The clinical use of testosterone for replacement therapy (to boost low testosterone levels) began approximately 70 years ago.
Symptoms of low testosterone include:
- Reduced spacial awareness
- Hypoactive sexual desire disorder, leading to reduced sexual activity
- Chronic fatigue
- Erectile dysfunction and impaired sexual function
- Liver disease (high testosterone protects against it)
- Poor cognitive function
- Mood disorders (depression and anxiety)
- Low muscle mass
- Increased fat mass
- Insulin resistance
Restoring testosterone can cause a significant improvement in all those areas.
Over the decades, numerous testosterone replacement therapy options have been developed primarily focusing on different routes of delivery.
Currently, the different testosterone products use to restore hormone levels approved for use by the United States Food and Drug Administration encompass buccal, nasal, subdermal, transdermal (topical creams), and intramuscular injection (IM).
Back in 1935, when they first created testosterone, they realized that taking unmodified testosterone (like the one you produce in your testicles) orally has very weak effects, due to poor bioavailability and rapid breakdown by the liver.
Therefore they created a modified version, namely 17α-methyltestosterone. However, it had bad liver side effects.
A is testosterone and B is 17α-methyltestosterone.
It was only in the 1970s that they explored better ways of taking oral testosterone. Instead of modifying it at the 17α position, they modified it at the 17β position. This eliminated the liver toxicity aspect and other adverse events.
The end result was testosterone undecanoate. It’s testosterone with an 11-carbon fatty acid attached. The body can cleave the undecanoate from testosterone and then break it down with beta-oxidation. Safe.
A is testosterone undecanoate; B is testosterone cypionate and C is testosterone enanthate.
The new formulation is not liver-toxic, and testosterone itself is actually liver-protective (R, R).
Natural testosterone vs testosterone undecanoate
We have 2 main forms of oral testosterone.
Unmodified testosterone (AKA testosterone crystals or testosterone base or one of the bioidentical hormones (natural testosterone)) and testosterone undecanoate.
Oral unmodified testosterone on serum testosterone
There are 4 major downsides to oral unmodified testosterone.
- It is first metabolized (broken down) by the intestinal wall,
- then what is left is transported via the portal vein to the liver. In the liver, it undergoes extensive metabolism (detoxification; more than 90% of the dose is inactivated during the first liver passage without reaching systemic circulation (R)).
- The liver upregulates testosterone detoxification over time, thus reducing the boost in serum T you get from oral T.
- Unmodified testosterone has a short(er) half-life.
Liver metabolism of oral testosterone
The first major metabolism of oral testosterone is via conversion to androstenedione (a weak androgen) and the second biggest is via conversion to testosterone glucuronide (for excretion). Androstenedione is then converted to estrone and androsterone (a 5 alpha reduced steroid).
“this finding suggests that “back‐formation” of AED (androstenedione) via 17 β‐HSD2 is the primary route of metabolism of oral testosterone.” (R)
As per my androstenedione article, androstenedione increases estrone and estradiol much more than it increases testosterone or DHT. These conversions dramatically reduce the effectiveness of oral testosterone.
Based on this study, 200mg of testosterone base increased serum total testosterone by 7nmol/L for about 8 hours (R). That’s only about 200ng/dl. For example, going from 500ng/dl to 700ng/dl after taking 200mg of testosterone base.
Bumping the dose to 800mg led to only another 7nmol/L (ng/dl) increase (500ng/dl to 900ng/dl with an 800mg dose). So there isn’t a linear increase in serum testosterone with oral unmodified testosterone. This is due to a saturation in testosterone absorption as well as rapid breakdown in the gut and liver.
The liver upregulates testosterone detox over time
The final downside is that the liver becomes more effective at breaking testosterone down the longer you take it.
This study is a perfect example. They gave men 400mg testosterone x2 daily (the biggest boost was testosterone + dutasteride). On day 28, the average testosterone was 20% to 30% lower in all groups on testosterone and dutasteride, and 50% lower in the testosterone-only group compared with day 1 (R). 50% faster metabolism after just 28 days.
Here is another study to illustrate the point. After just 9 days, the boost in serum testosterone after taking 300mg testosterone was significantly smaller compared to day 1.
Unmodified testosterone half-life
As you’ve seen from the graphs above, the effects of oral testosterone barely last 4 hours. This means that you need to take 200-300mg every 2-4 hours just to maintain adequate levels.
- Oral unmodified testosterone has a bioavailability of only 3.66 ± 2.45% (R). A healthy male produces 6-8mg of testosterone daily. So to replace that, you need to take about 200mg.
- Once you’ve taken 200mg, most of the testosterone will be converted to testosterone glucuronide, androstenedione and DHT, thus minimizing the boost in serum testosterone.
- The liver becomes increasingly effective at metabolizing testosterone and will reduce its effectiveness over time (as fast as 9 days).
As a side note, contrary to what some people might believe, taking unmodified testosterone with a fatty meal doesn’t enhance its absorption.
To demonstrate, 100mg of testosterone base increased serum testosterone by about 13nmol/L and this boost wasn’t enhanced with a fatty meal. As you can also see, the effects didn’t last very long (only about 4 hours) (R).
Testosterone undecanoate on serum testosterone
To bypass intestinal wall breakdown, poor oral bioavailability, rapid liver metabolism, and short half-life, scientists modified testosterone to make it more lipophilic (fat loving). This allows testosterone to be absorbed via the lymphatic system, instead of the portal vein. This increases bioavailability to 97% and bypasses intestinal and liver metabolism (R). This also extended the effects of testosterone.
The absorption of testosterone undecanoate on its own is also not very great, but it (unlike unmodified testosterone) significantly increased when combined with a fatty meal (59%) (R).
When taken in the fasted state, testosterone undecanoate has more or less the same bioavailability as unmodified testosterone, but with fat, it’s significantly better.
In terms of how long it lasts, unmodified testosterone peaks around 1 hour in the blood, whereas TU peaks up to 4 hours later (R).
The reason why the half-life matters so much is because of the average baseline testosterone you’ll have (keeping it in the normal range). The problem with a short half-life, is that trough serum testosterone levels are often not elevated from low baseline levels. And serum T levels may not stay within the adult male reference range throughout the day (R).
Something with a longer half-life will raise the trough, because before T goes too low, you take another dose.
This study shows it nicely. 100mg TU x2 daily wasn’t enough to fix hypogonadism. 200mg once a day kept the average T too low. 200mg x2 daily was better, but the trough was still in the hypogonadal range.
300mg TU twice daily was perfect for optimizing average testosterone and preventing testosterone during the trough to dip too low (R).
This is in line with what the FDA has approved. The FDA-approved TU formulation, Jatenzo®, recommends a starting dose of 237 mg (150 mg of unesterified testosterone equivalents based on molecular weight) and a maximum dose of 396 mg (250 mg testosterone equivalents) twice daily.
If I dissolve testosterone base in oil, will it have the same bioavailability as testosterone undecanoate?
No, testosterone undecanoate is still superior in absorption and half-life when both are taken with a meal.
This study compared taking 120mg testosterone base dissolved in oil (NT) with only 80mg testosterone undecanoate (TU) (R). TU was still vastly superior based on the blood test.
Will the increase in DHT from oral testosterone worsen prostate growth?
No, high serum testosterone and DHT induced by hormone therapy are protective against prostate cancer and especially aggressive prostate cancer (R).
Testosterone undecanoate is better than testosterone base, because…
- It can achieve much higher levels (when taken with a meal). Unmodified testosterone requires higher doses to get the same effects compared to lower doses TU.
- The half-life is much better, which creates a higher average.
- The body becomes really good at detoxing non-modified T as you can see by the 9-day study.
How I would use testosterone base orally
If you want to use testosterone orally, I’d use it in doses of 300mg x3 daily, 7 days on 7 days off to get optimal levels and to minimize the liver detoxification upregulation.
My preferred way of taking testosterone
Topical testosterone would be my favorite since I don’t like injecting myself. It also follows a natural curve where it’s highest when you apply it and then it steadily decreases as the day goes on. And you only have to take it once a day.
If I wanted to be fertile on TRT, I’d temporarily switch to intranasal testosterone until she conceives, then switch back to topical T.
As a nice hack to finish this article off, combine your oral testosterone with strawberries. Strawberries decrease the intestinal breakdown of testosterone undecanoate (R).
If you’re interested in optimizing testosterone naturally, get your copy of my blueprint below.
>1000ng/dl Testosterone: My Step-by-Step Guide on How I Do It Naturally!
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