Prostate Problems: Genetic reasons and research on solutions

Prostate cancer is one of the most common cancers in men. In the US and EU, it is the second most common cancer diagnosis — and the second highest cause of cancer-related deaths in males. (Lung cancer is the most common cause of cancer deaths.)[ref] Currently, 1 in 8 men can expect to be diagnosed with prostate cancer in their lifetime, but the good news is that the 5-year survival rate is 99% when caught early.[ref]

Part of the susceptibility to prostate cancer and other benign prostate problems is genetic. This article explains the genetic variants that increase your risk of prostate problems. Importantly, some of the prostate risk genetic variants are related to environmental toxins that you can mitigate.

What causes prostate problems?

This article dives into all things prostate – from benign prostate hyperplasia (BPH) to prostate cancer. Before going any further, I want to reiterate that I’m simply presenting information from research studies. Please talk with your doctor for medical advice.

Prostate problems are common in older men and can include:

• prostatitis (inflammation of the prostate)
• benign prostate hyperplasia (enlarged prostate that is not malignant)
• prostate cancer

Prostate-specific antigen (PSA) levels are used to screen for prostate issues. High PSA levels can indicate prostatitis, BPH, or prostate cancer. The name prostate-specific is a bit of a misnomer since women also produce PSA at lower levels.

What does the prostate do?

The prostate is a gland in the male reproductive system that surrounds the urethra just below the bladder. It secretes a part of the fluid that becomes semen and protects sperm. Additionally, it acts as a muscle important in controlling urination. When the prostate is enlarged, it can push on the bladder and decrease urine flow through the urethra.

Oxidative stress at the heart of prostate cancer and BPH:

One of the most critical molecular pathways in the development of prostate cancer involves a complex interaction between oxidative stress, chronic inflammation, and androgen receptor (AR) driven signaling. Additionally, it has been suggested that oxidative stress is essential for the formation of the aggressive phenotype in addition to being fundamental to PC growth.

Oxidative stress is the state in a cell when reactive oxygen species (ROS) is higher than normal. ROS are molecules with free radicals derived from oxygen through redox reactions. Examples of reactive oxygen species include hydrogen peroxide, superoxide, and hydroxyl radicals. ROS at low levels has important signaling properties within a cell, but a higher levels, ROS is very detrimental.

Oxidative stress can cause vascular tissue damage, interfere with the way that proteins in cells are supposed to work, and cause damage to the nuclear DNA. Oxidative stress can also negatively impact stem cells and a cell’s ability to repair the damage.[ref]

What causes oxidative stress in the prostate?

Oxidative stress increases in aging as well as through exposure to toxicants and dietary choices.

Oxidative stress from diet:
For example, omega-6 fats are found in large quantities in our modern diet (corn oil, fried foods, mayo, and sauces, etc.). The peroxidation of these omega-6 fatty acids causes inflammation in the prostate, and higher levels of these peroxidation metabolites are found in men with BPH and high PSA levels.[ref] The modern diet has a lot higher intake of omega-6 fats than humans have eaten historically. It may be one possible explanation for the increase in prostate problems since the 1950s.[ref]

Prostate cells turn over rapidly and have fewer DNA repair enzymes, thus leaving them vulnerable to damage from oxidative stress. This damage then leads to the activation of inflammatory pathways.[ref]

Decreased antioxidants:
In men with BPH, research shows they have a decrease in antioxidant defenses. In other words, the excess of ROS in the prostate can’t be countered by the body’s built-in antioxidant defenses.[ref] This could be due to a lack of micronutrients in the diet or continuing exposure to a toxicant that causes oxidative stress.

Age is an important factor:
One reason that aging is associated with oxidative stress is an increase in cellular senescence. Senescent cells are at the end of their cellular life and unable to divide. This process is normal, and senescent cells are cleared out throughout life. But in older people, there is an increase in senescence above what can be easily cleared out. It is a problem because senescent cells give off inflammatory cytokines (which normally are the signal that causes the immune system to clear them out). An excess of senescent cells then leads to elevated inflammation, which is directly linked in research to the development of BPH.[ref]

cellular senescence = increased inflammation in the prostate = BPH

Toxins:
Exposure to toxicants also increases oxidative stress in the prostate. Here are just a few examples:

• Farmers exposed to high levels of pesticides are at a four-fold increased risk of prostate cancer.[ref]
• Dioxins are persistent organic pollutants that increase the risk of prostate cancer.[ref]
• Phthalates are chemicals found in artificial fragrances (think air fresheners, laundry detergents, shampoo) and plastics. Phthalates act as endocrine disruptors and are associated with oxidative stress in BPH and prostate cancer.[ref]
• Exposure to trace metals, such as cadmium, mercury, or nickel, is also associated with prostate diseases.[ref]
• BPA, an estrogen mimic found in plastics, is linked to enlarged prostate and prostate cancer risk.[ref][ref]

How do cells take care of oxidative stress?

Cells can respond to excess reactive oxygen species (ROS) with several built-in antioxidant defenses. Essentially, molecules that contain free oxygen are highly reactive. ROS isn’t completely bad and is utilized by cells in specific ways for cell signaling. However, the level of ROS is tightly controlled in cells. Excess reactive oxygen species (ROS), termed oxidative stress, can lead to cell damage, including DNA damage or cell death.

Cells have multiple ways of controlling the level of ROS, including endogenous antioxidants such as glutathione, superoxide dismutases (SOD), and catalase.

One way cells control oxidative stress is through the Nrf2 pathway. Activation of Nrf2 calls up antioxidant response genes, including the glutathione transferase enzyme (GSTs). As part of Phase II detoxification, GSTs are the enzymes responsible for causing the reaction between glutathione and other substances, such as toxicants, to make them water-soluble and able to easily be excreted.[ref]

I’ll come back to these oxidative stress enzymes in the genetics section…

Related article: Nrf2 Pathway: Increasing the body’s ability to get rid of toxins

What causes prostate cancer?

Essentially, cancer is caused by out-of-control cell growth. Mutations or breaks in cellular DNA in specific genes are the driving factors in cancerous cells. The mutations occur either in genes that promote cancer (oncogenes) or in genes that stop cell growth is what causes cancer cells to replicate. While mutations happen all the time during DNA replication, we have built-in DNA repair mechanisms that usually catch and correct the mutations. Excessive damage to DNA, such as from genotoxic substances or radiation, can result in cancer-causing mutations that replicate and result in tumors.[ref]

Commonly, mutations found in prostate cancer cells are in the TP53 (tumor protein p53) gene.[ref] TP53 is a tumor suppressor gene that keeps cells from dividing and growing uncontrolled. Mutations that prevent TP53 from working can lead to cancer.

Hormones, testosterone, and the prostate:

Let’s dig into how and why hormones impact the prostate.

Androgen hormones are the steroid hormones responsible for male characteristics (lower voice, facial hair, muscle mass, Adam’s apple). Androgens include testosterone, dihydrotestosterone (DHT), Dehydroepiandrosterone (DHEA), and Dehydroepiandrosterone sulfate (DHEA-S). Women also produce these hormones, just at lower levels than men do. Likewise, men produce estrogen, just at much lower levels than women.

Prostate cancer is considered ‘androgen-dependent’ cancer, meaning that initial cancer cell proliferation and survival depend on the androgen hormones.

Estrogens, on the other hand, are protective against prostate cancer due to their anti-androgenic effects. Women produce estrogen mainly in the ovaries, but for men, estrogen is created through the conversion of androgen precursors by an enzyme called aromatase. The aromatase enzyme is encoded by the CYP19A1 gene (coming back to that in the genetics section), and aromatase is produced in the gonads and prostate.[ref]

Hormones in Cancer vs. BPH: One difference between benign prostate hyperplasia (BPH) and prostate cancer is the production of aromatase (and thus estrogen) in the prostate cells. Researchers found that in BPH cells, aromatase was produced, creating estrogens from testosterone. But in the prostate cancer biopsies, very little aromatase was present, thus making no detectable estrogens.[ref]

One thing to note here is that circulating levels of androgens and estrogens don’t necessarily show what is happening in the prostate cells. Researchers are finding that the tissue-specific levels of androgens and aromatase in the prostate drive the difference between BPH and prostate cancer.[ref]

Lifehacks:

Everything presented here is for informational purposes only. Talk with your doctor, of course, if you have any medical questions or questions about interactions with supplements. Prostate cancer, or BPH, isn’t a DIY healthcare situation.

The rest of this article is for Genetic Lifehacks members only.  Consider joining today to see the rest of this article.

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