Contemporary challenges and advanced technologies in the management of subfertile men with varicocele

Desafíos contemporáneos y tecnologías avanzadas en el manejo de hombres subfértiles con varicocele

Varicocele, closely linked to male fertility, requires urgent and focused research due to many unresolved questions. The absence of clear reference values distinguishing “normal” from “abnormal” semen parameters in the 6th World Health Organization (WHO) laboratory manual significantly complicates diagnosis and treatment. Additionally, the clinical relevance of total progressively motile sperm count (TMSC) remains unclear, leaving practitioners without critical guidance. The decision to perform varicocelectomy, particularly in cases of isolated teratozoospermia, is fraught with uncertainty. Furthermore, the best treatment strategy for those experiencing subfertility after varicocele surgery is still undetermined, adding another layer of complexity. These pressing issues, along with contentious debates surrounding isolated teratozoospermia treatment, highlight the need for large-scale multicenter randomized clinical trials. Such studies are essential to fully understand varicocele’s impact on male fertility and to develop evidence-based management protocols.

Resumen

El varicocele, estrechamente vinculado a la fertilidad masculina, requiere una investigación urgente y focalizada debido a muchas preguntas sin resolver. La ausencia de valores de referencia claros que distingan los parámetros del semen “normales” de los “anormales” en el sexto manual de laboratorio de la Organización Mundial de la Salud (OMS) complica significativamente el diagnóstico y el tratamiento. Además, la relevancia clínica del conteo total de espermatozoides móviles progresivamente (TMSC) sigue vaga, dejando a los profesionales sin una guía crítica. La decisión de realizar una varicocelectomía, especialmente en casos de teratozoospermia aislada, está llena de incertidumbre. Además, la mejor estrategia de tratamiento para aquellos que experimentan subfertilidad después de la cirugía de varicocele aún no se ha determinado, añadiendo otra capa de complejidad. Estas cuestiones urgentes, junto con los debates contenciosos en torno al tratamiento de la teratozoospermia aislada, subrayan la necesidad de ensayos clínicos aleatorizados multicéntricos a gran escala. Tales estudios son esenciales para comprender completamente el impacto del varicocele en la fertilidad masculina y para desarrollar protocolos de manejo basados en la evidencia.

Varicocele; Varicocelectomy; Semen parameters; Subfertility

Palabras Clave

Varicocele; Varicocelectomía; Parámetros del semen; Subfertilidad

[1] [1] Salonia A, Bettocchi C, Capogrosso P, Carvalho J, Corona G, Dinkelman-Smit M, et al. EAU Guidelines on sexual and reproductive health, chapter 11—male infertility. 2023. Available at: https://d56bochluxqnz.cloudfront.net/documents/full-guideline/EAU-Guidelines-on-Sexual-and-Reproductive-Health-2024_2024-05-23-101205_nmbi.pdf (Accessed: 15 June 2023).

[2] Fang Y, Su Y, Xu J, Hu Z, Zhao K, Liu C, et al. Varicocele-mediated male infertility: from the perspective of testicular immunity and inflammation. Frontiers in Immunology. 2021; 12: 729539.

[3] Huyghe E, Methorst C, Faix A. Varicocele and male infertility. Progrès en Urologie. 2023; 33: 624–635. (In French)

[4] Lewis SEM. Revisiting the impact of varicocele and its treatments on male fertility. Reproductive BioMedicine Online. 2022; 45: 1061–1063.

[5] Vu Tan L, Phuc Cam Hoang N, Ba Tien Dung M, Vinh Phu P, Martinez M, Minh Duc N. Spontaneous pregnancies post-microsurgical varicocelectomy in infertile men with severe oligozoospermia: a preliminary vietnamese report. La Clinica Terapeutica. 2023; 174: 126–131.

[6] Persad E, O’Loughlin CA, Kaur S, Wagner G, Matyas N, Hassler-Di Fratta MR, et al. Surgical or radiological treatment for varicoceles in subfertile men. Cochrane Database of Systematic Reviews. 2021; 4: CD000479.

[7] Bozhedomov VAB, Shomarufov ABS, Bozhedomova GEB, Okhobotov DAO, Kamalov DMK, Kamalov AAK. Varicocele and reproductive function: epidemiology and infertility risk (the eamination of 3632 patients). Urologiia. 2021; 3: 122–128. (In Russian)

[8] Kroese AC, de Lange NM, Collins J, Evers JL. Surgery or embolization for varicoceles in subfertile men. Cochrane Database of Systematic Reviews. 2012; 10: CD000479.

[9] Damsgaard J, Joensen UN, Carlsen E, Erenpreiss J, Blomberg Jensen M, Matulevicius V, et al., Varicocele is associated with impaired semen quality and reproductive hormone levels: a study of 7035 healthy young men from six european countries. European Urology. 2016; 70: 1019–1029.

[10] Agarwal A, Cannarella R, Saleh R, Boitrelle F, Gül M, Toprak T, et al. Impact of varicocele repair on semen parameters in infertile men: a systematic review and meta-analysis. World Journal of Men’s Health. 2023; 41: 289–310.

[11] Schlegel PN, Sigman M, Collura B, De Jonge CJ, Eisenberg ML, Lamb DJ, et al. Diagnosis and treatment of infertility in men: aua\/asrm guideline part II. Journal of Urology. 2021; 205: 44–51.

[12] Cayan S, Shavakhabov S, Kadioğlu A. Treatment of palpable varicocele review in infertile men: a meta-analysis to define the best technique. Journal of Andrology. 2009; 30: 33–40.

[13] Ding H, Tian J, Du W, Zhang L, Wang H, Wang Z. Open non-microsurgical, laparoscopic or open microsurgical varicocelectomy for male infertility: a meta-analysis of randomized controlled trials. BJU International. 2012; 110: 1536–1542.

[14] Masterson TA, Greer AB, Ramasamy R. Time to improvement in semen parameters after microsurgical varicocelectomy in men with severe oligospermia. Canadian Urological Association Journal. 2019; 13: E66–E69.

[15] Pazir Y, Erdem S, Cilesiz NC, Kadioglu A. Determination of the time for improvement in semen parameters after varicocelectomy. Andrologia. 2021; 53: e13895.

[16] Bozhedomov VAB, Shomarufov ABS, Bozhedomova GEB, Ohobotov DAO, Kamalov DMK, Sorokin NIS, et al. Varicocele and reproductive function: pathozoospermia treatment (a prospective comparative study). Urologiia. 2021; 2: 62–68.

[17] Abdel-Meguid TA, Al-Sayyad A, Tayib A, Farsi HM. Does varicocele repair improve male infertility? An evidence-based perspective from a randomized, controlled trial. European Urology. 2011; 59: 455–461.

[18] Almekaty K, Zahran MH, Zoeir A, Minhas S, Salem K. The role of artery-preserving varicocelectomy in subfertile men with severe oligozoospermia: a randomized controlled study. Andrology. 2019; 7: 193–198.

[19] Boeri L, Pozzi E, Capogrosso P, Fallara G, Belladelli F, Candela L, et al. Infertile men with semen parameters above WHO reference limits at first assessment may deserve a second semen analysis: challenging the guidelines in the real-life scenario. PLOS ONE. 2023; 18: e0280519.

[20] Shomarufov AB, Bozhedomov VA, Akilov FA, Mukhtarov ST, Giyasov SI, Abbosov SA, et al. Prediction of reproductive function recovery after microsurgical varicocelectomy in men from infertile couples: clinical and laboratory predictors. Andrologia. 2021; 53: e14101.

[21] Shomarufov AB, Bozhedomov VA, Sorokin NI, Matyukhov IP, Fozilov AA, Abbosov SA, et al. Predictors of microsurgical varicocelectomy efficacy in male infertility treatment: critical assessment and systematization. Asian Journal of Andrology. 2023; 25: 21–28.

[22] Boitrelle F, Shah R, Saleh R, Henkel R, Kandil H, Chung E, et al. The sixth edition of the WHO manual for human semen analysis: a critical review and SWOT analysis. Life. 2021; 11: 1368.

[23] Borges Jr E. Total motile sperm count: a better way to rate the severity of male factor infertility? JBRA Assisted Reproduction. 2016; 20: 47–48.

[24] Wang Q, Yu Y, Liu Y, Wang L. Outcome of varicocelectomy on different degrees of total motile sperm count: a systematic review and meta-analysis. Systems Biology in Reproductive Medicine. 2019; 65: 430–436.

[25] Tsampoukas G, Dellis A, Katsouri A, Brown D, Deliveliotis K, Moussa M, et al. Role of total motile sperm count in the evaluation of young men with bilateral subclinical varicocele and asthenospermia. Archivio Italiano di Urologia e Andrologia. 2020; 92: 366–370.

[26] Greenberg DR, Hudnall MT, Goyette BN, Fantus RJ, Dubin JM, Brannigan RE, et al. Predictors of semen parameters decline following the microsurgical varicocelectomy. Cureus. 2023; 15: e45061.

[27] Choe JH, Seo JT. Is varicocelectomy useful for subfertile men with isolated teratozoospermia? Urology. 2015; 86: 1123–1128.

[28] Cakiroglu B, Sinanoglu O, Gozukucuk R. The effect of varicocelectomy on sperm parameters in subfertile men with clinical varicoceles who have asthenozoospermia or teratozoospermia with normal sperm density. ISRN Urology. 2013; 2013: 698351.

[29] Fathi A, Castiglione F, Mohamed O, Alsagheer GA, Mahmoud O, Saber-Khalaf M. Varicocelectomy versus antioxidants in infertile men with isolated teratozoospermia: a retrospective analysis. Turkish Journal of Urology. 2021; 47: 279–284.

[30] Samplaski MK, Yu C, Kattan MW, Lo KC, Grober ED, Zini A, et al. Nomograms for predicting changes in semen parameters in infertile men after varicocele repair. Fertility and Sterility. 2014; 102: 68–74.

[31] Jang WS, Kim KH, Lim KT, Lee J, Heo JE, Kwon H, et al. External validation of the post-varicocele repair semen analysis nomogram to predict total motile sperm count: a multicenter study. Andrologia. 2020; 52: e13809.

[32] Liu X, Liu D, Pan C, Su H. Nomogram for predicting semen parameters improvement after microscopic varicocelectomy in infertile men with abnormal semen parameters. Journal of Personalized Medicine. 2022; 13: 11.

[33] Kandevani NY, Namdari F, Hamidi M, Dialameh H, Behzadi A. Developing a novel prediction model for the impact of varicocelectomy on postoperative fertility. European Journal of Translational Myology. 2022; 32: 10411.

[34] Samplaski MK, Jarvi KA. Prognostic factors for a favorable outcome after varicocele repair in adolescents and adults. Asian Journal of Andrology. 2016; 18: 217–221.

[35] Samplaski MK, Lo KC, Grober ED, Zini A, Jarvi KA. Varicocelectomy to “upgrade” semen quality to allow couples to use less invasive forms of assisted reproductive technology. Fertility and Sterility. 2017; 108: 609–612.

[36] Cayan S, Erdemir F, Ozbey I, Turek PJ, Kadioğlu A, Tellaloğlu S. Can varicocelectomy significantly change the way couples use assisted reproductive technologies? The Journal of Urology. 2002; 167: 1749–1752.

[37] Smits RM, Mackenzie-Proctor R, Yazdani A, Stankiewicz MT, Jordan V, Showell MG. Antioxidants for male subfertility. Cochrane Database of Systematic Reviews. 2019; 3: CD007411.

[38] Cannarella R, Crafa A, Sawaid Kaiyal R, Kuroda S, Barbagallo F, Alamo A, et al. Antioxidants for male infertility: therapeutic scheme and indications. A retrospective single-center real-life study. Minerva Endocrinology. 2024; 49: 13–24.

[39] Wang J, Wang T, Ding W, Wu J, Wu G, Wang Y, et al. Efficacy of antioxidant therapy on sperm quality measurements after varicocelectomy: a systematic review and meta-analysis. Andrologia. 2019; 51: e13396.

[40] Tsounapi P, Honda M, Dimitriadis F, Koukos S, Hikita K, Zachariou A, et al. Effects of a micronutrient supplementation combined with a phosphodiesterase type 5 inhibitor on sperm quantitative and qualitative parameters, percentage of mature spermatozoa and sperm capacity to undergo hyperactivation: a randomised controlled trial. Andrologia. 2018; 50: e13071.

[41] Barati E, Nikzad H, Karimian M. Oxidative stress and male infertility: current knowledge of pathophysiology and role of antioxidant therapy in disease management. Cellular and Molecular Life Sciences. 2020; 77: 93–113.

[42] Agarwal A, Leisegang K, Majzoub A, Henkel R, Finelli R, Panner Selvam MK, et al. Utility of antioxidants in the treatment of male infertility: clinical guidelines based on a systematic review and analysis of evidence. World Journal of Men’s Health. 2021; 39: 233–290.

[43] Shu T, Taghechian S, Wang R. Initial experience with robot-assisted varicocelectomy. Asian Journal of Andrology. 2008; 10: 146–148.

[44] Parekattil SJ, Gudeloglu A. Robotic assisted andrological surgery. Asian Journal of Andrology. 2013; 15: 67–74.

[45] McCullough A, Elebyjian L, Ellen J, Mechlin C. A retrospective review of single-institution outcomes with robotic-assisted microsurgical varicocelectomy. Asian Journal of Andrology. 2018; 20: 189–194.

[46] Douroumis K, Spartalis E, Stravodimos K, Levis PK, Tsourouflis G, Dimitroulis D, et al. Robotic-assisted microsurgery in andrology: a systematic review. Asian Journal of Andrology. 2023; 25: 454–461.

[47] Amartya D, Atmoko W, Duarsa GWK, Parikesit D, Birowo P. Video exoscope as a cost-effective alternative to surgical microscope in microsurgical subinguinal varicocelectomy in Indonesia: a case report. Urology Case Reports. 2023; 51: 102613.

[48] Cho CL, Chu RWH. Use of video microsurgery platform in microsurgical subinguinal varicocelectomy with indocyanine green angiography. Surgical Practice. 2019; 23: 20–24.

[49] Cho CL, Chu RWH. Indocyanine green angiography and lymphography in microsurgical subinguinal varicocelectomy with evolving video microsurgery and fluorescence imaging platforms. Hong Kong Academy of Medicine. 2022; 28: 181.e1–181.e2.

[50] Duarsa GWK, Kloping YP, Duarsa GWD, Daryanto B, Satyagraha P. Video-assisted telescope operating monitor 3D system in microsurgical varicocelectomy: a preliminary report. Surgical Innovation. 2014; 31: 240–244.

[51] Pafitanis G, Hadjiandreou M, Alamri A, Uff C, Walsh D, Myers S. The exoscope versus operating microscope in microvascular surgery: a simulation non-inferiority trial. Archives of Plastic Surgery. 2020; 47: 242–249.

[52] Mohd Hashim MH, Fam XI, Azizi MH, Khoo HC, Shukor S. Microscopic subinguinal varicocelectomy with video telescopic operating microscope (VITOM) telescope: outcome analysis. Translational Andrology and Urology. 2024; 13: 560–567.

[53] Maheshwari A, Muneer A, Lucky M, Mathur R, McEleny K; British Association of Urological Surgeons and the British Fertility Society. A review of varicocele treatment and fertility outcomes. Human Fertility. 2020; 25: 209–216.

[54] White J, Cartaya S, Black K, Ledesma B, Arbelaez MCS, Muthigi A, et al. Are varicoceles the holy grail of Andrology? International Journal of Impotence Research. 2024; 36: 177–180.

[55] Esteves SC. Evolution of the World Health Organization semen analysis manual: where are we? Nature Reviews Urology. 2022; 19: 439–446.

[56] Chung E, Arafa M, Boitrelle F, Kandil H, Henkel R, Saleh R, et al. The new 6th edition of the WHO laboratory manual for the examination and processing of human semen: is it a step toward better standard operating procedure? Asian Journal of Andrology. 2022; 24: 123–124.

[57] Björndahl L. A paradigmatic shift in the care of male factor infertility: how can the recommendations for basic semen examination in the sixth edition of the WHO manual and the ISO 23162:2021 standard help? Reproductive BioMedicine Online. 2022; 45: 731–736.

[58] Ayala C, Steinberger E, Smith DP. The influence of semen analysis parameters on the fertility potential of infertile couples. Journal of Andrology. 1996; 17: 718–725.

[59] Hariri MK, Rajabalian MB, Narouie B, Ahmadaghayi S, Rostami G, Ezoji K, et al. Semen parameter enhancement after varicocelectomy: insights into varicose vein diameter and BMI influence: a cross-sectional study. To be published in Urologia. 2024. [Preprint].

[60] Atmoko W, Savira M, Shah R, Chung E, Agarwal A. Isolated teratozoospermia: revisiting its relevance in male infertility: a narrative review. Translational Andrology and Urology. 2024; 13: 260–273.

[61] Darves-Bornoz A, Panken E, Brannigan RE, Halpern JA. Robotic surgery for male infertility. Urologic Clinics of North America. 2021; 48: 127–135.