Adult male cancer patients, who wish to preserve their fertility, have options to cryopreserve sperm through semen samples to be used for future-assisted reproductive techniques, including intrauterine insemination (IUI), in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI). Additionally, percutaneous epididymal sperm aspiration (PESA), testicular sperm extraction (TESE), testicular sperm aspiration (TESA), and microsurgical epididymal sperm aspiration (MESA) can be used to collect sperm or haploid gametes in patients with azoospermia or oligospermia. IVF and ICSI could then be performed with as little as a single haploid gamete. Assisted reproductive technologies (ART) have been widely used in the USA since 1981, in over 440 fertility clinics nationwide [110]. Unfortunately, prepubertal boys are unable to provide sperm samples, as they have not undergone the hormonal changes necessary to undergo complete spermatogenesis. There are currently no regular procedures for preserving gametes from prepubertal boys. An experimental procedure where testicular tissue is cryopreserved is recommended as a potential fertility-saving option by the American Society for Reproductive Medicine for prepubertal patients undergoing gonadotoxic cancer treatments [93]. These techniques are performed throughout the world in the hopes of one day utilizing advanced technologies to grow or transplant spermatogonial stem cells (SSCs) for future use in ART technologies or to restore fertility in cancer survivors in the future [111–116].

Patients undergoing potentially sterilizing techniques are willing to participate in studies that may promote the availability of their tissue for later use [112], and retrieval of tissue biopsies as part of a treatment regimen for prepubertal or peripubertal boys has been shown to be safe and effective [111, 112]. Cryopreservation was accepted by 93.5 % of patients asked, and all cryopreserved patient tissue contained visible spermatogonia [111]. Experimental procedures to obtain mature sperm can occur as a transplantation of SSCs into depleted tubules or transplantation of testicular tissue. SSCs are stem cells that produce sperm continuously throughout the adult male’s life and exist as mitotically active cells within even prepubertal boys. SSCs are susceptible to chemotherapy and radiation therapy, especially in prepubertal boys where they are more mitotically active as they populate the tubules in preparation for the initiation of spermatogenesis at puberty, called spermarche. First attempts to grow and differentiate human SSCs in small animal hosts demonstrated some survival and potential proliferation. SSCs were isolated from human tissue biopsies from adult patients with a variety of diagnosed azoospermia or oligospermia causes. They were then transplanted into the seminiferous tubules of immunocompromised mouse testes, who had undergone germ cell ablation. Human germ cells were most abundant 1 month after transplantation and almost absent by 6 months post transplant [117]. Analysis of xenotransplant of SSCs into mouse recipients may indicate that the somatic cell compartment or stem cell niche may be the limiting factor for activation of meiosis and spermatocyte differentiation. Testis biopsies that maintain the SSC and somatic cell niche from neonatal mice, pigs, goats, and rhesus monkeys were grafted into immunocompromised mice [118]. These grafts produced complete spermatogenesis with viable sperm that were then used for ICSI into rhesus monkey eggs, for example [118, 119].

As in the experimental ovarian tissue transplant techniques performed for women, there are legitimate concerns about the safety of transferring cells retrieved prior to cancer treatment, especially for leukemia patients [120]. Therefore, sorting methods for enriching the SSC population, while eliminating the cancer cells, needs to be standardized and transplants need to be handled with caution. Additional methods for growing SSCs in vitro and utilizing ART techniques that utilize haploid male gametes in vitro could surpass the concern for transferring cancer into recipients. Testis biopsies isolated prior to gonadotoxic therapies could preserve the chance of restoring fertility later in life through SSC transplant or through in vitro or in situ differentiation of SSCs into haploid gametes. The xenotransplant successes described above maintain that mitotically active SSC supported within the appropriate niche could provide a source of donor-specific haploid cells that could be used in ART to produce offspring. Transplantation of these niches into the patient could additionally provide the necessary endocrine restoration as well.

Puberty is an important physiological, psychological, and physical transition from adolescence to adulthood. It lays the groundwork for adult reproductive capacity and further differentiation of organ systems that respond to the increased hormonal milieu, including neurons, chondrocytes, and cells within the reproductive tract. In the absence of puberty, individuals would not establish normal neuronal growth and connectivity, normal height, or reproductive maturity. The current options for fertility and hormone restoration for prepubertal cancer survivors are inadequate. Some experimental paradigms utilizing tissue extraction that would house the follicle reserve in females and the SSCs in males are promising. Isolated follicles and haploid spermatogonia could provide a potential gamete and, therefore, the option for biological offspring following ART procedures. However, this does not address the need to restore natural hormone cyclicity. Some promising results from ovarian cortical tissue transplants ensure that a surgical procedure with ovarian cells could restore limited hormone cyclicity and fertility. However, these tissues could also reinoculate the patient with cancer cells, as they are taken and preserved prior to treatment. A collaborative effort between reproductive biologists, endocrinologists, regenerative medicine scientists, clinicians, and engineers is necessary to develop a transplant that could provide long-term endocrine function and fertility in patients with hypogonadism or premature gonadal failure.