiluminescence immunoassay). This isn’t an ideal approach for a couple of reasons:

• ECLIA is not an accurate total testosterone panel in many instances.

• Total testosterone doesn’t tell the full story, and your free testosterone level can actually matter more when it comes to screening for hypogonadism and related symptoms.

What total testosterone panel do we want, then? While the ECLIA panel can be sufficient for mid-range testosterone levels, it fails to accurately detect levels on the margins, which obviously becomes paramount when screening for hypogonadism (i.e. low testosterone), because the difference between a level of 300 vs. 400 ng/dL can matter greatly when making a proper diagnosis. Given this in conjunction with how many men these days sit at “low-normal” in the reference range, it’s always best to call for a liquid chromatography-tandem mass spectrometry panel, or Total Testostosterone LC-MS/MS. This is the “gold standard” version of the test, and it’s highly accurate across all levels of testosterone.

As mentioned, when it comes to free testosterone, this level is often more important than total testosterone when it comes to symptoms of hypogonadism. This is because free testosterone is that which is actually circulating unbound and able to be used by the body. Still, both levels do matter, especially in relation to one another. Men should have a free testosterone level between 2 and 3% of their total testosterone, assuming the total level is adequate to begin with.

When testing free testosterone, you’ll almost always see the “Free Testosterone (Direct)” panel called for, and this drives me absolutely crazy. Most providers apparently have no idea that this version has been proven to be inaccurate across all ranges of free testosterone, the extent of which can vary based on a multitude of circumstances. Even seemingly small discrepancies in measurements between different panels can add up when trying to determine an accurate clinical picture.

The gold standard test for free testosterone is the “Testosterone, Free (Dialysis)” panel, but if you’re unable to have this test called or your doctor still decides to call for the direct version of the panel, you can simply calculate your free testosterone level using an online calculator as long as you have your total testosterone level, SHBG level (more on this to come), and albumin level (measured in your CMP). A calculated free testosterone level is typically just as reliable as a dialysis panel.

A final word about testosterone levels: Don’t assume that your level is normal (let alone optimal) just because you’re technically “in-range” and your provider says so. On top of the reference ranges being abysmal these days (that’s another topic for another day), it is important to understand that these ranges do not account for age, and the ranges themselves are derived simply from average levels seen across the total population, with the goal posts having been moved up several times in more recent years. Due to the endocrinological assault we face in the modern world from various different angles, current average male testosterone levels are markedly lower than those of our fathers and grandfathers, and all men, ages 18-88, are lumped into the same reference range.

Hopefully, it should be obvious why an 18 year old man’s testosterone level should be 2-3x higher than that of an 88 year old’s, so if you’re a younger man that technically falls on the lower end of “in-range” and your sleep, diet, training, and overall lifestyle is optimized, something is probably wrong. When I was dealing with some health issues that were affecting my hormones, I personally had several different providers gaslight me and tell me that my total testosterone level of 400-450 was fine, despite experiencing clear and obvious hypogonadal symptoms such as reduced motivation and drive, mood issues, poor work capacity and recovery in the gym, less muscle tone and stubborn fat around my abdomen that I couldn’t get rid of no matter what I did, and less-than-optimal sexual functioning.

Estradiol (E2, Sensitive)

While estrogen is often thought of as a female hormone (there are actually three different types of estrogens, with estradiol, or E2, relevant for men), men have and need it as well, albeit in much lesser amounts. Estradiol is a metabolic byproduct of testosterone, produced via a process called aromatization. It is perhaps the most misunderstood hormone in men, and although it seems to be associated with only negative effects, E2 is actually neuro- and cardioprotective, crucial for maintaining bone density, and also plays a prominent role in sexual function as well as metabolic health. For these reasons, having too little estradiol is just as bad as (and sometimes, even worse than) having too much of it.

Just like I see on virtually every panel called for free testosterone, I’ve literally never seen a provider call for a male estradiol panel properly. It is beyond me how medical providers don’t know that a sensitive panel (Estradiol, Sensitive) must be used to obtain anywhere near an accurate reading. This is because a standard estradiol test simply cannot accurately determine a man’s level given that we have so much less of this hormone than women do.

I have personally seen large discrepancies between standard vs. sensitive E2 testing in regard to my own panels. When I was calling my own labs to get to the bottom of my health issues, I once ordered a standard as well as sensitive estradiol test on the same set of labs just to compare results, and found that the standard panel was double the value of what the sensitive, accurate panel measured.

Prolactin

Although prolactin is a hormone most relevant to women (it quite literally stimulates lactation, hence the name “pro-lactin”), men have it as well in lesser amounts, and it can become an issue when levels are abnormally elevated.

Think of prolactin and dopamine, the “feel good” neurotransmitter most responsible for motivation (although this is a bit oversimplified), as inversely related. Adequate dopamine activity in the hypothalamus of the brain regulates prolactin secretion and keeps the body’s level within a normal range. If dopaminergic functioning is diminished, however, it can cause an increase in prolactin. For this reason, an elevated prolactin level can cause symptoms of low libido, erectile dysfunction, lack of motivation, depressive symptoms, and even the dreaded gynecomastia (male breast enlargement).

In some cases, it also can meaningfully reduce testosterone levels.

When a man’s prolactin level appears mildly elevated on labs, it is usually transient, which can be due to several potential reasons, including recent ejaculation (which causes prolactin to temporarily increase), poor sleep quality (REM sleep helps keep prolactin in check), as a byproduct of elevated estradiol levels, hypothyroidism, or even medications such as opioids, antipsychotic drugs, and sometimes SSRI antidepressants, all of which lower dopamine levels in the brain either directly or indirectly.

In these cases, an elevated prolactin level will return to normal when the underlying cause is normalized or removed. Less commonly, however, prolactin will be more substantially elevated, which is typically the result of a benign tumor on the pituitary gland called a prolactinoma. When this is the case, it will be confirmed via MRI of the pituitary gland, and can be easily treated with dopamine agonist medications.

SHBG

Sex hormone-binding globulin, or SHBG, is technically a protein that is produced by the liver, but it binds to sex hormones. SHBG regulates the bioavailability of testosterone and estradiol, which is particularly relevant as it pertains to free testosterone levels. Put simply, the higher your SHBG level is, the less free testosterone is able to circulate and be used by the body. Remembering that free testosterone is often most important when it comes to hypogonadal symptoms, testing for SHBG is critical.

A common hypogonadal pattern often seen is a high SHBG level with a low-normal or even normal total but low free testosterone level in men experiencing symptoms. As always when it comes to hormones, balance is key, and having extremely low SHBG level isn’t ideal either, often pointing to conditions such fatty liver disease, insulin resistance, and/or thyroid issues.

LH & FSH

Luteinizing hormone and follicle-stimulating hormone are pituitary hormones essential for reproductive function. Think of each of these as a “signal” generated by the brain to tell the testicles to produce testosterone and sperm.

Testing levels of each is necessary when hypogonadism is suspected, since elevated levels of either or both of these hormones typically indicates what is known as primary hypogonadism (failure of the testicles to make testosterone/sperm), whereas low levels of either or both typically indicates secondary hypogonadism (failure of the pituitary gland the send the signal).

These hormones can provide necessary insight into what’s driving any abnormalities in testosterone levels, because sometimes, the problem may be reversible. I’ve seen men put on TRT who probably could have avoided or delayed it if their provider had bothered to conduct a proper investigation involving these panels.

Thyroid

TSH

The thyroid is the body’s primary metabolic organ, and thyroid-stimulating hormone is produced by the pituitary gland as the “signal” for it to function properly and make T3 and T4 hormones, much the way LH and FSH do when it comes to signaling the testicles to make tesosterone and sperm. Having an elevated TSH level accompanied by symptoms such as weight gain, fatigue, mood and/or libido issues, and cold intolerance is typically seen in hypothyroidism, while having a low TSH level with symptoms such as unexplained weight loss, anxiety, hyperhidrosis, and heat intolerance suggests hyperthyroidism (a much more rare and medically urgent condition).

It is important to note that the established range for TSH level is typically somewhere around 0.5-4.5 mIU/L in adults, but any level above 2.5 warrants further investigation for hypothyroidism, especially when symptoms are present. Also, note that symptoms of hypothyroidism and hypogonadism can often look identical in men, so having comprehensive lab panels is critical for determining what's what. Sometimes, TSH level can even be normal in the presence of hypothyroidism (especially early-on in the condition), which is why having the next two panels alongside it aren’t optional.

Free T3 & Free T4

While many providers think a TSH level alone is sufficient for an accurate picture of thyroid health, it is simply not enough information. TSH signals the thyroid to produce triiodothyronine (T3) and thyroxine (T4), the hormones that are responsible for the organ's output and effect on metabolic function. T4 is the initial hormone synthesized that converts to T3, and we want to test for free T3 and free T4, as these are the active, unbound versions of each hormone that the body can utilize.

When providers do decide to test for a free T4 level, they often do so without testing for free T3, as a common thought process seems to be that if TSH is in-range and free T4 is adequate, free T3 must be as well given the conversion process. This is as much of a mistake as is only checking total testosterone and not free testosterone or estradiol. Many hormones metabolize into other hormones via conversion pathways, but assuming a downstream hormone is functioning properly by looking at hormones upstream simply ignores the many ways in which things can and often do go wrong in these pathways.

For the purposes of this article and routine or first-screen lab panels, free T3 and free T4 along with TSH are adequate when assessing thyroid function, but if any of these values are out of range or even marginal (especially if symptoms are present), further testing with panels such as thyroid peroxidase (TPO) and thyroglobulin (Tg) antibodies are necessary to rule out autoimmune issues such as Hashimoto's. In these cases, panels such as reverse T3, total T3, and total T4 are also sometimes relevant. Assessing trace mineral levels that are necessary for thyroid function, such as selenium and iodine (with iodine level only being accurate when tested in urine), can also be useful.

Adrenals

DHEA-S

Dehydroepiandrosterone, or DHEA (the “-S” stands for “sulfate”, which is the metabolite most accurately tested for in the blood) is a hormone produced primarily by the adrenal glands, serving as a precursor to testosterone. It also functions as a neurosteroid and an androgen and estrogen itself, and it is mechanistically similar to caffeine in many ways. It is involved in dopaminergic and serotonergic pathways, as well as in cellular mitochondrial function. In relation to pregnenolone, the next hormone on our list, it is the "yang" to its "yin" (more on this in that section).

During puberty, DHEA level rises until it peaks in early adulthood, and then gradually declines with age. Because DHEA converts downstream into testosterone, it is essential for supporting the androgen pathway, and it plays a role in its own regard in sexual function, bone density, body composition, mood, and many other things we associate with testosterone itself. During times of stress and/or physical pain, DHEA will often increase, sometimes alongside cortisol, demonstrating its function as an adrenal hormone.

Testing for DHEA-S level is crucial in all men, especially as we age. When indicated, it must be replaced for optimal hormonal functioning, which can be done via prescription or over-the-counter supplementation. Since a quality, micronized form and individualized, precise dosing under the supervision of a qualified provider is highly recommended, a compounded prescription is advised whenever possible.

Pregnenolone-S

Pregnenolone (with the “-S” once again referring to “sulfate” as the metabolite to test for) is often referred to as the “mother of all hormones”. Referring back to Part 1 of this article series, I discussed how cholesterol is the material required to produce all hormones in the body, with pregnenolone being the first step in the conversion process to all other downstream hormones. I could honestly write an entire article on just pregnenolone, as its true power is almost always misunderstood, and it is rarely discussed, tested for, or dosed properly.

Though technically classified as an adrenal hormone, pregnenolone is also synthesized in the testicles as well as the brain, with the latter being where its true effects are perhaps the most pronounced. It acts as a powerful neurosteroid and has neuroprotective properties, while also being involved in many cognitive processes, including learning, memory, and mood, to name a few. After converting directly from cholesterol, pregnenolone is unique in that it can be utilized downstream by either the progesterone or DHEA pathway, often biasing toward the progesterone pathway in men.

Although progesterone is often thought of as a female hormone, men have small amounts of it as well, and it can be quite important for us. Progesterone, particularly by way of its downstream metabolite, allopregnanolone, is a natural, very powerful modulator of the GABA-A receptor. GABA is the main inhibitory neurotransmitter in the body, and anyone familiar with the calming, sedating properties of drugs such as benzodiazepines as well as alcohol knows how powerful GABA is, as these substances bind to and strongly modulate GABA-A receptor sites.

Pregnenolone also modulates the CB1 receptor in the body’s endocannabinoid system, which makes it capable of reducing the effects (and for many people, the negative effects) of cannabis intoxication. It is due to these GABA-A- and CB1-related mechanisms that those who find themselves overly-sensitive to caffeine, other stimulants, or cannabis are often low in pregnenolone.

Pregnenolone is also often low in those who have suffered from traumatic brain injury, as well as in those with prolonged stress, trauma, and/or chronic pain. Replacing it can be nothing short of life-changing for those in need, as it was for me (check out my video for a deeper dive on this incredibly powerful hormone).

Like DHEA, pregnenolone also decreases with age, and as mentioned, these two hormones tend to act in a “yin-yang” relationship, where DHEA often serves as the “gas pedal” with stimulatory properties, while pregnenolone acts as the “brakes” with calming properties. While these juxtaposing effects are not always the case and a bit oversimplified, they highlight the necessary balance of these hormones in concert with one another, as well as all other hormones downstream.

I’ve never personally seen a provider call for a pregnenolone panel, and the few out there who are even aware enough to test for it often cite its short half-life in the blood as a reason not to. While this is fair and true, observing trends of this hormone across multiple labs in conjunction with symptoms can be telling. If you’re suffering from issues with memory, mood (especially non-specific, constant or generalized anxiety), or intolerances to substances (especially caffeine, other stimulants, or cannabis) and your level is below 50 ng/dL, especially on repeat testing, a pregnenolone replacement trial is warranted. In addition, if you have a history of TBI, chronic stress/trauma, and/or chronic pain, in my experience, low pregnenolone is almost always a given.

As with DHEA, pregnenolone can be obtained via compounded prescription or over-the-counter, though a micronized, precisely-dosed prescription is highly preferential. Through my own experience replacing pregnenolone as well as coaching clients when it comes to this hormone, I have found that small amounts can go a long way, and increasing even a little bit too much from one dose to the next can cause unwanted side effects, so precise dosing is crucial.

Before moving on, it's only right that I give a shout-out to the GOAT of men’s hormones, Dave Lee, for truly pioneering this space when it comes to DHEA and pregnenolone. Most of this information is me simply reporting on the results of his legwork, and I owe my own success with pregnenolone to his efforts.

Cortisol (AM)

Cortisol, often known as the “stress hormone”, can be somewhat commonly elevated (and less commonly, low), but I usually won’t call for a panel up-front due to several reasons.

For one, a 24-hour salivary test is necessary for an accurate overall picture of cortisol, as levels fluctuate markedly with circadian rhythm. In addition, when it comes to men, an elevated cortisol level is typically a secondary issue, often due to things such as suboptimal testosterone levels or suboptimal thyroid function. A morning cortisol panel can sometimes become more useful as a follow-up test when symptoms such as anxiety, fatigue, or metabolic issues aren’t resolved by optimizing other things.

Cortisol production is also heavily influenced by factors such as sleep, caloric intake and nutrition, training volume and intensity, and overall stress levels, so if your lifestyle factors aren’t in check, testing for this hormone is usually a waste of time until you get things dialed in.

Wrapping It Up (“TL;DR”)

That concludes my three-part article on the comprehensive lab panels men don’t want to skip when it comes to total health and wellness optimization. To recap, here is the list:

Basic Panels

• CBC (with differential and platelets)

• CMP

• HbA1c → optional (useful when metabolic issues are suspected)

• Insulin → optional (useful when metabolic issues are suspected)

• Lipid → optional (becomes more useful when other labs and lifestyle factors are dialed in)

  
  

Essential Vitamins/Minerals

• Vitamin D

• B12

• Folate (B9)

• B6

• Ferritin

• Magnesium → don’t worry about testing (serum level only reflects <1% in the body - just supplement)

• Vitamin C → optional but not necessary (just supplement)

• MMA & Homocysteine → follow-up tests that are useful when B12, Folate, or B6 level is marginal and/or deficiency is suspected

  
  

Sex Hormones

• Total Testosterone (LC-MS/MS)

• Free Testosterone (Dialysis) → optional (can calculate accurate level with Total T+SHBG+Albumin)

• Estradiol (E2, Sensitive)

• Prolactin

• SHBG

• LH & FSH → when hypogonadism is suspected

  
  

Thyroid

• TSH

• Free T3

• Free T4

• Follow-up tests such as TPO & Tg Antibodies, RT3, Total T3 & T4, and trace minerals such as Selenium and Iodine are warranted when further investigating any abnormal values and/or symptoms

  
  

Adrenals

• DHEA-S

• Pregnenolone-S

• Cortisol (AM) → optional (abnormality is typically a secondary issue when other labs or lifestyle factors need to be addressed)