Key Points

• GnRH antagonists are orally-administered pharmacologic agents that prevent the production of gonadal steroids (estradiol and progesterone) from the ovary resulting in a medically induced but reversible menopausal state.
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• Unlike GnRH agonists, there is no initial GnRH-induced “flare” from the pituitary thereby preventing the  transient hyperestrogenemia and resultant and sometimes prolonged episode of heavy uterine bleeding.
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• Similar to GnRH agonists, the antagonists have been shown to be effective in suppressing bleeding and reducing uterine and leiomyoma volume.

• The availability of GnRH antagonist preparations vary worldwide but include options packaged with with  gonadal steroid (estrogen and progestin) “add back” that prevents the trabecular bone loss and vasomotor and other symptoms associated with suppression of ovarian function. Such formulations have been approved for multiyear use.

Background Basic Pharmacology

The growth dependence of uterine leiomyomas on estrogens, and especially progesterone, creates an opportunity for pharmacological intervention. The immediate stimulants of ovarian estradiol and progesterone production, follicle stimulating hormone (FSH) and lutenizing hormone (LH), are released from the anterior pituitary under the control of Gonadotropin Releasing Hormone, or GnRH, which originates in the hypothalamus (see section X). The original way of downregulating FSH and LH was the GnRH agonist, which, when given continuously (as opposed to a physiologic pulsatile administration) downregulates the GnRH receptors with resulting hypoestrogenemia and a medically-induced yet reversible menopause.  GnRH receptor antagonists create a similar state by binding reversibly to the GnRH receptor thereby preventing the release of FSH and LH, resulting in a precipitous drop in estradiol from 24 to 72 hours following the initiation of therapy. While GnRH agonists must be given parenterally, GnRH antagonists have been developed to be administered orally. Unlike GnRH agonists, GnRH antagonists bind reversibly to GnRH receptors without stimulating them preventing the initial "flare" of estradiol and the typical associated episode of heavy uterine bleeding.

Clinical Evidence
There have been several studies designed to demonstrate the effectiveness of GnRH antagonists, mostly for the impact on heavy menstrual bleeding, but also related to uterine and leiomyoma volume, and on potential adverse effects such as osteopenia and vasomotor symptoms. A systematic review and meta-analysis evaluated the use of GnRH antagonists for oral administration (22). They showed that elagolix at doses of 600 mg, 400 mg and 200 mg is effective in suppressing bleeding, with a greater likelihood of amenorrhea at higher doses and without add back treatment. Changes in uterine volume were more pronounced in therapies without adjuvant replacement therapy. All treatments were associated with improved quality of life scores (22). As a finding, they showed that elagolix was associated with a significant increase in low-density lipoprotein (LDL) levels. Changes in uterine volume were more pronounced in therapies without adjuvant replacement therapy probably related to the progestin content. All treatments were associated with improved quality of life scores (22). As a finding, they showed that elagolix was associated with a significant increase in low-density lipoprotein (LDL) levels.

A study published in 2019 compared the antagonist relugolix at a dose of 40 mg orally each day with the agonist leuprolide at a monthly injectable dose of 1.88 mg or 3.75 mg (23). As findings they found that the reduction in myoma size, uterine volume and increases in hemoglobin levels were comparable in the two groups. Relugolix was associated with an earlier effect on menstrual bleeding than leuprorelin, and was generally well tolerated (23).

Available Formulations

A drug containing relugolix 40 mg + estradiol 1mg + norethisterone acetate 0.5 mg is currently marketed in the UK, recommended in a NICE guideline published in 2020 (24). This drug is taken orally at a similar time starting in the first 5 days of the menstrual cycle and is administered continuously until manopause (25). It has been shown that its use for two years does not induce significant bone loss (26).

Linzagolix, a new antagonist is under study. The action of this drug is dose-dependent and rapidly reversible on the pituitary-gonadal axis. Phase III trials demonstrated that linzagolix is effective in the treatment of heavy menstrual bleeding related to fibroids with a good safety profile (27).

Administration

Elagolix: Elagolix is the most studied drug of its class in benign gynecological disease treatment. It has been approved by the FDA firstly for use in endometriosis in July 2018, and then in May 2020 for the treatment of uterine fibroids. It’s approved use is 300 mg every 12 hours in combination with add-back therapy (estradiol (E2) 1 mg/norethindrone acetate (NETA) 0.5 mg [E2/NETA] once daily). It can be administered for up to 24 months. 

Relugolix: Relugolix has been approved by the FDA for use in uterine fibroids on May 2021 as a first once-daily treatment for heavy menstrual bleeding associated with uterine fibroids. The first tablet should be taken within 5 days of the start of menstruation and the recommended dose is one tablet daily containing 40 mg of relugolix. Also need a combination with add-back therapy for bone mineral density preservation. It is administered orally and can be administered for up to 24 months until to 52 weeks

Linzagolix: It is a novel GnRH receptor antagonist, which was tried to be used in endometriosis, adenomyosis, and uterine fibroids. The drug is now awaiting FDA approval for fibroids as the one and only GnRH receptor antagonist with flexible dosing options. It is recommended a dose of 100 mg for the chronic treatment of women who cannot or do not want to take a hormonal addback therapy. There are studies until 2020 where its specific use for uterine leiomyomas has not yet been approved.