From the Guidelines
If your total testosterone levels are normal but your free testosterone is low, you should consult with an endocrinologist or urologist for proper evaluation and treatment, as low free testosterone can cause symptoms like fatigue, decreased libido, erectile dysfunction, and mood changes despite normal total testosterone levels. This condition typically occurs when you have adequate total testosterone but too much of it is bound to proteins like sex hormone-binding globulin (SHBG), leaving insufficient free testosterone available for biological activity. According to the 2023 standards of care in diabetes, in men with symptoms or signs of low testosterone (hypogonadism), a morning total testosterone level should be measured using an accurate and reliable assay, and in men who have total testosterone levels close to the lower limit, it is reasonable to determine free testosterone concentrations either directly from equilibrium dialysis assays or by calculations that use total testosterone, sex hormone binding globulin, and albumin concentrations 1.
Evaluation and Treatment
Treatment options may include lifestyle modifications such as weight loss, improved sleep, stress reduction, and regular exercise. Medication options might include SHBG-lowering drugs or testosterone replacement therapy (TRT) using gels, patches, injections, or pellets, typically starting at lower doses and adjusting based on symptoms and follow-up blood tests. Before starting any treatment, comprehensive testing should include:
- Total testosterone
- Free testosterone
- SHBG
- Estradiol
- Complete blood count
- Prostate-specific antigen (PSA) for men over 40.
Importance of Accurate Diagnosis
It is essential to note that only the unbound hormone can enter cells and exert biological effects, which is why low free testosterone can cause symptoms despite normal total testosterone levels. The benefits of testosterone replacement in men with symptomatic hypogonadism may include improved sexual function, well-being, muscle mass and strength, and bone density, as stated in the 2023 standards of care in diabetes 1.
From the FDA Drug Label
The patients had an average serum testosterone concentration of <300 ng/dL, as determined by two morning samples collected on the same visit. The primary endpoint was the percentage of patients with Cavg within the normal range of 300 ng/dL to 1000 ng/dL on Day 112. Table 6: Mean (SD) Testosterone Concentrations (Cavg and Cmax) by final dose on Days 112 and 364 Cavg (ng/dL) 303 (135) 457 (275) 524 (228) 643 (285) 537 (240) 561 (259)
The question of total testosterone normal and low free testosterone is not directly addressed in the provided drug label 2. The label discusses total testosterone concentrations and the efficacy of testosterone gel 1.62% in maintaining normal total testosterone levels, but it does not provide information on free testosterone levels.
- Total testosterone levels are reported to be within the normal range for a significant percentage of patients.
- However, free testosterone is not mentioned, and therefore, no conclusion can be drawn about the relationship between total and free testosterone in this context.
From the Research
Total Testosterone Normal and Low Free Testosterone
- Total testosterone levels are influenced by sex hormone-binding globulin (SHBG) concentrations, which can be affected by various factors such as obesity and ageing 3.
- Low free testosterone, even in the presence of normal total testosterone, is associated with androgen deficiency-related symptoms, including decreased libido, erectile dysfunction, and depressed mood 4.
- Men with normal total testosterone and low free testosterone tend to be older and in poorer health, with higher SHBG and luteinizing hormone (LH) levels, and report more sexual and physical symptoms 4.
Diagnosis and Treatment
- Guidelines suggest using total testosterone to diagnose androgen deficiency, but calculated free testosterone (cFT) should be assessed in men with suspected hypogonadal symptoms, especially those with normal total testosterone and low free testosterone 4.
- Testosterone replacement therapy (TRT) can improve symptoms and signs of testosterone deficiency, but its effectiveness may vary depending on individual characteristics, such as age and SHBG levels 5, 6.
- TRT has been shown to increase serum testosterone levels to physiologic range, but its long-term safety, particularly in older men with a history of heart failure, is still a concern 5.
Factors Influencing Testosterone Levels
- Obesity is associated with lower SHBG and total testosterone concentrations, but calculated free testosterone concentrations do not differ between obese and non-obese men 3.
- Ageing is associated with increased SHBG, but the association of obesity with lowered SHBG is greater than the association of ageing with increased SHBG 3.
- Metformin and testosterone therapy have been shown to reduce insulin resistance in men with obesity and low testosterone, but the combination of both therapies may not be superior to testosterone alone 7.