PSA

What Is The Difference Between PSA And Free PSA?

PSA is an essential diagnostic and screening tool for prostate cancer. It is famous as a part of the prevention of prostate cancer. However, there are some misconceptions and concepts to understand before starting to use it.

There’s a free PSA, which is different than total PSA measures. Sometimes people wonder which one is better or more accurate. Do you need to have them both measured?

In this article, we are going to clear out this common doubt. Additionally, we will dig into the concept of PSA and evaluate it as a screening tool.

What is free PSA?

PSA is short for prostate-specific antigen. It is a protein synthesized by different tissues, but especially by the human prostate. In various circumstances, the body creates and releases PSA to the bloodstream, including ejaculation.

In the ejaculate, the PSA is an important protein that makes semen more fluid to facilitate conception.

This protein can be found in the semen, but it can also be measured in the blood. PSA in the blood can run through our veins in two different forms. One of them is by floating freely in the plasma. Another is by binding to another protein that facilitates transportation.

When we measure free PSA, we are only counting PSA that is running freely in the blood. A significant proportion of PSA runs in the blood bound to another protein. Thus, free PSA levels are naturally lower than total PSA, and there are many other differences we will address further (1).

What is the difference between PSA and free PSA?

As mentioned in the paragraphs above, PSA and free PSA are almost the same things. The main difference is that free PSA runs freely in the blood. In contrast, a total PSA test measures free and bound PSA in the blood.

What PSA does as an enzyme is breaking down proteins in semen and making it liquid and more fluid. The ultimate purpose is allowing semen to move more quickly into the vagina. In turn, this facilitates the movement of sperm cells into the fallopian tubes.

PSA is primarily released to the semen, but it is also found in the blood. Any mechanical stimulation to the prostate causes a release of PSA to the blood. Prostate massage, ejaculation, and various prostate problems make it release more PSA. This can be measured as free PSA, bound PSA, or total PSA.

Free PSA is not bound to proteins in the blood, such as albumin, which serve as transporters. Bound PSA is attached to albumin and other carrier proteins in the blood.

When bound, hormones, proteins, and enzymes are unavailable, and their functions are silenced. Then, what we call total PSA is the measure of bound and free PSA without any distinction.

In a blood test, you typically get two different results: total PSA and free PSA. The proportion of bound PSA can be found by subtracting total minus free PSA (2).

Do I need to have both tests?

In most cases, doctors do not need free PSA levels. However, whether or not you need to have both tests depends on your individual circumstance. As mentioned above, PSA levels increase when you have sex, and after a prostate massage.

You can have many other conditions that increase your PSA levels, including prostatitis. Thus, if your doctor is trying to rule out prostate cancer, PSA is an important measure, but it is not fail-safe. We may detect a higher level of PSA that is not due to prostate cancer but prostatitis.

This can be confirmed by taking a look at the sensitivity and specificity of PSA. This test has more than 90% of specificity, which means that it detects most cases of cancer. But it has very low sensitivity, meaning that even men with low PSA may have prostate cancer.

Moreover, as we age, our PSA levels change dramatically. Thus, we should consider higher baseline levels in older people. If you have an elevated PSA, remember that 75% of people with a high PSA don’t have cancer. But instead of relying on a prostate biopsy to rule out cancer, there are other less invasive ways (1).

Some urologists would prefer to run a free PSA test instead of recommending a prostate biopsy. That’s because there are many consequences after a prostate biopsy. For example, you can have bleeding episodes and pain in your urinary tract.

To avoid complications of prostate biopsy, a free PSA is performed first. Using this information, doctors can calculate a PSA ratio by dividing free PSA by the total PSA. A lower proportion of free PSA can be indicative of cancer (3).

This is typically required when the patient has a PSA higher than 4 ng/mL but lower than 10 ng/mL. This has been described as a gray area. When a patient is in this gray area, doctors need more clues before any final diagnosis. In such cases, a free PSA can be an affirmative measure to avoid performing unnecessary biopsies.

What is a normal PSA level

When trying to figure out normal levels of PSA, you may come across outdated information about it. In the past, the PSA test was recommended every year for the early detection of prostate cancer. It was considered that 4 ng/mL was the upper limit of PSA levels.

In these cases, men with a PSA higher than 4 ng/mL was recommended a prostate biopsy. But this medical practice was replaced when researchers understood the variations of PSA.

Now we understand that it is not possible to point out a specific normal level of PSA. Levels of PSA vary over time as we age. Our baseline levels increase as we grow older, and they may be way over 4 ng/mL in a normal man. Similarly, according to a study, men with a PSA lower than 4 ng/dL may also have prostate cancer (4).

When a man is under treatment of prostate cancer or its symptoms, PSA levels fluctuate even more. For example, prostate surgery and a prostate biopsy increase the PSA level. Dutasteride, finasteride, and other medications to treat BPH lower PSA levels.

Thus, PSA levels should be evaluated individually, following historical baseline levels and its variations. In a general sense, we know that elevated PSA levels are associated with a larger prostate.

In the majority of cases, patients under 50 years of age have a normal range of 0 to 2.5 ng/mL. Every 10 years past, the upper limit increases by 1 ng/dL, and patients 70 years and older usually have less than 6.5 ng/dL. Thus, a senior with a PSA higher than 4 ng/dL should not undergo a prostate biopsy, as it was believed in the past.

What does a high PSA indicate?

As you have seen above, upper limits are just a reference range. A PSA level that is higher than the reference range should be evaluated individually. If you have a high PSA but no symptoms of prostate cancer, your doctor will likely repeat the exam.

If the second test is confirmatory of an elevated PSA and you still don’t have symptoms, your doctor will probably recommend continuing to perform PSA tests regularly. What we want is to evaluate how these levels change over time.

In the past, PSA levels were recommended as an annual screening test for prostate cancer. However, studies showed that relying too much on PSA is not a good idea. Many prostate biopsies were being performed in healthy men, with undesired side effects. Thus, instead of performing annual PSA tests in every patient, doctors prefer to recommend the test in patients suspicious of prostate cancer.

In other cases, doctors may also recommend the test if they find a suspicious lump during a rectal examination. A high PSA and a suspicious lump in a rectal exam should be carefully evaluated. One way to do it will be through a transrectal ultrasound and other imaging tests. Your doctor may also want to rule out a urinary infection through a urine test.

A prostate biopsy is only recommended when all of the above is made, and prostate cancer is still highly suspicious. During a prostate biopsy, your doctor will obtain various samples of the prostate by with hollow needles.

The needle is usually inserted through the rectum because its anterior wall is in direct contact with the prostate. Then, a pathologist will examine the samples of prostate tissue under the microscope. He will be able to tell whether or not there is a change compatible with prostate cancer cells.

However, it should not be performed in all patients suspicious of prostate cancer. A prostate biopsy causes significant bleeding and pain. These symptoms are usually very severe and sometimes persistent to any treatment. Thus, the procedure is recommended in patients under the gray area, where the diagnosis is not certain (5).

What factors affect PSA levels?

As mentioned earlier in this article, many different factors affect your PSA levels. Thus, a higher or lower PSA level is not always indicative of cancer or good prostate health. The most important factors that affect PSA levels are as follows (6):

  • Age: As we age, the PSA level is usually increased. After 50 years old, it is expected that the upper limit increases by 1 ng/dL every 10 years. This usually responds to benign prostatic hyperplasia. A larger prostate is associated with a larger PSA and a higher risk of prostate cancer.

  • Prostate cancer: Both benign prostate growth and prostate cancer cause a higher level of PSA. Any increase in prostate volume modulates this blood marker. However, in prostate cancer, the increase is usually violent and reaches very high levels. PSA levels are usually associated with the aggressiveness of cancer. They are useful in calculating the Gleason score. Still, there are cases of prostate cancer with low PSA levels.

  • Prostatitis: It is an inflammation of the prostate gland. As such, prostatitis does not cause a significant increase in the prostate gland. However, the inflammatory process releases PSA into the bloodstream. Thus, if you have a high PSA and urinary symptoms, prostatitis is an important diagnosis to rule out.

  • Urinary infections: Similar to prostatitis, a urinary infection causes inflammation of the urinary tract. When the inflammation process is in the urinary bladder, it is close to the prostate. Proximity to the site of inflammation causes the same effect as prostatitis. PSA levels increase in the blood, making it an important diagnosis to rule out.

  • Prostate massage: Mechanical stimulation of the prostate can release PSA to the blood. Thus, a PSA test should not be performed after a prostate massage or rectal exam. Some cases of physical trauma may also stimulate the release of PSA in the blood.

  • Ejaculation: Sexual activity releases PSA to the semen and the blood. That’s why it is recommended to abstain from sexual activity before a PSA test. 24 hours is usually enough time to avoid a false positive.

  • Medications: Many drugs can lower PSA or increase normal levels. Thus, tell your doctor if you are using non-steroidal anti-inflammatory drugs, statins, finasteride, dutasteride, or betamethasone.

  • Obesity: Obese patients may display lower PSA levels than normal-weight patients. This should be taken into consideration when measuring blood levels of this marker.

How can you naturally lower PSA

Similar to medications and other factors listed above, there are many natural ways to lower your PSA. For example, you can try the following:

  • Eating antioxidant fruits: Inflammation and free radicals contribute to PSA levels. By eating more antioxidant fruits, you will be combating your prostate hyperplasia. If your prostate gland stops growing, it will maintain or even reduce PSA levels. Antioxidant fruits include berries, leafy greens, and pomegranate.

  • Eating less meat and dairy: Red meat and dairy are associated with increased inflammation. By reducing the consumption of these food groups, we will be able to control inflammation. An inflamed prostate releases more PSA, and that’s why we recommend this dietary change.

  • Eating more tomatoes: Tomatoes have lycopene, a very important antioxidant. This substance does not only reduce PSA but also protects your body against prostate cancer.

  • Exercise and weight control: Obesity reduces PSA levels, but that’s not a good thing. These health conditions contribute to prostate cancer. Thus, if you want to maintain healthy levels of PSA, exercise, and control your weight.

  • Stress management: Stress affects the majority of glands and hormones in the body, including the prostate. Maintaining a relaxed body and mind will help you maintain lower PSA levels.

  • Green tea: It is a beneficial drink to prevent prostate cancer and high PSA levels. It slows down the growth rate of the prostate and contributes to a man’s health in many ways.

  • Vitamin D: This is an essential vitamin we can get after sunlight exposure. Not having enough levels of vitamin D increases the chance of prostate cancer. Thus, fortified foods and supplements with vitamin D may be required in areas with insufficient sunlight.

Keep in mind that PSA is a necessary measure to detect prostate cancer. Thus, be sure to tell your doctor that you are trying natural methods to reduce your PSA levels. They usually reduce a high PSA level by controlling your prostate growth. However, it is a useful piece of information that your doctor needs to evaluate the historical changes in your PSA test.

Conclusion

PSA tests are handy to screen and diagnose prostate cancer. However, it is only a part of the screening process. It is not the only tool and not the most accurate.

Many different factors influence PSA levels, including ejaculation, prostatitis, the patient’s age, and infections of the urinary tract. All of them can give a patient a false positive by increasing PSA levels without prostate cancer.

That’s why affirmative measures are important. Free PSA test, unlike total serum PSA, is a measurement of unbound prostate-specific antigen. This measurement is useful to confirm a high level of PSA in suspicious patients.

It is one of many tests performed in patients with an elevated PSA before prostate biopsy. A biopsy is only performed in patients who are highly suspicious but still need confirmation for diagnosis.

Sources

  1. Saini, S. (2016). PSA and beyond: alternative prostate cancer biomarkers. Cellular Oncology, 39(2), 97-106.
  2. Sawyers, C., Ulmert, D., Lewis, J., Evans, M., & Lija, H. (2019). U.S. Patent Application No. 16/430,041.
  3. Prcic, A., Begic, E., & Hiros, M. (2016). Actual contribution of free to total PSA ratio in prostate diseases differentiation. Medical Archives, 70(4), 288.
  4. Thompson, I. M., Pauler, D. K., Goodman, P. J., Tangen, C. M., Lucia, M. S., Parnes, H. L., … & Crowley, J. J. (2004). Prevalence of prostate cancer among men with a prostate-specific antigen level≤ 4.0 ng per milliliter. New England Journal of Medicine, 350(22), 2239-2246.
  5. Mottet, N., Bellmunt, J., Bolla, M., Briers, E., Cumberbatch, M. G., De Santis, M., … & Lam, T. B. (2017). EAU-ESTRO-SIOG guidelines on prostate cancer. Part 1: screening, diagnosis, and local treatment with curative intent. European urology, 71(4), 618-629.
  6. Ilic, D., Djulbegovic, M., Jung, J. H., Hwang, E. C., Zhou, Q., Cleves, A., … & Dahm, P. (2018). Prostate cancer screening with prostate-specific antigen (PSA) test: a systematic review and meta-analysis. bmj, 362, k3519.

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