Stesura Seveso Archivio Italiano di Urologia e Andrologia 2024; 96(1):12238 1 ORIGINAL PAPER high cure and long-term survival rates, the fertility burden on survivors is still a major concern. Studies have demon- strated a reduction in semen parameters, notably pre- orchiectomy sperm concentration and total sperm count, as well as a decrease in fertility among patients with TCa compared to their healthy counterparts (4). Moreover, patients with TCa often need additional treat- ments which further impair spermatogenesis and fertility. Despite advancements in these treatments, the gonado- toxic effects of chemotherapy and radiation, coupled with the potential for impaired ejaculation and subsequent infertility following retroperitoneal lymph node dissection (RPLND), contribute to a consistent decrease in fertility among males undergoing additional therapy post- orchiectomy (5). In that regard, there is a need for literature investigating the potential role of TCa stage in the fertility potential of these patients. The aim of our study was to evaluate the impact of TCa stage and histology on preorchiectomy semen parameters, as a surrogate for fertility. We also analyzed the role of elevated tumor markers on sperm abnormalities. MATERIALS AND METHODS Patient selection We retrospectively collected data on all patients who con- secutively received radical orchiectomy for presumed TCa and who underwent semen cryopreservation before orchiectomy, between March 2010 and March 2023. We excluded patients with bilateral tumors, patients without germ cell tumor (GCT) on final pathology, patients who did not undergo semen cryopreservation and patients who underwent cryopreservation after orchiectomy. The study was approved by the Ethical Committee of our center. Variables Our database included data regarding age at diagnosis, body mass index (BMI), tumor size, tumor histology, clin- ical stage, serum tumor markers, namely alpha-fetoprotein (a-FP), beta subunit of human chorionic gonadotropin (b-hCG) and lactate dehydrogenase (LDH), and semen Purpose: To evaluate the influence of testicu- lar cancer histology and stage on sperm parameters in cryopreserved samples collected prior to orchiec- tomy. Materials and methods: We conducted a retrospective analysis of tumor histology, stage and sperm parameters of patients who underwent pre-orchiectomy sperm cryopreservation for testicu- lar cancer between March 2010 and March 2023. The World Health Organization (WHO) 2010 sperm reference values were used to identify patients with subnormal semen parameters and to further categorize patients by sperm alteration. Localized dis- ease was classified as Stage I, while metastatic disease encom- passed Stages II and III. Continuous variables were compared using t-test or Mann Whitney U test, and categorical variables using Chi-square and Fisher´s exact test. Results: A total of 64 patients was identified, 48 (75%) classified as stage I and 16 (25%) classified as stage II/III. No difference was found in semen parameters between patients with semino- ma and patients with non-seminoma germ cell tumor (NSGCT). Patients with stage II/III disease had significantly lower percent- ages of progressive motility (36% vs 53%, p = 0.021) and total motility (60% vs 69%, p = 0.015) than stage I patients. When categorizing by sperm alterations according to WHO 2010 reference values, patients with stage II/III disease had significantly higher proportions of asthenozoospermia (38% vs 15%, p = 0.048) and teratozoospermia (63% vs 31%, p = 0.027) than stage I patients. Elevated tumor markers were not associated with sperm abnormalities. Conclusions: Patients with metastatic testicular cancer present with worse sperm quality than patients with localized disease. Sperm cryopreservation should be offered to all patients with testicular cancer, and especially emphasized in patients with metastatic disease. KEY WORDS: Testicular cancer; Male infertility; Cryopreservation; Sperm parameters; Orchiectomy. Submitted 28 December 2023; Accepted 29 December 2023 INTRODUCTION Testicular cancer (TCa) is the most common malignant tumor in young adult men aged 15-40 years, and accounts for about 1% of all neoplasms in men (1). The incidence of TCa has been steadily increasing in recent years, pre- dominantly in developed countries (2, 3).Despite having Semen parameters in testicular tumor patients before orchiectomy: What is the impact of testicular tumor stage and histology? Gonçalo Mendes 1, Bernardo Teixeira 1, Mariana Madanelo 1, Alexandra Rocha 1, Sofia Mesquita 1, João Vital 2, Miguel Monteiro 1, Avelino Fraga 1, Nuno Louro 1 1 Department of Urology, Santo António University Hospital Center, Porto, Portugal; 2 Department of Urology, Hospital of Funchal, Funchal, Portugal. DOI: 10.4081/aiua.2024.12238 Summary Archivio Italiano di Urologia e Andrologia 2024; 96(1):12238 G. Mendes, B. Teixeira, M. Madanelo, et al. 2 parameters. Serum tumor markers were considered ele- vated if they were above the upper normal limit provided by the laboratory (a-FP 0-7 µg/L, b-hCG 0-2 U/L, LDH 135-225 U/L). Semen parameters reviewed included patient´s semen volume, sperm concentration, progres- sive motility, total motility and morphology. The World Health Organization (WHO) 2010 sperm reference values (6) were used to identify patients with subnormal semen parameters and to further categorize patients by sperm alteration (oligozoospermia was defined as < 15 million spermatozoa/mL, asthenozoospermia as < 32% progres- sive motile spermatozoa and teratozoospermia as < 4% normal forms). Stage I disease was considered localized disease, whereas Stage II/III disease was considered metastatic disease. Statistical analysis Continuous variables with normal distribution are pre- sented as mean ± standard deviation and compared by Student´s t-test, while continuous variables with non-nor- mal distribution are presented as medians accompanied by interquartile ranges (IQRs) and compared by the Mann- Whitney-U test. Categorical variables are presented as proportions, and comparisons of two categorical variables are performed with the Pearson’s Chi-square test and Fisher exact test. A multivariate regression analysis was performed. Statistical analyses were conducted using SPSS Statistics version 27. All tests were two-sided, and statistical significance was set at p < 0.05. RESULTS A total of 123 patients were diagnosed with TCa at our institution in the studied time- frame. A total of 64 patients (52%) were included (patients who underwent semen cryopreservation before orchiectomy). Of these, 48 patients (75%) classified as stage I and 16 patients (25%) classified as stage II/III. According to histology, 33 patients (52%) were seminoma and 31 patients (48%) were non-seminoma GCT (NSGCT). Baseline characteristics are presented in Table 1. Age, BMI and tumor size were sim- ilar between groups. There was a significant- ly bigger proportion of NSGCT in stage II/III patients as compared to patients in the stage I group (75% vs 40%, p = 0.014). A comparison of sperm parameters between both groups according to histology (semino- ma vs NSGCT) is presented in Table 2. All semen parameters were similar between groups, and therefore no difference was observed between patients with seminoma and patients with NSGCT. A comparison of sperm parameters between both groups according to stage (stage I vs stage II/III) is presented in Table 3. In gen- eral, all sperm parameters where lower in the stage II/III patients. Stage II/III patients had significantly lower percentage of pro- gressive motility (35.51% in stage II/III vs 53.00% in stage I, p = 0.021) and significantly lower per- centage of total motility (59.95% in stage II/III vs 69.10% in stage I, p = 0.015). Additionally, there was a trend towards lower progressive motility and lower total motil- ity (as absolute numbers) in stage II/III patients, as well as a tendency to a lesser percentage of morphologically nor- mal spermatozoids in this group. Sperm parameters were further categorized according to the WHO 2010 sperm reference values, and the groups according to stage (I vs II/III) were compared. The results are presented in Table 3. Stage II/III patients had a sig- nificantly higher proportion of asthenozoospermia (38% in stage II/III vs 15% in stage I, p = 0.048) and a signifi- cantly higher proportion of teratozoospermia (63% in stage II/III vs 31% in stage I, p = 0.027). Despite not reaching statistical significance, patients in stage II/III Table 1. Baseline characteristics of the patients. Stage I Stage II/III P (n = 48) (n = 16) Age 31.00 ± 5.88 30.69 ± 12.34 0.923 BMI 24.84 ± 4.33 26.67 ± 4.03 0.506 Tumor size 38.85 ± 21.59 42.88 ± 23.07 0.528 Histology Seminoma 29 (60%) 4 (25%) 0.014 NSCGT 19 (40%) 12 (75%) BMI: body mass index; NSGCT: non-seminoma germ cell tumor. Table 2. Comparison of preorchiectomy sperm parameters according to tumor histology. Total Seminoma NSGCT p (n = 64) (n = 33) (n = 31) Semen volume (mL) 2.95 ± 1.60 3.09 ± 1.56 2.79 ± 1.66 0.468 Sperm concentration (millions/mL) 31.50 (10.48-70.00) 37.00 (15.50-84.50) 28.00 (9.00-66.00) 0.330 Progressive motility (millions/mL) 19.21 (3.98-39.31) 22.08 (4.11-42.88) 11.50 (3.38-33.53) 0.295 Progressive motility (%) 48.63 ± 22.20 50.61 ± 23.36 46.52 ± 21.07 0.465 Total motility (millions/mL) 21.83 (6.35-51.32) 26.91 (7.00-54.20) 16.40 (5.75-43.20) 0.347 Total motility (%) 65.55 (52.45-77.75) 67.00 (52.95-79.80) 64.50 (52.30-74.50) 0.444 Normal morphology (millions/mL) 1.56 (0.29-4.83) 1.70 (0.52-5.51) 1.55 (0.26-4.20) 0.493 Normal morphology (%) 4.00 (2.25-7.00) 5.00 (3.00-7.00) 4.00 (2.00-8.00) 0.866 NSGCT: non-seminoma germ cell tumor. Table 3. Comparison of preorchiectomy sperm parameters according to tumor stage. Total Stage I Stage II/III p (n = 64) (n = 48) (n = 16) Semen volume (mL) 2.95 ± 1.60 3.01 ± 1.71 2.75 ± 1.28 0.578 Sperm concentration (millions/mL) 31.50 (10.48-70.00) 33.50 (15.25-73.00) 23.00 (0.03-47.00) 0.129 Progressive motility (millions/mL) 19.21 (3.98-39.31) 20.79 (5.33-42.48) 9.65 (0.01-30.84) 0.077 Progressive motility (%) 48.63 ± 22.20 53.00 ± 19.29 35.51 ± 25.67 0.021 Total motility (millions/mL) 21.83 (6.35-51.32) 24.43 (8.37-54.06) 12.45 (0.01-36.32) 0.088 Total motility (%) 65.55 (52.45-77.75) 69.10 (55.43-79.25) 59.95 (5.00-66.68) 0.015 Normal morphology (millions/mL) 1.56 (0.29-4.83) 1.63 (0.50-5.40) 0.80 (0.01-4.15) 0.195 Normal morphology (%) 4.00 (2.25-7.00) 5.00 (3.00-7.00) 3.00 (0.00-7.50) 0.102 Archivio Italiano di Urologia e Andrologia 2024; 96(1):12238 3 Semen parameters in testicular tumor group also had higher percentage of oligozoospermia (44% in stage II/III vs 23% in stage I, p = 0.108). The pro- portion of patients with azoospermia was similar between groups. On multivariate regression analysis, elevated tumor markers (AFP, b-hCG and LDH) were not associated with abnormalities in sperm parameters (Table 5). Three patients (5%) used their cryopreserved semen for assisted reproduction techniques (ART); two patients had a seminoma and one patient had a NSGCT. Two patients had stage I disease and one patient had stage II/III disease. Non-cryopreserved paternity data was unavailable. DISCUSSION Testicular cancer can play a major role in infertility. Analysis of cryopreservation data demonstrates that nor- mal sperm quality is observed in less than half of men with TCa before treatment, and 10-35% suffer from infer- tility. Fertility may be impacted by TCa through a multi- tude of axis, including intrinsic infertility associated with the testicular dysgenesis syndrome, the testicular tumor local effect, and systemic effects of hormones secreted by the tumor (7). There is a paucity of literature on the impact of tumor stage and histology in sperm outcomes of patients with TCa, with a previous study failing to demonstrate any relation between these factors (8). To the best of our knowledge, this is the largest series on the impact of tumor stage and histology on sperm quality. In our study, we demonstrated that patients with metastatic disease (stage II/III) have worse sperm parameters than patients with localized disease (stage I), namely lower progressive and total motility and a higher proportion of asthenozoospermia and teratozoospermia. Tumor histol- ogy showed no influence on sperm parameters in indi- viduals with TCa and elevated tumor markers were not associated with sperm abnormalities. TCa can have local adverse effects on spermatogenesis through local growth of the testicular tumor. The occur- rence of spermatogenesis defects is most prominent in the vicinity of malignant tumors (9), a trend not observed in benign tumors (10). Larger tumor size is correlated with lower levels of spermatogenesis in the ipsilateral testis (11). In fact, testicular tumors > 4 cm exhibit a significant decrease in spermatogenesis compared to tumors < 4 cm (12). TCa can also exert deleterious effects on sperm quality through secreted hormones. Elevated serum lev- els of a-FP or b-hCG can disrupt the physiologic feed- back mechanism of the hypothalamic-pituitary-gonadal (HPG) axis, which directly regulates testicular function, and hence spermatogenesis (13). Disruptions in the lev- els of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone are associated with spermatogen- esis and a reduction in sperm concentration (5). It has also been demonstrated that any kind of cancer, includ- ing TCa, may lead to worse sperm quality, with sperm parameters below the WHO reference values; causative factors have been hypothesized to be a rise in pro-inflam- matory circulating cytokines and interleukins (14). Moreover, testicular cancer is associated with elevated oxidative stress and DNA fragmentation, both potentially contributing to decreased fertility (15, 16). Despite these detrimental effects of testicular tumor on sperm quality, orchiectomy does not result in improvement of sper- matogenesis; instead, it further deteriorates sperm quali- ty. Petersen et al. (17) demonstrated a reduction in sperm concentration, total sperm count and serum inhibin B levels in patients who underwent radical orchiectomy for TCa, as well as de novo azoospermia in 9% of patients. A more recent multicenter study evaluating pre and post orchiectomy semen samples concluded that sperm con- centration significantly decreased after orchiectomy (18). These studies highlight the importance of cryopreserva- tion, which should ideally be done before orchiectomy, since there is currently no evidence that expedited radical orchiectomy translates into oncological benefit (19). Furthermore, in this setting we might find patients who are amenable to surgical testicular sperm extraction (TESE) at the time of orchiectomy (onco-TESE) (7). Patients with TCa may be subject to additional treatments other than radical orchiectomy, and these treatments may further impair the fertility of these patients. Chemotherapy in TCa is dependent on platinum-based agents (cisplatin and carboplatin), which may be com- bined with other agents, such as bleomycin and etoposide (7). By penetrating the testis blood barrier and targeting actively dividing cells, chemotherapy significantly impairs spermatogenesis, resulting in oligozoospermia and azoospermia. There is a well-established correlation between the failure to conceive and the cumulative dose of chemotherapy (20, 21). In a study of 1191 TCa sur- vivors, higher doses of chemotherapy translated into a significant impairment of spermatogenesis, resulting in only 29% of patients being normozoospermic after 11 Table 4. Comparison of categories of preorchiectomy sperm alterations according to the WHO 2010 sperm reference values and to tumor stage. Stage I Stage II/III P (n = 48) (n = 16) Oligozoospermia (< 15 millions/mL) n (%) 11 (23%) 7 (44%) 0.108 Asthenozoospermia (< 32% progressive motility) n (%) 7 (15%) 6 (38%) 0.048 Teratozoospermia (< 4% normal forms) n (%) 15 (31%) 10 (63%) 0.027 Azoospermia (complete absence of spermatozoa) 2 (4%) 1 (6%) 1.000 Any abnormality n (%) 21 (44%) 10 (63%) 0.194 Table 5. Multivariate regression analysis for the role of elevated tumor markers as predictors of any abnormality in sperm parameters in patients with testicular cancer. Covariate OR 95% CI P Elevated a-FP 2.859 0.693, 11.787 0.146 Elevated β-hCG 0.486 0.125, 1.890 0.297 Elevated LDH 2.748 0.895, 8.436 0.097 CI: confidence interval; OR: odds ratio. Archivio Italiano di Urologia e Andrologia 2024; 96(1):12238 G. Mendes, B. Teixeira, M. Madanelo, et al. 4 years of follow-up (22). There is potential for recovery of spermatogenesis, in a time-dependent manner, with 48% and 80% of patients with normal pretreatment sperm concentrations recovering spermatogenesis by 2 and 5 years, respectively (23). Radiation therapy is another modality for treatment of TCa. It may be applied to retroperitoneal metastases, in which case the testes are exposed to scatter radiation only, generally at low doses which protect fertility, or directly to the testes, in case of germ cell neoplasia in situ; in the latter case, with radia- tion doses of 16-20 Gy frequently used, there are high rates of irreversible azoospermia (5). Finally, RPLND is another modality of additional treatment in TCa. RPLND might cause retrograde ejaculation or anejaculation due to damage of lumbar plexus and splenic nerves, which renders the patients infertile. Despite the very high rates of ejaculatory function preservation with modern nerve sparing techniques, fibrosis might still make this tech- nique difficult, resulting in substantial rates of anejacula- tion (7). Our study concluded that patients with metasta- tic disease (stage II/III) have significantly worse semen parameters than patients with localized disease (stage I); these findings underscore the need for cryopreservation especially in metastatic patients, and a greater emphasis should be placed on cryopreservation in this subset of patients, given that treatment of these patients with one or more of these modalities of adjuvant treatment is gen- erally the rule. Only a few studies have evaluated the potential role of histology and stage on sperm quality (8, 24, 25). Fraietta et al. (24) reviewed the data of 100 patients with TCa and analyzed the patients’ sperm quality according to histo- logic type (seminoma vs NSGCT) and concluded that patients with seminoma had a higher number of motile and morphologically normal spermatozoids than those with NSGCT. A more recent study by Badia et al. (8) con- cluded that histology did not influence semen parame- ters, as these were similar between patients with semino- ma and NSGCT. This aligns with the results of our study, where we showcased that patients with distinct histology exhibited comparable semen parameters. As for the role of stage, Halstuch et al. (25) demonstrated that severe oligozoospermia (< 5 million/mL) was more common in metastatic than non-metastatic NSGCT. The same con- clusion could not be drawn for patients with seminoma. Badia et al. (8) also evaluated the role of stage on semen parameters, and again concluded that semen parameters were similar in TCa patients with localized and metastat- ic disease. These results are conflicting with the results of our study. We did demonstrate differences between dif- ferent stages, with metastatic disease showing less pro- gressive and total motility and a higher proportion of asthenozoospermia and teratozoospermia, and this was demonstrated for patients with stage II/III irrespective of histology. Rates of oligozoospermia were, however, simi- lar between groups, despite a tendency towards less oligozoospermia in localized disease. Moreover, despite the previously noted effect of secreted hormones, we did not demonstrate and association between elevated tumor markers and sperm abnormalities. We hypothesize that it is the systemic inflammatory process of metastatic testic- ular cancer, rather than the hormonal burden of elevated tumor markers, that might be responsible for a detrimen- tal effect on spermatogenesis. Semen cryopreservation should be discussed and offered to all patients with TCa, ideally before orchiectomy to maximize chances of fertility, and if not done before orchiectomy should be pursued prior to chemotherapy or radiation therapy (26). Despite these recommendations, only 24-30% of TCa patients undergo sperm cryopreser- vation (24, 27-29). In our study, 64 patients (52%) out of 123 patients diagnosed with TCa underwent semen cry- opreservation before orchiectomy, with an additional 12 (10%) patients undergoing semen cryopreservation after orchiectomy and before adjuvant treatments, which translated into a total sperm cryopreservation rate of 62%. The timing of cryopreservation is of importance, as noted by the work of Rives et al. (18), in which they demonstrated that mean sperm concentration before orchiectomy was significantly higher than after surgery (32x106/mL vs 24x106/mL). Moreover, as previously noted, semen cryopreservation before orchiectomy has the potential for selection of patients for onco-TESE, which is another advantage (7). It is also worth noting that despite advancements in ART in the last years, sperm cryopreservation remains the most cost-effective strategy for fertility preservation (30). Therefore, it is the authors’ opinion that semen cryop- reservation should be offered in every patient with TCa, if possible before orchiectomy, and in light of the results of our study a heightened emphasis should be placed on patients with metastatic disease, as these display overall worse sperm quality and will most probably be subject to additional treatments. Our study has several limitations that deserve acknowl- edgment. The main shortcomings come from its retro- spective nature. We could only analyze the information on the medical records, and as a consequence the success rate of pregnancies from cryopreserved sperm samples could not be evaluated. Furthermore, we used decreased semen parameters as a surrogate for decreased fertility, even though a direct relationship between the two hasn’t been established. Additionally, despite our institution being a high-volume referral center for TCa, the relative- ly short sample size of 64 patients may limit statistical power. In that sense, further studies, preferably prospec- tive and multicenter, are needed in the future to support our findings. CONCLUSIONS Testicular cancer has the potential for infertility. Patients with metastatic testicular cancer (stage II/III) have worse sperm quality, namely less progressive and total motility of spermatozoids and a bigger proportion of astheno- zoospermia and teratozoospermia than patients with localized testicular cancer (stage I). Histology appears to play no major role in sperm quality and elevated tumor markers were not shown to be associated with sperm abnormalities. Sperm cryopreservation should be offered to all patients with testicular cancer, ideally before orchiectomy, and this should be further emphasized in patients with metastatic disease. Further studies are rec- ommended to validate these findings. Archivio Italiano di Urologia e Andrologia 2024; 96(1):12238 5 Semen parameters in testicular tumor REFERENCES 1. Park JS, Kim J, Elghiaty A, Ham WS. Recent global trends in tes- ticular cancer incidence and mortality. Medicine. 2018; 97:e12390. 2. Nigam M, Aschebrook-Kilfoy B, Shikanov S, Eggener S. Increasing incidence of testicular cancer in the United States and Europe between 1992 and 2009. World J Urol. 2015; 33:623-31. 3. Gurney JK, Florio AA, Znaor A, et al. International Trends in the Incidence of Testicular Cancer: Lessons from 35 Years and 41 Countries. Eur Urol. 2019; 76:615-23. 4. 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Correspondence Gonçalo Mendes, MD (Corresponding Author) goncalo.grilomendes@gmail.com Bernardo Teixeira, MD bernardolat@gmail.com Mariana Madanelo, MD marianacmadanelo@gmail.com Alexandra Rocha, MD marialexandrarocha@gmail.com Sofia Mesquita, MD sofiaoplmesquita@gmail.com Miguel Monteiro, MD mmonteiro.iam@gmail.com Avelino Fraga, MD avfraga@gmail.com Nuno Louro, MD nunorlouro@gmail.com Department of Urology, Santo António University Hospital Center, Porto, Portugal João Vital, MD joaopvital@gmail.com Department of Urology, Hospital of Funchal, Funchal, Portugal Conflict of interest: The authors declare no potential conflict of interest.