How Does Hormone Therapy for Prostate Cancer Work?

Testosterone is a wonderful thing that makes men MEN. In adult males, roughly 10% of testosterone is converted to dihydrotestosterone (DHT). Both testosterone and DHT are androgens (hormones) produced by the testes and adrenal gland. They circulate through the body, shaping male sexual development and adult male sexual function. But they would be ineffective without small proteins called androgen receptors (ARs) that put these hormones to use at the cellular level.

Androgen receptors in prostate cells

Each cell in our body has an outer membrane that holds the cell’s contents. When circulating androgens come into contact with a prostate cell, they cross through the membrane into the cell where they bind with ARs. Once it is bound with an androgen, it is activated to enter the cell’s nucleus that contains your DNA. The bound AR now binds with DNA. DNA is like a musical score for a symphony; the printed notes on paper don’t produce music until a conductor directs instruments to play their notes when it’s their turn, bringing the music to life. When AR binds with DNA, it behaves similar to a conductor.

Like a maestro directing violins, brass, reeds, etc. to play their notes, the AR bound to DNA can direct the expression of genes. Gene expression means “switching on” the instructions it contains, thereby influencing the behavior of that cell, e.g. to duplicate itself. Thus, both androgens and their ARs are essential for the growth and reproduction of prostate gland cells. To recap the steps:

  • Androgens circulate through the body and can freely enter cells such as prostate cells.
  • Like a key in a lock, testosterone or DHT bind to an AR.
  • The bound AR can now enter the cell’s nucleus where, in turn, it binds with DNA.
  • The bound AR then determines which genes can be expressed and which can’t.
  • The cumulative effect of expressed genes determines the cell’s identity and behavior.

Androgen receptors and prostate cancer

Just as healthy prostate cells depend on androgens and the action of their ARs, so do prostate cancer cells. To extend the image of a conductor and orchestra, if something suddenly caused the conductor to ignore other instruments except for the violins, directing them to play all the notes that weren’t even written for them while waving his baton wildly, the symphony would become chaotic.

Though no one yet knows exactly what starts the chain reaction of rogue prostate cancer (PCa) cells, we know that they “hijack” and exploit healthy cell processes. PCa cells appear able to “feed on” androgens and ramp up excessive amounts of AR gene expression so they can multiply.[i] Cellular chaos is the result. Therefore, hormone therapy for PCa is all about depriving PCa of androgens and their ARs. This is why it is also called Androgen Deprivation Therapy (ADT).

Depriving prostate cancer of androgens and the action of ARs

How do you deprive a man of his male hormones? In 1941, Charles Huggins published a paper showing that for patients with painful metastatic PCa, lowering their testosterone levels either by castration (surgical removal of testes) or injecting female hormones (estrogens) brought relief. It was not a cure nor did it work equally well for everyone, but on average, suffering was reduced and life was extended.  However, androgens were not completely removed because the adrenal gland and other cells still produced small amounts. While many PCa cells appeared to die off without androgens, remaining PCa cells seemed to “figure out” how to thrive with even very small amounts of the hormones, especially DHT which is particularly powerful when it binds with ARs.

Today’s pharmaceuticals

Over the next 6 decades, researchers developed medications to accomplish ADT without administering estrogens or performing surgical castration. Today, there are two classes of drugs: those that reduce testosterone levels, and those that block them from binding with ARs.

Drugs that lower androgen levels are called luteinizing hormone-releasing hormone (LHRH) agonists. They are administered as injections or implants under the skin, and cause the testes to stop producing androgens. The most common trade names include Lupron, Eligard, and Zoladex. However, other cells in the body, including PCa cells, can still make androgens in very small amounts but they need an enzyme called CYP17 to do so. Another drug called Zytiga blocks this enzyme and can be given in combination with LHRH agonists.

Drugs that block androgens from binding with ARs are called anti-androgens. They are designed to bind with ARs so that androgens can’t do so, thus blocking the ability of ARs to influence gene expression in PCa cells. Anti-androgens can be used alone but more commonly they are added to LHRH agonist therapy (combined hormone blockade). The most common trade names include Casodex, Eulexin, and Nilandron.

There is also a new type of drug usually used when PCa “outsmarts” ADT (castration-resistant prostate cancer or CRPC). These drugs (trade names Xtandi and Erleada) block the AR signals that trigger gene expression, making it impossible for the cell to reproduce itself and thus slowing PCa growth and spread.

Hormone therapy side effects

Because ADT shuts down androgen production and the AR effect on gene expression, male characteristics are affected. Men on ADT may experience loss of sexual desire and function, breast tenderness and enlargement, loss of muscle tone, loss of bone density, shrinking of penis and testicles, hot flashes, mood swings, depression, weight gain, fatigue, and mental fogginess. Some studies have linked ADT with other systemic problems such as cardiovascular disease, high blood pressure, and diabetes, but the jury is still out on these.

There is no doubt that under a doctor’s supervision, ADT extends life and reduces the severity of PCa metastasis. Some protocols have fewer sexual side effects than others. Talk with your doctor if you have questions or concerns about hormone therapy for prostate cancer.

NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.

[i] Hoang DT, Iczkowski KA, Kilari D, See W, Nevalainen MT. Androgen receptor-dependent and -independent mechanisms driving prostate cancer progression: Opportunities for therapeutic targeting from multiple angles. Oncotarget. 2017 Jan 10; 8(2): 3724–3745.

 

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