A gonadotropin-releasing hormone agonist (GnRH agonist) is a type of medication which affects

gonadotropin Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/ chorioni ...

s and

sex hormone Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effect ...

s. They are used for a variety of indications including in

fertility medicine Reproductive endocrinology and infertility (REI) is a surgical subspecialty of obstetrics and gynecology that trains physicians in reproductive medicine addressing hormonal functioning as it pertains to reproduction as well as the issue of infert ...

and to lower sex hormone levels in the treatment of hormone-sensitive cancers such as

prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that su ...

and

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...

, certain gynecological disorders like heavy periods and

endometriosis Endometriosis is a disease of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside the uterus. Most often this is on the ovaries, fa ...

, high testosterone levels in women, early puberty in children, as a part of

transgender hormone therapy Transgender hormone therapy, also called hormone replacement therapy (HRT) or gender-affirming hormone therapy (GAHT), is a form of hormone therapy in which sex hormones and other hormonal medications are administered to transgender or gender non ...

, and to delay puberty in

transgender youth Transgender youth are children or adolescents who do not identify with the sex they were assigned at birth. Because transgender youth are usually dependent on their parents for care, shelter, financial support, and other needs, transgender y ...

among other uses. GnRH agonists are given by injections into fat, as implants placed into fat, and as

nasal spray Nasal sprays are used to deliver medications locally in the nasal cavities or systemically. They are used locally for conditions such as nasal congestion and allergic rhinitis. In some situations, the nasal delivery route is preferred for syst ...

Side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s of GnRH agonists are related to

deficiency and include

symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showi ...

s of low testosterone levels and low estrogen levels such as

hot flash Hot flashes (also known as hot flushes) are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, an ...

es,

sexual dysfunction Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction a ...

, vaginal atrophy, penile atrophy,

osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone a ...

infertility Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal st ...

, and diminished sex-specific physical characteristics. They are

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...

s of the

GnRH receptor The gonadotropin-releasing hormone receptor (GnRHR), also known as the luteinizing hormone releasing hormone receptor (LHRHR), is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. It is the receptor of gonadotropin- ...

and work by increasing or decreasing the

release Release may refer to: * Art release, the public distribution of an artistic production, such as a film, album, or song * Legal release, a legal instrument * News release, a communication directed at the news media * Release (ISUP), a code to iden ...

of gonadotropins and the production of sex hormones by the

gonad A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sp ...

s. When used to suppress gonadotropin release, GnRH agonists can lower sex hormone levels by 95% in both sexes. GnRH was discovered in 1971, and GnRH analogues were introduced for medical use in the 1980s. Their nonproprietary names usually end in ''-relin''. The most well-known and widely used GnRH analogues are

leuprorelin Leuprorelin, also known as leuprolide, is a manufactured version of a hormone used to treat prostate cancer, breast cancer, endometriosis, uterine fibroids, as part of transgender hormone therapy, for early puberty, or to perform chemical c ...

(brand name Lupron) and

triptorelin Triptorelin, sold under the brand name Decapeptyl among others, is a medication that acts as an agonist analog of gonadotropin-releasing hormone, repressing expression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). It is a ...

(brand name Decapeptyl). GnRH analogues are available as

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ...

s. Despite this, they continue to be very expensive.

Medical uses

GnRH agonists are useful in: * Suppression of spontaneous ovulation as part of

controlled ovarian hyperstimulation Controlled ovarian hyperstimulation is a technique used in assisted reproduction involving the use of fertility medications to induce ovulation by multiple ovarian follicles. These multiple follicles can be taken out by oocyte retrieval (egg collec ...

, which is an essential component in ''in vitro'' fertilisation (IVF). Typically, after GnRH agonists have induced a state of hypoestrogenism, exogenous FSH is given to stimulate ovarian follicle, followed by

human chorionic gonadotropin Human chorionic gonadotropin (hCG) is a hormone for the maternal recognition of pregnancy produced by trophoblast cells that are surrounding a growing embryo (syncytiotrophoblast initially), which eventually forms the placenta after implantatio ...

s (hCG) to trigger oocyte release. GnRH agonists routinely used for this purpose are: buserelin, leuprorelin, nafarelin, and triptorelin. *

Final maturation induction Induction of final maturation of oocytes is a procedure that is usually performed as part of controlled ovarian hyperstimulation to render the oocytes fully developed and thereby resulting in optimal pregnancy chances. It is basically a replacement ...

after having performed controlled ovarian hyperstimulation. Usage of GnRH agonist for this purpose necessitates using a

GnRH antagonist Gonadotropin-releasing hormone antagonists (GnRH antagonists) are a class of medications that antagonize the gonadotropin-releasing hormone receptor (GnRH receptor) and thus the action of gonadotropin-releasing hormone (GnRH). They are used in ...

instead of a GnRH agonist for suppression of spontaneous ovulation, because using GnRH agonist for that purpose as well inactivates the axis for which it is intended to work for final maturation induction. * Treatment of

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

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

and have been used in patients with

. * Delaying puberty in individuals with

precocious puberty In medicine, precocious puberty is puberty occurring at an unusually early age. In most cases, the process is normal in every aspect except the unusually early age and simply represents a variation of normal development. In a minority of childr ...

. * Delaying puberty pending treatment decisions in children with

gender dysphoria Gender dysphoria (GD) is the distress a person experiences due to a mismatch between their gender identitytheir personal sense of their own genderand their sex assigned at birth. The diagnostic label gender identity disorder (GID) was used unti ...

. * Management of female disorders that are dependent on

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...

production. Women with

menorrhagia Heavy menstrual bleeding (HMB), previously known as menorrhagia or hypermenorrhea, is a menstrual period with excessively heavy flow. It is a type of abnormal uterine bleeding (AUB). Abnormal uterine bleeding can be caused by structural abnor ...

adenomyosis Adenomyosis is a medical condition characterized by the growth of cells that proliferate on the inside of the uterus ( endometrium) atypically located among the cells of the uterine wall ( myometrium), as a result, thickening of the uterus occurs. ...

, or

uterine fibroid Uterine fibroids, also known as uterine leiomyomas or fibroids, are benign smooth muscle tumors of the uterus. Most women with fibroids have no symptoms while others may have painful or heavy periods. If large enough, they may push on the bl ...

s may receive GnRH agonists to suppress ovarian activity and induce a hypoestrogenic state. * Suppressing sex hormone levels in transgender people, especially

transgender women A trans woman or a transgender woman is a woman who was assigned male at birth. Trans women have a female gender identity, may experience gender dysphoria, and may transition; this process commonly includes hormone replacement therapy and so ...

. * Severe cases of

hyperandrogenism Hyperandrogenism is a medical condition characterized by high levels of androgens. It is more common in women than men. Symptoms of hyperandrogenism may include acne, seborrhea (inflamed skin), hair loss on the scalp, increased body or facia ...

, such as in

congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cortex ...

. * As part of the pharmacologic treatment of paraphilic disorders in sexual offenders or men with a high risk of sexual offending. Women of reproductive age who undergo cytotoxic

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...

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.

Available forms

GnRH agonists that have been marketed and are available for medical use include

buserelin Buserelin, sold under the brand name Suprefact among others, is a medication which is used primarily in the treatment of prostate cancer and endometriosis. It is also used for other indications such as the treatment of premenopausal breast cancer ...

, gonadorelin,

goserelin Goserelin, sold under the brand name Zoladex among others, is a medication which is used to suppress production of the sex hormones (testosterone and estrogen), particularly in the treatment of breast and prostate cancer. It is an injectable gona ...

histrelin Histrelin acetate, sold under the brand names Vantas and Supprelin LA among others, is a nonapeptide analogue of gonadotropin-releasing hormone (GnRH) with added potency.

nafarelin Nafarelin, sold under the brand name Synarel among others, is a gonadotropin-releasing hormone agonist (GnRH agonist) medication which is used in the treatment of endometriosis and early puberty.https://www.accessdata.fda.gov/drugsatfda_docs/label ...

, and

. GnRH agonists that are used mostly or exclusively in

veterinary medicine Veterinary medicine is the branch of medicine that deals with the prevention, management, diagnosis, and treatment of disease, disorder, and injury in animals. Along with this, it deals with animal rearing, husbandry, breeding, research on nutri ...

include

deslorelin Deslorelin, sold under the brand names Ovuplant, SucroMate, and Suprelorin among others, is an injectable gonadotropin releasing hormone superagonist (GnRH agonist) which is used in veterinary medicine for various indications. Uses Veterinary ...

and fertirelin. GnRH agonists can be administered by injection, by

implant Implant can refer to: Medicine * Implant (medicine), or specifically: **Brain implant **Breast implant ** Buttock implant **Cochlear implant **Contraceptive implant **Dental implant ** Fetal tissue implant ** Implantable cardioverter-defibrillato ...

, or

intranasally Nasal administration, popularly known as snorting, is a route of administration in which drugs are insufflated through the nose. It can be a form of either topical administration or systemic administration, as the drugs thus locally delivered ...

as a

. Injectables have been formulated for daily, monthly, and quarterly use, and implants are available that can last from one month to a year. With the exception of gonadorelin, which is used as a progonadotropin, all approved GnRH agonists are used as

antigonadotropin An antigonadotropin is a drug which suppresses the activity and/or downstream effects of one or both of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This results in an inhibition of the hypothalamic-pitui ...

s. The clinically used desensitizing GnRH agonists are available in the following

pharmaceutical formulation Pharmaceutical formulation, in pharmaceutics, is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product. The word ''formulation'' is often used in a way that includes dosage ...

s: * Short-acting injection (once per day):

histrelin Histrelin acetate, sold under the brand names Vantas and Supprelin LA among others, is a nonapeptide analogue of gonadotropin-releasing hormone (GnRH) with added potency.

* Long-acting depot injection or injected pellet (once every one to six months):

* Injected implant (once every one to three months):

* Surgically implanted pellet (once per year):

histrelin Histrelin acetate, sold under the brand names Vantas and Supprelin LA among others, is a nonapeptide analogue of gonadotropin-releasing hormone (GnRH) with added potency.

* Nasal spray (two to three times per day):

Contraindications

GnRH agonists are

pregnancy category The pregnancy category of a medication 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 ...

X drugs.

Side effects

Common side effects of the GnRH agonists and antagonists include symptoms of hypogonadism such as hot flashes, gynecomastia, fatigue, weight gain, fluid retention, erectile dysfunction and decreased libido. Long term therapy can result in metabolic abnormalities, weight gain, worsening of diabetes and osteoporosis. Rare, but potentially serious adverse events include transient worsening of prostate cancer due to surge in testosterone with initial injection of GnRH agonists and pituitary apoplexy in patients with pituitary adenoma. Single instances of clinically apparent liver injury have been reported with some GnRH agonists (histrelin, goserelin), but the reports were not very convincing. There is no evidence to indicate that there is cross sensitivity to liver injury among the various GnRH analogues despite their similarity in structure. There is also a report that GnRH agonists used in the treatment of advanced

may increase the risk of heart problems by 30%.

Pharmacology

GnRH agonists act as

s of the

, the

biological target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...

gonadotropin-releasing hormone Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released ...

(GnRH). These drugs can be both

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

s and

small-molecule Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ...

s. They are modeled after the hypothalamic neurohormone GnRH, which interacts with the GnRH receptor to elicit its biologic response, the release of the

pituitary In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The hypoph ...

hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...

follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, ...

(FSH) and

luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) ...

(LH). However, after the initial "flare" response, continued stimulation with GnRH agonists desensitizes the pituitary gland (by causing GnRH receptor downregulation) to GnRH. Pituitary desensitization reduces the secretion of LH and FSH and thus induces a state of hypogonadotropic hypogonadal anovulation, sometimes referred to as "pseudomenopause" or "medical oophorectomy." GnRH agonists are able to completely shutdown gonadal testosterone production and thereby suppress circulating testosterone levels by 95% or into the castrate/female range in men. 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"). Levels of LH may increase by up to 10-fold, while levels of testosterone generally increase to 140 to 200% of baseline values. However, after continuous administration, a profound hypogonadal effect (i.e. decrease in FSH and LH) is achieved through receptor

downregulation In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary pr ...

by internalization of receptors. Generally this induced and reversible

hypogonadism Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estroge ...

is the therapeutic goal. During the flare, peak levels of testosterone occur after 2 to 4 days, baseline testosterone levels are returned to by 7 to 8 days, and castrate levels of testosterone are achieved by 2 to 4 weeks. Following the cessation of exogenous GnRH agonists, it takes 5 to 8 days before normal gonadotropin secretion is completely restored. Various medications can be used to prevent the testosterone flare and/or its effects at the initiation of GnRH agonist therapy. These include

s such as

progestogen Progestogens, also sometimes written progestagens or gestagens, are a class of natural or synthetic steroid hormones that bind to and activate the progesterone receptors (PR). Progesterone is the major and most important progestogen in the bod ...

s like

cyproterone acetate Cyproterone acetate (CPA), sold alone under the brand name Androcur or with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the treatment of androgen-dependent condition ...

and chlormadinone acetate and

s like

diethylstilbestrol Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication, which is presently rarely used. In the past, it was widely used for a variety of indications, including pregnancy support for those with ...

, fosfestrol (diethylstilbestrol diphosphate), and

estramustine phosphate Estramustine phosphate (EMP), also known as estradiol normustine phosphate and sold under the brand names Emcyt and Estracyt, is a dual estrogen and chemotherapy medication which is used in the treatment of prostate cancer in men. It is taken ...

;

antiandrogen Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the ...

s such as nonsteroidal antiandrogens like flutamide, nilutamide, and

bicalutamide Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical remo ...

; and

androgen synthesis inhibitor An androgen synthesis inhibitor is a type of drug which inhibits the enzymatic synthesis of androgens, such as testosterone and dihydrotestosterone (DHT). They include: * CYP17A1 inhibitors (17α-hydroxylase/17,20-lyase inhibitors): inhibit the syn ...

s such as

ketoconazole Ketoconazole, sold under the brand name Nizoral among others, is an antiandrogen and antifungal medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous ca ...

and

abiraterone acetate Abiraterone acetate, sold under the brand name Zytiga among others, is a medication used to treat prostate cancer. Specifically it is used together with a corticosteroid for metastasis, metastatic Prostate cancer#Castration-resistant cancer, ca ...

Chemistry

GnRH agonists are synthetically modeled after the natural GnRH decapeptide with specific modifications, usually double and single substitutions and typically in position 6 (amino acid substitution), 9 (alkylation) and 10 (deletion). These substitutions inhibit rapid degradation. Agonists with two substitutions include:

histrelin Histrelin acetate, sold under the brand names Vantas and Supprelin LA among others, is a nonapeptide analogue of gonadotropin-releasing hormone (GnRH) with added potency.

, and

. The agents

and

are agonists with single substitutions at position 6.

Veterinary uses

GnRH analogues are also used in

. Uses include: * Temporary suppression of fertility in female dogs * Induction of ovulation in mares

References

External links

Buserelin website

Lupron, by manufacturer

10th International Symposium on GnRH

SupprelinLA, by Endo Pharmaceuticals, Inc.

Information of use of Zoladex in prostate cancer
{{DEFAULTSORT:Gonadotropin-Releasing Hormone Agonist Antiandrogens Antiestrogens Antigonadotropins Fertility medicine Hormonal antineoplastic drugs Gonadotropin-releasing hormone and gonadotropins Progonadotropins

Medical uses

Available forms

Contraindications

Side effects

Pharmacology

Chemistry

Veterinary uses

See also

References

External links