Free Testosterone Threshold for Hypogonadism in Males
In a 45-year-old male, free testosterone below 220 pmol/L (approximately 6.3 ng/dL) measured by equilibrium dialysis, combined with specific hypogonadal symptoms, establishes the diagnosis of hypogonadism. 1
Diagnostic Thresholds
Total Testosterone Criteria
- Two separate morning (8-10 AM) fasting measurements below 300 ng/dL (10.4 nmol/L) are required to establish biochemical hypogonadism 1, 2
- Total testosterone above 350 ng/dL typically does not require replacement therapy 2
- Levels between 231-346 ng/dL represent a gray zone requiring free testosterone measurement and symptom assessment 2
Free Testosterone Criteria
- Free testosterone below 220 pmol/L (6.3 ng/dL) by equilibrium dialysis is the gold standard threshold for diagnosing hypogonadism 1
- Free testosterone measurement is essential when total testosterone is borderline (231-346 ng/dL), particularly in men with obesity or diabetes where low sex hormone-binding globulin (SHBG) may artificially lower total testosterone 1, 3
- The European Male Ageing Study established that free testosterone below 220 pmol/L combined with three sexual symptoms (erectile dysfunction, reduced frequency of sexual thoughts, and reduced morning erections) defines true hypogonadism 4
Critical Diagnostic Requirements
Symptom Confirmation Required
- Biochemical evidence alone is insufficient—specific hypogonadal symptoms must be present 1, 5
- Primary symptoms warranting treatment include diminished libido, erectile dysfunction, and reduced spontaneous erections 1, 3
- Secondary symptoms include decreased sense of vitality, reduced muscle mass, and increased visceral adiposity 1, 5
Measurement Methodology
- Free testosterone must be measured by equilibrium dialysis, not calculated methods or free androgen index 1, 3
- Calculated free testosterone methods show significant variability with mean biases ranging from 5.8% to 56.0% 6
- Free androgen index correlates poorly with true free testosterone (r²=0.21-0.46) and over-estimates free testosterone at low SHBG concentrations 6
Common Diagnostic Pitfalls
Avoid Single Measurements
- Testosterone exhibits significant diurnal variation—single measurements are insufficient for diagnosis 3
- Both total and free testosterone must be confirmed low on at least two separate morning assessments 1, 3
Distinguish Primary from Secondary Hypogonadism
- After confirming low testosterone, measure LH and FSH to determine the type of hypogonadism 1, 3
- This distinction has critical treatment implications, particularly for fertility preservation 1
- Men with secondary hypogonadism seeking fertility require gonadotropin therapy (hCG plus FSH), not testosterone replacement 1
Evaluate for Reversible Causes
- Obesity-associated secondary hypogonadism may improve with weight loss through low-calorie diets and exercise before initiating testosterone therapy 1
- Chronic diseases (type 2 diabetes, metabolic syndrome, COPD, cardiovascular disease) are associated with high prevalence of hypogonadism 5, 4
- Medications including opiates and corticosteroids commonly cause hypogonadism 5
Treatment Threshold Algorithm
For a 45-year-old male:
- If free testosterone ≥220 pmol/L: No testosterone replacement indicated regardless of symptoms 1, 4
- If free testosterone <220 pmol/L with confirmed hypogonadal symptoms on two separate morning measurements: Testosterone replacement therapy is indicated 1, 3
- Target mid-normal testosterone levels (500-600 ng/dL) during treatment 1, 2