Fertility preservation in females with malignant disease-1: causes, clinical needs and indications/ Malignitesi olan kadinlarda dogurganligin korunmasi-1: nedenler, klinik gereksinimler ve endikasyonlar.
Cancer incidence is gradually increasing while deaths caused by malignant diseases decrease. When all female cancers are considered, despite an increase in the cancer incidence by 0.3% annually from 1987 to 1999, the death rates for all cancers combined decreased by 0.6% annually from 1992 to 1999 as a result of improvements in current treatment modalities including surgical techniques, radiation therapy, multi-agent chemotherapy, and hematopoietic stem cell transplantation (HSCT) [1, 2]. By 2010, one in every 250 persons is estimated to have survived childhood malignancies. Thus, more patients survive cancer every year but face the challenging long-term side effects, especially related to their reproductive system. The risk of ovarian failure may increase up to nine-fold in female cancer survivors receiving cyclophosphamide-based combination chemotherapy [3, 4], and ovarian failure is almost inevitable in patients undergoing preconditioning with chemoradiation before HSCT . It is also reported that an ovarian radiation dose of more than 6 Gy usually results in permanent infertility . Chemo-/radiotherapy sequelae may impair the quality of the pregnancy as well, with an increased risk of early pregnancy loss, premature labor, and low birth weight, even if the patients were not sterilized after treatments [7-9].
The introduction of assisted reproduction and its current worldwide utilization has resulted in the development of successful cryopreservation techniques for surplus embryos. The techniques created for embryo cryopreservation have further been applied to the unfertilized mature and immature human oocyte [10, 11] and ovarian tissue [12-17]. Currently, embryo cryopreservation is the preferred method to preserve future fertility because of reasonable post-thaw survival, implantation, and delivery rates, if the patient has a life-partner or access to a sperm donation program. However, oocyte or ovarian cryopreservation can be the solitary option for young or unmarried female patients. Pre-pubertal children, on the grounds of ethical concerns regarding ovulation induction and oocyte retrieval, and women who cannot delay cancer treatment for the 2-4 week period necessary to perform ovulation induction, are not candidates for embryo cryopreservation.
Numerous non-neoplastic diseases are also treated with cytotoxic chemotherapy and radiation. In some of them, chemotherapy or radiation therapy is also used in extreme doses to ablate the preexisting bone marrow in HSCT. The indications for HSCT that extend beyond cancer now include some autoimmune diseases unresponsive to immunosuppressive therapy, diseases associated with genetically abnormal stem cells (hemoglobinopathies and enzyme deficiency disorders), and those associated with the deficiency of bone marrow stem cell products [18-23]. In this article, the current indications and techniques of fertility preservation will be reviewed from the gynecologic point of view, which mainly focuses on embryo, oocyte and ovarian cryopreservation.
Chemotherapy-and radiotherapy-associated gonadal damage
Multiagent chemotherapy constitutes the basis of the modern cancer treatment. Ovaries, which are stocked with irreplaceable follicles, are extremely sensitive to most cytotoxic drugs [23, 24]. The end result of the chemotherapy can range from damage to steroid-producing cells and/or oocytes of developing ovarian follicles (granulosa and theca cells), which can cause temporary amenorrhea, to apoptotic death of primordial follicles, which results in premature ovarian failure (POF). Ultrastructurally, ovarian exposure to chemotherapeutics is associated with marked follicle loss . Factors that can potentially modify the risk of chemotherapy-induced ovarian failure are summarized in Table 1.
Some chemotherapeutic agents are more commonly associated with permanent and irreversible gonadal damage, such as cyclophosphamide, chlorambucil, melphalan, busulfan, nitrogen mustard, procarbazine, ifosfamide, and thiotepa [23, 26-30]. Among the moderately gonadotoxic agents are cisplatin and adriamycin, while bleomycin, actinomycin D, vincristine, methotrexate, and 5-fluorouracil are associated with mild or no gonadotoxicity (Table 2). Although there is limited evidence, paclitaxel may also be gonadotoxic, but this remains to be verified . In Table 2, we classify the gonadal risk of commonly used chemotherapeutic agents after a comprehensive literature search .
Cyclophosphamide is the most recognized agent to cause damage to oocytes and granulosa cells. In a recent mouse study, cyclophosphamide-induced follicular damage occurred in a dose-dependent manner, even at low doses of 20 mg/kg . Relative risk of POF was reported to be between 4 and 9.3 in patients receiving cyclophosphamide [34, 35]. During the last 10-15 years before the onset of menopause, primordial follicle loss is accelerated, which is reflected by a constant decrease in inhibin B levels and increase in follicle-stimulating hormone (FSH) levels. As a consequence, a smaller number of follicles that are more prone to cell division errors begin to grow each cycle, until menopause occurs, when the number of follicles falls below 1.000. Because of this, older women with a low primordial follicle pool have a higher risk of developing ovarian failure compared with young women with higher primordial follicle numbers. Consistent with this biological fact, earlier studies demonstrated that a cumulative cyclophosphamide dose of 5.2 g caused amenorrhea in women in their forties, 9.3 g in women in their thirties, and 20.4 g in women in their twenties .
Hematopoietic stem cell transplantation and the risk of ovarian failure
There has been a dramatic increase in the survival of childhood cancer patients in recent years as a result of HSCT. On the contrary, high-dose chemotherapy used for conditioning before HSCT is extremely gonadotoxic, as has been consistently demonstrated in the previous studies. In the acute ovarian failure of childhood cancer survivor study  that included 3309 childhood cancer survivors, exposure to more than 1000 cGy ovarian radiation, age and treatment with cyclophosphamide or procarbazine were found as independent risk factors for development of POF in a multivariable logistic regression model. An important finding from the previous studies is that despite timely menarche, FSH concentrations show a tendency to rise to menopausal levels in children exposed to high-dose chemotherapy during the pre-pubertal period. This highlights the fact that occurrence of timely menarche does not guarantee preserved ovarian function. Brachet et al.  found that seven of 10 children with sickle cell disease receiving busulfan (14 or 16 mg/kg) and cyclophosphamide (200 mg/kg) as preconditioning before HSCT developed POF. In the remaining three who had spontaneous puberty, serum FSH levels were very high at the time of puberty and slowly normalized thereafter. It is important to underline that three girls with ovarian function recovery differed from the seven others by the lower busulphan dose of the conditioning regimen they received (14 rather than 16 mg/kg). In a survey including 2819 childhood cancer survivors, Sklar et al.  demonstrated that children who receive chemotherapy are at an extremely high risk for POF. In that study, the authors followed a cohort of children who were diagnosed with a malignancy before the age of 21 and were menstruating for at least five years afterward. The patients in the study group were compared with their 1065 siblings. The median age at diagnosis was 7 (range, 0-20) and the median age at study was 29 (range, 18-50). The risk of developing ovarian failure was found 13.2-fold increased (range, 3.26-53.51) in those exposed to chemotherapy compared with their siblings. Although rare, resumption of menstruation years after the diagnosis of POF has also been reported .
How to assess post-chemotherapy gonadal function?
Most of the long-term follow-up studies assessing post-chemotherapy ovarian function rely on menstruation as the only surrogate marker. Even though irregular menstruation or amenorrhea is highly likely to occur during the chemotherapy, even lasting for a considerable period after completion of the chemotherapy, many patients return to a pre-chemotherapy menstrual pattern. Hormonal reversal of a hypergonadotropic state that commonly occurs during the courses of chemotherapy to a normo-gonadotropic state may also be expected . However, these women will always have a high risk of developing premature menopause during their later reproductive life. The fact that ovulation may occur despite loss of half of the follicular pool in rodents indicates that indirect assessment of ovarian reserve is an unreliable tool . Ovarian reserve diminishes when FSH levels on the third day of the menstrual cycle are more than 12 IU/ml or estradiol is more than 75 pg/ ml, whereas ovarian failure is diagnosed when FSH is found as more than 40 mIU/ml in two measurements regardless of menstrual bleeding. Anti-Mullerian hormone (AMH) has recently been suggested as the most reliable marker of ovarian reserve . In normal ovulating women, serum AMH levels are relatively constant during the menstrual cycle, serum concentrations of which show a rapid decline after 37 years. Anderson et al.  showed that compared with estradiol and FSH, AMH showed a more rapid and sustained change after chemotherapy. Moreover, the decrease in AMH occurred without a significant decrease in inhibin-B or increase in FSH concentrations. The severity and rapidity of the decrease in AMH concentrations compared with the partial decline in inhibin-B concentrations might reflect primordial and preantral follicles as the primary site of toxicity. This supports the observation that, even though there may be no clinical signs of ovarian failure, there is always damage to follicular reserve in proportion to the cumulative dose of chemotherapeutic agents that might not be detectable with routinely used laboratory tests. It is important to note that AMH is not influenced by confounding factors such as oral contraceptive use, day of menstrual cycle, or pregnancy. In a study assessing postchemotherapy ovarian function , despite the fact that all eight breast cancer study patients resumed menstruation after chemotherapy, three had irregular menstrual cycles, and five had undetectable inhibin-B levels or FSH values more than 50 IU/ml, suggesting some degree of impairment in ovarian reserve. Another study  found that, compared with FSH and inhibin-B, AMH constitutes the most sensitive predictor of ovarian reserve in women treated with chemotherapy for Hodgkin's lymphoma. Furthermore, most women who reported one or more pregnancies had normal AMH levels for age at the time of the study. Similarly, it has been demonstrated that in breast cancer patients, AMH levels declined despite continued menstrual activity  and ovarian reserve markers were altered in those who seemingly had normal menstruation postchemotherapy . Giuseppe et al.  assessed FSH, luteinizing hormone (LH), AMH, inhibin-B, and antral follicle count (AFC) and suggested the combination of AFC and AMH as having the best predictive value for ovarian reserve with a high sensitivity (83%) and specificity (88%) in patients treated with chemotherapy for Hodgkin's lymphoma. In 25 patients with hematological malignancies, serum AMH concentrations were measured before and after cancer therapy and compared with normoovulatory controls. Despite having menstrual cycles and despite some patients conceiving spontaneously after chemotherapy, AMH levels and AFC were decreased, showing some degree of ovarian damage .
Ionizing radiation is a well-recognized cause of ovarian damage and permanent infertility. Gonadal damage occurs not only by direct exposure to radiation such as in the case of pelvic or low abdominal irradiation, but scattering of radiation may also cause considerable damage even if gonads are outside the radiation field. Radiation causes a dose-related reduction in the primordial follicle pool . The human oocyte is extremely sensitive to radiation, and irradiation at ovarian dose >6 Gy usually causes irreversible ovarian failure . Wallace et al. [50, 51] demonstrated that <4 Gy is enough to destroy half of the oocyte population (LDL50 <4 Gy); however, very recently, using a revised mathematical model, the same authors suggested that the LDL50 of the oocytes was <2 Gy. Age at the time of exposure to radiotherapy, extent and type of radiation therapy (e.g. abdominal, pelvic external beam irradiation, intracavitary brachytherapy) and fractionation schedule are important prognostic indicators for development of ovarian failure [52-56]. In mice, radiation-induced chromosome damage in the oocytes was more evident in older compared with younger animals . In general, irradiation is more toxic when given in single dose compared to fractionated doses. Stillman et al.  investigated the risk of ovarian failure among 182 long-term survivors of childhood cancers receiving abdominal radiotherapy. The mean follow-up was 16.4 years. Ovarian failure occurred in 68% of the patients when both ovaries were in the irradiation field, and in 14% of the patients when both ovaries were at the edge of the treatment field. None of the 122 children developed ovarian failure when one or both ovaries were outside the abdominal treatment field. In another study, failure in pubertal development or premature menopause was observed in 37 of 38 patients who received external abdominal irradiation during childhood for intraabdominal tumors in doses ranging from 20 to 30 Gy . Sanders et al.  reported the probability of ovarian failure in patients receiving cyclophosphamide and total body irradiation for HSCT as 1.00 at one year. Failure in pubertal development may be the first sign of ovarian failure in these patients who received radiotherapy during childhood.
Indications for fertility preservation
As a result of improvements in cancer treatment and in the ability to detect tumors in their early stages by well-established screening programs for some cancers, life expectancy has strikingly increased. Furthermore, a cure is now possible for many childhood and adult cancers. Notably, cure rates approximate 90% in certain childhood cancers. A beneficial effect of cytotoxic treatment in various non-malignant diseases has also been repeatedly demonstrated. The idea of cryopreserving ovarian tissue is based on the finding that the ovarian cortex harbors primordial follicles that are more resistant to cryo-injury than are mature oocytes. Although the clinical indications for ovarian tissue cryopreservation are almost identical to those for the oocyte, there are fewer logistical restrictions in offering this technique. Despite the limited data on successful pregnancy rates, ovarian tissue cryopreservation has broader applications and, in theory, a greater fertility potential than oocyte cryopreservation because of the far larger number of oocytes preserved. Extending indications for ovarian tissue cryopreservation are listed below. A detailed list of indications is presented in Table 3 .
Cancers in children
Adult and childhood cancers are the most common indication for fertility preservation. Even though cancer is still the second leading cause of death in children, there has been remarkable improvement in the cure rates of many childhood cancers over the last three decades . Among the most common cancers encountered during childhood are leukemia, Hodgkin's and non-Hodgkin's lymphomas, tumors of the central nervous system, soft tissue sarcomas, and renal tumors [61-66]. Acute lymphoblastic leukemia is the most common childhood cancer, with more than 2.100 new cases and 2,000 long-term survivors each year [66, 67]. The five-year survival rate for all childhood cancers is approximately 80%, with a higher percentage for lymphomas (94%) and Wilms' tumor (91%) [66-69]. Although many children survive cancer because of improved treatment modalities, they are certainly not immune to the gonadotoxic effects of various cancer treatments. Ovarian tissue cryopreservation may be the only acceptable method for any pre-pubertal or pre-menarchal female patients receiving chemotherapy, pelvic radiotherapy, HSCT, or oophorectomy for benign disease or prophylaxis . The greatest benefit from the procedure is expected in children, since they have the highest number of primordial follicles . With ovarian tissue freezing, no ovarian stimulation is needed; therefore, time restrictions for cancer therapy are fewer, and there is no risk of stimulating estrogen-sensitive cancer following ovarian stimulation . Additionally, it avoids ethical concerns regarding ovarian stimulation and oocyte retrieval in children.
Cancers in adults
The death rates from cancer in women have fallen, despite increased incidence during the 1990s. Approximately 8% of these cancers occur in reproductive aged women under the age of 40 years. Breast cancer, the most common cancer in women during the reproductive years, afflicted approximately 216,000 women in the United States in 2004 . The five-year survival rate in breast cancer now approaches 90%. Most of the patients with breast cancer are subjected to cyclophosphamide-based gonadotoxic chemotherapy. In breast cancer, fortunately, unlike other malignant diseases, there is approximately a six-week hiatus between the initial surgery and chemotherapy. These patients may resort to assisted reproductive technologies during this time period. However, in theory, conventional ovarian stimulation protocols are thought to affect the growth of breast cancer as a result of supraphysiological estrogen concentrations. Novel stimulation protocols with tamoxifen and aromatase inhibitors are suggested as safer protocols in these patients. In addition, since occult ovarian metastasis is extremely rare, with the exception of stage IV disease and lobular carcinoma, these patients may resort to ovarian tissue cryopreservation [23,70]. Cancer of the cervix is a serious health problem afflicting 500.000 women worldwide each year, with almost half of them under the age of 35 . Patients with advanced stage disease and those with early stage disease who are found to have high risk factors receive pelvic or pelvic/paraaortic radiation therapy. Squamous cell cancer of the cervix, which is the most often encountered subtype, rarely metastasizes to the ovaries, whereas this may occur at a rate as high as 12% for adenocarcinoma and adenosquamous carcinoma. Ovarian transposition might be performed; however, success rates vary greatly because of damage to the vasculature during the procedure. Ovulation induction might be risky since there is risk of bleeding from the fragile cervix during oocyte retrieval. Ovarian tissue can be removed in selected patients for cryopreservation during primary cancer surgery. Another group of patients that are potential candidates for ovarian cryopreservation are those carrying BRCA I and II mutations. Despite the fact that the risk of peritoneal cancer cannot be totally eliminated in BRCA-positive patients, prophylactic oophorectomy is suggested as soon as childbearing is completed or by the age 35-40 years to decrease the risk of ovarian and breast cancer [72,73]. Cortical pieces of ovarian tissue in those with a desire for fertility can be frozen for future use.
Autoimmune diseases can also affect women of reproductive age. There have been an increasing number of reports regarding the use of cytotoxic treatment, especially with cyclophosphamide, in autoimmune diseases, including systemic lupus erythematosus, steroid- resistant glomerulonephritis, Behcet's disease, inflammatory bowel diseases, and pemphigus vulgaris [74-78]. Pieces of ovarian tissue may be harvested for possible future use in these patients in order to retain fertility.
When the risk of ovarian involvement with cancer cells is high, some other experimental options may be considered. It has been possible to isolate primordial follicles from human ovarian tissue, but there has been no success in growing them in vitro to get a healthy offspring . Early stage preantral follicles can only be grown for brief periods of time in three-dimensional culture systems. Another potential approach is xenografting human ovarian tissue in immunodeficient mice, where human follicles can be grown to antral stages and ovulated. However, the applicability of xenografting in the clinical setting has not been determined due to the risk of trans-species viral infections [80, 81]. The mechanism of age-related as well as chemo- or radiotherapy-induced loss in the ovarian germ cell population is proposed to be mediated by programmed cell death, i.e. apoptosis. Sphingosine-1phosphate (S1P), a bioactive sphingolipid metabolite, is an important lipid mediator and has many actions both inside and outside the cell. It was demonstrated that wild-type mice treated with S1P resisted both developmental and cancer therapy-induced apoptosis. Radiation-induced oocyte loss could be completely prevented by S1P therapy in wild-type mice, and no genomic damage in mice pretreated with S1P before receiving ionizing radiation could be demonstrated . Another experimental approach has become a current issue with a report by Silber et al. , in which a transplantation of ovarian cortical tissue took place between 24-year-old monozygotic twins, one of whom suffered POF. The question arises of whether allogeneic ovarian transplantation is possible in the future for females with ovarian dysfunction following cancer therapies.
Fertility preservation requires a multimodality approach. Depending on a patient's age, the type of cancer treated, time constraints, availability of a partner, and whether there is ovarian involvement, a different procedure may be needed for each cancer survivor facing treatment-related infertility. Physicians should take a comprehensive approach in counseling their patients regarding fertility preservation procedures.
Received: December 23, 2008 Accepted: April 8, 2009
Gelis tarihi: 23 Aralik 2008 Kabul tarihi: 08 Nisan 2009
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Address for Correspondence: Dr. Murat Sonmezer, Ankara University School of Medicine, Department of Obstetric and Gynecology, IVF Unit, Ankara Turkey Phone: +90 312 595 70 27 E-mail: firstname.lastname@example.org
Murat Sonmezer, Sinan Ozkavukcu Department of Obstetrics and Gynecology, IVF Unit, Ankara University School of Medicine, Ankara, Turkey
Table 1. Factors that can modify the risk of chemotherapy-related gonadal failure Age of the patient Type of chemotherapeutic agents Cumulative dose of alkylating agent Concomitant use of abdominopelvic radiation therapy Ovarian reserve Schedule of implementation Table 2. The degree of gonadotoxicity associated with chemotherapeutic agents High ovarian failure risk Cyclophosphamide Chlorambucil Melphalan Busulfan Nitrogen mustard Procarbazine Moderate ovarian failure risk Cisplatin Adriamycin Paclitaxel No or low ovarian failure risk Methotrexate 5-Fluorouracil Vincristine Actinomycin D Bleomycin Commonly used novel agents with as yet undetermined risk Irinotecan Imatinib Table 3. Indications of fertility preservation Cancer in children Hodgkin and non-Hodgkin lymphoma Leukemias Ewing's sarcoma Neuroblastoma Wilms' tumor Pelvic osteosarcoma Genital rhabdomyosarcoma Breast cancer * Infiltrative ductal histological subtype Stage I-III Cancer of the cervix Squamous cell carcinoma Adeno/adenosquamous carcinoma Autoimmune and hematological diseases Systemic lupus erythematosus Behcet's disease Steroid-resistant glomerulonephritis Inflammatory bowel disease Sickle cell disease Rheumatoid arthritis Progressive systemic sclerosis Pemphigus vulgaris Juvenile idiopathic arthritis Multiple sclerosis Autoimmune thrombocytopenia Aplastic anemia Benign ovarian disease Endometriosis Benign ovarian lesions requiring repeated surgeries Patients receiving pelvic radiation Solid organ tumors presenting in the pelvis Osteosarcoma Ewing's sarcoma Tumors of the spinal cord Retroperitoneal sarcoma Rectal cancer Benign bone tumors Vanishing bone disease Prophylactic oophorectomy BRCA-I and II germline mutation carriers Hematopoietic stem cell transplantation Malignant diseases Genetic, hematological, and autoimmune disorders Patients undergoing surgery for gynecological cancers ** * Ovarian cryopreservation is not recommended in advanced stage breast cancer. Compared to infiltrative ductal histologic subtype, infiltrative lobular breast cancer is more prone to metastasize to the ovaries in the early stages ** Fertility-preserving surgery includes conization or trachelectomy for early stage cervical cancer, fertility-preserving surgery for early stage ovarian cancer and hormonal treatment for endometrial cancer
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|Author:||Sonmezer, Murat; Ozkavukcu, Sinan|
|Publication:||Turkish Journal of Hematology|
|Date:||Sep 1, 2009|
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