Hormone Therapy, Testosterone and Cancer of the Prostate
It is possible to interfere with the body's production of testosterone using medications that disrupt the process. The signal to produce testosterone originates in an area of the brain called the hypothalamus. At regular intervals, the hypothalamus secretes luteinizing hormone-releasing hormone (LHRH), which stimulates the pituitary gland to produce luteinizing hormone and follicle-stimulating hormone. Luteinizing hormone signals specialized cells in the testicles (Leydig cells) to secrete testosterone into the bloodstream; follicle-stimulating hormone stimulates sperm production.
When testosterone reaches the prostate, it is converted to dihydrotestosterone (DHT)a more potent form of testosteroneby the enzyme 5-alpha-reductase. The drugs used for medical castration inhibit this sequence of events at various stages.
Estrogen preparations. A synthetic form of the female hormone estrogen can lower testosterone levels to the castrate range by blocking the release of luteinizing hormone from the pituitary gland. Daily doses of synthetic estrogen (Premarin) are as effective as surgical castration, although the hormone takes longer to work, with testosterone levels falling over a two-week period.
The most significant side effect of synthetic estrogen is an increased risk of cardiovascular events. These include
- heart attack
- blood clots in the legs or lungs
- inflammation of the veins (phlebitis)
- swelling (edema) of the legs
Because of these risks, men with a history of heart disease or thrombophlebitis (vein inflammation due to a blood clot) should not use estrogen therapy. In other men, these side effects can be minimized by using low doses of estrogen.
Taking an aspirin every other day also helps to lower the risk of heart attack and blood clots. Edema can be treated with diuretics (drugs that promote water loss through the urine). Other side effects include nausea and vomiting, breast enlargement, and ED.
With the approval of LHRH agonists, estrogens are no longer widely used. However, there is renewed interest in diethylstilbestrol (DES), a form of estrogen used in the 1960s for advanced prostate cancer. Researchers are also investigating the potential of an estrogen patch to lower testosterone levels without some of the side effects associated with other types of hormone therapy.
LHRH agonists. Also known as gonadotropin-releasing hormone (GnRH) agonists, LHRH agonists are synthetic agents with chemical structures almost identical to natural LHRH. Initially, they behave like LHRH and stimulate the release of luteinizing hormone from the pituitary gland, which causes an increase in testosterone production. But after a short period, they block the release of luteinizing hormone and reduce testosterone secretion from the testicles. The result is testosterone levels similar to those that occur after surgical castration or with estrogen. LHRH agonists are equivalent to surgical castration and estrogen in their ability to delay progression of cancer and prolong survival.
Commonly used LHRH agonists are goserelin (Zoladex), leuprolide (Eligard, Lupron), and triptorelin (Trelstar). LHRH agonists are traditionally given as injections monthly or up to several months depending on the dosage. Another option is an implanted drug delivery system (Viadur) that releases leuprolide continuously for one year.
The initial increase in testosterone with LHRH agonists may be severe enough to increase bone pain in men with prostate cancer that has spread to the bones. This can be prevented with an anti-androgen until testosterone levels fall to the castrate range about two to three weeks later. Other side effects of the LHRH agonists include
- loss of libido
- hot flashes
- weight gain
- decreased bone and muscle mass
The bisphosphonates pamidronate (Aredia) and zoledronic acid (Zometa) have been shown to prevent bone loss associated with LHRH agonists, and zoledronic acid may actually boost bone density. Some men experience irritation at the injection sites. LHRH agonists are less likely than estrogen to cause breast enlargement, nausea, vomiting, or cardiovascular problems.
LHRH antagonists. LHRH antagonists, also known as GnRH receptor antagonists, work by targeting and blocking luteinizing hormone receptors in the pituitary. This causes the testicles to decrease testosterone production.
The newest LHRH antagonist is degarelix (Firmagon), which was approved by the FDA in 2008 for use in men with advanced prostate cancer. The medication has been shown to begin working more quickly than the LHRH agonist leuprolide and to be equally effective at reducing testosterone levels. Another advantage of Firmagon over LHRH agonists is that it doesn't appear to cause a temporary surge in testosterone levels at the start of treatment.
The most common side effects are pain and swelling at the injection site, hot flashes, weight gain, and signs of liver abnormalities on lab tests. These abnormalities generally improve when the medication is stopped.
Anti-androgens. To stimulate prostate cells (both cancerous and noncancerous), testosterone must first bind to specific androgen receptors ("docking sites") on the cells. Drugs called anti-androgens can occupy these receptors, preventing testosterone from binding to them and stimulating the cells.
Because anti-androgens do not block testosterone productiona characteristic that sets them apart from the other types of hormone therapyerectile function may be preserved in some patients. Three anti-androgens are approved by the FDA to treat advanced prostate cancer: bicalutamide (Casodex), flutamide (available only as a generic), and nilutamide (Nilandron).
When used alone, anti-androgens may not be as effective as medical or surgical castration. In addition, anti-androgens can cause hot flashes, breast enlargement, diarrhea, and, in rare instances, liver damage. Men taking an anti-androgen must have their liver function tested a few months after starting treatment. Signs of liver problems include nausea, vomiting, fatigue, and jaundice. Nilandron may slow the eyes' ability to adapt to darkness. This side effect lasts about four to six weeks.
In 40 to 75 percent of men taking an anti-androgen, PSA levels increase, indicating disease progression. If the medication is discontinued, PSA levels fall. Why this occurs is not clear. Possibly a mutation in the cancer cells causes them to respond to anti-androgen stimulation.
Total androgen blockade. The adrenal glands also produce small amounts of androgens, including testosterone. In an attempt to eliminate all androgen stimulation of cancer cells, some doctors use anti-androgens along with surgical or medical castration. The combination of an anti-androgen (to block the effect of adrenal androgens) and castration (which halts testosterone production in the testicles) is referred to as total androgen blockade or total androgen suppression.
Despite promising preliminary findings, numerous studies have failed to demonstrate that total androgen blockade prolongs life any better than blocking testicular androgens alone. For example, a recent analysis of numerous studies found no difference in survival between men treated with total androgen blockade and those who underwent surgical castration or took LHRH agonists alone.
Similarly, the largest clinical trial to date of total androgen blockade found no survival advantage among men treated with total androgen blockade (orchiectomy plus flutamide) compared with those treated with orchiectomy alone.
Intermittent androgen suppression. In this approach, androgen is blocked chemically (using an LHRH agonist or gonadotropin- releasing hormone antagonist alone or in combination with an anti-androgen) until PSA levels fall. Treatment is then discontinued until PSA levels begin to climb again. The rationale for this approach is the belief that hormone therapy encourages the growth of androgen-insensitive cancer cells (the cells that allow the tumor to continue to grow despite hormone therapy).
Some doctors believe that cycling therapy on and off may delay the emergence of these deadly cells. This practice, known as intermittent androgen suppression, is associated with fewer side effects because the therapy is discontinued for periods of time. More studies are needed to determine whether intermittent androgen suppression is as effective at slowing disease progression as continuous androgen suppression. Nonetheless, many oncologists routinely use this approach.
Other options. Testosterone levels can be reduced within 24 hours with the drug ketoconazole (Nizoral). The drug is approved by the FDA to treat fungal infections, but it also inhibits the production of adrenal and testicular androgens. Nizoral is used only when lowering androgens rapidly might be beneficial (to alleviate pain, for example). In addition, it is used only in the short term, because it raises luteinizing hormone levels, which can cause rising testosterone levels and lead to disease progression. Nizoral can also cause liver problems.