Fertility-preservation in endometrial cancer: is it safe? Review of the literature

Márcia Mendonça Carneiro; Rívia Mara Lamaita; Márcia Cristina França Ferreira; Agnaldo Lopes Silva-Filho

JBRA Assist. Reprod. 2016;20 (4):232-239
REVIEW ARTICLE
doi: 10.5935/1518-0557.20160045

Fertility-preservation in endometrial cancer: is it safe? Review of the literature

Márcia Mendonça Carneiro^1,2, Rívia Mara Lamaita^1,2, Márcia Cristina França Ferreira^1,2, Agnaldo Lopes Silva-Filho¹

¹Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais/MG - Brazil
²Center for Human Reproduction, Mater Dei Hospital, Belo Horizonte/MG - Brazil

Received May 31, 2016
Accepted September 01, 2016

Corresponding author:
Márcia Mendonça Carneiro
Department of Obstetrics and Gynecology,
Universidade Federal de Minas Gerais,
Belo Horizonte/MG - Brazil
E-mail:marciamc.ufmg@gmail.com

CONFLICT OF INTERESTS
No conflict of interest have been declared.

ABSTRACT
Almost 5% of women with endometrial cancer are under age 40, and they often have well-differentiated endometrioid estrogen-dependent tumors. Cancer survival rates have improved over the last decades so strategies to avoid or reduce the reproductive damage caused by oncologic treatment are needed. We reviewed the published literature to find evidence to answer the following questions: How should we manage women in reproductive age with endometrial cancer? How safe is fertility preservation in endometrial cancer? Can pregnancy influence endometrial cancer recurrence? What are the fertility sparing options available? Progestins may be prescribed after careful evaluation and counseling. Suitable patients should be selected using imaging methods and endometrial sampling since surgical staging will not be performed. Conservative treatment should only be offered to patients with grade 1 well-differentiated tumors, absence of lymph vascular space invasion, no evidence of myometrial invasion, metastatic disease or suspicious adnexal masses, and expression of progesterone receptors in the endometrium. The presence of co-existing ovarian metastatic of synchronous cancer should be investigated and ruled out before the decision to preserve the ovaries. The availability of Assisted Reproductive Technology (ART) has made it possible for women with endometrial cancer to give birth to a child without compromising their prognoses. Gamete, embryo or ovarian tissue cryopreservation techniques can be employed, although the latter remains experimental. Unfortunately, fertility preservation is rarely considered. Current recommendations for conservative management are based on the overall favorable prognosis of grade 1 minimally invasive tumors. Selected patients with endometrial cancer may be candidates to a safe fertility-preserving management.

Keywords: Assisted reproductive technology, cancer of the endometrium, female infertility, reproductive endocrinology.

INTRODUCTION
Cancer still represents an enormous global health burden, and published data reveals about 14.1 million new cancer cases, and 8.2 million cancer deaths in 2012 worldwide (Torre et al., 2015). Cure remains the most important therapeutic goal and current available therapies are based on surgery, cytotoxic medications and/or radiation. Such procedures unfortunately result in partial or total loss of fertility. Cancer incidence is on the rise worldwide, largely due to the adoption of behaviors and lifestyle factors known to cause cancer such as smoking, aging and growth of the world population (Jemal et al., 2011;Torre et al., 2015). Cancer survival rates have improved over the last two decades putting quality-of-life issues in the spotlight for women who survive the disease and this includes fertility care (Lee et al., 2006; Jeruss & Woodruff, 2009). The development of assisted reproductive technology (ART) and cryopreservation techniques provided options for female fertility preservation such as oocyte, embryo or ovarian tissue freezing (Lee et al., 2006; Rowan, 2010;von Wolff et al., 2015; Lambertini et al., 2016)
As gynecologic malignancies often affect young women who are still in their reproductive years, and women are postponing childbearing, the incidence of cancer in those who still want to get pregnant has somewhat increased. Rates of permanent infertility and compromised fertility after cancer treatment vary and depend on many factors (Bogani et al., 2016; Lambertini et al., 2016). The effects of chemotherapy and radiation therapy on fertility depend on a number of factors: the drug or size/location of the radiation field, dose, dose-intensity, method of administration, disease, age, gender, and the pretreatment fertility of the patient (Salama et al., 2013; Lawrenz et al., 2016). Safe conservative options that preserve fertility are available and may be adopted for those who have not depleted their child-bearing wishes (Rowan, 2010; Levine et al., 2015; Druckenmiller et al., 2016; Fournier, 2016). New methods for women, such as in vitro follicle maturation and techniques for tissue transplantation, are on the horizon (Loren et al., 2013). The FIGO Committee for the Ethical Aspects of Human Reproduction and Women’s Health states that cancer treatment is the primary medical goal, and the risks of delaying treatment in order to induce ovarian stimulation and retrieval or ovarian removal or transplant must be carefully considered and should not have a significant impact on treatment (FIGO, 2006).
Endometrial cancer (EC) is the most frequent gynecologic cancer in developed countries killing 34,700 women in 2012 (Torre et al., 2015; Bogani et al., 2016). Although it is primarily a disease of postmenopausal women, 25% are premenopausal and 3-5% are under age 40 (Zivanovic et al., 2009). In this younger group with endometrial cancer a history of ovary dysfunction, anovulation, infertility and obesity are often found. Frequently, these women have never been pregnant and have a strong desire to preserve fertility. In such women endometrial carcinoma is usually an estrogen-dependent well-differentiated endometrioid carcinoma, which does not tend to invade the myometrium and is associated with good prognosis (Benshushan, 2004; Zivanovic et al., 2009; Bogani et al., 2016). Therefore, selected patients with endometrial cancer may be candidates to a conservative approach preserving a potential fertility (Carneiro et al., 2012).
Recent improvement in the prognosis of cancer patients has drawn attention to fertility issues. Unfortunately, there is a lack of large prospective cohort studies and randomized trials on these topics and, therefore, the safety of such approaches raises concerns among healthcare providers, patients and families. We set out to perform a review of the relevant articles without language restriction based on a PUBMED search using the keywords: “fertility preservation”, “endometrial cancer”, “surgical treatment”, “pregnancy”, “chemotherapy” and “radiation”. We reviewed the published literature about safe fertility-preserving management in endometrial malignancies, focusing on patient selection criteria, available treatment options and follow-up. We focused on finding evidence to answer the following relevant clinical questions: How should we manage women at reproductive age with endometrial cancer? How safe is fertility preservation in endometrial cancer? Can pregnancy influence endometrial cancer recurrence? What are the fertility sparing options available?

How should we manage women at reproductive age with endometrial cancer?
The standard treatment for endometrioid carcinoma includes staging laparotomy, total abdominal hysterectomy and bilateral salpingo-oophorectomy with pelvic washing and lymph node sampling when appropriate. The 5-year survival rate after this approach is approximately 94% (Bakkum-Gamez et al., 2008). Conservative treatment approaches, with uterine and ovarian preservation may be considered if there is a strong desire to preserve fertility. (Zivanovic et al.,2009; Bogani et al., 2015). Currently, fertility preservation options in endometrial cancer are limited to hormonal methods (Ushijima et al., 2007; Signorelli et al., 2009; Gressel et al., 2015). Patients desiring to proceed with conservative hormonal management should be extensively counseled regarding potential risks as no scientifically proven optimal progestin regimen exists (Eskander et al., 2011; Loren et al., 2013; von Wolff et al., 2015). Response to treatment may vary depending on tumor receptor status, ranging from 26 to 89% in estrogen and progesterone positive tumors but can be as low as 8-17% when these receptors are absent (Chiva et al., 2008; Hahn et al., 2009; Yu et al., 2009).
The conservative treatment of endometrial carcinoma may be recommended when patient desires to preserve fertility, the tumor is endometrioid, its clinical stage is IA FIGO and histological FIGO grade I. It is important to emphasize that such an approach is not standard and should be considered only if the patient insists (Bogani et al., 2016 ; Gressel et al., 2015). Careful and thorough counseling is mandatory in this setting (Loren et al., 2013; Lambertini et al., 2016). Published data reveals that maintaining the uterus and the ovaries in carefully selected cases with endometrial cancer confers only a very small risk as an increasing number of studies show encouraging results with fertility preserving treatments for endometrial cancer with high dose progestins (Signorelli et al., 2009; Rodolakis et al., 2015).
Thus, selection of women suitable for such conservative management, as well as treatment options, follow-up, recurrence, obstetric outcomes, and survival rates are vital parameters when counseling these women (Rodolakis et al., 2015; von Wolff et al., 2015).
Adequate clinical staging of endometrial cancer remains a challenge while surgical staging is the gold standard. Prognosis is established based on histological grade, depth of myometrial invasion, cervical involvement, vascular space involvement, pelvic and aortic lymph node metastases, adnexal metastases, and positive peritoneal cytology (Guan et al., 2011). Apparently, the stage of the tumor is the most important factor in predicting patients’ outcome as it determines the mode of treatment and significantly influences survival (Gressel et al., 2015; Bogani et al., 2016). No optimal method of evaluation prior to conservative management has been identified so far, hence multiple noninvasive or minimally invasive diagnostic methods are employed to attempt to ‘clinically stage’ a patient (Zivanovic et al., 2009; Bogani et al., 2016).
Routine blood and urine exams should be performed and serum levels of CA 125 should be obtained, once its elevated levels suggest advanced disease. Endometrial biopsy is mandatory in the initial evaluation, since histological grade of the tumor is one of the most important prognostic factors (Clarke & Gilks, 2010). To improve the accuracy of clinical staging, different radiological modalities have been used. Transvaginal ultrasound (TVUS), computed tomography (CT) and magnetic resonance imaging (MRI) have been tested and studies revealed no significant difference in their performance. However, contrast-enhanced MRI performed significantly better in the evaluation of the myometrial invasion than non-enhanced MRI, CT or TVUS (P<0, 02) (Kinkel et al., 1999). When evaluation is inconclusive, thorough laparoscopic exploration with peritoneal cytology, pelvic lymph nodes sampling and adnexal evaluation should be considered before conservative treatment is deployed (Signorelli et al., 2009; Bogani et al., 2016).

How safe is fertility preservation in endometrial cancer?
Endometrial carcinoma in patients under the age of 45 is rather uncommon and appears to have more favorable outcome than in older patients (Gressel et al., 2015). Premenopausal women appear to have a higher rate of low-grade tumors and lower stage of disease resulting in a favorable 5-year disease-specific survival rate of 93%, in contrast to older patients (86%) (Crissman et al.,1981; Kalogiannidis et al., 2011).
Nonetheless, the endometrial carcinoma found at younger ages increases the risk of cancer associated with the Lynch/Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome as well as synchronous or metachronous ovarian cancers occurring outside the setting of Lynch/HNPCC (Evans-Metcalf et al., 1998; Richter et al., 2009). In this setting, clinical stage I endometrial carcinoma with metastases to the ovary is rare, comprising only 5% of the cases. The incidence of any stage endometrial carcinoma with a synchronous ovarian malignancy could be as high as 10 to 29.4% (Chiva et al., 2008; Navarria et al., 2009).
Evans-Metcalf ER, Brooks SE, Reale FR, Baker SP. Profile of women 45 years of age and younger with endometrial cancer. Obstet Gynecol 1998;91(3):349–354.
In a study which included 1,365 women with endometrial cancer (Navarria et al. 2009), found no significant difference regarding tumor characteristics and survival between young and older patients, except stage of disease (more stage II in the younger group) and rate of synchronous ovarian malignancy (14% in the younger group).
Another study reported a significantly higher rate of ovarian involvement (25%) and recommended prudence when considering ovarian sparing in young endometrial cancer patients with early stage disease (Walsh et al., 2005). Richter et al. (2009) evaluated 251 patients with endometrial cancer (75.3% stage I) aged 45 or younger. Eleven patients (4.4%) presented with a synchronous serous ovarian malignancy and those submitted to bilateral salpingo-oophorectomy had a significant longer disease-free survival, but no improvement in overall survival. Sun et al. (2013) also found that ovarian preservation has no statistically significant impact on the overall survival of young patients with early-stage endometrial cancer.
Ovarian sparing in young patients does not seem to adversely impact the recurrence of early stage endometrial cancer either (Lee et al., 2009). One study involving 402 young women with endometrial cancer who underwent hysterectomy with ovarian sparing concluded that, in the absence of risk factors, a conservative approach to surgical staging is feasible, safe and not associated with an increase in cancer-related mortality (Wright et al., 2009).
Although endometrial carcinoma is believed to be a hormone-dependent tumor, there is no direct evidence that sparing the ovaries would raise recurrence rates (Lee et al., 2009; Sun et al., 2013; Wright et al., 2016). Ovarian metastases and synchronous primary ovarian cancer in patients with stage I endometrial carcinoma seem to correlate with histological type, depth of myometrial invasion, cervix invasion (including mucosa or/and stroma), uterine serosa extension, fallopian tube involvement, retroperitoneal lymph node metastases, positive peritoneal cytology and CA125 level (Pan et al., 2011).
Thus, ovarian preservation at the time of operation, in younger women with stage I endometrial cancer, is worth considering only if ovarian metastasis or synchronous ovarian primary cancer are ruled out. Indeed, the possibility of hidden ovarian metastases call for great caution, especially for patients with high-risk factors (Pan et al., 2011; Sun et al., 2013). Nevertheless, the ovaries should be preserved in women younger then 45 after a thorough preoperative evaluation and extensive intraoperative exploration. Ovarian preservation apparently had no effect on overall survival and the findings were validated by meta-analysis (Sun et al., 2013).
Wright et al. (2016) used The National Cancer Database to search for women younger than 50 years of age with stage I endometrioid adenocarcinoma of the endometrium who underwent surgical treatment. The cohort selected 15,648 women: 1,121 (7.2%) who had ovarian preservation and 14,527 (92.8%) who underwent oophorectomy. Data analysis with multivariable models examined predictors of ovarian sparing and the association between ovarian sparing and survival. They concluded that ovarian sparing was not independently associated with survival nor there was an association between ovarian preservation and survival. Unfortunately, despite these reassuring data, the majority of young women with endometrial cancer still undergo oophorectomy.

Can pregnancy influence endometrial cancer recurrence?
It is very important to emphasize the need to discuss with the patient the risks of conservative treatment. Although the degree of histological differentiation is a sensitive indicator of tumor spread, 2.8% of all grade 1 lesions have pelvic node involvement, and 1.7% bear para-aortic node involvement. Moreover, 10% of grade 1 tumors have deep muscle invasion, 6% of clinical stage I and hidden stage II patients have spread of tumor to the adnexa and 19% of patients have coexisting ovarian neoplasm (Crissman et al., 1981).
Progestin therapy remains the most common option when fertility-sparing is considered, as it is highly effective in selected cases. Various doses of different progestational agents have been used in an effort to preserve fertility in patients with clinical stage I endometrial carcinoma. Oral medroxyprogesterone acetate (MPA) at a dose of 100-800 mg/day; megestrol acetate (MA) at a dose of 40-160 mg/day and a combination of tamoxifen and a progestin have been used with similar results (Zhou et al., 2015; Inoue et al., 2016). The follow-up of these patients under conservative treatment in the first year included serial TVUS, endometrial biopsy and CA-125. Periodic endometrial samplings should be performed every 1 to 6 months. Close follow-up during and after the period treatment is strictly recommended. (Pronin et al., 2015;.Park & Nam, 2015).
Fung-Kee-Fung (2006) published a systematic review of sixteen non-comparative retrospective studies in an attempt to establish the optimum follow-up for women treated with potentially curative treatment for endometrial cancer. Routine testing seems to be of limited benefit for patients at low risk of disease since most recurrences occur within 3 years in high risk patients, and involve symptoms (Fung-Kee-Fung et al., 2006; Mazzon et al., 2010).
To date, the time required for response to conservative treatment and its duration have not been established. Published data reveals that the minimal time to response was 3.6 months and the treatment was maintained for 5.4 months (Gotlieb et al., 2003). Although today there is no consensus as to which progestational agent to use, or treatment dose and length, it appears that 62-75% of women with clinical stage I and well differentiated adenocarcinoma respond well to progestational treatment within 3 to 9 months and the majority will have long term response (Pronin et al., 2015;.Park & Nam, 2015). As long as an accurate pretreatment assessment is performed, progestin therapy is an appropriate option to preserve fertility in young women with well-differentiated endometrial carcinoma or severe atypical endometrial hyperplasia (Pronin et al., 2015; Inoue et al., 2016). The absence of progesterone receptors (PR), however, can jeopardize the success of progestin as a treatment (Yang et al., 2005). Nevertheless, there is no need to check for PR expression routinely, because a significant number of PR negative tumors will respond to treatment (Rodokakis et al., 2015).
Eskander et al. (2011) recommend that candidates to hormonal fertility-sparing treatment should fulfill the following criteria: (1) grade 1 well-differentiated tumor; (2) absence of lymph vascular space invasion (LVSI) on adequate curettage specimen; (3) no evidence of myometrial invasion on MRI; (4) no evidence of metastatic disease on CT imaging; (5) no evidence of a suspicious adnexal mass on CT or TVUS; and (6) strong and diffuse immunohistochemical expression of progesterone receptors on endometrial biopsy or curettage specimen.
The overall response rate, evaluated by endometrial biopsy every three months, to either medroxyprogesterone acetate or megestrol acetate was 73% in a median time of 4 months (range 1–15 months). The relapse rate was 36% in a median follow-up time of 22 months (range 6–73 months). Overall, 40% of patients who responded successfully, conceived; half of them using assisted reproductive technology (ART) so as to achieve an immediate pregnancy (Kalogiannidis &, Agorastos, 2011).
There are reports of many pregnancies after conservative management of endometrial carcinoma, some after ART (Fujimoto et al., 2014; Koskas et al., 2014) Combining conservative treatment with ART may result in healthy infants without an adverse effect on oncologic prognosis (Elizur et al., 2007; Bozdag et al., 2009; Mao et al.,2010). Introduction of infertility treatment ART soon after achieving tumor remission by MPA would be beneficial for patients in this setting. Although preliminary results are encouraging, the majority of the series reported so far are retrospective, included only a small number of patients, and used different treatment methods and inclusion criteria, making the extraction of useful conclusions rather difficult (Koskas et al., 2014; Rodolakis et al., 2015; Inoue et al., 2016). The recommendations of the European Society of Gynecological Oncology Task Force for Fertility Preservation state that MPA or MA are the progestins to be used as more studies are needed to further elucidate the role of the levonorgestrel intrauterine device (LNG-IUD) (Rodolakis et al., 2015).

What are the available strategies of fertility preservation?
For patients planning to have chemotherapy, radiotherapy or scheduled to undergo bilateral oophorectomy, the loss of ovarian function will result in premature ovarian failure and permanent loss of fertility. Potential strategies for such women include embryo or oocyte cryopreservation (Gressel et al., 2015; Zapardiel et al., 2016). However, embryo cryopreservation is not suitable for children and unmarried women as it involves a male partner, unless sperm donation is acceptable (Zapardiel et al., 2016). Embryo cryopreservation also requires superovulation, which is time consuming and not without side effects. Cancer patients respond to gonadotropins but stimulation lasts longer and a higher total dose is required. No significant differences in the number of oocytes retrieved, matured oocytes and the fertilization rate were found (Knopman et al., 2009).
The safety of ART in women with a past history of gynaecological cancer raises concerns, though some studies report reassuring data. Ovulation induction does not appear to be associated with increased risk of relapse, and subsequent pregnancies do not worsen oncological outcomes (Matthews et al., 2012; Fujimoto et al., 2014; Zapardiel et al., 2016). The impact of high serum estradiol levels on endometrial carcinoma is uncertain, although some data suggest an adverse effect of ovarian stimulation. It seems that there is no clearly optimal duration, protocol or number of attempts for ovarian stimulation in women with early-stage endometrial carcinoma (Zapardiel et al., 2016).
There are strategies to keep estrogen levels low during controlled ovarian hyperstimulation (COH) so that estrogen-dependent cancer patients are safe and cancer recurrence is not increased (Oktay et al., 2010). Studies involving breast cancer patients revealed that the use of aromatase-inhibitors combined with a gonadotropin-releasing hormone agonist (GNRHa) to trigger ovulation, instead of human chorionic gonadotropin (hCG), may reduce estrogen exposure and the incidence of Ovarian Hyperstimulation Syndrome. GnRHa ovulation trigger resulted in a larger number and higher percentage of mature oocytes and a higher number of cryopreserved embryos or oocytes compared with hCG cycles (Oktay et al., 2010). Recent evidence also indicates that there are multiple main follicle recruitment waves during the menstrual cycle and hence the concept of a narrow window of opportunity for follicle recruitment may not be accurate. Therefore, the current availability of GnRH antagonists combined with multiple recruitment waves allows the beginning of random-start controlled ovarian hyperstimulation (COH) in the late follicular or luteal phase of the menstrual cycle for embryo cryopreservation in cancer patients. Unfortunately, published data regarding late-follicular or luteal-start COH and emergency fertility sparing is still limited to case series (Sönmezer et al., 2011; Kreskin et al., 2014).
The American Society for Reproductive Medicine (ASRM) has recently reviewed the evidence on fertilization and pregnancy rates obtained after oocyte vitrification and warming. Published data, although limited, shows results that are similar to those obtained when fresh oocytes are used in IVF/ICSI cycles. As for chromosomal abnormalities, birth defects and developmental alterations, there is no increase in comparison to pregnancies after conventional IVF/ICSI and the general population. Therefore, the ASRM recommends that oocyte vitrification and warming should no longer be regarded as experimental (ASRM & SART, 2013), a decision endorsed by the American College of Obstetricians and Gynecologists’ Committee on Gynecologic Practice (ACOG, 2014). Available data is still scant to recommend oocyte cryopreservation for the sole purpose of circumventing reproductive aging in otherwise healthy women.
Results from clinical trials and observational studies show that the cryopreservation of unfertilized oocytes represents an acceptable and often viable alternative, particularly for single women, and that it should be offered as a routine technique for female patients before chemo and/or radiotherapy (Noyes et al., 2010; Noyes et al., 2011; Cobo et al., 2011). Apparently, fresh and frozen oocytes result in comparable pregnancy rates in IVF cycles, endorsing the use of such technologies in well-selected patients aged 35 years and younger (Cobo et al., 2011; Garcia-Velasco et al., 2013; ACOG, 2014).
In spite of being a standardized technique, results after oocyte vitrification vary depending on a host of variables including the specific population, methodologies applied, particular protocols, types of device and cryoprotectants. Although protocols may seem simple to use, success relies on the availability of experienced hands in the laboratory (Cobo et al., 2013).
The safety of the technique can be assessed looking at 936 babies born from frozen oocytes from multiple centers around the world with no apparent increase in the rate of congenital anomalies (Noyes et al., 2009). Oocyte vitrification appears to be an efficient method to preserve oocytes, regarding oocyte survival, fertilization, embryo development and pregnancy rates as well as neonatal data, but further large controlled clinical trials are needed to corroborate such early reassuring outcomes (ASRM & SART, 2013; Garcia-Velasco et al., 2013; ACOG, 2014).
Ovarian tissue cryopreservation is a promising strategy that offers the possibility to restore fertility by autotransplantation or in vitro culture and oocyte maturation (Ledda et al., 2001). It offers the advantages of enabling the storage of a large number of gametes and be rapidly performed, at any period of the cycle, without delaying the oncological treatment (Lotz et al., 2016). However, several considerations involve the creation of a bank of frozen ovarian tissue and, although several protocols of slow freezing and fast thawing showed exciting results, the real consequences of cryopreservation and the ideal protocol remain uncertain. In addition, ovarian tissue cryopreservation is still considered experimental (Salama & Woodruff, 2015).
Autotransplantation of ovarian tissue has yielded 60 live births to date, including one from tissue that was cryostored in adolescence. Advantages include immediate initiation of oncologic treatment, ability to restore physiological ovarian function and no need for ovarian hyperstimulation. In addition, it may be the only option for fertility preservation for prepubertal girls or young women with estrogen-sensitive cancers. However, it is assumed that autografting cryopreserved-thawed ovarian cortical tissue poses a risk of reseeding the malignancy (Salama & Woodruff, 2015; Abir et al., 2016).
Technical difficulties and the complex human folliculogenesis process will probably delay the development of in vitro culture systems to support human primordial follicular growth until the ovulatory stage (Salama & Woodruff, 2015).
After transplantation, follicular development and restoration of hormone secretion have been investigated in animal and human studies (Torrents et al., 2003). In humans, since the first live birth after autotransplantation of cryopreserved ovarian tissue reported in 2004, ovarian cortex transplantation has led to the birth of 60 healthy babies, and one pregnancy after IVF (Donnez et al., 2013; Donnez & Dolmans, 2015).
Imbert et al. (2014) retrospectively analyzed ovarian function and fertility recovery rates, as well as ovarian tissue characteristics, of 225 women who underwent ovarian tissue cryopreservation. Ovarian function returned in 71 post-pubertal patients without the need for grafts of cryopreserved tissue. Thirty-three spontaneous pregnancies were reported, leading to 34 live births. Among the 13 pre-pubertal patients who reached pubertal age during the follow-up, 10 had premature ovarian failure (POF). Eight patients received cryopreserved ovarian grafts to reverse POF and three of them had already become pregnant. Dittrich et al. (2015) also reported the results of 20 orthotopic retransplantations of cryopreserved ovarian tissue after cancer treatment. Ovarian activity resumed in all patients except one. Seven patients conceived, with one miscarriage and four ongoing pregnancies.
Data published on the restoration of ovarian function, pregnancies and live birth rates suggests that preserving fertility by cryopreserving ovarian tissue is a successful and safe clinical option that can be considered for selected cancer patients (Imbert et al., 2014; ASRM, 2014; Dittrich et al., 2015). The ASRM (2014) stresses that ovarian tissue cryopreservation and subsequent transplantation can only be recommended as an experimental protocol in carefully selected patients. It should not be offered with the intent to delay pregnancy or for benign conditions in that there is a potential risk of reintroducing malignancy.
Non-invasive techniques have been used in an attempt to minimize the gonadotoxic effect of chemotherapy by using GnRHa or oral contraceptives (OC) to stop the maturation of the dividing oocyte, producing its involution and avoiding the noxious effect of the chemotherapy on the dividing cell (Blumenfeld & von Wolff, 2008). Studies have shown an 11.1% incidence of premature ovarian failure in patients who received GnRH-a, compared with a 55.5% incidence in the controls. Others argue that there is absence of conclusive evidence regarding the safety and efficacy of GnRHa treatment in protecting against chemotherapy-induced gonadal injury (Blumenfeld et al., 2007; Badawy et al., 2009; Gerber et al., 2011). Possible mechanisms of action include reduction of the number of primordial follicles entering the differentiation stage, diminished ovarian perfusion and delivery of chemotherapy to the ovaries, and maybe a direct effect with on the upregulation of an intragonadal antiapoptotic molecule (Blumenfeld & von Wolff, 2008). Nevertheless, the available evidence is still limited on the fertility preserving effect of OC. Two studies showed lower premature ovarian failure rates in OC-treated patients: 13.2% compared with 29.8% among the controls (Blumenfeld & von Wolff, 2008).
Controversy remains regarding the use of gonadotrophin releasing hormone agonist (GnRH-a) or combined oral contraceptive administered at time of the gonadotoxic therapy to prevent premature ovarian failure in women. The available published data from both human and animal studies show mixed results. The best way to preserve fertility and ovarian function in young women undergoing chemotherapy still remains to be determined. In the absence of a consensus, each case should be carefully evaluated, considering the patient’s wishes and expectations, the type of chemotherapy, age, obstetric history, ovarian reserve (combining multiple indicators such as basal hormone profile, anti müllerian hormone -AMH- and antral follicle count), as well as family history of premature ovarian failure (Chahvar et al., 2014). Currently, the ASCO guideline (ASCO, 2013) reports that there is insufficient evidence regarding the effectiveness of GnRHa and other means of ovarian suppression in fertility preservation.

Final considerations
In spite of the importance of this topic, fertility preservation methods are still relatively infrequently applied in the cancer population, limiting the development of knowledge on the success and effects of different interventions. The American Society of Clinical Oncology highlights that the fertility preservation literature reveals a paucity of large and/or randomized studies.
Current recommendations for conservative management are based on the overall favorable prognosis of grade 1 minimally invasive tumors, supported by a few case series and case reports, but no prospective data. Selected patients with endometrial cancer may be candidates to a safe fertility-preserving management strategy. Two issues are extremely relavant when a conservative approach is considered: first, the evaluation of the tumor’s individual pathology biology (histological type, grade, myometrial invasion, and presence of lymphovascular space invasion); and second, choosing the optimal approaches for fertility sparing and follow up. Large multicentric trials are needed so as to define the best selection criteria for a conservative treatment, endocrine regimen of choice, optimal dosing, duration and follow-up protocols.

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