Introduction

Recent advances in the treatment of cancer have led to greater longevity among men in reproductive ages with a 75% five-year cancer survival rate in boys aged 15 years or younger [1] and 66% among men aged 15–44 [2]. There is increased recognition that quality of life including paternity is significant issues for cancer survivors. We will focus primarily on patients with testicular cancer and lymphoma that generally affects younger patients in the reproductive window with an excellent overall survival. However, one must realize in our modern society the age of desiring paternity has increased due to postponement of marriage as well as for other social reasons. Therefore, this chapter will focus not only on those who completed chemotherapy as children but adult cancer patients as well.

Low Testosterone in Men with Cancer

Mounting evidence also demonstrates hypothalamic–pituitary–gonadal (HPG) axis dysfunction resulting in hypogonadism among cancer survivors. The prevalence of testosterone deficiency among men with cancer has been reported to be between 40% and 90% [3, 4]. Innate to having cancer, central gonadotropin suppression occurs in addition to the presence of an inflammatory state among men with cancer, and is thought to contribute to Leydig cell dysfunction resulting in impaired testosterone production [5–9]. Other mechanisms of downregulating testosterone production include up-regulation of ghrelin that subsequently suppresses LH and testosterone production [10, 11]. Low leptin levels have also been observed in men with cancer and associated cachexia, and leptin is required for normal gonadotropin release [12]. Beyond the impact of physiological changes of malignancy, oncologic treatments also have profound impact on testosterone production. Opioid use for cancer patients with discomfort has demonstrated hypogonadism rates beyond 75% and it has been well documented that opioid consumption significantly downregulates serum testosterone values which are necessary for sperm production [13, 14]. Chemotherapy has been shown to have a direct and dose-dependent impact on Leydig cell dysfunction and impairment in testosterone production, particularly among alkylating agents [15, 16]. Radiotherapy has also been shown to impact Leydig cell function resulting in increased LH and FSH with associated decreased testosterone levels with as little as 3.3 Gy [17].

Cytotoxic Treatment Effects on Spermatogenesis

The effect of chemotherapeutics on spermatogenesis varies by both the drug administered as well as the cumulative dosage and will be discussed in other chapters. However, it is obvious that due to their high proliferative index, chemotherapeutics are particularly toxic to germ cells. Specifically, differentiating spermatogonia are among the most rapidly dividing germ cells and are the most sensitive to cytotoxic treatments [18, 19]. The most offensive chemotherapeutic agents include: cyclophosphamide, ifosfamide, busulfan, procarbazine, melphalan, chlormethine, and chlorambucil. Intermediate risk cytotoxic agents include: cisplatin, doxorubicin, and carboplatin; low risk agents include vinblastine, bleomycin, vincristine, methotrexate, dactinomycin, and mercaptopurine [20]. The extent of germ cell loss is often difficult to predict, but alkylating agents and combination antineoplastic therapies have been shown to have the most dramatic effects on spermatogonial stem cell apoptosis and depletion [21]. Of significance, preservation of populations of spermatogonial stem cells is necessary to facilitate future potential spermatogenesis. Other forms of biological agents used to treat cancers of men in reproductive ages have limited evidence regarding their effects on spermatogenesis to date; however, tyrosine kinase inhibitors for example can induce oligozoospermia and affect sperm function [22, 23]. Bone marrow and stem cell transplantations with associated chemotherapy and radiotherapy result in infertility among two thirds of pediatric cancer patients [24].

There is no diagnostic test to determine whether or when spermatogenesis will return after chemotherapy. Depending upon the treatment regimen, spermatogenesis may not fully disappear in all men, and may return within 12 weeks in many [25]. Men with return of sperm to the ejaculate may even conceive naturally and all reproductive options are open to them. However, a focus on men who are rendered azoospermic after therapy remains a clinically important subgroup of patients who are candidates for treatment. Up to 13.8% of men are azoospermic prior to chemotherapy [26, 27]. What are we to do with this population? This chapter will discuss the treatment options available to males azoospermic prior to chemotherapy as well as those men with post-chemotherapy azoospermia. Although advanced reproductive techniques are now available to the post-chemotherapy population, it remains an obvious recommendation that men bank sperm prior to any chemotherapy or gonadal radiation treatment, optimizing options for effective treatment. This is best reflected in the most recent 2018 American Society for Oncology Guidelines which state that healthcare providers should discuss infertility with all patients proposed to undergo treatment of their cancer and that fertility preservation should be discussed, including the opportunity for referral to fertility specialists [28].

Sperm Banking Before Chemotherapy/Radiotherapy

In most cases, sperm collection and cryopreservation of sperm is a simple task prior to the initiation of chemotherapy or radiation therapy. In men with normal ejaculation, sperm cryopreservation involved the collection of a masturbatory sample that is subsequently cryopreserved. Barriers to universal sperm banking are variable but may include inadequate counseling by physicians, inability to afford sperm banking, limited sperm quality for cryopreservation, prepubertal or young emotional age of the patient, religious restrictions on sexual activity, or the sense of urgency to begin cancer treatment.

Unfortunately, low rates of sperm banking prevail. One study that examined young adult survivors of childhood cancer found that nearly 60% reported uncertainty about their fertility status, and only half recalled a healthcare provider discussing potential reproductive problems associated with treatment [29]. A survey of cancer patients treated at two major cancer centers revealed that only 51% of respondents had been offered sperm banking and only 24% of respondents actually banked sperm [30]. A lack of information was the most common reason for not banking sperm in up to 25% of patients in this study [30]. Surveys in the United States [31, 32], United Kingdom [33], Australia, and New Zealand [34] show that many oncologists do not routinely provide information on and referrals for banking sperm to teenagers and young men, despite claiming that sperm banking should be offered to all men at risk of infertility from cancer treatment. Sperm banking seemed to be offered less when the patients had aggressive disease or poor prognosis [32]. But even with successful banking, rates of subsequent utilization of cryopreserved sperm appear to be low. Several reports from sperm banking facilities concur that <20% of men who store sperm before cancer treatment end up using it to try to conceive [27, 35–37]. Of course, such numbers could be artificially suppressed by: (1) lack of survivorship for some patients who elect to bank sperm; (2) the long delay between medical therapy for cancer and subsequent election to have children; (3) recoverability of sperm production for some men despite toxic treatment regimens; and (4) the lack of insurance support for assisted reproductive treatments in many areas of the United States. Therefore, all men should be offered and the majority should undergo sperm banking. For the minority of patients who are azoospermic at the time of presentation, more advanced sperm retrieval techniques may be needed to cryopreserve sperm. These techniques may include microdissection testicular sperm extraction, or standard random-biopsy testicular sperm extraction. Among men who are unable to provide an ejaculated sample but are likely to have adequate sperm production, electroejaculation, testicular sperm aspiration, and testicular percutaneous biopsy are feasible options at some facilities. Among adolescent populations that are post-pubescent but unable to masturbate to provide a sample, electroejaculation under general anesthetic or small TESE are reasonable options to provide fertility preservation and not delay oncologic treatment. Furthermore, pre-pubescent boys have not yet initiated the full extent of spermatogenesis. Some programs are performing investigational testis biopsies and cryopreservation of the derived spermatogonial stem cells. Future hopes of in vitro propagation of stem cells to spermatozoa or autotransplant back into the same individual later in life are potential options, but are not currently available interventions. At present, animal models are being tested with encouraging results [38].

Chance of Recovery of Spermatogenesis

The chance of recovery of spermatogenesis depends on the chemotherapeutic regimen as well as the baseline function of the patient. Notably, alkylating agents such as cyclophosphamide have been the most extensively studied in this group of drugs and seem to have the most dramatic reproductive effects. However, sperm will return to the ejaculate in numbers sufficient for natural conception in many if not most patients depending on the chemotherapeutic regimen, radiation treatment, surgical treatment, and baseline semen parameters. Recovery of sperm following radiation is dose-dependent. Sperm has been shown to return around nine months with gonadal radiation doses of 0.5–0.8 Gy, but is typically delayed for 14–26 months for men with gonadal doses of 1.7 Gy [21]. However, a cumulative dose of 2.5 Gy or single dose of 6 Gy has been demonstrated to produce permanent azoospermia in the large majority of men [39]. However, Leydig cells may retain function at doses up to 20 Gy and thus, these patients may appear to have intact gonadal function despite severely impaired spermatogenesis [40, 41]. Depending upon the agent and dose used, spermatogenesis recovery after chemotherapy is most likely to occur within the first two years, but recovery can still exist up to five years in a proportion of patients and case reports have suggested recovery up to 20 years after radiation [21, 42]. For patients with return of sperm to the ejaculate, reproduction may involve spontaneous conception to intrauterine insemination (IUI) to in vitro fertilization (IVF). However, Schmidt et al., in a review of 67 cancer survivors, found that 57% of men were azoospermic after chemotherapy [43]. The rest of this chapter will focus on the treatment options available to those who remain persistently azoospermic or severely oligozoospermic.

At present, only crude measures of predicting the return of spermatogenesis after chemotherapy are available. During chemotherapy, follicle stimulating hormone (FSH) levels invariably increase associated with the destruction of germ cells. Kader and Rostom [44] found that persistently elevated levels of FSH at two years after chemotherapy is associated with a higher chance of azoospermia. It is worth noting, however, that in our microdissection testicular sperm extraction (mTESE) series of men with nonobstructive azoospermia, we have not found FSH to be a predictor of sperm retrieval (to be discussed later) [45]. New developments in the field of predicting sperm retrieval following microdissection testicular sperm extraction include using an anti-Müllerian hormone (AMH) value of less than 4.62 ng/ml or AMH to testosterone ratio of less than 1.02, which demonstrated a predictive accuracy of 93% and 95% respectively [46]. This study only evaluated idiopathic nonobstructive azoospermia, and to our knowledge has not been applied to the onco-fertility population. Additionally, early reports of contrast enhanced ultrasound have reported that regions of increased perfusion are associated with sperm retrieval rates of 63.1% in idiopathic nonobstructive azoospermia patients, while sperm retrieval rates of 34.7% were identified in areas of poorer perfusion [47]. Although multiple approaches are being investigated to predict or guide sperm retrieval among men with NOA, further studies are necessary to validate these strategies and implement them into the onco-fertility cohort.

Treatment Options for Azoospermic Men After Chemotherapy

Traditionally the patient who present with azoospermia following chemotherapy have been considered sterile if they did not bank sperm prior to chemotherapy. However, advances in assisted reproductive techniques have enabled even many of these men to successfully father children with progression in techniques to recovery of sperm during testicular sperm extraction. The realization that the testicle is not uniform with respect to spermatogenesis allows reproductive surgeons to target dilated tubules with regions of active spermatogenesis through microdissection TESE (microTESE); this has allowed retrieval of sperm among over 50% of men once deemed sterile. With the introduction of intracytoplasmic sperm injection (ICSI), we now have the ability to enable conception with very low numbers of sperm. For the man who is azoospermic after chemotherapy there remains a number of choices for reproduction, including the use of previous cryopreserved sperm as well as use of fresh sperm retrieved either by electroejaculation (in the event of ejaculatory dysfunction or failure of emission) or microdissection testicular sperm extraction. Finally, if a patient is unable or unwilling to successfully pursue any of the previous options the option of donor sperm remains in addition to adoption.

Use of Cryopreserved Sperm

The existence of previously cryopreserved sperm greatly simplifies the algorithm for the post-chemotherapeutic azoospermic man. This allows the couple to proceed directly to IVF-ICSI or IUI in some instances with robust motile number of sperm [48]. Use of cryopreserved sperm have demonstrated favorable results. Hourvitz reported on 118 couples undergoing 169 IVF–ICSI cycles at Weill Cornell [49]. Over an 11-year interval, using cryopreserved sperm for ICSI, a fertilization rate (per injected egg) was 77.6%, with a clinical pregnancy rate of 57% (96/169) and a 50% delivery rate (85/169). As a historical control, a similar population was evaluated over a two-year period at the same institution prior to the routine use of ICSI. Using conventional IVF, the fertilization rate was 32% and the delivery rate was 24% (13/54) [49]. Agarwal et al., in a retrospective study of 29 patients, reported the outcome of use of cryopreserved sperm from men with various malignancies [37]. They showed that with assisted reproductive technology (ART), couples with cryopreserved sperm prior to cancer therapy can be successfully treated to achieve pregnancy. Schmidt et al., in a study of patients presenting to a Danish fertility clinic, noted that 22/35 live births in their series were due to the use of cryopreserved sperm [43]. Recently, a retrospective series of 682 men with cryopreserved sperm among cancer patients led to 10.3% of patients using their sperm for attempted ART cycles; this led to 37.4% pregnancy rate among ICSI attempts and 11.5% pregnancy rate among IUI cycles comparable to other patient populations. Other reports suggest up to 15% of men will access their cryopreserved specimens due to sustained posttreatment azoospermia [50]. The mean duration of cryopreservation was four years, but extended up to 20 years [51]. Thus, the use of cryopreserved sperm is both viable and successful for many years beyond cancer treatment. In general, the freeze-thaw process is considered to cause most of the sperm damage or loss with cryopreservation, not the duration of time that sperm are frozen.

In the Patient Who is Azoospermic Prior to Chemotherapy

Patients with leukemia, lymphoma and testicular cancer often present with suboptimal semen parameters [52–55]. Whether one type of malignancy is associated with worse sperm quality is controversial [26, 56, 57]. However, it is notable that up to 13.8% of cancer patients presenting to sperm banks are azoospermic [26, 27]. For the patient azoospermic prior to chemotherapy, there is an even greater urgency with regard to the expediency of treatment. Time is critical and these patients must balance the urgency of getting necessary chemotherapy with the additional worry of successful preservation of spermatozoa. Any fertility treatment must be of minimal morbidity limiting any delay of the patient from the needed chemotherapeutics. For these patients, there is the option of cryopreservation of testicular spermatozoa from normal testis, cryopreservation of spermatozoa from the diseased testis, or preserving epididymal or vasal sperm (for obstructed patients). It is likely that in this setting, yield of spermatozoa from any of these sperm retrieval techniques may be low. The advent of ICSI has made treatment of these patients feasible, since only small numbers of sperm are needed for successful IVF.

Sperm extraction is possible from the contralateral normal testis or from the affected testis (if retrieval is done after separation of the testis from the patient) for men with testicular cancer at the time of orchiectomy. In patients with lymphoma, sperm extraction can be done in either one side or both testes simultaneously prior to chemotherapy. In 2003, Schrader et al. reported 31 men with either testicular cancer or lymphoma [58]. In testicular cancer patients, the TESE sample came from the contralateral testicle, which was also evaluated for concomitant carcinoma in situ (CIS). The lymphoma patients underwent bilateral TESE. The sperm retrieval rate was 43% (6/14) in testicular cancer and 47% (8/17) in patients with Hodgkin’s or non- Hodgkin’s lymphoma [58]. A recent series reported similar sperm retrieval rates of 37.5% in testis cancers and 33.3% among non-testicular malignancies [59]. Onco-TESE is a viable option for recovering sperm in a significant proportion of men presenting with azoospermia prior to initiation of chemotherapy and has resulted in normal offspring, using the retrieved sperm with ICSI.

There also is the possibility of vasal or epididymal sperm extraction after orchiectomy from the orchiectomy specimen. Baniel and Sella reported three azoospermic patients with testicular cancer who at the time of radical orchiectomy had vasal and epididymal sperm preserved [60]. After the specimen had been resected, sterile extraction of sperm with cryopreservation of sperm from the vas and epididymis was done. They reported two pregnancies from three couples [60].

Preserving tissue or sperm from the tumor containing testis can be done on a separate sterile field (“a backtable” or “ex-vivo”) after orchiectomy or, in cases of partial orchiectomy, the surrounding normal testicular parenchyma can be examined and sent for cryopreservation. A number of groups have reported on these techniques in a limited number of patients with good success at sperm retrieval and subsequent pregnancies [61–63].

Use of Spermatozoa from Men Who Have Received Chemotherapy or Radiation

Men who have received chemotherapy, and even men who had non-gonadal radiation therapy, will have increased rates of sperm aneuploidy for 6 months or more after treatment [64]. Specifically following treatment of testis cancer, increased aneuploidy rates are observed for 12 months following radiotherapy and 24 months following at least 2 cycles of Bleomycin etoposide and cisplatin (BEP) with nearly 40% of men having sustained increased levels of sperm aneuploidy at 24 months [65]. A variable increase in sperm DNA fragmentation has also been observed after chemotherapy, much of which will return to baseline within one year after treatment; however, reports have been heterogeneous with many not demonstrating increased DNA fragmentation post-cytotoxic therapy [66]. Some studies have suggested an increase in birth defects for offspring of men treated with chemotherapy or non-gonadal radiation within the past year. Taken together, these data suggest caution in suggesting that patients attempt to have children early after chemotherapy or radiation treatment. Many experts would recommend avoiding using sperm for conception within one to two years of chemotherapy or radiation; use of cryopreserved sperm obtained prior to treatment is suggested.

In the Patient Who is Anejaculatory after Chemotherapy and is Oligozoospermic or Normozoospermic

Any retroperitoneal surgery such as retroperitoneal lymphadenectomy may affect the sympathetic chain or structurally compromise the bladder neck and may affect antegrade ejaculation. Partial ejaculatory function may be preserved depending on the degree of nerve sparing. The preservation of ejaculatory function obviously has a tremendous impact on fertility rates. In Norwegian testicular cancer survivors who had chemotherapy, those with intact antegrade ejaculation have an 83% paternity rate, while rates for paternity were only 10% in the anejaculatory group [67].

An option for anejaculatory patients is to undergo electroejaculation. This is a procedure typically performed under general anesthesia in the sensate patient. We do not routinely catheterize the patient prior to electroejaculation. The patient is placed in the lateral decubitus position. Anoscopy is performed to confirm that the rectum is empty and no rectal mucosal abnormalities are present. The rectal probe is inserted completely into the rectum with the electrodes oriented anteriorly, over the prostate and seminal vesicles. Stimulation is carried out with a standard electrical stimulation system. The pattern of electrical stimulation has been empirically evaluated but appears to work best with a gradually increasing voltage “peaked” sine wave stimulation that is abruptly ceased, with at least 5–7 s delays between stimulations. The procedure is also monitored by observation of penile tumescence and rectal temperature. Typically, penile tumescence is noted first, followed by seminal emission. Electrical stimulation should stop when seminal emission ceases, rectal temperature of 38°C is observed, or a maximum of 30 volts is attained. Anoscopy is performed again to ensure that there is no rectal mucosal injury, which is a potential complication of this procedure. The patient is turned supine and urethral catheterization is carried out. An initial retrograde specimen is diluted in human tubal fluid (HTF) buffered with HEPES and plasmanate, p. 7.4, and sent for immediate processing, as is the antegrade ejaculate. The bladder is then irrigated with HTF, and this second retrograde specimen is sent for immediate processing as well.

Ohl et al. performed electroejaculation in 24 testicular cancer patients (23 of which had undergone retroperitoneal lymphadenectomy) and observed seminal emission in all 24 patients [68]. Greater than 10 million motile and progressive sperm were obtained in 88% (21/24) of patients. In total, 17 couples underwent IUI and the overall cycle fecundity rate was 9%. Seven clinical pregnancies were detected and there were five live births. Electroejaculation has also been successfully combined with IVF (and obtained a 53% fertilization rate [69]) as well as IVF/ICSI with a 75.5% fertilization rate [70]. At Weill Cornell, we have reported a fertilization rate of 75.5%, a clinical pregnancy rate of 56% per retrieval and an implantation rate of 33% per embryo [70].

Rosenlund et al. evaluated 17 couples treated for testicular cancer where most (14/17) received chemotherapy and most patients acquired sperm through electroejaculation [71]. They employed IVF or ICSI and had a fertilization rate of 55–57% in both groups, and the ongoing pregnancy rate for the whole cohort was 57% per cycle [71]. The study demonstrated that treated testicular cancer patients can successfully undergo ART with electroejaculated spermatozoa.

Patients Azoospermic after Chemotherapy

Prolonged azoospermia after chemotherapy can be due to the patient’s chemotherapeutic regimen, the use of radiation, the extent of surgery, the disease itself, the baseline function of the patient or any combination of the aforementioned factors. While these men were once considered sterile, the use of advanced reproductive techniques has enabled paternity in a subset of this population. Specifically, the realization that the testis is not uniform and that there may be focal regions of spermatogenesis within select seminiferous tubules in these patients has enabled us to retrieve sperm in patients with nonobstructive azoospermia using mTESE [72].

For men who are azoospermic after chemotherapy, spontaneous recovery may occur in at least a subset of patients within two to eight years. For men treated with alkylating agents, the duration of azoospermia may be longer, so a period of observation prior to attempted testicular sperm extraction is recommended. For men treated with platinum-based regimens, most men who will have sperm return to the ejaculate can have sperm detected within two years. As in any patients with nonobstructive azoospermia, percutaneous aspirations or biopsies, while possible, are more likely to yield low numbers of sperm and require multiple treatments. In our view, the low yield, uncertainty of sperm retrieval and intratesticular bleeding/scarring make these procedures less favorable, especially in this patient population with multiple insults to spermatogenesis. The risk of testicular injury along with low spermatozoa yields led to the development of mTESE [72]. Our data and that of others suggest that mTESE yields the highest sperm retrieval rate in this population and is considered the gold standard therapy.

Evaluation prior to mTESE includes a thorough history, sexual history, chemotherapy history, physical exam and hormonal profile. On physical exam, attention is paid to the fullness of the epididymis as well as testicular volumes. The most predictive factors to confirm nonobstructive azoospermia, rather than obstructive azoospermia, includes FSH greater than 7.6 and testis long axis greater than 4.6 cm predicting NOA [73].

The technique of mTESE is as follows. This technique involves placing a wide incision in the tunica albuginea in an avascular region and eversion of the testicular parenchyma for microdissection (Figure 14.1). With high power magnification, subtunical vessels as well as intratesticular vessels can be identified and preserved. Microscopic dissection and direct examination of seminiferous tubules allow identification of the rare regions that contain sperm in men with nonobstructive azoospermia (NOA). The tubules with spermatozoa are wider and more opaque than the fibrotic Sertoli cell-only tubules (Figure 14.2). Overall, mTESE has been shown to result in a higher number of sperm harvested, increased chance of retrieving sperm and decreased testicular tissue removed [72, 74]. The only predictor of successful treatment is the most advanced stage seen on biopsy and not the predominant stage [75]. Testicular volume, serum FSH levels and the etiology of NOA appear to have little or no effect on the chance of sperm retrieval [45, 75, 76]. Postoperative ultrasound has demonstrated fewer acute and chronic changes after microdissection as compared to conventional TESE [77]. Of course, an increased number of biopsies is always counterbalanced by a greater risk of damage to the vascularity of the testis, and so the surgeon must be constantly aware of this. For selection of the initial side, we prefer to start on the side with larger testicular volume or the side with the more advanced spermatogenic pattern seen on histology if a prior biopsy was done (with the most advanced being normal spermatogenesis followed by late maturation arrest, early maturation arrest and Sertoli-cell only pattern, in that order).

Figure 14.1 Microdissection Testicular Sperm Extraction. (microTESE). (A) An equatorial incision is made in the tunica albuginea. (B) The testicle is bi-valved exposing the seminiferous tubules. (C) The seminiferous tubules are carefully evaluated using an operating microscope until dilated tubules are identified. (D) Once the microTESE is complete, hemostasis is achieved with bipolar cautery and the tunical albuginea is closed with a running monofilament suture.

(Reproduced with permission from AUA Update Series, Flannigan & Schlegel Lesson 9, Volume 36, 2017)

Figure 14.2 Intraoperative picture of dilated and opaque tubules more likely to harbor spermatogenesis, as indicated by forceps

At Weill Cornell Medicine, we have performed 81 mTESEs in 70 post-chemotherapy patients. These patients presented with a variety of malignancies, with the most common being Hodgkin’s lymphoma, leukemia, testicular cancer and non-Hodgkin’s lymphoma (Table 14.1). The mean number of years since chemotherapy was 18.6 years (range 1–34 years). The mean male age at mTESE was 35.3 years (range 22–53 years) and the mean female age was 32.5 years (range 21–43 years). Mean baseline FSH was 24.0 (range 4.2–62.7) and mean testosterone was 352 (range 64–814). Our sperm retrieval rate was 43.2% (35/81). Sperm retrieval rate was greatest among testicular cancer patients (85.7%), followed by leukemia (50%), neuroblastoma (50%), non-Hodgkin’s lymphoma (36.4%), Hodgkin’s lymphoma (25.9%), and sarcoma (14.3%) Fertilization rate was 57.0% 192/337. Clinical pregnancies were defined as a heartbeat seen on transvaginal ultrasound 32 days after embryo transfer. The live birth rate was 42.9% (15/35) with 10 singleton deliveries and 5 twin deliveries. We noted a lower sperm retrieval rate with lymphoma 34% (14/41) than for testicular cancers 85% (11/13) [78].

Table 14.1 Patients with underlying medical conditions treated with chemotherapy

Medical condition	No. of patients (n = 81)	Percentage
Hodgkin’s lymphoma	29	35.8
Testicular cancer	13	16.0
Leukemia (AML, ALL)	13	16.0
Non-Hodgkin’s lymphoma	12	14.8
Sarcoma	7	8.6
Neuroblastoma	3	3.7
Medulloblastoma	1	1.2
Wilms’ tumor	1	1.2
Mediastinal germ cell tumor	1	1.2
Nephrotic syndrome	1	1.2

ALL. Acute lymphoblastic leukemia: AML. Acute myeloid leukemia.

Damani et al. reviewed the University of California, San Francisco (UCSF) and Boston University experience in 2003 [79]. The series consisted of 23 patients who underwent chemotherapy for a number of reasons but mostly for testicular cancer. It is not clear if some anejaculatory men were included in this experience. They either underwent conventional testicular sperm extraction or fine needle aspiration mapping and subsequent TESE. Sperm was successfully extracted in 65% (15/23) and a total of 26 cycles of ICSI were performed. The mean fertilization rate was 65% with a delivery/ongoing pregnancy rate of 20.8% in 11 couples. In a study of 12 patients post-chemotherapy, a multi- biopsy approach TESE was undertaken and sperm successfully retrieved in 5/17. Eight ICSI cycles were performed with a fertilization rate per injected oocyte of 68%. There was only one live birth from seven embryo transfers [80].

Donor Sperm (Third-Party Reproduction)

Additional counseling is recommended for those patients who choose the assistance of third-party reproduction. There is universal agreement that the psychosocial, emotional, and ethical complexities of donor conception require thorough exploration both for those donating and those receiving gametes [81–83]. In many clinics, a mental health professional (MHP) meets with prospective known donors and recipients to explain the psychosocial implications of third-party reproduction. It has been argued that the assistance of an MHP is essential to promote complete examination of the many dilemmas faced by those who receive gametes [84–86].

The MHP may need to help a patient address previously unresolved grief regarding the cancer diagnosis and treatment. When donor back-up treatment is being considered, it should be carefully explored prior to treatment and should not be a decision by default at the last minute (e.g., after poor TESE results and oocyte retrieval during an IVF cycle). Often times, a patient’s hopes that viable sperm will be found may interfere with their ability to fully consider all aspects of a donor sperm back-up plan and psychosocial issues may need to be revisited if the backup plan becomes a reality. While a patient may have grieved at the time of the cancer diagnosis, a diagnosis of infertility may reopen the grieving process by adding another dimension to the illness and may interfere with and/or postpone the desire to move forward with a donor.

Couples embarking on the path of third-party reproduction must mutually agree that their best alternative to genetic parenthood is the use of donated sperm or embryos. They must think about what it means to be a parent and how parenting a child who is not genetically connected to both of them may be different from parenting a child who is genetically connected to only one of them. Couples who feel strongly about their genetic lineage may view donor sperm/embryo as severing their ancestral ties. The ultimate loss of one’s ability to create a child can create a powerful emotional crisis as well as feelings of sadness, anger, and bereavement. There are several psychological losses to overcome in nonbiological parenting: loss of biological posterity; loss of self-esteem and a sense of wholeness; loss of the ability to “give” one’s partner a child; loss of the fantasized child that will embody the best of both parents; loss of a sense of control, health, and well-being; and loss of the belief in the fairness of life. Resolution of these losses is best conceived as a process [87, 88].

In addition to thinking about how a third party, known or unknown, will affect their feelings about themselves and their relationship, most importantly, couples must think about their relationship with their potential child. Recipients must decide whether or not they plan to tell the potential child about how he or she was conceived and how much interaction, if any, they want the donor to have with the child. Couples often carry many fears and fantasies about gamete donation, including concerns that the donor will try to reclaim the offspring or that the child will wish to seek out his or her “real” mother or father. The man who is unable to use his own gametes may wonder if he is capable of loving “someone else’s child.” For some couples, this process brings up thoughts and feelings about adultery, and they must work toward separating the act of sexual intimacy from the act of procreation. Others fear that the biological and genetic inequality of donor sperm may eventually threaten their relationship.

Anonymous Versus Known Sperm Donation

There are three main types of gamete donation [89]. In anonymous donation, donors are typically selected from sperm banks and couples choose their donors from profiles with nonidentifiable information such as physical characteristics, intelligence, academic history, professional background, hobbies, nationality, social history, religion, and blood type. In other countries, it is sometimes the doctor that selects the donor according to phenotypological similarities with the male partner. The issue of an identified, known, or interfamilial donor is another option for couples. When the donor is willing to disclose their identity, sometimes including meeting the parents (and possibly the child) in the future, the donor is referred to as a known or identified donor. A directed donor is a friend or relative of the intended parents who chooses to donate solely to that specific family.

The decision to use a known or unknown donor is only one of the many choices that affect all parties involved, including the potential offspring. Those who support anonymous sperm donation insist that anonymity is beneficial to the donor, the recipients, and the donor offspring. Some intended parents strongly desire anonymous donation because they wish to maintain privacy about the donor decision, while others come to the process with additional losses because they do not know anyone who would be appropriate as a donor. Most individuals and couples who choose anonymous donation feel protected by the anonymity and feel that it creates a psychological barrier between them and the donor, enabling them to feel more secure as a family. Recipient parents do not want the child to be confused about who his or her parents are or reject the nongenetic parent. They may also wish to conceal the donation from disapproving family members, especially those for cultures less accepting of sperm donation. Many intended parents worry that if their family knew about the donation, the child would not be loved or accepted in the same way as a full genetic child [90–92]. They typically feel that telling the child of his or her birth by sperm donation would subject the child to social or psychological disorders, which could be especially unsettling if the child wanted to find out more information about the donor but could not. With expanded genetic testing through commercial entities evaluating ancestry and internet sites promoting “donor sibling” registries, it is progressively likely that the offspring of “anonymous” sperm donation may be easily able to identify and locate the sperm donor.

In recent years, a strong tendency in favor of non-anonymous sperm donation has emerged in Europe and Australia. Several countries have enacted laws or are taking into consideration permitting children to gain access to information about their genetic fathers once the child has reached maturity [93]. Proponents of non-anonymous sperm donation argue that human beings have a fundamental interest, and perhaps even a legal right, to know their biological origins. Not telling the child of his or her origins violates that child’s autonomy. Proponents believe that disclosure is a key part of open and honest communication with children, which helps to avoid secrets in the family that can damage family relationships and generate possible strain and anxieties.

Those who support known or non-anonymous donation feel more comfortable in having control over the source of the gametes as well as the knowledge of medical and social histories. Intended parents feel comforted by knowing firsthand the donor’s personality, temperament, and physical attributes, and may feel relieved with not having to deal with the social and relational confusion inherent in familial donation. Some choose a close friend, while others fear that sperm donation could jeopardize their relationship if something went wrong or if they did not conceive, or if the donor became attached to the child and viewed it as his. In some cases, known donors also give the child the option of knowing his or her full genetic history, which some donor recipient parents feel may help facilitate a more secure identity for their children.

Gamete donation has made it possible for participants to cross generational lines and has raised many complicated ethical issues. In 2012, the American Society for Reproductive Medicine (ASRM) issued an Ethics Committee Report on family members as gametes donors and surrogates [94]. While this report approved of many types of interfamilial gamete donations, it recommended a careful screening to ensure that the decision to donate gametes to a family member protected the autonomy of the donor and that free decisions are made in an informed manner. It also advised that semen donation should not be carried out in those situations in which the child would result from an incestuous (father-to-daughter donation) or consanguineous union (brother-to-sister donation) putting the child at risk of genetic abnormalities. Whereas, brother to brother donation is the most acceptable intrafamilial sperm donation. Furthermore, it recommends that family members (the extended family of the infertile couple) must be accepting of the resulting child. Interfamilial donations that the participants plan to keep secret from the larger family system should be carefully evaluated.

When an identified, known, or interfamilial donor is being used, there are specific psychological issues that need to be systematically addressed by the infertility counselor. It is necessary to assess the relationship between the participants to establish whether the reproductive plan is in the best interests of all of those involved, including the potential child. It is also important to obtain the history of the relationship between the donor and the recipient parents to ensure that there is no coercion or other “hidden” agendas. The nature of the relationship and boundaries between the potential child and the donor must be carefully examined and clearly defined for all parties. Should the relationship between the donor and the parents be strained at some time in the future, there is potential for traumatization of the potential child as well as other family members [92, 93]. In some cases, it is the counselor who needs to help one party say no to an uncomfortable request. In child-to-parent donations, the counselor must address the imbalance of power and the inherent boundary violations that may leave the family system or the relationships vulnerable and at risk. Because most children feel indebted to their parents to some degree, these children are not truly free to say no to their parent’s request in the same way they are free to say no to anyone else. In addition, many experts feel that the nature of the relationship may be violated as children are providing for their parents while these parents are still competent. The infertility counselor must also consider a son or daughter’s relationship with the stepparent to make sure that there are no sexual overtones. In the case of a father donating to a son, some professionals feel more supportive, because the concept of a parent giving to their child is already built into the parent–child relationship [90, 95, 96].

Oftentimes couples may ask a brother to donate while others may ask another relative such as a cousin or a nephew. Brother-to-brother donations may appear to be ideal on many levels because of their similar genetic makeup and continuity of the bloodline, but it is only as good as the health of the relationships between the two siblings and their respective spouses. If couples choose a sibling to donate, old patterns of sibling rivalry may get stirred up. There are also many social and emotional entanglements that could occur in the family if their child, for example, has an uncle who is considered his “genetic father” and a cousin who is his half-sibling. When third parties are involved in family building, especially when they are a family member, recipient parents may fear that their children are likely to form a stronger attachment to the donor than to them. When a family gamete cycle fails to result in pregnancy, all involved are extremely disappointed, and as family members search for an explanation, old family dynamics may be reenacted resulting in blame or feelings of guilt [95, 96].

It is critical for all of the parties involved in any type of known donation to have a clear understanding of boundaries and to think through scenarios that may challenge these arrangements in the future. All parties should be in agreement regarding disclosure to others as well as to the potential child. Ultimately, the donor should feel comfortable allowing the recipients to make all decisions related to disclosure, the pregnancy, and the upbringing of the potential child. The infertility counselor must help all of the parties involved explore their motivations, concerns, expectations, wants, hopes, and fears regarding the process.