Triptorelin – a GnRH Agonist Peptide, Useful in Treatment of Prostate Cancer, Endometriosis, CPP
Gonadotropin releasing hormones (GnRH), secreted by the hypothalamus, are responsible for the synthesis and secretion of the follicle stimulating hormone (FSH) and luteinizing hormone (LH). These activities of the Endocrine system are low during the childhood phase but are at its peak during puberty.
GnRH activity is vital for human fertility. Fertility is affected when GnRH pulsatility gets impaired due to excessive malnutrition, aging and disorders such as hypogonadotropic hypogonadism and polycystic ovary syndrome (PCOS)(1).
While there are medications to treat disorders and possibly combat aging side effects, there are various side effects associated with it. The synthetic peptide called Triptorelin is a known compound, which helps fight GnRH deficiency or inefficiency with minimal adverse impacts and high biocompatibility.
What is Triptorelin?
Triptorelin is a synthetic peptide composed of ten amino acids and is similar to gonadotropin releasing hormones (GnRH)(2).
Triptorelin acts on the pituitary gland to stimulate the synthesis and release of the LH and FSH hormones, which are both vital for testosterone production in males and for estrogen synthesis in females (3).
Professor Andrew Schally and his colleagues first discovered and identified the GnRH hormone in 1971 and also determined the decapeptide amino acid sequence (4).
Professor Schally was awarded the Nobel Prize in 1977 for this discovery (4).
How Does Triptorelin Work?
As an agonist analog of gonadotropin releasing hormone (GnRH), Triptorelin binds to the receptors in the pituitary gland which stimulates the secretion of LH and FSH. This at first causes an upsurge in the initial phase of LH and FSH stimulation. Later, as the receptors become less sensitive to the compound (i.e., downregulation of the receptors), it leads to reduced release of LH and FSH.
The reduction in the levels of LH and FSH hormones eventually leads to decrease in the levels of male and female hormonal levels, namely testosterone and estrogen. This event later leads to the suppression of steroidogenesis by ovaries and testicles(5). Usually, after continuous use of the peptide, within the first four weeks of use, it causes a sustained decline in the LH and FSH secretion.
Advantages of Using Triptorelin
The main uses of the peptide are (6):
- Treating prostate cancer in men
- Potentially treating breast cancer in women
- Treating central precocious puberty (CPP) in children. This condition is characterized by early puberty in children (before 9 years in boys; and before 8 years in girls)
- Protecting fertility
- Potential use in combating endometriosis
- Possible use to restore immune function
Research and Clinical Studies
Treatment of Prostate Cancer
The prostate is a small gland in males producing seminal fluid to transport the sperm. This is one of the most common types of cancer in men (7).
One of the most prominent ways to treat prostate cancer is androgen deprivation therapy (ADT). Usually, for the treatment, the plasma levels of testosterone are reduced to <50 ng/dl (8). As part of this study (8), a retrospective analysis was conducted where the efficacy of 1, 3, and 6-month treatment with Triptorelin was studied. 920 male patients, aged between 42 and 96 years, suffering from prostate cancer were enrolled in this study. These patients were either never treated for their prostate cancer or had undergone complete washout prior to commencing this study. During the 12 months, the testosterone levels were analyzed after 1, 3, 6, 9 and 12 months of peptide treatment. Upon analyzing, it was found that 80%, 92%, 93%, 90% and 91% of patients (respectively) showed plasma testosterone levels of <20 ng/dl. This demonstrated that Triptorelin effectively reduces the levels of testosterone, which can thus be used in treating prostate cancer.
Role in Endometriosis Treatment
Endometriosis is an ailment characterized by a condition where the tissue of the uterus grows outwardly in the body outside of the womb. This leads to excessive stomach ache, heavy menstruation and infertility (9).
In this clinical trial (10), 45 women suffering from endometriosis were treated with a 3.75mg dose of Triptorelin via intramuscular route every 4 weeks. To analyze the peptide efficacy, parameters such as symptom relief, reduction in endometrium size, hormonal effects, modulations in bone mineral density and regular menstruation were measured after the treatment.
After 8 weeks, the pain associated symptoms had decreased in all candidates. The levels of FH and LSH had decreased in all patients, while the cholesterol and triglycerides level had slightly increased. Menstruation commenced typically 2 to 3 days after Triptorelin administration.
Some adverse effects observed included excessive sweating at nights, vaginal dryness, nausea, and headache. Overall, the study demonstrated that long term treatment of the peptide can be used to treat and manage endometriosis.
Adjuvant Therapeutic Agent for Breast Cancer Treatment
In this randomized phase III clinical trial (11), 1065 premenopausal females diagnosed with early breast cancer were enrolled. All candidates received Triptorelin as well as either Tamoxifen, Letrozole or Zoledronic acid for five years. While Tamoxifen and Letrozole are used to treat breast cancer, Zoledronic acid is mainly used to treat osteoporosis conditions.
After 64 months and follow up analysis, the disease-free rate in the candidates was determined to be 85%, 93.2% and 93.3% in patients co-treated with Tamoxifen, Letrozole or Zoledronic acid.
Throughout this period, the treatment was stopped in about 7-16% of patients either due to refusal or due to toxic adverse effects. This study demonstrated that the peptide can successfully be used to co-treat and co-manage breast cancer.
Use in Fertility Preservation
Triptorelin can be administered in post pubertal females who are receiving chemotherapy in order to suppress menstruation and decrease the risk of hemorrhage.
In this study (12), all female patients undergoing chemotherapy who were also treated with Triptorelin, from 2000 to 2015, were monitored. The candidates were evaluated for their long-term ovarian functions – whether there were any signs of damage, miscarriages, and pregnancies.
Out of the 36 patients, 27 candidates maintained optimal ovarian functions, five of whom also achieved a physiological pregnancy. 9 patients had undergone hematopoietic stem cell transplantation (HSCT), four of whom developed ovarian failure.
This study demonstrates that Triptorelin can potentially be used to prevent ovarian failure in patients treated without HSCT.
Role in Treatment of Central Precocious Puberty (CPP)
This was the first study conducted to examine the effects of Triptorelin 22.5 mg dose in treating Central Precocious Puberty (CPP). The study(14) was conducted for 48 weeks, and the main objective was to achieve LH suppression at prepubertal levels.
44 children (39 girls and 5 boys), who were never previously treated for CPP, were enrolled in this study. They were all administered with the peptide at a dose of 22.5 mg via the intramuscular route twice, with an interval of 24 weeks in between.
At the end of this study, it was seen that the peptide caused suppression of LH at month 6 and maintained the levels through month 12 in 41 patients. There were no reported cases of any drug associated adverse events.
This study demonstrated that Triptorelin was safe to be administered in young children in order to treat the rare body condition where the children’s body matures at an unusually early stage. Furthermore, the extended interval of 24 weeks may help improve drug compliance and better drug management.
Triptorelin Side Effects
Some known adverse or side effects caused by exogenous administration of Triptorelin include:
- Tenderness in breast
- Modifications in breast size
- Mood swings
- Skin rashes
- Changes in weight
- Excessive night sweating
- Fluid retention
Below listed are extremely rare yet potentially occurring adverse events caused upon using Triptorelin (3):
- Long term use leading to diabetes, osteoporosis, and metabolic changes
Chronic, long-term use of Triptorelin may lead to increased levels of serum enzyme in ~5% of patients. However, these levels are rarely extremely high and may be mild, able to resolve on their own without any dose modulations or peptide discontinuations (3).
Precautions to Be Considered Before Drug Administration
Triptorelin is not recommended to be administered while being on other medications and with having pre-existing health conditions(6). It is recommended to consult the medical practitioner in both cases as it may require some dose alterations.
Peptide Drug Profile
Triptorelin (as brand Trelstar) is an injectable suspension administered via the intramuscular route at the dose rate of 3.75 mg (every 4 weeks), 11.25 mg (every 12 weeks) and 22.5 mg (every 24 weeks)(3).
Pharmacokinetics and Pharmacodynamics
GnRH agonists such as Triptorelin are the derivative analogues of native, naturally occurring molecules where one of the amino acids at position 6 is substituted. As a result of this alteration, the peptide is highly resistant towards enzymatic lysis and has higher affinity towards its receptors. Due to this increased resistance towards breakdown, the peptides have a longer half-life than normal (13).
While the peptide metabolism is not fully known, it gets eliminated from the body mostly via urine elimination (5). The average half life of the peptide is approximately 3 hours, which may be impacted if the patient is suffering from either renal or hepatic impairment (5).
Triptorelin is a gonadotropin releasing hormone (GnRH) agonist decapeptide that helps optimize the levels of gonadotropins luteinizing hormone and follicle stimulating hormone. While also available in its generic form, this peptide is mainly sold under the brand name Trelstar in the US (6).
Triptorelin primarily acts on the pituitary gland receptors and causes its downregulation, which helps suppress the LH and FSH levels. This can be extremely useful in the treatment of major ailments such as prostate cancer, endometriosis and Central Precocious Puberty.
While Triptorelin has been approved for use in the US since 2000 for the treatment of prostate cancer (3), research is still ongoing to fully utilize the benefits of this peptide in treating other common disorders.
1. Tsutsumi, Rie, and Nicholas J G Webster. “GnRH pulsatility, the pituitary response and reproductive dysfunction.” Endocrine journal vol. 56,6 (2009): 729-37. doi:10.1507/endocrj.k09e-185. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4307809/
2. National Center for Biotechnology Information. PubChem Compound Summary for CID 25074470, Triptorelin. https://pubchem.ncbi.nlm.nih.gov/compound/Triptorelin.
3. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Triptorelin. https://www.ncbi.nlm.nih.gov/books/NBK548756/
4. Lepor, Herbert. “Comparison of single-agent androgen suppression for advanced prostate cancer.” Reviews in urology vol. 7 Suppl 5 (2005): S3-S12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1477619/
5. Triptorelin. https://www.drugs.com/ppa/triptorelin.html
6. Triptorelin (Intramuscular Route). https://www.mayoclinic.org/drugs-supplements/triptorelin-intramuscular-route/description/drg-20066536
7. Prostate cancer. https://www.mayoclinic.org/diseases-conditions/prostate-cancer/symptoms-causes/syc-20353087
8. Breul J, Lundström E, Purcea D, Venetz WP, Cabri P, Dutailly P, Goldfischer ER. Efficacy of Testosterone Suppression with Sustained-Release Triptorelin in Advanced Prostate Cancer. Adv Ther. 2017 Feb;34(2):513-523. doi: 10.1007/s12325-016-0466-7. Epub 2016 Dec 27. https://pubmed.ncbi.nlm.nih.gov/28028737/
9. Endometriosis Health Center. https://www.webmd.com/women/endometriosis/default.htm
10. Choktanasiri W, Boonkasemsanti W, Sittisomwong T, Kunathikom S, Suksompong S, Udomsubpayakul U, Rojanasakul A. Long-acting triptorelin for the treatment of endometriosis. Int J Gynaecol Obstet. 1996 Sep;54(3):237-43. https://pubmed.ncbi.nlm.nih.gov/8889631/
11. Francesco Perrone et al, Adjuvant zoledronic acid and letrozole plus ovarian function suppression in premenopausal breast cancer: HOBOE phase 3 randomised trial. June 01, 2019. https://doi.org/10.1016/j.ejca.2019.05.004
12. Meli M, Caruso-Nicoletti M, La Spina M, Nigro LL, Samperi P, D’Amico S, Bellia F, Miraglia V, Licciardello M, Cannata E, Marino S, Cimino C, Puglisi F, Valvo LL, Pezzulla A, Russo G, Di Cataldo A. Triptorelin for Fertility Preservation in Adolescents Treated With Chemotherapy for Cancer. J Pediatr Hematol Oncol. 2018 May;40(4):269-276. https://pubmed.ncbi.nlm.nih.gov/29620680/
13. Lahlou N. Pharmacocinétique et pharmacodynamique de la triptoréline [Pharmacokinetics and pharmacodynamics of triptorelin]. Ann Urol (Paris). 2005 Oct;39 Suppl 3:S78-84. French. https://pubmed.ncbi.nlm.nih.gov/16302716/
14. Klein K, Yang J, Aisenberg J, Wright N, Kaplowitz P, Lahlou N, Linares J, Lundström E, Purcea D, Cassorla F. Efficacy and safety of triptorelin 6-month formulation in patients with central precocious puberty. J Pediatr Endocrinol Metab. 2016 Nov 1;29(11):1241-1248. https://pubmed.ncbi.nlm.nih.gov/26887034/
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