Evaluation and Preservation of Fertility in Patients with Testicular Cancer

Introduction and Epidemiology

The development of testicular cancer (TC) appears to share common etiological factors with other types of testicular dysfunction such as testicular dysgenesis, androgen insensitivity syndrome, and cryptorchidism. These associations lend themselves to the concept of hormonal factors as one of the etiologies of TC. ¹ TC is well-documented to be associated with impaired spermatogenic function, and sperm count decline in patients with TC has been reported by Petersen et al. ² After orchiectomy, sperm counts are further reduced to less than half of the values in healthy men, and azoospermia is reported in 10–56% of cases. Semen quality also decreases after orchiectomy in patients with TC. Local tumor effect, cancer diagnosis, and abnormal spermatogenesis in the contralateral testis have all been proposed as contributory factors in this setting. ² In patients with TC, biopsy of the contralateral testis has shown severely disordered spermatogenesis in 24% of cases and elevated follicle-stimulating hormone (FSH) levels in most of these patients, consistent with primary spermatogenic failure. ³

Men with TC generally have normal androgen levels before orchiectomy. Human chorionic gonadotropin (hCG) secreted by some testis cancer cells may exert luteinizing hormone (LH)-like effects on normal hormone-producing testicular tissue, resulting in a 1.3-fold and 2.3-fold increase of testosterone and estradiol levels respectively and a reflexive low LH level. Another possible explanation for low LH levels in these patients could be diminished LH-releasing hormone from the hypothalamus secondary to cancer itself. ² Following orchiectomy, FSH is usually increased, inhibin B decreased, and androgen production maintained by increased LH stimulation. Due to the deteriorating effect of orchiectomy on semen parameters, it is recommended that semen cryopreservation take place even before orchiectomy. ⁴

Pre-existing Infertility

It is suggested that factor(s) that decrease the testis fertility capacity may also contribute to germ cell malignant degeneration. ⁵ Epidemiologically, the incidence of TC in infertile men is much higher than the general population (50–1000 times); however, both pathologies are prevalent among young patients. Although history of cryptorchidism and chromosomal aberrations are considered to be common risk factors for infertility and TC, infertility by itself could increase the risk of developing TC. ⁶ Genetic and histologic data also support the association between male infertility and TC. ⁷ Having a child moderately decreases the risk of developing TC, but fathering more than one child confers no additional benefit to reducing a man's risk of TC. ⁵

The strongest evidence about the relationship between impaired fertility and TC comes from a Danish study looking at the semen analysis of more than 30,000 couples evaluated for fertility issues. TC risk increased up to ninefold in men who had a low sperm count, low sperm motility, and a high percentage of abnormal spermatozoa. ⁸ Men with oligospermia, asthenospermia, and teratospermia had a 2.3, 2.5, and 3.0 standardized incidence ratio (SIR) of TC, respectively. ⁹

Reproductive disorders may develop throughout fetal and neonatal life, and in utero exposure to estrogen is reported to be a risk factor for both subfertility and TC. ¹⁰ Though the mechanism is not completely understood, estrogen is proposed to interfere with the hypothalamic–pituitary–testis axis and disrupt normal testis endocrine function, resulting in abnormal function of sertoli cells and secondary infertility. This disruption also impairs normal differentiation of germ cells, predisposing them to develop carcinoma. ⁶

Sperm Banking and Other Technologies

Factors associated with the diagnosis and treatment of germ cell tumors have the potential to affect fertility significantly. The majority of chemotherapeutic agents adversely affect spermatogenesis. Although many patients have transient azoospermia, up to 60% of patients will regain spermatogenesis up to four years after treatment completion with the combination of bleomycin, etoposide, and cisplatin. ¹¹ Based on experimental animal studies, couples are generally instructed to practice reliable contraception during and up to at least six months after completion of chemotherapy, although robust human studies are lacking. ¹² Ejaculatory dysfunction may result from retroperitoneal lymph node dissection, and radiation for seminoma can have adverse effects on spermatogenesis and testosterone production. That is why, for these patients, it is recommended to bank sperm before undergoing any cancer treatment. ¹³ Although seemingly simple, a number of medical, psychosocial, and temporal issues may prevent patients from sperm cryopreservation. Disappointingly, many patients are not offered the opportunity to cryopreserve sperm during the optimal time prior to treatment initiation. Studies indicate that young patients and their families seek information regarding sperm cryopreservation early after the initial cancer diagnosis in order to have the opportunity to bank more than once. ¹⁴ It is important to consider all pubertal patients as appropriate candidates for sperm banking, regardless of the concept that therapy may not affect spermatogenesis. Many clinicians are under the erroneous assumption that the single remaining testicle will eventually normalize hormonal and sperm production to pre-orchiectomy levels.

Since Bunge et al. reported the first human pregnancy using frozen sperm in 1953, ¹⁵ assisted reproductive techniques have used cryopreserved sperm to achieve pregnancy with a relatively high success rate, even with very low numbers of viable sperm. ¹³ In developed countries' medical care settings, cryobanks are now widely available and methods of sperm cryopreservation have been well-established. Sperm samples can be obtained via masturbation from adolescents as young as 13 with similar results to older patients. ¹⁶ In one prospective study, 5.2% of the men returned for infertility treatment a median of 18 months after banking. Cryopreserved samples were used for intrauterine insemination in four couples (12.5%) resulting in two deliveries, and intracytoplasmic sperm injection (ICSI) was used for 28 couples (87.5%) resulting in nine deliveries. ¹⁶ Cryopreservation during orchiectomy is also possible in patients who have been unable to bank sperm prior to the procedure, have no sperm seen on ejaculate, and/or have prior ejaculatory dysfunction. Immediately following orchiectomy, grossly normal areas of the testicle can be dissected and sent for sperm retrieval and preservation.

Given this, prospects for future reproduction are rather good for adolescents and young men undergoing treatment for germ cell tumors, with semen cryopreservation giving additional hope for patients who do not regain normal spermatogenesis or ejaculatory function. All patients undergoing treatment for germ cell tumors should be given the option of semen cryopreservation, ideally prior to orchiectomy. Even if the specimen quality is extremely poor, the presence of any viable sperm can significantly increase chances for fathering children through assisted reproductive technologies, which are only bound to improve with time.

Preservation of Antegrade Ejaculatory Function During RPLND

Conventional bilateral retroperitoneal lymph node dissection (RPLND) typically results in impairment of seminal emission and ejaculatory dysfunction. Postganglionic sympathetic fibers arising from L2–L4 (lumbar splanchnic nerves) and the hypogastric plexus have been recognized as critical structures in the preservation of antegrade ejaculation.^17,18 In experienced hands, primary nerve-sparing RPLND results in preservation antegrade emission in more than 95% of patients. ¹⁹ Following the success of nerve-sparing surgery in patients with stage I testicular germ cell tumors, a similar technique in the post-chemotherapy setting was initially performed in low-volume residual retroperitoneal masses with excellent results,^20–22 and recently the indication has extended to include patients with advanced-stage testis cancers who have relatively large residual retroperitoneal tumors. Indiana University reported that out of 38 patients who underwent nerve-sparing post-chemotherapy RPLND, 34 (89.5%) preserved antegrade ejaculatory function without any cancer recurrence during a mean follow-up of 34 months. ²¹ Similarly, Coogan et al. reported preservation of ejaculatory function in 62 of 81 patients (76.5%) after nerve-sparing RPLND, without any retroperitoneal recurrence after a mean follow-up of 36 months. ²⁰ Even when the nerves are involved with the tumor on one side, unilateral nerve-sparing procedures still yield excellent results. Sheinfeld et al. at Memorial Sloan-Kettering Cancer Center reported results of nerve-sparing RPLND in 136 patients (from a total of 341 patients) and found that post-operative antegrade ejaculation was reported by 107 patients (79%). Right-sided primary TC and residual masses greater than or equal to 5 cm were associated with retrograde ejaculation. ²³

Retrograde ejaculation should be distinguished from anorgasmia and is typically defined as emission of less than 1 cc of semen. Analysis of post-ejaculate urine showing more than 10–15 sperm/high power field (hpf) is confirmatory. Typical treatment for retrograde ejaculation is aimed at increasing the sympathetic tone of the internal sphincter at the bladder neck, as well as the vas deferens. Medications include phenylpropanolamine (75 mg twice daily), ephedrine (25–50 mg four times daily), pseudephedrine (60 mg four times daily), and imipramine (25 mg twice daily). Medication may be given at a desired time rather than continuously. In patients with retrograde ejaculation, sperm may also be retrieved from the bladder post-ejaculation for intrauterine insemination. Ideally, the urine pH should be alkalinized with sodium bicarbonate (650 mg four times daily) in order to preserve the sperm. The retrieved sperm can then be gently centrifuged and washed in insemination media.

Fertility and Chemotherapy

Following modern guidelines for care, approximately half of patients with testicular nonseminoma will require chemotherapy, either for regional or systemic disease at presentation or for relapse after active surveillance for early-stage disease. For patients with seminoma—a biologically less aggressive disease presenting a decade older than nonseminoma—only about 25% of patients will require chemotherapy. ²⁴ Chemotherapy in the modern era is most typically only three cycles of bleomycin, etoposide, and cisplatin, as the vast majority of patients present with good risk disease and do not require salvage chemotherapy.

Fertility preservation in patients with TC is complicated by many of the disease-associated factors described above. Initial studies from the early 1980s noted that approximately 75% of patients were oligospermic, 17% azospermic, and only 6% met the criteria for sperm banking prior to chemotherapy. Virtually all patients were azospermic within two months of chemotherapy initiation, but nearly half of chemotherapy-treated patients had endogenous recovery to normal within two to three years post-chemotherapy. ²⁵ It must be remembered that these results were in an era prior to modern sperm-banking technologies and chemotherapy was substantially different, particularly in terms of higher cumulative doses of cisplatin.

Lampe et al. from the United Kingdom reported a multivariate analysis performed to evaluate recovery of spermatogenesis after orchiectomy and platinum-based chemotherapy in 178 patients treated between 1979 and 1991. ²⁶ Sperm counts were done for all patients before and following primary chemotherapy. Normospermic (NS) was defined as a sperm count greater than 10×10⁶/mL, oligospermic (OS) was defined as counts of 1–9×10⁶/mL, and azoospermic (AS) was defined as counts of less than 1×10⁶/mL. Of the 170 patients analyzed, all had spermatogenesis reassessed at least one year post-chemotherapy. Results showed that of 89 patients with normospermia pre-chemotherapy, post-chemotherapy 57 (64%) were normospermic, 14 (16%) were oligospermic, and 20 (18%) were azospermic. Recovery continued beyond one year, with spermatogenesis returning to 48% by two years and 80% by five years. In 43 patients whose pre-chemotherapy (CT) counts were OS, the post-CT count was NS in 23%, OS in 40%, and AS in 37%. Of 41 patients whose pre-chemotheraphy (CT) count was AS, the post-CT count was NS in 15%, OS in 29%, and AS in 56%. Multivariate analysis showed a reduced probability of recovery to OS among 57 patients aged 30 years or more (risk ratio 0.4; 95% confidence interval [CI], 0.2–0.9) and in the 26 patients treated with more than four cycles of cisplatin-based chemotherapy (risk ratio 0.2; 95% CI, 0.1–0.6).

In the modern era, most patients with normospermia prior to the initiation of therapy will recover endogenous spermatogenesis back to baseline levels within five years. ²⁶ Despite this, it is critical that fertility preservation is discussed with all patients prior to initiation of chemotherapy and patients interested in maximizing the chance of subsequent fertility be referred to a fertility center to discuss sperm banking. It is very uncommon that the medical condition is so aggressive that a patient cannot take a week to 10 days to accomplish this important function. There is emerging evidence that cancer providers make such referrals less than half the time. ²⁷

A practical guide to managing fertility preservation in patients with TC includes discussing fertility issues with all patients and repeating this at each of the following time points: at the time of suspected diagnosis, after diagnosis and prior to selection of treatment approach, and at any therapeutic juncture (e.g., initiation of chemotherapy, radiation therapy, or planned retroperitoneal surgery). Patients facing treatments that can impair fertility and who are interested in maximizing their chance of fathering children should be referred to a fertility center as early as possible. Typically, early-stage patients who have a low prospect of requiring active interventions are counseled to wait and see if therapy will be required and are referred only when the need for active therapies are demonstrated.

Fertility and Radiation Therapy

In the modern era, there has been a marked reduction in the use of radiation to manage TC. Prophylactic abdominal radiation therapy as a mainstay of treatment for clinical stage I seminoma has been in decline for the last decade and is not recommended in most evidence-based guidelines. As well, the traditional fields for prophylactic abdominal radiation (hockey stick or dogleg field [DL]) have been replaced by low-dose para-aortic (PA) radiation only without fields incorporating the ipsilateral groin, based on the definitive study by Fossa et al. ²⁸ In this European multi-center study, patients demonstrated recovery of spermatogenesis within 18 months of radiation treatment. Improved spermatogenesis was seen in the para-aortic arm compared with the DL arm, despite more frequent scrotal shielding in the DL arm. In patients with normospermia (>10×10⁶/mL) before radiotherapy, median recovery time was 13 months for PA patients and 20 months for DL patients. In those with counts less than or equal to 10×10⁶/mL pre-radiotherapy, the median time to the first normal sperm count was 24 months for PA patients and 37 months for DL patients. The long-term impact of port size was minimal, with 92% of DL patients obtaining sperm counts of greater than 10×10⁶/mL within three years of treatment.

In some countries, patients with a diagnosis of TC often undergo a biopsy of the contralateral testis to evaluate for the presence of testicular interepithelial neoplasia (TIN). The approximately 5% of patients demonstrating contralateral TIN are offered low-dose radiation (18–20 cGY). Low-dose reliably eradicates TIN and significantly lowers the risk of a second primary cancer and preserves hormonal function of the testis. However, spermatogenesis is also reliably eradicated in the process. Patients facing radiation therapy to the testis should be referred to a fertility center prior to initiation of treatment.

Practical and Social Aspects of Fertility Preservation in Males

Preservation of fertility for patients facing cancer treatments has become a significant plank in survivorship plans for adolescents and young adults, as well as anyone who desires to retain fertility. Recently, organizations and foundations such as Fertile Hope have been launched that incorporate these precepts and work to advocate for awareness of fertility preservation options for males and females, engage governments and insurers regarding coverage of fertility benefits for patients and families facing cancer and cancer treatments, and provide information and education for patients and providers, as well as regional directories of services.

Sperm banking is not without costs, both for initial analysis and freezing, as well as for annual maintenance. Costs in the United States average $100–$200 for initial semen analysis and freezing and at least $50 per year for storage (often requiring five years to be paid in advance). Subsequent utilization of frozen sperm to achieve pregnancy ranges from $500–$1000 for intrauterine insemination (IUI) up to $10,000–$20,000 for intracytoplasmic sperm injection (ICSI).

In some studies, requests for utilizing banked sperm among patients with TC is quite low, presumably due to endogenous recovery, lack of desire for family, impaired bonding and relationship formation after cancer, or other cultural or societal reasons. ²⁹

Conclusions

Advances in the awareness of fertility effects of cancer treatments have profoundly influenced treatment paradigms and helped lead to the development of treatment approaches with less potential for fertility compromise. In testicular cancer, concerns regarding fertility impairment associated with standard treatments has fostered the development of nerve-sparing RPLNDs, active surveillance options for early-stage seminoma and nonseminoma, and reductions in the use of radiation therapy and the cumulative doses of chemotherapy, particularly cisplatin. Advances in reproductive technology by which pregnancies can be achieved with very low sperm counts has added to the fact that fertility potential can be preserved in the vast majority of TC patients. Successful pregnancies and births are the likely outcome for most patients. The key to such outcomes is awareness at the outset of diagnosis and treatment, open and frequent discussions with patients regarding available options, and utilization of the emerging reproductive science and technologies as appropriate.