Gonadotropin-releasing hormone agonist

A gonadotropin-releasing hormone agonist (GnRH agonist) 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.

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 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:

1. leuprolide (Lupron, Eligard)
2. buserelin (Suprefact, Suprecor)
3. nafarelin (Synarel)
4. histrelin (Supprelin)
5. goserelin (Zoladex)
6. deslorelin (Suprelorin, Ovuplant)

Triptorelin is an agonist with only a single substitution at position 6.

Leuprolide	Buserelin	Nafarelin	Histrelin
Goserelin	Deslorelin

Administration

These medications can be administered intranasally, by injection, 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 cancers 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 cancer and have been used in patients with breast cancer.
• Treatment of delaying puberty in individuals with precocious puberty.
• Management of female disorders that are dependent on estrogen productions. Women with menorrhagia, endometriosis. adenomyosis, or uterine fibroids may receive GnRH agonists to suppress ovarian activity and induce a hypoestrogenic state.
• Sex reassignment of male to female transsexuals.
• IVF therapy: they allow for better control of ovarian stimulation 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 gonadotropins (hCG) to trigger ovulation.
• Severe cases of congenital adrenal hyperplasia
• Temporary Suppression of Fertility in Male Dogs
• Induction of Ovulation in Mares

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.

Side effects

Side effects of the GnRH agonists are signs and symptoms of hypoestrogenism, 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%^[1].

See also

• Gonadotropin-releasing hormone antagonists

A recently published study by Keating et al was reported in the Journal of the National Cancer Institute , in which they analyzed Veterans Healthcare Administration data from 37443 patients with prostate cancer in order to determine the impact of orchiectomy, antiandrogen or GnRH agonist treatment on risk of diabetes, heart disease or stroke.

Overall, 39% of the members of this cohort received some sort of androgen deprivation treatment, and application of GnRH agonist was by far the most widely used therapeutic strategy (by 96% of treated patients). Strikingly, this treatment was also associated with a statistically significant increase in risk for developing diabetes, coronary heart disease, myocardial infarction, sudden cardiac death and stroke. These data represent for the first time that GnRH agonist has been formally associated with stroke risk, raising concerns that should be noted by physicians considering such treatment for their patients. On the other hand, oral antiandrogen treatment appears relatively safe within the context of this study; even when applied in combination with GnRH agonist, the only notable increase in risk was for coronary heart disease.

Interestingly, the researchers also found that patients who were currently receiving androgen deprivation treatment were specifically at greater risk for myocardial infarction than patients who had simply received such treatment at some point during the full course of the study, raising the possibility that ongoing therapy may have a direct effect on thrombosis formation.

Above quotes from Prostate Cancer and Prostatic Diseases (2010) 13, 2-5; dol: 10.1038/pcan.2009.66

Original research paper: Keating NL et al. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst 2010; 102: 39-46

External links

• Use of agonists in endometriosis
• Lupron, by manufacturer
• Buserelin website
• Information of use of Zoladex in prostate cancer
• 10th International Symposium on GnRH

References