Fertility Preservation for Cancer Patients: A Review
Tosin Ajala, 1 Junaid Rafi, 1 Peter Larsen-Disney, 2 and Richard Howell2
1 Department of Obstetrics and Gynecology, Basingstoke and North Hampshire NHS Trust, Basingstoke RG24 9NA, UK
2Department of Obstetrics and Gynaecology, Brighton and Sussex University Hospitals, Eastern Road, Brighton BN2 5BE, UK
This article was published in Obstetrics and Gynecology International journal
Infertility can arise as a consequence of the treatment of oncological conditions. The parallel and continuous improvement in both the management of oncology and fertility cases in recent times has brought to the forefront the potential for fertility preservation in patients being treated for cancer. Oncologists should be aware of situations where their treatment will affect fertility in patients who are being treated for cancer and they should also be aware of the pathways available for procedures such as cryopreservation of gametes and / or embryos. Improved cancer, which is associated with increased cure rates and long-term survival, coupled with advances in fertility treatment, means that it is imperative that fertility preservation is considered as part of the care offered to these patients. This can only be approached within a multidisciplinary setting. There are obvious challenges that remain to be resolved, especially in the area of fertility preservation in prepubertal patients. These include ethical issues, such as valid consent and research in the field of tissue retrieval, cryopreservation, and transplantation.
Infertility can arise as a consequence of the treatment of oncological conditions. The parallel and continuous improvement in both the management of oncology and fertility cases in recent times has brought to the forefront the potential for fertility preservation in patients being treated for cancer.
Infertility can arise as a consequence of the treatment of oncological conditions. The parallel and continuous improvement in both the management of oncology and fertility cases in recent times has brought to the forefront the potential for fertility preservation in patients being treated for cancer. With the publication of NICE Guidance on the applications of cryopreservation in cancer treatment , the emphasis on life style versus health issues within fertility for cancer patients should shift. Clearly, oncologists should be aware of situations where their treatment will affect fertility in patients who are being treated for cancer, and they should also be aware of the pathways available for procedures such as cryopreservation of gametes and / or embryos. The NICE Guidance has been developed on the back of a working party from the Royal College of Physicians and the Royal College of Radiologists, who have recommended the procedures to be followed before chemotherapy and radiation therapy that are likely to affect fertility; and also the management of post-treatment infertility. The British Fertility Society has produced a strategy for the development of policy and practice in fertility preservation for survivors of cancer .
It should be remembered that the NHS will currently only fund one IVF for any woman with infertility and this is only available to women who meet strict inclusion criteria usually including no previous children to either a partner between 23 and 39 years of age and a body mass index less than 30.
2. The Impact of Oncology Therapy on Fertility
2.1. Surgical Management
Surgery can impact on fertility in one of two ways. It can either render someone infertile by the removal of reproductive organs or in the case of the male it can interfere with potency or ejaculation. There is no doubt, however, that in recent years there has been a tendency toward more conservative treatment for many malignancies affecting reproductive organs.
2.1.1. Female Patients
In women, there has been a tendency towards less radical approaches to cervical cancer with the development of loop excision techniques for very early cancer of the cervix and more recently the development of radical trachelectomy [3, 4] which allows for a radical approach to cancer of the cervix that is treatable surgically, but with the preservation of the uterus and thus fertility.Endometrial cancer is usually a disease of the postmenopausal group or at least in those who have completed their family, and therefore it is unusual for the treatment of this disease, which involves hysterectomy and bilateral oophorectomy, to affect fertility. Epithelial ovarian cancer continues to be treated radically with loss of reproductive organs but increasing understanding of germ cell malignancies and borderline tumors of the ovary has led to a more conservative approach to these neoplasms and often a single oophorectomy will be performed where in the past hysterectomy and / or bilateral oophorectomy would have been the treatment of choice. It is unusual for vulval carcinoma to be seen in the reproductive age group, and although it may have a major psychosexual impact, it would be unusual for a surgical approach to these to impact on fertility.
2.1.2. Male Patients
Testicular cancer is the most prevalent cancer affecting the reproductive organs of the male, and tends to occur in an age where child bearing remains a potential issue. The majority of these are treated with a unilateral orchiectomy [5, 6] and staging thus conserving reproductive capacity.Other tumors affecting the reproductive organs in the male tend to occur in a much older age group where fertility issues may not be of importance. Surgery for other pelvic malignancies such as bladder, prostate, and rectum can clearly interfere with potency or ejaculation, however, the age dependence of these tumors would suggest that most of these occur in a larger group of patients where fertility issues are unlikely to be of major importance . Thus, fertility services are unlikely to be as important to this older group of individuals.
3. Chemotherapy Effects on Fertility
Chemotherapy can produce significant effects on patient fertility. These effects are dependent on a number of factors :
(i) radical versus adjuvant chemotherapy. Radical chemotherapy generally has more profound effects on fertility than adjuvant chemotherapy, (ii) single agent versus combination chemotherapy.Increasing complexities of regimens are more likely to have impacts on fertility than single agent, (iii) dose-dependent effects. Increasing doses are likely to have more profound effects on fertility than lower doses, (iv) drug-dependent effects. Different agents have a markedly different impact on fertility with some chemo-therapeutic agents sparing fertility while others are extremely toxic in this regard, (v) age-dependent effects. In the female in particular, age has a profound effect on chemotherapy toxicity. Women undergoing chemotherapy under the age of 40 have a much higher chance of regaining normal ovarian function while the majority of women over 40 administered toxic chemotherapy will be given menopausal by their treatment. Presumably part of the reason for this is the fact that the natural attrition rate of the oocyte has a large drop in oocyte numbers over age 40 (reduced ovarian reserve) and this corresponds to reduced live birth rates in fertility patients over the age of 40 vi) male versus female physiology. The testis in the male is exquisitely sensitive to chemotherapy whereas, as has already been stated, the female is variable in terms of tolerance to chemotherapy agents.Detailed information regarding fertility effects of many chemotherapy regimes is missing,
3.1. Toxic Effects of Commonly Used Chemotherapeutic Agents on the Testis
Gonadal toxicity of the testis affects spermatogenesis more than it does testosterone production.This stems from the increased cyto-sensitivity of the germinal epithelium in comparison to that of the leydig cells. The germinal cell division is extremely high through increased meiotic and mitotic activity thus allowing for increased sensitivity to cytotoxic agents [8-10]. Sexual maturation of the testis also influences the degree of gonadal damage experienced when exposed to cytotoxic drugs, the prepubertal testis being less susceptible than post-pubertal testis . The extent to which spermatogenesis is affected is influenced by the type of cytotoxic agent (s) and the dose to which it is exposed [8-10]. Table 1 illustrates the degree of gonadal dysfunction of commonly used cytotoxic agents.
3.2. Toxic Effects of Commonly Used Chemotherapeutic Agents on Ovary
A fixed number of primordial follicles present at birth from the ovarian reserve into puberty.Postpuberts of these primordial follicles contain single oocytes arrested in the prophase of the first meiotic division and are highly sensitive to cytotoxic drugs leading to cellular death . Follicular depletion has been shown to be physiologically age dependent, the maximum rate of depletion occurring around the age of 38 when the reserve is just about 10% the number present at menarche . The gonadal toxic effect is therefore not only dependent on the type (s) and dosage of the cytotoxic drug (s) employed but also on the age of the woman.
(i) Adriamycin and cyclophosphamide have a 38% ovarian failure rate in women aged over 40 years at 2 years post chemotherapy. (ii) Cyclophosphamide, Hydroxyldaunorubicin (Adriamycin) Oncovin (vincristine), and Prednisolone do not usually lead to permanent amenorrhea in women (iii) ABVD (Doxorubicin, Bleomycin, Vincristine, and Dacarbazine) used in the treatment of Hodgkin's disease is significantly less toxic in terms of fertility than the older MOPP Mechlorethamine, Vincristine, Procarbazine and Prednisolone) (iv) Bleomycin and doxorubicin have minimal effects on fertility (v) Vinca alkaloids and antimetabolites have very mild effects on fertility (Methotrexate very mild at 6 gm total dose). not clearly defined in terms of their impact on fertility.(vii) Cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) and classical breast cancer regimen will render 71% of women over 40 years of amenorrhoeic at 2 years.
4. Radiotherapy Effects on Fertility
The principle of radiotherapy is based on the ionization of cellular atoms and molecules leading to the destruction of DNA structures within the cell structure. A chain of events is set up, disrupting the cell cycle leading to apoptosis of the cells. Radiotherapy has its use in oncology because, unlike malignant cells, most normal cells have the inert ability to recover from the effects of radiotherapy.
Clearly radiotherapy can be administered as external therapy (teletherapy), or as intracavity (brachytherapy) treatments. In addition to this, radiotherapy can be given with curative intent or as adjuvant therapy often postoperatively.
The direct effects of radiotherapy are dose dependent and are also dependent on the field applied to the individual. It is important to consider the effect of scattered radiation as well as direct irradiation when assessing potential effects on fertility. For example, although pelvic irradiation may not directly hit the testis in the male patient, scatter of radiotherapy will result from this area which may have an impact on fertility [13, 14].
4.1. Female Patients
Radiotherapy effects on the female are dose dependent. The application of 14.3 Gray to an ovary in a woman over 30 years of age will usually render her irreversibly infertile and menopausal . A dose of 6 Gray to the ovary of a woman less than 30 years of age is usually reversible, but ultimately will bring menopause forwards. Thus, women are not only concerned with issues of fertility but also with hormone production, as both seem to be equally affected by radiotherapy.
Although the uterus is relatively resistant to radiation, there is no doubt that uterine irradiation is harmful , and even if fertility is conserved, uterine irradiation will result in poor implantation . This is due to a number of factors including decreased uterine volume and blood flow, which have been shown to result in increased mid-trimester losses, preterm labor and intrauterine growth retardation . The vagina is relatively radio-resistant, however, irradiation of this organ carries with it the risk of loss of lubrication and stenosis which may result in physical impairments to fertility as well as major psychosexual issues .
4.2. Male Patients
The effect of radiotherapy on male fertility is also dose dependent. The application of more than 6 Gray to the testes will result in irreversible azoospermia. At levels of 3.5 Gray, sterility does occur, but this is reversible though such recovery will take 18 to 24 months. Treatment age (the younger the better) and normal pre-treatment of sperm count influence the recovery rate . Fractional radiotherapy to testes for the treatment of carcinoma of the testis usually involves high doses of radiotherapy leading to permanent azoospermia [21-23]. Interestingly, the Leydig cells of the testis seem far more resistant to radiation, and therefore testosterone production is generally less impaired in patients receiving even relatively high doses of radiotherapy relative to its effects on sperm production . In addition, libido and erection will usually remain normal in the male and its sterility that is the main concern. However, it is not unusual for patients who have had pelvic irradiation to suffer from erectile dysfunction as a long-term complication. This can be explained by radiation induced vascular disease leading to reduced blood flow in the pelvic and penile vessels .
5. Fertility Preservation for Female Cancer Patients
5.1. Options for Fertility Conservation
5.1.1. Hormone Protection by Suppressing Ovaries
GNRH analogues have been used during chemotherapy to suppress ovarian cycling and induce a temporary medical menopause. The action of GnRH analogues is not clearly understood as primordial and primary follicles do not have GnRH receptors and it is possible that GnRH analogues preserve those follicles that have already initiated growth. Several studies in animals have suggested that this maneuver may be offered, but its benefit in human therapy remains debatable.The human studies currently available are limited in design and lack of long-term follow-up .The Option Trial in Oestrogen Non-Responsive Premenopausal Breast Cancer Patients Receiving Adjuvant or Neo-Adjuvant Chemotherapy for breast cancer looked at hormone suppression using GNRH analogues and progestogens and examined the impact of this on fertility. It concluded that using goserelin concurrently with chemotherapy is associated with a high rate of ovarian function preservation .
5.1.2. Ovarian Transposition (Oophorepexy)
The aim is to surgically remove the ovaries from the direct field of radiation. It is useful during the treatment of gynaecological cases and haematological cancers such as Hodgkin's lymphomas. Most ovarian transpositions have been performed laparoscopically and there have been suggestions that lateral transposition may be more protective than median transposition of the ovaries [29, 30].
5.1.3. Storage by Cryopreservation of Embryos, Oocytes, or Ovarian Tissue
The choice of what tissue type should be preserved depends on the type of cancer, the patient's age, and whether she has a partner. Often it's time, however, that is the limiting factor in this choice.
5.2. Embryo Storage
Embryo storage is ideal for an adult woman in a stable relationship as it is an established technique that has been available since mid 1980s. IVF offers a success rate of approximately 30% per cycle, and this is similar to the natural conception rate that is achievable by healthy couples without assisted reproduction techniques [31, 32]. It involves stimulating the ovaries using gonadotrophins which results in high estrogen levels, and of course this raises concerns for some tumors such as breast cancers with estrogen receptor positivity. It is still unclear what the risks of such techniques in terms of tumor progression or relapse in a hormone-dependent cancer are. Some groups have attempted to address this by using tamoxifen or letrozole alone or in combination with standard IVF stimulation for women with breast cancer  or endometrial cancer. Patient numbers are small and long-term studies are currently not available.
IVF stimulation takes a minimum of two to three weeks depending on the patient's menstrual cycle and could be anything up to five weeks. After the stimulation of follicles to maturation, an egg collection procedure is usually performed as a day case under sedation or a general anesthetic where vaginal ultrasound is used to guide transvaginal collection of eggs. IVF is then given to fertilize the patient's eggs with the partner's sperm prior to freezing the embryo. Currently there is limited availability of donor sperm for adult women trying to preserve reproductive potential while undertaking chemotherapy.
5.3. Oocyte Storage
This technique is suitable for adults and for older teenagers who do not have a current partner. It is important to realize that this is a new technique and success rates are low at present with perhaps less than 5% success rates achievable per cycle [34, 35]. Clearly, this figure may be improved with improved techniques in the future, but currently less than 100 pregnancies have been documented worldwide using this technique. The technique involves stimulation of ovaries, harvesting eggs and then freezing them, which is technically very difficult. Stored eggs can be later thawed and IVF techniques with ICSI can be used. Oocytes are much more sensitive to damage from cryopreservation techniques than embryos (probably secondary to spindle damage from ice crystal formation). The formation of ice crystals and the attendant cellular damage during freezing can be avoided by vitrification. For younger patients, oocyte storage may be an option, as harvest techniques may include transabdominal ultrasound and laparoscopy for retrieval of eggs instead of subjecting the patient to transvaginal technique.
5.4. Ovarian Tissue Storage
This is a technique that can be used by adults and children, but it is very experimental at the present time. Optimal treatment benefit can only be expected in the presence of a healthy ovarian reserve, as it is less likely to be beneficial to the older patient over 40 years of age. Laparoscopy is required to undergo a biopsy of an ovary or to remove the entire ovary for preservation. The first case of an ovarian transplant operation was reported in 2000 . (all cases of successful post-implantation pregnancy reported to date have utilized the entire cortical ovarian tissue) . It is therefore an invasive procedure under general anesthetic and carries a mortality rate of 1 in 12,000. Tissue obtained is cut into thin sections and then cryopreserved in a relatively straightforward fashion. Fewer than 15 patients worldwide have their thawed ovarian tissue reimplanted via either orthotopic or heterotopic transplantation. Until recently, there was no case reported of a successful live birth after orthotopic transplantation of cryopreserved ovarian tissue.Donnez et al.  reported in The Lancet in 2004 and live birth after transplanting cryopreserved ovarian tissue back into the pelvis of a woman following treatment for Stage 4 non-Hodgkin's lymphoma and Meirow et al. in 2005 reported a further live birth in another young woman who had also been treated for non-Hodgkin's lymphoma. In another case reported in 2005, laparoscopic cortical ovarian transplantation was performed between a set of 24-year-old monozygotic twins. The recipient twin had documented clinical premature ovarian failure.
The risk of re-implanting tissue with occult cancer while small remains significant. Only patients with cancer cases associated with low risk of ovarian metastasis such as squamous cell carcinoma of the cervix, Wilm's tumor, Hodgkin's and non-Hodgkin's lymphoma should be considered for future autotransplantation. Patients with moderate and in particular high risk of ovarian involvement should not be considered for future autotransplantation .
6. Fertility Preservation in the Male Cancer Patient
Sperm cryopreservation remains the obvious choice for males capable of producing a seed sample.Testicular sperm extraction (TESE) and epididymal aspiration of sperm to be used for ICSI in cases of azoospermia or ductal blockage. This is mainly achieved through masturbation, but can also be achieved through testicular biopsy and testicular sperm extraction. Sperm collection should be performed prior to treatment to avoid the collection of potentially abnormal DNA containing cells.
Other forms of potential male fertility conserving methods such as hormonal gonadoprotection and testicular tissue cryopreservation with subsequent transplantation have either been found unhelpful or still in the experimental stages . Gonadal shielding is also limited in its value.
6.1. Practical Laboratory Issues for Sperm Banking
A critical factor for male patients requiring sperm banking is the timing of the sample as it is essential that this occurs before chemotherapy or radiation therapy is undertaken. Prescreening is required and patients are checked for Hepatitis B and C, Syphilis, HIV and CMV. (HFEA (006)), the HFEA (006), and the HFEA (006). MS consent to storage of sperm.
Patients are then required to attend a Reproductive Medicine Center to produce a seed sample (ideally this should be three samples a few days apart). Samples are then stored in liquid nitrogen at minus 196 degrees centigrade in two separate locations for 10 years. Each sample undergoes a standard diagnosis of semen analysis and is assessed against standard criteria (WHO 2000).
6.2. Long-Term Considerations
Approximately 50% of sperm stored will be lost during preservation and storage process. Potential damage to cryopreserved sperm includes osmotic injuries from cryoprotective agents, hypothermic injury  and oxidative damage .
Most patients receive an annual letter from the Andrology Unit storing their seeds to check that the patient wants the sample to be kept in storage. For patients to be eligible for seed storage, they must be under 55 years of age, they must be able to give informed consent for the storage, screening and fate of the sperm. It is certainly feasible to store sperm for many years and, at present, patients are not charged for this facility but the question of whether the NHS should be formally funding this remains unanswered.
7. The Challenge for Children
Examination of the trends in five-year-survival rates for the most common childhood malignancies reveals sustained improvements in cure rates. Over the twenty-five year-period from 1964, the five-year survival for acute lymphocytic lymphoma has risen from near 0% to close to 70%, for non-Hodgkin's lymphoma has risen from approximately 20% to nearly 80% and for Wilms -tumour has risen from 25% to about 80% . Even since that time, five-year survival rates have continued to rise slowly for these common forms of childhood malignancy. Although the challenge for poor tumor prognosis such as neuroblastoma remains, for other tumors the goal of the future is to maintain improvements in cure rates and minimize late effects for curable tumors.
7.1. Young Male Patients
The testicle is responsible for spermatogenesis (production of mature sperm). In addition to this, it carries out steroidogenesis (the production of steroid hormones including testosterone). Damage to the Leydig cells of the testis results in reduced testosterone production and an elevated luteinizing hormone levels (from the pituitary gland). Damage to the germinal epithelial of the testes results in elevated follicular stimulating hormone (FSH) levels, low inhibin B levels and impaired spermatogenesis.
As previously discussed, a radiation dose greater than 6 Gray to the germinal epithelium will result in permanent azoospermia. In the prepubertal male, irradiation greater than 20 Gray to the Leydig cells of the testis will cause significant damage in terms of testosterone production but in the post-pubertal male a level of greater than 30 Gray is required to cause this level of damage.
A study by Thomson et al.  examined male fertility after childhood cancer and examined seed analyzes in long-term cancer survivors compared to controls. In the control group (untreated), 85% of subjects had a normal seed analysis, approximately 10% had poor motility and 5% had oligospermia. The findings were quite different in the cancer survivors group: 30% had normal sperm analysis, almost 30% had poor motility, 15% had oligospermia and over 20% had azoospermia. Of the subjects who actually produced sperm, it was clear that the concentration of sperm produced was significantly less than that of the control group. An analysis of sperm DNA integrity as a measure of sperm quality showed no significant difference between control and cancer survivor groups. Thus, it can be concluded that subfertility associated with previous treatment of childhood cancer may be due to azoospermia or oligospermia where there is a significant reduction in sperm concentration but normal sperm quality.
7.1.2. Strategies for Fertility Preservation in Young Males Undergoing Treatment for Cancer
Sperm banking remains the obvious choice for males capable of producing a seed sample, however young men will only start producing sperm cells suitable for cryopreservation around the age of 12-13 years . Certainly sperm retrieval should be offered to patients in whom the risk of infertility is high, but there is now a good evidence base to suggest that if the testicular volume is less than 10 mls, it is very unlikely that the patient will demonstrate any significant spermatogenesis . Thus, sperm retrieval should be limited to males where the testicular volume is greater than 10 mls and samples should ideally be produced by ejaculation. In the situation where young males are unable to ejaculate then rectal electro stimulation  or testicular / epididymal  aspiration may be offered and can be successfully taken. Sperm banking can then be done with the expectation that the seed can be used at a later date. At present, the use of stored sperm is likely to require assisted conception methods such as intracytoplasmic sperm injection (ICSI) to optimize the likelihood of successful fertilization .
7.1.3. Questions Related to Sperm Storage
A number of questions are raised by the opportunity to provide sperm storage for young male cancer patients.
(1) Who exactly will need it?
(2) Who will raise the issue of sperm storage with the patient?
(3) Where will the patient produce the sample for storage?
(4) When, in relation to his treatment, should the patient produce a sample? Situations arise where a patient is too ill or indeed has to be treated so acutely that there is insufficient time to offer this option?
(5) Is it appropriate to discuss the issue of sperm storage with a patient who is struggling to cope with his diagnosis and future treatment?
(6) What is the cost of storage of sperm? There is a one-year audit of all 22 United Kingdom Children's Cancer Study Group (UK CCSG) centers, which is the Multi-Center Research Ethics Committee (MREC) and The Human Fertilization and Embryology Authority (HFEA) approved. Part one of the study looks at what, if anything, was discussed with regard to infertility with the cancer patient and what risk of infertility was given. Part two of the audit details on the quality of the stored material, how it was obtained and what was discussed. The results of this study should be available next year but pilot interviews with adolescent males by Glaser et al.  have revealed a number of common themes. Patients strongly believe their choice is of paramount importance and they strongly feel the need for information on sperm storage. Many patients sought increased input on the importance of fertility preservation and stressed the importance of communication with professionals on this subject. In addition to this, a common theme was that patients felt extremely pressurered about making sperm storage in this setting.
7.2. The Legal Aspects of Fertility Preservation Young Cancer Patients
At present, in the United Kingdom, a young person older than 16 years of age is presumed capable of giving valid consent for the treatment and removal of gametes (under common law) and the storage and use of these gametes (governed by the HFE Act of 1990) . A young person less than 16 years of age is presumed unable to give consent for the treatment, removal of gametes and / or storage and use of these gametes. However, Gillick competent  is permitted to, in accordance with 1990 , have been able to demonstrate the capacity to accept this valid consent. Act as long as he is fully informed and understands the proposed line of treatment, benefits and attendant risk. A further issue is that young people less than 16 years of age who are not competent may rely on their parents to consent to medical procedures that are considered to be in their best interests.Unfortunately, parents are not allowed to give consent to the storage and use of gametes, and therefore there is no option to preserve fertility in the prepubertal boy.
Experimentation is underway on the storage and use of gonadal tissue from children , however this has major ethical issues, not least of which is consent (which is valid only if it is voluntarily obtained from an informed, competent person). Proxy consent may be performed in a therapeutic setting if it is considered to be in the best interests of the patient, but the question remains whether the removal of gonadal tissue is actually fulfilling this criterion. The Human Fertilization and Embryology Authority (HFEA) 1990 Act has jurisdiction over the storage and use of live human gametes and embryos created in vitro, and by definition a gamete is a "reproductive cell with a haploid set of chromosomes that is able to take part in fertilization with another of the opposite sex to form a zygote ". The implications of this act mean that no license is required to store gonadal tissue from prepubertal children because they do not contain gametes and therefore primordial follicles in the cortical strips of ovaries may be stored for girls whose parents consent their child's name because they believe that retrieval and storage of this tissue is in the best interests of the girl. However, the boys with Tanner Stage 2  or greater development may have tissue stored in accordance with the 1990 Act, if they can give written informed consent, parents are not allowed on their child's behalf in this setting.
8. Fertility Treatment and Cancer Prognosis
A concern regarding assisted reproduction techniques is that women have to undergo hormonal manipulation and a possible association between the use of fertility drugs and the risk of specific cancers, this has not been convincingly demonstrated in epidemiological studies. With regard to cancer risk, the only consistent association observed is an increased risk of endometrial cancer for women with subfertility due to hormonal disorders. While the positive findings in some studies on fertility and ovarian cancer risk have aroused serious concern, the associations observed in most of these reports appear to be due to bias or chance rather than being causal .
The link between ovarian cancer and fertility drugs has not been established and fertility therapy does not increase the risk of ovarian cancer in infertile patients who have an increased baseline risk as a result of their infertility .
However, it was reported at the Society of Gynecological Oncologists Annual Meeting that the long-term risk for invasive ovarian cancer among women receiving treatment for IVF compared with subfertile women not treated (relative risk 1.51) and for borderline tumors was increased 4.40).Ovarian stimulation for in vitro fertilization (IVF) may increase the risk of ovarian malignancies, particularly borderline tumors of the ovary, according to findings from a 15-year follow-up of a large Dutch cohort study .
9. Pregnancy and its effect on different cancers
The studies support a protective relationship between parity and the incidence of ovarian cancer [57-59]. Nulliparity increases the baseline risk twofold. Infertility appears to increase the risk in those patients who do not subsequently conceive [60-62].
Also in breast cancer nulliparity is associated with increased risk and parity reduces risk, although a Swedish  and Norwegian  study provided evidence that the risk of breast cancer is transiently increased after pregnancy followed by a subsequent decrease in risk; also early menarche and late age at first pregnancy are associated with increased risk . Parity (high progesterone dose in pregnancy) is a protective while nulliparity and anovulatory cycles are the risk factor for endometrial cancer.
Improved cancer, which is associated with increased cure rates and long-term survival, coupled with advances in fertility treatment, means that it is imperative that fertility preservation is considered as part of the care offered to these patients. This can only be approached within a multidisciplinary setting. There are obvious challenges that remain to be resolved, especially in the area of fertility preservation in prepubertal patients. These include ethical issues such as valid consent and research in the field of tissue retrieval, cryopreservation and transplantation.
NHS National Institute for Clinical Excellence, Clinical Guideline, 11th 2004.
British Fertility Society, "A Strategy for Fertility Services for Survivors of Childhood Cancer," Human Fertility, Vol. 6, no. 2, pp. A1-A40, 2003. View at Google Scholar
Y. Sonoda, NR Abu-Rustum, ML Gemignani et al., "A fertility-saving alternative to radical hysterectomy: how many patients may be eligible?" Gynecologic Oncology, vol. 95, no. 3, pp. 534-538, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
M. Plante, M.-C. Renaud, IA Hoskins, and M. Roy, "Vaginal radical trachelectomy: a valuable fertility-conserving option in the management of early-stage cervical cancer. A series of 50 pregnancies and review of the literature, "Gynecologic Oncology, vol. 98, no. 1, pp. 3-10, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
M. Brydoy, SD Fossa, O. Klepp et al., "Paternity Following Treatment for Testicular Cancer," Journal of the National Cancer Institute, vol. 97, no. 21, pp. 1580-1588, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
RA Huddart, A. Norman, C. Moynihan et al., & Quot; Fertility, gonadal and sexual function in survivors of testicular cancer, & quot; British Journal of Cancer, Vol. 2, pp. 200-207, 2005. View at Publisher · View at PubMed · View at Scopus
S. Howell and S. Shalet, "Gonadal damage from chemotherapy and radiotherapy," Endocrinology and Metabolism Clinics of North America , vol. 27, no. 4, pp. 927-943, 1998. View at Scholar
RL Schilsky, BJ Lewis, RJ Sherins and RC Young, "Gonadal dysfunction in patients receiving chemotherapy for cancer," Annals of Internal Medicine, vol. , no. 1, pp. 109-114, 1980. View at Google Scholar · View at Scopus
SA Rivkees and JD Crawford, "The relationship of gonadal activity and chemotherapy-induced gonadal damage," Journal of the American Medical Association, vol 259, no. 14, pp. 2123-2125, 1988. View at Google Scholar · View at Scopus
HP Roeser, AE Stocks, and AJ Smith, "Testicular damage due to cytotoxic drugs and recovery after cessation of therapy", Australian and New Zealand Journal of Medicine , vol. 8, no. 3, pp. 250-254, 1978. View at Google Scholar · View at Scopus
GL Warne, KF Fairley, JB Hobbs, and FIR Martin, & quot; Cyclophosphamide induced ovarian failure, & quot; The New England Journal of Medicine, . 22, pp. 1159-1162, 1973. View at Google Scholar · View at Scopus
SJ Richardson, V. Senikas, and JF Nelson, "Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion," Journal of Clinical Endocrinology and Metabolism, Vol. 6, pp. 1231-1237, 1987. View at Google Scholar · View at Scopus
G. J. Budgell, RA Cowan, and AR Hounsell, "Prediction of Scattered Dose to Testicles in Abdominopelvic Radiotherapy," Clinical Oncology, Vol. 13, no. 2, pp. 120-125, 2001. View at Google Scholar · View at Scopus
RM Hermann, H. Henkel, H. Christiansen et al., & Quot; Testicular Dose and Hormonal Changes After Radiotherapy of Rectal Cancer, & quot; Radiotherapy and Oncology, vol. 75, no. 1, pp. 83-88, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
WHB Wallace, AB Thomson, F. Saran, and TW Kelsey, "Predicting age of ovarian failure after radiation to a field that includes the ovaries," International Journal of Radiation Oncology Biology Physics, vol. 3, pp. 738-744, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
H. OD Critchley, WHB Wallace, SM Shalet, H. Mamtora, J. Higginson, and DC Anderson, Abdominal irradiation in childhood; the potential for pregnancy, "British Journal of Obstetrics and Gynecology, vol. 99, no. 5, pp. 392-394, 1992. View at Google Scholar · View at Scopus
H. O. Critchley and WH Wallace, "Impact of cancer treatment on uterine function," Journal of the National Cancer Institute Monographs, no. 34, pp. 64-68, 2005. View at Google Scholar · View at Scopus
EC Larsen, K. Schmiegelow, C. Rechnitzer, A. Loft, J. Müller, and AN Andersen, "Radiotherapy at a young age reduces uterine volume of childhood cancer survivors," Acta Obstetricia et Gynecologica Scandinavica, vol 83, no. 1, pp. 96-102, 2004. View at Publisher · View at Google Scholar · View at Scopus
L.-M. Liao, J. Doyle, NS Crouch, and SM Creighton, "Dilation as treatment for vaginal agenesis and hypoplasia: a pilot exploration of benefits and barriers as perceived by patients", Journal of Obstetrics and Gynecology, vol. 2, pp. 144-148, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
N. Aass, SD Fossa, L. Theodorsen, and N. Norman, "Prediction of long-term gonadal toxicity after standard treatment for testicular cancer," European Journal of Cancer, vol. 27, no. 9, pp. 1087-1091, 1991. View at Publisher · View at Scopus
PM Petersen, A. Giwercman, G. Daugaard et al., Effect of graded testicular doses of radiotherapy in patients treated for carcinoma- in-situ in the testis, "Journal of Clinical Oncology, vol. 20, no. 6, pp. 1537-1543, 2002. View at Publisher · View at Google Scholar · View at Scopus
P. Albers, W. Albrecht, F. Algaba et al., Guidelines on Testicular Cancer, European Urology, vol. 48 , no. 6, pp. 885-894, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
L. Gandini, P. Sgrò, F. Lombardo et al., "Effect of Chemo- or Radiotherapy on Sperm Parameters of Testicular Cancer Patients," Human Reproduction, Vol. 21, no. 11, pp. 2882-2889, 2006. View at Publisher · View at PubMed · View at Scopus
PM Petersen, G. Daugaard, M. Rörth et al., "Endocrine function in patients treated for in situ carcinoma in the testis with irradiation, Acta Pathologica, Microbiologica et Immunologica Scandinavica, vol. 111, no. 1, pp. 93-99, 2003. View at Publisher · View at Google Scholar · View at Scopus
SR Basavaraju and CE Easterly, "Pathophysiological effects of radiation on atherosclerosis development and progression, and the incidence of cardiovascular complications," Medical Physics, vol. 29, no. 10, pp. 2391-2403, 2002. View at Publisher View at Scopus
K. Ataya, LV Rao, E. Lawrence, and R. Kimmel, Luteinizing hormone-releasing hormone agonist inhibits cyclophosphamide-induced ovarian follicular depletion in rhesus monkeys, & quot; Biology of Reproduction, Vol. 52, no. 2, pp. 365-372, 1995. View at Publisher · View at Google Scholar · View at Scopus
F. Recchia, G. Sica, S. De Filippis, G. Saggio, M. Rosselli, and S. Rea, "Goserelin as an ovarian protection in the adjuvant treatment of premenopausal breast cancer: a Phase II pilot study," Anti-Cancer Drugs, Vol. 13, no. 4, pp. 417-424, 2002. View at Publisher · View at Google Scholar · View at Scopus
A. Urruticoechea, M. Arnedos, G. Walsh, M. Dowsett, and IE Smith, "Ovarian protection with goserelin during adjuvant chemotherapy for pre-menopausal women with early breast cancer (EBC), & quot; Breast Cancer Research and Treatment, vol. 110, no. 3, pp. 411-416, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
K.-G. Huang, C.-L. Lee, C.-S. Tsai, C.-M. Han, and L.-L. Hwang, "A new approach for laparoscopic ovarian transposition before pelvic irradiation," Gynecologic Oncology, vol. 105, no. 1, pp. 234-237, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
FM Howard, "Laparoscopic lateral ovarian transposition before radiation treatment of Hodgkin's disease," Journal of the American Association of Gynecologic Laparoscopists , vol. 4, no. 5, pp. 601-604, 1997.
LL Veeck, R. Bodine, RN Clarke et al., "High pregnancy rates can be achieved after freezing and thawing human blastocysts," Fertility and Sterility, vol. 82, no. 5, pp. 1418-1427, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
TS Kosasa, PI McNamee, C. Morton et al., "Pregnancy rates after transfer of cryopreserved blastocysts cultured in a sequential media," American Journal of Obstetrics and Gynecology, vol. 192, no. 6, pp. 2035-2040, 2005. View at publisher · View at Google Scholar · View at PubMed · View at Scopus
K. Oktay, E. Buyuk, N. Libertella, M. Akar, and Z. Rosenwaks, "Fertility preservation in breast cancer patients: a prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation, "Journal of Clinical Oncology, vol. 23, no. 19, pp. 4347-4353, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
K. Oktay, AP Cil, and H. Bang, "Efficacy of oocyte cryopreservation: a meta-analysis," Fertility and Sterility, vol. 86, no. 1, pp. 70-80, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
GB La Sala, A. Nicoli, MT Villani, M. Pescarini, A. Gallinelli, and I. Blickstein, "Outcome of 518 salvage oocyte-cryopreservation cycles performed as a routine procedure in an in vitro fertilization program," Fertility and Sterility, vol. 86, no. 5, pp. 1423-1427, 2006. View at Publisher · View at PubMed · View at Scopus
K. Oktay and G. Karlikaya, "Ovarian function after transplantation of frozen, banked autologous ovarian tissue," The New England Journal of Medicine, vol. 342, no. 25, p. 1919, 2000. View at Publisher · View at Google Scholar · View at Scopus
K. Oktay and E. Buyuk, "Ovarian transplantation in humans: Indications, techniques and risk of reseeding cancer", European Journal of Obstetrics, Gynecology and Reproductive Biology, vol. 113, supplement 1, pp. S45-S47, 2004. View at publisher · View at Google Scholar · View at PubMed · View at Scopus
P. J. Donnez, MM Dolmans, D. Demylle et al., & quot; Livebirth after orthotopic transplantation of cryopreserved ovarian tissue & quot ;, The Lancet, Vol. 364, no. 9443, pp. 1405-1410, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
D. Meirow, J. Levron, T. Eldar-Geva et al., "Pregnancy after transplantation of cryopreserved ovarian tissue in a patient with ovarian failure after chemotherapy", The New England Journal of Medicine, Vol. 353, no. 3, pp. 318-321, 2005. View at Publishers View at PubMed View at Scopus
SJ Silber, KM Lenahan, DJ Levine et al., "Ovarian transplantation between monozygotic twins discordant for premature ovarian failure, "The New England Journal of Medicine, vol. 353, no. 1, pp. 58-63, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
M. Sonmezer, MI Shamonki, and K. Oktay, "Ovarian tissue cryopreservation: benefits and risks," Cell and Tissue Research, vol. 322, no. 1, pp. 125-132, 2005. View at publisher · View at Google Scholar · View at PubMed · View at Scopus
SJ Lee, LR Schover, AH Partridge et al., & Quot; American Society of Clinical Oncology recommendations on fertility preservation in cancer patients, "Journal of Clinical Oncology, vol. 24, no. 18, pp. 2917-2931, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
L. Robertson, JL Bailey, and MM Buhr, & quot; Effects of cold shock and phospholipase A2 on intact sperm and sperm head plasma membranes, & quot; Molecular Reproduction and Development, Vol. 2, pp. 143-149, 1990. View at Publisher · View at PubMed · View at Scopus
JF Griveau and D. Le Lannou, "Reactive oxygen species and human spermatozoa: physiology and pathology," International Journal of Andrology, vol. 20, no. 2, pp. 61-69, 1997. View at Google Scholar
View at Google Scholar View at Google Scholar
AB Thomson, HOD Critchley, CJH Kelnar, and WHB Wallace, "Late reproductive sequelae following treatment of childhood cancer and options for fertility preservation," Best Practice and Research, Clinical Endocrinology and Metabolism, Vol. 2, pp. 311-334, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
I. Aslam, S. Fishel, H. Moore, K. Dowell, and S. Thornton, "Fertility preservation of boys undergoing anti-cancer therapy: a review of the existing situation and prospects for the future, "Human Reproduction, vol. 15, no. 10, pp. 2154-2159, 2000. View at Google Scholar · View at Scopus
B. Rosenlund, P. Sjoblom, M. Tornblom, C. Hultling, and T. Hillensjo, "In-vitro fertilization and intracytoplasmic sperm injection in the treatment of infertility after testicular cancer," Human Reproduction, Vol. 13, no. 2, pp. 414-418, 1998. View at Scholar, J., Schurzer,
K., Fiedler, IV Hertwig et al., & Quot; Sperm retrieval procedures and intracytoplasmatic spermatozoa injection with epididymal and testicular sperm & quot ;, Urologia Internationalis, vol. 70, no. 2, pp. 119-123, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
AW Glaser, L. Phelan, M. Crawshaw, S. Jagdev, and J. Hale, "Fertility preservation in adolescent males with cancer in the United Kingdom: a survey of practice," Archives of Disease in Childhood, vol. . 8, pp. 736-737, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
S. Elliston, "If you know what is good for you: refusal of consent to medical treatment by children," in Contemporary Issues in Law, Medicine and Ethics, SAM McLean, Ed., Dartmouth Publications, Aldershot, UK, 1996. View at Google Scholar
S. McLean, "Consent and the Law: Review of the Current Provisions in the Human Fertilization and Embryology Act 1990 for the UK Health Ministers. Consultation document and questionnaire, "Human Reproduction Update, Vol. 3, no. 6, pp. 593-621, 1997. View at Publisher · View at Google Scholar · View at Scopus
J. M. Tanner, Foetus in Man: Physical Growth from Conception to Maturity, Castlemead, London, UK, 2nd edition, 1989.
H. Klip , CW Burger, P. Kenemans, and FE van Leeuwen, & quot; Cancer Risk Associated with Subfertility and Ovulation Induction: Review, & quot; Cancer Causes and Control, Vol 11, no. 4, pp. 319-344, 2000. View at Publisher · View at Google Scholar · View at Scopus
S. Kashyap and OK Davis, "Ovarian cancer and fertility medications: a critical appraisal," Seminars in Reproductive Medicine, vol. 21, no. 1, pp. 65-71, 2003. View at Google Scholar · View at Scopus
RH Carlson, & quot; IVF ovarian stimulation increases the risk of borderline ovarian tumors in 15-year follow-up, & quot; Oncology Times, Vol. in the US Scholar
R. P. Marrs and SC Hartz, Comments on the Possible Association between Ovulation Inducing Agents and Ovarian Cancer, The American Fertility Society, Birmingham, UK, 1993.
AS Whittemore, ML Wu, RS Paffenbarger Jr. et al., "Epithelial Ovarian cancer and the ability to conceive, "Cancer Research, vol. 49, no. 14, pp. 4047-4052, 1989. View at Google Scholar · View at Scopus
Dj Joly, AM Lilienfeld, EL Diamond, and IDJ Bross, "An Epidemiological Study of the Relationship of Reproductive Experience to Ovary Cancer," American Journal of Epidemiology, Vol. 99, no. 3, pp. 190-209, 1974. View at Google Scholar · View at Scopus
PC Nasca, P. Greenwald, and S. Chorost, An epidemiological case-control study of ovarian cancer and reproductive factors, American Journal of Epidemiology, vol. 119, no. 5, pp. 705-713, 1984. View at Google Scholar. View at Scopus
M. L. Wu, AS Whittemore, RS Paffenbarger Jr. et al., & Quot; Personal and environmental characteristics related to epithelial ovarian cancer. I. Reproductive and Menstrual Events and Oral Contraceptive Use, "American Journal of Epidemiology, vol. 128, no. 6, pp. 1216-1227, 1988. View at Google Scholar · View at Scopus
BJ Mosgaard, Ø. Lidegaard, SK Kjaer, G. Schou, and AN Andersen, "Ovarian stimulation and borderline ovarian tumors: a case-control study," Fertility and Sterility, vol 70, no. 6, pp. 1049-1055, 1998. View at Publisher · View at Google Scholar · View at Scopus
DA Leon, LM Carpenter, MJM Broeders, J. Gunnarskog, and MFG Murphy, "Breast cancer in Swedish women Before age 50: Evidence of a double effect of completed pregnancy, & quot; Cancer Causes and Control, Vol. 6, no. 4, pp. 283-291, 1995. View at Publisher · View at Google Scholar · View at Scopus
G. Albrektsen, I. Heuch, and G. Kvale, "The short-term and long-term effect of a pregnancy on breast cancer risk: a prospective study of 802 457 parous Norwegian women", British Journal of Cancer, vol 72 , no. 2, pp. 480-484, 1995. View at Google Scholar · View at Scopus
RCOG Green top Guideline no.