ABSTRACT
This study analyzed semen parameters in patients with testicular germ cell cancer and a history of cryptorchidism. Among testicular cancer patients referred for sperm cryopreservation, the semen of 9 patients with a history of cryptorchidism, including three cases of bilateral cryptorchidism and one case of cryptorchidism with bilateral metachronous tumor, was analyzed. Eight patients underwent orchidopexy during childhood. The tumor was observed on the contralateral side of the undescended testis, except in the bilateral metachronous tumor and cryptorchidism cases. Five patients, including the one who developed a metachronous testicular tumor on the undescended testis, showed azoospermia even though in three of them, semen was collected before undergoing orchiectomy. Clinical urologists should recognize that spermatogenesis is severely impaired in these patients and consider cryopreservation before orchiectomy or onco-TESE.
Introduction
Treatments for testicular tumors have improved in recent years. As a result, for many young patients, marriage and the ability to father children are important determinants of their post-treatment quality of life. Unfortunately, in some cases, patients require chemotherapy or radiation which can induce spermatogenesis disorders. This has led to the referral of many young male patients for sperm cryopreservation prior to treatment.
Testicular germ cell tumor, is the most common type of testicular cancer, of which cryptorchidism, and male infertility are closely related entities. A history of cryptorchidism is a risk factor for testicular malignancy. There are reports that the risk of testicular cancer increases by 2–4.8 times when there is a history of cryptorchidism (Dieckmann and Pichlmeier Citation2004; Thorup and Cortes Citation2016; Schneuer et al. Citation2018) and the incidence becomes even higher when surgical intervention is delayed (Garner et al. Citation2005; Thorup and Cortes Citation2016; Schneuer et al. Citation2018).
The relationship between undescended testes and male infertility is not entirely understood. There is evidence that surgery for a unilateral undescended testis can improve paternity up to 90% (Lee et al. Citation2000, Citation2001). However, semen parameters remain abnormal in 16–23% of patients who undergo unilateral orchidopexy (Gracia et al. Citation2000; Vinardi et al. Citation2001; Cortes et al. Citation2003). Additionally, spermatogenesis is more strongly disordered in bilateral cases than in unilateral cases. Without surgery, 88.6% of patients exhibit azoospermia (Hadziselimovic and Herzog Citation2001), and even with surgery, only 42–50% patients experience normal semen parameters (Gracia et al. Citation2000; Vinardi et al. Citation2001; Cortes et al. Citation2003).
Spermatogenesis is known to be impaired in patients with a testicular tumor (Moody et al. Citation2019). In our reproduction center, 55% of patients referred for sperm cryopreservation, before chemotherapy had some kind of abnormality in their semen parameters (data not shown). As such, patients diagnosed with testicular cancer who also have a history of cryptorchidism may be at very high risk of infertility due to testicular damage resulting from the tumor coupled with an already deteriorated spermatogenesis. There are, however, only a few reports analyzing the semen quality of these patients.
Since 2002, in the Reproduction Center of Ichikawa General Hospital, Tokyo Dental College, we have cryopreserved sperm for patients with testicular cancer who are going to receive chemotherapy or radiation. Among them, there were patients who also had a history of cryptorchidism. The present study aimed to analyze the sperm quality of the patients retrospectively and elucidate the frequency of azoospermia. This study also aimed to notify clinical urologists of the severity and inform the preoperative collection or preparation of onco-TESE.
Results
Among 190 Japanese patients with testicular germ cell tumors who were referred to our Reproduction Center for sperm cryopreservation, we assessed the semen quality and background characteristics of nine patients (mean age, 27.6 years) with a history of cryptorchidism (three bilateral cases and six unilateral cases including a case with bilateral metachronous tumor).
The background characteristics and semen analysis results are shown in . In six patients with unilateral cryptorchidism, except in the bilateral metachronous tumor case, the undescended testis existed on the contralateral side of the tumor. Orchidopexy was performed in eight of nine patients when they were children. All patients were referred to our hospital within one month after orchiectomy. None of them had received chemotherapy before cryopreservation. Only one patient was married, and none had conceived a child.
Table 1. Background characteristics of the nine patients
Table 2. Semen analysis of the nine patients
Five patients visited before they received orchiectomy. In the case with metachronous bilateral tumors, the semen was obtained before the remaining testis was lost. The five patients, including a case who had developed a metachronous testicular tumor on an undescended testis, showed azoospermia. Azoospermia was observed in two cases even though the sperm had been collected before orchiectomy. In four other cases, although all of them showed teratozoospermia and two showed asthenozoospermia, sperm concentration was normal.
Discussion
In our study, azoospermia was observed in more than half of patients with cryptorchidism, even though three of these patients provided semen samples before orchiectomy. Rives et al. (Citation2012) reported that azoospermia and severe oligozoospermia were observed in 13.5% and 25.6% of patients with testicular tumor and cryptorchidism, respectively, smaller percentages than that in our study. One reason for this discrepancy may be that except for one of our cases, the undescended testes was observed in the contralateral side of the testicular tumor. In past reports, although more than 80% of patients with unilateral cryptorchidism were able to recover their semen parameters or paternity after surgery (Gracia et al. Citation2000; Vinardi et al. Citation2001; Cortes et al. Citation2003), the volume of the undescended testis was smaller than that of the contralateral normal testis (Beltran-Brown and Villegas-Alvarez Citation1988; Puri and Sparnon Citation1990; Taskinen and Wikstrom Citation1997; Lee et al. Citation2000, Citation2001). This indicates that the function of the undescended testis may not recover completely; hence, semen parameters or paternity would depend on the contralateral normal testis. In our study, most patients unfortunately developed testicular cancer on the contralateral side of the undescended testis; we suspect that semen parameters consequently decreased.
Another possible contributing factor in our cases is the delayed timing of orchidopexy. As germ cell damage starts at 2 or 3 years of age and affects future spermatogenesis, surgery is recommended before that time (Schindler et al. Citation1987; Chan et al. Citation2014; Radmayr et al. Citation2016; Thorup and Cortes Citation2016; Schneuer et al. Citation2018). In cases 1, 2, and 3, patients may have received orchidopexy too late. Meanwhile, in two cases with bilateral cryptorchidism (cases 5 and 7), sperm concentration was normal even though spermatogenesis of bilateral cases is known to be more deteriorated than in unilateral cases. Especially in case 7, we suspect that the early timing of orchidopexy (at 3 years of age) and collection of semen before orchiectomy resulted in a positive result. Additionally, the younger age in cases 5 and 7 might have been an advantage (20 and 21 years, respectively). The relationship between age and spermatogenesis in patients with cryptorchidism is unclear, but there are some reports on negative effects of aging in Klinefelter syndrome (Okada et al. Citation2005) and testicular tumor (Suzuki et al. Citation2015).
The negative influence of testicular neoplasm would be another factor because the tumor is known to affect the spermatogenesis of the contralateral testis (Moody et al. Citation2019). As all patients referred to our hospital within one month after orchiectomy, worsened spermatogenesis induced by the tumor might not have recovered. Moreover, the patients who were referred to our hospital needed to receive adjuvant therapy, which suggested that the stage of cancer was advanced. Therefore, the adverse effect of the tumor was supposed to remain. We might elucidate whether poor quality semen results were temporary if we could compare the semen parameters between pre- and post-orchiectomy, especially a few months later. However, it might be difficult to wait a couple of months delaying anti-cancer therapy.
Onco-TESE is the method for extracting sperm from a surgically removed testis affected by cancer; this method was first reported by Schrader et al. (Citation2003). Onco-TESE has been performed for patients with bilateral testicular tumors (Tsutsumi et al. Citation2017; Hamano et al. Citation2018); however, no cases of testicular cancer with a history of undescended testis have been reported. In our study, more than half of the patients showed azoospermia and could not cryopreserve their sperm; however, they might have been able to preserve their sperm had they received onco-TESE. We presume that urologists, especially in Japan, are not sufficiently aware of the severity of impaired spermatogenesis due to testicular tumor complicated by cryptorchidism. Meanwhile, there might be patients’ related factors causing hesitation to refer to a reproduction clinic such as cost, emotional status, low interest in future fathering, and time (Sonnenburg et al. Citation2015; Parekh et al. Citation2020). Yumura et al. (Citation2018) reported the current status of sperm banking in Japan, and mentioned the importance of systematization for cryopreservation. We suppose that clinicians need to be well-informed to refer these patients to reproduction centers preoperatively where they can cryopreserve their sperm or perform onco-TESE. In addition, we have to provide relevant information and support to patients.
In conclusion, spermatogenesis is strongly impaired in patients with an advanced testicular tumor and a history of contralateral cryptorchidism. We would like to conduct a study with a larger size and collect detailed data to determine patients whose semen parameters are worsened. Clinical urologists should recognize this situation and offer such patients the option of cryopreservation or onco-TESE before they remove the testis. We hope that reproductive medicine can protect their future fertility.
Materials and methods
Semen analysis
Semen samples were collected three times by masturbation after 2–5 days of sexual abstinence. A part of the semen sample was obtained to calculate the parameters before freezing and the best data were used for this study.
Semen parameters were measured under a microscope manually according to the Semen Analysis Standardization Guideline (Japanese Urology Association Citation2003) which is compliant with the WHO Laboratory Manual for the Examination of Human and Sperm-cervical Mucus Interaction (Citation1999). Briefly, sperm concentration was calculated using a Neubauer hemocytometer. Sperm motility was calculated by counting more than 200 spermatozoa. Sperm morphology was assessed according to Kruger’s strict criteria for staining with Diff-Quick. Normal findings were as follows: concentration, ≥ 20 million/mL (≤20 million/mL was considered oligozoospermia); motility, ≥ 40% (≤40% was considered asthenozoospermia); morphology, ≥ 15% (≤15% was considered teratozoospermia).
Ethics approval
This study was approved by the Ichikawa General Hospital Scientific Council and Ethics Commission. Informed consent was obtained from all participants before the start of this study.
Authors' contributions
Data analysis and drafting of the manuscript: JH.
Review of the manuscript: KN and MO.
Acknowledgments
We thank M. Okazaki for providing assistance in analyzing semen samples and collecting data.
Disclosure statement
The authors report no conflict of interest.
References
- Beltran-Brown F, Villegas-Alvarez F. 1988. Clinical classification for undescended testes: experience in 1,010 orchidopexies. J Pediatr Surg. 23(5):444–447. doi:10.1016/S0022-3468(88)80445-7.
- Chan E, Wayne C, Nasr A. 2014. FRCSC for Canadian association of pediatric surgeon evidence-based resource. 2014. Ideal timing of orchiopexy: a systematic review. Pediatr Surg Int. 30(1):87–97. doi:10.1007/s00383-013-3429-y.
- Cortes D, Thorup J, Lindenberg S, Visfeldt J. 2003. Infertility despite surgery for cryptorchidism in childhood can be classified by patients with normal or elevated follicle-stimulating hormone and identified at orchidopexy. BJU Int. 91(7):670–674. doi:10.1046/j.1464-410X.2003.04177.x.
- Dieckmann KP, Pichlmeier U. 2004. Clinical epidemiology of testicular germ cell tumors. World J Urol. 22(1):2–14. doi:10.1007/s00345-004-0398-8.
- Garner MJ, Turner MC, Ghadirian P, Krewski D. 2005. Epidemiology of testicular cancer: an overview. Int J Cancer. 116(3):331–339. doi:10.1002/ijc.21032.
- Gracia J, Sánchez Zalabardo J, Sánchez García J, García C, Ferrández A. 2000. Clinical, physical, sperm and hormonal data in 251 adults operated on for cryptorchidism in childhood. BJU Int. 85(9):1100–1103. doi:10.1046/j.1464-410x.2000.00662.x.
- Hadziselimovic F, Herzog B. 2001. Importance of early postnatal germ cell maturation for fertility of cryptorchid males. Horm Res. 55(1):6–10. doi:10.1159/000049956.
- Hamano I, Hatakeyama S, Nakamura R, Fukuhara R, Noro D, Seino H, Yoneyama T, Hashimoto Y, Koie T, Yokoyama Y, et al. 2018. Onco-testicular sperm extraction (Onco-TESE) from a single testis with metachronous bilateral testicular cancer: a case report. Basic Clin Androl. 28:1. doi:10.1186/s12610-018-0066-2.
- Japanese Urology Association. 2003. Semen analyses standardization guideline. Tokyo:Kanehara press.
- Lee PA, Coughlin MT, Bellinger MF. 2000. Paternity and hormone levels after unilateral cryptorchidism: association with pretreatment testicular location. J Urol. 164(5):1697–1701. doi:10.1016/S0022-5347(05)67087-5.
- Lee PA, Coughlin MT, Bellinger MF. 2001. No relationship of testicular size at orchiopexy with fertility in men who previously had unilateral cryptorchidism. J Urol. 166(1):236–239. doi:10.1016/S0022-5347(05)66134-4.
- Moody JA, Ahmed K, Yap T, Minhas S, Shabbir M. 2019. Fertility managment in testicular cancer: the need to establish a standardized and evidence-based patient-centric pathway. BJU Int. 123(1):160–172. doi:10.1111/bju.14455.
- Okada H, Goda K, Yamamoto Y, Sofikitis N, Miyagawa I, Mio Y, Koshida M, Horie S. 2005. Age as a limiting factor for successful sperm retrieval in patients with nonmosaic Klinefelter’s syndrome. Fertil Steril. 84(6):1662–1664. doi:10.1016/j.fertnstert.2005.05.053.
- Parekh NV, Lundy SD, Vij SC. 2020. Fertility considerations in men with testicular cancer. Transl Androl Urol. 9(Suppl 1):S14–S23. doi:10.21037/tau.2019.08.08.
- Puri P, Sparnon A. 1990. Relationship of primary site of testis to final testicular size in cryptorchid patients. Br J Urol. 66(2):208–210. doi:10.1111/j.1464-410X.1990.tb14906.x.
- Radmayr C, Dogan HS, Hoebeke P, Kocvara R, Nijman R, Silay S, Stein R, Undre S, Tekgul S. 2016. Management of undescended testes: European association of urology/European society for paediatric urology guidelines. J Pediatr Urol. 12(6):335–343. doi:10.1016/j.jpurol.2016.07.014.
- Rives N, Perdrix A, Hennebicq S, Saïas-Magnan J, Melin MC, Berthaut I, Barthélémy C, Daudin M, Szerman E, Bresson JL, et al. 2012. The semen quality of 1158 men with testicular cancer at the time of cryopreservation: results of the French National CECOS network. J Androl. 33(6):1394–1401. doi:10.2164/jandrol.112.016592.
- Schindler AM, Diaz P, Cuendet A, Sizonenko PC. 1987. Cryptorchidism: a morphological study of 670 biopsies. Helv Paediatr Acta. 42(2–3):145–158.
- Schneuer FJ, Milne E, Jamieson SE, Pereira G, Hansen M, Barker A, Holland AA, Bower C, Nassar N. 2018. Association between male genital anomalies and adult male reproductive disorders: a population-based data linkage study spanning more than 40 years. Lancet Child Adolesc Health. 2(19):736–743.
- Schrader M, Müller M, Sofikitis N, Straub B, Krause H, Miller K. 2003. “Onco-TESE”: testicular sperm extraction in azoospermic cancer patients before chemotherapy-new guidelines? Urology. 61(2):421–425. doi:10.1016/S0090-4295(02)02264-1.
- Sonnenburg DW, Brames MJ, Case-Eads S, Einhorn LH. 2015. Utilization of sperm banking and barriers to its use in testicular cancer patients. Support Care Cancer. 23(9):2763–2768. doi:10.1007/s00520-015-2641-9.
- Suzuki K, Shin T, Shimomura Y, Iwahata T, Okada H. 2015. Spermatogenesis in tumor-bearing testes in germ cell testicular cancer patients. Human Reprod. 30(12):2853–2858.
- Taskinen S, Wikstrom S. 1997. Effect of age at operation, location of testis and preoperative hormonal treatment on testicular growth after cryptorchidism. J Urol. 158(2):471–473. doi:10.1016/S0022-5347(01)64505-1.
- Thorup J, Cortes D. 2016. Long-term follow-up after treatment of cryptorchidism. Eur J Pediatr Surg. 26(5):427–431. doi:10.1055/s-0036-1592138.
- Tsutsumi S, Kawahara T, Takeshima T, Chiba S, Uemura K, Otani M, Shimokihara K, Hayashi Y, Mochizuki T, Takamoto D, et al. 2017. Onco-testicular sperm extraction (onco-TESE) for bilateral testicular tumors: two case reports. J Med Case Rep. 11(1):139. doi:10.1186/s13256-017-1303-6.
- Vinardi S, Magro P, Manenti M, Lala R, Costantino S, Cortese MG, Canavese F. 2001. Testicular function in men treated in childhood for undescended testes. J Pediatr Surg. 36(2):385–388. doi:10.1053/jpsu.2001.20723.
- World Health Organization. 1999. WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 4th ed. New York: Cambridge University Press.
- Yumura Y, Tsujimura A, Okada H, Ota K, Kitazawa M, Suzuki T, kakinuma T, Takae S, Suzuki N, Iwamoto T. 2018. Current status of sperm banking for young cancer patients in Japanese nationwide survey. Asian J Androl. 20(4):336–341. doi:10.4103/aja.aja_74_17.