Placenta
Volume 29, Supplement 2 , Pages 152-159, October 2008

Pregnancy and Assisted Reproduction Techniques in Men and Women after Cancer Treatment

  • T. Gurgan

      Affiliations

    • Department of Obstetrics and Gynecology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
    • ,
  • C. Salman

      Affiliations

    • Department of Obstetrics and Gynecology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
    • ,
  • A. Demirol

      Affiliations

    • Infertility and IVF Center, CLINIC Women Health, Çankaya caddesi, 20/3, Çankaya, 06680 Ankara, Turkey
    • Corresponding Author InformationCorresponding author. Tel.: +90 312 442 7404; fax: +90 312 442 7407.

Accepted 17 July 2008.

Article Outline

Abstract 

There are many male and female patients of young age diagnosed with some form of invasive cancer. With current treatment regimens, including aggressive chemotherapy, radiotherapy, bone marrow transplantation, and surgery, the cure rate for some malignancies now is very high. These treatments, however, can lead to gonadal failure and permanent infertility. Fertility preservation is a significant concern for such men and women faced with cancer treatment. Several alternatives have been attempted in an effort to preserve fertility in young women undergoing cancer treatment. Although ovarian tissue cryopreservation has recently been the focus of intense investigation, cryopreservation of embryos and mature oocytes has several advantages over ovarian tissue preservation. Also there are some strategies for minimizing female gonadal toxicity caused by cancer therapy including use of radiation shields, transposition of the ovaries out of the irradiation field, and suppression of ovaries by administration of gonadotropin releasing hormone agonists during adjuvant chemotherapy. In addition, fertility-saving surgical approaches are used in selected women with gynecologic cancers instead of more radical surgical procedures. Similarly, fertility preservation options such as conservative surgical approaches including partial orchiectomy with or without cryopreservation in testicular cancer patients and at least sperm cryopreservation in other male cancer patients should be offered before initiating therapy. Use of embryonic stem cells as a source of gametes also emerges as a hope in male and female cancer survivors.

Keywords: Cancer treatment, Pregnancy, Assisted reproductive technology

 

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1. Introduction 

Today, 1 in 700 young adults is a cancer survivor and it is estimated that 1 in every 250 adults will be a childhood cancer survivor in 2010 [1], [2]. In United States, more than 20,000 children and young people of reproductive age are exposed to of chemotherapy and/or radiotherapy every year [3]. Also, delaying childbearing for social or financial reasons leads to more women suffering from fertility threats due to early-stage cancers being discovered [4].

Advances gradually obtained in cancer management performed using surgery, radiotherapy and chemotherapy have resulted in significantly improved cure rates especially in young patients with certain malignancies. Thus, the patients may hope to achieve relatively higher cure rates associated with long-term survival [5]. Nevertheless, currently used cancer therapies are often detrimental to fertility. The ovaries are highly susceptible to such therapies and may be damaged significantly after chemotherapy and/or radiotherapy. The ovaries contain a limited number of follicles which decrease with aging. The number of follicles is 200,000 at puberty and the progressive decrease leads to only 400 follicles at the time of menopause. The use of cancer therapies, namely chemotherapy and radiotherapy, results in reduced follicle stores and ovarian atrophy [5], [6]. Therefore, the patient may suffer from premature menopause and infertility which may impact her quality of life and self-esteem significantly [6].

The most common adverse effect of cancer therapies is premature menopause. Even if the patient experiences normal menstrual cycles after cancer therapy, premature menopause will be more likely due to the reduced follicular reserve [5].

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2. The effects of chemotherapy on ovarian functions 

The ovarian damage and failure are common long-term side effects of chemotherapy [6]. After chemotherapy, the rate of amenorrhea varies from 40% to 68%. Chemotherapy damages the growth and maturation of ovarian follicles. Fibrosis and follicular destruction are the first histologically detected lesions within the ovaries [5]. Progressive depletion of primordial follicles is noted on histology and this explains the risk of premature ovarian failure occurring years after exposure [7]. In animal models, the doses of drug enough to destroy half of primordial follicles did not affect reproductive performance after treatment. Therefore, regular menses observed after the cessation of chemotherapy does not imply that the ovaries are not damaged. The number of primordial follicles reflects the ovarian damage caused by chemotherapy more accurately. Also, the ovarian follicles are more chemo-sensitive during the proliferative phase of the menstrual cycle [5].

The adverse effects of chemotherapy on ovarian functions depend on the type of agents used, the dose of the drugs and the age of the patient [5].

2.1. The type of agents 

There are five main groups of chemotherapeutic agents including alkylating agents, platinum derivatives, antibiotics, antimetabolites and plant alkaloids [6]. Most of these agents inhibit the replication by acting on the cells during the DNA synthesis or mitosis [5]. They are usually used in combination in an attempt to increase the therapeutic activity. However, the combinations also increase the adverse effects [6]. The risk of ovarian failure is much more likely with alkylating agents such as cyclophosphamide and procarbazine compared to other drugs. The alkylating agents were shown to impose the highest risk of ovarian failure with an odds ratio of 3.98 [7]. However, other commonly used agents including platinum compounds (cisplatinum and carboplatinum), taxanes (paclitaxel and docetaxel) and anthracyclines (daunorubicin, doxorubicin, and epirubicin) are much less toxic to ovaries and risk of ovarian failure is low [5].

In a study which was performed to quantify the impact of chemotherapy on primordial follicle reserve and stromal function in the human ovary, it was found that patients treated with alkylating agents had significantly lower primordial follicle counts compared with those who received non-alkylating agents (mean primordial follicle counts were 2.9±1.1 vs. 7.9±1.6, p<0.05) and with those who did not receive any chemotherapy (mean primordial follicle counts were 2.9±1.1 vs. 9.6±2.2, p<0.05) [8]. The rate of chemotherapy-related amenorrhea may be as high as 68% in breast cancer patients treated with cyclophosphamide, methotrexate, and fluorouracil (CMF) [9]. In Hodgkin's disease, the aggressive combined chemotherapy regimens including cyclophosphamide and/or procarbazine results in ovarian failure in 38–57% of patients [10].

In patients with germ cell tumors treated with bleomycin, etoposide and cisplatinum (BEP), the rate of definitive amenorrhea was only 1% [11].

2.2. The dose of drugs 

The higher doses or longer therapy durations are associated with a higher risk of ovarian failure. The amenorrhea rates were reported to be significantly higher in patients treated with combined chemotherapy for 36weeks compared with patients treated for 12weeks for breast cancer (83% vs. 55%) [12]. A similar effect was observed in patients receiving cyclophosphamide for systemic lupus erythematosus. The rate of sustained amenorrhea was 12% in patients who received 7 doses while it was 39% in patients who received 15 doses or more [13].

2.3. The age of the patients 

Premenarchal girls fail to start menstruation during chemotherapy, but menarche generally appears shortly after the cessation of the treatment [14]. Most adolescent girls develop amenorrhea during chemotherapy, but primary ovarian failure is rarely seen unless they receive a combination of radio-chemotherapy. On the other hand, anovulation or luteal phase abnormalities may be expected because of the central effects of stress and anxiety associated with cancer [15]. In patients given only melphelan, amenorrhea was seen in 73% of the patients over 40years of age while only 22% of patients under 39years of age developed amenorrhea [16]. Also, melphalan and 5-fluorouracil was reported to be associated with amenorrhea in 64% of patients over 34years of age and in 21% of the patients under 34years of age [14], [16]. The rates of premature ovarian failure were 13%, 50%, and 100% in patients aged under 20years, 20–30years, and over 30years, respectively [17]. As a result, chemotherapeutics may be well tolerated in younger patients probably due to their larger follicle stores while older women have a much higher rate of complete ovarian failure and permanent infertility.

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3. The effects of radiotherapy on ovarian functions 

Ionizing radiation has adverse effects on ovarian functions. According to animal models, the number of degenerated primordial follicles increases after irradiation. The ratio of normal to atretic primordial follicles and the ratio of normal to atretic primary follicles decreases with time after irradiation. Therefore, it is concluded that the ionizing radiation acutely induces the degeneration of primordial and primary follicles. The pattern of degeneration may be apoptosis of one or more granulosa cells with a relatively intact oocyte, apoptosis of an oocyte with intact follicle cell, or apoptotic degenerations of both kinds of cells [18]. Ovarian follicles are more radiosensitive during the proliferative phase of the menstrual cycle [5].

The degree and persistence of the adverse effects of radiation depend on the age of patient, the dose of radiation and the irradiation field [6].

3.1. The age of patients 

Younger patients are more likely to preserve residual ovarian function because of the greater primordial follicle reserve [5].

The sterilizing dose of radiotherapy at which premature ovarian failure occurs after treatment in 97.5% of patients decreases with increasing age at treatment. This dose was reported to be 20.3Gy at birth, 18.4Gy at 10years, 16.5Gy at 20years, and 14.3Gy at 30years [19].

3.2. The dose of radiation 

When the radiation dose is lower, the number of intact follicles and the possibility of biological repair of the damaged follicles will be higher [5]. The estimated radiation dose enough to damage half of human ovarian follicles was reported to be lower than 2Gy [19]. The mean tolerance dose for sterilization was reported to be between 5 and 10Gy [20].

Also, a single dose of radiotherapy is more toxic than fractionated doses. Total body irradiation of ≤10Gy given as a single dose before puberty caused ovarian failure in 55–80% of patients. However, total body irradiation with fractionated doses was associated with a lower rate of ovarian failure even in higher total doses [5], [21].

3.3. The irradiation field 

The location of the ovaries in relation to the radiotherapy fields is a significant risk factor for subsequent ovarian failure. Total body, craniospinal axis, whole abdominal, or pelvic irradiation expose the ovaries to irradiation and may be associated with premature ovarian failure [19].

Among long-term female survivors of childhood acute lymphoblastic leukemia treated with radiotherapy, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and pubertal development was assessed. Overall, 36% had elevated levels of FSH and/or LH. Craniospinal plus abdominal radiotherapy and abnormal FSH/LH levels were shown to be significantly associated with lack of pubertal development and delayed onset of menses [22]. In another study, it was reported that ovarian failure was found in 68% of patients who had both ovaries within abdominal radiotherapy fields, in 14% of patients whose ovaries were at the edge of the radiotherapy field, and in none of the patients with one or both ovaries outside of the radiotherapy treatment field. The risk of ovarian failure was 19.7 times higher in patients with both ovaries in the field compared with other irradiated patients [23].

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4. The effect of cancer and cancer treatment on male fertility 

Some patients may suffer form impaired fertility even before commencing cancer therapy because of anatomical changes, hormonal imbalance or gonadal damage which may affect sperm numbers, motility, morphology or DNA integrity [24]. Furthermore, cancer may affect fertility adversely due to the catabolic state, malnutrition, increased stress hormones, and decreased gonadotropins [25].

4.1. Testicular cancer 

Although testicular cancer is a rare disease accounting for 1–1.5% of all male cancers, it is the most common cancer affecting men in their 20s and 30s [26]. Excellent response to radiation and chemotherapy results in over 90% of survival and concerns about fertility are significant for both patients and clinicians [27].

Testicular cancer is associated with impaired spermatogenic function and some patients already have impaired Leydig cell function before orchiectomy. In patients with unilateral testicular cancer, a high prevalence of abnormalities of spermatogenesis is seen in the contralateral testis. Recovery of spermatogenesis may be late after treatment. In some patients, this may take more than 5years. Sufficient androgen production is seen in the majority of the patients but some patients also suffer from testosterone deficiency [28]. Currently, the exact mechanism responsible for the decreased sperm quality is not known. A pre-existing germ cell defect may be responsible for both cancer and defective spermatogenesis. Also, paracrine action of the substances originating from the tumor itself may lead to a local effect. Hormonal imbalance caused by cancer may alter the process of spermatogenesis. Fertility preservation options such as partial orchiectomy with or without cryopreservation or at least sperm cryopreservation should be offered for all patients with testicular cancer before initiating therapy [28].

4.2. Effects of radiotherapy 

Radiotherapy affects male gonads of all ages depending on the dose, therapy field and fractionation. Spermatogenesis is highly susceptible to radiation and even doses exceeding 1.2Gy is harmful, while doses more than 4Gy may damage spermatogenesis permanently. However, compared with germinal epithelium, Leydig cells are more resistant and they preserve the functions up to 20Gy before puberty and 30Gy after puberty. Therefore, although spermatogenesis is severely impaired, puberty is expected with normal testosterone levels [29].

Sperm counts reach to lowest levels 4–6months after the completion of treatment and pretreatment levels are regained in 10–24months. Men who receive higher doses need longer periods to regain pretreatment sperm counts. Permanent gonadal failure is seen in nearly 80% of patients after total body irradiation for stem cell transplantation [30]. The surviving stem cells are responsible for the recovery of spermatogenesis. Complete recovery (return to pre-irradiation levels) is obtained in 9–18months after a dose of 1Gy or less, in 30months after 2–3Gy and in 5years or more after 4Gy and above [31]. It was shown that in men who regain spermatogenesis after radiotherapy the frequencies of both numerical and structural abnormalities were significantly increased. Also, radiotherapy was shown to increase the chromosomal abnormalities in sperms. The frequency of sperm chromosomal abnormalities is related to testicular radiation dose [32].

4.3. Effects of chemotherapy 

Chemotherapy may cause gonadal damage and impair spermatogenesis since rapidly dividing cells are mostly affected. Type and the dose of the agent and the age of the patient are the factors determining the extent of this damage [33]. Chemotherapy seems to kill both differentiating spermatogonia and stem cells and deplete the proliferating germ cell pool. In a study evaluating testicular functions in survivors of childhood cancer, approximately 1/3 of individuals were found to be azoospermic and approximately 1/5 were oligozoospermic. Sperm and inhibin B concentrations were significantly lower and FSH concentrations were significantly higher in the non-azoospermic group compared with controls. Only 1/3 of cancer survivors had normal semen quality. However, the produced sperms seem to carry as much healthy DNA as those produced by a control group. So assisted conception can be considered as safe for these men [34].

In the prepubertal testis, there is a steady turnover of early germ cells that undergo spontaneous degeneration before the haploid stage is reached. This is probably the reason why the prepubertal testis is very vulnerable to chemotherapy in contrast to prepubertal ovary [4].

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5. Minimizing gonadal toxicity caused by cancer therapy and strategies for preserving fertility in female patients 

5.1. Ovarian transposition (oophoropexy) 

Transposition of the ovaries out of the irradiation field is most commonly indicated in patients with Hodgkin's disease, cervical and vaginal cancer, and sarcomas of the pelvic region [4]. This procedure reduces the ovarian dose to approximately 5–10%. Ovarian transposition may be performed by laparotomy during the surgical treatment for malignancy. The procedure may also be achieved laparoscopically in most of the patients as a safe and effective option for preserving ovarian functions. The laparoscopic approach has the advantages of fewer adhesions and early postoperative initiation of radiotherapy [4], [35]. Ovarian failure might result if the ovaries are not removed far enough, or if they migrate back to their original position. Although the transposition procedure reduces the damage caused by radiotherapy, it cannot protect against damage caused by systemic chemotherapy. Main complications of the procedure include the injury to the vascular supply of the ovaries, infarction of the fallopian tube, and ovarian cyst formation. Also, risk of early menopause is increased in patients subjected to ovarian transposition [7].

5.2. Suppression of ovaries 

Since dividing cells are more sensitive to adverse effects of chemotherapy, inhibition of the pituitary–gonadal axis by using sex steroids or GnRH agonists may render the ovaries less susceptible. This hypothesis is also supported by the fact that compared with prepubertal girls, the ovaries of adult women are much more affected by chemotherapy. In female patients with Hodgkin lymphoma, it was also shown that monthly injection of GnRH agonist administered before starting chemotherapy until its conclusion up to a maximum of 6months significantly reduced ovarian damage caused by chemotherapy. Ninety-seven percent of women resumed ovulation and regular menses in a study group compared with 63% in a control group [36]. In another study, among women with Hodgkin lymphoma, administration of triptorelin, a GnRH analogue, during chemotherapy was associated with significantly fewer premature ovarian failure cases 6 and 12months after the end of chemotherapy [37].

5.3. Embryo cryopreservation 

Embryo cryopreservation is the only established method of fertility preservation according to the Ethics Committee of the American Society for Reproductive Medicine [38]. However, the patient should be pubertal, be married or have a partner, and undergo a cycle of ovarian stimulation for this option to be put into practice. It would not be possible in prepubertal patients or in patients requiring initiation of chemotherapy immediately. Also, it should be avoided if ovarian stimulation is contraindicated according to the type of cancer (i.e. hormone sensitive tumors such as breast cancer) [39].

5.4. Oocyte cryopreservation 

Oocyte cryopreservation could not be done reliably to date. However, it is an alternative option for patients of reproductive age who are single or without a partner. The oocytes are cryopreserved either as mature or as immature oocytes [39]. Mature oocyte cryopreservation is reasonable for women without a partner if they have enough time for ovarian stimulation before initiating cancer therapy. However, this technique is not effective and the reported mean pregnancy rate per thawed oocyte is lower than 2%, since oocyte freezing is accompanied by various types of cell injury [39].

Freezing immature oocytes followed by in vitro maturation did not seem to be successful in the beginning. However, in the course of time the concentration and type of cryoprotectant and the exposure time were perceived to have important effects on the oocytes’ competence and development after vitrification. As a result, accelerated oocyte maturation was achieved [40]. Finally, Chian et al. reported the first healthy live birth from immature oocytes retrieved in a natural menstrual cycle, followed by in vitro maturation and cryopreservation of the oocytes by vitrification [41].

Also, before the initiation of cancer therapy, the oocytes may be retrieved from the excised ovarian tissue. In vitro maturation and cryopreservation by vitrification may be performed afterwards. This fertility preservation technique could be combined with ovarian tissue cryobanking [42].

5.5. Ovarian tissue cryopreservation 

Cryopreservation of ovarian tissue is the only option available for prepubertal girls and for women who cannot delay the start of chemotherapy. Theoretically ovarian tissue can be frozen as fragments of ovarian cortex, as entire ovary with its vascular pedicle, or as isolated follicles [39]. Human ovarian cryopreservation and transplantation procedures have so far been almost exclusively limited to avascular cortical fragments, both in experimental and in clinical studies and, for now, this is the only procedure that has yielded live births in humans after autologous transplantation [43], [44]. Here, the cortical ovarian tissue is reimplanted into the pelvis (orthotopic site) or the forearm or the abdominal wall (heterotopic site) once the treatment is completed and the patient is disease-free [39].

Although ovarian tissue banking has been successfully accomplished only at a few centers to date throughout the world, it certainly has great potential. In fact, some authors suggest that cryopreservation of ovarian tissue for later use in autotransplantation should be offered to all young women diagnosed with cancer [43].

5.6. Radiation shields 

Whenever possible, shielding the gonads may effectively reduce the adverse effects of radiotherapy on gonadal functions. This option may not be applicable if the ovaries are in the radiation field and therefore shielding results in an unfavorable oncologic outcome.

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6. Minimizing gonadal toxicity caused by cancer therapy and strategies for preserving fertility in male patients 

6.1. Sperm cryopreservation 

Semen cryobanking before cancer therapies affecting the reproductive system is a widely available and relatively inexpensive option with good results and reasonable chances of pregnancy after therapy [45]. The banking of at least three samples with an abstinence period of at least 48h between the samples is recommended. Therefore, the process is completed in 5–8days. Additional samples and longer abstinence periods such as 72–96h to achieve higher total sperm counts may also be considered [46].

Although cryopreservation and thawing processes are associated with a variable loss of sperm viability and motility, poor semen quality has not been shown to affect fertilization or pregnancy rates after cryopreservation and IVF-ICSI as long as live sperm can be recovered [47]. In patients in whom chemotherapy or radiation treatment has already been initiated, collection and cryopreservation of semen are still feasible during treatment at least until azoospermia ensues. Normal reproductive outcomes may be expected with thawed semen collected during therapy [48].

6.2. Testicular tissue cryopreservation 

Although sperm cryopreservation is widely used as an effective fertility preservation option, it is only applicable for post-pubertal males who can provide functional germ cells. Prepubertal patients cannot benefit from sperm cryopreservation. Also, the cryopreserved samples are a finite resource and do not offer the possibility of restoring natural fertility. The only technology that has the potential to restore natural fertility from a patient's own germ cells is testicular tissue cryopreservation, which may be used both for prepubertal and adult males with cancer [49]. The cryopreserved testicular tissue may be thawed and reimplanted after the treatment is finished [50]. The cryopreserved testicular tissue may be reimplanted into the testis or grafted to an ectopic site (e.g., under the skin) of a cancer survivor. Both approaches have been tested in animal models and give promise for the development of clinical applications [49]. In a recently published study which aimed to find optimal methods for cryopreservation of testicular tissue from prepubertal boys, it was shown that slow programmed freezing with dimethyl sulfoxide as a cryoprotectant was efficient in maintaining the spermatogonia, Sertoli cells and stromal compartment during freezing, thawing and tissue culture [51].

6.3. In vitro spermatogenesis 

In vitro maturation of germ cells and stimulating their differentiation into spermatozoa may be useful in patients who have received gonadotoxic therapy in whom the supporting Sertoli cells are unable to support spermatogenesis [4]. In vitro culture with recombinant follicle-stimulating hormone and testosterone was shown to lead to the formation of morphologically abnormal, but developmentally competent spermatids, which were used for intracytoplasmic sperm injection and resulted in pregnancies [52].

6.4. Use of embryonic stem cells in male and female cancer survivors 

A review of the literature shows that embryonic stem cells support the earliest stages of germ lineage formation in cell culture, but they do not generate functional haploid gametes and it is currently not possible to make clinical applications in infertility. Therefore, employing embryonic stem cells as a source of gametes to treat male and female infertility seems to be a distant hope due to the inefficiency of in vitro terminal gametogenesis from embryonic stem cells and the paucity of data documenting reproductive function [53]. As a result, it is also too early for the use of embryonic stem cells in male and female cancer survivors as well.

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7. Fertility after gynecologic cancers 

7.1. Cervical cancer 

Radical abdominal hysterectomy with lymphadenectomy forms the mainstay of treatment for early-stage cervical carcinoma. However, approximately 50% of patients younger than 40years of age with operable stage I cervical cancer may be candidates for fertility-saving radical trachelectomy [54]. Radical trachelectomy may be performed via the vaginal route, abdominal route or be laparoscopically assisted [55].

The general eligibility criteria for radical vaginal trachelectomy include the following: women less than 40years of age who have a strong desire to preserve fertility, no clinical evidence of impaired fertility, lesion size less than 2cm, International Federation of Gynecology and Obstetrics (FIGO) stages IA–IB1, no involvement of the upper endocervical canal, and negative regional lymph nodes [56].

In a large review of literature regarding the results and complications of pregnancies after radical trachelectomy, it was reported that 43% of patients attempted to conceive during the follow-up period and 70% of the patients attempting to conceive succeeded. A total of 161 pregnancies were reported, resulting in 49% term deliveries. In about 15% of the patients who tried to conceive, cervical stenosis was found and resulted in menstrual disorders or fertility problems. Repeated surgical dilatation resolved this problem in most cases. Complications during pregnancy involved second trimester loss in 8% and premature delivery in 20% of patients [57]. Therefore, fertility after radical trachelectomy is highly feasible. However, risks of second trimester losses and premature deliveries caused by premature rupture of membranes should be kept in mind, and pregnant patients need to be carefully followed for cervical incompetence and other risk factors for premature rupture of membranes.

The role of neoadjuvant chemotherapy to reduce the tumor burden as part of planned fertility-sparing therapy in cervical carcinoma is under investigation, and preliminary results are encouraging. A longer follow-up is needed to determine the oncologic and reproductive outcome of this approach [58].

7.2. Uterine cancer 

Endometrial cancer primarily occurs in the postmenopausal women older than 60years old. However, 5% of patients are younger than 40years of age [59,60]. The standard therapy for endometrial carcinoma includes staging laparotomy with peritoneal cytology, total abdominal hysterectomy with bilateral salpingo-oophorectomy, and retroperitoneal lymph node dissection which sacrifices childbearing potential in young patients. Successful hormone therapy for early-stage low-grade endometrial cancer in young women with a desire to preserve fertility has been reported in the literature [61].

Although ideal candidates are patients with well-differentiated disease confined only to the endometrium, the optimal criteria for selection of patients for hormonal treatment are unknown. On the other hand, a thorough evaluation and extensive representative sampling of the endometrium are important. The dose and type of progestin used, the duration of treatment and optimal follow-up methods and intervals have not yet been clearly established. A careful clinical evaluation before and after treatment is inevitable. Although the hormonal treatment is proven to be successful in selected cases, the potential risks of such an approach should be discussed in detail with the patient [61].

Response to hormonal treatment is obtained within a period of 3.5months exposed with normal pathology on follow-up endometrial samplings. Recurrences may be managed successfully with repeated progestin therapy. Combining conservative treatment with assisted reproductive technologies may result in healthy infants without an adverse effect on oncologic prognosis [62], [63], [64]. Approximately 60% of fertilization rate and 50% of healthy infant delivery rate may be obtained. Therefore, in vitro fertilization treatment of infertile women conservatively treated for well-differentiated endometrial adenocarcinoma is highly successful.

7.3. Ovarian cancer 

While the most of the ovarian cancers are detected in advanced stages and occur in postmenopausal women, nearly 15% are seen in younger women who may wish to preserve their fertility potential. Patients who are candidates for fertility preservation are those with malignant germ cell tumors, sex cord-stromal tumors, tumors of low malignant potential, and stage IA invasive epithelial ovarian cancer. Such patients may be subjected to ovarian cystectomy, unilateral salpingo-oophorectomy or unilateral salpingo-oophorectomy plus contralateral cystectomy with comprehensive surgical staging [65].

Malignant germ cell tumor of the ovary is a rare disease comprising approximately 5% of all ovarian malignancies. It principally affects girls and young women, with an average age during the teenage years. With the exception of dysgerminoma, which is bilateral in 15% of cases, they are almost always unilateral. Also, 60% are confined to the ovary. Therefore, fertility-saving surgery is possible in a large proportion of patients and the surgical management usually consists of unilateral salpingo-oophorectomy with surgical staging. Postoperatively, patients are given postoperative chemotherapy in the form of bleomycin, etoposide, and cisplatin (BEP) except for those having stage I dysgerminoma and stage IA, grade 1 immature teratoma. Surgery and postoperative chemotherapy may result in premature menopause, but at least 80% of these patients may expect to preserve reproductive function. Cure rates approach 100% for early-stage disease and 75% or more for advanced-stage disease. As a result, excellent opportunity for future childbearing is expected. Several successful pregnancies have been reported after therapy for germ cell tumors of the ovary [66].

Sex cord-stromal tumors of the ovary may affect women of all ages. The most commonly seen type is granulosa cell tumor in which the tumor is confined to one ovary in over 90% of cases [67]. Furthermore, the juvenile form is usually seen in children. Therefore, fertility preservation may be considered in a significant percentage of patients. For patients with certain risk factors, adjuvant platinum-based chemotherapy is used postoperatively. Successful subsequent pregnancies have been reported in the literature [65].

Tumors of low malignant potential or borderline ovarian tumors constitute approximately 10–15% of all epithelial ovarian malignancies [68]. Their prognosis is generally good even in the presence of widespread disease and overall 5-year survival rate is approximately 80–90% for all stages. Borderline tumors tend to affect younger women when compared with invasive tumors and nearly 25% of patients are less than 40years of age at the time of diagnosis [69]. Although the management is the same as that of malignant tumors in terms of staging and surgical treatment, a conservative surgical approach is generally considered to be acceptable in order to preserve fertility potential. A review of the literature documented that 37% of patients with borderline ovarian tumor were treated with conservative surgery. Of these 95% had stage 1 or 2 disease and 5% had stage 3 disease. The recurrence rate after conservative treatment was 16% with only five recorded disease-related deaths. The majority of women undergoing conservative surgery were 40years of age or less. In total, 254 pregnancies were achieved in 206 patients. Among patients wishing to conceive, the pregnancy rate was 48%. Overall, 22% of patients conceived. The majority of pregnancies were spontaneous. The rate of assisted reproduction was similar to the rate observed in the general population. Also, congenital malformations were not seen more than expected [70]. The decision for further surgery after completion of the family should be managed on an individual basis [70].

Invasive epithelial ovarian cancer is generally seen in postmenopausal women. The disease is detected in advanced stages in over 70% of patients and therefore the overall prognosis is poor. Nevertheless, approximately 25% of tumors are stage I and a 5-year survival rate of nearly 90% is expected in such patients. Fertility-saving surgery with comprehensive surgical staging may only be considered in selected young patients with disease confined to one ovary. After surgery, platinum-based chemotherapy should be given in the presence of high-risk factors [6]. The recurrence rates were reported to be similar to those observed in patients treated with radical surgery [71]. The estimated survival rates for patients treated conservatively for stage 1 disease was 98% at 5years and 93% at 10years. Among patients who attempted pregnancy, 71% conceived [72]. Therefore, given the excellent oncologic outcomes in appropriate cases, fertility-saving surgery should be considered as a treatment option in women with stage I epithelial ovarian cancer who desire future childbearing. On the other hand, the question of whether hysterectomy and contralateral adnexectomy should be undertaken following completion of childbearing in such patients still remains to be answered. The potential for a second primary or recurrent ovarian cancer in these patients may necessitate a completion surgery. However, the acceptable salvage rate of patients with recurrent disease and the long-term disease-free survival in patients without a completion surgery may also justify an expectant management [72].

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8. Fertility after breast cancer 

Breast cancer is the most common invasive cancer in women [73]. Earlier detection of disease and more effective treatments have led to both an improved prognosis and thus an increasing number of long-term survivors [74]. As a result, issues of long-term toxicity from oncological treatment, including premature ovarian failure and childbearing potential, are becoming more important for breast cancer survivors.

The incidence of ovarian dysfunction after therapy is related to patient age, the agents used and the total dose administered. Chemotherapy-related amenorrhea in premenopausal women with breast cancer ranges from 33% to 68%. Ovarian failure was permanent in most women older than 40years, whereas it was reversible in 40–50% of the younger ones [75]. On the other hand, in a study published by Recchia et al., use of goserelin, a luteinizing hormone-releasing hormone agonist for ovarian protection during adjuvant chemotherapy in premenopausal women with estrogen receptor-positive, high-risk, early stage breast carcinoma, long-term ovarian function was protected with improved oncologic outcome [76]. Use of goserelin before and during chemotherapy in young patients with breast cancer was shown to prevent premature menopause in the majority of patients in another study [77] Furthermore, addition of a luteinizing hormone-releasing hormone agonist to tamoxifen, chemotherapy, or both in premenopausal hormone-receptor-positive breast cancer patients may reduce the rates of recurrence and death after recurrence [78].

Since estrogen plays a major role in breast carcinogenesis, advice on pregnancy in breast cancer survivors may cause concerns about the possible adverse impacts of high serum gestational estrogen levels. Fortunately, a review of the literature failed to show that a subsequent pregnancy increases the risk of recurrence and death in breast cancer survivors and some series have even detected longer survival for patients who get pregnant after breast cancer treatment. A subsequent pregnancy appeared to improve survival in women who waited at least 24months to conceive whereas a non-significant protective effect was seen for those who waited at least 6months to become pregnant. Most of the recurrences develop within 2–3years after diagnosis, therefore breast cancer patients should postpone pregnancy for at least 3years [75].

In vitro fertilization with embryo cryopreservation is the most established method of fertility preservation in these patients, but it requires approximately 2weeks of ovarian stimulation. In breast cancer patients, the interval of 6–8weeks between surgery and chemotherapy is sufficient for ovarian stimulation [79]. However, ovulation induction may raise doubts concerning safety in these patients. Therefore, modifications in ovulation induction protocols including use of tamoxifen and aromatase inhibitors are strongly warranted to decrease peak estradiol levels [80].

Less than 8% of fertile breast cancer survivors conceive, resulting in a very low amount of data regarding the obstetric outcomes [81]. Nevertheless, the available data appear to show no increase in the incidence of prematurity, stillbirth or congenital malformations in the infants [75]. As a conclusion, pregnancy is a viable option for women treated for early-stage breast cancer and does not appear to cause detrimental effects to either the mother or her offspring [75].

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9. Conclusion 

In the past, cancer survivors tended to be most concerned about the recurrence of the disease and the side effects associated with treatment. However, as survival rates have increased in time mostly due to the effective treatment modalities and improved diagnostic methods leading to early diagnosis, patients are also concerned about quality-of-life issues such as preserving their fertility potential. Therefore, fertility preservation options should be put forward for all young patients desiring future childbearing unless such options do not adversely affect the oncological outcomes. Nevertheless, since none of the currently available methods for fertility preservation is ideal and guarantees future fertility, the patients should be encouraged to consider a combination of several methods. There is no contraindication to combine in vitro fertilization and embryo cryopreservation for a couple or unfertilized ova vitrification for the single young woman, with GnRH analogue administration and in high-risk cases also ovarian tissue cryopreservation.

However, patients are generally advised to wait 2years after treatment for any malignancy before attempting pregnancy, but the optimal interval between the cure of the disease and conception must be carefully determined by a multidisciplinary team including the oncologist and obstetrician. Gynecologic surgery and chemotherapy can have an impact not only on fertility, but also on the course of a next pregnancy since some reports documented increased risk of miscarriage and premature delivery in these patients [82]. These risks must be taken into account by the obstetrician and the pregnancy should be managed as a high-risk one.

It is also strongly recommended that the patients who regain ovarian functions after cancer therapy should not delay childbearing for too many years. However, conceptions less than 6–12months after treatment should be avoided because of the possible toxicity of treatment modalities on growing oocytes. Early fertilization after chemotherapy can result in a high rate of pregnancy failures and malformations. This should be considered during oocyte retrieval, in vitro fertilization and embryo cryopreservation in patients currently receiving chemotherapy [83].

The patient and the family should be counseled extensively. The alternatives to the traditional and standard radical procedures should be discussed in detail and the limitation of available data regarding conservative treatment options should be explained clearly. The patients should be aware that by accepting fertility-saving treatment approaches, they are assuming a small, but undefined risk for recurrence of the disease. In addition, some will need to undergo assisted reproductive technologies in order to conceive.

Finally, all children born from cancer survivors should be carefully followed up to find out whether the incidence of congenital and chromosomal abnormalities is increased.

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10. Conflict of interest 

The authors state that there is no financial support, nor is there an association with any companies.

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PII: S0143-4004(08)00212-9

doi:10.1016/j.placenta.2008.07.007

Placenta
Volume 29, Supplement 2 , Pages 152-159, October 2008

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