Approximately one third of men with prostate cancer will eventually need androgen deprivation therapy. While this treatment was first used for advanced, metastatic prostate cancer, androgen deprivation therapy is increasingly used for other indications as well. Many patients undergoing radiation therapy for aggressive prostate cancer are treated concurrently with androgen deprivation therapy to maximize treatment outcomes. Men with PSA recurrence after prostatectomy are also placed on this therapy. Despite the frequency with which androgen deprivation therapy is used, many men undergoing the treatment don’t know how it works. In this post, I will introduce androgen deprivation therapy. Specifically, I will focus on the first line androgen deprivation therapy and how it works.
The Food of Prostate Cancer
One of the most important discoveries related to prostate cancer was that androgens serve as the fuel or food of prostate cells and prostate cancer cells. Androgens are basically male hormones. They are the compounds, circulating in the bloodstream, which give men their masculine features. The most famous androgen, testosterone, is mainly produced in the testes. Other, less potent androgens are also produced in the adrenal glands. Once produced, testosterone and the adrenal androgens are secreted into the bloodstream and travel to the prostate.
Testosterone binds to a target on prostate cells called the androgen receptor. By binding the androgen receptor, testosterone initiates a cascade of events that stimulates further growth and multiplication of the prostate cells. The same occurs with prostate cancer cells which, fueled by testosterone, multiply and spread to distant sites in the body.
Starving the Beast
The understanding that prostate cancer feeds on testosterone was perhaps the fundamental discovery in the battle against the disease. With this understanding, the next obvious step was to try to prevent prostate cancer cells from obtaining their fuel. The most direct way of ridding the body of testosterone is to get rid of the source: the testicles. As a result, the first form of androgen deprivation therapy was simple surgical castration. By surgically removing the testicles, doctors were able to dramatically and rapidly decrease the level of circulating testosterone and, in turn, significantly slow down the growth of advanced prostate cancer. Of course, surgical castration has its downsides. Most men are psychologically impacted by having their testicles removed and would rather avoid surgery. As a result, the search began for a chemical means to decrease the amount of testosterone in the body.
Chemical Castration
A turning point in the treatment of prostate cancer came with the discovery that the production of testosterone in the testicles is not constant or automatic Rather, it is regulated. Studies demonstrated that the presence of testosterone or estrogen (the female equivalent of testosterone) in the bloodstream have a negative effect on the production of testosterone by the testicles. In other words, the body regulates the amount of sex hormones in the blood stream by a process of negative feedback: large amounts of circulating sex hormones actually inhibit the testicles from producing more testosterone. Negative feedback is a useful regulatory tool that the body uses to make sure that too much of given compound is not produced or present at a given time.
The discovery of negative feedback led to the use of an estrogen-like compound called DES in treating advanced prostate cancer. Scientists reasoned that the presence of this ingested estrogen analog in the bloodstream could provide the negative feedback to the testicles needed to stop testosterone production. As a result, they reasoned, prostate cancer would be starved of its vital fuel. Turns out, they were right. The use of DES worked incredibly well in reducing the growth and extent of prostate cancer. However, it was soon discovered that men treated with DES suffered from heart attacks and other blood clots. As a result, DES was no longer offered for men with advanced prostate cancer.
The real breakthrough in androgen deprivation therapy came in the late 1970s when the actual mechanism behind the negative feedback regulation of testosterone production was revealed. At that time, it was demonstrated that the negative feedback which regulates testosterone production by the testicles is actually carried out by hormones produced in the brain. A part of the brain called the hypothalamus produces a compound called gonadotropin releasing hormone(GNRH) which stimulates another part of the brain called the pituitary gland to produce a hormone called leutinizing hormone(LH). LH travels from the brain through the blood stream and into the testicles to stimulate the production of testosterone. High levels of testosterone and/or estrogen circulate through the bloodstream to the brain to provide the negative feedback. This negative feedback allowed DES (a compound very similar to estrogen) to successfully decrease testosterone production and limit the growth of prostate cancer.
Stemming from this discovery was the further understanding that the hypothalamus usually emits GNRH in spurts rather than in a continuous fashion. As long as this hormone is released in this fashion, the pituitary gland will continue to produce LH. In turn, the LH will then stimulate testosterone production by the testicles. However, researchers found that if the GNRH is secreted continuously it would actually decrease LHRH by the pituitary which would then decrease the production of testosterone by the testicles. With this discovery, modern androgen deprivation was born in the form of GNRH agonists like Leuprolide and Goserilin. These monumental drugs, used in mainstream androgen deprivation protocols today, work by maintaining a steady, continuous flow of GNRH which serves to shut down production of LH by the pituitary and, subsequently, stops the production of testosterone by the testicles.
Several years later, this discovery of the pathway and regulation mechanisms of testosterone production led to the development of another class of drugs used in androgen deprivation. Rather than relying on GNRH analogs that shut down the production of LHRH in the pituitary, researchers developed a compound that inactivates GNRH altogether. These GNRH antagonists, like Abarelix and Degarelix, have some important advantages over GNRH agonist drugs. However, due to cost issues and some important side effects, these drugs have not reached the same level of mainstream use as GNRH agonists except for certain specific indications. I will further explore this issue in a future post.
Take Home Message
Modern androgen deprivation therapy has evolved greatly over time. From surgical castration to GNRH agonists and antagonists, the treatment of advanced prostate cancer has become more and more refined as discoveries have shed greater light on how the food of prostate cancer is created and regulated. Understanding this background can help men undergoing androgen deprivation therapy have a better grasp of the rationale behind the often complex twists and turns experienced during their battle against advanced prostate cancer. In future posts, I will build upon this background to explain some limitations and pitfalls of androgen deprivation therapy as well as to describe what happens when such first-line therapy fails.
