Mechanism of Action Used clinically, GnRH agonists are modifications of the native molecule to either increase receptor affinity or decrease degradation (20). Their use leads to a persistent activation of GnRH receptors, as if continuous GnRH exposure existed. As would be predicted by the constant GnRH infusion experiments, this leads to suppression of gonadotropin secretion. An initial release of gonadotropins is followed by a profound suppression of secretion. The initial release of gonadotropins represents the secretion of pituitary stores in response to receptor binding and activation. With continued activation of the gonadotroph GnRH receptor, however, there is a down-regulation effect and a decrease in the concentration of GnRH receptors. As a result, gonadotropin secretion decreases and sex steroid production falls to castrate levels (21).
Additional modification of the GnRH molecule results in an analogue that has no intrinsic activity but competes with GnRH for the same receptor site (22). These GnRH antagonists produce a competitive blockade of GnRH receptors, preventing stimulation by endogenous GnRH and causing an immediate fall in gonadotropin and sex steroid secretion (23). The clinical effect is observed within 24 to 72 hours. Moreover, antagonists may not function solely as competitive inhibitors; evidence suggests they may also produce down-regulation of GnRH receptors, further contributing to the loss of gonadotropin activity (24).
Structure—Agonists and Antagonists As a peptide hormone, GnRH is degraded by enzymatic cleavage of bonds between its amino acids. Pharmacologic alterations of the structure of GnRH led to the creation of agonists and antagonists (Fig. 7.4). The primary sites of enzymatic cleavage are between amino acids 5 and 6, 6 and 7, and 9 and 10. Substitution of the position-6 amino acid glycine with large bulky amino acid analogues makes degradation more difficult and creates a form of GnRH with a relatively long half-life. Substitution at the carboxyl terminus produces a form of GnRH with increased receptor affinity. The resulting high affinity and slow degradation produces a molecule that mimics continuous exposure to native GnRH (20). Thus, as with constant GnRH exposure, down-regulation occurs. GnRH agonists are widely used to treat disorders that are dependent on ovarian hormones (21). They are used to control ovulation induction cycles and to treat precocious puberty, ovarian hyperandrogenism, leiomyomas, endometriosis, and hormonally dependent cancers. The development of GnRH antagonists proved more difficult because a molecule was needed that maintained the binding and degradation resistance of agonists but failed to activate the receptor. Early attempts involved modification of amino acids 1 and 2, as well as those previously utilized for agonists. Commercial antagonists have structural modifications at amino acids 1, 2, 3, 6, 8, and 10. The treatment spectrum is expected to be similar to that of GnRH agonists, but with more rapid onset of action.
Nonpeptide, small molecule structures with high affinity for the GnRH receptor were developed (25). These compounds demonstrated the ability to suppress the reproductive axis in a dose-related manner via oral administration, unlike the parenteral approach required with traditional peptide analogues (26). Investigation may elucidate an expanded therapeutic role for these antagonists.
Endogenous Opioids and Effects on GnRH The endogenous opioids are three related families of naturally occurring substances produced in the CNS that represent the natural ligands for the opioid receptors (27–29). There are three major classes of endogenous opioids, each derived from precursor molecules: 1.