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GnRH Agonists: Treatment of Advanced Prostate Cancer

Indications for GnRH Agonists

GnRH agonists are the therapeutic option in advanced prostate cancer in the following situations, please see section treatment of metastatic prostate cancer for details:

• Hormonal treatment of metastatic prostate cancer as an alternative to surgical castration.
• GnRH agonists are prescribed either alone or in combination with flutamide or bicalutamide for maximum androgen blockade.
• Conservative treatment of locally advanced prostate cancer with lower urinary tract symptoms (LUTS).
• Neoadjuvant treatment before brachytherapy for prostate cancer to shrink large prostate glands.

Mechanism of Action of Buserelin, Goserelin, Histrelin, Leuprorelin and Triptorelin

GnRH Agonists bind with a long half-life to the GnRH receptor. Initially, there is an increase in FSH and LH secretion (so-called "flare effect"). GnRH agonists (synonym: LHRH agonist) prevent the pulsatile stimulation of the LHRH receptor due to a longer half-life and receptor binding time, this leads to downregulation of receptors and to a profound hypogonadal effect (i.e. decrease in FSH, LH and testosterone) within 10 days. A sufficient castration concentration is below 0.5 ng/ml testosterone.

Pharmacokinetics of GnRH Agonists

GnRH agonists are subcutaneous depot preparations, which are administered monthly or every three months. There are also implants available with annual application (histrelin).

Side Effects of GnRH Agonists

Osteoporosis, hot flashes, decreased libido, loss of erectile function, impaired memory function, physical weakness, fatigue, testicular atrophy, gynecomastia and depression are typical side effects of treatment with GnRH agonists due to hypogonadism. Other side effects include: flare up of serum testosterone at baseline with possible worsening of symptoms of advanced prostate cancer, allergies or infections at the injection site. There exist case reports of pituitary adenomas.

Sometimes GnRH agonists are not sufficient effective and miss to reach a testosterone concentration below 0.5 ng/ml (castration level). Testosterone concentration should be measured in cases of insufficient treatment effect or disease progression. Insufficient castration levels are managed with a switch to a different GnRH agonist or GnRH antagonist or surgical castration.

Contraindications

• After surgical castration
• In case of allergy and intolerance
• Prostate cancer metastases to the vertebrae with compression of the spinal cord: GnRH antagonists or surgical castration are better alternatives

Dosage of GnRH Agonists:

Bicalutamide or flutamide must be given for 14 days with the initiation of therapy to block the initial testosterone flare up.

Buserelin:

Goserelin:

Histrelin:

Leuprorelin:

Triptorelin:

References

  Deutsche Version: GnRH Agonisten