Fertility Preservation in Female Patients with Cancer. Part I: Challenges and Future Prospects in Developing Countries; A Narrative Review Study

Abstract

While international guidelines on oncofertility practice have been published in developed countries, there is limited information available on oncofertility practice in developing countries, which often face limitations in their cancer health support networks. As survival rates improve in the field of cancer and other diseases, there is a growing need for stronger oncofertility services in developing countries. Given that 50% of cancer patients are under the age of 65, many of these patients are of reproductive age and preserving their fertility health prior to starting treatment is valuable. However, due to resource limitations and the heavy burden of treatment costs imposed on these patients and their families, fertility preservation (FP) may not be a top priority for them. As a result, many healthcare providers and their patients focus on eliminating cancer and its related treatments while overlooking the importance of fertility as a factor that can significantly impact their future quality of life. In this review, we have tried to increase the knowledge of healthcare providers involved in the oncofertility network by reviewing current cancer treatments, FP options in female cancer patients, and their challenges in developing countries.

Introduction

Given the recent advances in oncology and the increased survival rate of cancer patients, especially in fertile ages, improving the quality of life of these patients is an important issue. The duality of facing a life-threatening diagnosis on the one hand and the desire to have children on the other hand is a major challenge for cancer patients and health care providers. Therefore, the future fertility of these patients must be carefully considered. It is necessary for these patients to receive various counseling during treatment so that they can preserve their fertility before, during, and after cancer treatment using different techniques. Patients need to become familiar with fertility preservation (FP) treatment options as quickly as possible and make a final decision on the type of treatment in this critical situation (1).

The World Health Organization (WHO) forecasts that, by 2030, yearly cancer cases among women in their reproductive years will reach 1.4 million (2). One study reported that the incidence of cancer among Iranian women under 45 years of age was 286 per 100,000 individuals. Approximately 51.7% of recovered individuals reported that their most important wish was to achieve fertility using their eggs. Furthermore, it has been reported that even among women who initially stated that preserving fertility was not important to them, this issue later became significant. For this reason, the American Society of Clinical Oncology (ASCO) recommends that cancer patients who are in reproductive age should be referred to specialists in this field for consultation (3). In addition, FP may be an option for patients with harmful gene mutations (such as BRCA1 and BRCA2) that raise their cancer risk. As genetic testing becomes more accurate in detecting variants that predispose some patients to gynecological cancers, more patients will look for FP before undergoing preventive surgeries. The lifetime risk of ovarian cancer for BRCA1 and BRCA2 mutation carriers is 44 and 17%, respectively (4). There is evidence of an association between BRCA1/2 mutations and diminished ovarian reserve. Hence, young healthy BRCA carriers are recommended to consult a specialist about their fertility options, and also it is important to enhance the availability of genetic testing results before the consultation to detect pathogenic variants (2, 5).

Research has identified several common barriers to oncofertility care in developing countries, including a lack of sufficient information from oncologists, limited funding, high treatment costs, and cultural misconceptions with negative impacts on assisted reproductive technology (ART) and FP techniques. Additionally, resistance to accepting new technologies in this field may arise due to a lack of sufficient information from providers (6). The practice of FP may precipitate additional ethical quandaries for women. Specifically, the trans-vaginal method of oocyte retrieval could engender apprehensions among some women regarding the preservation of the hymen, traditionally viewed as a symbol of chastity. Nevertheless, it is important to note that societal norms and moral standards are not static and can be recontextualized through societal evolution and discourse (7).

In this review, we have tried to increase the knowledge of healthcare providers involved in the oncofertility network by reviewing current cancer treatments, FP options in female cancer patients, and their challenges in developing countries.

Current cancer treatments

Surgery

Oophorectomy and total hysterectomy permanently affect fertility. Additionally, other surgeries that affect the bladder, large intestine, and rectum may impair the ability to carry a pregnancy to term. Conservative surgery, such as trachelectomy and ovarian cystectomy, is the best option for preserving fertility. The option of FP through surgery is increasingly being made available to women with gynecological cancer who wish to maintain their ability to have children. Fertility-sparing surgery (FSS) serves as a feasible mechanism to empower young gynecological cancer patients to achieve their fertility aspirations without compromising their oncological prognosis. FSS could be performed in patients with early-stage cervical cancer (stage IA1-IB1), borderline ovarian tumors, stage I (lowgrade) endometrioid ovarian cancer, stage IA grade 1 epithelial ovarian cancer, and non-epithelial ovarian cancer (especially malignant ovarian germ cell tumors) (8).

For instance, the FSS procedure in ovarian cancers involves the execution of unilateral (salpingooophorectomy), with the uterus and contralateral ovary remaining in situ to preserve fertility. In cases of early-stage cervical cancer, hysterectomy with ovarian preservation is considered. Ovarian transposition prior to radiation therapy is recommended to preserve ovarian function in advanced local cervical cancers (9, 10). The conventional technique for managing endometrial cancer in young women of reproductive age is hysterectomy and bilateral salpingo-oophorectomy with or without lymphadenectomy which can be curative for early-stage endometrial cancer, but this is not appropriate for women who desire future fertility (11, 12). Radiation therapy, chemotherapy, and progestins are potential components of conservative management for endometrial cancer. The choice between surgical and conservative management depends on multiple factors, such as the stage and grade of the tumor, the patient’s general health status, and their FP desire. Conservative management of endometrial cancer (CMEC) may be suitable for patients who wish to retain their fertility or for those with advanced disease who are unfit for surgery. It is important to note that the current evidence on the comparative effectiveness of surgical and conservative management for endometrial cancer is limited and individualized treatment decisions should be made according to the patient's unique circumstances (13). The survey results on the preoperative infertility evaluation before CMEC among 103 clinicians showed a high consensus on ovarian reserve assessment and a low consensus on tubal patency assessment. On the other hand, the oncological management of CMEC patients among EC clinicians, showing high agreement with guidelines but also uncertainty on some aspects (14).

It is important to note that FSS may not be suitable for all cancer types and stages. A thorough and detailed discussion of the risks, benefits, and alternative methods must take place before deciding to undergo this procedure. Furthermore, it is strongly recommended to conduct multidisciplinary meetings involving gynecologic oncologists, infertility specialists, and other relevant services (8).

Chemotherapy

Chemotherapy is effective in treating cancer and improving survival rates. However, chemotherapeutic agents have the potential for gonadotoxicity, either directly by affecting the ovaries or indirectly by affecting the hypothalamus-pituitary-ovary (HPO) axis. These agents destroy ovarian follicles and granulosa cells, as well as oocytes (15). The damage caused by these agents is related to the dose, drug type, and duration of treatment and increases with age. As women age increase, their fertility naturally decreases due to a decline in the number and quality of eggs. This process can be accelerated by chemotherapy, which can have a destructive effect on fertility such that older women are more prone to menopause compared to younger women even with low doses of chemotherapy (16). The ultimate results of chemotherapy include a decline in estrogen and anti-mullerian hormone (AMH) levels and an increase in follicle-stimulating hormone (FSH) levels (15). Chemotherapy often causes a substantial decline in AMH levels relative to the levels before treatment, and the extent of recovery is influenced by factors such as the type of chemotherapy, age, and AMH levels prior to treatment. By measuring AMH, the gonadotoxicity of different treatment regimens can be evaluated (17). High FSH levels are highly specific for predicting poor ovarian response, but they have low sensitivity to detect these women and this sensitivity declines with the threshold value used. Moreover, young women with amenorrhea and high FSH levels may have premature ovarian insufficiency. Estradiol level in the early follicular phase, by itself, is not a good marker of ovarian reserve, but it may help to interpret the basal FSH level, especially when FSH levels are normal (18). Amenorrhea is a common phenomenon that occurs after chemotherapy and can be transient or permanent due to the loss of mature or primordial follicles, respectively known as acute ovarian failure. Reduced uterine size and pregnancy rate, abortion, low birth weight, and preterm delivery are common features that occur after chemotherapy and radiotherapy (19).

Based on the risk of gonadotoxicity of chemotherapeutic agents, four categories can be mentioned: high, medium, low, and unknown risks. Alkylating agents such as cyclophosphamide, doxorubicin, chlorambucil, melphalan, thiotepa, procarbazine, ifosfamide, and busulfan are reported to be more harmful to the ovaries by reducing ovarian reserve due to a decrease in the number of primordial follicles. The proposed mechanism of action of cyclophosphamide is inducing apoptosis through DNA double-strand breaks and oxidative stress. Anthracyclines, topoisomerase inhibitors, and platinum anti-neoplastic agents (i.e., cisplatin and carboplatin) are considered to have a moderate risk. The combination of several agents can increase follicular loss. Non-alkylating agents such as methotrexate, dactinomycin, bleomycin, mercaptopurine, 5-Fluorouracil, and vinblastine are considered to have much less severe adverse effects (mild or low risk) on fertility such as premature menopause. The last classification has unknown risk, which includes monoclonal antibodies (e.g., trastuzumab, pertuzumab, cetuximab), oxaliplatin, irinotecan, erlotinib, imatinib, daunorubicin, and paclitaxel (20, 21).

Gonadotoxic agents can cause primary ovarian insufficiency (POI) mainly through apoptosis and up regulation of the ABL/TAp63 and PI3K/Akt/mTOR pathways (burnout effect). Several drugs, including sphingosine-1-phosphate (S1P), AS101, and imatinib, have been designed to reduce chemotherapeutic-induced apoptosis in these cells (22).

Radiotherapy

Important factors related to fertility in radiotherapy are the dose and site of irradiation. Irradiation to the pelvis, abdomen, and brain (through the HPO axis) reduces the probability of biological conception. Radiotherapy exposure to the brain, especially the hypothalamuspituitary axis, impairs the function of the pituitary gland (hypopituitarism), resulting in the suppression of gonadotrophin hormones and subsequent ovarian dysfunction (23, 24). Oocytes are among the most sensitive cells to irradiation. Like chemotherapy, radiotherapy can also cause a decline in ovarian reserve and hormone imbalances due to disruption in estrogen production. Hyperprolactinemia is a consequence of irradiation that can cause secondary infertility (25). Like chemotherapy, ovarian sensitivity to radiotherapy increases with age. For example, abdominal or pelvic radiation doses greater than 6, 10, and 15 Gray (Gy) in adults, post-pubertal girls, and prepubertal girls respectively are associated with an increased risk of infertility and reduced ability to carry a pregnancy to term. An irradiation dose of 20 Gy or greater or total body irradiation (TBI) of 15 Gy can cause permanent infertility and POI, respectively (15). Other parameters include the dose and number of irradiations. Possible protective methods for reproductive organs during radiation include the use of a shield or barrier to reduce radiation damage to these organs. If the treatment procedure involves only radiotherapy, ovarian transposition is an option (25).

Hematopoietic stem cell transplantation

The indications for hematopoietic stem cell transplantation (HSCT) are blood diseases, which encompass cancerous blood diseases, such as leukemia, lymphoma, multiple myeloma and noncancerous blood diseases, such as aplastic anemia, thalassemia and fanconi anemia (26). HSCT is usually carried out after the conventional treatment and may entail chemotherapy and radiotherapy. The type of disease, the donor cell source, the patient’s age, the patient’s overall health and the condition of the patient’s bone marrow are some of the factors that influence the choice of HSCT for each patient (27). Following HSCT, infertility due to primary or secondary amenorrhoea affects about 80% of female patients. HSCT can cause reproductive-related complications with or without TBI, such as uterine dysfunction, uterine bleeding, premature ovarian failure, genital graft-versushost disease (GVHD) (frequently overlooked) and more problems during pregnancy (28).

Fertility preservation options in female cancer patients

Since these treatment protocols are associated with a risk of infertility, several ARTs have been utilized to help patients become pregnant following cancer therapies. There are several types of FP methods available, and the choice of method depends on various factors such as the patient’s age (prepubertal or postpubertal), type of malignancy, and type and duration of treatment. For example, ovarian tissue cryopreservation (OTC) is the only method that can be carried out in children and prepubertal girls. If the patient is at high risk of amenorrhea, clinicians may use two or even three methods of FP in combination (29). Embryo and oocyte cryopreservation are predominantly employed methodologies for FP and are often referred to as the 'gold standard' techniques. These procedures necessitate an approximate duration of 2 weeks prior to the initiation of any oncological treatment for the stimulation and retrieval of oocytes. Conversely, OTC is typically classified as experimental. Nonetheless, it remains the sole option for patients who necessitate immediate therapeutic intervention (30).

Oocyte cryopreservation

Oocyte cryopreservation (OC) is an ART that is similar to embryo cryopreservation (EC), except that fertilization does not occur. This method may be an alternative for patients who have ethical or legal concerns regarding EC or who do not have a male partner (31). This procedure is time-consuming, and if cancer treatment cannot be delayed for 2 weeks, OTC is recommended.

Two protocols are established for this purpose: “Conventional” and “Random Start”. Conventional [or early follicular phase start controlled ovarian stimulation (COS)] entails the introduction of gonadotropins at the onset of menstruation, accompanied by the use of either a gonadotropin-releasing hormone agonist (GnRH-a) or antagonist (GnRH-anta) to inhibit ovulation. Recent findings indicate that ovarian stimulation can be started on any day of the menstrual cycle, referred to as a random start (or late follicular or luteal phase start), by using GnRH-anta (32).

Adverse effects of COS include ovarian hyperstimulation syndrome (OHSS). Several strategies have been employed to mitigate the risk of OHSS, including the implementation of a low gonadotropin dose protocol utilizing a GnRH-anta as well as a GnRH-a trigger in place of the conventional human chorionic gonadotropin (HCG) trigger (32, 33). Ovarian stimulation also elevates estrogen levels, which may cause the deterioration of breast and hormone-dependent cancers (34). One particular concern for estrogen-receptor-positive breast and gynecologic neoplasms such as endometrial cancer is that fertilitysparing measures such as ovarian stimulation that raises estrogen levels may have the potential to increase the risk of cancer recurrence. Aromatase inhibitor (letrozole) or tamoxifen based stimulation protocols are now well established and can alleviate these concerns (3, 34, 35).

Based on the type and concentration of cryoprotectants, the timing of equilibration, cooling rates, and cryopreservation equipment used, variables vary between the various protocols that have been introduced. Cryoprotectants are divided into two categories: permeating, which can pass through the cell membrane [such as dimethyl sulfoxide (DMSO), glycerol, ethylene glycol, and 1, 2-propanediol], and non-permeating (such as sucrose, glucose, fructose, and trehalose). Slowfreezing and vitrification are the two main methods used for cryopreservation. Several studies have reported that vitrification yields better outcomes and is safer than slow-freezing due to the absence of ice crystal formation. Freezing can occur at both the cleavage stage (days 2 to 3) and the blastocyst stage (days 5 to 6), with the blastocyst stage being preferred (36).

It is important to note that the pregnancy rate from vitrified and fresh oocytes is comparable and largely depends on the age of the patient and the number of mature oocytes obtained during the process (37). The live birth rate (LBR) following the procedure of OC is reported to be 32%. A review of 58 studies with 609 babies born from frozen oocytes showed no difference in the incidence of birth defects, compared to babies conceived naturally. The study suggested that OC may be a more common choice for preserving fertility, especially for women with cancer. The rates of embryonic aneuploidy did not differ between women who underwent in vitro fertilization (IVF) with oocytes that were cryopreserved and those who used their oocytes that were fresh, according to one randomized control trial. And, the mean birth weight and the occurrence of congenital anomalies were comparable among 200 live births resulting from oocyte cryopreservation and those from standard IVF or spontaneous pregnancies, according to another study (38, 39).

Embryo cryopreservation

EC is the procedure of retrieving oocytes, fertilizing them with sperm through IVF, and then freezing the resulting embryos. It is considered the gold standard in FP (15). In the process of EC, sperm is indeed required for the creation of embryos. If the male partner withdraws consent in the future, it is likely that the woman will face legal and ethical challenges in using the embryos. On the other hand, the male partner should have undergone a semen analysis, which observed a period of 3-5 days of abstinence, in accordance with the WHO 2020 criteria. The initial procurement of semen was conducted around 5-6 hours prior to the microinjection of oocytes (40, 41). This method may be appropriate for individuals with various types of cancer, including leukemia, breast cancer, lymphoma, gastrointestinal tract cancer, gynecological cancer, melanoma, germ cell tumor, brain tumor, and sarcoma. The average pregnancy rate following frozen embryo transfer is reported to be between 30 to 35% (42). For married individuals, it is recommended that both oocyte and EC methods be implemented. This ensures that in the event of separation or the death of the male partner, the patient retains the option to utilize these resources.

According to one study, the proportion of women who had a live birth after breast cancer diagnosis was 19% for those with a history of FP and 9% for those without, after 5 years, and 41 and 16%, respectively, after 10 years. For the first live birth after BC, at least 20% of the pregnancies in the group with FP history and 4% in the group without were achieved through ART. These findings suggest generally positive long-term reproductive outcomes for women who were diagnosed with BC during their fertile years but also emphasize the need for FP counseling in this group (43). The study of Abel et al. (44) indicated that breast cancer patients who recovered their ovarian function should be given the option of natural conception prior to using cryopreserved tissue. On the other hand, for those who did not try to conceive naturally, using eggs or embryos that were cryopreserved before treatment had a high probability of success.

One of the long-term concerns regarding IVF is the increased cancer risk among IVF offspring compared to naturally conceived offspring. A recent cohort study involving 275,686 IVF offspring and 2,266,847 naturally conceived offspring showed that the overall cancer incidence (per million children) in the IVF group was about 17% higher than in the natural conception group. The health outcomes of the second or subsequent generations of IVF offspring have not been investigated, as OC and EC are relatively novel FP methods (45).

In vitro maturation

This protocol aims to overcome the adverse effects of COS. Immature oocytes can be retrieved independently of COS and then cryopreserved following IVM. The IVM procedure includes culturing (24 to 48 hours) of immature cumulus-oocyte complexes (COCs) obtained from antral follicles with minimal or without FSH stimulation. To enhance the success rate of IVM, gonadotrophins may be administered (priming) before retrieval. Compared to IVF, this procedure may increase the risk of blood contamination which entails simultaneous aspiration and needle-forced detachment of granulosa cells from the small antral follicles. IVM could also be performed after ex vivo extraction of oocytes following ovariectomy in ovarian cancer patients (46).

Taken together, the advantages of IVM include eliminating the use of expensive medications and the need for frequent monitoring, being less timeconsuming (2 to 10 days), avoidance of hormone usage in hormone-sensitive tumors, and oocytes retrieval can be performed at any point during the menstrual cycle, including the luteal phase (47). However, the lower success rate compared to conventional IVF procedures should be considered. Therefore, IVM is considered as an experimental technique (48). It was reported that the procedures of IVM of the oocytes achieved up to 35% clinical pregnancy rate in young women, similar to IVF in many programs.

Ovarian tissue cryopreservation

As previously mentioned, OTC is the preferred method for FP in pre-pubertal patients. In contrast to the aforementioned techniques, OTC does not need ovarian stimulation. However, this procedure is also age-dependent and not recommended for patients older than 35 years due to the limited number of immature oocytes in follicles. Previously, it was considered experimental; however, the American Society for Reproductive Medicine (ASRM) proposed OTC as an established method (49). OTC indications (Edinburgh criteria) encompassed a patient demographic under 35 years of age exhibiting greater than 50% risk of chemotherapy-induced ovarian failure, an absence of surgical contraindication, and a viable probability of survival. Patients who have previously undergone low gonadotoxic treatment or a prior round of chemotherapy can be offered OTC as a FP option (46). The majority of patients who are referred for OTC are individuals who have undergone gonadotoxic treatment for a range of cancers, including hematological forms such as lymphoma or leukemia, as well as solid malignancies like breast cancer, early endometrial carcinoma, and sarcoma (50, 51). The foremost consideration before hematopoietic stem cell transplantation should be the OTC. The usage of any procured tissue from patients with leukemia for autotransplantation should be avoided owing to the heightened likelihood of the reintroduction of cancerous cells. In the event that the time interval preceding chemotherapy administration is less than two weeks, particularly in a neo-adjuvant circumstance, it is imperative to note that ovarian stimulation is not a viable option. As such, the prudent course of action would be to consider OTC (51). It should be considered that in patients older than 35 and/or with low ovarian reserve [AMH <0.5 ng/ml and antral follicle count (AFC) <5], it is not recommended to perform OTC (50). OTC is contraindicated in ovarian carcinoma including borderline ovarian tumor and epithelial ovarian cancer, stage IV breast cancer, and other cancers that have metastasized to the ovaries (30, 51). Furthermore, it is important to note that certain conditions such as neuroblastoma and leukemia [especially acute lymphoblastic leukemia (ALL)] are considered high risk, with a greater than 10% likelihood of ovarian metastasis (52). However, OTC may be considered a feasible option for patients with BRCA1- and BRCA2-positive breast cancer. It is recommended that the transplants be removed upon completion of family planning (51).

In OTC, the ovarian tissue, either whole or in part, is collected via laparoscopy or laparotomy, and the cortex is cryopreserved (29). Typically, a laparoscopic procedure, performed as a day-case, involves the removal of no more than half of one ovary from the side opposite the mesentery using scissors, eschewing the use of electrical coagulation. The cortical tissue is subsequently prepared to a thickness of approximately 1 mm, segmented into small fragments, and then cryopreserved. The recommendation typically advocates for the removal of an entire ovary only in the case of prepubertal girls, attributed to the relatively small size of the ovaries. The wound surface is meticulously cleansed to identify the small, predominantly subcortical, sources of bleeding and selectively coagulate them. There is no requirement for the closure of the wound surface. A minor portion of the excised ovarian tissue is placed in formalin and dispatched to the pathologist to exclude the possibility of metastases (53).

The initiation of chemotherapy is typically observed three days after OTC, while the commencement of radiation therapy is recommended to occur seven to fourteen days subsequent to the operation (54).

Ovarian tissue transplantation

There are two different protocols that can be followed. If there is a risk of malignancy, mature oocytes are obtained from primordial follicles in vitro and then fertilized and transferred to the uterus. Alternatively, these follicles can be placed on a scaffold of alginate or fibrin (artificial ovary) and then transplanted orthotopically or heterotopically. In cases where there is no risk of malignancy, the ovarian tissue can be directly transplanted orthotopically or heterotopically (in subcutaneous tissue such as the forearm, chest wall, and abdominal wall), a procedure known as ovarian tissue transplantation (OTT) (55). The technique of orthotopic reimplantation has been demonstrated to be the most successful in terms of restoring ovarian hormonal function and FP. To transplant ovarian tissue orthotopically, thin strips of thawed tissue, less than 1.0-1.5 mm thick, are placed into the medullary segment of the existing ovary or a proximal peritoneal pocket (56, 57). The principal obstacle confronting the implementation of this technology pertains to the protracted revascularization and the consequent ischemia, fibrosis, and subsequent decay of the primordial follicles. Following transplantation, grafts become hormonally active in a span of three to four months, at which juncture oocyte harvesting may be endeavored, with or without the support of exogenous gonadotropins to elicit follicle development. The success rate following the reimplantation of ovarian tissue is on the rise, with the LBR currently estimated to be approximately 35-40% (58).

Two recent systematic reviews and meta-analyses have evaluated the long-term pregnancy outcomes of three main FP methods (OC, EC, and OTC). Xu et al. (59) reported after any FP intervention, the LBR was 0.046 in total. A mere 8% of women returned to employ their frozen reproductive material, resulting in 210 live births in sum, including assisted conceptions after EC/OC/OTC and natural conceptions after OTC. The probability of live birth was the highest for women who had EC, followed by the OTC group and OC group. The study of Fraison et al. (38) included women who received cancer treatment or haematopoietic stem cell transplantation. They reported that the LBR after IVF using frozen embryos and oocytes was 41 and 32%, respectively. The LBRs for IVF and for natural conception after OTT were 21 and 33%, respectively.

Ovarian transposition (oophoropexy)

Oophoropexy is a surgical option that involves moving the ovaries to the pelvic wall, behind the uterus, intraperitoneal or retroperitoneal of the muscle psoas, or paracolic gutters above the pelvis mainly laparoscopically to protect them from radiation damage. It should be mentioned that oophoropexy is not suitable for patients undergoing whole body or spine radiation (37, 60).

The transection of the ovarian ligament and mobilization of the ovary is a crucial step in surgical procedures. Preservation of blood supply is imperative and can be achieved through the infundibulopelvic ligament. It is of utmost importance to proceed with care to prevent torsion and extension of the ovarian vessels as this may significantly diminish blood supply to the ovaries ultimately impacting ovarian reserve (61). In patients who are scheduled to receive pelvic radiation, ovarian transposition can be performed concurrently with OTC (46). It is important to note that remigration of the ovaries may occur so the timing of surgery and radiation should be closely coordinated (3).

Patients who are younger than 35 years old should be considered for treatment due to their ovarian reserve, the probability of successful oophoropexy, and the radioresistance of their ovaries. Those individuals who possess a lack of involvement in lymphovascular invasion, are deemed to be the most suitable candidates to reduce the risk of ovarian metastasis (61). Patients with cervical, rectal, and colon cancer, pelvic, Hodgkin lymphoma, and Ewing’s sarcoma are other candidates (57). Before undergoing oophoropexy and receiving treatment, patients must be thoroughly assessed and advised regarding the risks of ovarian metastasis and the possibility of successful ovarian preservation. It is recommended that oophoropexy be done bilaterally if possible and that the ovaries be placed superior and lateral to the radiotherapy field (61).

The procedure in question carries a number of inherent risks, namely ovarian cysts, adhesions, pelvic pain, ovarian migration, premature ovarian failure (POF), and tubal injury. It is noteworthy that certain malignancies have a slight chance of metastatic disease spreading to the ovary, and therefore transposition may exacerbate the situation. In cases where pelvic radiotherapy is planned without the inclusion of chemotherapy, women may be presented with the option of ovarian transposition (46). Performing oophoropexy may potentially sustain ovarian hormonal functionality for a period of time; thus British fertility society has rated the recommendation level of this technique as D (the lowest level) (57, 61).

Ovarian suppression

GnRH analogues are chemicals that may be used as an option when oocyte, embryo, or OTC methods are not feasible, commonly in younger patients, particularly those with breast cancer. GnRH-a can decrease the risk of ovarian insufficiency caused by chemotherapy. These analogues have been reported to be administered to premenopausal patients with estrogen receptor-negative neoplasms. GnRH-a (such as Goserelin, Triptorelin, Diphereline, and Leuprolide) can limit gonadotropin [FSH and luteinizing hormone (LH)] concentrations and ovarian blood flow through the down regulation of the GnRH receptor. This suppresses ovarian function and protects against chemotherapy-induced POI. It has been reported that GnRH-a can elevate levels of S1P, which counteracts burn-out. Interestingly, the rates of menses recovery and pregnancy in women who received GnRH-a in addition to chemotherapy were higher compared to patients who only received chemotherapy. However, the combination of GnRH-a with taxanes had an unfavorable effect on menses recovery (62). Another benefit of GnRH-a is its ability to decrease vaginal hemorrhage. Mild side effects of GnRH-a may include hot flashes, headaches, sweating, and vaginal dryness (3). The effectiveness of ovarian suppression in reducing the risk of POF is disputed. However, recent evidence indicates a slight advantage. One meta-analysis of 12 randomized controlled trials (1231 breast cancer patients) showed that women who received LH releasing (LHRH) agonists during chemotherapy had lower rates of POF (18.5 versus 33.5%), lower rates of amenorrhea 1 year after treatment (31 versus 43%), and higher rates of pregnancy (9.2 versus 5.5%) (63). Examining 873 patients from five clinical trials of breast cancer cases, the patients in the GnRH agonist group had lower rates of POF (14.1 versus 30.9%) and higher rates of post-treatment pregnancy (10.3 versus 5.5%) with no significant differences in diseasefree survival or overall survival (64).

Several guidelines have discussed the use of GnRH-a in ovarian suppression. According to the European Society of Human Reproduction and Embryology (ESHRE), GnRH-a ought not to be deemed as a commensurate or substitutive choice for FP; nevertheless, they may be proffered subsequent to cryopreservation methodologies or in instances where they are not feasible. The use of GnRH-a during chemotherapy can be presented as an option for protecting ovarian function in premenopausal breast cancer patients who are undergoing chemotherapy. However, there is limited evidence regarding their protective effect on the ovarian reserve and the potential for future pregnancies (46).

The Spanish Society of Medical Oncology (SEOM) mentioned that the use of GnRH-a could be an option to discuss with patients with early-stage receptor-negative breast cancer if embryo or oocyte cryopreservation is not feasible (evidence IIB). The use of GnRH-a to preserve fertility in women with other cancers should not be recommended (evidence IIB) (65). The National Comprehensive Cancer Network (NCCN) concluded that it is imperative to conduct further research despite the indications that menstrual suppression using GnRH-a may potentially safeguard ovarian function based on available data (66). Finally, based on ASCO opinion, GnRH-a as a method of FP does not possess the status of a validated approach and therefore patients should be advised to opt for methods that have demonstrated efficacy in preserving fertility.

In summary, of the seven guidelines identified, two advocates for the utilization of GnRH-a as a means of FP in premenopausal patients with breast cancer, three recommend the use of GnRH-a for FP in premenopausal patients with estrogen receptor-negative breast cancer, and two do not endorse GnRH-a as a viable method of FP (3).

Fertility preservation challenges in female cancer patients

Oncofertility is a new science that has many challenges both in developed countries and, with a higher probability, in developing countries. Oncofertility practice faces multiple challenges in developing countries, such as low awareness, cultural and religious barriers, financial constraints, and limited access to healthcare resources (67). In this section, we briefly review some of these challenges all over the world but in developing countries, some of them are more prominent.

Medical challenges

Lack of awareness among oncologists about FP options and failure to refer patients in a timely manner for FP procedures; as well as lack of inter-institutional communication and shortage of specialists in the field of oncofertility (6). Physicians who have higher knowledge scores are more likely to have more discussions and engage in more consultation and referral. Moreover, physicians who have positive views on FP are more inclined to consult and refer more (68). The extent to which survivors comprehend and assimilate fertility-related information may influence FP choices. Survivors who do not fully grasp the possible impact of cancer and treatments on fertility may not seek FP. Patients who lack adequate fertility information can face higher levels of decisional conflict, affecting their capacity to make decisions that align with their values, and resulting in decisional regret (69). Consequently, many patients become infertile and sterile. The only remaining options for these patients to have children are adoption or third-party reproduction methods such as egg donation, sperm donation, embryo donation and surrogacy (6).

Economic challenges

Insufficient insurance coverage for oncofertility services, lack of financial and research support institutions, and the fact that most fertility assistance services are provided in private centers, with the majority of the cost of services being borne by patients. Patients who want FP often face no or limited insurance coverage for FP. For women, oocyte and embryo preservation cost between $10,000 and $15,000 on average nationally. For both sexes, extra costs are often incurred, including yearly storage fees. Even though financial assistance programs (e.g., grants by nonprofit organizations) exist, they normally only fund a fraction of FP costs. The responsibility of paying for FP falls on families and patients at a time when they have other considerable cancer-related expenses. Cost, rather than the aspiration for biological parenthood, may affect FP decisions instead (69).

Social challenges

Conservative cultural and religious attitudes towards FP options. FP involves many dilemmas for adolescent populations, such as virginity loss due to the trans-vaginal procedure during oocyte retrieval which is a very tough condition for the parents, especially in some cultural perspectives. To preserve the integrity of the hymen during follicle puncture, which is highly valued in Iranian culture, the following procedure is recommended. After administering anesthesia, the infertility specialist places the patient in the lithotomy position and exposes the hymen by retracting the labia minora. Then lubricates (OIL FOR TISSUE CULTURE, ART-4008-5P, 230915-017826, Cooper Surgical, Inc. Trumbull, CT 06611, USA) her little finger and gently probes the edges of the hymen. She gradually dilates the hymen by inserting the little finger into the vagina. The infertility specialist then assists the patient by introducing the ring finger and further dilating the hymen until the ring finger can move freely. The same process is repeated with the middle finger, the index finger, the thumb, and finally both the index and middle fingers together. The procedure takes 10-15 minutes to complete. After this, a suitable speculum can be inserted without causing any damage to the hymen (70).

Legal challenges

Restrictions imposed by countries’ laws on fertility assistance services (6). The decision making of the patient or their guardian is the main source of legal issues related to fertility preservation. These issues include: obtaining informed consent as a minor or an adult; participating in a research project or a routine medical procedure; and determining the future use and disposal of the preserved gametes and/or reproductive tissue, which may require female patients to use a gestational surrogate (71, 72).

Ethical challenges

Parents are often tasked with making decisions on behalf of their children. Consequently, adult factors, such as the desire for biological offspring, are likely to influence these decisions. Reproductive tissue engineering (REPROTEN) is a promising approach to restore fertility and enhance the quality of life of patients with genitourinary disorders by creating, substituting, or renewing cells, tissues, and organs of the genitourinary system. In vitro, culture of oocytes, Induction of female germ cells from pluripotent stem cells (PSC), Ovaria-related organoids construction, and artificial ovary construction are these techniques. In spite of REPROTEN’s remarkable achievements, it still faces ethical and technical hurdles that demand attention (73, 74).

International challenges

The lack of a referral network across the country is a challenge for international network activity. Access to services is still limited even in developed countries with specialized health networks and high levels of awareness and knowledge, and no practical program has been published to develop the field of oncofertility in low- and middle-income countries (75).

Systemic factors

Provision of information on FP options, coordination and integration in the provision of information by the service delivery team, access to services, ease of receiving services, and costs.

Human factors

Issues related to adolescents, involvement of the patient’s spouse with the subject, involvement of the patient’s family, decision-making regarding cryopreservation of gametes, embryos or tissue, and psychological support (76).

Equity in the provision of FP services

Despite advances in technology and knowledge in the field of oncofertility, there is a large gap in the structure of its management strategies worldwide. This has resulted in inequality in access to service providers among young women and girls diagnosed with cancer. Compared to men, women in countries with low and middle incomes face unequal access to resources, such as healthcare, employment, or education (77). Additionally, even though both men and women can access FP methods, women seem to be worse off than men when they encounter similar clinical situations and say they receive less information and access to FP than men (78). According to a study, there was a lack of adequate information on fertility for cancer patients of reproductive age, with female patients being more affected. Given the intricacy of FP for female patients, oncologists and hematologists should devote extra time to address fertility matters with women who are still menstruating. In contrast to adolescent boys and adult men who have easy access to sperm banking as an option, adolescent girls and adult women face significant obstacles to preserving their fertility, including the need for surgical procedures following ovarian stimulation to obtain oocytes or embryos. The process of sperm storage and freezing usually delays cancer treatment by 24-72 hours; however, oocyte or embryo storage options for FP in women can delay cancer treatment by 2-6 weeks. While EC is the first and most popular FP option worldwide, OTC is not available globally. Currently, there are a limited number of centers with experience in establishing ovarian tissue storage banks. It seems that in order to provide equitable FP services to cancer patients, scientists in this field should develop advanced FP technologies. On the other hand, Inhorn’s study investigated the stories of 14 religious (Jewish, Christian, and Muslim) women with high levels of education in the US and Israel who had completed at least one cycle of elective egg freezing. These women dealt with challenges in finding appropriate mates and employed EEF to prolong their reproductive chances and reduce their worries. The women comprehended or adjusted religious restrictions on EEF differently, thinking that their pursuit of religiously sanctioned reproduction justified the methods (79). Different religions have diverse attitudes and beliefs on the moral aspects of artificial reproduction. Most forms of artificial reproduction are acceptable in Hinduism and Buddhism, while Christianity and Islam have varying degrees of acceptance depending on the branches or sects within the religious group. For instance, all forms of assisted reproductive techniques are prohibited in Roman Catholicism, while Orthodox Christians have different opinions on them. Religious beliefs are among the factors that influence the patient’s decision on the preservation options that are available to them. In addition, it is claimed that women with cancer may have religious or ethical concerns about EC (80, 81). Muslim jurists’ main concern regarding technology such as oncofertility is to ensure paternity, as it is with IVF. The new technology poses minimal legal issues as long as the woman who owns the ovarian tissue is the one from whom it is taken, and any eggs that are produced in the future are fertilized with her husband’s sperm. However, if the egg or sperm is from a donor, the juridical issues related to IVF and oncofertility become more complicated due to the resemblance to adultery and the uncertainty of paternity (82).

Financial costs of FP services

The financial costs of FP services are one of the main challenges in this field. At the global level, financial support in the form of financial reimbursement remains a complex issue, and FP programs impose significant costs on individuals, limiting access to these therapeutic services for low-income individuals (89). Interestingly, these costs are solely for the collection and storage of gametes or embryos, and if patients wish to use their biological reserves for pregnancy after cancer treatment, an additional cost is imposed on them, which in most cases is not covered by insurance (83). It is worth noting that patients undergoing FP treatments are unable to take advantage of insurance benefits due to the current definition of infertility, which is based on 6-12 months of trying to conceive. In this regard, patients can be introduced to national humanitarian programs or institutions that reduce tissue storage and transfer costs and provide low-cost drugs to patients (84).

Systematic registration of information related to FP services

The lack of a systematic registry of information related to FP services, including the type of cancer in patients who have received FP services and their oncology and fertility outcomes, as well as statistics on the number of cryopreserved oocytes, embryos, and ovarian tissue, is one of the challenges in this field. To improve services, it is certainly necessary to evaluate the pregnancy rate and LBR for each FP option, as well as the pregnancy outcomes and long-term oncology prognosis of patients; in addition, the short-term and long-term health of the resulting infants should also be considered (85).

Challenges in decision-making regarding FP

There is a structural gap in health care policies. Currently, management strategies for FP are weak and imbalanced globally. International surveys show a lack of awareness about infertility and FP programs; therefore, health care must be organized to respond to this need. To develop infertility structures, a multidisciplinary project that enables specialists from different fields to interact with each other should be implemented (75). The increasing intervention of public health care systems in FP services in different countries will pave the way for the development of targeted strategies in the coming years. Lack of time and awareness has been identified as the main barriers to discussing FP; moreover, the lack of integration in counseling and referral standards for patients makes it difficult for patients to accept FP methods. The training of health service providers is also a challenge to meet the quality of life needs of these patients (86). Further information on the risks associated with FP options, better communication, access to supportive counseling systems to help make better decisions, availability of referral pathways, full patient awareness of the effects of cancer treatment on fertility, and the consequences of delaying cancer treatment due to FP are among the expectations of cancer patients from the health service delivery system. It is suggested that these issues be included in informed consent forms for FP procedures (87).

Despite all the mentioned issues, decision-making regarding FP, even if the patient receives sufficient information about the available options and has the financial resources for these procedures, is a very complex process. Our knowledge of the biological and psychosocial consequences of using different FP methods, including standard and experimental options, is limited. In the meantime, psychological and sexual issues must also be considered; because these issues have significant effects on fertility and future family formation by these individuals (83).

On the other hand, the ethical and legal dimensions of this issue should not be neglected. It should be noted that in the process of FP, the preparation of cells or tissues for reproductive purposes takes place in a difficult and stressful situation and decision-making is intensified by the pressure caused by the need to quickly start cancer treatment due to the threat to the patient's life; in addition, in this situation, it seems unlikely that the patient will fully understand the points related to cell or tissue extraction. On the other hand, any provision of information to the patient must be done specifically with regard to the cultural and religious beliefs of the patient and their family (88). Many women who have survived cancer are unable to use their cryopreserved oocytes; because they do not have a partner to form an embryo and transfer it to the uterus. In the case of other couples, the end of a marital relationship leads to legal disputes over the use or destruction of gametes or cryopreserved embryos; also, in the case of the death of the patient, difficult decisions arise regarding the outcome of stored cells or tissues. These issues highlight the importance of a comprehensive FP program based on ethical and legal expertise.

The most important topic that should be discussed during counseling is focusing on the potential effects of cancer treatment on individual fertility; although the emphasis has been placed on discussing individual fertility assessment to guide decision-making in patient treatment processes. Other topics under discussion include various FP techniques, technical aspects, advantages and disadvantages, and success rates of each, as well as issues related to treatment costs and insurance services that should be emphasized; while decision-making regarding cryopreserved biological materials (ovary or oocyte) in case of death or disability should be considered. The possibility of benefiting from options such as adoption, donated gametes or embryos, and surrogate uteruses in the future should also be explained to individuals (89).

Alternative family building

Several decision aids and interventions are available for young adult females who contemplate FP prior to treatment. However, none of them addresses the posttreatment family-building decisions, which are more complicated and involve more alternatives and challenges, such as choosing between IVF or surrogacy (with/without autologous/cryopreserved/donated gametes and statespecific regulations) or domestic or intercountry adoption (with various country options). Survivors require more guidance and support to examine their options, anticipate possible challenges, and take proactive measures to attain their family aspirations. Some of the factors that survivors should consider include fertility assessment, legal implications, and financial expenses (90).

Organizing clinical protocols for cancer treatment

The creation and implementation of uniform guidelines and policies regarding the provision of FP services, including treatment protocols and standardization of procedures, is essential to overcome differences of opinion regarding the provision of these therapeutic services and to prevent delays in cancer treatment (87).

Conclusion

While international guidelines on oncofertility practice have been published in developed countries, there is limited information available on oncofertility practice in developing countries, which often face limitations in their cancer health support networks. As survival rates improve in the field of cancer and other diseases, there is a growing need for stronger oncofertility services in developing countries. Given that 50% of cancer patients are under the age of 65, many of these patients are of reproductive age and preserving their fertility health prior to starting treatment is valuable. However, due to resource limitations and the heavy burden of treatment costs imposed on these patients and their families, FP may not be a top priority for them. As a result, many healthcare providers and their patients focus on eliminating cancer and its related treatments while overlooking the importance of fertility as a factor that can significantly impact their future quality of life.

Authors’ Contributions

E.M.M., A.Y., F.Gh.; Have made contributions to the writing of the manuscript. All authors have approved the submitted version of the manuscript and agreed to be personally accountable for the author's contributions and to ensure that questions related to the accuracy or integrity of any part of the work. All authors read and approved the final manuscript.