Facts About Gonadorelin – a GnRH Agonist Peptide
Gonadotropin hormone releasing hormones (GnRH) are vital chemicals regulating the reproductive axis in humans. The regular secretion of these GnRH hormones set a flow in the secretion of gonadotropins, i.e. follicle stimulating hormone (FSH) and luteinizing hormone (LH), both of which then help manage and regulate the endocrine functioning and maturation of the gonads (1).
Maintaining the functioning and maturation of the gonads is critical as these gonads are responsible for the synthesis of sex hormones in the body, which thereby influence the working of the reproductive system (1).
Hypogonadotropic Hypogonadism is one of the main causes of GnRH deficiency in humans.
There are several causes of this ailment including, but not limited to, damage to the pituitary and hypothalamus gland, mainly from injury or tumor, genetic defects, and irregular doses of steroidal medications (2).
While there are several pharmaceutical medications to treat and manage GnRH deficiency, one of the best therapeutic agents is a synthetic peptide called Gonadorelin.
What is Gonadorelin
Gonadorelin is a synthetic peptide composed of ten amino acids, all joined to one another in a sequential form (3). Gonadorelin is structurally similar to the endogenous GnRH, except for 1-2 amino acid changes in the sequence (4).
Identical to the endogenous GnRH hormones, Gonadorelin is a peptide hormone that acts a GnRH agonist and helps regulate the levels of gonadotropins in the body, thereby managing the reproductive system in humans (3).
Gonadotropin releasing hormones (GnRH) were first discovered in the early 1970s by Professor Andrew Schally and his colleagues, who also determined the decapeptide amino acid sequence (5).
Since its discovery, GnRH has been extensively studied and researched on to fully understand its therapeutic benefits and help mankind combat various ailments, especially the ones pertaining to the reproductive axis.
Functioning of Gonadorelin
The peptide stimulates the synthesis and release of gonadotropins LS and FSH in the body by stimulating the anterior pituitary gland (5). This is mainly the reason why they are called the GnRH agonists, as they stimulate the same effect as GnRH.
When administered at high, sustained doses, Gonadorelin also causes downregulation of the GnRH receptors located at the pituitary gland. This is the peptide hormone that binds to the receptors, which at first, for a short period, stimulates the secretion of the gonadotropins. Eventually, the receptors become less sensitive towards this peptide, aka downregulation of the receptors, which then reversibly inhibits the release of LH and FSH (5).
Therapeutic Benefits of Gonadorelin
The biological advantages of the peptide include (7):
- As a diagnostic tool to determine if the hypothalamus and pituitary gland function well
- To induce ovulation in women with irregular menstrual cycles
- Potential agent to treat breast cancer
- To combat prostate cancer
- Potentially reduce the risk of dementia
- May be used to treat ovarian cancer and osteoporosis in women
Research and Clinical Studies
Treatment of Breast Cancer
One of the causes of breast cancer is the excessive exposure of breast cells to the breast cell mitogens, namely estrogen and progesterone. By blocking the effect of these mitogens, and thereby reducing the exposure of the breast cells to them, the risk of breast cancer can be reduced (8).
One of the ways to effectively reduce the risk of breast cancer is by using GnRH agonists such as Gonadorelin. It is predicted that by using these peptide hormones for 10 years, the risk of breast cancer is reduced by 50%, and by using it for 15 years, the risk is reduced by 70% (8).
Furthermore, studies (9) have shown that gonadotropin releasing hormone analogs, such as Gonadorelin, are safe to use in postmenopausal women who are at increased risk of breast cancer. These women with high testosterone levels, which is a marker for ovarian hyperandrogenemia (a condition characterized by excessive androgen synthesis), are at higher risk of breast cancer. The source of androgen, and thereby the potential source of breast cancer, can be counteracted with the use of GnRH analogs, which lead to reduction in the substrate for estrogen synthesis, but does not inhibit the synthesis of estrogen completely.
Treatment of Prostate Cancer
Prostate Cancer has become one of the most common causes of male death associated with cancer, only second to lung cancer. While there are several therapeutic options to treat prostate cancer, optimal hormonal therapy is one of the novel, least non-invasive therapy used so far (10).
Hormonal therapy includes the use of GnRH analogs such as Gonadorelin and other similar compounds. These compounds inhibit the production of LH hormones due to the downregulation of the GnRH receptors, which thereby cause a decline in the testosterone and dihydrotestosterone production. Development of the prostate cancer cells depends on these testosterone levels, which, by the use of GnRH analogs, can be effectively inhibited.
Studies (10) have shown that GnRH analogs are efficacious in treating prostate cancer when administered either daily or as monthly depots. Administering these analogs in conjunction to radiotherapy or chemotherapy may also be a useful option in treating patients with highly progressive cancer.
Role in Suppression of Spermatogenesis and Gonadotropins
In this study(11), seven healthy men were treated with 400 micrograms of GnRH analogue every day for up to 16 weeks via subcutaneous route, and with 200 mg of testosterone enanthate dose administered bimonthly via injectable route. Basal serum FSH, LH and T levels were checked throughout the treatment.
After 14 to 16 weeks, it was noticed that the average sperm count had reduced by 93%, also causing azoospermia in three men. Azoospermia is a condition characterized by a complete absence of sperms in the ejaculate.
Subsequently, once the treatment was stopped, the average sperm count returned to normal indicating that the effect of the peptide hormone is reversible.
Based on this study, it can also be predicted that the effects are dose dependent, and a higher dose of GnRH analog, such as Gonadorelin, will induce further reduction in sperm count, potentially azoospermia, in all men.
Potential to Prevent Dementia
Research(12) has shown that sex hormones, specifically the LH hormone, act on the brain, primarily the hippocampus, which is the memory center of the brain, and cause its dysfunction. This dysfunction leads to decreased memory performance, thereby inducing dementia and Alzheimer’s disease.
One of the ways to prevent the development of dementia is to block the production and release of LH hormone, which can be achieved by GnRH analogs such as Gonadorelin.
Testosterone helps preserve memory function and is beneficial to brain function. Hence, inhibiting the entire gonadal axis is not fully beneficial. This is why GnRH, which has selective inhibitory effects on LH hormone, is being studied in humans, to help prevent any development of dementia and Alzheimer’s disease(13). The results so far have been promising, however, more analysis and clinical trials are anticipated.
Role as Diagnostic Agent
In this study (14), synthetic Gonadorelin was administered in 11 healthy women during the middle of the follicular phase of the menstrual cycle. All patients showed a significant increase in the basal levels of gonadotropins.
In addition, 10 patients suffering from amenorrhea were also injected with 80 micrograms of Gonadorelin via the intravenous route. Amenorrhea is an ailment characterized by irregular periods, with no menstruation for long periods up to 3 months. After the first 80 microgram dose, the basal levels of gonadotropins, particularly the LH levels, increased within the first hour of administration.
Interestingly, when a second dose of 80 microgram Gonadorelin was administered in the same 10 patients after 2 hours, the levels of gonadotropins did not show any significant increment.
This study shows that the pituitary secretion of LH and FSH hormones by Gonadorelin does not depend on the basal levels of these hormones, however, it depends on the functioning of the hypothalamic and pituitary axis. The higher the severity of the hypothalamic and pituitary axis disturbance, the more the secretion of the gonadotropins.
Hence, Gonadorelin is a promising supplement to diagnostic tests to determine the functioning of the gonadal axis.
Side Effects Caused by Gonadorelin
The known side effects caused by the exogenous administration of the peptide include:
- Abdominal pain
- Redness, pain, swelling at the site of injection
Gonadorelin use in the presence of other medical ailments
Gonadorelin should be avoided in the presence of other medical problems as listed below (7):
- Gonadotropin releasing hormone adenoma: This condition is characterized by an occurrence of non-carcinogenic tumors. This event is an extremely rare condition; however, it is extremely crucial to monitor Gonadorelin administration, if taken with this condition, as it may lead to sudden blindness.
- Presence of hormone dependent tumors: Gonadorelin should not be administered in patients having tumors that can be worsened by the increased presence of androgens in the body.
Gonadorelin is also not recommended to be co-administered while being on other medications and with having pre-existing health conditions (7).
Peptide Drug Profile – Pharmacokinetics and Pharmacodynamics
Gonadorelin is known to have a short distribution half-life of 2 to 10 minutes, as it is fully distributed and starts showing effects in this time frame.
The terminal half-life of the peptide is up to 40 minutes. The peptide undergoes hydrolysis by the endogenous enzymes and is broken down into smaller, inactive peptide components (15).
Gonadorelin is a potent gonadotropin releasing hormone (GnRH) agonist hormone decapeptide that helps optimize the levels of gonadotropins luteinizing hormone and follicle stimulating hormone in the body. Gonadotropin is available under the brand name Factrel in the US.
Gonadorelin mainly acts on the GnRH receptors located in the pituitary gland and helps regulate the levels of LH and FSH synthesis and release. Gonadorelin is used to treat breast cancer and prostate cancer and is now being researched for its role in dementia, osteoporosis and ovarian cancer.
While Gonadorelin has been studied and approved for use in prostate cancer treatment, the peptide is still being researched to fully explore its benefits and take advantage of its potential in the therapeutic world.
1. Marques P, Skorupskaite K, George JT, et al. Physiology of GNRH and Gonadotropin Secretion. [Updated 2018 Jun 19]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext. South Dartmouth (MA): MDText.com, Inc. https://www.ncbi.nlm.nih.gov/books/NBK279070/
2. Hypogonadotropic Hypogonadism. https://www.pennmedicine.org/for-patients-and-visitors/patient-information/conditions-treated-a-to-z/hypogonadotropic-hypogonadism
3. National Center for Biotechnology Information. PubChem Compound Summary for CID 638793, Gonadorelin. https://pubchem.ncbi.nlm.nih.gov/compound/Gonadorelin.
4. Philip GA Thomas, Alain Fontbonne, Drugs and reproduction. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/gonadorelin-acetate
5. Lepor, Herbert. “Comparison of single-agent androgen suppression for advanced prostate cancer.” Reviews in urology vol. 7 Suppl 5,Suppl 5 (2005): S3-S12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1477619/
6. FDA-Approved Drugs. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=018123
7. Gonadorelin (Intravenous Route, Injection Route). https://www.mayoclinic.org/drugs-supplements/gonadorelin-intravenous-route-injection-route/description/drg-20067426
8. Spicer DV, Pike MC. Sex steroids and breast cancer prevention. J Natl Cancer Inst Monogr. 1994;(16):139-47. https://pubmed.ncbi.nlm.nih.gov/7999456/
9. Secreto G, Sieri S, Agnoli C, Grioni S, Muti P, Zumoff B, Sant M, Meneghini E, Krogh V. A novel approach to breast cancer prevention: reducing excessive ovarian androgen production in elderly women. Breast Cancer Res Treat. 2016 Aug;158(3):553-61. https://pubmed.ncbi.nlm.nih.gov/27393623/
10. Zerbib M. Analogues de la GnRH dans le traitement du cancer de la prostate [GnRH analogs and prostate cancer treatment]. Ann Urol (Paris). 2005 Oct;39 Suppl 3:S66-72. French. doi: 10.1016/s0003-4401(05)80011-7. https://pubmed.ncbi.nlm.nih.gov/16302714/
11. Bhasin S, Yuan QX, Steiner BS, Swerdloff RS. Hormonal effects of gonadotropin-releasing hormone (GnRH) agonist in men: effects of long term treatment with GnRH agonist infusion and androgen. J Clin Endocrinol Metab. 1987 Sep;65(3):568-74. https://pubmed.ncbi.nlm.nih.gov/3114307/
12. Rao CV. Involvement of Luteinizing Hormone in Alzheimer Disease Development in Elderly Women. Reprod Sci. 2017 Mar;24(3):355-368. https://pubmed.ncbi.nlm.nih.gov/27436369/
13. R.L Bowen, et al, Not All Androgen Deprivation Therapies Are Created Equal: Leuprolide and the Decreased Risk of Developing Alzheimer’s Disease, J. Clin. Oncol., vol 34, no. 23, p.2800, Aug 2016. https://ascopubs.org/doi/full/10.1200/JCO.2015.66.3997
14. Vesper B, Rohde W, Groot-Wassink T. Ein Beitrag zur klinischen Anwendung von Gonadorelin als Diagnostikum im Einfach- und Doppelbelastungstest [Clinical use of Gonadorelin as a diagnostic agent in one- and two-step tests]. Zentralbl Gynakol. 1986;108(23):1442-52. https://pubmed.ncbi.nlm.nih.gov/3103350/
15. Gonadorelin. https://go.drugbank.com/drugs/DB00644
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