Initially, the GnRH receptor agonist effect stimulates the HPO axis; this causes increased FSH and estrogen secretion without a significant change in GnRH levels.
With prolonged use, leuprolide causes desensitization and downregulation of pituitary GnRH receptors, which eventually leads to low FSH and estrogen levels. Because leuprolide is an exogenous GnRH analogue, its prolonged use also decreases endogenous GnRH levels.