Leuprolide: A Gonadotropin-Releasing Hormone Analog for the Palliative Treatment of Prostatic Cancer

Abstract

Leuprolide is the first member of the class of gonadotropin-releasing hormone (GnRH) agonist analog to be released in the U.S. The pharmacology of leuprolide is complex and not yet completely defined. This agonist analog is more potent than natural GnRH and appears to be capable of occupying pituitary GnRH receptors. This results in a "down regulation" of the receptors' activity and gonadotropin release, ultimately decreasing serum testosterone levels to those seen following castration. Leuprolide has been found effective in the palliative treatment of advanced cases of prostatic cancer and is not associated with the cardiovascular and thromboembolic toxicity seen with conventional diethylstilbestrol therapy. Leuprolide is administered by daily subcutaneous injections and has been generally well tolerated. The most common adverse effects are hot flashes and a possible flare-up of prostatic carcinoma symptoms on initial dosing. As clinical experience grows in the use of GnRH agonist analog, GnRH will assume a greater role in the treatment of metastatic prostatic cancer.

Effect of Agitation Regimen on the in vitro Release of Leuprolide from Poly(Lactic-Co-Glycolic) Acid Microparticles

“…Among marketed formulations, those containing leuprolide were successfully developed for long‐term testosterone suppression in the treatment of prostate cancer 4–6. Leuprolide acetate, a peptide, is a potent agonist of luteinizing hormone‐releasing hormone, which inhibits the secretion of pituitary gonadotropin when administered chronically in therapeutic doses 7,8…”

Osteoporosis in Men Treated With Androgen Suppression Therapy for Prostate Cancer

“…Hypogonadism (defined as serum testosterone less than 10 nmol/L) usually is achieved within three to four weeks and can be maintained for the duration of treatment (Plosker & Brogden). Up to 80% of patients with local or metastatic prostate cancer are estimated to partially or completely respond to androgen suppression (Wolciechowski et al, 1986). Several studies document the effects of LHRH agonist therapy on BMD of patients with prostate cancer.…”

Leuprorelin Acetate in Prostate Cancer: A European Update

“…Natural LHRH was first isolated and identified in 1971 11 . Leuprorelin was first synthesised in 1974 by Takeda Chemical Industries, Japan, 12 and is a synthetic nonapeptide analogue of naturally occurring porcine LHRH 13 . It has a longer half‐life than natural LHRH due to its enhanced binding affinity and increased resistance to peptidase degradation, associated with amino acid substitutions at positions 6 and 10 of porcine LHRH.…”

“…Leuprorelin is 80 times more potent than natural LHRH 9 . Sustained occupation of pituitary GnRH receptors by leuprorelin results in densensitisation and/or downregulation of receptors in the anterior pituitary, thereby suppressing gonadotrophin release and reducing testosterone release by the human testes to castrate levels 13 . There is also evidence that leuprorelin may act directly on cell growth in human prostatic cancer cells, behaving like a negative growth factor 14 …”