Gonadotropin-releasing hormone antagonist
Encyclopedia
Gonadotrophin-releasing hormone (GnRH) antagonists (receptor
blockers) are a class of compounds that are similar in structure to natural GnRH (a hormone
made by neurons in the hypothalamus) but that have an antagonistic effect. GnRH antagonists are peptide
molecules that are made up multiple, often synthetically produced amino acids. GnRH antagonists compete with natural GnRH for binding to GnRH receptors, thus decreasing or blocking GnRH action in the body.
, 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 oestrogen 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:
(abarelix) or subcutaneous injection
(cetrorelix, degarelix and ganirelix).
) 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.
in patients undergoing exogenous stimulation 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. The GnRH antagonists that are currently licensed for use in fertility treatment are cetrorelix and ganirelix.
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.
, 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
has been linked with immediate-onset systemic allergic reactions.
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
blockers) are a class of compounds that are similar in structure to natural GnRH (a hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
made by neurons in the hypothalamus) but that have an antagonistic effect. GnRH antagonists are peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
molecules that are made up multiple, often synthetically produced amino acids. GnRH antagonists compete with natural GnRH for binding to GnRH receptors, thus decreasing or blocking GnRH action in the body.
Mode of action
GnRH antagonists competitively and reversibly bind to GnRH receptors in the pituitary glandPituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
, blocking the release of luteinising hormone (LH) and follicle-stimulating hormone
Follicle-stimulating hormone
Follicle-stimulating hormone is a hormone found in humans and other animals. It is synthesized and secreted by gonadotrophs of the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and Luteinizing hormone act...
(FSH) from the pituitary. In men, the reduction in LH subsequently leads to rapid suppression of testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
release from the testes; in women it leads to suppression of estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
release from the ovaries.
Unlike the GnRH agonists, which cause an initial stimulation of the hypothalamic-pituitary-gonadal axis
Hypothalamic-pituitary-gonadal axis
The hypothalamic–pituitary–gonadal axis refers to the effects of the hypothalamus, pituitary gland, and gonads as if these individual endocrine glands were a single entity as a whole...
(HPGA), leading to a surge in testosterone or oestrogen 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:
- CetrorelixCetrorelixCetrorelix acetate is an injectable gonadotropin-releasing hormone antagonist . A synthetic decapeptide, it is used to treat hormone-sensitive cancers of the prostate and breast and some benign gynaecological disorders...
- GanirelixGanirelixGanirelix acetate is an injectable gonadotropin-releasing hormone antagonist . It is primarily used in assisted reproduction to control ovulation. The drug works by blocking the action of GnRH upon the pituitary, thus rapidly suppressing the production and action of LH and FSH...
- AbarelixAbarelixAbarelix is an injectable gonadotropin-releasing hormone antagonist . It is primarily used in oncology to reduce the amount of testosterone made in patients with advanced symptomatic prostate cancer for which no other treatment options are available...
- DegarelixDegarelixDegarelix or degarelix acetate is a hormonal therapy used in the treatment of prostate cancer. During development it was known as FE200486....
Administration
GnRH antagonists are administered by either intramuscular injectionIntramuscular injection
Intramuscular injection is the injection of a substance directly into a muscle. In medicine, it is one of several alternative methods for the administration of medications . It is used for particular forms of medication that are administered in small amounts...
(abarelix) or subcutaneous injection
Subcutaneous injection
A subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, collectively referred to as the...
(cetrorelix, degarelix and ganirelix).
Prostate cancer
Testosterone promotes growth of many prostate tumours and therefore reducing circulating testosterone to very low (castrationCastration
Castration is any action, surgical, chemical, or otherwise, by which a male loses the functions of the testicles or a female loses the functions of the ovaries.-Humans:...
) 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
Bone pain
Bone pain is a debilitating form of pain emanating from the bone tissue. It occurs as a result of a wide range of diseases and/or physical conditions and may severely impair the quality of life for patients who suffer from it...
, ureteral obstruction, and spinal cord compression
Spinal cord compression
Spinal cord compression develops when the spinal cord is compressed by bone fragments from a vertebral fracture, a tumor, abscess, ruptured intervertebral disc or other lesion...
. 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
Antiandrogen
Antiandrogens, or androgen antagonists, first discovered in the 1960s, prevent androgens from expressing their biological effects on responsive tissues. Antiandrogens alter the androgen pathway by blocking the appropriate receptors, competing for binding sites on the cell's surface, or affecting...
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
Abarelix
Abarelix is an injectable gonadotropin-releasing hormone antagonist . It is primarily used in oncology to reduce the amount of testosterone made in patients with advanced symptomatic prostate cancer for which no other treatment options are available...
was withdrawn from the US market in 2005 and is now only marketed in Germany for use in patients with symptomatic prostate cancer. Degarelix
Degarelix
Degarelix or degarelix acetate is a hormonal therapy used in the treatment of prostate cancer. During development it was known as FE200486....
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 ovulationOvulation
Ovulation is the process in a female's menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum . Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle...
in patients undergoing exogenous stimulation with FSH in preparation for In-vitro fertilisation IVF. Typically they are administered in the mid-follicular phase
Follicular phase
The follicular phase is the phase of the estrous cycle, during which follicles in the ovary mature. It ends with ovulation. The main hormone controlling this stage is estradiol....
in stimulated cycles after administration of gonadotropins and prior to the administration of hCG – which is given to stimulate ovulation. 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 cancerBreast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
and some benign disorders such as endometriosis
Endometriosis
Endometriosis is a gynecological medical condition in which cells from the lining of the uterus appear and flourish outside the uterine cavity, most commonly on the ovaries. The uterine cavity is lined by endometrial cells, which are under the influence of female hormones...
and uterine
Uterine
The word uterine can refer to different meanings:* relating to or near the uterus or womb* having the same mother, but different fathers, see matrilineality...
fibroids.
In men, they are being investigated in the treatment of benign prostatic hyperplasia
Benign prostatic hyperplasia
Benign prostatic hyperplasia also known as benign prostatic hypertrophy , benign enlargement of the prostate , and adenofibromyomatous hyperplasia, refers to the increase in size of the prostate....
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, headacheHeadache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and weight gain
Weight gain
Weight gain is an increase in body weight. This can be either an increase in muscle mass, fat deposits, or excess fluids such as water.-Description:...
. 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
Abarelix
Abarelix is an injectable gonadotropin-releasing hormone antagonist . It is primarily used in oncology to reduce the amount of testosterone made in patients with advanced symptomatic prostate cancer for which no other treatment options are available...
has been linked with immediate-onset systemic allergic reactions.