Testosterone, the primary male sex hormone, exists in two main forms in the bloodstream: total testosterone and free testosterone. Total testosterone includes both bound (attached to proteins like SHBG and albumin) and free testosterone (unbound and biologically active). Free testosterone is the form that directly affects muscle growth, libido, and overall vitality. Understanding the balance between these two can help assess hormonal health, athletic performance, and potential deficiencies.

What is “total and free testosterone”?

Total and Free Testosterone refer to the different forms of testosterone circulating in the bloodstream.

• Total Testosterone is the sum of all testosterone in the body, including both bound and free forms. Most of it is attached to proteins like sex hormone-binding globulin (SHBG) and albumin, which regulate its activity.
• Free Testosterone is the unbound form, making up a small percentage of total testosterone but being the most biologically active. It plays a direct role in muscle growth, energy levels, libido, and overall hormonal balance.

Is it always necessary to measure both total and free testosterone?

It is not always required to perform both measurements. Usually, the total testosterone level is measured initially. However:

• If symptoms are present: If total testosterone is normal but hypogonadism symptoms (for example, low libido, fatigue, decrease in muscle mass) persist, measuring free testosterone may provide additional information.
• Age and SHBG levels: Particularly in older men or in cases where SHBG levels are abnormal, free testosterone offers a more accurate assessment.

In short, while measuring total testosterone is sufficient in most cases, measuring free testosterone may also be necessary depending on clinical symptoms and individual circumstances.

Reference values for testosterone

Testosterone levels vary by age, sex, and the specific laboratory assay used. Here are some general reference ranges:

Adult Men

• Total Testosterone: ~300–1,000 ng/dL (10.4–34.7 nmol/L)
• Free Testosterone: ~5–21 ng/dL (values can also be expressed as a percentage of total testosterone, typically 1–3%)

Adult Women

• Total Testosterone: ~15–70 ng/dL (0.5–2.4 nmol/L)
• Free Testosterone: ~0.3–1.9 ng/dL (often measured in pg/mL; conversion may vary by assay)

Note:
These ranges are approximate and can vary between different laboratories and assay methods. Always refer to your specific lab’s reference values for the most accurate interpretation.

Preferred timing for testosterone measurement

Testosterone levels exhibit a diurnal rhythm, meaning they are highest in the early morning. For both total and free testosterone measurements, the optimal time to collect a blood sample is typically between 7:00 AM and 10:00 AM. This ensures that the levels measured reflect the peak daily concentration, providing a more accurate assessment of hormonal status.

Clinical importance of total and free testosterone

Both total and free testosterone levels are critical for diagnosing and managing various health conditions. Their clinical importance includes:

Diagnosing Testosterone Deficiency (Hypogonadism)

• Total testosterone levels help identify overall testosterone production.
• Free testosterone is more indicative of symptoms, especially in cases where SHBG levels are abnormal.
• Low levels can lead to fatigue, low libido, muscle loss, and depression.

Evaluating Andropause (Age-Related Testosterone Decline)

• With aging, SHBG levels increase, reducing free testosterone even if total testosterone appears normal.
• Measuring free testosterone is crucial in older men experiencing energy loss, mood changes, and reduced muscle mass.

Assessing Fertility Issues

• Low testosterone can contribute to low sperm production and infertility.
• High SHBG may reduce free testosterone, affecting reproductive function.

Monitoring Hormone Therapy (TRT & Anabolic Steroid Use)

• Athletes and patients on testosterone replacement therapy (TRT) require monitoring to avoid excessive hormone levels.
• Free testosterone helps assess biological availability and effectiveness of treatment.

Detecting Hormonal Imbalances (PCOS, Hyperandrogenism in Women)

• In women, elevated free testosterone may indicate polycystic ovary syndrome (PCOS), causing symptoms like acne, hair growth, and menstrual irregularities.

Evaluating Metabolic and Cardiovascular Health

• Low testosterone levels are linked to obesity, insulin resistance, and heart disease.
• Free testosterone plays a role in maintaining muscle mass and metabolic function.

Factors affecting total and free testosterone levels

Testosterone levels can be influenced by various biological, lifestyle, and medical factors. Both total testosterone and free testosterone levels can fluctuate due to the following:

Age

• Testosterone naturally declines with age, typically by 1-2% per year after the age of 30.
• SHBG levels increase with age, reducing free testosterone availability.

Sex Hormone-Binding Globulin (SHBG) Levels

• High SHBG binds more testosterone, reducing free testosterone levels.
• Low SHBG increases free testosterone but may indicate underlying conditions like insulin resistance.

Body Composition

• Obesity leads to increased aromatization, converting testosterone into estrogen, reducing overall levels.
• Low body fat and high muscle mass support higher testosterone production.

Lifestyle Factors

• Exercise: Strength training and high-intensity workouts boost testosterone, while excessive endurance training can lower it.
• Diet:
  • Healthy fats (omega-3s, monounsaturated fats) support testosterone production.
  • Zinc and vitamin D are crucial for maintaining optimal levels.
  • Excessive alcohol and processed foods can decrease testosterone.
• Sleep: Poor sleep quality or less than 6 hours per night reduces testosterone production.

Stress and Cortisol

• Chronic stress increases cortisol, which suppresses testosterone production.
• High cortisol levels reduce free testosterone, impacting energy, mood, and muscle growth.

Medical Conditions

• Hypogonadism (Testosterone Deficiency): A medical condition where the body produces insufficient testosterone.
• Diabetes & Insulin Resistance: Can lower testosterone and increase SHBG levels.
• Liver Disease: Affects SHBG production, altering free testosterone levels.
• Thyroid Disorders:
  • Hypothyroidism can lower total testosterone.
  • Hyperthyroidism may increase SHBG, reducing free testosterone.

Medications & Substance Use

• Anabolic steroids & TRT: Can suppress natural testosterone production when misused.
• Opioids & Corticosteroids: Long-term use can significantly reduce testosterone.
• Antidepressants & Blood Pressure Medications: Some drugs may lower testosterone levels.

Genetics & Individual Variation

• Genetic factors influence testosterone production, SHBG levels, and receptor sensitivity.
• Some individuals naturally have higher or lower testosterone levels despite similar lifestyle habits.

Environmental Factors

• Endocrine Disruptors (Plastics, Pesticides, BPA): Chemical exposure can reduce testosterone levels.
• Pollution & Toxins: Heavy metals and pollutants can disrupt hormonal balance.

Time of Day

• Testosterone levels are highest in the morning and gradually decline throughout the day.
• This is why morning blood tests are often recommended for accurate measurement.

Which is more important: Total testosterone or free testosterone?

Both total testosterone and free testosterone are important, but their relevance depends on the specific clinical situation.

Total Testosterone: The Overall Measure

• Measures all testosterone in the blood, including both bound (inactive) and free (active) forms.
• Used as a general screening test for testosterone deficiency or excess.
• However, it doesn’t always reflect the actual biological activity, especially if SHBG (sex hormone-binding globulin) levels are abnormal.

Free Testosterone: The Active Form

• Represents the unbound and bioavailable testosterone that directly influences muscle growth, libido, energy, and mood.
• More important in symptomatic individuals with normal total testosterone but low free testosterone (e.g., older men, those with high SHBG).
• Can be a better marker for conditions like andropause, infertility, and metabolic disorders.

Which One Matters More?

• For general testosterone assessment → Total Testosterone
• For evaluating symptoms like fatigue, low libido, or muscle loss → Free Testosterone
• For older men (since SHBG increases with age) → Free Testosterone
• For hormone therapy monitoring → Both should be measured

When total/ free testosterone levels need to be treated?

Treatment for abnormal total and free testosterone levels is considered when both laboratory results and clinical symptoms indicate a deficiency or imbalance that affects quality of life. Here are key points to consider:

• Symptomatic Individuals:
  Treatment is usually warranted if a patient shows symptoms such as low libido, fatigue, depression, loss of muscle mass, or infertility, along with consistently low testosterone levels.
• Confirmed Low Levels:
  • Low Total Testosterone: Often used as a screening tool. Values below the clinically accepted threshold (commonly around 300 ng/dL in men, though this can vary) may warrant further evaluation and potential treatment.
  • Low Free Testosterone: Even if total testosterone is borderline, low free testosterone (the biologically active portion) can cause symptoms and may be an indication for treatment, especially in older men where SHBG levels are elevated.
• Underlying Causes:
  Before initiating treatment, it’s important to identify and address any underlying conditions (like hypogonadism, metabolic disorders, or thyroid dysfunction) that might be contributing to low testosterone levels.
• Individualized Approach:
  Treatment decisions should be personalized based on factors such as age, overall health, and the presence of comorbid conditions. For instance, testosterone replacement therapy (TRT) is considered in men with confirmed hypogonadism and persistent symptoms after a thorough evaluation.
• Monitoring:
  Once treatment is initiated, both total and free testosterone levels are monitored to ensure efficacy and adjust dosage as needed.

Summary

Total testosterone measures all the testosterone in the bloodstream, including both the protein-bound and the biologically active free testosterone. Free testosterone is the unbound portion that directly influences bodily functions such as libido, muscle mass, and energy levels. Assessing both provides a more complete picture of hormonal health and helps in diagnosing conditions like hypogonadism, ensuring accurate treatment decisions.

Prof. Dr. Emin ÖZBEK

Urologist

Istanbul- TURKIYE