Luteinizing Hormone-Releasing Hormone Analogues

The brain controls testosterone production by the testicles. Leuteinizing hormone-releasing hormone analogues are chemicals that stimulate the production of the luteinizing hormone, which tells the testicles to produce testosterone. Initially, when a man takes an LHRH analogue, there is an increased production of LH and of testosterone. This superstimulation tells the brain to stop producing LHRH and, subsequently, the testicles stop producing testosterone. It takes about 5 to 8 days for the LHRH analogues to drop the testosterone levels significantly. The increase in testosterone that sometimes occurs initially with LHRH analogues may affect patients with bone metastases, and there may be a worsening of their bone pain, which is called the flare reaction^[1]. Such men with metastatic disease will be given an antiandrogen before starting the LHRH analogue to prevent the flare phenomenon.

LHRH analogues are given as shots either monthly, every 3 months, every 4 months, every 6 months, or yearly. There are six forms of LHRH analogues: leuprolide acetate for intramuscular injection (Lupron Depot), triptorelin pamoate suspension for intramuscular injection (Trelstar Depot and Trelstar LA), leuprolide acetate for subcutaneous injection (Eligard), leuprolide acetate subcutaneous implant placement (Viadur), histrelin acetate for subcutaneous implant (Vantas), and goserelin acetate implant (Zoladex). They work in essentially the same way but differ in how they are given (Table 8). The advantage of this form of therapy is that it does not require removal of the testicles; however, it is expensive and requires more frequent visits to the doctor's office.

Intermittent hormone therapy is an alternative to standard hormone therapy. With intermittent hormone therapy you are treated for a period of time, usually until your PSA drops to a certain level, then the hormones are stopped until your PSA rises to a certain level. The idea of intermittent hormone therapy is that the prostate cancer cells that survive while you are on hormone therapy (hormone insensitive) become hormone sensitive again when they are exposed to androgens.

Table 8. Commonly Used Antiandrogens, LHRH Analogues and Antagonists

Abbreviations: mos, months; PO, orally; SQ^ subcutaneously; comb rx, combination treatment; IM, intramus'

Possible advantages of intermittent androgen suppression include preservation of androgen sensitivity of the tumor, possible prolonged survival, improved quality of life because of recovery of libido and potency and improved sense of well-being, decrease in treatment costs, increased sensitivity of the prostate cancer to chemotherapy, and the fact that it can be used to treat all stages of prostate cancer. Intermittent hormone therapy appears to affect bone mineral density loss at 6 years.

The long-term effects of intermittent hormone therapy are not well known. The duration of the hormone therapy, the best time to restart hormone therapy, how to tell whether the disease is progressing, and who is the ideal patient for intermittent hormone therapy are not well defined. One potential way to give intermittent androgen suppression therapy (androgen blockade) is shown in Table 9.

LHRH analogues often are used alone as primary, secondary, or neoadjuvant therapy. Over time, the PSA level may increase. When the PSA increases, your doctor may check your serum testosterone level to make sure that the LHRH analogue is dropping the testosterone level to almost undetectable levels. In some cases with use of the LHRH analogue on an every-3-to 4-month basis, the testosterone suppression may not be adequate, and switching to a more frequent dosing interval, such as an every 28-day formulation, may be more effective. When a man is receiving hormone therapy, the testosterone level should be < 20 ng/dL. When the PSA increases despite LHRH analogues, the LHRH analogues are continued, and another medication, an antiandrogen, is added. This combined therapy is called

Table 9. Intermittent Androgen Blockage

Ellsworth, P. 100 Questions and Answers About Prostate Cancer, 2e. Jones and Bartlett Publishers, LLC, 2009.

total androgen blockade and is often effective in treating the prostate cancer for 3 to 6 months.

Antiandrogens

Antiandrogens^[2] are receptor blockers; they prevent the attachment of the androgens, both those produced by the testicles and those produced by the adrenal glands, to the prostate cancer cells, thus preventing them from acting on these cells. Because these chemicals do not actually affect testosterone production, the testosterone level remains normal or may be slightly elevated if they are used alone. Thus, these medications do not affect libido or erectile function when used alone. However, antiandrogens are more commonly used in combination with LHRH analogues. One antiandrogen, bicalu-tamide (Casodex) is approved for use as a monotherapy in Europe but has not been approved by the FDA.

There are three commonly used antiandrogens: bicalutamide (Casodex), flutamide (Eulexin), and nilutamide (Nilandron) (Table 8). As with all medications, these have side effects, which are listed in Table 8. When antiandrogens are used in combination with LHRH analogues, this is called total androgen blockade^[3]. Total androgen blockade is used for individuals whose PSA increases significantly while they are taking LHRH analogues.

Newer Therapies

Aberelix is a GnRH antagonist. Unlike the LHRH agonists, the GnRH antagonist does not initially cause an increase in testosterone level. Instead, it works to decrease testosterone more quickly. Aberelix can cause serious and life-threatening allergic reactions and therefore it is no longer available for use in the treatment of prostate cancer. Patients who have been previously prescribed by doctors enrolled in a special program, the Plenaxis PLUS Program, can continue to receive Aberelix as long as they continue to do well with the medication.

Degarelix is an LHRH antagonist which has been demonstrated in clinical trials to rapidly decrease serum testosterone (within 3 days) and is not associated with the initial surge of testosterone and risk of flare that is seen with LHRH agonists. It has been recently approved by the FDA. The starting dose is 240 mg given as two subcutaneous injections of 120 mg, then maintenance doses of 80 mg as one subcutaneous injection every 28 days. Phase III studies have demonstrated that degarelix is at least as effective as leuprolide (Lupron Depot®) in sustaining castrate levels or lower of testosterone and had a statistically significant faster decrease in testosterone levels.

GnRH antagonist

A form of hormone therapy which works at the level of the brain to directly suppress the production of testosterone without initially raising the testosterone level.

Delacroix is an LHRH antagonist which has been demonstrated in clinical trials to rapidly decrease serum testosterone (within 3 days) and is not associated with the initial surge of testosterone and risk of flare that is seen with GnRH agonist.

• [1] A temporary increase in tumor growth and symptoms that is caused by the initial use of LHRH agonists. It is prevented by the use of an antiandrogen one week before LHRH agonist therapy begins.
• [2] Drugs that counteract the action of testosterone.
• [3] The total blockage of all male hormones (those produced by the testicles and the adrenals) using surgery and/or medications.