Native GnRH has a short half-life due to rapid cleavage of bonds between amino acids 5–6, 6–7, 9–10. By altering amino acids at this position, analogues of GnRH can be synthesized with different properties (Fig. 9.2) [2].

Substitution of amino acid glycine at position 10 at ‘c’ terminus was a first major modification. This was for increasing the potency. But 90 % of its biological activity was lost with splitting of glycine at 10. It was restored by attachment of NH₂-ethylamide to proline at position 9 [1].

Replacement of glycine at postion 6 by D amino acids decreases enzymatic degradation. Hence it renders more stability. These modifications also have higher receptor binding affinity.

The introduction of larger, hydrophobic and more lipophilic D amino acids at position 6 can further increase the affinity. Increased lipophilicity is associated with prolonged half-life [1].

Substitution of amino acids at positions 1, 2, 3, 6, 8 and 10 produces antagonist (Figs. 9.3 and 9.4) [3].

Native GnRH has got a half-life of 2–4 min. GnRH neuronal system releases it in pulsatile fashion. It is necessary for rhythmic secretion of FSH and LH. The pulse frequency is approximately 1 per hour during follicular phase and 1 per 3 h in luteal phase.

It results in gonadal stimulation without down-regulation of anterior pituitary.

GnRH can produce its biological effect if it covers receptors episodically. Hence it gives time for replenishment of receptors. Receptors have three important segments which include hormone-specific external binding, transmembranous region and internal site controlling the process of internalization.

Gonadotrophin will be secreted only in response to pulsatile release of GnRH. A change in frequency or amplitude or both is associated with irregular gonadotropin release. Continuous delivery is ineffective and can lead to suppression of gonadotropic pituitary function. Similarly, prolonged stimulation of receptor by GnRH molecule results in down-regulation. (loss of ability of receptor to respond with original sensitivity). The receptor after being internalized does not return to cell surface for further action. So GnRH limits its own activity by down-regulation.

They are structural modifications of natural GnRH. There are two types of GnRH analogues that are used: GnRH agonist and GnRH antagonist.

The agonist was developed with the idea of increasing the stability, potency and receptor affinity.

An increased potency could be achieved by replacing glycine for D amino acids at position 6 and by replacing gly-NH₂ at position 10 by ethyl amide. It has 100–200 times more affinity to the receptors than native GnRH. Such structural modifications render these compounds more hydrophobic and more resistant to enzymatic degradation.

In 1978, it was discovered that repeated administration of GnRH agonist produced a transient increase in gonadal function. The mechanism of action is ‘flare effect’ followed by down-regulation. Within 12 h of administration it induces liberation of high amounts of LH and FSH. It also increases the number of receptors (fivefold increase in FSH, tenfold increase in LH and fourfold increase in E2 receptors). This is known as up-regulation. This is rationale for using GnRH agonist as trigger in antagonist cycles.

The continuous occupation of the receptors leads to desensitization due to clustering and internalization of receptors resulting in fall of FSH and LH levels. This is known as down-regulation which results in arrest of follicles and fall in sex steroids. This effect is completely reversible as soon as therapy is stopped. This is a basis for clinical use of agonist in ovulation induction and controlled ovarian hyperstimulation. GnRH agonists, when chronically administered, result in marked reductions in blood levels of testosterone and oestrogen.