Sexual function and fertility preservation in testicular cancer survivors

4.1 Orchiectomy

Testicular tumors are generally removed by radical unilateral orchiectomy. While we counsel patients that the majority of men will still be able to father a child after this treatment alone, this may still have an impact on the patient’s sexual function and fertility. There is an expected 50% decrease in post-operative sperm concentration within the first few months following surgery, with no change in serum testosterone levels [35, 36]. Studies have shown that 40% of patients are oliogozoospermic or azoospermic in the month following orchiectomy, with gradual recovery of spermatogenesis two to three years after surgery [37]. Nine percent of men with previously normal sperm counts will become azoospermic after orchiectomy, without recovery of sperm production [35]. Men with elevated pre-surgical FSH (follicle-stimulating hormone) levels are less likely to have spermatogenesis recovery, as this usually indicates baseline spermatogenic dysfunction [34, 38, 39]. Post-radical orchiectomy patients are also more likely to have elevated LH levels, indicating a predisposition to Leydig cell dysfunction and hypogonadism [36]. In addition to sperm concentration, asthenospermia (motility <40%) and teratozoospermia (morphology <4%) have been found in 50% of post-orchiectomy patients with TC [40, 41, 42].

In order to preserve sperm cell production, partial orchiectomy may be an option for carefully selected patients with a small tumor in a solitary testis, small bilateral tumors, or increased suspicion for a benign tumor [36]. Partial orchiectomy is an effective means of tumor control for prepubertal benign teratomas, with techniques adopted for adult testicular cancer. These patients require closer follow-up to monitor for TC recurrence with routine surveillance ultrasounds and tumor markers [32, 33, 36].

To evaluate fertility of TC patients, Jacobsen et al. [43] studied 36 patients and found that 28 patients fathered at least 1 child after orchiectomy, including 19 patients who had not fathered a child prior to being diagnosed with testicular cancer, with median time from orchiectomy to first fatherhood after orchiectomy at 18 months. In terms of testicular endocrine function, men without detectable hCG were found to have an increase in median follicle-stimulating hormone (FSH) from 5.7 IU/L before to 10.0 IU/L after orchiectomy (p < 0.001), indicative of spermatogenic dysfunction [35]. Median inhibin B levels were also significantly decreased from 108 pg/L before to 95 pg/L after orchiectomy (p = 0.003) [35].

4.2 Chemotherapy

Postoperative chemotherapy can temporarily or permanently impair spermatogenesis and fertility. Alkylating agents, especially cyclophosphamide and ifosfamide, pose the highest risk of azoospermia. Rapidly dividing spermatocytes are particularly sensitive to alkylating agents [44]. The most common chemotherapy regimen used in testicular cancer is bleomycin, etoposide, and cisplatin (BEP). BEP has been shown to temporarily impair spermatogenesis, with return after 12 months if two or fewer cycles were used. Patients who were treated with greater than 3 courses or with radiotherapy had spermatogenesis return after 24 months from the end of treatment [45]. Because of the risk of underlying DNA damage to sperm from chemotherapy and radiation, it is the recommendation by the American Society of Reproductive Medicine (ASRM) and the American Urological Association (AUA) that conception is not attempted with freshly ejaculated or extracted sperm within 2 years of receiving chemotherapy or radiation [46]. Studies of children with a paternal history of cancer were more likely to have major congenital abnormalities if conceived within 2 years of paternal receipt of chemotherapy/radiation [47].

Spermatogenic side effects of chemotherapy may vary depending on pubertal status, type of chemotherapy, and number of treatment cycles. Alkylating agents carry a risk for azoospermia. Additionally, cumulative doses of platinum-based agents such as cisplatin that are less than or equal to 400–600 mg/m² will temporarily damage both spermatogenesis and testicular endocrine function, with more permanent damage conferred at greater doses [48, 49, 50]. This temporary damage occurs by causing more injury to rapidly proliferating type B spermatogonia, with minimal damage to type A spermatogonia [51]. Type A spermatogonia are primitive stem cells that undergo active mitosis, and type B spermatogonia are differentiated progenitors that give rise to spermatocytes [52]. Thus, with preservation of the primitive stem cells, sperm counts may be replenished; indeed, this temporary azoospermia typically resolves in 2 years in 50% of cases and in 5 years in 80% of cases [53].

Irreversible loss of spermatogenesis can occur at greater doses due to partial or complete destruction of type A spermatogonia [51]. A large follow-up survey study of 1462 patients showed that paternity was dependent on number of cycles of cisplatin-based chemotherapy. All men receiving 2 cycles, 83% with 3 cycles, and 76% after 4 cycles were able to conceive [54]. Another follow-up survey of 554 men found that high-dose cisplatin with a cumulative dose greater than 850 mg had a paternity rate of 38% compared to 62% in the low-dose cisplatin group that received less than 850 mg/m² [55]. It is important to consider the possible impact of chemotherapy on the offspring of cancer patients. These offspring may be at a higher risk of congenital malformations due to the mutagenic nature of treatments received by their parents [56, 57].

4.3 Radiation therapy

Radiation therapy (XRT), despite gonadal shielding, can pose gonadotoxic effects due to scatter radiation [58]. Testicular function is normally affected by XRT in a dose dependent manner. Semen parameters are significantly affected by radiation doses as low as 0.1 Gy [59]. Recovery of spermatogenesis is dependent on radiation dosage. Radiation doses less than 1 Gy can take up to 18 months and less than 4 Gy up to 5 years to recover. Radiation doses exceeding 4 Gy can lead to irreversible damage to spermatogenesis [60]. Leydig cells are more resistant to the gonadotoxic effects of XRT and require on average higher dosages greater than 20 Gy to cause primary hypogonadism [61]. Of note, germinal epithelium of the testis that are exposed to 3–7 week fractionated courses can experience more gonadal damage than with single doses [48]. When radiation is fractionated, cumulative doses that exceed greater than 2.5 Gy can irreversibly impair spermatogenesis [48]. Moreover, prior studies have found that radiotherapy seemed to have a more deleterious effect on fertility compared with chemotherapy alone [62].

Radiation therapy is especially harmful in cells with high replication rates, notably in both cancer cells and normal spermatogonia [63]. It increases sperm DNA damage, which limits replication and persists for 1–2 years following treatment [60]. This radiation induced DNA damage detected in primary spermatocytes continues to be present in mature spermatozoa as well [64]. A study of 96 TC patients found that the proportion of spermatozoa with DNA strand breaks was significantly higher in XRT patients during the first 2 years after therapy [60]. Elevated DNA damage is associated with poor oocyte fertilization, embryo development, implantation, and lower live birth rates [65].

4.4 Retroperitoneal lymph node dissection

Prior to the advent of chemotherapy and accurate cross-sectional imaging, the burden of disease of testicular cancer was great, and a wide surgical resection of retroperitoneal disease was needed to ensure patients with cancer-free survival. As a result, bilateral and suprahilar RPLNDs were routinely performed, with resection of or injury to post-ganglionic sympathetic nerves off the sympathetic chain and subsequent loss of antegrade ejaculatory function in 90% of patients [66, 67]. This has significant repercussions for reproductive age patients, who without forward ejaculation rely on adjunctive measures such as electroejaculation versus sperm extractions from the testis. The loss of forward ejaculation can be diagnosed through post-ejaculate urinalysis, wherein the presence of sperm in the urine is an indicator of retrograde ejaculation [68]. Sperm in the urine may be used for intrauterine insemination versus in vitro fertilization, depending on sperm concentration. While modified templates and meticulous attention to nerve sparing can preserve ejaculatory function, significant risk of nerve damage persists [69].

Electroejaculation (EEJ) uses a waveform generator in a burst or continuous fashion via a rectal probe to stimulate the seminal vesicles and sympathetic nerves at the aortic bifurcation and obturator nerves for forward ejaculation. This is typically performed under anesthesia to minimize patient discomfort. Although antegrade ejaculation may be achieved in >85% of patients, it typically requires milking from the urethra into a sterile container. The semen is then prepared for intrauterine insemination [70].

Alternatively, patients may consider testicular sperm extraction. Testicular sperm is not motile, and thus must be used for in vitro fertilization with intracytoplasmic sperm injection, a labor-intensive and costly form of assisted reproductive technology. To reduce rates of retrograde ejaculation, modified templates have been proposed which limit suprahilar, interiliac, and contralateral dissection [66, 71, 72, 73]. Anatomical mapping studies of retroperitoneal metastases have resulted in modified RPLND that maximize antegrade ejaculation by limiting dissection in areas that have reduced risk of metastatic disease [66, 74, 75, 76]. Unilateral dissection leads to loss of antegrade ejaculation in 30% to 50% of patients, contributing to issues of primary hypo-fertility in 25% to 40% of TC patients [77]. In a cohort of 167 TC patients by Donohue et al. [78] undergoing prospective nerve-sparing modified unilateral template, the ejaculation rate was 98%.

A study of 341 patients undergoing RPLND found that a right-sided primary testicular tumor (OR 0.4, 95% CI 0.1–1.0, p = 0.044) and residual masses ≥5 cm (OR 0.1, 95% CI 0.0–0.7, p = 0.020) were most likely to be associated with retrograde ejaculation [79]. Another study surveyed 297 testicular cancer survivors for paternity. The paternity rate in patients treated with surgery alone (orchiectomy +/− RPLND) was 59%. In comparison, paternity rates were 68% and 50% in patients treated radiotherapy alone and chemotherapy alone, respectively. Paternity was lowest in patients’ post-non-nerve sparing RPLND, versus 62% in patients with nerve sparing RPLND (p < 0.0001) [80]. Thus, loss of ejaculation greatly impacts patients’ fertility and should be preserved when possible.

5.1 Post-pubertal fertility preservation

Sperm cryopreservation has been established as the primary method for fertility preservation in post-pubertal male patients. Prior studies have shown sperm cryopreservation to be not only the most cost-efficient, but also the most productive and robust technique for fertility preservation [81, 82]. Given that cytotoxic treatments including radiation and chemotherapy can lead to testicular failure, freezing of spermatozoa is a suitable solution for fertility preservation in TC patients [83]. Frozen-thawed semen can then be used intrauterine insemination, in vitro fertilization, or intracytoplasmic sperm injection [84]. It has been reported that cancer patients who have undergone sperm cryopreservation are also better able to cope with their diagnosis and treatment [85].

Sperm cryopreservation is performed by Andrology laboratories, which are commonly located in reproductive endocrinology or urology practices. Patients who do not have access to these labs may now even take advantage of mail-in kits, such as Overnite Male® (https://hospital.uillinois.edu/primary-and-specialty-care/urology/andrology/over-nite-male-kits), or Fellow® (https://www.meetfellow.com/kit), or Legacy® (https://www.givelegacy.com/). These kits use sperm preservation medium to keep sperm alive for ~24 hours. Thus, patients can ejaculate at home and mail the kit back via overnight shipping to a CLIA (Clinical Laboratory Improvement Amendments)-certified lab, where the semen in processed and frozen for future use.

For a majority of neurologically intact, post-pubertal TC patients, ejaculation is considered the most straightforward approach to collection of sperm [86]. However, more invasive means are available for patients who are unable to provide a sample through ejaculation. As noted in the previous section, men may consider electroejaculation as a bridge to intrauterine insemination or in vitro fertilization. Men with normal testicular function may undergo percutaneous epididymal sperm aspiration (PESA) or testicular sperm aspiration (TESA), where a small syringe is inserted into the epididymis or testis respectively to retrieve sperm. According to the AUA, 10% of TC patients present with azoospermia secondary to spermatogenic dysfunction, and thus do not have sperm within the ejaculate [87]. For these patients, a microsurgical testicular sperm extraction has the highest likelihood of isolating sperm for cryopreservation. In this surgery, the testis is searched for foci of spermatogenesis, usually in areas with larger and more opaque seminiferous tubules. These tubules are biopsied and sent to the andrology lab for processing. If sperm is recovered, it is cryopreserved in a similar fashion to ejaculated sperm. Prior studies have shown that almost half of men with significantly large volumes of TC still bear areas of spermatogenesis [88]. Additionally, some TC patients with nonobstructive azoospermia have been shown to recover spermatogenesis after treatment and may choose to have surgical testicular sperm extraction (TESE) performed at the time of orchiectomy as a means for fertility preservation [89].

Many techniques are available for the cryopreservation of sperm, including slow freezing and rapid freezing as conventional methods [83]. An alternative method to these freezing techniques is vitrification, which allows for the preservation of spermatozoa without the use of permeable cryoprotectants [90]. Cryopreservation may induce changes that reduce the integrity of sperm plasma membranes and ultimately influence fertilization potential [91, 92], although pregnancy outcomes have not been found to differ between frozen vs. thawed sperm [93].

Testicular cancer patients may also experience erectile dysfunction. Options for management include testosterone replacement therapy (TRT) and PDE-5 (Phosphodiesterase-5) inhibitors as first line therapies for ED in hypogonadal and eugonadal patients, respectively. Intracavernosal injection therapy, vacuum erectile devices (VEDs) with constriction bands, intraurethral prostaglandin suppositories and surgical placement of a penile prosthesis are considered for non-responders [94]. Up to 15% of TC survivors experience symptomatic hypogonadism [87]. Testosterone affects nitric oxide synthase release, PDE-5 expression, and cavernosal nerve function—all important factors in maintaining erectile function. Furthermore, PDE-5 inhibitors have been shown to be more efficacious in men with normal serum testosterone levels [95].

PDE-5 inhibitors are a first line therapy for erectile dysfunction. By preventing phosphodiesterase-5 mediated degradation of cGMP (cyclic guanosine monophosphate), PDE-5 inhibitors promote arterial inflow into the corpora cavernosa [96]. VEDs are plastic cylinders that are placed over the penis to create a vacuum, which pulls blood into the penis [96]. They should be used in conjunction with a constriction band at the base of the penis to trap the blood and maintain the erection when the suction is released. Intracavernosal injections are another option for erectile dysfunction patients. Vasoactive substances, which increase arterial inflow into the corpora via the cAMP (cyclic adenosine monophosphate) pathway, are injected into the lateral aspect of the penis through a small gauge needle. These substances may include any combination of alprostadil, papaverine, phentolamine, and/or atropine [97]. An erection typically occurs within 10–15 minutes of the injection [96]. For patients who cannot use injections, alprostadil is also available as an intraurethral gel [98]. Patients who do not respond to first or second line therapies may consider a malleable or inflatable penile prosthesis [96].

5.2 Pre-pubertal fertility preservation

If the testicular cancer patient is pre-pubertal the testicle is unlikely to be producing sperm, thus obtaining ejaculated sperm impossible. Cryopreservation in the prepubertal population depends on the experimental preservation of germ cells with stem cell capability within the cryopreserved tissue. Currently, there are no established methods to use these germ cells for fertility. Subsequent methods for generation of viable sperm such as autologous testicular tissue grafting, spermatogonial stem cells (SSC) transplantation, and in vitro spermatogenesis all remain experimental [99, 100]. Of these methods, SSC transplantation is the only one that may reestablish fertility by natural conception and has restored spermatogenesis in non-human primates leading to viable embryos and even offspring [101, 102]. Given the presence of immature germ cell divisions, the prepubertal testis is highly sensitive to radiation and chemotherapy [103]. Leukemic infiltration in the testis of pre-pubertal patients may require direct irradiation of the testicles. This direct irradiation can later cause infertility secondary to oligospermia or azoospermia despite the development of normal secondary sexual characteristics [104]. Fractionation involves using small and incremented doses of radiation therapy over time to overcome the acute toxicity induced by a large single dose. Fractionation has been found to be beneficial for reducing dosage per session, but it also reduces time available for tissue healing and repair [105]. Although susceptibility may vary depending on the treatment, damage to the prepubertal testis can persist well into adulthood after treatment has ended [106]. Moreover, the pharmacological protection of the testis during oncologic treatment is a developing field in male onco-fertility.

Pharmacological agents may be administered collectively with chemotherapy to maintain testicular fertility. Although such strategies are experimental, they may offer non-invasive approaches to preserving fertility in TC patients who cannot leverage sperm cryopreservation [99]. Specifically, the clinical application of granulocyte colony-stimulating factor (G-CSF) may serve a role in male fertility preservation. In preclinical studies, G-CSF conferred a protective role by stimulating spermatogenesis of residual undifferentiated spermatogonia and improving spermatogenic recovery after exposure to high-dose alkylating agents [99]. In addition, antioxidant treatment with melatonin has been proposed to protect against oxidative stress and germline toxicity induced by alkylating agents such as busulfan. Studies in mice showed that melatonin reduces reactive oxygen species and apoptosis of spermatogonia associated with busulfan treatment [107]. These non-invasive approaches are considered experimental.