Free Prostate-Specific Antigen

Prostate-specific antigen (PSA) is an enzyme produced by prostate epithelial and cancer cells, widely used as a serum marker for cancer detection. 

While PSA testing has significantly influenced prostate cancer diagnosis and management, its specificity is limited due to overlapping levels in cancerous and non-cancerous conditions. 

Free PSA (fPSA) represents the unbound form of PSA in the blood, and measuring the ratio of free to total PSA can improve diagnostic accuracy. 

This ratio is particularly useful for men with PSA levels between 4.0 and 10.0 ng/mL, as it helps differentiate between prostate cancer and benign prostatic diseases, reducing unnecessary biopsies. 

A lower percentage of free PSA generally indicates a higher risk of prostate cancer, enhancing the specificity of PSA testing and providing a valuable tool in clinical decision-making.

What is PSA, Prostate Specific Antigen? [3., 7.] 

Prostate-specific antigen (PSA) is an androgen-regulated serine protease enzyme produced by prostate epithelial cells and prostate cancer (PCa) cells, and it is the most commonly used serum marker for cancer detection. 

A member of the tissue kallikrein family, PSA is a major protein in semen, where it functions to cleave semenogelins in the seminal coagulum. 

Semenogelins are proteins found in semen that form the gel-like structure of the seminal fluid after ejaculation. They help to initially thicken the semen, which can protect sperm and facilitate its delivery. PSA (prostate-specific antigen) then breaks down these proteins to liquefy the semen, allowing sperm to swim freely and increase the chances of successful fertilization.

Secreted as an inactive proenzyme (proPSA), PSA is activated by the cleavage of seven N-terminal amino acids.

Intact PSA that enters circulation is rapidly bound by protease inhibitors, primarily alpha1-antichymotrypsin, with a fraction remaining as free PSA. 

In prostate cancer, the efficiency of PSA inactivation and conversion from proPSA is reduced, leading to elevated serum total PSA levels. 

PSA screening has significantly influenced PCa diagnosis and management, though its specificity is limited, as levels can overlap between cancerous and non-cancerous conditions. 

Measuring the ratio of free to total PSA can improve specificity, and ongoing research into proPSA forms may enhance early-stage PCa detection. [6.] PSA is also crucial for monitoring therapy responses and exploring its potential as a therapeutic target.

What is Free PSA? [9.] 

Free PSA is the portion of PSA that is not attached to other proteins in the blood. It is one of two main forms of PSA found in the bloodstream, the other being bound PSA. The free PSA test measures only this unbound form of PSA.

The ratio of free PSA to total PSA (which includes both free and bound forms) is often used to help assess the risk of prostate cancer. A higher percentage of free PSA generally indicates a lower risk of prostate cancer, while a lower percentage suggests a higher risk.

What is the Free to Total PSA Ratio? [8.] 

The free-to-total PSA ratio is used to improve the detection of prostate cancer in men with PSA levels between 4.0 and 10.0 ng/ml, a range where PSA alone lacks specificity and can lead to unnecessary biopsies. 

By comparing the proportion of free PSA to total PSA, the ratio helps distinguish between cancer and non-cancer conditions. 

Studies found that a negative test result can reduce the probability of cancer to about 10%, but the test's overall discriminating power is modest. [8.] 

Methodological flaws and the need for an optimal cut point mean that further research is necessary to improve the accuracy and utility of this screening method.

PSA and Prostate Cancer Screening

Prostate Cancer [9.] 

Prostate cancer is the most frequently diagnosed cancer in men in 112 countries and the leading cause of cancer death in 48 countries. It is the fifth leading cause of male cancer-related deaths worldwide, with over 1.4 million new cases and 375,304 deaths annually. 

In the U.S., it is the second leading cause of cancer death among men, with an estimated 288,300 new cases and 34,700 deaths in 2023.

The incidence of prostate cancer in Black men is 70% higher than in White males. Black men in the US have the highest lifetime risk of dying from prostate cancer at 4.2%. In contrast, American Indians and Alaskan Natives have less than half the incidence rate of Black men, but their mortality rate is only slightly less.

The median age of death due to prostate cancer is 80 years, with 75% of prostate cancer-specific mortalities occurring in those older than 75. The average age at the time of diagnosis is 66 years. 

Prostate cancer is relatively rare in individuals younger than 50 years, accounting for about 1% to 3% of all such malignancies; however, when it does occur in this younger age group, it tends to be quite aggressive.

Prostate Cancer Screening Guidelines [9.] 

General Screening Recommendations

Shared decision-making is recommended for men aged 55 to 69 years considering periodic PSA testing. 

Routine PSA screening is not recommended for men aged over 70 years due to minimal potential survival benefits and significant adverse effects associated with treatment in this age group. 

Screening intervals and starting ages are adjusted based on individual risk factors, including ethnicity and family history.

Routine PSA Screening is not typically recommended for men younger than 40 years.

Screening for High-Risk Individuals

For high-risk individuals aged 40-45: PSA testing may be offered to high-risk patients. 

High-risk individuals include men of African descent, those with a close family member with prostate cancer (especially if diagnosed before age 60, had metastatic disease, or died from it), individuals with a strong family history of malignancies (Lynch syndrome, breast, and ovarian cancers), men with known associated germline mutations (BRCA1, BRCA2, ATM, CHEK2, etc.), and Vietnam War veterans with known Agent Orange exposure.

Between ages 45-54, screening may begin for high-risk patients, especially those with a family history of prostate cancer or other associated risk factors.

Screening Frequency

Annual screenings are recommended until a significant cancer is discovered, the patient decides to stop screening, or medical comorbidities limit life expectancy to less than 10 years.

Screening Tools and Strategies

• Digital Rectal Examination (DRE): Not recommended alone for screening without PSA testing due to low sensitivity and specificity.

• Free and Total PSA: Can help stratify the relative risk of prostate cancer if total PSA is <10 ng/mL.

Prostate-Specific Antigen (PSA) in Prostate Cancer Screening

PSA is a glycoprotein enzyme produced by the prostate, crucial for reducing seminal viscosity and improving sperm motility. 

Elevated PSA levels, often associated with prostate malignancy, are key for screening. However, high PSA levels are not specific to cancer and can be caused by benign conditions.  In fact, most cases of high PSA levels are not due to cancer.  [9.] 

Other causes of elevated PSA include benign prostatic hypertrophy (BPH), prostatitis, recent vigorous exercise such as cycling, urinary tract infection, recent digital rectal examinations, and recent sexual activity .  [2., 9., 12.]

Additionally, PSA levels are normally expected to rise with age.  [2., 9.]

Conversely, some medications such as finasteride and dutasteride, 5-alpha reductase inhibitors, can lower PSA levels.  [2.]

PSA is a marker that can be helpful to monitor risk of prostate cancer, especially in high-risk individuals.  It should be interpreted within the context of an individual’s personal and family medical history, symptomatology, and alongside other parameters including laboratory assessment, digital rectal exams, imaging and biopsy.  

However, early detection of prostate cancer may not prevent death.  Additionally, a PSA screening test may provide false-positive results, putting the individual through unnecessary screening tests as well as anxiety and discomfort.  

To avoid unnecessary worry, biopsy procedures and cancer treatment, individuals should participate in shared decision-making with their healthcare provider to determine an appropriate plan for screening for prostate cancer.   

“Normal” PSA Levels [2., 13.]

There is no definitive normal or abnormal PSA level in the blood. 

Historically, PSA levels of 4.0 ng/mL and below were deemed normal. However, some individuals with PSA levels under 4.0 ng/mL may still have prostate cancer, and many with PSA levels between 4 and 10 ng/mL do not have the disease.

PSA Screening Process [9.]

Sensitivity and Specificity

PSA is a sensitive but nonspecific marker for prostate cancer. Elevated PSA levels require confirmation with two separate abnormal results, 8 weeks apart.

Age-Specific Ranges:

Normal PSA levels increase with age. 

Ranges are:

• 40-49 years: 0-2.5 ng/mL

• 50-59 years: 0-3.5 ng/mL

• 60-69 years: 0-4.5 ng/mL

• 70-79 years: 0-6.5 ng/mL

Prostate Cancer Screening Benefits and Controversies

Benefits

PSA screening has reduced prostate cancer mortality and metastatic disease incidence.

Controversies

Overdiagnosis and overtreatment of indolent cancers are major concerns, leading to unnecessary biopsies and anxiety. However, stopping PSA screening has increased the incidence of higher-stage diseases.

Symptoms of Prostate Cancer [10., 11.]

The main symptoms of prostate cancer include: 

Urinary symptoms:

• Frequent urination, especially at night

• Difficulty starting or holding back urination

• Weak, dribbling, or interrupted urine flow

• Painful or burning urination

• Blood in the urine (hematuria)

Sexual symptoms:

• Difficulty achieving or maintaining an erection

• Painful ejaculation

• Blood in the semen

• Decreased volume of ejaculation

Pain and discomfort:

• Frequent pain or stiffness in the lower back, hips, or upper thighs

• Bone pain (in advanced cases, due to metastasis)

Other symptoms (especially in advanced cases):

• Unexplained weight loss

• Fatigue

• Swelling in the legs or feet

• Weakness or numbness in the legs or feet

• Loss of bladder or bowel control (from cancer pressing on the spinal cord)

It's important to note that most prostate cancers are found early through screening, before symptoms develop.

Many of these symptoms can also be caused by non-cancerous conditions like benign prostatic hyperplasia (BPH).

Early prostate cancer often causes no symptoms.

Free PSA Laboratory Testing

Test Information, Sample Collection and Preparation 

PSA may be tested as total PSA levels, free PSA levels, or both.  Both measurements are typically used for men aged 50 years and older with a PSA between 4.0-10.0 ng/mL, with a normal digital rectal examination.

Sample collection requires a blood draw via venipuncture.  

The option to order a total PSA test with a reflex to add free PSA is available from many labs.  

Prostate stimulation including a digital rectal examination, transrectal ultrasound, sexual activity, and recent vigorous exercise such as cycling should be avoided for 2-3 days prior to the procedure.  This test should not be performed less than six weeks after a prostate biopsy.  [1.] 

Interpretation of Free PSA Levels

Optimal Levels of Free PSA

The normal range for Free PSA can vary depending on a patient's age.  

Broadly speaking, a man’s risk of prostate cancer increases with increasing PSA levels.  Optimal PSA levels remain low, although normally PSA levels increase with age.  

Free PSA levels are typically given as a % of total PSA available.  Lower % of free PSA correlates to a higher risk of prostate cancer.  [1.] 

Clinical Significance of High Free PSA Levels

A higher free PSA level correlates with a reduced risk of prostate cancer.

Clinical Significance of Low Free PSA Levels

A lower free PSA level correlates with an increased risk of prostate cancer.  Further assessment may be warranted.  

Free PSA Related Biomarkers

PSA Density [4.] 

PSA density (PSAD) is calculated by dividing the serum prostate-specific antigen (PSA) level (ng/mL) by the volume of the prostate gland (mL). The prostate volume is typically measured using transrectal ultrasound (TRUS) or magnetic resonance imaging (MRI).

The PSAD test helps differentiate between benign prostatic hyperplasia (BPH) and prostate cancer, especially in patients with borderline PSA levels (4-10 ng/mL). It is used to decide whether a prostate biopsy is necessary.

The optimal PSA density cutoffs to diagnose clinically significant prostate cancer and rule out prostatic inflammation were identified as 0.10 ng/mL² for biopsy-naive patients and 0.15 ng/mL² for patients with a previous negative biopsy.

PSA density outperforms PSA alone in predicting clinically significant prostate cancer, particularly in patients with PSA levels in the "gray zone" (between 4 and 10 ng/mL) and those with PSA > 10 ng/mL. This makes it a valuable tool in deciding whether a patient should undergo a prostate biopsy.

By using PSA density, clinicians can potentially reduce the number of unnecessary biopsies in patients whose elevated PSA levels are due to benign conditions rather than cancer.

Free to Total PSA Ratio [5.] 

The free PSA to total PSA ratio helps distinguish between prostate cancer and benign conditions, particularly in men with total PSA levels in the "gray zone" of 4-10 ng/mL. 

In men with PSA levels between 4.0 and 10.0 ng/mL and a benign digital rectal examination (DRE), this test improves diagnostic accuracy and reduces unnecessary biopsies.

A lower percentage of free PSA is associated with a higher risk of prostate cancer, allowing for more informed decision-making regarding the need for biopsy and reduce unnecessary biopsies.

Some studies suggest that a lower free PSA percentage may be associated with more aggressive forms of prostate cancer.

Active Surveillance [6.] 

For low-risk patients, active surveillance avoids immediate treatment, intervening only if the cancer progresses. This reduces treatment-associated complications and maintains quality of life.

FAQ: Free PSA (Prostate-Specific Antigen)

What is Free PSA?

Free PSA (Prostate-Specific Antigen) refers to the unbound form of PSA circulating in the bloodstream. 

PSA is a protein produced by the prostate gland, and it can exist in two forms in the blood: free (unbound) and complexed (bound to other proteins).

What is the Function of PSA in the Body?

PSA helps to liquefy semen in the male reproductive system, allowing sperm to swim freely. In medical diagnostics, PSA levels are used to screen for and monitor prostate health.

How is Free PSA Measured?

Free PSA is measured through a blood test that quantifies the amount of PSA that is not bound to proteins. This test is often used in conjunction with the total PSA test to improve the accuracy of prostate cancer screening.

What is a Normal Free PSA Level?

Normal free PSA levels can vary, but typically, free PSA levels are interpreted in conjunction with total PSA levels. 

A higher ratio of free PSA to total PSA is generally considered a sign of benign prostate conditions, while a lower ratio may indicate a higher risk of prostate cancer. 

Specific normal ranges can vary based on the laboratory and individual factors, so it is essential to consult with a healthcare provider for accurate interpretation.

What Do Elevated Levels of Free PSA Indicate?

Elevated levels of free PSA can indicate:

• Benign prostatic hyperplasia (BPH): An enlarged prostate gland, which is common in older men.

• Prostatitis: Inflammation of the prostate gland.

• Prostate cancer: Higher levels can sometimes indicate prostate cancer, but this is usually evaluated in the context of the ratio of free to total PSA.

• Elevated PSA levels can also be attributed to conditions such as urinary tract infection as well as recent prostate stimulation.  

What Do Low Levels of Free PSA indicate?

Low levels of free PSA, particularly in relation to total PSA levels, can indicate a higher likelihood of prostate cancer. The free-to-total PSA ratio helps differentiate between benign and malignant prostate conditions.

How are Abnormal Free PSA Levels Managed?

Management of abnormal free PSA levels depends on the underlying cause:

• Benign conditions (BPH or prostatitis):

• Medications to reduce prostate size or treat inflammation

• Lifestyle changes, such as reducing caffeine and alcohol intake

• Regular monitoring of PSA levels

• Prostate cancer:

• Further diagnostic tests, such as a prostate biopsy, MRI, or ultrasound

• Treatment options may include surgery, radiation therapy, hormone therapy, or active surveillance, depending on the cancer's stage and aggressiveness

Can Lifestyle Changes Affect Free PSA levels?

Yes, lifestyle changes can impact PSA levels and overall prostate health:

• Diet: Eating a healthy diet rich in fruits, vegetables, and low in red meat and high-fat dairy products

• Exercise: Regular physical activity can help maintain a healthy prostate

• Avoiding irritants: Reducing intake of caffeine, alcohol, and spicy foods can help manage symptoms of prostate enlargement

• Regular check-ups: Monitoring prostate health through regular medical check-ups and discussions with a healthcare provider.

Where Can I Find More Information About Free PSA and Prostate Health?

For more information about free PSA and prostate health, consider consulting:

• Healthcare providers: Medical professionals can provide personalized advice and diagnosis

• Scientific literature: Research articles and reviews on PSA and prostate health

• Reputable health organizations: Websites of organizations such as the American Urological Association (AUA), National Institutes of Health (NIH), and American Cancer Society (ACS).