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The Use of LHRH Agonists in Treatment of Advanced Disease

Last Revised January 12, 1996
[developments since this was written may change the information]

Introduction | What are LHRH agonists, and how do they work? | The clinical effectiveness of LHRH agonists in prostate cancer | The side effects of LHRH agonist therapy


Introduction

The luteinizing hormone-releasing hormone (LHRH) agonists were synthesized in the 1970s and first became available for the treatment of prostate cancer in the 1980s. Their use has initiated a revolution in the treatment of prostate cancer.

Two LHRH agonists are commonly used in treatment of prostate cancer: leuprolide acetate (Lupron/TAP Pharmaceuticals) and goserelin acetate (Zoladex/Zeneca Pharmaceuticals). Other LHRH agonists are also available and used outside the US (e.g., buserelin acetate and tripterelin).

In the past decade, the use of LHRH agonist therapy has almost totally eclipsed the use of DES and other estrogens in the treatment of advanced prostate cancer for the very simple reason that these products are safer that estrogens and are not associated with the cardiovascular risk factors which have been observed with estrogen therapy.

What are LHRH agonists, and how do they work?

LHRH agonists are synthetic analogs of the normal human hormone luteinizing hormone-releasing hormone, which is produced in the human hypothalamus and stimulates the production of a second hormone known as luteinizing hormone (LH). It is luteinizing hormone which subsequently stimulates the production of testosterone in men.

All LHRH agonists are small synthetic proteins which are structurally similar to normal human LHRH. However, they are much more powerful than the normal form. When a man with prostate cancer is first given an LHRH agonist injection, it has several effects:

  • First, it stimulates production of luteinizing hormone, which stimulates production of testosterone, which means that for a couple of weeks the patient's testosterone level will usually rise instead of falling. The increase in the patient's testosterone level can stimulate briefly increased growth of prostate and prostate cancer cells, with such associated symptoms as increased bone pain, if the patient already has metastases to the bone. This has become known as the "flare response." It should be emphasized that this response is transient in most patients, lasting for perhaps 7-10 days.

  • Second, because the patient now has elevated levels of an LHRH agonist, the body stops producing any new normal LHRH. As a consequence, there is no further production or either LH or testosterone. With no new testosterone being produced, the level of testosterone in the body rapidly drops by about 90 or 95% of its normal level. This very low level of testosterone is often known as "castrate level" because it is equivalent to the testosterone level of a man who has been surgically castrated by an orchiectomy.

  • Third, because the testosterone level has dropped to castrate level, growth of prostate cells and prostate cancer cells is slowed to very low levels because there is very little testosterone to stimulate growth.

Thus injection of LHRH agonists can be used to control the growth and spread of prostate cancer by largely shutting down the certain normal hormonal functions in the male. Of course, this method of controlling prostate cancer comes at a cost.

The clinical effectiveness of LHRH agonists in prostate cancer

The clinical effectiveness of LHRH agonists in the treatment of prostate cancer was first demonstrated in the US in 1984 in a major clinical trial comparing the clinical effect of a daily injection of the LHRH agonist leuprolide acetate to the effectiveness of a daily oral dose of 3 mg of DES in patients with stage D2 prostate cancer. This trial clearly demonstrated that leuprolide acetate was just as effective as 3 mg of DES but that leuprolide acetate showed none of the potentially severe cardiovascular risks associated with DES. Several later studies conducted in other countries and using other LHRH agonists have now confirmed this original study.

Of course LHRH agonists do not work in every patient with advanced prostate cancer. Some patients just do not respond sufficiently to treatment with LHRH agonists because their disease has already progressed too far. Others are among the unfortunate minority of patients who are unable to tolerate LHRH agonist therapy because they suffer severe side effects to these drugs.

The side effects of LHRH agonist therapy

We have already seen one of the immediate side effects of LHRH agonist therapy, which is the initial "flare reaction". This frequently results when the patient first starts to receive an LHRH agonist. The long-term clinical impact of this "flare" is still not fully understood: it may or may not be clinically significant. However, in the patient who already has symptoms of bone pain because of metastases to the skeleton, it is obviously important to control this flare as much as possible in order to prevent any additional pain. Such control of the flare reaction is commonly carried out by simultaneous short-term use of nonsteroidal antiandrogens, which can prevent the worst effects of a short-term increase in testosterone levels. (Note that it is commonplace for the antiandrogen therapy to be initiated shortly before the LHRH agonist therapy in order to maximize the likelihood that any flare reaction will be controlled.)

The major long-term side effects of LHRH agonists in the treatment of prostate cancer are as follows:

  • Impotence is observed in almost every patient while he is being treated with an LHRH agonist. Impotence occurs because the normal testosterone levels have been reduced to castrate levels.

  • Hot flashes, similar to those which occur in women during menopause, are common and can often be more pronounced than those observed in patients who are treated by surgical orchiectomy. A variety of methods are still being investigated in order to provide patients with methods to alleviate these hot flashes.

  • Gynecomastia or nipple tenderness in which there is mild swelling or at least tenderness of the man's breasts.

Less common but regularly observed side effects of LHRH agonist therapy can also include sweating, headaches, nausea and vomiting, weight gain, and changes in the texture of the hair and the skin. It should be noted that some unfortunate patients can have very bad side effect problems with almost any pharmaceutical, however safe it is in most people. Because so many patients have now received leuprolide acetate (Lupron/TAP Pharmaceuticals), there is even a Web site specifically directed to patients with severe reactions to this LHRH agonist and their problems. However, it should be recognized that patients with these severe problems are exceptions to the norm.


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The content in this section of the Phoenix 5 site was originally developed by CoMed Communications (a Vox Medica company) as part of The Prostate Cancer InfoLink. It is reproduced here with the permission of Vox Medica.

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