MOLECULAR APPROACH TO PREMATURE EJACULATION: A PILOT STUDY ON S1P SERUM LEVELS AND S1PR1, S1PR2, S1PR3 POLYMORPHISMS
Year 2024,
, 253 - 261, 30.09.2024
Didem Turgut Coşan
,
Gülcan Güleç
,
İbrahim Uğur Çalış
,
Melis Danişman Sonkurt
,
İyimser Ure
,
Fezan Mutlu
Abstract
Objective: Sphingosine-1-phosphate (S1P) and its receptors are involved in various sexual functions, particularly in smooth muscle regulation and vascular responses. However, the role of S1P and its receptors in premature ejaculation (PE) remains unclear. This study investigates the relationship between single nucleotide polymorphisms (SNPs) in the S1PR1, S1PR2, and S1PR3 genes and plasma S1P levels in individuals with PE. Materials and Methods: The study included 100 individuals with PE and 100 healthy controls recruited from urology and psychiatry clinics. DNA was isolated from blood samples, and PCR was used to identify SNPs in the S1PR1 (rs2038366), S1PR2 (rs56357614), and S1PR3 (rs7022797) genes. Plasma S1P levels were measured using ELISA. Results: A significant association was observed between the heterozygous GT genotype of the S1PR1 gene and an increased risk of PE (OR 2.25, 95% CI 1.215–4.168, p = 0.0099). No significant associations were found between S1PR2 or S1PR3 polymorphisms and PE. Plasma S1P levels were significantly lower in the PE group (median 253.25 ng/L) compared to the control group (median 430.82 ng/L) (p < 0.001). Conclusion: S1PR1 gene polymorphism and reduced plasma S1P levels may be linked to the pathophysiology of PE. In contrast, S1PR2 and S1PR3 do not appear to be associated. Further research with larger samples is needed to confirm these findings.
Supporting Institution
Eskisehir Osmangazi University, Scientific Research Project Commission
Project Number
Eskisehir Osmangazi University, Scientific Research Project Commission (grant number 201811D39)
References
- 1. Canat L, Değirmentepe RB, Atalay HA, Alkan İ, Özbir S, Çulha MG, Ötünçtemur A. The relationship between female sexual function index domains and premature ejaculation. International urology and nephrology. 2018;50(4):633-7.
- 2. Steggall MJ. Premature ejaculation: definition, assessment and management. Trends in Urology, Gynaecology & Sexual Health. 2010;15(3):39-43.
- 3. McMahon CG, Althof S, Waldinger MD, Porst H, Dean J, Sharlip I, et al. An evidence‐based definition of lifelong premature ejaculation: Report of the International Society for Sexual Medicine Ad Hoc Committee for the Definition of Premature Ejaculation. BJU international. 2008;102(3):338-50.
- 4. Cinar O, Durmus N, Aslan G, Demir O, Evcim A, Gidener S, Esen A. Effects of the dopamine D3 receptor agonist 7‐hydroxy‐2‐(di‐N‐propylamino) tetralin in hyperthyroidism‐induced premature ejaculation rat model. Andrologia. 2018;50(4):e12956.
- 5. Watterson KR, Ratz PH, Spiegel S. The role of sphingosine-1-phosphate in smooth muscle contraction. Cellular signalling. 2005;17(3):289-98.
- 6. Ling B, Chen L, Alcorn J, Ma B, Yang J. Sphingosine-1-phosphate: a potential therapeutic agent against human breast cancer. Investigational new drugs. 2011;29(2):396-9.
- 7. Yin J, Guo Ym, Chen P, Xiao H, Wang Xh, DiSanto ME, Zhang Xh. Testosterone regulates the expression and functional activity of sphingosine‐1‐phosphate receptors in the rat corpus cavernosum. Journal of cellular and molecular medicine. 2018;22(3):1507-16.
- 8. Kim RH, Takabe K, Milstien S, Spiegel S. Export and functions of sphingosine-1-phosphate. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids. 2009;1791(7):692-6.
- 9. Sarkar S, Maceyka M, Hait NC, Paugh SW, Sankala H, Milstien S, Spiegel S. Sphingosine kinase 1 is required for migration, proliferation and survival of MCF‐7 human breast cancer cells. FEBS letters. 2005;579(24):5313-7.
- 10. Michel MC, Mulders AC, Jongsma M, Alewijnse AE, Peters SL. Vascular effects of sphingolipids. Acta Paediatrica. 2007;96:44-8.
- 11. Geho DH, Bandle RW, Clair T, Liotta LA. Physiological mechanisms of tumor-cell invasion and migration. Physiology. 2005;20(3):194-200.
- 12. Im D-S, Clemens J, Macdonald TL, Lynch KR. Characterization of the Human and Mouse Sphingosine 1-Phosphate Receptor, S1P5 (Edg-8): Structure− Activity Relationship of Sphingosine1-Phosphate Receptors. Biochemistry. 2001;40(46):14053-60.
- 13. Im D-S, Heise CE, Ancellin N, O'Dowd BF, Shei G-j, Heavens RP, et al. Characterization of a novel sphingosine 1-phosphate receptor, Edg-8. Journal of Biological Chemistry. 2000;275(19):14281-6.
- 14. Igarashi J, Michel T. Sphingosine-1-phosphate and modulation of vascular tone. Cardiovascular research. 2009;82(2):212-20.
- 15. Schuchardt M, Tölle M, Prüfer J, van der Giet M. Pharmacological relevance and potential of sphingosine 1‐phosphate in the vascular system. British journal of pharmacology. 2011;163(6):1140-62.
- 16. Takuwa N, Du W, Kaneko E, Okamoto Y, Yoshioka K, Takuwa Y. Tumor-suppressive sphingosine-1-phosphate receptor-2 counteracting tumor-promoting sphingosine-1-phosphate receptor-1 and sphingosine kinase 1—Jekyll Hidden behind Hyde. American journal of cancer research. 2011;1(4):460.
- 17. Takuwa Y, Okamoto Y, Yoshioka K, Takuwa N. Sphingosine-1-phosphate signaling and biological activities in the cardiovascular system. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids. 2008;1781(9):483-8.
- 18. Aydin M, Downing K, Villegas G, Zhang X, Chua R, Melman A, DiSanto ME. The sphingosine‐1‐phosphate pathway is upregulated in response to partial urethral obstruction in male rats and activates RhoA/Rho‐kinase signalling. BJU international. 2010;106(4):562-71.
- 19. Chiba Y, Suzuki K, Uechi M, Kurihara E, Goto K, Sakai H, Misawa M. Downregulation of sphingosine-1-phosphate receptors in bronchial smooth muscle of mouse experimental asthma. Pharmacological research. 2010;62(4):357-63.
- 20. Zhang Xh, Melman A, DiSanto ME. Update on corpus cavernosum smooth muscle contractile pathways in erectile function: a role for testosterone? The journal of sexual medicine. 2011;8(7):1865-79.
21. Coşan DT, Çalış İU, Güleç GK. Membran Fosfolipidlerinden Sfingozin-1-Fosfat ve Reseptörlerinin Erektil Disfonksiyondaki Rolü. Tıp Fakültesi Klinikleri Dergisi.1(3):17-
- 22. di Villa Bianca RdE, Sorrentino R, Sorrentino R, Imbimbo C, Palmieri A, Fusco F, et al. Sphingosine 1-phosphate induces endothelial nitric-oxide synthase activation through phosphorylation in human corpus cavernosum. Journal of Pharmacology and Experimental Therapeutics. 2006;316(2):703-8.
- 23. Nazlıkul Hs. Erektil Disfonksiyon. Bilimsel Tamamlayıcı Tıp Regülasyon ve Nöral Terapi Dergisi.10(2):1-7.
- 24. Soltau I, Mudersbach E, Geissen M, Schwedhelm E, Winkler MS, Geffken M, et al. Serum-sphingosine-1-phosphate concentrations are inversely associated with atherosclerotic diseases in humans. PLoS One. 2016;11(12).
- 25. Winkler MS, Nierhaus A, Holzmann M, Mudersbach E, Bauer A, Robbe L, et al. Decreased serum concentrations of sphingosine-1-phosphate in sepsis. Critical Care. 2015;19(1):372.
- 26. Cho MC, Song WH, Paick J-S. Suppression of cavernosal fibrosis in a rat model. Sexual medicine reviews. 2018;6(4):572-82.
- 27. Sassoli C, Pierucci F, Zecchi-Orlandini S, Meacci E. Sphingosine 1-phosphate (S1P)/S1P receptor signaling and mechanotransduction: implications for intrinsic tissue repair/regeneration. International journal of molecular sciences. 2019;20(22):5545.
- 28. Guo L, Ou X, Li H, Han Z. Roles of sphingosine-1-phosphate in reproduction. Reproductive Sciences. 2014;21(5):550-4.
ERKEN BOŞALMA ÜZERINE MOLEKÜLER YAKLAŞIM: S1P SERUM SEVİYELERİ VE S1PR1, S1PR2, S1PR3 POLİMORFIZMLERİ ÜZERİNE BİR PİLOT ÇALIŞMA
Year 2024,
, 253 - 261, 30.09.2024
Didem Turgut Coşan
,
Gülcan Güleç
,
İbrahim Uğur Çalış
,
Melis Danişman Sonkurt
,
İyimser Ure
,
Fezan Mutlu
Abstract
Amaç: S1P (Sfingozin-1-Fosfat) ve reseptörlerinin çeşitli cinsel fonksiyonlarda, özellikle düz kas regülasyonu ve vasküler yanıtlarda rol aldığı bilinmektedir. Bununla birlikte, S1P ve reseptörlerinin erken boşalma (EB) üzerindeki rolü belirsizdir. Bu çalışma, S1PR1, S1PR2 ve S1PR3 genlerindeki tek nükleotid polimorfizmleri (SNP'ler) ile plazma S1P seviyelerinin EB'li bireylerdeki ilişkisini araştırmaktadır.
Gereç ve Yöntemler: Çalışmaya üroloji ve psikiyatri kliniklerinden alınan 100 EB'li birey ve 100 sağlıklı kontrol dahil edilmiştir. Kan örneklerinden DNA izole edilmiş ve S1PR1 (rs2038366), S1PR2 (rs56357614) ve S1PR3 (rs7022797) genlerinde SNP'ler PCR kullanılarak belirlenmiştir. Plazma S1P seviyeleri ELISA ile ölçülmüştür.
Sonuçlar: S1PR1 genindeki heterozigot GT genotipi ile EB riskinde anlamlı bir ilişki bulunmuştur (OR 2.25, %95 CI 1.215–4.168, p = 0.0099). S1PR2 veya S1PR3 polimorfizmleri ile EB arasında anlamlı bir ilişki bulunamamıştır. Plazma S1P seviyeleri, EB grubunda (medyan 253.25 ng/L) kontrol grubuna göre (medyan 430.82 ng/L) anlamlı olarak daha düşük bulunmuştur (p < 0.001).
Sonuç: S1PR1 gen polimorfizmi ve düşük plazma S1P seviyeleri, EB'nin patofizyolojisi ile ilişkili olabilir. Buna karşın, S1PR2 ve S1PR3 bu durumla ilişkili görünmemektedir. Bu bulguları doğrulamak ve daha kesin sonuçlar elde etmek için, daha geniş katılımcı gruplarıyla yapılacak çalışmalara ihtiyaç duyulmaktadır.
Project Number
Eskisehir Osmangazi University, Scientific Research Project Commission (grant number 201811D39)
References
- 1. Canat L, Değirmentepe RB, Atalay HA, Alkan İ, Özbir S, Çulha MG, Ötünçtemur A. The relationship between female sexual function index domains and premature ejaculation. International urology and nephrology. 2018;50(4):633-7.
- 2. Steggall MJ. Premature ejaculation: definition, assessment and management. Trends in Urology, Gynaecology & Sexual Health. 2010;15(3):39-43.
- 3. McMahon CG, Althof S, Waldinger MD, Porst H, Dean J, Sharlip I, et al. An evidence‐based definition of lifelong premature ejaculation: Report of the International Society for Sexual Medicine Ad Hoc Committee for the Definition of Premature Ejaculation. BJU international. 2008;102(3):338-50.
- 4. Cinar O, Durmus N, Aslan G, Demir O, Evcim A, Gidener S, Esen A. Effects of the dopamine D3 receptor agonist 7‐hydroxy‐2‐(di‐N‐propylamino) tetralin in hyperthyroidism‐induced premature ejaculation rat model. Andrologia. 2018;50(4):e12956.
- 5. Watterson KR, Ratz PH, Spiegel S. The role of sphingosine-1-phosphate in smooth muscle contraction. Cellular signalling. 2005;17(3):289-98.
- 6. Ling B, Chen L, Alcorn J, Ma B, Yang J. Sphingosine-1-phosphate: a potential therapeutic agent against human breast cancer. Investigational new drugs. 2011;29(2):396-9.
- 7. Yin J, Guo Ym, Chen P, Xiao H, Wang Xh, DiSanto ME, Zhang Xh. Testosterone regulates the expression and functional activity of sphingosine‐1‐phosphate receptors in the rat corpus cavernosum. Journal of cellular and molecular medicine. 2018;22(3):1507-16.
- 8. Kim RH, Takabe K, Milstien S, Spiegel S. Export and functions of sphingosine-1-phosphate. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids. 2009;1791(7):692-6.
- 9. Sarkar S, Maceyka M, Hait NC, Paugh SW, Sankala H, Milstien S, Spiegel S. Sphingosine kinase 1 is required for migration, proliferation and survival of MCF‐7 human breast cancer cells. FEBS letters. 2005;579(24):5313-7.
- 10. Michel MC, Mulders AC, Jongsma M, Alewijnse AE, Peters SL. Vascular effects of sphingolipids. Acta Paediatrica. 2007;96:44-8.
- 11. Geho DH, Bandle RW, Clair T, Liotta LA. Physiological mechanisms of tumor-cell invasion and migration. Physiology. 2005;20(3):194-200.
- 12. Im D-S, Clemens J, Macdonald TL, Lynch KR. Characterization of the Human and Mouse Sphingosine 1-Phosphate Receptor, S1P5 (Edg-8): Structure− Activity Relationship of Sphingosine1-Phosphate Receptors. Biochemistry. 2001;40(46):14053-60.
- 13. Im D-S, Heise CE, Ancellin N, O'Dowd BF, Shei G-j, Heavens RP, et al. Characterization of a novel sphingosine 1-phosphate receptor, Edg-8. Journal of Biological Chemistry. 2000;275(19):14281-6.
- 14. Igarashi J, Michel T. Sphingosine-1-phosphate and modulation of vascular tone. Cardiovascular research. 2009;82(2):212-20.
- 15. Schuchardt M, Tölle M, Prüfer J, van der Giet M. Pharmacological relevance and potential of sphingosine 1‐phosphate in the vascular system. British journal of pharmacology. 2011;163(6):1140-62.
- 16. Takuwa N, Du W, Kaneko E, Okamoto Y, Yoshioka K, Takuwa Y. Tumor-suppressive sphingosine-1-phosphate receptor-2 counteracting tumor-promoting sphingosine-1-phosphate receptor-1 and sphingosine kinase 1—Jekyll Hidden behind Hyde. American journal of cancer research. 2011;1(4):460.
- 17. Takuwa Y, Okamoto Y, Yoshioka K, Takuwa N. Sphingosine-1-phosphate signaling and biological activities in the cardiovascular system. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids. 2008;1781(9):483-8.
- 18. Aydin M, Downing K, Villegas G, Zhang X, Chua R, Melman A, DiSanto ME. The sphingosine‐1‐phosphate pathway is upregulated in response to partial urethral obstruction in male rats and activates RhoA/Rho‐kinase signalling. BJU international. 2010;106(4):562-71.
- 19. Chiba Y, Suzuki K, Uechi M, Kurihara E, Goto K, Sakai H, Misawa M. Downregulation of sphingosine-1-phosphate receptors in bronchial smooth muscle of mouse experimental asthma. Pharmacological research. 2010;62(4):357-63.
- 20. Zhang Xh, Melman A, DiSanto ME. Update on corpus cavernosum smooth muscle contractile pathways in erectile function: a role for testosterone? The journal of sexual medicine. 2011;8(7):1865-79.
21. Coşan DT, Çalış İU, Güleç GK. Membran Fosfolipidlerinden Sfingozin-1-Fosfat ve Reseptörlerinin Erektil Disfonksiyondaki Rolü. Tıp Fakültesi Klinikleri Dergisi.1(3):17-
- 22. di Villa Bianca RdE, Sorrentino R, Sorrentino R, Imbimbo C, Palmieri A, Fusco F, et al. Sphingosine 1-phosphate induces endothelial nitric-oxide synthase activation through phosphorylation in human corpus cavernosum. Journal of Pharmacology and Experimental Therapeutics. 2006;316(2):703-8.
- 23. Nazlıkul Hs. Erektil Disfonksiyon. Bilimsel Tamamlayıcı Tıp Regülasyon ve Nöral Terapi Dergisi.10(2):1-7.
- 24. Soltau I, Mudersbach E, Geissen M, Schwedhelm E, Winkler MS, Geffken M, et al. Serum-sphingosine-1-phosphate concentrations are inversely associated with atherosclerotic diseases in humans. PLoS One. 2016;11(12).
- 25. Winkler MS, Nierhaus A, Holzmann M, Mudersbach E, Bauer A, Robbe L, et al. Decreased serum concentrations of sphingosine-1-phosphate in sepsis. Critical Care. 2015;19(1):372.
- 26. Cho MC, Song WH, Paick J-S. Suppression of cavernosal fibrosis in a rat model. Sexual medicine reviews. 2018;6(4):572-82.
- 27. Sassoli C, Pierucci F, Zecchi-Orlandini S, Meacci E. Sphingosine 1-phosphate (S1P)/S1P receptor signaling and mechanotransduction: implications for intrinsic tissue repair/regeneration. International journal of molecular sciences. 2019;20(22):5545.
- 28. Guo L, Ou X, Li H, Han Z. Roles of sphingosine-1-phosphate in reproduction. Reproductive Sciences. 2014;21(5):550-4.