The Male Testis and Spermatogenesis

The male testicle is composed of three major cell types: gonocytes (primitive germ cells) that develop into sperm, Sertoli cells that provide support to developing germ cells, and Leydig cells that synthesize testosterone [9]. At puberty, spermatogenesis takes place in the seminiferous epithelium where spermatogonia divide to form spermatocytes and then undergo meiosis. The resulting spermatids transform into motile spermatozoa that are capable of fertilizing female oocytes [10]. In a normally functioning male testicle, gonocytes divide without limitation, either becoming a self-renewing supply of additional immature spermatogonial stem cells (SSCs) or differentiating into mature sperm. Maintenance of spermatogenesis throughout the male’s life cycle is dependent on the presence of these rare SSCs and their capacity for both self-renewal and differentiation [10].

Effects of Gonadotoxic Treatments on Testicular Function

Chemotherapy

The high mitotic rate of the germinal epithelium within the testis makes it especially vulnerable to the cytotoxic mechanisms of certain chemotherapeutic agents [11]. Conversely, Leydig cells are far more resistant than testicular germ cells to the cytotoxic effect of chemotherapy. As a result, it is more common for a male cancer survivor to experience impaired sperm making ability while maintaining adequate testosterone production for pubertal progression, libido, and normal sexual function [12].

Most males exposed to chemotherapy will experience at least some acute impact on sperm production. As highly sensitive, rapidly dividing spermatogonia are destroyed, there is a maturation depletion and loss of mature spermatozoa in the months after exposure to chemotherapy [13]. This decline is often transient and the extent of any permanent damage is agent- and dose-dependent and related to the overall impact of the agent on germ cell proliferation. Recovery of spermatogenesis may occur. The timing of this recovery is variable, it may occur over years, and complete recovery may not ever be achieved [13]. While it was once proposed that younger age at time of exposure to cytotoxic agents was protective due to the pre-pubescent state of the testicle (no active spermatogenesis), this is no longer believed to be true [14].

The most common chemotherapeutic agents associated with a permanent impact on spermatogenesis are alkylating and alkylating-like agents, including cyclophosphamide, ifosfamide, procarbazine, chlorambucil, nitrosoureas, platinum derivatives, melphalan, and busulfan (Table 9.1). These agents are cell cycle nonspecific and act by damaging DNA so as to prevent cellular division. Therefore, in addition to impacting rapidly dividing spermatogonia, alkylating agents also damage cells with low proliferation rates, including SSCs [15].

Table 9.1 Risk factors: male

Chemotherapy

Cyclophosphamide, 7.5–9.5 g/m2

Ifosfamide, 42–60 g/m2 Procarbazine, 4 g/m2

Chlorambucil

Nitrosoureas

Cisplatin, >500 mg/m2

Melphalan, 140 mg/m2

Busulfan, 600 mg/m2

Increased risk with multiple gonadotoxic agents

Radiation

Testes (direct)

Total body irradiation (TBI)

Hypothalamic pituitary axis (HPA) (>3000 cGy)

Scatter dosing from radiation to adjacent regions of the body

(pelvis, bladder/prostate, abdomen, flank, lower spine,

inguinal, upper thigh)

Radiation Dosing Considerations

Germ Cell Damage

10–99 cGy, temporary oligospermia/azoospermia; will recover

100–600 cGy prolonged azoospermia, possibly permanent,

time to recovery variable, can take years

800–1000 cGy, azoospermia, likely permanent

1200–2400 cGy permanent azospermia

Leydig Cell Damage

Prepubertal testicle, ≥2000 cGy

Adult testicle, ≥3000 cGy

Cyclophosphamide alone is a potent alkylating agent. Studies have reported that cyclophosphamide in the cumulative dose range of 7.5–9.5 g/m² is known to cause varying degrees of impaired spermatogenesis [16–18]. A recent evaluation by Green et al. of 214 adult male survivors of pediatric cancer that received varying amounts of alkylating agents demonstrated that a cyclophosphamide equivalent dose (CED) less than 4 g/m² was unlikely to impair spermatogenesis, while the mean CED dose associated with oligospermia and azoospermia was 8.4 g/m² and 10.8 g/m², respectively. There was, however, significant overlap in this study in dosing above 4 g/m² in terms of normo/oligo and azoospermia outcomes, indicating that other factors including genetic variations, differences in drug metabolism, health behaviors like drug and alcohol use, obesity or genitourinary abnormalities could also contribute to abnormal spermatogenesis outcomes in these male survivors [19].

Males treated for Hodgkin lymphoma often are exposed to multiple alkylating agents. Analysis of fertility outcomes in this group highlights the gonadotoxic potential of other alkylating agents like procarbazine and mechlorethamine as well as the synergistic impact of regimens containing multiple alkylating agents. MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) regimens are highly gonadotoxic, causing azoospermia in 80–90 % of patients after three courses or more [20–22]. In a longitudinal analysis of semen parameters in 202 patients pre- and post-ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and of 42 patients pre- and post-BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), COPP/ABVD (cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine), OPP/ABVD (vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine) or MOPP and inguinal radiotherapy, those with six or more BEACOPP, COPP/ABVD, OPP/ABVD, or MOPP cycles experienced permanent absence of sperm in the seminal fluid, and even when less than six cycles were given, spermatogenesis only recovered after three to five years and semen quality was highly impaired [23]. In an effort to reduce the gonadotoxic profile of Hodgkin therapy, regimens are now being utilized which attempt to reduce or remove alkylator exposure while maintaining acceptable survival outcomes. A German analysis of 761 male survivors of Hodgkin lymphoma treated with ABVD, combined BEACOPP and ABVD or BEACOPP only, found that 88% of patients with six to eight cycles of BEACOPP; 75% of patients with two cycles of escalated BEACOPP plus ABVD and 50% of patients with four cycles of ABVD had follicle stimulating hormone (FSH) and inhibin levels consistent with oligospermia [24]. This highlights the findings of previous studies that support the lower gonadotoxic potential of the ABVD regimen [25].

Platinum derivatives like cisplatin are common agents used for contemporary treatment of sarcomas, germ cell tumors, and central nervous system tumors. Unlike the data on cyclophosphamide, there is less information available that clearly defines the pathogenesis and prevalence of impaired sperm production with these drugs. Cisplatin-based regimens for the treatment of testicular cancers and germ cell tumors often result in temporary impairment of spermatogenesis but recovery of sperm making ability is seen over time [26]. Studies have shown that adult testicular tumor patients treated with cumulative doses of cisplatin above 400–500 mg/m² were at greater risk for azoospermia than those treated with doses below this threshold [27, 28]. In another study of sarcoma patients treated with cisplatin without Ifosfamide, only 43% of men treated with doses of cisplatin greater than 600 mg/m² recovered sperm counts above 10 million/mL as compared to 95% of those who received lower doses [29].

The alkylating agent ifosfamide is often used in the management of pediatric sarcomas and is associated with impaired spermatogenesis. A study of gonadal dysfunction in 199 male childhood cancer survivors by Brignardello et al. demonstrated that sarcomas were the diagnosis with the highest risk of infertility [30]. In an analysis of male survivors of pediatric osteosarcoma who were a median of nine years from the completion of therapy, the incidence of azoospermia related to ifosfamide therapy (median dose 42 g/m²) versus those males who did not received ifosfamide was statistically significant (p = 0.005) and the degree of sterility was dose-dependent [31]. More recent studies of ifosfamide in sarcoma patients established that ifosfamide at doses greater than 60 g/m² are associated with increased risk of infertility [32, 33].

Transplant conditioning agents can also place a male at risk for adverse reproductive outcomes. Conditioning regimens that include myeloblative doses of busulfan (600 mg/m²) or melphalan (140 mg/m²) are associated with decreased spermatogenesis and infertility [34, 35].

Radiation

The germinal cells of the testicle are extremely sensitive to the effects of radiation. Radiation directly to the testes, total body irradiation (TBI), craniospinal radiation, or scatter dosing from radiation to adjacent regions of the body (pelvis, abdomen, or upper thigh) can cause temporary or permanent azoospermia (Table 9.1). Radiation doses as low as 10 cGy can cause temporary oligiospermia and doses of 200–300 cGy can lead to prolonged or permanent azoospermia [36]. Direct testicular doses of 1200–2400 cGy are consistently associated with permanent azoospermia as well as decreased testosterone levels. Unlike germ cell damage, where younger age at exposure to radiation or chemotherapy does not influence the risk for gonadal damage, Leydig cells may be more likely to be damaged by radiation administered to prepubertal testis than to the mature testis. Doses of radiation >2000 cGy to the prepubertal testicle will cause Leydig cell dysfunction, but adult male Leydig cells will not be damaged until the dose exceeds 3000 cGy [37].

In patients with ALL, radiation is administered directly to the testes (either for prophylaxis or for relapse) to total doses as high as 2400 cGy, resulting in both azoospermia and Leydig cell dysfunction [38, 39]. In a study of 23 male leukemia patients receiving craniospinal radiation (1800–2400 cGy), germ cell damage was noted in 17% of patients, likely related to scatter dose to the testes [40]. Shapiro et al. studied patients treated for soft tissue sarcomas and found that scatter dose greater than or equal to 50 cGy to the testes resulted in greater elevation in FSH than those with lower scatter dosing, and that these elevations persisted as long as 30 months out from the radiation exposure [41]. Improvements in radiation delivery techniques including targeted radiation (conformal or intensity-modulated radiation therapy) and particle therapy (protons) may help to minimize scatter to testicular tissue and further reduce the impact of exposure on spermatogenesis. Gonadal shielding with a lead protective cup has been shown to produce a 3- to 10-fold reduction in testicular dose, depending on the distance of the testes from the proximal edge of the radiation field [42].

TBI is an important part of many conditioning regimens for stem cell transplant and is associated with infertility. Reports indicate that sterility following TBI containing preparative regimens for stem cell transplant occurs in approximately 80% of males [43]. Gonadal shielding may be a reasonable option to consider in non-myeloablative TBI-based regimens, especially in those cases where nonmalignant conditions are being treated. Sayan et al. have reported that a simple lead block used during the administration of non myeloblative TBI (200–300 cGy) reduces transmission of dosing to the testicles as much as 73%, thereby mitigating the deleterious impact on spermantogenesis [44].

Dosing schedule is also an important consideration when assessing the gonadal toxicity of radiation. In most treatment regimens, fractionated dosing schedules (smaller doses administered over days to weeks) are more common than single dose schedules. However, fractionated radiation is associated with longer time to recovery of spermatogenesis than with single doses, and permanent azoospermia occurs with lower total doses of fractionated radiation than with single dose [45, 46]. Increased toxicity with fractionated dosing is likely because at any given time, some spermatogonia are not proliferating and are essentially radioresistant, and therefore, not damaged by a single-dose radiation schedule [13].

Surgery

Retroperitoneal lymph-node dissection (for staging), retroperitoneal tumor resection, cystectomy, radical prostatectomy, spinal surgery, or other pelvic surgery can damage ejaculatory function, impairing sexual function, but not necessarily spermatogenesis. In young adult patients with testicular cancers that require orchiectomy, impaired spermatogenesis is noted both before and after surgical removal of the testicle, indicating that both the diagnosis itself and the surgery likely have some impact on sperm production [47]. Interpretation of data on spermatogenesis in young males with orchiectomy for other pediatric genitourinary malignancies is difficult, given the confounding effect of chemotherapy and or radiation on outcomes [48].

Damage to the Hypothalamic Pituitary Axis

Impaired spermatogenesis can be associated with damage to the HPA from surgery, tumor location or radiation therapy [49]. If the HPA is damaged, the signaling mechanisms of sex hormones like gonadotropin releasing hormone (GnRH), FSH, and luteinizing hormone (LH) are impaired, preventing normal pubertal progression in children and normal functioning of the ovaries or testes in adults [50]. The impact of cranial radiation on gonadotropins is dose-dependent. Studies in children being treated with high-dose cranial radiation (>3000 cGy) have documented gonadotropin deficiency in 30%, with increasing prevalence with time since irradiation [51, 52]. Fertility issues related to hypothalamic hypogonadism can be medically treated so that pregnancy can be achieved. Males with HPA damage can consider treatment with exogenous gonadotropins to stimulate spermatogenesis to achieve pregnancy [37].

Fertility Preservation Options: Males

Sperm Banking

Collection of sperm by masturbation and freezing specimens for future use is a proven and relatively inexpensive method for fertility preservation in males (Table 9.2). The initial processing and freeze is often covered by insurance but long-term storage costs (around $300 annually) are not. All males who are Tanner III or greater should have ejaculate that contains mature sperm and should be encouraged to sperm bank at the time of diagnosis. Whenever possible, sperm should be frozen prior to the initiation of any chemotherapy [53]. Patient, parent, and provider factors play a role in decision making about sperm banking. A recent cross-sectional survey of 146 adolescent males newly diagnosed with cancer demonstrated that successful banking at diagnosis was associated with greater adolescent self-efficacy, parent and provider recommendations to bank, and consultation with a fertility specialist [54]. Another survey of decision making in 50 adolescents and their parents who were offered sperm banking at diagnosis demonstrated that parents play an important role in the decision to sperm bank, whereas finances, ethics, and religion are not important considerations in this cohort [55].

Table 9.2 Fertility preservation options: Males

Fertility preservation options
Sperm banking Appropriate for Tanner III or greater males Considered gold standard for fertility preservation Attempt before any therapy is ideal Processing and freeze may be covered by insurance; annual storage fee not typically covered
Testicular tissue cryopreservation Freeze testicular tissue from prepubertal testis Expand spermatagonial stem cells in number for autotransplantation or maturation in vivo Considered experimental No human birth from frozen testicular tissue Should be done as part of institutional review board (IRB) protocol Not covered by insurance
Gonadal shielding Lead block to testicles can significantly reduce transmission of radiation to testicles Not always clinically appropriate in terms of patient’s disease/cure

Data from a cohort of 339 young male patients who attempted to bank demonstrated that 78% of those who attempted were able to produce a specimen (median of seven banked straws) and although there were differences in semen quality across age (poorer quality in younger patients) and diagnostic groups, there was still adequate material for cryopreservation by World Health Organization criteria [56]. Advances in reproductive technologies continue to redefine what is considered an acceptable semen specimen. Techniques like intra-cytoplasmic sperm injection (ICSI) allow pregnancy even when only a small number of spermatozoa are available, and frozen specimens are associated with similar rates of fertilization and clinical pregnancy outcomes when compared to fresh [57]. Therefore, freezing semen samples of suboptimal quality is becoming less of a concern for fertility preservation in cancer patients.

Collection of a specimen by masturbation is not always successful despite an attempt and there are cases where patient embarrassment or religious prohibitions on self-arousal/stimulation pose a barrier to specimen collection. In this circumstance, alternative methods to collect sperm may be considered, including testicular sperm extraction or electroejaculation under sedation/anesthesia [58, 59].

Testicular Tissue Cryopreservation

The prepubertal testis does not contain mature sperm and prepubertal boys cannot produce a specimen for freezing by masturbation. Testicular tissue cryopreservation has emerged as a potential option for preserving fertility in prepubertal males (Table 9.2). Ideally, prepubertal testicular tissue could be acquired and banked prior to initiating gonadotoxic cancer therapy. Years later, once the patient is ready to begin a family, this tissue could then be thawed and the stored germ cells reimplanted into the patient’s own testis. Alternatively, the stored cells could be matured in vitro until they can achieve fertilization with assisted reproductive technologies. In the laboratory, investigators have demonstrated that microinjecting a crude suspension of germ cells into mice rendered sterile can restore spermatogenesis and fertility, resulting in restored spermatogenesis and reproduction in vivo [60]. Similar results have also been achieved in rats and larger mammals including monkeys [61]. Translation of this science to achieve human pregnancies has not yet been achieved. Functional assays have been developed to identify SSCs in human tissue and research is now focused on ex vivo expansion of these cells and the self-renewal promoting factors of the SSC niche [10]. Recent discoveries in the laboratory have shown that testicular endothelial cells are a critical part of the SSC niche, producing glial cell line–derived neurotrophic factor (GDNF) and other factors to support human SSCs in long-term culture [62]. Freezing testicular tissue in prepubertal males is considered experimental, is not covered by insurance, and is primarily offered through IRB approved research protocols [63].

The Female Ovary and Oogenesis

At birth, the ovaries contain 1–2 million follicles, which house the germ cells capable of becoming mature ova. No new oocytes or follicles are produced after birth. Ovarian primordial follicles are the principal functional units of the human ovary, and reside primarily in the cortex of the organ [9]. Each follicle has an immature primary oocyte (the germ cell) and surrounding somatic cells [64]. The oocyte grows in size and matures as the follicle develops in a process known as folliculogenesis. The female’s fixed pool of oocytes is depleted naturally, through atresia and ovulation, during the first 40–50 years of a woman’s life [65]. Exposure to toxins, radiation, surgery, and certain medications (including chemotherapy) can accelerate the depletion of the oocyte pool [66]. This depletion can subsequently cause acute ovarian failure or premature ovarian insufficiency in some females. Associated hormonal imbalances can also contribute to other long-term health problems including osteoporosis, cardiovascular disease, genitourinary dysfunction, vasomotor symptoms, and neurological deficits [67]. In a study of the self-reported menopausal status of 2930 female survivors of pediatric and young adult cancer, the risk of nonsurgical premature ovarian insufficiency (POI) was shown to be increased when compared with sibling controls, with a cumulative incidence of approximately 9.1% by age 40 years [68]. In addition, a study of 921 female childhood cancer survivors in the St Jude Lifetime Cohort, which included clinical assessment for amenorrhea and serial serum measures of FSH, reported the prevalence of POI as 10.9% [69].

Effects of Gonadotoxic Treatments on Ovarian Function

Chemotherapy

Most chemotherapeutic agents will have some effect on the mature follicles in the ovary. DNA damage and apoptosis occur, leading to an acute period of amenorrhea in pubertal females. The impact of this damage is transient, and regular menses will resume once the antral follicle count is restored from the dormant follicle pool [70]. However, certain agents (particularly alkylators) can cause significant damage to the oocyte itself and to the somatic cells of dormant and growing primordial follicles, decreasing overall ovarian reserve (Table 9.3). Some females may experience total destruction of the primordial pool and acute ovarian failure [71, 72], while others will resume some normal function but may have accelerated folliculogenesis of a diminished primordial pool with apoptosis and premature ovarian insufficiency [67].

Table 9.3 Risk factors: Female

Chemotherapy

Cyclophosfamide

Ifosfamide

Busulfan

BCNU/CCNU

Chlorambucil

Mechlorethamine

Procarbazine

Melphalan

Thiotepa No clear data on dose thresholds Increased risk with increasing dose Younger females (larger pool of primordial follicles) can tolerate larger cumulative doses than older women

Radiation

Abdomen, pelvis, and lower spine (lumbar, sacral)

TBI

Craniospinal (scatter)

HPA (>3000 cGy)

Radiation Dosing Considerations

Oocyte Damage

<200 cGy reduces primordial follicle pool by 50%

500–1000 cGy, pubertal ovary, increasing risk for ovarian insufficiency

>1000 cGy, prepubertal ovary, increasing risk for ovarian insufficiency

Uterine Damage

<400 cGy, no damage

1400–3000 cGy likely uterine damage

Age at exposure, chemotherapy agent, and cumulative dose are all important factors to consider in terms of overall risk for ovarian dysfunction. Younger females can generally tolerate larger cumulative exposures with less impact on the primordial follicle pool than a woman who is closer in age to natural menopause [73].

Alkylating agents are the class of drugs known to be most often associated with gonandotoxicity in females. Drugs like cyclophosphamide, ifosfamide, busulfan, BCNU/CCNU, chlorambucil, procarbazine, melphalan, and thiotepa are associated with ovarian dysfunction [74–76]. Females exposed to higher doses of alkylating agents have an increased risk of POI compared with patients who are treated with a lower dose [77]. Based on currently available data, it is challenging to define specific dose thresholds for these agents in relation to ovarian dysfunction. Because there is variability in ovarian reserve among females of the same age, the same dose of an agent in one female may not have the same impact on another of similar age. In addition, most cohort studies have focused on alkylating agents as a group, rather than evaluating the risk of a single drug and there is variation across studies in scoring and calculating alkylator exposures [78]. However, a recent meta-analysis of 45 studies of chemotherapy-related ovarian damage in childhood and adolescent survivors (encompassing 5,607 females) found that the most important risk factors for ovarian dysfunction were exposure to alkylating agents, specifically procarbazine and busulfan, and older age at treatment [79].

Transplant conditioning regimens are associated with increased risk for ovarian dysfunction. Although TBI containing regimens are more gonadotoxic, myeloblative therapy with chemotherapy alone still carries risk. Busulfan containing regimens appear to have the greatest impact on ovarian function, with some reports of premature ovarian failure as high as 100% [80]. Recovery of ovarian function and the ability to achieve pregnancy is possible with cyclophosphamide alone conditioning for hematopoietic stem cell transplant [81, 82]. A study of ovarian function in 92 females treated with allogeneic transplant showed that the majority of recipients conditioned with only cyclophosphamide versus TBI (p < 0.001) or versus Busulfan-based regimens (p < 0.01) showed preserved ovarian function and required no estrogen replacement at a mean age of 23 ± 6.3 years [83]. Regimens utilizing low-dose cyclophosphamide for transplant in nonmalignant hematological conditions have also demonstrated less toxicity with recovery of ovarian function over time [84]. Melphalan alone also appears to be less toxic than busulfan, and reduced intensity dosing of this agent further increases the likelihood of recovery of ovarian function [85, 86].

Radiation

The ovaries are sensitive to the toxic effects of radiation and damage depends on how much of the radiation is absorbed and the age at the time of exposure. Females exposed to radiation to the abdomen, pelvis, and lower spine (lumbar, sacral) are at risk for developing ovarian failure, especially if the gonads are in the radiation field and will receive direct exposure (Table 9.3). Radiotherapy to a field that includes the ovaries causes depletion of the nongrowing follicle pool in a dose-dependent manner. The dose to deplete the primordial follicle pool by 50% has been estimated to be less than 200 cGy [87]. Single-dose delivery schedules are more toxic than fractionated dosing [88]. Mathematical models have been developed to estimate the sterilizing dose of radiation for age and to further predict the age of ovarian failure after treatment with a known dose of radiotherapy. The effective sterilizing dose, defined as the dose of fractionated radiotherapy at which premature ovarian failure occurs immediately after treatment in 97.5% of patients, decreases with increasing age at treatment. At birth, these models estimate the sterilizing dose is 2030 cGy; at 10 years 1840 cGy; at 20 years 1650 cGy, and at 30 years 1430 cGy.

Abdominal and Pelvic Radiation

Early studies on the impact of whole abdomen radiation (dose range 2000 cGy to 3000 cGy) in patients treated for Wilms tumor and other solid intraabdominal tumors showed that 27 of 38 patients failed to undergo or complete pubertal development (pubertal failure) and another 10 patients demonstrated premature menopause (median age 23.5 years). Flank radiation in the same dose range resulted in less pubertal failure [89]. A more recent analysis of the prevalence of primary ovarian insufficiency in 921 female childhood cancer survivors (200 of whom received radiation in the region of the ovary) demonstrated that ovarian radiation at any dose is an independent risk factor for ovarian insufficiency, with doses <1000 cGy associated with a hazard ratio of 13.85 (95% CI, 6.50–29.51) and doses ≥1000 cGy, a hazard ratio of 132.34 (95% CI, 62.88–278.53). Furthermore, this study also highlighted the synergistic effect of combined therapy with radiation and alkylating agents, with the highest risk seen in females who are treated with both modalities [69].

The uterus can also be impacted by radiation to the abdomen, spine or pelvis, or with TBI. Damage to the endometrial, myometrial, and vascular structures of the uterus can be associated with infertility as well as with poor pregnancy outcomes including miscarriage, pre-term labor, still birth, and restricted fetal growth [90]. Uterine radiation doses of <400 cGy do not appear to impair uterine function. While there is no clear data on the exact threshold dose of radiation to the uterus above which sustaining pregnancy is unlikely, it is estimated that doses in the range of 1400–3000 cGy will cause uterine damage [88]. Some guidelines suggest that patients receiving >2500 cGy to the uterus in childhood be counseled to avoid attempting pregnancy [91].

Radiation to Hypothalamic Pituitary Axis and Craniospinal Region

Radiation to the HPA can cause imbalances in gonadotropins that are essential for regulating ovarian function. Deficiencies in LH and FSH are associated with oligomenorrhea or amenorrhea, ovulatory impairments, failed implantation, and early pregnancy loss. The risk of gonadotropin deficiencies increases with radiation doses to the HPA of 3000–4000 cGy or higher [50, 75]. A recent analysis of 1,110 survivors in the German Childhood Cancer Registry demonstrated that female survivors receiving ≥3000 cGy to the pituitary gland reported fewer pregnancies, were more often infertile and had a higher frequency of permanent amenorrhea [92]. Other research has shown that lower radiation doses to the HPA may also impact fertility and successful pregnancy. In a cohort of 3,619 female childhood cancer survivors who received hypothalamic pituitary radiation and no or negligible scatter to the ovaries, models showed a significant decrease in the risk (occurrence) of pregnancy with hypothalamic radiation doses ≥2200cGy than compared with those survivors receiving no radiation to this region [93].

Craniospinal radiation may be associated with impaired ovarian function due to the radiation that exits the abdomen and pelvis during treatment of the spine. Craniospinal doses of 1800–2400 cGy used for the treatment of childhood leukemia have been shown to be associated with abnormal FSH and LH levels and ovarian dysfunction [94, 95]. Patients with CNS tumors often require treatment with combined modality therapy including both exposure to alkylating chemotherapy and radiation to the brain and spine. In a recent study of 30 females treated for embryonal central nervous system tumors with craniospinal radiation (range 2300–3900 cGy) plus cyclophosphamide, the cumulative incidence of primary ovarian insufficiency was 82.8%, though recovery of ovarian function was observed in 38.5% of females [96].

The use of oophoropexy (ovarian transposition) before craniospinal radiation can reduce the amount of exposure to the ovaries, allowing for preservation of the primordial follicle pool. However, this method does not offer protection to the uterus and other pelvic structures. Proton beam radiation significantly reduces exposure to both the ovaries and uterus, and, when available, is the preferred method for fertility preservation in females facing craniospinal radiation [97, 98].

Total Body Irradiation for Transplant Conditioning

Transplant conditioning with high-dose TBI poses the most significant risk for ovarian failure in females undergoing bone marrow transplant [99]. Age at exposure may temper the impact of fractionated TBI on ovarian function. Studies have shown that TBI administered after puberty is almost always linked to gonadal failure, but if given before the onset of puberty, about 50% of patients will demonstrate spontaneous pubertal progression with normalization of gonadotropins over time [99, 100]. Even when function normalizes, however, onset of menopause may be premature, and the overall fertile window truncated. This is an important consideration for future family planning. The overall pregnancy rate after stem cell transplant with TBI is estimated to be 3% [101] but multiple studies have documented successful pregnancies and live births [35, 102]. Pregnancies after TBI should be considered high risk, with close monitoring for complications including preterm labor and low birth weight [102].