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Keywords:

  • fertility;
  • adolescent;
  • ovarian protection;
  • gonadal function;
  • assisted reproductive technology

Abstract

  1. Top of page
  2. Abstract
  3. Ovarian Physiology
  4. Chemotherapy
  5. Radiation Therapy
  6. Multimodality Therapy
  7. Infertility in Childhood Cancer Survivors
  8. Preservation of Fertility in Young Women
  9. Ovarian Protection
  10. Cryopreservation
  11. Posttreatment
  12. DISCUSSION
  13. REFERENCES

The use of multiple agent chemotherapy and combined modality treatment of childhood and adolescent cancers has markedly increased survival rates. Thus, the majority of young cancer patients survive into adulthood and the potential long-term consequences of the therapies are of ongoing concern. Alkylating agents have proven to be the most toxic to the ovaries; however radiation is also extremely gonadotoxic. In addition, combination of these modalities will produce additive effects in terms of ovarian damage (follicle depletion). As a result, there are increasing numbers of young cancer survivors with impaired or absent gonadal function. Advances in the field of assisted reproductive technology (ART) provide hope that the reproductive impact of cancer therapy can be reduced. Those technologies that may be applicable prior to gonadotoxic therapy are pretreatment ovarian protection with oral contraceptives or gonadotropin releasing hormone agonist; ART using pretreatment cryopreservation of embryos or gametes; posttreatment ART with donor gametes or embryos; or adoption. However, ovarian protection is not of proven benefit and oocyte/ovary cryopreservation has had only limited success to date. Information regarding cancer treatment's possible effects on fertility and ways to potentially circumvent these should be part of routine counseling to allow the patient to make an informed decision. Cancer 2006. © 2006 American Cancer Society.

Over the last 3 decades the use of multiple agent chemotherapy and combined modality treatment of childhood and adolescent cancers has increased survival rates markedly.1 Thus, the majority of young cancer patients will survive into adulthood and, as a result, the potential long-term consequences of the therapies that produce survival are of ongoing concern. The effects of chemotherapy and radiation depend on the age of the patient, cumulative dose, and duration of treatment. Alkylating agents have proven to be the most toxic to the ovaries; however radiation is also extremely gonadotoxic. In addition, the combination of these modalities will produce additive effects in terms of ovarian damage (follicle de pletion).2–4 As a result, there are increasing numbers of young cancer survivors with impaired or absent gonadal function, a concern that affects both patients and their health care providers. Advances in the field of assisted reproductive technology provide hope that the reproductive impact of cancer therapy can be reduced. Those technologies that may be applicable prior to gonadotoxic therapy will be discussed.

Ovarian Physiology

  1. Top of page
  2. Abstract
  3. Ovarian Physiology
  4. Chemotherapy
  5. Radiation Therapy
  6. Multimodality Therapy
  7. Infertility in Childhood Cancer Survivors
  8. Preservation of Fertility in Young Women
  9. Ovarian Protection
  10. Cryopreservation
  11. Posttreatment
  12. DISCUSSION
  13. REFERENCES

The maximum number of female germ cells (primordial follicles), 7 million, is reached in utero at approximately 20 weeks of gestational age. At birth the number has declined, through atresia, to 1–2 million. By puberty only 300,000 resting primordial follicles remain and approximately 400 of these will mature to ovulate over the reproductive years. Through the years primordial follicles continue to either ovulate or undergo atresia with menopause occurring once the number has reached 1000, usually in the early fifties.5 Anything that contributes to the depletion of primordial follicles, such as radiation or chemotherapy, will decrease the age of menopause.

In the pre-menarchal ovary follicles begin growth, independent of gonadotropins, but invariably end in atresia. After puberty primordial follicles also begin growth independent of gonadotropin stimulation; however, once the follicle has multiple layers of granulosa cells it becomes gonadotropin-dependent for continued growth and steroid production. The exact mechanism by which follicles are chosen to grow is unknown. Several follicles will be at different stages of development at any one time though most undergo atresia. In each cycle approximately 1000 resting follicles begin growth and it takes 85 days until the dominant follicle ovulates.6

The interaction between the dominant follicle and the hypothalamus eventually triggers a surge of luteinizing hormone, which is responsible for the final maturation of the oocyte prior to ovulation and fertilization. The primordial follicle enters the first meiotic division and arrests in prophase until just before ovulation when meiosis I is completed. It proceeds to metaphase II until fertilization when meiosis is completed.5

Chemotherapy

  1. Top of page
  2. Abstract
  3. Ovarian Physiology
  4. Chemotherapy
  5. Radiation Therapy
  6. Multimodality Therapy
  7. Infertility in Childhood Cancer Survivors
  8. Preservation of Fertility in Young Women
  9. Ovarian Protection
  10. Cryopreservation
  11. Posttreatment
  12. DISCUSSION
  13. REFERENCES

Although the majority of female children and adolescents will maintain fertility after chemotherapy for most pediatric malignancies, multiple studies associate an increased risk of ovarian failure following chemotherapy, especially alkylating agents.7–10 Cyclophosphamide is the agent most often implicated in causing ovarian damage, though others (chlorambucil, busulfan, procarbazine, melphalan) are also considered high risk.11 The relative risk for premature ovarian failure after chemotherapy ranges from 2 to 9 when compared with age matched controls.7–9 The risk depends on the specific drugs (and combinations), age of the patient, dose intensity, and cumulative dose. The pre-menarchal ovary appears to be relatively resistant to damage.7, 8 As women age, their ovarian reserve declines physiologically, and the dose of cyclophosphamide and other chemotherapeutic agents needed to cause ovarian failure decreases.10 For example, in women over the age of 40, 5 g of cyclophosphamide will cause ovarian failure, whereas 9 and 20 g are required in women aged 30–40 and 20–30, respectively.12

Combination chemotherapy, which are commonly used, are associated with gonadal toxicity though the contribution of each drug is difficult to determine as it may not be strictly additive.11 However, newer regimens appear to be less gonadotoxic.3, 13 Conditions most commonly associated with postchemotherapy gonadal failure (greater than 80%) are chemotherapy for bone marrow transplantation, Hodgkin's disease, Ewing's sarcoma, and soft tissue sarcoma.11, 14 It should be recognized that it is difficult to determine, with any accuracy, who will have decreased ovarian reserve or premature ovarian failure after therapy for most other pediatric malignancies.

Radiation Therapy

  1. Top of page
  2. Abstract
  3. Ovarian Physiology
  4. Chemotherapy
  5. Radiation Therapy
  6. Multimodality Therapy
  7. Infertility in Childhood Cancer Survivors
  8. Preservation of Fertility in Young Women
  9. Ovarian Protection
  10. Cryopreservation
  11. Posttreatment
  12. DISCUSSION
  13. REFERENCES

As with chemotherapy, the effect of radiation on ovarian function depends on the age of the individual, field of treatment, total irradiation dose, and dose per fraction. The median lethal dose (LD50) for human oocytes is now considered less than 2 Gy, while doses in the range of 10–20 Gy in children and 4–6 Gy in adults are associated with permanent ovarian damage.15, 16 In childhood and adolescence, patients who receive total body irradiation (TBI) of 14.4 Gy prior to bone marrow transplantation are at the greatest risk of ovarian failure.17, 18 In patients older than 10 years, TBI causes premature ovarian failure in over 90%; in those less than 10, the ovaries appear to be somewhat resistant to damage but premature menopause is also frequent in this group.10, 16, 17

Pelvic irradiation has also been associated with abnormal uterine function, possibly contributing to infertility, especially in those exposed in childhood.18 The anomalies include reductions in uterine volume, endometrial thickness, and blood flow. This may explain the slightly, but not statistically significant increase in the rate of miscarriage, and the increased incidence of low birth weight in offspring of women who received pelvic irradiation.17, 19

Cranial irradiation doses of 35–45 Gy are associated with disruption of the hypothalamic–pituitary–gonadal axis. This causes deficient plasma gonadotrophin levels and potentially pubertal delay or secondary amenorrhea; however as the gonads are unaffected the potential for fertility remains once gonadotrophins are replaced.20

Multimodality Therapy

  1. Top of page
  2. Abstract
  3. Ovarian Physiology
  4. Chemotherapy
  5. Radiation Therapy
  6. Multimodality Therapy
  7. Infertility in Childhood Cancer Survivors
  8. Preservation of Fertility in Young Women
  9. Ovarian Protection
  10. Cryopreservation
  11. Posttreatment
  12. DISCUSSION
  13. REFERENCES

Combined therapy with chemotherapy and radiotherapy can severely deplete follicular numbers and thus compromise ovarian stores. In a multicentered study, comparing 1067 long-term survivors of childhood or adolescent cancer with age-matched siblings, the risk of early menopause was 3.66 (CI: 1.34–9.99) with radiation alone, 9.17 (CI: 2.67–31.49) for alkylating agents alone, and 27.39 (CI: 12.42–60.35) for combined modality.7 In an Ontario-based study, childhood cancer survivors who received both alkylating agents and abdominal-pelvic radiation had a relative risk of 2.58 for premature ovarian failure when compared with those treated with surgery alone.21

Despite this knowledge, it is not possible to develop an equation that accurately predicts those individuals who will or will not acquire premature ovarian failure because of cancer therapy. This becomes even more difficult when combination therapies are used.

Infertility in Childhood Cancer Survivors

  1. Top of page
  2. Abstract
  3. Ovarian Physiology
  4. Chemotherapy
  5. Radiation Therapy
  6. Multimodality Therapy
  7. Infertility in Childhood Cancer Survivors
  8. Preservation of Fertility in Young Women
  9. Ovarian Protection
  10. Cryopreservation
  11. Posttreatment
  12. DISCUSSION
  13. REFERENCES

In the pre-menarchal child the failure to develop signs of puberty by the age of 14, or arrested puberty, should initiate investigation for ovarian failure. In the post-menarchal female there may be transient ovarian disruption and amenorrhea, associated with hypoestrogenism, for up to 2 years after the last course of therapy. Ovarian function may then recover but there is no way to predict how long function will remain, though individuals under the age of 30 have the best chance of ovarian recovery.15 It is therefore important to counsel long-term cancer survivors that, even if they have regular menses and ovulatory function, they may undergo premature menopause and should consider not delaying pregnancy.

At the time of cancer therapy future fertility is often not a concern for the individual, depending on their age. As survivors move beyond their illness and wish to continue a normal life, they possess a positive attitude towards parenthood.22 There are those who have concerns about fertility and the risk of their therapy on future children, though there is reassuring data that suggest no increased risk of abnormalities in children of patients who received chemotherapy.19, 23

Since accurate predictions of subsequent ovarian failure or fertile lifespan cannot be made prior to gonadotoxic therapy, there should be consideration, depending on the therapy, for the preservation of fecundity prior to treatment.

Preservation of Fertility in Young Women

  1. Top of page
  2. Abstract
  3. Ovarian Physiology
  4. Chemotherapy
  5. Radiation Therapy
  6. Multimodality Therapy
  7. Infertility in Childhood Cancer Survivors
  8. Preservation of Fertility in Young Women
  9. Ovarian Protection
  10. Cryopreservation
  11. Posttreatment
  12. DISCUSSION
  13. REFERENCES

There are no strategies that will guarantee the preservation of fertility in those about to undergo cancer therapy, though the following strategies may provide hope: pretreatment ovarian protection; assisted reproductive technology (ART) using pretreatment cryopreservation of embryos or gametes; or posttreatment ART with donor gametes or embryos.

Ovarian Protection

  1. Top of page
  2. Abstract
  3. Ovarian Physiology
  4. Chemotherapy
  5. Radiation Therapy
  6. Multimodality Therapy
  7. Infertility in Childhood Cancer Survivors
  8. Preservation of Fertility in Young Women
  9. Ovarian Protection
  10. Cryopreservation
  11. Posttreatment
  12. DISCUSSION
  13. REFERENCES

Prior to pelvic radiation the ovaries can be translocated out of the field of radiation, though scatter effects cannot be avoided completely and anatomic infertility (too great a distance from the ovary to the fallopian tube for either fertilization or transport of the embryo to the uterus) may result.24 It has been proposed that ovarian suppression with oral contraceptives (OCs) or gonadotropin releasing hormone agonists (GnRH-agonist) may reduce the gonadotoxic effects of cancer therapy.25–28 Oral contraceptives and GnRH-agonists produce reversible suppression of gonadotropin secretion causing secondary inhibition of follicle growth beyond the multilayered granulosa cell stage. The hypothesis, from observational studies of prepubescent gonadal resistance to gonadotoxic therapy, supposes that a quiescent ovary, with a reduced number of active follicles and more resting follicles, will reduce the damage caused by gonadotoxic therapies. A small animal study suggests a role for GnRH agonist in protecting rat ovaries from chemotherapy.28 The same has been proposed of OCs and GnRH-agonist in small, retrospective, poorly designed, human studies.25–27 In addition, there are biologically implausible aspects surrounding ovarian protection through gonadotropin suppression. For example, the recruitment of resting follicles is gonadotropin independent and not until the final stages of growth does the follicle need gonadotropin support. Furthermore, in follicle stimulating hormone (FSH) knock-out studies, as well as in humans with defective FSH receptors, or after hypophysectomy, the early stages of follicle development remain unaffected.29 As well, OC users when compared with nonusers do not enter menopause at a later age, suggesting that OC users do not have increased ovarian reserve. An in vitro study indicates that chemotherapy affects primordial follicles via the induction of apoptotic changes in the pregranulosa cells, which leads to follicle loss.6 A large, prospective, controlled trial would be needed to determine the true value of ovarian suppression with GnRH-agonists in reducing the effects of gonadotoxic therapy.

Cryopreservation

  1. Top of page
  2. Abstract
  3. Ovarian Physiology
  4. Chemotherapy
  5. Radiation Therapy
  6. Multimodality Therapy
  7. Infertility in Childhood Cancer Survivors
  8. Preservation of Fertility in Young Women
  9. Ovarian Protection
  10. Cryopreservation
  11. Posttreatment
  12. DISCUSSION
  13. REFERENCES

One of the standard methods to enhance fecundity and reduce exposure to exogenous gonadotropins, in couples with reduced fertility, is embryo cryopreservation. However, as children and young adults do not usually have partners, ovarian hyperstimulation to generate supernumerary mature oocytes for in vitro fertilization (IVF), followed by embryo cryopreservation, is not a feasible option.

Although human embryo cryopreservation is now routine, oocyte cryopreservation remains a research endeavor.30 Oocyte quality is a decisive factor for embryo quality and resultant pregnancy rates, and cryopreservation of mature oocytes is associated with problems related to their large volume and degree of specialization. Following cryopreservation, anomalies of the zona pellucida (ZP) and meiotic spindle can be found; respectively these are associated with reduced fertilization rates and increased aneuploidy. Hardening of the ZP can be overcome by intracytoplasmic sperm injection and spindle anomalies through freezing at the germinal vesical (GV) stage (immature oocyte), though optimal culture conditions to mature oocytes in the GV stage, either fresh or frozen, have not been established. The efficacy of mature oocyte cryopreservation, expressed as the number of children born per frozen-thawed oocyte, is less than 1%.6 However, recent advances in culture techniques for mature oocytes appear to have overcome some of the obstacles and the pregnancy rates are expected to increase in the near future. Mature oocyte cryopreservation requires ovarian hyperstimulation protocols to maximize the number of oocytes retrieved as well as the needle aspiration of the follicles and this process can take up to a month.

Cryopreservation of ovarian tissue circumvents some of the problems associated with cryopreservation of mature and immature oocytes. In addition there are approximately 120 small follicles in a 4 mm disk of ovary from a 30 year old woman, whereas a stimulated cycle typically generates 8–12 oocytes.31 An entire ovary or 1–2 mm cortical ovarian strips can be obtained laparoscopically. Examination of frozen-thawed, human ovarian tissue confirms the viability of primordial follicles that survive (10%–85%).32 Primordial follicles contain oocytes that are much smaller than the mature cells and they appear to be more tolerant to freezing and thawing. Factors that contribute to this are the absence of the ZP, few support cells, low metabolic rate of the oocyte as it rests in prophase I of meiosis, and few chill sensitive lipids.33 In humans, the only practical strategy is to reimplant frozen-thawed ovarian tissue to the ovarian fossa or an ectopic site. Once engrafted, estrogen production from the ovarian tissue, indicative of follicular activity, has been demonstrated though successful pregnancy has not yet been reported.34 In mice and sheep there have been live births reported from frozen-thawed ovarian tissue grafted to the ovarian bursae and the rates are comparable to fresh ovarian grafts.35, 36 Further development in the methods used to freeze ovarian tissue could significantly improve the viability of frozen-thawed ovarian autografts.

In the long-term, in vitro culture of thawed primordial follicles is attractive, as this would eliminate the potential for reimplanting residual cancer cells and possibly avoid follicle wastage through ischemia or normal atresia. However, the difficulties surrounding the technology of maturing primordial oocytes to mature oocytes, in vitro, will be challenging because of the myriad of molecular interactions that can ultimately impact on the development of the zygote. In spite of these hurdles, ovarian and more so mature oocyte cryopreservation is offered in several centers around the world prior to gonadotoxic therapy (the latter is now offered, experimentally, to mature women who wish to delay their reproduction). Although this remains experimental, it serves to advance the technology, with the expectation that methods will evolve in sufficient time for women to use their gametes to produce a child.

Posttreatment

  1. Top of page
  2. Abstract
  3. Ovarian Physiology
  4. Chemotherapy
  5. Radiation Therapy
  6. Multimodality Therapy
  7. Infertility in Childhood Cancer Survivors
  8. Preservation of Fertility in Young Women
  9. Ovarian Protection
  10. Cryopreservation
  11. Posttreatment
  12. DISCUSSION
  13. REFERENCES

When women cannot conceive due to premature ovarian failure, there remains the option of pregnancy with a donated gamete (fertilized by the partner's sperm), or with a donated embryo. For those women who are infertile because of hypothalamic damage from cranial radiation exogenous gonadotrophins can be given to drive the production of ovarian steroids and ovulation. The success rate is similar to normal ovulatory women as long as the health of the reproductive tract has been maintained with exogenous reproductive steroids (estrogen and progesterone).

DISCUSSION

  1. Top of page
  2. Abstract
  3. Ovarian Physiology
  4. Chemotherapy
  5. Radiation Therapy
  6. Multimodality Therapy
  7. Infertility in Childhood Cancer Survivors
  8. Preservation of Fertility in Young Women
  9. Ovarian Protection
  10. Cryopreservation
  11. Posttreatment
  12. DISCUSSION
  13. REFERENCES

There are an increasing number of survivors from childhood and adolescent cancer as a result of multimodality therapy. Alkylating agents and radiation therapy, especially TBI, are most likely to cause ovarian damage depending on the age, dose intensity, and cumulative dose. Though most young women will maintain their fertility after cancer therapy it is difficult to predict who will or will not sustain ovarian damage. For the very young, future fertility is not a concern until they are older, but some young women have immediate concerns if informed about the potential for therapy to reduce their fertility. There are limited options to preserve fertility and none guarantees fertility. Ovarian protection with OCs and GnRH agonists is not proven and ART strategies are either not practical (embryo cryopreservation) or developing technologies (primordial follicle/mature follicle/ovarian cryopreservation). It is important to fully inform patients, and/or their guardians, about the potential long-term effects of various cancer therapies, as well as actions that may reduce these effects. The explanation of the pros and cons of all aspects of treatment empowers the patient to make decisions about her therapy.

REFERENCES

  1. Top of page
  2. Abstract
  3. Ovarian Physiology
  4. Chemotherapy
  5. Radiation Therapy
  6. Multimodality Therapy
  7. Infertility in Childhood Cancer Survivors
  8. Preservation of Fertility in Young Women
  9. Ovarian Protection
  10. Cryopreservation
  11. Posttreatment
  12. DISCUSSION
  13. REFERENCES