Gonadotropin-releasing hormone agonist
Encyclopedia
A gonadotropin-releasing hormone agonist (GnRH agonist, GnRH–A) is a synthetic peptide
modeled after the hypothalamic neurohormone
GnRH that interacts with the gonadotropin-releasing hormone receptor
to elicit its biologic response, the release of the pituitary hormones FSH
and LH
.
GnRH agonists are pregnancy category
X drugs.
However after about ten days a profound hypogonadal effect (i.e. decrease in FSH and LH) is achieved through receptor downregulation by internalization of receptors. Generally this induced and reversible hypogonadism
is the therapeutic goal.
Triptorelin
is an agonist with only a single substitution at position 6.
, or by implant. Injectables have been formulated for daily, monthly, and quarterly use; and implants can last from 1 to 12 months.
Women of reproductive age who undergo cytotoxic chemotherapy
have been pretreated with GnRH agonists to reduce the risk of oocyte loss during such therapy and preserve ovarian function. Further studies are necessary to prove that this approach is useful.
, including hot flashes, headaches, and osteoporosis. In patients under long-term therapy, small amounts of estrogens could be given back (“add-back regimen”) to combat such side effects and to prevent bone wastage. Generally, long-term patients, both male and female, tend to undergo annual DEXA
scans to appraise bone density.
There is also a report that GnRH agonists used in the treatment of advanced prostate cancer
may increase the risk of heart problems by 30%.
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...
modeled after the hypothalamic neurohormone
Neurohormone
A neurohormone is any hormone produced and released by neurons.Examples include:*Thyrotropin-releasing hormone *Gonadotropin-releasing hormone *Adrenocorticotropin-releasing hormone*Oxytocin*Antidiuretic hormone *Epinephrine...
GnRH that interacts with the gonadotropin-releasing hormone receptor
Gonadotropin-releasing hormone receptor
The gonadotropin-releasing hormone receptor , also known as the luteinizing hormone releasing hormone receptor , is a member of the seven-transmembrane, G-protein coupled receptor family...
to elicit its biologic response, the release of the pituitary hormones FSH
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...
and LH
Luteinizing hormone
Luteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...
.
GnRH agonists are pregnancy category
Pregnancy category
The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does not include any risks conferred by pharmaceutical agents or their metabolites that are present in breast...
X drugs.
Flare effect and downregulation
Agonists do not quickly dissociate from the GnRH receptor. As a result initially there is an increase in FSH and LH secretion (so-called "flare effect").However after about ten days a profound hypogonadal effect (i.e. decrease in FSH and LH) is achieved through receptor downregulation by internalization of receptors. Generally this induced and reversible hypogonadism
Hypogonadism
Hypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
is the therapeutic goal.
Agonists with double and single substitutions
GnRH agonists are synthetically modeled after the natural GnRH decapeptide with specific amino acid substitutions typically in position 6 and 10. These substitutions inhibit rapid degradation. Agonists with 2 substitutions include:- leuprolideLeuprolideLeuprorelin or leuprolide acetate is a GnRH analog. Proper Sequence: Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt - Mode of action:Leuprolide acts as an agonist at pituitary GnRH receptors...
(Lupron, Eligard) - buserelinBuserelinBuserelin is a Gonadotropin-releasing hormone agonist . By causing constant stimulation of the pituitary, it decreases pituitary secretion of gonadotropins luteinizing hormone and follicle stimulating hormone...
(Suprefact, Suprecor) - nafarelinNafarelinNafarelin is a gonadotropin-releasing hormone agonist . By causing constant stimulation of the pituitary, it decreases pituitary secretion of gonadotropins luteinizing hormone and follicle stimulating hormone...
(Synarel) - histrelinHistrelinHistrelin acetate is a nonapeptide analog of gonadotropin-releasing hormone with added potency. When present in the bloodstream, it acts on particular cells of the pituitary gland called gonadotropes. Histrelin stimulates these cells to release luteinizing hormone and follicle-stimulating hormone...
(Supprelin) - goserelinGoserelinGoserelin acetate is an injectable gonadotropin releasing hormone superagonist , also known as a luteinizing hormone releasing hormone agonist. Structurally, it is a decapeptide...
(Zoladex) - deslorelinDeslorelinDeslorelin acetate is an injectable gonadotropin releasing hormone super-agonist also known as an LHRH agonist. It stops the production of sex hormones ....
(Suprelorin, Ovuplant)
Triptorelin
Triptorelin
Triptorelin, a decapeptide , is a gonadotropin-releasing hormone agonist used at the acetate or pamoate salts. By causing constant stimulation of the pituitary, it decreases pituitary secretion of gonadotropins luteinizing hormone and follicle stimulating hormone...
is an agonist with only a single substitution at position 6.
Administration
These medications can be administered intranasally, by injectionInjection (medicine)
An injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...
, or by implant. Injectables have been formulated for daily, monthly, and quarterly use; and implants can last from 1 to 12 months.
Uses
GnRH agonists are useful in:- Treatment of cancerCancerCancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
s that are hormonally sensitive and where a hypogonadal state decreases the chances of a recurrence. Thus they are commonly employed in the medical management of prostate cancerProstate cancerProstate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
and have been used in patients with breast cancerBreast cancerBreast 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...
. - Treatment of delaying puberty in individuals with precocious pubertyPrecocious pubertyAs a medical term, precocious puberty describes puberty occurring at an unusually early age. In most of these children, the process is normal in every respect except the unusually early age, and simply represents a variation of normal development. In a minority of children, the early development is...
. - Management of female disorders that are dependent on estrogenEstrogenEstrogens , 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...
productions. Women with menorrhagiaMenorrhagiaMenorrhagia is an abnormally heavy and prolonged menstrual period at regular intervals. Causes may be due to abnormal blood clotting, disruption of normal hormonal regulation of periods or disorders of the endometrial lining of the uterus...
, endometriosisEndometriosisEndometriosis 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...
, adenomyosisAdenomyosisAdenomyosis is a medical condition characterized by the presence of ectopic glandular tissue found in muscle. The term adenomyosis is derived from the terms adeno- , myo- , and -osis...
, or uterine fibroids may receive GnRH agonists to suppress ovarian activity and induce a hypoestrogenic state. - Sex reassignmentSex reassignmentSex reassignment may refer to:* Sex reassignment, changing the sex assignment of an infant or child by parents and doctors, usually because of fuller understanding of an intersex condition....
of male to female transsexuals. - IVFIn vitro fertilisationIn vitro fertilisation is a process by which egg cells are fertilised by sperm outside the body: in vitro. IVF is a major treatment in infertility when other methods of assisted reproductive technology have failed...
therapy: they allow for better control of ovarian hyperstimulation during the administration of exogenous FSH. Typically, after GnRH agonists have induced a state of hypoestrogenism, exogenous FSH is given to stimulate ovarian follicle, followed by human chorionic gonadotropinHuman chorionic gonadotropinHuman chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not...
s (hCG) to trigger oocyte release. GnRH agonists routinely used for this purpose are: buserelin, leuprorelin, nafarelin, and triptorelin. GnRH agonists are also provide a valid alternative to oocyte release triggering with HCG, resulting in an elimination of the risk of ovarian hyperstimulation syndromeOvarian hyperstimulation syndromeOvarian hyperstimulation syndrome is a complication from some forms of fertility medication. Most cases are mild, but a small proportion are severe.-Causative medications:...
. The delivery rate is approximately 6% less than with hCG triggering. - Severe cases of congenital adrenal hyperplasiaCongenital adrenal hyperplasiaCongenital adrenal hyperplasia refers to any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands ....
- Temporary Suppression of Fertility in Male Dogs
- Induction of Ovulation in Mares
Women of reproductive age who undergo cytotoxic chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
have been pretreated with GnRH agonists to reduce the risk of oocyte loss during such therapy and preserve ovarian function. Further studies are necessary to prove that this approach is useful.
Side effects
Side effects of the GnRH agonists are signs and symptoms of hypoestrogenismHypoestrogenism
Hypoestrogenism refers to a lower than normal level of estrogen, the primary sex hormone for women. In general, lower levels of estrogen may cause differences in the breasts, genitals, urinary tract and skin....
, including hot flashes, headaches, and osteoporosis. In patients under long-term therapy, small amounts of estrogens could be given back (“add-back regimen”) to combat such side effects and to prevent bone wastage. Generally, long-term patients, both male and female, tend to undergo annual DEXA
Dual energy X-ray absorptiometry
Dual-emission X-ray absorptiometry is a means of measuring bone mineral density . Two X-ray beams with differing energy levels are aimed at the patient's bones. When soft tissue absorption is subtracted out, the BMD can be determined from the absorption of each beam by bone...
scans to appraise bone density.
There is also a report that GnRH agonists used in the treatment of advanced prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
may increase the risk of heart problems by 30%.