Gonadotropin-Releasing Hormone and the Urinary System: Analyzing Contradictory Findings of Efficacy and Safety Studies (Review)

INTRODUCTION. Gonadotropin-releasing hormone (GnRH) products are used to treat reproductive system disorders both in females (for temporary medically induced menopause) and males (in order to suppress certain functions in benign and malignant diseases). The urinary and reproductive systems are closely linked in their ontogenesis and phylogenesis. A summary and critical analysis of the existing data will allow us to assess the effects of GnRH products on the urinary system and identify areas for further research.

AIM. This study aimed to identify benefits and risks of GnRH therapy for the urinary system in order to optimize hormone therapy in various conditions.

DISCUSSION. Analysed preclinical and clinical studies showed that GnRH and its metabolites are primarily excreted by the kidneys. GnRH therapy affects the renal system: nephrolithiasis may develop due to calcium olism disorders; cases of acute kidney injury, including acute renal failure, have been reported as well. Bladder structures include GnRH receptors, resulting in high GnRH binding to bladder cells and effective GnRH therapy. However, there are sex-specific differences; high GnRH and its receptors in bladder cancer are associated with better overall survival in men. High expression of GnRH receptors on cancer cells determines the success of GnRH therapy in the bladder tumours. GnRH analogues show a positive clinical effect in women with age-related menopausal incontinence, directly influencing bladder tissue, the sphincter system, and urethra. However, the data in some of the reviewed articles were insufficiently substantiated and lacked statistical validation. A number of studies reported no effect of GnRH therapy on renal and urethral function, or on bladder tumour outcomes.

CONCLUSIONS. The apparent lack of data and inconsistent publications on each aspect of GnRH influencing the urinary system indicate a paucity of research for this issue. Further applied and fundamental research of GnRH effects on the urinary tract is warranted to assess the benefit-risk ratio, develop less toxic anticancer agents, and effectively prevent and treat adverse reactions during hormone therapy for various diseases.

1. Tsutsui K, Ubuka T. How to contribute to the progress of neuroendocrinology: Discovery of GnIH and progress of GnIH research. Front Endocrinol (Lausanne). 2018;9:662. https://doi.org/10.3389/fendo.2018.00662

2. Schally AV, Guillemin R. Isolation and chemical characterization of a beta-CRF from pig posterior pituitary glands. Proc Soc Exp Biol Med. 1963;112:1014–7. https://doi.org/10.3181/00379727-112-28238

3. Stamatiades GA, Toufaily C, Kim HK, et al. Deletion of Gαq/11 or Gαs proteins in gonadotropes differentially affects gonadotropin production and secretion in mice. Endocrinology. 2022;163(2):bqab247. https://doi.org/10.1210/endocr/bqab247

4. Schally AV, Coy DH, Arimura A. LH-RH agonists and antagonists. Int J Gynaecol Obstet. 1980;18(5):318–24. https://doi.org/10.1002/j.1879-3479.1980.tb00507.x

5. Sandow J. Clinical applications of LHRH and its analogues. Clin Endocrinol (Oxf). 1983;18(6):571–92. https://doi.org/10.1111/j.1365-2265.1983.tb00595.x

6. Furr BJ. Pharmacology of the luteinising hormone-releasing hormone (LHRH) analogue. Zoladex Horm Res. 1989;32 Suppl 1:86–92. https://doi.org/10.1159/000181318

7. Maiborodin IV, Pichigina AK, Maiborodina VI, Lushnikova EL. Physiological aspects of the application of gonadotropin-releasing hormone agonists in obstetric-gynecological clinic and experiment. J Evol Biochem Phys. 2022;58(6):1865–78. https://doi.org/10.1134/S0022093022060163

8. Maiborodin IV, Sheplev BV. Andrological aspects of the effects of gonadotropin-releasing hormone agonists in experiment and clinic. Acta Biomedica Scientifica. 2024;9(6):85–99 (In Russ.). https://doi.org/10.29413/ABS.2024-9.6.9

9. Hao D, Sun L, Hu X, Hao X. 99mTc-LHRH in tumor receptor imaging. Oncol Lett. 2017;14(1):569–78. https://doi.org/10.3892/ol.2017.6246

10. Cardwell AM, Maleki F, Sadeghzadeh N, et al. Evaluation of a New 99mTc-labeled GnRH analogue as a possible imaging agent for prostate cancer detection. Anticancer Agents Med Chem. 2020;20(14):1695–703. https://doi.org/10.2174/1871520620666200619175352

11. Farahani AM, Maleki F, Sadeghzadeh N, et al. 99mTc-(EDDA/tricine)-HYNIC-GnRH analogue as a potential imaging probe for diagnosis of prostate cancer. Chem Biol Drug Des. 2020;96(2):850–60. https://doi.org/10.1111/cbdd.13693

12. Zvereva I, Dudko G, Dikunets M. Determination of GnRH and its synthetic analogues’ abuse in doping control: Small bioactive peptide UPLC-MS/MS method extension by addition of in vitro and in vivo metabolism data; evaluation of LH and steroid profile parameter fluctuations as suitable biomarkers. Drug Test Anal. 2018;10(4):711–22. https://doi.org/10.1002/dta.2256

13. Jyrkäs J, Lassila T, Tolonen A. Extrahepatic in vitro metabolism of peptides; comparison of human kidney and intestinal S9 fraction, human plasma and proximal tubule cells, using cyclosporine A, leuprorelin, and cetrorelix as model compounds. J Pharm Biomed Anal. 2023;225:115219. https://doi.org/10.1016/j.jpba.2022.115219

14. Yu Z, Yang J, Huang WJ, et al. Follicle stimulating hormone promotes production of renin through its receptor in juxtaglomerular cells of kidney. Diabetol Metab Syndr. 2022;14:65. https://doi.org/10.1186/s13098-022-00816-x

15. Teoh JY, Tian XY, Wong CY, et al. Endothelial dysfunction after androgen deprivation therapy and the possible underlying mechanisms. Prostate. 2022;82(1):13–25. https://doi.org/10.1002/pros.24244

16. Busby ER, Sherwood NM. Gonadotropin-releasing hormone receptor (Gnrhr) gene knock out: Normal growth and development of sensory, motor and spatial orientation behavior but altered metabolism in neonatal and prepubertal mice. PLoS One. 2017;12(3):e0174452. https://doi.org/10.1371/journal.pone.0174452

17. Díaz Convalía EJ, Cano-García MDC, Miján-Ortiz JL, et al. Androgen deprivation therapy in prostate cancer and risk of developing renal calculi: Results of a case-control study. Med Clin (Barc). 2017;148(11):495–7. https://doi.org/10.1016/j.medcli.2017.01.021

18. Mayrhofer G, Wegner D, Voß T. Urolithiasis bei der langzeitherapie mit GnRH-agonisten bei paraphilien — 3 Fallberichte. Aktuelle Urol. 2016;47(6):487–90 (In German). https://doi.org/10.1055/s-0042-112999

19. Diaz-Convalia E, Arrabal-Polo MA, Cano-Garcia MDC, et al. Risk of renal stone formation in patients treated with luteinising hormone-releasing hormone analogues for prostate cancer: Importance of bone metabolism and urine calcium. Int Urol Nephrol. 2018;50(3):419–25. https://doi.org/10.1007/s11255-018-1793-1

20. Cardwell CR, O’Sullivan JM, Jain S, et al. Hormone therapy use and the risk of acute kidney injury in patients with prostate cancer: A population-based cohort study. Prostate Cancer Prostatic Dis. 2021;24(4):1055–62. https://doi.org/10.1038/s41391-021-00348-x

21. Cirkel U, Schweppe KW, Ochs H, Schneider HP. Metabolische effekte und allgemeine nebenwirkungen bei endometriosebehandlung mit einem LHRH-Agonisten. Geburtshilfe Frauenheilkd. 1987;47(3):154–7 (In German). https://doi.org/10.1055/s-2008-1035798

22. Cirkel U, Schweppe KW, Ochs H, et al. LH-RH agonist (buserelin): Treatment of endometriosis. Clinical, laparoscopic, endocrine and metabolic evaluation. Arch Gynecol Obstet. 1989;246(3):139–51. https://doi.org/10.1007/BF00934075

23. Raitz von Frentz M, Schweppe KW. Ovarielle suppression durch das GnRH-analogon Buserelin zur behandlung der endometriose. Klinische, biochemische und pelviskopische untersuchungen. -Geburtshilfe Frauenheilkd. 1990;50(8):634–9 (In German). https://doi.org/10.1055/s-2008-1026515

24. Chen SC, Ng HT, Tzeng CR, et al. Buserelin treatment of endometriosis in Chinese women. Zhonghua Yi Xue Za Zhi (Taipei). 1991;47(1):1–6. https://pubmed.ncbi.nlm.nih.gov/1848456

25. Barrington JW, Roberts A. Acute renal failure precipitated by luteinizing-hormone releasing hormone analogue for the treatment of endometriosis. Br J Urol. 1994;74(5):672. https://doi.org/10.1111/j.1464-410x.1994.tb09206.x

26. Khalil MA, Ghazni MS, Tan J, et al. Spontaneous bacterial peritonitis and anasarca in a female patient with ovarian hyperstimulation syndrome complicated by respiratory and kidney failure. Case Rep Gastroenterol. 2016;10(2):423–30. https://doi.org/10.1159/000446766

27. Pereira N, Lekovich JP, Kligman I, Rosenwaks Z. Severe ovarian hyperstimulation syndrome after combined GnRH-agonist and low-dose human chorionic gonadotropin trigger in a patient with a single kidney. Gynecol Endocrinol. 2017;33(8):593–7. https://doi.org/10.1080/09513590.2017.1318372

28. Bakhtiani P, Srivastava R, Geffner M. Puberty today, gone tomorrow: Transient refractory central precocious puberty in a toddler with end-stage kidney disease. Horm Res Paediatr. 2024;97(1):109–15. https://doi.org/10.1159/000536323

29. Shanehsazzadeh S, Lahooti A, Sadeghi HR, Jalilian AR. Estimation of human effective absorbed dose of 67Ga-cDTPA-gonadorelin based on biodistribution rat data. Nucl Med Commun. 2011;32(1):37–43. https://doi.org/10.1097/MNM.0b013e328340b916

30. Coit VA, Dowell FJ, Evans NP. Neutering affects mRNA expression levels for the LH- and GnRH-receptors in the canine urinary bladder. Theriogenology. 2009;71(2):239–47. https://doi.org/10.1016/j.theriogenology.2008.06.093

31. Russo A, Castiglione F, Salonia A, et al. Effects of the gonadotropin-releasing hormone antagonist ganirelix on normal micturition and prostaglandin E(2)-induced detrusor overactivity in conscious female rats. Eur Urol. 2011;59(5):868–74. https://doi.org/10.1016/j.eururo.2010.12.007

32. Medina-Aguiñaga D, Munoz A, Luna M, et al. Administration of leuprolide acetate, a GnRH agonist, improves urodynamic parameters in ovariectomized rats. Neurourol Urodyn. 2018;37(5):1574–82. https://doi.org/10.1002/nau.23505

33. Bujok J, Wincewicz E, Czerski A, Zawadzki W. Influence of ovariohysterectomy and deslorelin acetate on the spontaneous activity of the rabbit urinary bladder in vitro. Theriogenology. 2016;85(3):441–6. https://doi.org/10.1016/j.theriogenology.2015.09.018

34. Reichler IM, Hubler M, Jöchle W, et al. The effect of GnRH analogs on urinary incontinence after ablation of the ovaries in dogs. Theriogenology. 2003;60(7):1207–16. https://doi.org/10.1016/s0093-691x(02)01368-7

35. Reichler IM, Barth A, Piché CA, et al. Urodynamic parameters and plasma LH/FSH in spayed Beagle bitches before and 8 weeks after GnRH depot analogue treatment. Theriogenology. 2006;66(9):2127–36. https://doi.org/10.1016/j.theriogenology.2006.06.009

36. Liang W, Afshar K, Stothers L, Laher I. The influence of ovariectomy and estrogen replacement on voiding patterns and detrusor muscarinic receptor affinity in the rat. Life Sci. 2002;71(3):351–62. https://doi.org/10.1016/s0024-3205(02)01645-4

37. Palacios JL, Luquin S, Quintanar JL, Munoz A. Continuous administration of leuprolide acetate improves urinary function in male rats with severe thoracic spinal cord injury. Life Sci. 2022;310:121113. https://doi.org/10.1016/j.lfs.2022.121113

38. Szabó Z, Dezső B, Fodor K, et al. Expression of luteinizing hormone-releasing hormone (LHRH) and type-I LHRH receptor in transitional cell carcinoma type of human bladder cancer. Molecules. 2021;26(5):1253. https://doi.org/10.3390/molecules26051253

39. Szepeshazi K, Schally AV, Keller G, et al. Receptor-targeted therapy of human experimental urinary bladder cancers with cytotoxic LH-RH analog AN-152 [AEZS-108]. Oncotarget. 2012;3(7):686–99. https://doi.org/10.18632/oncotarget.546

40. Engel JB, Tinneberg HR, Rick FG, et al. Targeting of peptide cytotoxins to LHRH receptors for treatment of cancer. Curr Drug Targets. 2016;17(5):488–94. https://doi.org/10.2174/138945011705160303154717

41. Gründker C, Emons G. The role of gonadotropin-releasing hormone in cancer cell proliferation and metastasis. Front Endocrinol (Lausanne). 2017;8:187. https://doi.org/10.3389/fendo.2017.00187

42. Suo L, Chang X, Xu N, Ji H. The anti-proliferative activity of GnRH through downregulation of the Akt/ERK pathways in pancreatic cancer. Front Endocrinol (Lausanne). 2019;10:370. https://doi.org/10.3389/fendo.2019.00370

43. Emons G, Gründker C, Günthert AR, et al. GnRH antagonists in the treatment of gynecological and breast cancers. Endocr Relat Cancer. 2003;10(2):291–9. https://doi.org/10.1677/erc.0,0100291

44. Montagnani Marelli M, Moretti RM, Januszkiewicz-Caulier J, et al. Gonadotropin-releasing hormone (GnRH) receptors in tumors: A new rationale for the therapeutical application of GnRH analogs in cancer patients? Curr Cancer Drug Targets. 2006;6(3):257–69. https://doi.org/10.2174/156800906776842966

45. Cheung LW, Wong AS. Gonadotropin-releasing hormone: GnRH receptor signaling in extrapituitary tissues. FEBS J. 2008;275(22):5479–95. https://doi.org/10.1111/j.1742-4658.2008.06677.x

46. So WK, Cheng JC, Poon SL, Leung PC. Gonadotropin-releasing hormone and ovarian cancer: a functional and mechanistic overview. FEBS J. 2008;275(22):5496–511. https://doi.org/10.1111/j.1742-4658.2008.06679.x

47. Wu SC, Kwon D, Jue JS, et al. Androgen suppression therapy is associated with lower recurrence of non-muscle-invasive bladder cancer. Eur Urol Focus. 2021;7(1):142–7. https://doi.org/10.1016/j.euf.2019.04.021

48. Kourbanhoussen K, McMartin C, Lodde M, et al. Switching cancers: A systematic review assessing the role of androgen suppressive therapy in bladder cancer. Eur Urol Focus. 2021;7(5):1044–51. https://doi.org/10.1016/j.euf.2020.10.002

49. Song Y, Qin C, Zhang C, et al. GNRH family genes contributed to gender-specific disparity of bladder cancer prognosis through exerting opposite regulatory roles between males and females. J Cancer Res Clin Oncol. 2023;149(10):6827–40. https://doi.org/10.1007/s00432-023-04640-2

50. Yikilmaz TN, Ozturk E, Hizli F, et al. Effect of hormonal therapy for volume reduction, lower urinary tract symptom relief and voiding symptoms in prostate cancer: Leuprolide vs goserelin. Urol J. 2019;16(2):157–61. https://doi.org/10.22037/uj.v0i0.4245

51. Eriguchi T, Kawamorita N, Hayashi N, et al. High luteinizing hormone weakens urinary continence mechanisms in association with prostaglandin E2 elevation in a postmenopausal rat model. Neurourol Urodyn. 2018;37(4):1294–301. https://doi.org/10.1002/nau.23470

52. Hinerman-Mulroy A, Merrick GS, Butler WM, et al. Androgen deprivation-induced changes in prostate anatomy predict urinary morbidity after permanent interstitial brachytherapy. Int J Radiat Oncol Biol Phys. 2004;59(5):1367–82. https://doi.org/10.1016/j.ijrobp.2004.01.017