17,18 LHRH Agonists LHRH agonists are decapeptides that exert a nonpulsatile, constant stimulation to the anterior pituitary gland, which in turn decreases LH and testosterone production. This class was originally developed as a new form of birth control.19 The binding affinity of synthesized LHRH analogues is significantly longer than the native peptide, hence removing the pulsatile signaling to the anterior pituitary
gland. The receptor binding of native LHRH is about 6 minutes versus 3.5 Inhibitors,research,lifescience,medical hours for leuprolide and 5.5 hours for triptorelin.20 Increased binding affinity may be due to reduced susceptibility to enzymatic degradation compared with natural LHRH. Synthetic analogues, generated by only a single amino acid substitution at position 6, are generally 100 times more potent than natural Inhibitors,research,lifescience,medical LHRH. After treatment, LH release is transiently increased up to 2 weeks after the initial dose, referred to as the flare or hormonal surge. After this transient increase in LH and, thus, testosterone Inhibitors,research,lifescience,medical levels, the LH and follicle-stimulating hormone (FSH) production is downregulated and testosterone production is inhibited. The flare can be hazardous in some patients, such as those with increasing severity of bone pain from metastasis or ureteral or bladder outlet obstruction, or in whom neurologic compromise is imminent from metastatic
disease of the spine. The initial use of a nonsteroidal antiandrogen such as bicalutamide can be effective in blocking the clinical flare. LHRH analogues
are Inhibitors,research,lifescience,medical found in a variety of formulations, and, depending on the medication, can be administered every 1 to 12 months. The currently available medications in the United States see more include different formulations of leuprolide, goserelin, histrelin, and triptorelin in a variety of dosing intervals ranging from monthly to yearly (Table 1). Associated side effects include hot flashes, decreased libido, erectile Inhibitors,research,lifescience,medical dysfunction, loss of bone mineral density, anemia, and mood changes. Table 1 LHRH Agonists and Antagonists for Primary Androgen Ablation for Prostate Cancer LHRH Antagonists Abarelix is an LHRH antagonist that directly inhibits binding onto the LH receptor in the anterior Sclareol pituitary gland. Unlike LHRH analogues, there is no hormonal surge. This drug was taken off the US market due to financial and safety concerns, but may still be used in men who were treated before May 2005. It is available in several countries outside of the United States. This medication was limited by a chance of anaphylaxis and the possibility of an increased QT interval.21 The latest LHRH antagonist is degarelix, widely available in Europe and recently approved in the United States. It does not appear to have the adverse safety profile that was attributed to abarelix.