Liver Enzyme Trends in Patients Using Enclomiphene: A Retrospective Analysis

Enclomiphene is a selective estrogen receptor modulator that restores endogenous testosterone production in men by stimulating the hypothalamic–pituitary–gonadal axis.1 It is prescribed for men presenting with symptoms of testosterone deficiency, regardless of whether they meet biochemical thresholds for hypogonadism.

As an oral therapy, enclomiphene undergoes hepatic metabolism, primarily via the CYP2D6 enzyme system.2 This naturally raises theoretical concerns about liver safety, since many oral compounds are processed through hepatic pathways. However, neither preclinical nor clinical studies have demonstrated hepatotoxicity associated with enclomiphene.

Liver function tests are the standard clinical tools for assessing hepatocellular and biliary integrity. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) are the most common enzymes evaluated.3 In this analysis, only ALT and GGT were included, as these assays are available through CLIA-certified platforms compatible with at-home blood collection. Reference standards were based on Mayo Clinic guidelines, which define upper limits of normal as 55 U/L for ALT and 51 U/L for GGT.4

This study represents the largest real-world dataset of enclomiphene-treated men in which liver enzyme trends were monitored. The objective was to determine whether treatment with enclomiphene produces any clinically meaningful change in hepatic enzyme activity.

To evaluate whether enclomiphene therapy causes significant or clinically relevant changes in ALT and GGT, and to confirm that mean enzyme values remain within standard reference ranges across treatment doses.

This retrospective analysis included 1,205 men aged 20 to 84 years treated with enclomiphene in an outpatient setting. Laboratory data were collected through an at-home blood collection system using CLIA-certified assays.

Analytes measured included total and free testosterone, estradiol (E2), sex hormone–binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and the liver enzymes ALT and GGT. Reference limits were set at ≤55 U/L for ALT and ≤51 U/L for GGT.5

Participants were stratified by daily dose: 6.25 mg (n = 135), 12.5 mg (n = 587), and 25 mg (n = 483). Treatment duration averaged 3.3 months (range 1–15 months). Baseline and most recent laboratory values were compared using paired t-tests.

The primary endpoint was the mean change in ALT and GGT between baseline and follow-up. The secondary endpoint was the proportion of patients exceeding reference limits.

Population Characteristics

A total of 1,205 men were included. The mean age was 42.8 years, and the mean treatment duration was 3.3 months. All participants were male and received one of three daily doses.

Dose-Stratified Hormonal and Biochemical Changes

Hormonal responses followed expected trends, with significant increases in total and free testosterone across all doses (p < 0.001). ALT and GGT rose modestly but remained far below reference thresholds.

Across all dose levels, mean ALT and GGT values at follow-up remained approximately 10 U/L, well within the Mayo Clinic upper limits of normal (55 U/L and 51 U/L, respectively). No participants exhibited liver enzyme elevations greater than three times the reference limit, and no hepatic adverse events were reported.

The data demonstrates that enclomiphene does not produce clinically meaningful changes in liver enzyme activity, even with sustained oral dosing. Although small mean increases in ALT and GGT reached statistical significance, their absolute values remained far below any level associated with hepatic injury.

In practice, such minor variations are common and often unrelated to true hepatic dysfunction. ALT and AST are also present in skeletal muscle, and mild, transient elevations can occur following physical exertion or muscle strain.5 This reinforces that statistically detectable changes do not necessarily indicate clinical harm.

The consistency of results across three dosing groups and more than 1,200 patients confirms the hepatic safety of enclomiphene therapy. Despite hepatic metabolism via CYP2D6, no signal of liver enzyme elevation or toxicity was observed.

This dataset, the largest of its kind, provides strong real-world evidence supporting the hepatic safety of enclomiphene in clinical use.

In this retrospective review of 1,205 men treated with enclomiphene, serum ALT and GGT remained within normal limits across all doses. While small, statistically significant increases were observed, they were clinically insignificant and not indicative of hepatic injury.

These findings confirm that enclomiphene is a liver-safe oral SERM appropriate for men treated for symptoms related to testosterone deficiency, regardless of diagnostic category, at any of the standard daily doses of 6.25 mg, 12.5 mg, or 25 mg.