TRT And Liver Enzymes On Oral Testosterone

Newer oral testosterone formulations haven't been shown to raise liver enzymes the way older versions did. Methyltestosterone, the only oral testosterone option prescribed in the U.S. through the 1980s, caused hepatotoxicity through first-pass hepatic metabolism. Current oral testosterone undecanoate products (Jatenzo, Tlando, Kyzatrex) absorb through the lymphatic system instead, largely bypassing first-pass hepatic metabolism. A two-year study found no clinically significant changes in ALP, AST, ALT, or bilirubin with twice-daily oral testosterone undecanoate in hypogonadal men (Honig et al., 2022).

TRT and liver enzymes became a clinical concern because early oral testosterone required hepatic first-pass metabolism. Modern oral formulations use lymphatic absorption to avoid hepatic processing, and multiple clinical trials have not demonstrated liver toxicity in men treated for diagnosed hypogonadism over study periods of one to two years.

The difference between old and new oral formulations comes down to chemistry: methyltestosterone is a 17-alpha alkylated androgen the liver must process directly, while testosterone undecanoate is a nonmethylated prodrug that reaches circulation through intestinal lymphatics (Endocrine Society, 2018). Marek Health providers determine which formulation fits each patient's clinical profile based on labs, symptoms, and medical history.

Do newer oral TRT formulations affect liver enzymes?

The Honig et al. two-year analysis followed hypogonadal men taking oral testosterone undecanoate for two years and found no clinically significant changes in alkaline phosphatase, AST, ALT, or bilirubin. Small increases in PSA and hematocrit occurred, consistent with all TRT formulations.

The one-year SOAR trial of 315 men went further. Among those with elevated liver enzymes at baseline, the oral formulation was associated with reductions in ALT, AST, ALP, and GGT, with normalization rates from 31% (GGT) to 67% (ALP) (Kaminetsky et al., 2020). A separate open-label Phase 2 imaging study (N=36) found approximately 40% reduction in liver fat after four months in men with baseline liver fat at or above 10% (Kaminetsky et al., 2020). The percentage of patients classified as free of metabolic liver disease nearly doubled over 16 weeks, rising from 34% at baseline to 63%.

A 2025 systematic review in Clinical and Translational Gastroenterology pooled data from nine studies, including three randomized controlled trials, and found testosterone therapy associated with greater decreases in liver enzymes compared to controls in men with metabolic dysfunction-associated steatotic liver disease (Zeng et al., 2025).

These results don't mean oral TRT treats liver disease. They show modern oral formulations don't carry the hepatic risk of their alkylated predecessors, and that testosterone replacement in hypogonadal men may have secondary liver-related effects worth studying.

How does oral TRT compare to injections and topicals?

All FDA-approved TRT formulations carry class-wide risks including elevated hematocrit and blood pressure effects per the February 2025 FDA labeling update (FDA, 2025). The TRAVERSE trial showed a neutral primary cardiac endpoint but higher rates of atrial fibrillation and pulmonary embolism in the testosterone group (Lincoff et al., 2023).

All three oral testosterone undecanoate products require twice-daily dosing with food for proper absorption. Missing meals can reduce drug levels, which providers may consider when selecting a formulation for patients with inconsistent eating patterns.

Shorter-acting oral formulations may produce fewer erythrocytosis events than longer-acting injectables, though head-to-head data remain limited. Topical options avoid hepatic metabolism but carry transference risk to household contacts.

Can men with pre-existing liver conditions start TRT?

Pre-existing liver disease doesn't automatically rule out testosterone replacement, but it changes the clinical evaluation. The Endocrine Society guideline lists severe liver disease as a relative contraindication, meaning providers weigh the benefit of treating a confirmed deficiency against the individual's hepatic risk (Endocrine Society, 2018).

For men with metabolic dysfunction-associated steatotic liver disease, the available data haven't shown worsening of liver function on oral testosterone undecanoate. The SOAR trial included men with elevated baseline liver enzymes who showed reductions rather than increases during treatment. These findings come from relatively small studies with limited follow-up, though, and they don't establish TRT and liver enzymes as a settled question across all liver conditions.

A provider evaluating a patient with concurrent liver disease would typically review baseline liver enzymes, assess the severity and cause of the condition, and select a TRT formulation based on that individual's clinical picture. More frequent lab monitoring may be appropriate in this population.

What liver monitoring does TRT require?

The AUA guideline doesn't mandate routine liver function testing for non-alkylated TRT formulations (Mulhall et al., 2018). Standard monitoring focuses on total and free testosterone, hematocrit, PSA, and estradiol levels. The Endocrine Society guideline similarly prioritizes formulation selection and monitoring of established risk markers.

Providers may still include liver enzymes in baseline panels for patients with pre-existing liver conditions or elevated BMI. Some providers choose to include a baseline liver panel and follow-up at three to six months as a reference point, even when guidelines don't require it. TRT and liver enzymes remain a reasonable monitoring consideration, and a licensed clinician can set the right testing schedule based on individual health history.

Disclaimer: This blog post is intended for informational purposes only and should not be considered medical advice. Always consult a healthcare professional before making changes to your health routine.

FAQs

Does TRT raise liver enzymes?

Modern TRT formulations, including injectable, topical, and newer oral testosterone undecanoate, don't cause clinically significant increases in liver enzymes. Older 17-alpha alkylated oral testosterone (methyltestosterone) did carry hepatotoxicity risk, but these products are no longer routinely prescribed. A two-year study of oral testosterone undecanoate found no meaningful changes in ALP, AST, ALT, or bilirubin.

Is oral testosterone safe for the liver?

Current oral testosterone undecanoate products (Jatenzo, Tlando, Kyzatrex) have not demonstrated liver toxicity in clinical trials, because they absorb through the lymphatic system rather than undergoing hepatic first-pass metabolism. Published trials have not identified clinically meaningful hepatotoxicity with these formulations over study periods of one to two years.

What liver tests should be done while on TRT?

The AUA guideline doesn't require routine liver function testing for patients on non-alkylated TRT formulations. Standard monitoring focuses on testosterone levels, hematocrit, PSA, and estradiol. Providers may include baseline liver enzyme panels for patients with pre-existing liver conditions or elevated BMI.

Does TRT affect liver enzyme levels in men with metabolic liver disease?

Some research suggests testosterone therapy may affect liver fat and enzyme levels in hypogonadal men with metabolic liver disease. One small open-label study (N=36) found approximately 40% reduction in liver fat after four months of oral testosterone undecanoate treatment in men with baseline liver fat at or above 10%, and a 2025 systematic review reported decreases in AST, ALT, GGT, and ALP compared to controls. These findings don't support using TRT as a liver treatment, and larger controlled trials are needed.

What is the difference between methyltestosterone and testosterone undecanoate?

Methyltestosterone is a 17-alpha alkylated oral androgen that requires first-pass hepatic metabolism, which can cause liver damage. Testosterone undecanoate is a nonmethylated prodrug that absorbs through intestinal lymphatics, bypassing the liver. This mechanistic difference is why current oral TRT products carry a different safety profile than the older formulation.

How often should liver enzymes be checked on TRT?

Current clinical guidelines don't require routine liver enzyme monitoring for patients on standard TRT formulations (injectable, topical, or newer oral undecanoate). The monitoring schedule is typically set by the prescribing clinician based on the patient's medical history, baseline lab values, and the specific formulation used. Patients with pre-existing liver conditions may need more frequent testing.

References 

• AUA Testosterone Deficiency Guideline. J Urol. 2018;200(2):423-432.

• Clin Transl Gastroenterol. 2025;16(1):e00787.

• Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744.

• FDA class-wide labeling changes for testosterone products. Feb 2025.

• J Sex Med. 2022;19(12):1750-1758.

• J Urol. 2020;203(Suppl 4):e383.

• N Engl J Med. 2023;389(2):107-117.