From the Guidelines
If free testosterone is low but total testosterone is normal, the next step is to investigate and address potential causes of low free testosterone, starting with lifestyle modifications and evaluation of underlying conditions, as recommended by the most recent guidelines 1.
Approach to Low Free Testosterone
To address low free testosterone levels, consider the following steps:
- Evaluate and treat potential underlying conditions:
- Check thyroid function (TSH, free T4)
- Assess liver function (ALT, AST, albumin)
- Screen for diabetes (HbA1c, fasting glucose)
- Consider sleep study if sleep apnea is suspected
- Optimize lifestyle factors:
- Improve sleep hygiene (7-9 hours per night)
- Reduce stress through relaxation techniques or counseling
- Maintain a healthy body weight
- Exercise regularly, focusing on resistance training
- Review medications:
- Adjust or discontinue medications that may affect testosterone binding, such as certain anticonvulsants or glucocorticoids, if possible
- Consider supplementation:
- Zinc (30-50 mg daily)
- Vitamin D (2000-5000 IU daily, if deficient)
- Magnesium (200-400 mg daily)
- Monitor SHBG (Sex Hormone Binding Globulin) levels:
- If elevated, address underlying causes (e.g., hyperthyroidism, liver disease)
Rationale
The approach outlined above is based on the most recent guidelines from the American College of Physicians 1 and the American Urological Association 1, which emphasize the importance of lifestyle modifications and evaluation of underlying conditions in addressing low testosterone levels. Additionally, the guidelines recommend against initiating testosterone treatment in men with age-related low testosterone to improve energy, vitality, physical function, or cognition 1. By addressing the underlying causes of low free testosterone and optimizing lifestyle factors, it is possible to improve symptoms and overall health without immediately resorting to testosterone replacement therapy.
From the Research
Next Steps for Low Free Testosterone and Normal Total Testosterone
If free testosterone is low but total testosterone is within normal limits, the following steps can be considered:
- Measurement of morning total testosterone level by a reliable assay as the initial diagnostic test, and confirmation of the diagnosis by repeating the measurement of morning total testosterone and, in some men, measurement of free or bioavailable testosterone level, using validated assays 2
- Assessment of free testosterone levels, as routine assessment of free testosterone can improve the diagnostic accuracy of functional hypogonadism, especially in men with sexual symptoms 3
- Evaluation of clinical and biochemical parameters of androgen deficiency, such as age, haematocrit, gonadotropins, gynecomastia, BMI, and number of co-morbidities, which are associated with free testosterone levels 3
- Consideration of a trial period of testosterone treatment, as men with sexual symptoms of hypogonadism may respond well to testosterone replacement therapy across a wide range of initial total testosterone values, including men with low-normal total testosterone levels 4
Key Considerations
- The diagnosis of hypogonadism should be made only in men with consistent symptoms and signs and unequivocally low serum testosterone levels 2
- Total testosterone levels of less than 8 nmol/l highly support a diagnosis of hypogonadism, whereas levels greater than 12 nmol/l are likely to be normal, and the grey zone between 8 and 12 nmol/l requires further evaluation and assessment of free or non-sex hormone-binding globulin-bound (bioavailable) testosterone 5
- Testosterone replacement therapy should be considered for men with symptomatic androgen deficiency to induce and maintain secondary sex characteristics and to improve their sexual function, sense of well-being, muscle mass and strength, and bone mineral density, but should be used with caution in certain patient populations, such as those with breast or prostate cancer, or uncontrolled heart failure 2