The Efficacy of LHRH Analog Treatments on Prostate Cancer

Abstract

Luteinizing hormone-releasing hormone (LHRH) analogs are a promising androgen deprivation treatment option for patients suffering from prostate cancer. However, there has been no survey of LHRH analog treatment efficacy that considers potential side effects and compatibility with other therapies, such as external beam radiotherapy. Previous work in the field has revealed the function, side effects, and effectiveness of individual LHRH analogs, as well as in combination with external beam radiotherapy. The main issue is that there is no comprehensive overview of the full effects of agonists and antagonists on the human body. This review considers peer-reviewed studies from the past five years about the efficacy of various LHRH agonists and antagonists in the PubMed database. It finds that antagonists generally have reduced side effects such as cardiovascular disease, and reduce the amount of LHRH present in the body. This review also finds that antagonists combined with external beam radiotherapy are linked to a lower incidence of cardiovascular events when compared to agonists combined with external beam radiotherapy. Although this review covers a broad range of the efficacy of LHRH analogs, recent research on the biological effects of LHRH analogs on the human body is limited. More research must be done to thoroughly investigate this type of androgen deprivation therapy and create an effective treatment plan for those with prostate cancer. 

Keywords: LHRH analogs, prostate cancer, external beam radiotherapy, efficacy, cardiovascular side effects

Introduction

Researchers have been exploring the correlation between LHRH and various reproductive cancers since the 1970s. LHRH, or luteinizing hormone-releasing hormone, stimulates the release of luteinizing hormone (LH) in the pituitary gland [1]. The hypothalamus releases LHRH to the anterior pituitary gland, which then releases LH. LH acts on gonads, i.e., testes and ovaries, where it increases the production of sex hormones, namely testosterone or estradiol and progesterone, respectively. These hormones act as inhibitors in a negative feedback loop, signaling that sex hormone production can slow down. This signal is taken back to the hypothalamus where it decreases the amount of LHRH released.

LHRH has been found to be overexpressed in many types of cancer, especially reproductive cancers [2]. The exact role of LHRH in these cancers has not been discovered, but many believe that it could be a localized control mechanism for tumor development [3]. This hormone is always present in the human body but only becomes a serious problem when overexpressed [2]. Because of this, LHRH analogs have been the subject of study for anticancer drugs. LHRH analogs are drugs that act like LHRH, but work to suppress the production of LH. This prevents the growth of reproductive tumors by stopping the production of testosterone [4].

LHRH analogs are molecules that mimic the hormone LHRH but do not stimulate LH production. Administration of LHRH analogs is considered to be a type of androgen deprivation therapy, or ADT, as LHRH analogs inhibit LH production, which reduces sex hormone production. Within LHRH analogs, there is a further categorization of agonists and antagonists. Agonists work by overwhelming LHRH receptors in the pituitary gland, to the point where they become desensitized. First, this creates a great increase in androgens and estrogens, after which the endocrine system takes over, stopping the production of LHRH. This leads to an overall decrease in the production of testosterone. Since the agonist treatment depends on the endocrine system to stop LHRH production, a surge in androgens is necessary to provide negative feedback to the hypothalamus [5]. Antagonists work more directly by binding to and inhibiting LHRH receptors, which blocks the production of LH and testosterone or estrogen [5]. One major advantage that antagonist treatment offers over agonist treatment is that it does not cause a surge in testosterone levels. This surge can cause the tumor to grow for a short period of time before it is suppressed [5]. Instead, antagonists prevent LHRH from even being produced in the first place. To truly understand how these two medications work and how effective they are, the efficacy of each type of medication should be measured and compared.

As a majority of reproductive cancers have LHRH expressed in the tumor, using drugs that deactivate these receptors would help fight various cancers [2]. LHRH analogs have been found to reduce the size of reproductive tumors, so they should be thoroughly studied to analyze their efficacy, both alone and in combination with other treatments. The side effects of LHRH analogs should also be studied to gain a more complete picture of how these drugs work. Understanding the efficacy of these drugs would help inform patients about what may be the best treatment for them. This review aims to discover how different types of LHRH drugs can be used to treat prostate cancer, by exploring their efficacies, cardiovascular side effects, and combinatory effects with external beam radiotherapy.

Efficacy of LHRH Analogs

Research has studied the effectiveness of LHRH analog regimens for prostate cancer. Morote et al. surveyed patients with prostate cancer, particularly those with LUTS, or lower urinary tract symptoms [6]. The researchers compiled data from 28 hospitals to track the effectiveness of LHRH analogs. Patients answered the International Prostate Symptom Score (IPSS) survey while undergoing treatment, where they described their symptoms and answered quality of life questions. The authors found that there was an overall decrease in LUTS during LHRH treatment. However, there was no specific improvement for one symptom; the type of improvement varied between patients throughout the study [6]. This study provides a general overview of the effectiveness of LHRH analogs and their effects on prostate cancer symptoms. A limitation of this study is that it does not directly measure the effectiveness of specific LHRH analogs, like the agonist class or the antagonist class, against specific biomarkers of cancer. Since treating the symptoms of a disease does not necessarily mean that the underlying cause is treated, more studies need to be done on the mode of action of agonists and antagonists.

Agonists currently on the market for prostate cancer include goserelin, triptorelin, and leuprolide. A 2019 study by Shim et al. describes how these three agonists affect the testosterone levels of prostate cancer patients. Through their research, they found that all three agonists cause patients’ serum testosterone level to fall within an effective castration range. By achieving chemical castration through low levels of testosterone, patients’ prostate cancer is not exacerbated by LHRH agonists. LHRH agonists compete with LHRH at the anterior pituitary gland, so there is still a high level of LHRH left in the body. This deters testosterone from being produced as the body believes there is an adequate amount of testosterone, even though LH production is being blocked by the agonists [7]. High levels of testosterone induce lower levels of LHRH through a negative feedback loop, so LHRH activity is effectively reduced, which potentially reduces tumor growth. Triptorelin was the strongest agonist, even though all of them had comparable effects. It had the lowest serum testosterone level, and most patients were defined as being chemically castrated. However, there did not seem to be a clearly defined benefit to lowering testosterone levels [1]. This study continues the investigation of LHRH analogs and explores more about how prostate cancer patients fare under agonist administration. This study cannot be used as direct evidence that agonist treatment is effective against prostate cancer since tumor growth or tumor volume were not directly measured. More studies need to be done to explore the relationship between testosterone levels and prostate cancer after agonist treatment. 

Antagonists currently approved for patient administration include degarelix and relugolix. Sari Motlagh et al. performed a systematic review of the efficacy and side effects of relugolix versus degarelix [8]. The authors used LHRH agonists as a reference point [8]. After comparing the data received from four articles, they found that relugolix was likely to be more effective than degarelix and LHRH agonists. They also found that relugolix and LHRH agonists had a lower likelihood of adverse effects than degarelix [8]. This review goes into more depth than previous work by describing a subset of LHRH analogs and examining the effects antagonists specifically have on prostate cancer patients. This review mentions the side effects that arise due to LHRH antagonist administration but does not describe in detail the specific rates of the adverse effects. This would provide a better review of what drugs specifically cause adverse effects, helping to create a more effective and safe treatment for prostate cancer patients.

Side Effects of LHRH Analogs - Cardiovascular Disease

A well-documented problem for prostate cancer patients is that their medication ends up causing many side effects, especially cardiovascular ones. Finding a medication that does not significantly increase the risk for heart attacks or strokes is important in considering the effectiveness of treatments [9]. In the HERO trial, Shore et al. compared the efficacy and side effects of relugolix, an antagonist, with leuprolide, an agonist [9]. They found that relugolix was more effective than leuprolide in testosterone suppression, and correlated to a lower incidence of cardiovascular problems [9]. A problem with this study, however, is that it was written for the purpose of explicitly comparing the cardiovascular disease incidence between medications. In order to have definitive evidence of one medication being better than the other in terms of side effects, a study must primarily focus on comparing the effects of the two medications instead of using it as a measure to answer a different hypothesis. While this study does not directly focus on cardiovascular events as the main point, other scientists have furthered the investigation into cardiovascular events and their relation to LHRH analogs.

To further the previous study, a direct comparison between LHRH agonists and antagonists was made to explore possible side effects. A 2021 study by Margel et al. studied the serum levels of cardiac biomarkers and the incidence of cardiovascular events occurring in 80 prostate cancer patients who either received an agonist or antagonist treatment. The authors found that high levels of NTproBNP and hsTn, which are biomarkers of increased risk of a cardiovascular event, were seen in the agonist treatment group but not in the antagonist group. The study also found that LHRH agonists were associated with more cardiovascular events and cardiovascular disease than LHRH antagonists [10]. This supports previously established evidence that cardiovascular events are linked to LHRH agonist usage. This study describes itself as an extension of the HERO trial by defining measures of cardiovascular events and tracking them in patients with prostate cancer. Making this study more comprehensive by surveying international patients and increasing the sample size would help extrapolate the results.

Other studies attempt to extrapolate the previous results by engaging international patients. Lopes et al. sought to clarify the connection between LHRH agonists, LHRH antagonists, and their respective cardiovascular effects [11]. The researchers found no significant difference in major adverse cardiovascular events (MACEs) between agonist treatment and antagonist treatment. However, minimal data was collected as the authors could not recruit as many participants as they had planned. There were also few MACEs in the patients that were enrolled, leading to inconclusive results. Wide confidence intervals and low statistical power were reported due to a change in ADT protocols over the study timeframe [11]. To address the major enrollment issues, the authors could narrow their enrollment window to a certain timeframe to prevent a change in protocol. They could also involve more hospitals so that there is a higher rate of prostate cancer patient enrollment. This study attempts to support and improve previous studies by creating a comprehensive randomized trial to describe LHRH agonist and antagonist cardiovascular events. Researchers should pursue a mixed and randomized population of prostate cancer patients to test the overall incidence of cardiovascular side effects from agonist or antagonist treatment. Because of the lack of conclusive evidence from this study, scientists should prioritize obtaining high-quality data to understand the impact of cardiovascular side effects.

Combinatory Effects with External Beam Radiotherapy

Further research has investigated the effects of different androgen deprivation therapies when combined with another cancer treatment, namely external beam radiotherapy (EBRT). Radiotherapy uses directed X-rays or other particles to treat various types of cancers. External beam radiotherapy specifically focuses a radioactive source outside the body on the site of the tumor [12]. Hata et al. examined 78 prostate cancer patients who underwent EBRT after beginning treatment with agonists (goserelin or leuprorelin) or antagonists (degarelix) [13]. They used a toxicity grading scale and the IPSS scale to quantify LUTS, and track how these symptoms changed over the treatment regimen. The authors found that antagonists are more helpful than agonists when either is combined with EBRT in patients with moderate to severe symptoms at the beginning of treatment. This study provides a complete overview of LHRH analog treatment with EBRT, which gives a solid preliminary understanding of the efficacy of these treatments. Gaining more insight into which antagonists specifically are effective with EBRT would help determine effective treatment plans for patients. 

Efforts to investigate specific antagonist therapies with EBRT have been undertaken. A 2020 study by Dearnaley et al. examines the efficacy of relugolix after EBRT. The researchers evaluate the efficacy of relugolix against degarelix, used here as a reference control. Dearnaley et al. found that relugolix in combination with EBRT had a 95% rate of chemical castration, which indicates high efficacy when compared to other LHRH agonists [14]. The study could be further improved by directly comparing relugolix and degarelix to find if one is a better supplement to EBRT. The authors do present evidence that relugolix might be more effective than degarelix, but in order to firmly establish this, studies must make it the primary research objective.

Conclusion

In this review, we examined the current state of LHRH analog treatments, their cardiovascular-related side effects, and their effectiveness when combined with external beam radiotherapy. This review discussed how LHRH agonists and antagonists work to prevent the exacerbation of prostate cancer. It found that overall, antagonists are more effective, result in fewer cardiovascular side effects, and function better with EBRT than agonists. With this information, patients and healthcare providers alike can have safer and higher quality treatments to help relieve the symptoms of prostate cancer. Constantly improving the treatments available to prostate cancer patients will help them recover faster. Although great strides have been made in LHRH analog research, work must still be done to directly measure the decrease in tumor volume due to a change in hormone levels.

About the Author: Sriya Pappula

Sriya Pappula is a fourth-year Biochemistry and Molecular Biology major with a double minor in Education and Public Health. She is interested in learning about biologically significant molecules and how they can shape how our body does or does not function. She initially wrote this literature review for her UWP 102B class and decided to connect it to the topics in her research lab. Sriya is currently an undergraduate research assistant whose primary focus is on biochemical research at the molecular medicine level at the Lam Lab at the UC Davis School of Medicine. Her main focus is cancer research and anticancer peptides, which stimulated her interest in writing this paper. She hopes that this paper will stimulate interest in cancer research among the undergraduate audience and demystify at least one aspect of how cancer research is carried out both in clinical and basic science settings. She wants to become a pediatrician and specialize in oncology, so familiarizing herself with the state of cancer research and its development is important to her. Sriya currently volunteers at Clínica Tepati as a Health Educator, since she is passionate about educating underserved communities about their health. She also serves as Preparedness Education Committee Chair in the American Red Cross Club at UC Davis. In her free time, she likes to listen to music and hang out with her friends around downtown Davis.

Author's Note

I started this piece for an assignment for my UWP 102B class. Our assignment was to write a literature review on a topic related to biology that interested us. I knew right away that I wanted to find a topic related to cancer biology, as I am currently conducting research in a cancer biology lab. I heard about LHRH analogs and their potential as a solution to cancer through my lab and wanted to learn more about it. I wanted to write this piece to make cancer biology more accessible to the general undergraduate populace. I know that when I first started learning about LHRH analogs, it was difficult to decode what research scientists were currently conducting, so I hope this review helps readers understand more about the complexities of cancer treatment.

References

1. Shim, Myungsun, et al. “Effectiveness of Three Different Luteinizing Hormone-Releasing Hormone Agonists in the Chemical Castration of Patients with Prostate Cancer: Goserelin versus Triptorelin versus Leuprolide.” Investigative and Clinical Urology, vol. 60, no. 4, July 2019, pp. 244–50. PubMed Central, https://doi.org/10.4111/icu.2019.60.4.244.
2. Obayemi, J. D., et al. “LHRH-Conjugated Drugs as Targeted Therapeutic Agents for the Specific Targeting and Localized Treatment of Triple Negative Breast Cancer.” Scientific Reports, vol. 10, no. 1, May 2020, p. 8212. PubMed, https://doi.org/10.1038/s41598-020-64979-1.
3. Li, Xiaoning, et al. “LHRH-Targeted Drug Delivery Systems for Cancer Therapy.” Mini Reviews in Medicinal Chemistry, vol. 17, no. 3, 2017, pp. 258–67.
4. Schally, Andrew V., and Ana Maria Comaru-Schally. “Mode of Action of LHRH Analogs.” Holland-Frei Cancer Medicine. 6th Edition, BC Decker, 2003. www.ncbi.nlm.nih.gov, https://www.ncbi.nlm.nih.gov/books/NBK12517/.
5. Turner, Bruce, and Lawrence Drudge-Coates. “New Pharmacological Treatments for Prostate Cancer.” Nurse Prescribing, vol. 10, Oct. 2012, pp. 498–502. ResearchGate, https://doi.org/10.12968/npre.2012.10.10.498.
6. Morote, Juan, et al. “Effect of LHRH Analogs on Lower Urinary Tract Symptoms Associated with Advanced Prostate Cancer in Real Clinical Practice: ANALUTS Study.” Neurourology and Urodynamics, vol. 41, no. 8, Nov. 2022, pp. 1824–33. PubMed, https://doi.org/10.1002/nau.25031.
7. Nasser, Nicola J. “Androgen Flare after LHRH Initiation Is the Side Effect That Makes Most of the Beneficial Effect When It Coincides with Radiation Therapy for Prostate Cancer.” Cancers, vol. 14, no. 8, 8, Jan. 2022, p. 1959. www.mdpi.com, https://doi.org/10.3390/cancers14081959.
8. Sari Motlagh, Reza, et al. “The Efficacy and Safety of Relugolix Compared with Degarelix in Advanced Prostate Cancer Patients: A Network Meta-Analysis of Randomized Trials.” European Urology Oncology, vol. 5, no. 2, Apr. 2022, pp. 138–45. ScienceDirect, https://doi.org/10.1016/j.euo.2021.07.002.
9. Shore, Neal D., et al. “Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer.” The New England Journal of Medicine, vol. 382, no. 23, June 2020, pp. 2187–96. PubMed, https://doi.org/10.1056/NEJMoa2004325.
10. Margel, David, et al. “Cardiac Biomarkers in Patients with Prostate Cancer and Cardiovascular Disease Receiving Gonadotrophin Releasing Hormone Agonist vs Antagonist.” Prostate Cancer and Prostatic Diseases, vol. 24, no. 1, Mar. 2021, pp. 177–85. PubMed, https://doi.org/10.1038/s41391-020-0264-9.
11. Lopes, Renato D., et al. “Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Prostate Cancer: The Primary Results of the PRONOUNCE Randomized Trial.” Circulation, vol. 144, no. 16, Oct. 2021, pp. 1295–307. PubMed, https://doi.org/10.1161/CIRCULATIONAHA.121.056810.
12. Maani, Elizabeth V., and Christopher V. Maani. “Radiation Therapy.” StatPearls, StatPearls Publishing, Jan. 2024. PubMed, http://www.ncbi.nlm.nih.gov/books/NBK537036/.
13. Hata, Shinro, et al. “Degarelix as a Neoadjuvant Hormonal Therapy for Acute Urinary Tract Toxicity Associated with External Beam Radiotherapy for Intermediate- and High-Risk Prostate Cancer: A Propensity Score Matched Analysis.” Japanese Journal of Clinical Oncology, vol. 51, no. 3, Mar. 2021, pp. 478–83. PubMed, https://doi.org/10.1093/jjco/hyaa163.
14. Dearnaley, David P., et al. “The Oral Gonadotropin-Releasing Hormone Receptor Antagonist Relugolix as Neoadjuvant/Adjuvant Androgen Deprivation Therapy to External Beam Radiotherapy in Patients with Localised Intermediate-Risk Prostate Cancer: A Randomised, Open-Label, Parallel-Group Phase 2 Trial.” European Urology, vol. 78, no. 2, Aug. 2020, pp. 184–92. ScienceDirect, https://doi.org/10.1016/j.eururo.2020.03.001.