Gonadotropin releasing hormone agonists (GnRH-A)

A gonadotropin-releasing hormone agonist (GnRH agonist) affects gonadotropins and sex hormones.


GnRH agonists act as agonists of the GnRH receptor, the biological target of gonadotropin-releasing hormone (GnRH). 


Gonadotropin-releasing hormone agonists can be both peptides and small-molecules. 


GnRH agonists indications include: 


Fertility medicine 


To lower sex hormone levels in the treatment of hormone-sensitive cancers such as prostate cancer and breast cancer


Certain gynecological disorders like heavy periods and endometriosis


High testosterone levels in women, early puberty in children, as a part of transgender hormone therapy, and to delay puberty in transgender youth.



GnRH agonists side effects are related to sex hormone deficiency and include: symptoms of low testosterone levels and low estrogen levels such as hot flashes, headaches, sexual dysfunction, vaginal atrophy, penile atrophy, osteoporosis, infertility, and diminished sex-specific physical characteristics. 


Long-term male and female patients should undergo annual DEXA scans to appraise bone density.

 

As  agonists of the GnRH receptor they  work by increasing or decreasing the release of gonadotropins and the production of sex hormones by the gonads. 


GnRH agonists can lower sex hormone levels by 95% in both sexes.


GnRH agonists are useful in:


Suppression of spontaneous ovulation is an essential component in in vitro fertilization (IVF). 


After GnRH agonists have induced a state of hypoestrogenism, exogenous FSH is given to stimulate ovarian follicle.


This is followed by human chorionic gonadotropins (hCG) to trigger oocyte release. 


GnRH agonists routinely used for this purpose are: buserelin, leuprorelin, nafarelin, and triptorelin.


After controlled ovarian hyperstimulation by GnRH agonist to suppress spontaneous ovulation, using a GnRH antagonist promotes final maturation induction.


GnRh agonists are commonly used in the medical management of prostate cancer and have been used in patients with breast cancer.


GnRh agonists are used to  delay puberty in individuals with precocious puberty, and pending treatment decisions in children with gender dysphoria.


Management of female disorders dependent on estrogen production: Women with menorrhagia, endometriosis, adenomyosis, or uterine fibroids may receive GnRH agonists to suppress ovarian activity and induce a hypoestrogenic state.


Suppressing sex hormone levels in transgender people, especially transgender women.


Hyperandrogenism, such as in congenital adrenal hyperplasia.


Pharmacologic treatment of sexual offenders or men with a high risk of sexual offending.


GnRH agonists that have been marketed and are available for medical use include buserelin, gonadorelin, goserelin, histrelin, leuprorelin, nafarelin, and triptorelin. 


GnRH agonists can be administered by injection, by implant, or intranasally as a nasal spray. 


Injectable GnRH  have been formulated for daily, monthly, and quarterly use, and implants are available that can last from one month to a year. 


All  approved GnRH agonists are used as antigonadotropins.


Treatment supplants the physiologic effect of pulsatile endogenous GnRH by down regulating its receptors in the pituitary gland leading to castrate levels of testosterone by 3 weeks.

Initially causes a surge of testosterone and can cause a flare reaction in metastatic prostate cancer.


Physiologically released from the hypothalamus in a pulsatile manner and goes to the anterior pituitary gland where it stimulates release of luteinizing hormone.

There is an initial “flare” response, but continued stimulation with GnRH agonists desensitizes the pituitary gland causing GnRH receptor downregulation to GnRH. 


The pituitary desensitization reduces the secretion of LH and FSH and thus induces a state of hypogonadotropic hypogonadal anovulation, “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, so initially there is an increase in FSH and LH secretion (so-called the flare effect.


With the flare effect LH levels may increase by up to 10-fold, while levels of testosterone generally increase to 140 to 200% of baseline values.


With continued  administration, a profound hypogonadal effect with decreased FSH and LH is achieved through receptor downregulation by internalization of receptors.


Continued  administration induces a reversible hypogonadism state that is its therapeutic goal. 


With 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 cessation of an  GnRH agonist it takes 5 to 8 days before normal gonadotropin secretion is completely restored.


To prevent flare some recommend that patients with metastatic prostate cancer be pre-treated with an androgen agonist to block the effects of testosterone surge on peripheral androgen receptors.

Agents used to prevent the testosterone flare and/or its effects at the initiation of GnRH agonist therapy: antigonadotropins such as progestogens like cyproterone acetate and chlormadinone acetate and estrogens like diethylstilbestrol, and estramustine phosphate; antiandrogens such as nonsteroidal antiandrogens like flutamide, nilutamide, and bicalutamide; and androgen synthesis inhibitors such as ketoconazole and abiraterone acetate.


Associated with an increased risk of developing diabetes, heart disease, myocardial infarction, and sudden cardiac death than men not on hormonal therapy for prostate cancer.

Elevated risks of diabetes and cardiovascular disease can begin as soon as 1-4 months after the initiation of treatment and remains elevated with continued use of the drug.

GnRH agonist use associated with a 44% increase incidence of diabetes, 16% increase in coronary heart disease, 11% increase in myocardial infarction, and a 16% increase in sudden cardiac death in Seer data (Keating NL et al).


GnRH agonists used in the treatment of advanced prostate cancer may increase the risk of cardiac problems by 30%.


Can be used for medical castration and they do not cause testosterone surge.

Associated with anaphylaxis in 3.7% of cases.

When Utilized for palliation in advanced prostate cancer in patients there may be an  initial increase in testosterone levels: with  a risk of neurological damage if metastases is present, where there is ureteral or bladder outlet obstruction from malignant disease or severe bone pain from metastases is present.


It is recommended adding an anti-androgen for the first few weeks after the initiation of a Gonadal hormone releasing hormone agonist.

Leuprorelin, is one of the most widely used GnRH agonists.



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