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The luteinizing hormone releasing hormone (LHRH)

Posted Sep 17 2008 1:55pm

Note: The terms “luteinizing hormone” (LH) and “gonadatropin” (Gn) are variously used by different authorities. Thus, LHRH and GnRH are also interchangeable terms in the medical literature. As far as The “New” Prostate Cancer InfoLink is aware, neither term is considered to be “absolutely correct.” We have chosen to use the terms LH and LHRH throughout this web site as a matter of consistency.

Introduction

The first luteinizing hormone-releasing hormone (LHRH) agonists were synthesized in the 1970s and leuprolide acetate became available for the treatment of prostate cancer in the 1980s. 

Today there are several LHRH agonists commonly used in treatment of prostate cancer. They include:

With the exceptions of the time for which each formulation can be used, and the ways in which they are administered, the clinical distinctions between these different formulations are relatively minor.

Other LHRH agonists are also available in certain parts of the world, but the products mentioned above dominate the global market for LHRH agonists used in the treatment of prostate cancer.

LHRH agonists are used in the following ways in the management of metastatic prostate cancer:

  • On their own for the long-term, continuous suppression of the male hormone testosterone
  • In combination with other drugs (such as nonsteroidal antiandrogens) for continous suppression of testosterone and other male hormones
  • On their own, in “bursts” of several months at a time, for “intermittant” suppression of tetosterone (so-called “intermittant hormone therapy or IHT)
  • In combination with other drugs (such as nonsteroidal antiandrogens), in “bursts” of several months at a time, for “intermittant” suppression of tetosterone

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, under normal circumstances, stimulates the production of testosterone in men.

All LHRH agonists are small synthetic proteins and 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, it has several effects:

  • First, it stimulates production of LH, which stimulates production of testosterone. This means that  for a couple of weeks the patient’s testosterone level will usually rise instead of falling. This increase in the patient’s testosterone level can briefly stimulate increased growth of prostate and prostate cancer cells (with associated symptoms, such as increased bone pain, if the patient already has metastases to the bone). This has become known as the “flare response.” This response is short-lived 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 to about 5 or 10 percent 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 manage the growth and spread of prostate cancer by largely shutting down certain normal hormonal functions in the male.

This method of controlling prostate cancer comes at a cost.

The Clinical Effectiveness of LHRH Agonists in Prostate Cancer

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.

Having said that, the vast majority of prostate cancer patient will respond relatively well to LHRH agonist therapy, and generally for considerable periods of time.

For various reasons discussed elsewhere on this web site, many men today start to receive LHRH agonist therapy long before they have any specific evidence of metatstatic prostate cancer, and it is not uncommon to come across men who have received hormone therapy either continuously or intermittently for 10 years or more. It is also true that some men may be able to stop hormone therapy entirely after a period of time, with a low and stable PSA. We do not know why this appears to be possible for some men and not for others.

In most cases, men with prostate cancer will (gradually) start to develop an increasing number of prostate cancer cells that are not responsive to hromone therapy, and there will come a point in time when their PSA starts to rise again regardless of LHRH and other forms of hormone therapy. These men have a form of the disease known as “hormone refractory” prostate cancer, which is a terminal stage of the disease.

As indicated above, for many men it may be a decade or more from the time that hormone therapy is started until a patient becomes hormone refractory. However, for some men, the progression from initiation of hormone therapy to hormone refractory status can be a great deal more rapid, occurring within 1-2 years from the start of hormone therapy. We have no real understanding at this time of why some men may progress so quickly, whereas others progress much more slowly.

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” mentioned above.

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 can be 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.
  • A significant number of men also seem to suffer from depression or depression-like symptoms as a consequence of LHRH agonist therapy.

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.

For full information on the possible adverse events associated with any drug, please see the full prescibing information for that specific product.

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