Liver Enzyme Trends in Patients Using Maximus’ Oral Native Testosterone: A Retrospective Analysis

Oral testosterone has historically been avoided in clinical practice due to concerns about liver toxicity. Early formulations such as methyltestosterone were chemically modified to resist hepatic metabolism through 17-alpha alkylation. While this modification improved oral bioavailability, it also introduced hepatotoxicity risks, including cholestatic jaundice, altered liver function tests, and in rare cases, hepatocellular carcinoma and peliosis hepatitis.1

As a result, oral testosterone use declined for several decades. Interest returned with the development of testosterone undecanoate, a formulation that uses the lymphatic system to avoid first-pass liver metabolism. Multiple studies have confirmed the hepatic safety of testosterone undecanoate, showing no consistent evidence of liver enzyme elevation or hepatotoxic injury.2

Since undecanoate is a modified form of testosterone, it is reasonable to expect that native, unesterified testosterone delivered through a similar route would also be safe for the liver. Native testosterone lacks ester chains and other structural modifications. However, most research on native oral testosterone has focused on single-dose pharmacokinetics, and long-term hepatic safety data remain limited.3

This study aimed to evaluate changes in liver enzyme values in patients using oral native testosterone over a 90-day period. The primary focus was on alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) as indicators of hepatic function.

A retrospective analysis was conducted on exactly 100 patients who were prescribed oral native testosterone and monitored through an at-home blood collection system. Due to constraints on blood volume and the availability of CLIA-waived assays, only ALT and GGT were measured. Aspartate aminotransferase (AST) was not included.

ALT, AST, and GGT are commonly used serum enzymes for evaluating liver injury and assessing hepatic function.4 Although AST is frequently part of liver panels, it is also found in skeletal muscle and cardiac tissue. ALT, while more liver-specific, like AST, may also rise temporarily after exercise.5 This makes interpretation of either enzyme difficult in isolation, especially in active patients. In contrast, GGT is minimally influenced by exercise and other non-hepatic factors. When used together, ALT and GGT can provide a reliable assessment of liver-specific stress in outpatient and remote testing settings.

Reference ranges were based on Mayo Clinic guidelines, which define the upper normal limit as 55 U/L for ALT and 51 U/L for GGT.6 Blood values were collected at least 90 days apart. Serum testosterone levels were also measured to assess treatment response (see Table 1).

To determine the appropriate statistical test, we assessed data normality using the Shapiro-Wilk test. Because the data were not normally distributed, we used the Wilcoxon Signed Rank test to compare pre- and post-treatment enzyme levels. A subgroup analysis was also conducted on patients with ALT or GGT values above the normal range at baseline.

Among the 100 patients in the study, the average individual change in ALT was -0.56 U/L and in GGT was -1.21 U/L. These changes were not statistically significant. The p-values were 0.9025 for ALT and 0.1184 for GGT (see Table 2). No evidence of liver enzyme elevation or hepatic injury was observed in the overall cohort.

In the subgroup of patients with elevated baseline enzyme values, ALT decreased from 62.78 to 44.67 U/L, and GGT decreased from 84.43 to 70.14 U/L. Both reductions were statistically significant. No adverse hepatic events were reported. Details of this subgroup analysis are summarized in Table 3a and Table 3b.

Treatment effectiveness was confirmed by increases in serum testosterone. The average individual increase was 505 ng/dL, with a post-treatment mean of 991 ng/dL. In total, 37 percent of patients reached levels above 1000 ng/dL, and 25 percent exceeded 1123 ng/dL. A full summary of testosterone outcomes is provided in Table 4.

This study found no evidence of hepatic injury after 90 days of oral native testosterone use. Liver enzyme levels remained stable across the overall cohort and improved significantly in patients who began with elevated values. These results align with prior data on testosterone undecanoate, which has consistently demonstrated a favorable liver safety profile. Native testosterone, being structurally simpler and bioidentical to the hormone naturally produced by the body, is metabolized through established pathways without the need to process ester chains or chemical modifications. Combined with its absorption through the lymphatic system, it would be expected to pose even less hepatic risk. This analysis supports that conclusion.

In a sample of 100 patients treated with oral native testosterone, no increases in ALT or GGT were observed over a 90-day period. Patients with elevated liver enzymes at baseline demonstrated statistically significant improvement. These findings confirm the hepatic safety of oral native testosterone and establish it as a viable option for testosterone therapy.