In 2014, an estimated 15,780 new cancer cases were diagnosed among children and adolescents younger than age 20 years, resulting in 1960 deaths. In addition, 1 in 285 children will be diagnosed with cancer before age 20, and approximately 0.2% of Americans aged 20 to 39 years are childhood cancer survivors.¹ Advances in cancer detection and therapy have greatly improved survival rates for young cancer patients; however, treatment of childhood cancers can adversely impact reproductive function (eg, men who survive childhood cancer are half as likely as their siblings to father a child).² Many cancer patients report a strong desire to be informed of existing options for fertility preservation and future reproduction.³ Therefore, the American Society of Clinical Oncology and the American Society for Reproductive Medicine recommend that consideration of fertility preservation be included prior to initiation of gonadotoxic cancer therapies, including surgery, chemotherapy, and radiotherapy.^4-6

Infertility as a result of cancer treatment can be psychologically upsetting for many patients,^3,7,8 and data suggest that those who pursued fertility preservation usually cope better with their cancer treatment.⁹ Infertile cancer survivors have an option to become parents through adoption or gamete donation, but most declare a preference for having a biological child.^3,10 Schover and colleagues³ found that 51% of newly diagnosed young male cancer patients reported a desire to have children in the future, and this rate increased to 77% for those who did not have children at the time of diagnosis. The desire to become a biological parent persists in male cancer survivors, as 70% reported wanting to father a child after chemotherapy treatment.⁹ A history of cancer treatment may be perceived by some to pose an increased risk to the health of future offspring; however, several studies have shown that male cancer survivors have not demonstrated an increased risk for having a child with birth defects or cancer.^11,12 Recently, a retrospective cohort study conducted in the United States showed no increased risk of malformations or premature birth in the offspring of male cancer survivors.¹³

The optimal time for consideration of fertility preservation is before the initiation of any oncologic therapy that can affect gametogenesis; thus, it is critical that fertility preservation is discussed with all patients at the time of diagnosis and before treatment starts. Practitioners who provide care for cancer patients should be aware of the relationship between cancer treatment and infertility. Moreover, they need to be able to appropriately refer patients to a reproductive medicine specialist in a timely fashion for further counseling and fertility preservation. Although fertility concerns are paramount to young adults with cancer, many oncologists still do not routinely address these concerns.^3,14 In a survey of 200 young male cancer survivors who were primarily treated at a comprehensive cancer center, only 51% recalled being offered sperm cryopreservation prior to their cancer treatment.³ Further, it is important to recognize the psychologic stressors associated with a new cancer diagnosis and associated late effects of cancer treatment, such as infertility or early menopause. Findings from several studies support the importance of counseling patients regarding their risk for fertility issues and educating providers regarding the potential fertility preservation options that are available. For example, Babb and colleagues¹⁵ found that, at many institutions, this counseling is already taking place and there is a high rate of discussion with newly diagnosed patients regarding infertility.

Effects of Cancer Treatment on Fertility in Men

The testis is extremely susceptible to the toxic effects of radiation and chemotherapy at all stages of life.¹⁶ Testicular damage can affect the somatic cells of the testis (Sertoli and Leydig cells) or the germ cells. Cytotoxic treatments target rapidly dividing cells and as a result, spermatogenesis can be disrupted following treatment. The mechanism of this damage has not been completely defined, but appears to be associated with depletion of the proliferating germ cell pool by the killing of cells at the stage of differentiating spermatogonial, as well as with stem cells themselves.¹⁷ Cytotoxic chemotherapy and radiotherapy may produce persistent damage to primordial sperm cells, leading to oligospermia (a sperm density in the ejaculate of less than 20 × 10⁶/mL) or azoospermia (no sperm in the ejaculate).

Germ cells in boys and men are very sensitive to several classes of chemotherapeutic agents, in particular alkylating agents. Chemotherapeutic agents are cytotoxic to cells that have a high mitotic rate. These drugs have the ability to cross the blood-testis barrier and can disrupt the germinal epithelium.¹⁸ The impact of combination chemotherapy on the spermatogenic epithelium is dependent on the type and dosage of the drugs used.^19-21 Chemotherapy-induced Leydig cell failure resulting in androgen insufficiency that requires testosterone replacement therapy is extremely rare; most boys who survive cancer undergo puberty and have normal adult circulating levels of testosterone.²²

Radiation therapy to the pelvis has been utilized in the treatment of many cancers, including prostate, bladder, penile, and testicular cancer. The testis is one of the most sensitive organs in the body to radiation due to its rapidly dividing germinal epithelium. Radiation-induced testicular dysfunction occurs in a dose-dependent fashion (Table 1).^23,24 Further, total body irradiation, which is often incorporated in the conditioning regimen prior to hematologic stem cell transplantation, is associated with 18% germ cell failure.²⁵ Following treatment with 10 or 13 Gy, azoospermia was found in 85% of men, and oligozoospermia was found in the remainder.²⁶ Cranial irradiation is responsible for the development of secondary gonadal failure in some long-term survivors but, overall, overt gonadotropin deficiency is rare and is mainly associated with high doses of radiation.²⁷

Fertility Preservation Strategies

Sperm Cryopreservation

Attempts at fertility preservation (Table 2) should be performed prior to the initiation of cancer therapy due to the vulnerability of the germinal epithelium to gonadotoxic treatment. It should be mentioned that patients diagnosed with cancer often have impaired sperm quality, even before cancer treatment. Pretreatment oligospermia is particularly common in patients with testicular and nontesticular germ cell tumors.²⁸ Sperm analysis has shown that sperm DNA integrity may be affected after just one treatment session. However, if a patient decides to wait until after cancer treatment or needs to initiate cancer therapy immediately, experts recommend waiting at least 12 months after the last treatment session before performing semen analysis.²⁹Obtaining semen for cryopreservation via masturbation and ejaculation is a common fertility preservation modality used for postpubertal boys and men undergoing treatment for cancer. Recent studies demonstrate that postpubertal boys and men can effectively collect and freeze sperm via masturbation prior to starting treatment for cancer.^30-32 Sperm can be cryopreserved in liquid nitrogen for several decades; according to one report, sperm frozen for 28 years was used successfully for in vitro fertilization (IVF) that resulted in a live birth.³³ Thawed sperm can be used not only for conventional IVF, but also for intrauterine insemination and intracytoplasmic sperm injection. Overall, IVF success rates with cryopreserved sperm from patients with a previous malignancy were comparable with patients who have cryopreserved sperm for other reasons.³⁴

Many male cancer survivors report that having the ability to bank sperm has been comforting to them.³⁵ Survivors who banked sperm prior to treatment have successfully fathered children using cryopreserved semen^15,36; however, despite expert consensus recommending sperm banking, as well as the relative ease and high success rates associated with sperm banking, the overall rate for referral and usage of assisted reproductive techniques in patients who cryopreserved sperm remains low.^37,38

Sperm Cryopreservation via Alternative Methods

On occasion, patients are unable to ejaculate for a variety of reasons, including sickness, age, pain, psychologic reasons, cultural factors, or religious beliefs.³⁹ Obtaining semen for cryopreservation by alternative methods, such as urine collection after retrograde ejaculation, electroejaculation (EEJ), and surgical sperm extraction, is an option for postpubertal boys and men who are unable to ejaculate via masturbation. For men who have retrograde ejaculation, collection and processing of urine after ejaculation usually allows for isolation of viable sperm for cryopreservation. The process involves medical urine alkalinization and instillation of sperm wash media into the bladder prior to ejaculation.^40,41

Additionally, EEJ can be used in patients who are unable to masturbate. EEJ is performed by application of electrical stimulation from a rectal probe to the short postsynaptic fibers in the wall of ejaculatory organs.⁴² This method has long been used in the treatment of anejaculation due to spinal cord injury and results in sperm retrieval in 90% of patients⁴³; Adank and associates⁴⁴ have recently reported its feasibility in boys diagnosed with cancer as an alternative to masturbation.

Surgical sperm extraction is an alternative method for patients who cannot ejaculate or have no viable sperm in the ejaculate. Sperm may be obtained via multiple techniques, including testicular sperm extraction, testicular sperm aspiration, and microsurgical epididimal sperm aspiration.^45,46 Sperm obtained during these procedures can be used for IVF and intracytoplasmic sperm injection.

Experimental Methods of Fertility Preservation

Testicular Tissue Cryopreservation

Testicular tissue cryopreservation, an emerging fertility preservation method, is available for prepubertal boys and postpubertal boys and men, and is considered experimental at this time. This method involves surgically removing a small portion of testicular tissue, and cryopreserving and storing the specimen.⁴⁷ Cryopreservation is performed using either slow-freezing protocol or vitrification, which involves the use of increasing concentrations of cryoprotectants and ultrarapid cooling to avoid ice crystal formation.⁴⁸ In postpubertal boys and men, the tissue can be thawed and subsequently transplanted, either by infusion of a testicular cell suspension into the seminiferous tubules⁴⁹ or via intratesticular grafting of tissue.⁴⁸ However, the immature gametes in the testicular tissue from prepubertal boys have yet to be matured for fertility preservation purposes.⁵⁰ There may be a risk of reseeding microscopic malignant cells if tissue is reimplanted (similar to the risk in women).⁵¹ Spermatogonial stem cells (SSCs) obtained via biopsy of a prepubertal human testis can theoretically be frozen prior to chemotherapy or radiation treatment and reintroduced into the testes after cure of the underlying disease.⁵² However, human testicular tissue has a post-thaw viability of up to 95%, compared with only 66% for post-thaw SSC suspension.⁵⁰ Cryopreserving testicular tissue allows preservation of supporting Sertoli cells, which may maintain cell-to-cell interactions and account for the improved SSC and germ cell survival.⁵³

Spermatogonial Stem Cell Cryopreservation

SSCs are adult tissue stem cells in the testes that maintain constant sperm production during the postpubertal life of men. Brinster and Zimmermann⁵² established the technique for SSC transplantation in mice in 1994, demonstrating that donor SSCs could engraft the seminiferous tubules of chemotherapy- treated recipient mice and regenerate spermatogenesis and fertility, leading to the production of viable offspring through normal breeding. Multiple laboratories have reported culturing human SSCs,^54-57including from the testes of prepubertal patients.^55,56 These preliminary human tissue studies are promising but challenged by the inability to evaluate the full spermatogenic potential of cultured cells by homologous species transplantation into human testes.

Fertility Preservation Strategies for Women

Effects of Cancer Treatment on Fertility in Women

Cancer treatments such as chemotherapy, radiation, and surgery can have gonadotoxic effects that go beyond fertility, such as an impact on growth, puberty, and sexual function.^58-60 As women have a finite number of primordial follicles that decline steadily after birth,⁶¹ cancer treatments in girls and women can be especially gonadotoxic.⁶⁰ A number of factors influence the estimated risk of infertility (eg, the risk of gonadotoxicity associated with cancer treatment is increased by the dose of radiation, age at treatment, chemotherapy agent, and dosage of chemotherapy).⁵⁸

Pelvic radiation therapy for childhood solid or hematologic cancers can have varying effects on the reproductive organs, including the ovaries and the uterus.⁶² The main effect of radiation to the gonads is reduction of oocyte numbers.^63,64 The threshold dose of radiation to the two ovaries and uterus is estimated to be 4 Gy, with possible subfertility with exposures of up to 15 Gy.^60,62,65 Radiation has also been shown to have an effect on uterine volume, elasticity, and vascularity, which impacts pregnancy later in life in the setting of childhood irradiation.⁶⁶ A limited number of studies investigating pregnancy after pelvic radiation have found increased rates of pregnancy complications, including preterm birth, low birth weight offspring, preeclampsia, and stillbirth.⁶⁷

Chemotherapy with alkylating agents such as chlorambucil, chlormethine, and cyclophosphamide, or cell-cycle-dependent agents such as doxorubicin and paclitaxel and docetaxel, can be quite gonadotoxic to oocytes.⁶⁸ Likely through apoptosis, germ cells go through elevated rates of cell death during treatment.^69,70 Given the finite number of primordial follicles and the biexponential decline in follicle number, younger women have increased reserve compared with women over age 40, making timing of treatment with these agents even more impactful on future fertility rates.⁷¹ At age 37, approximately 25,000 follicles are present in the ovary, but because of the biexponential decline, by age 51, only approximately 1000 follicles remain.⁷²

Breast cancer chemotherapy regimens vary depending on the character of the tumor, age of the patient, lymph node status, and menopausal status.⁷³ Although there are many different chemotherapy regimens, the agents most commonly used for adjuvant therapy include cyclophosphamide, methotrexate, paclitaxel, and docetaxel, and 5-fluorouracil or doxorubicin.⁷³ These regimens also often include endocrine-targeted treatments such as tamoxifen—a selective estrogen receptor modulator; anastrozole and letrozole—aromatase inhibitors; and fulvestrant—another estrogen antagonist.⁷⁴ Women with hormone-sensitive tumors may continue adjuvant therapy with tamoxifen for 5 to 10 years to reduce the risk of recurrence.⁷⁵ Although tamoxifen is not directly gonadotoxic, fertility is delayed until after this 5- to 10-year treatment duration.⁷⁶ Animal studies have also raised concern regarding the teratogenic effects of tamoxifen use in pregnancy, leading to a suggested discontinuation of tamoxifen for 12 months prior to conception.⁷⁷ With potential time delays when tamoxifen is used in women in their 30s and 40s, there is a higher risk of menopause prior to the opportunity to conceive. Given that breast cancer is the leading cancer affecting women, and the therapies used to treat breast cancer have been shown to have a significant impact on fertility later in life, many new strategies are being employed in an attempt to preserve the fertility in these women.

Fertility-preserving Strategies

Surgical Fertility-sparing Methods

There are multiple fertility-preserving approaches for women undergoing cancer treatment (Table 3). Some have been proven through clinical experience and others remain experimental. Moreover, some of these approaches have proven to be more effective than others. One method employed to preserve future fertility is fertility- sparing surgery. An example of this is a unilateral oophorectomy in cases of malignant ovarian germ cell tumors. The outcome and risk of recurrence is similar to that of a bilateral oophorectomy but has the advantage of sparing the contralateral ovary, which can provide a source for hormone production and fertility later in life.⁷⁸ Even early-stage cervical cancers may be treated with trachelectomy rather than hysterectomy, which allows for fertility maintenance at only a slightly decreased rate from baseline.⁷⁹

Embryo Cryopreservation

Embryo cryopreservation has been available for almost 30 years, is well studied, and available to most women who desire to conceive. The benefit of this method is that a number of embryos may be frozen, with pregnancy rates after thawing as high as 59%; with live birth rates at approximately 50%.^80,81 These rates are similar to those with IVF with fresh embryos. The drawbacks for this procedure include the need for a sexual partner or sperm donor; in addition, the egg donor must be postpubertal.

Oocyte Cryopreservation

Another method gaining popularity is oocyte cryopreservation. Although the first birth from a frozen oocyte used in IVF was reported in 1986, rates of oocyte survival after thawing and live pregnancy rates were previously low secondary to cyroinjury from slow-freeze techniques.⁸² Due to advancement in vitrification and rapid cooling with a cryoprotectant, oocytes can now be successfully frozen and thawed with similar rates of success to IVF, with intracytoplasmic sperm injection and live birth rates equal to those with fresh oocytes in healthy women under age 35.^83,84 This is an attractive option that does not require immediate sperm availability.

Experimental Methods of Fertility Preservation

In Vitro Maturation

In vitro maturation (IVM) is a method in which oocytes at different stages of maturation can be matured in vitro and used for successful IVF procedures or for cryopreservation of oocytes or embryos. This method is only appropriate for postpubertal girls and women, but has an important advantage over standard methods of ovarian stimulation. Women with breast cancer, whether hormone positive or not, are at risk of advancement of their cancer because of high levels of estradiol caused by gonadotropin stimulation during normal ovulation induction.⁸⁵ By using IVM, the immature oocytes (collected without stimulation) can be matured in vitro.⁸⁶ Women with breast cancer can undergo this method quickly after diagnosis prior to the start of treatment. They are able to avoid gonadotropin stimulation and high levels of circulating estradiol with the ability to maintain fertility after treatment.

Ovarian Tissue Cryopreservation

Although the above options are available for postpubertal girls and women wishing to preserve fertility, there are currently no established methods for the preservation of fertility among prepubertal girls undergoing cancer treatment. Pediatric cancer patients represent a growing population of patients who may benefit from investigational methods. One experimental option for this age group is ovarian tissue cryopreservation. The goal of this method is to preserve eggs within the primordial follicles in the ovarian cortex, as this contains a large number of eggs. This procedure is usually done laparoscopically prior to cancer treatment with either ovarian cortical biopsy or unilateral oophorectomy. Cortical tissue is then frozen; after cancer treatment is completed, thawed tissue is autotransplanted back into the patient.⁸⁷ The cortex may contain thousands of primordial follicles that can, after reimplantation, produce antral follicles and result in pregnancy either spontaneously or with assisted reproductive techniques; 20 live births have been reported with this method.⁸⁸ To date, this approach has been most effective if the thawed tissue is transplanted to the site of a native ovary that still contains the ovarian cortex.⁸⁸ Reimplantation at this site allows for grafting to the ovarian medulla, which has a vascular network to provide adequate blood supply, and if the fallopian tubes are still patent, can result in spontaneous pregnancy.⁸⁹ A limitation of this method is that women who have hematologic cancers or ovarian cancers should not undergo autologous reimplantation of ovarian tissue, as it may harbor cancer cells and carry a high risk of cancer recurrence.

Gonadotropin-releasing Hormone Agonists

One additional experimental option available to postpubertal girls and women undergoing cancer treatment is concomitant use of gonadotropin-releasing hormone analogs (GnRHas) for gonadal protection. The concept behind this method is to maintain a prepubertal hormone milieu in an effort to maintain ovarian follicles in a dormant state. The use of GnRHas during adjuvant chemotherapy for breast cancer has been well studied, but with disappointing results. Both nonrandomized⁹⁰ and randomized studies⁹¹ have examined the protective effects of goserelin, leuprolide, or triptorelin on ovarian protection during breast cancer treatment. The benefits of this treatment remain uncertain with conflicting results from the existing studies.⁹²

Conclusions

Given that many of the children and young adults diagnosed with cancer will go on to survive treatment, a focus on survivorship and fertility is of the utmost importance. Treatments need to be discussed early following cancer diagnosis and often need to be individualized based on the disease process and individual patient preference. With continued research and clinical progress in this area, fertility preservation can be a safe, affordable, and successful option for these cancer survivors. 

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