GnRH agonists and antagonists

My opinion:

Besides the irtypical usage in hormone dependent cancers (e.g. prostate, ovarian and breast cancer) to inhibit testosterone or estrogen production, this is a very relevant drug with large anti cancer potential in many other types of cancers. This is because many cancer cells have GnRH receptors. When using the GnRH agonist or antagonists, both will activate those receptors on the cancer cell and will trigger the collapse of cancer cells. Ref

There is a great amount of research indicating that GnRHa and GnRHanta are relevant for multiple types of cancers (since GnRH receptors are expressed in most cancer cells) including adrenal, prostate, breast, ovarian, endometrial, melanoma, glioblastoma, lung,pancreatic cancers, etc. Ref.

Summary & Mechanism

GnRH hormone is produces in the hypothalamus (in a pulsatile way). Once this hormone reaches the GnRH receptor at the pituitary gland, it will stimulate the release of two gonadotropins, LH and FSH, that in turn stimulate the sex steroid production, e.g. at the adrenals and ovary in women stimulating the production of testosterone and estrogen.

With GnRH modulators the GnRH receptor at pituitary gland will be inhibited and as a result the release of testosterone and estrogen will be inhibited. However, there is a major difference on how an agonist and an antagonist works. The agonist will first lead to a strong increase of the testosterone and estrogen release for a short while (which may accelerate cancer growth) after which will induce a desensitization of the GnRH receptors and as a result testosterone and estrogen production will be reduced and finally stooped. The antagonists on the other hand will directly stop the production of LH and FSH at pituitary, and as a result testosterone and estrogen production. From this perspective antagonist are preferred since they do not produce an initial flare of the sex steroids.

However, the GnRH antagonists come with a side effect and that is the release of histamine from mast cells. The histamine may also have cancer growth effects (reference needed) and it is known to stimulate the ACTH production, a hormone produced at pituitary which in turn is triggering the production of Cortisole at the adrenal level. Cortisole on the other hand may have strong negative effect on the immune system (lowering important components of the white blood cells) and lowers the conversion of T4 in T3. (note that an article on this website shows that T4 is promoting tumor growth and this). This is why, when usingGnRH antagonists we should use medication that has anti-histamine action. If that is not possible, that we may want to inhibit the cortisole production using medication such as ketoconazole (note that this has also anti cancer effects but that may induce some toxicity at the liver)

“The anticancer effect seem to be linked to specific intracellular signaling cascades that are coupled to GnRHreceptor in the different tissues: Gaq/phospholipase C pathway in gonadotropes and Gai/cAMP pathway in cancer. Intriguingly, in cancer cells, classical antagonistic GnRH analogs have been reported to behave as GnRH agonists by exerting an antitumor effect through activation of locally expressed GnRH-R.” Ref
The antitomor activity: antiproliferative, antimetastatic, and antiangiogenic (blocks VEGF production)

Case reports

Tbd

Anecdotal reports/stories

Tbd

Safety/Toxicity

Besides the hormonal change that GnRH modulators induces, as a side effect GnRH antagonists are also leading to a release of histamine from the mast cells that in turn may trigger a process that lowers the immune system.

In other words, this is what happens:
1. GnRH antagonist leading to histamine release (side effect)
2. Histamine leads to increased release of ACTH
3. Increased ACTH leads to increased Cortisole
4. Increased Cortisole leads to many negative effects including
– inhibits conversion of T4 in T3
– lowers white blood cells
– etc.
5. Low immune system leads to inflammation, infections, etc.

This is something we want to avoid in most cases (maybe not when there is an auto immune disease). As indicated above anti-histamine medication should be administrated if needed, specifically in hormonal active adrenal cancer.

Supplements such as Vitamin C, Fish oil, MSM, Bromelain, Olive leaf are also suggested to posses antihistamine properties Ref

Note that histamine is known to promote cancer growth and common antihistamine drugs such as Cimetidine and Cetirizine are known to stop that Ref1 Ref2

Here is an article showing the histamine release of Degarelix (Firmagon) compared to other GnRH antagonists. Note that while its profile is the best compared to the others, the histamine release is there.

Preparation & Administration

e.g. Degarelix (Firmagon), a GnRH antagonist:
– first administration 240 mg given as two subcutaneous injections of 120 mg at a concentration of 40 mg/mL
– maintenance dose administrated every28 days is80 mg given as one subcutaneous injection at a concentration of 20 mg/mL Ref

Add antihistamine drugs. I would probably consider both Cimetidine and Cetirizine.

Source & Cost

e.g. Degarelix (Firmagon), a GnRH antagonist costs about 250 euro first month than about 180 euro for each of the next months. It is available at the pharmacy with prescription.

Synergists & Antagonists

Tbd

Clinics Treating Patients with GnRH agonists or antag

Rosenberg Integrative Cancer Treatment and Research Institute http://www.newhopeforcancer.org/about.html

Marinus Am Stein
http://www.klinik-marinus.com/eng/contact.html

Other relevant links:

GnRH Receptors in Cancer: From Cell Biology to Novel Targeted Therapeutic Strategies. Available from: https://www.researchgate.net/publication/229015589_GnRH_Receptors_in_Cancer_From_Cell_Biology_to_Novel_Targeted_Therapeutic_Strategies

Gonadotropin releasing hormone antagonist treatment induces cell cycle arrest in gonadal somatic cell and adrenocortical tumourshttp://www.endocrine-abstracts.org/ea/0037/ea0037ep1134.htm

Experience with degarelix in the treatment of prostate cancer http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547532/

GnRH receptors in cancer: from cell biology to novel targeted therapeutic strategies. http://www.ncbi.nlm.nih.gov/pubmed/22778172
https://www.researchgate.net/publication/229015589_GnRH_receptors_in_cancer_from_cell_biology_to_novel_targeted_therapeutic_strategies

Transcript and protein profiling identifies signaling, growth arrest, apoptosis, and NF-B survival signatures following GNRH receptor activation. http://www.ncbi.nlm.nih.gov/pubmed/23202794

Diversity of actions of GnRHs mediated by ligand-induced selective signalling http://www.ncbi.nlm.nih.gov/pubmed/17976709

Disclaimer:

This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I providegeneral information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I amnot liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just myown personalopinion regardingwhat we have learned on this road.

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