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Clinical Brief


According to the National Cancer Institute’s Surveillance, Epidemiology and End Results Program, from 2009-2013,

the number of new cases of prostate cancer was 129.4 and the number of deaths was 20.7 per 100,000. In 2013, there were over 2.8 million men in the US who were living with prostate cancer and it appears that the numbers are increasing every year.

Most men know they have a prostate gland but I would guess that if you asked ten of them, you would probably get a handful of “uhhhh’s” and a few more blank looks. So let’s take a quick look at prostate function and then talk about how the DUTCHTEST helps reveal risk for prostate cancer and other problems.

The prostate is a walnut-sized gland that located below the bladder that secretes fluid into the urethra that nourishes and protects sperm. It is located below the bladder and above the penis just in front of the rectum. When the prostate is working well, it goes largely unnoticed, but when problems arise, urination and sexual function can both be compromised.

The three main problems associated with thyroid gland are:

  1. Prostatitis – a condition in which the prostate is inflamed from either a chronic bacterial infection or chronic irritation that causes discomfort;
  2. BPH or Benign Prostatic Hypertrophy – a condition that occurs in older males where the prostate becomes enlarged due to cell proliferation and causes narrowing of the urethra and resulting difficulty with urination;
  3. Prostate cancer – a condition in which normal prostate cells grow unchecked and spread to local nodes and distant organs if it is not diagnosed in time.

Screening for these conditions includes a thorough history, physical exams, diagnostic imaging,and laboratory testing. The Standard of Care for laboratory tests for risk of prostate cancer are PSA or prostate specific antigen tests. But in the last several years, many organizations have questioned the utility of routine screening because the screening may impart increased risk that may lead to unnecessary and damaging procedures to the prostate. Fortunately, there are new tests related to PSA that are being developed and analyzed and will potentially improve outcomes and decrease risk. But did you know that information from the DUTCHTEST can reveal an increased risk for developing problems with the prostate?  Let’s briefly introduce that information so we can help you understand how it might relate to your condition.

Increased Aromatization – Aromatization is a process in which the androgens androstenedione and testosterone are converted to estrogens throughout the body by an enzyme called aromatase. It is a normal process that is essential for sexual development and healthy sex hormone metabolism. In men, when aromatase is overactive, androgens are converted to E1 and E2 and you end up with excess estrogens. Abnormal aromatase activity has been shown to play a major role in breast and prostate tumorigenesis.4

While aromatase itself is not directly measured on the DUTCHTEST, the amounts and ratios of testosterone and estrogens can be very helpful in determining a treatment plan to reduce the risk for prostate cancer.

Low 2-OH-E1/4-OH-E1 ratio – On the DUTCHTEST, you can see both absolute numbers and ratios of some of the important estrone metabolites. The optimal ratios of the E1 metabolites are listed on our test in the pie chart under “Normal Estrogen Metabolism” and the patient results are shown in the pie chart at the bottom for comparison. Studies have shown that a low 2-OHE1/4-OHE1 ratio is associated with an increased risk for breast cancer, but there are also connections with prostate cancer that studies have noted.1,2

Low 2-methoxy-E1 – 2-methoxy-E1 is an antiproliferative estrogen metabolite of 2-OH-E1 and the end result of phase II detoxification of estrone. The conversion of 2-OH-E1 to 2-methoxy-E1 is carried out by an enzyme called COMT or Catechol-O-methyltransferase. Defects in the COMT enzyme result in decreased methylation of 2-OH-E1 and low methylation activity in the DUTCHTEST.  Low methylation activity and poor metabolism of 2-methoxy-E1 through this step is also associated with an increased risk for prostate tumor growth.5

Elevated 5a-DHT and 5a-reductase (5AR) activity -Until recently we believed that elevated systemic 5aDHT and increased 5a-reductase activity were associated with an increased risk for BPH and prostate cancer. Research in the last decade have shown that higher systemic levels of DHT are not associated with increased risk for prostate cancer or BPH.6 In addition, BPH and prostate cancer appear to be more closely associated with levels of 5AR types 1 and 2 in local tissue and so far we are unable to make any reliable correlations between local prostate levels of DHT or 5AR and systemic levels of DHT. 6,7 With that said it appears that the use of compounds that inhibit 5AR are associated with an increased risk for aggressive prostate cancers.8

So how does this affect the interpretation of the Dutchtest?  Well, it means that if you have an elevated 5aDHT or 5AR activity in male patients with prostate issues don’t assume that decreasing those numbers will fix the problem. With that said, you can still address these elevations with compounds that inhibit 5AR because both prostatitis and BPH respond to those therapies. In other words, treat the symptoms, not the labs.

Low melatonin

Melatonin is secreted from the pineal gland in response to low levels of light over a period of time. Levels increase at night as the light decreases and cortisol levels drop at the same time allowing us to go to sleep. Research has also shown that low melatonin is associated with an increased risk of several cancers including prostate cancer in men. One study testing a urinary metabolite showed a four fold increase in risk for prostate cancer in men with melatonin levels below the median when compared to those with levels above the median.9 Physicians who use the Dutchtest have found the melatonin analyte on the adrenal profile to be a useful tool in screening their patients for potential increased risk for cancers and other conditions.

Flat free cortisol line without the cortisol awakening response

The phrase, “flatline cortisol” is used to describe a test result that shows little to no cortisol production throughout the day. Here at PA, we screen every test result for a flatline cortisol and if we see one, which doesn’t happen very often, we flag it because it often means the person who submitted the sample is taking a steroid hormone prescription. Steroid hormones taken in any form in the right amounts will suppress adrenal output of cortisol and many times result in a flatline cortisol. There are instances where the HPA-axis is not functioning or where the adrenal glands are no longer able to produce cortisol. Many use the term adrenal failure or Addison’s Disease. So what’s the tie to prostate cancer? On the Dutchtest, we show the diurnal free cortisol pattern with a waking, morning, afternoon, and evening sample. If a patient shows that pattern and they are not using a steroid of any kind, they are likely unable to get out of bed in the morning. A flatline cortisol imparts an increased risk in mortality and when you observe that in a person who already has prostate cancer, the risk goes up.  So this is something you want to keep an eye open for.

References:

1, Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention.Cavalieri E1, Chakravarti D, Guttenplan J, Hart E, Ingle J, Jankowiak R, Muti P, Rogan E, Russo J, Santen R, Sutter T. Biochim Biophys Acta. 2006 Aug;1766(1):63-78. Epub 2006 Apr 19.

  1. Depurinating estrogen-DNA adducts, generators of cancer initiation: their minimization leads to cancer prevention.Cavalieri EL1,2, Rogan EG3,4. Clin Transl Med. 2016 Mar;5(1):12. doi: 10.1186/s40169-016-0088-3. Epub 2016 Mar 15.
  1. In touch with your feminine side: how oestrogen metabolism impacts prostate cancer. Rahman HP1, Hofland J2, Foster PA3.Endocr Relat Cancer. 2016 Jun;23(6):R249-66. doi: 10.1530/ERC-16-0118. Epub 2016 May 18.
  1. Aromatase and regulating the estrogen:androgen ratio in the prostate gland. Ellem SJ & Risbridger GP.  Journal of Steroid Biochemistry and Molecular Biology 118 246–251. 2010 (doi:10.1016/j.jsbmb.2009.10.015)

5. Polymorphisms of Estrogen Metabolism-Related Genes and Prostate Cancer Risk in Two Populations of African Ancestry. Brureau L1,2,3, Moningo D4, Emeville E1,5, Ferdinand S3,6, Punga A4, Lufuma S4, Blanchet P1,2,3, Romana M3,6, Multigner L1,5. PLoS One. 2016 Apr 13;11(4):e0153609. doi: 10.1371/journal.pone.0153609. eCollection 2016.

  1. Long-Term Effects of Dihydrotestosterone Treatment on Prostate Growth in Healthy, Middle-Aged Men Without Prostate Disease: A Randomized, Placebo-Controlled Trial”. Amanda Idan, BSc, MHSc; Kaye A. Griffiths, AMS,
  1. Dihydrotestosterone and the concept of 5alpha-reductase inhibition in human benign prostatic hyperplasia.

Bartsch G1, Rittmaster RS, Klocker H. World J Urol. 2002 Apr;19(6):413-25

  1. Questions and Answers: 5-alpha reductase inhibitors (5-ARIs) may increase the risk of a more serious form of prostate cancer. http://www.fda.gov/Drugs/DrugSafety/ucm258358.htm
  1. Urinary melatonin levels, sleep disruption, and risk of prostate cancer in elderly men. Sigurdardottir LG1, Markt SC2, Rider JR3, Haneuse S4, Fall K5, Schernhammer ES3, Tamimi RM3, Flynn-Evans E6, Batista JL3, Launer L7, Harris T7,Aspelund T8, Stampfer MJ3, Gudnason V9, Czeisler CA6, Lockley SW6, Valdimarsdottir UA10, Mucci LA11 Eur Urol. 2015 Feb;67(2):191-4. doi: 10.1016/j.eururo.2014.07.008. Epub 2014 Aug 5.
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