Fractionated testosterone gel replacement therapy in clinical practice: A real-world exploratory clinical experience

Background: Testosterone replacement therapy (TRT) with transdermal gel is widely used in men with hypogonadism. Guidelines recommend once-daily application with monitoring of serum testosterone at peak levels. However, real-world clinical experience suggests that peak-trough fluctuations in some patients, potentially affecting hormonal stability and treatment tolerability. The impact of dose fractionation remains unclear. Objectives: To compare hormonal profiles and biochemical safety parameters between once-daily and twice-daily (fractionated) testosterone gel administration in hypogonadal men receivingh the same total daily dose. Methods: We retrospectively identified hypogonadal men treated with 2% testosterone gel who transitioned from once-daily to twice-daily dosing, maintaining the same total daily dose. Eligible patients had serum total testosterone (TT) measurements available at both peak (3 h post-application) and nadir (pre-dose). Hormonal and laboratory parameters under the two regimens were compared. Results: Twelve patients met inclusion criteria. Fractionated dosing was associated with lower peak TT levels [9.0 (5.3-13.0) vs. 5.7 (3.6-7.1) ng/mL, paired difference - 3.6 ng/mL (95% CI: -4.9 to - 1.8)] and higher nadir TT levels [1.4 (1.1-1.8) vs. 3.2 (2.6-5.4) ng/mL, paired difference 2.6 ng/mL (95% CI: 1.2 to 5.1)], resulting in a reduced difference between peak-to-pre-dose difference within the observed sampling window. The proportion of patients achieving target TT levels at peak increased (33% vs. 83%). Calculated free testosterone showed a similar pattern. No clinically relevant differences were observed in luteinizing hormone, prostate-specific antigen, haematocrit, or haemoglobin. Conclusion: In this real-world cohort, fractionated testosterone gel administration was associated with a higher proportion of patients achieving biochemical targets and with a reduced peak-to-pre-dose difference within the observed sampling window, without short-term biochemical safety signals. These findings should be considered hypothesis-generating.