A study published in the May 2016 issue of the Journal of Urology confirms significant variability in reported testosterone reference ranges throughout U.S. labs, as well as concerning findings about how sites developed reference ranges. This circumstance not only affects how clinicians determine treatment, but also whether insurers approve therapy for men with low testosterone levels, according to the author of an accompanying editorial comment.
Numerous variables affect testosterone level results, including the patient’s age and weight, physiological variation, timing of the specimen draw, presence of comorbid conditions, and medications, all of which makes defining a clinically relevant lower limit of “normal” challenging. In particular, as levels approach hypogonadal states, the accuracy becomes increasingly unreliable.
Researchers from the University of Kansas Medical Center in Kansas City surveyed 120 academic and community hospital-associated laboratories in 47 states, 73% of which measured total testosterone on site using radioimmunoassay (RIA), enzyme immunoassay (EIA), and/or liquid chromatography-tandem mass spectrometry. Most (94.3%) used EIA via high-throughput analyzers.
They found wide variation between mean lower and upper limits for total testosterone reference ranges. Lower limits ranged from 160 to 300 ng/dL, with upper limits ranging from 726 to 1,130 ng/dL.
Since 2007, the Endocrine Society has advocated “reference intervals should be established by each laboratory, using well-defined and characterized populations.” However, the study found that just a third of those surveyed used age-stratified reference ranges. Instead, most labs adopted reference ranges from the product insert for the analyzer they were using. Yet, the authors found, manufacturers of frequently used analyzers “continue to perpetuate poorly supported normal reference ranges with small, uncharacterized samples of men.”
In addition, while the College of American Pathology recommends using a minimum of 20 samples from healthy individuals to perform validation studies, the authors found that labs performed such studies with little information on the subjects’ health, including basic medical screening. This, the authors noted, results in a “a paucity of ranges that reflect the local population.” While the Centers for Disease Control and Prevention and the National Institute of Standards and Technology offer a serum-based specimen calibration program, the program is not mandatory.
Such variation in testosterone reference values across the U.S. that are based on limited reference population data, the authors concluded, “should make providers interpret serum testosterone levels carefully in the evaluation and management of clinical hypogonadism.”
Insurance companies often require repeat “abnormal” testosterone levels before approving treatment, wrote Tobias S. Köhler, MD, chief of the division of male infertility at Southern Illinois University School of Medicine in Springfield, in an accompanying editorial. The findings of this study, he said, illustrate why men with symptomatic low testosterone are denied treatment.
Other key findings:
- Most facilities (84%) sent free testosterone studies to larger reference facilities, such as Quest Diagnostics, Mayo Medical, and ARUP laboratories.
- The use of in-house RIAs to detect free testosterone has dramatically declined, with just a third of surveyed laboratories reporting their use.
- Labs that do not use RIAs or send out their free testosterone tests relied on indirect methods by calculating free testosterone based on published formulas, most commonly the Vermeulen equation.