Utility of Directly Measured Free Testosterone in Predicting Benefit of Testosterone Therapy in Men with Hypogonadal Symptoms and Normal Total Testosterone

Abstract

ABSTRACT Introduction Hypogonadal symptoms, including decreased libido, erectile dysfunction, and decreased energy/fatigue, often related to a low total testosterone (TT) level, are common among aging men, affecting at least 20% of men age ≥ 45.(1) Testosterone exists in two main forms: bound to proteins (primarily SHBG and albumin) and largely inactive, and as unbound free testosterone (FT). Current guidelines from multiple professional associations advise clinicians to use the presence of hypogonadal symptoms along with low serum TT to determine the need for Testosterone Replacement Therapy (TRT). The use of FT levels to guide treatment has not been established. Equilibrium dialysis is the gold standard for measuring FT, but rarely used clinically due to practical limitations.(2,3) Many guidelines also discourage the use of commercially-available directly measured FT by analog enzyme immunoassay (EIA) due to variability and accuracy concerns.(3) Thus, in guideline-based practice, symptomatically hypogonadal men with normal TT levels but low EIA FT are not offered TRT, despite some evidence that these men may benefit from treatment.(2) Objective To examine the benefits and safety of TRT in men with hypogonadal symptoms who demonstrate a normal TT level but low directly measured FT, as measured by a single national lab company (LabCorp) using EIA. Methods The study is an analysis of prospectively-collected data for 63 consecutive men seen in our clinical practice with hypogonadal symptoms, normal TT (>265 ng/dL) and low FT (normal range 7.2-24.0pg/mL). All men began a standardized regimen of T-cypionate IM injections at a dose of 200mg every 2 weeks.(4) Men with prior TRT were excluded. Baseline blood tests were performed for TT, FT, E2, LH, PRL, CBC, and PSA. Follow up blood tests included TT, FT, E2, CBC, and PSA. Clinical response to TRT was based on documentation of improvement in hypogonadal symptoms, including ED as measured using the IIEF-5 questionnaire, as well as subjective patient reports of changes in libido, energy, etc. Results A total of 63 men with a mean age of 64.0 yrs. (range 34-86 yrs.) were included. Prior to TRT, mean TT was 375.3ng/dL (IQR [312.0-419.5]) and mean FT was 4.7pg/mL (3.9-5.8). At 3-month follow up, mean TT was 690.8 (420.8-883.8) and FT was 11.71 (7.4-14.1). Mean IIEF-5 score prior to TRT was 12.2 (5.0-19.8) and after TRT was 13.3 (5.8-21.3). Within the cohort, 85.4% reported subjective improvement in overall energy and libido after 3 months of TRT, with 59.4% of patients reporting significant improvement and 26% reporting mild but noticeable improvement. The remaining 14.6% reported minimal or no improvement. Nearly half reported improvement in erection function, assessed by IIEF-5 questionnaire. One patient (1.6%) developed de novo erythrocytosis, and three (4.8%) developed pathologic rise in PSA. Conclusions Our findings suggest that many men with hypogonadal symptoms, normal TT, and low EIA FT respond well to TRT, and that such treatment is safe. Until the creation of specific guidelines regarding use of FT to guide TRT treatment decisions, it may be of clinical benefit to treat men based on appropriate symptoms and low directly measured FT levels. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Boston Scientific