If you’re struggling with symptoms of low testosterone, like reduced sex drive and fatigue, testosterone replacement therapy (TRT) can help you feel like yourself again by restoring your T levels to a healthy range. But in the world of TRT options, which range from pellets and pills to injections and creams, it can be difficult to know which method is right for you. In this article, we’ll break down the pros and cons of oral TRT vs injectable TRT, including efficacy rates, side effects, and more.
Key takeaways
- Oral testosterone undecanoate is a convenient and effective treatment for low testosterone, avoiding some of the discomfort and risks associated with injections and topical creams. Newer formulations are designed to reduce the risk of liver toxicity.
- Testosterone injections provide more significant T level boosts but come with drawbacks like pain, side effects, and fertility concerns.
- The goal of oral TRT is to maintain levels within the normal range.
What is oral TRT?
Oral testosterone undecanoate is a prescription-only oral therapy for men with low testosterone levels. It helps to reduce symptoms like low libido, fatigue, erectile dysfunction, depression, and excess body fat by increasing testosterone synthetically. Oral TRT is an appealing alternative to other forms of testosterone therapy for those looking to avoid specific drawbacks like the pain associated with injections, transdermal irritation, or unintended interpersonal testosterone transfer associated with creams and gels.
While the earlier form of oral testosterone (methyltestosterone) was associated with liver toxicity, newer formulations, such as testosterone undecanoate, bypass the liver to be absorbed by the lymphatic system. This reduces the risk of hepatotoxicity, jaundice, and liver cancer.
How does oral testosterone work?
Testosterone undecanoate bypasses the liver and is absorbed by the intestinal lymphatic system. This is facilitated through the use of long‐chain fatty acids.
Once absorbed, testosterone undecanoate is metabolized through two distinct pathways, with the major active metabolites being hydrotestosterone (DHT) and estradiol. In healthy men, the plasma concentration of DHT is increased while using testosterone undecanoate. Testosterone and DHT then act on androgen receptors in the organs, bringing average serum testosterone levels to within the eugonadal range (typically 300–1000 ng/dl) to mirror the concentrations seen in healthy men.
How effective is oral TRT therapy?
Clinical studies have shown that oral TRT is an effective long-term treatment for men with low testosterone levels, and has a safety profile that’s fairly consistent with other approved testosterone products. In one two-year safety and efficacy analysis, oral testosterone undecanoate kept total testosterone levels in the normal range with no evidence of liver toxicity.
In another study comparing oral TRT to placebo, those taking oral TRT for three months saw an increase from 260±130 ng/dL to 400±180 ng/dL. The researchers noted that the results were statistically significant, meaning it’s unlikely the results could be due to chance. Subjects also reported improvements with sexual dysfunction and better overall quality of life.
In a placebo-controlled six-month study where participants were divided into a treatment group that took oral testosterone undecanoate capsules and a control group that took a placebo of vitamin E/C capsules, researchers found that serum total testosterone concentrations before and after taking oral TRT were (230 ±21) ng/L and (395±34) ng/dL, respectively, and free testosterone concentrations before and after taking oral TRT were (30.0±5.0) pg/mL and (62.1±9.0) pg/mL. At a six-month follow-up, the average total serum testosterone and free testosterone concentrations of patients in the treatment group remained within the eugonadal reference range for adult males and were also significantly higher than baseline levels.
Comparing different types of oral TRT
The most recent FDA-approved oral TRT medications include Tlando®, Jatenzo®, and Kyzatrex®, which all bypass the liver and are absorbed by the lymphatic system. All three medications have been shown to restore testosterone levels in hypogonadal men to within the normal range. Kyzatrex may show the most promise, with a 96% success rate in restoring hypogonadal men to normal testosterone levels at the end of a 90-day study and lower risk of hypertension when compared to Tlando and Jatenzo, though it can still increase blood pressure. Meanwhile, clinical trial results showed that 88% of patients treated with Kyzatrex achieved an average plasma total testosterone concentration within the normal range on the final day of the study.
Oral testosterone vs injection
Testosterone injections were long considered the gold standard in treating low testosterone, with its main selling points being extended dosing periods and reliable effects on the body. Injections tend to provide a more significant boost to testosterone levels, but there are some obvious drawbacks to consider.
For one, the method of delivery is off-putting for some. Injections can be painful and are sometimes associated with side effects like swelling at the injection site, muscle scarring, and risk of allergic reaction. In some cases, these difficulties may lead someone to discontinue treatment, which is likely why improved medication adherence is said to be a clinical advantage of oral TRT. Testosterone injections also carry a higher risk of long-term side effects, including infertility. This is attributed to the variable release of the hormone directly into the bloodstream, which can lead to peaks and troughs that extend beyond the normal range for serum testosterone levels.
Read on to find out more about how oral TRT compares to TRT injections.
Impact on T levels
As mentioned, testosterone injections are associated with “peaks and troughs,” which can lead to some impressive boosts to a user’s T levels. In a review comparing oral TRT to injections, oral TRT users displayed serum testosterone levels 489 ± 155 ng/dL at the end of a 105-day study. However, a 10-week study on injectable TRT found that users taking injections saw a jump from 72 ± 29 ng/dL to 767 ± 182 ng/dL.
The goal of oral TRT is to bring T levels to within the normal range. This is defined by some experts as 300–1000 ng/dL and by others as 450 -600 ng/dL. But numbers rarely tell the whole story. Determining success when treating low testosterone also needs to consider a medication’s impact on symptoms and the severity of any side effects that occur.
Impact on symptoms
Some research indicates that TRT injections are more effective at increasing muscle strength in comparison to oral testosterone and carries a lower risk of cardiovascular events. In terms of lean body mass, this comprehensive review points to a study in which weekly 100 mg testosterone injections led to a 5.0 ± 0.7 kg increase in lean body mass after 10 weeks, while 160 mg of oral TRT taken daily produced a 1.04 ± 0.07 kg increase.
Nonetheless, when it comes to improvements in body composition, quality of life in mood, and sexual function measures,the comprehensive review cited above found that oral TRTis similarly successful compared to other TRT modalities, including injections. One notable difference is that the peak and trough phenomenon exhibited with testosterone injections can lead to fluctuations in mood and libido, with symptoms of elevated mood and anxiety occurring at peak levels and fatigue, low mood, and libido at the lowest point — or trough — that comes before the next dose.
How quickly they work
The half-life of testosterone injections depends on which form of testosterone is injected. When injected muscularly, testosterone cypionate has a half-life of approximately eight days. In a review comparing different forms of injectable testosterone, they noted a small study where patients injected with 200 mg testosterone cypionate saw peak testosterone levels of 1,112 ± 297 ng/dL between days four and five after the injection. Levels started to decline after day five, reaching 400 ng/dL by day 14.
For patients injected with 200 mg of testosterone enanthate, T levels peaked above 1,200 ng/dL 48 hours after the last dose. After two weeks, the levels stayed steady, but they were at the lower end of the therapeutic range.
Meanwhile, patients injected with testosterone undecanoate reached a peak of 813 ng/dL by day seven, which declined to between 323 to 339 ng/dL 10 weeks after each injection. This was based on the recommended dosing schedule of 750-mg injections at weeks 0 and four and then every 10 weeks thereafter for a total of nine injections. When compared to testosterone cypionate and testosterone ethanate, troughs were seen later and resulted in fewer side effects.
Compared to all three forms of testosterone injections, oral TRT has a much shorter half-life, peaking at four to five hours after the dose. Levels decline at a constant rate and reach baseline about 12 hours later, unless a second dose is administered. This gradual decline helps to maintain therapeutic drug levels in the body over an extended period.
Side effects
Side effects of testosterone injections are well-documented. In addition to pain and swelling at the injection site, they include decreased sperm count and quality, testicular shrinkage, enlarged prostate, acne, sleep apnea, cardiovascular issues, and breast growth (due to increased estrogen). And due to the up and down effects of injections, this route is also associated with more intense and frequent mood swings.
Oral testosterone side effects include nausea, headaches, and upper respiratory tract infections in addition to an increased risk of high blood pressure (the risk is lower for Kyzatrex). Like TRT injections, oral TRT also increases estrogen and may suppress fertility, though not as severely as injectables. For instance, in one small study that looked into the use of testosterone undecanoate to control male fertility, 1 in 7 people given oral TRT for 10-12 weeks became azoospermic (meaning there is no sperm in their semen), but the sperm counts among the remaining individuals were either unaffected or slightly suppressed. Compare this to a 2019 study, in which TRT injections led to azoospermia in 65% of men within four months of starting, even though they had previously normal sperm counts.
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