Can Hormonal Effects of the Oral Gonadotropin Releasing Hormone (GnRH) Antagonist Withstand When Administered at Different Points in the Menstrual Cycle?

Gonadotropin-releasing hormone (GnRH) and its analogs have been utilized in clinical medicine since the early 1970s. The GnRH analog is more potent with a longer half-life than native GnRH. When administered continuously rather than in a more physiologic pulsatile manner, the initial stimulation of pituitary gonadotrophs is followed by pituitary desensitization1,2. This ultimately leads to inhibition of the pituitary-gonadal axis. This downregulation facilitates the use of GnRH agonists for the treatment of various medical conditions, including precocious puberty, endometriosis, uterine leiomyomata, prostate cancer, and assisted reproductive technology (ART)1,2.

Like GnRH agonists, antagonists of GnRH have proven to efficiently suppress pituitary and ovarian hormone production. However, unlike the agonist, the GnRH-antagonist competitively binds to the GnRH-receptor1,2. The antagonist bypasses the initial flare effect and does not require the initial period of administration for pituitary desensitization of GnRH receptors. As a result, there is rapid prevention of gonadotropin secretion and antagonist effect on the ovary1-4.

In addition to the enhanced efficiency of using a GnRH-antagonist, it has shown to be more tolerable with fewer side effects when compared to the older GnRH agonist1-5. Particularly in ART, GnRH agonists are associated with hot flashes, ovarian cyst formation, and ovarian hyperstimulation syndrome (OHSS)6. Conversely, GnRH antagonists have been shown to significantly reduce the incidence of OHSS, and are not associated with cyst development or hot flashes6. It is important to note that in ART literature, administration of a GnRH-antagonist has been via a subcutaneous injection, formulated as ganirelix, detirelix or cetrotide3-5.

Fluker et al investigated the impact of the subcutaneous GnRH-antagonist on gonadotropin and ovarian hormone production when administered at different points of the menstrual cycle: mid-follicular phase, preovulatory phase, and early luteal phase5. Investigators found that the GnRH-antagonist successfully suppressed gonadotropin hormones irrespective of phase of menstrual cycle. Suppression of ovarian hormones, and particularly suppression of the LH surge, was evident only when the GnRH-antagonist administered in mid-follicular and early luteal phases5.

In an effort to avoid a subcutaneous injection and ease patient administration, an oral GnRH-antagonist has recently been developed: Elagolix. Research has shown that elagolix similarly suppresses gonadotropin and ovarian hormones compared to its injectable formulary7.