Biological target GnRH receptor | Chemical class Peptides; Nonpeptides | |
 | ||
Synonyms GnRH blockers; GnRH inhibitors; Antigonadotropins Use Infertility; Prostate cancer; Precocious puberty; Breast cancer; Endometriosis; Uterine fibroids; Transgender people | ||
Gonadotrophin-releasing hormone (GnRH) antagonists (receptor blockers) are a class of drugs that antagonize the gonadotropin-releasing hormone receptor (GnRHR) and thus the action of GnRH. Some are similar in structure to natural GnRH (a hormone made by neurons in the hypothalamus) but that have an antagonistic effect. These GnRH antagonists are peptide molecules that are made up multiple, often synthetically produced amino acids. Others are small-molecule, non-peptide compounds. GnRH antagonists compete with natural GnRH for binding to GnRH receptors, thus decreasing or blocking GnRH action in the body.
Contents
Mode of action
GnRH antagonists competitively and reversibly bind to GnRH receptors in the pituitary gland, blocking the release of luteinising hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary. In men, the reduction in LH subsequently leads to rapid suppression of testosterone release from the testes; in women it leads to suppression of estrogen release from the ovaries.
Unlike the GnRH agonists, which cause an initial stimulation of the hypothalamic-pituitary-gonadal axis (HPGA), leading to a surge in testosterone or estrogen levels, GnRH antagonists have an immediate onset of action, rapidly reducing sex hormone levels without an initial surge.
Currently approved GnRH antagonists include the following:
Elagolix, a non-peptide, orally-active GnRH antagonist that is still in development, is currently in phase III clinical trials. Other non-peptide, orally-active GnRH antagonists that are also in development include relugolix (TAK-385), KLH-2109, and ASP-1707.
Administration
GnRH antagonists are administered by either intramuscular injection (abarelix) or subcutaneous injection (cetrorelix, degarelix and ganirelix).
Elagolix, which is currently in phase III clinical trials, is administered orally, as are relugolix (TAK-385), KLH-2109, and ASP-1707.
Prostate cancer
Testosterone promotes growth of many prostate tumours and therefore reducing circulating testosterone to very low (castration) levels is often the treatment goal in the management of men with advanced prostate cancer. GnRH antagonists are used to provide fast suppression of testosterone without the surge in testosterone levels that is seen when treating patients with GnRH agonists. In patients with advanced disease, this surge in testosterone can lead to a flare-up of the tumour, which can precipitate a range of clinical symptoms such as bone pain, ureteral obstruction, and spinal cord compression. Drug agencies have issued warnings regarding this phenomenon in the prescribing information for GnRH agonists. As testosterone surge does not occur with GnRH antagonists, there is no need for patients to receive an antiandrogen as flare protection during prostate cancer treatment. GnRH agonists also induce an increase in testosterone levels after each reinjection of the drug – a phenomenon that does not occur with GnRH antagonists.
The reduction in testosterone levels that occurs during GnRH antagonist therapy subsequently reduces the size of the prostate cancer. This in turn results in a reduction in prostate-specific antigen (PSA) levels in the patient’s blood and so measuring PSA levels is a way to monitor how patients with prostate cancer are responding to treatment. GnRH antagonists have an immediate onset of action leading to a fast and profound suppression of testosterone and are therefore especially valuable in the treatment of patients with prostate cancer, where fast control of disease is needed.
The GnRH antagonist abarelix was withdrawn from the US market in 2005 and is now only marketed in Germany for use in patients with symptomatic prostate cancer. Degarelix is a GnRH antagonist that is approved for use in patients with advanced hormone-sensitive prostate cancer throughout Europe and also in the USA.
Fertility treatment
GnRH antagonists are also used for short periods in the prevention of premature LH surge and endogenous ovulation in patients undergoing ovarian hyperstimulation with FSH in preparation for In-vitro fertilisation IVF. Typically they are administered in the mid-follicular phase in stimulated cycles after administration of gonadotropins and prior to the administration of hCG – which is given to stimulate ovulation. This protocol is likely beneficial in women expected to be hyper-responders, and probably also those expected to be poor responders to ovarian hyperstimulation. The GnRH antagonists that are currently licensed for use in fertility treatment are cetrorelix and ganirelix.
Other applications
GnRH antagonists are also being investigated in the treatment of women with hormone-sensitive breast cancer and some benign disorders such as endometriosis and uterine fibroids.
In men, they are being investigated in the treatment of benign prostatic hyperplasia and also as potential contraceptive agents.
Side effects
As with all hormonal therapies, GnRH antagonists are commonly associated with hormonal side effects such as hot flushes, headache, nausea and weight gain. When used in fertility treatment they can also be associated with abdominal pain and ovarian hyperstimulation. Subcutaneously administered agents are also associated with injection-site reactions and abarelix (neither of these being GnRH agonists, but rather both _antagonists_) has been linked with immediate-onset systemic allergic reactions.