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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