|Ahead of print publication
Fertility preservation in cancer patients
Yuan-Xue Jing, Li-Li Zhang, Hong-Xing Li, Feng Yue, Nai Hui Wang, Shi-Long Xue, Yi-Qing Wang, Xue-Hong Zhang
Reproductive Medicine Center, The First Hospital of Lanzhou University; Key Laboratory for Reproductive Medicine and Embryo of Gansu, Lanzhou 730000, China
|Date of Submission||23-Jun-2020|
|Date of Decision||18-Sep-2020|
|Date of Acceptance||23-Nov-2020|
|Date of Web Publication||19-Feb-2021|
Reproductive Medicine Center, The First Hospital of Lanzhou University, No. 1, Donggangxi Road, Chengguan District, Lanzhou 730000, Gansu
Source of Support: None, Conflict of Interest: None
Traditional radiotherapy and chemotherapy often cause irreversible damage to the fertility and endocrine function of cancer patients. The current methods of fertility preservation include freezing the sperms of adult and adolescent males after puberty; freezing the embryos, oocytes, and ovarian tissue of females; and drug intervention and fertility preservation surgery. This article reviews fertility preservation in cancer patients with respect to current methods, indications, and some more recently developed methods that remain under investigation.
Keywords: Cryopreservation of Ovarian Tissue; Cryopreservation of Testis Tissue; Cryopreserved Embryos and Oocytes; Fertility Preservation; In vitro Maturation
| Introduction|| |
The incidence of cancer has been increasing annually, whereas the average age of cancer patients has been decreasing. According to the International Agency for Research on Cancer, there were 18.1 million new cancer cases and 9.6 million cancer deaths worldwide in 2018. In the United States, 9% of cancer patients are aged <45 years and 1% are aged <20 years. With improvements in cancer diagnosis and treatment methods, the survival rate of cancer patients has significantly increased. However, the use of radiotherapy and chemotherapy for the treatment of tumors is associated with infertility or low fertility caused by damage to the gonads or germ cells, which seriously affects the quality of life of patients. With growing concerns regarding the reproductive problems associated with cancer therapy, oncologists and reproductive endocrinologists need to ensure treatment of the disease while making efforts to protect the fertility of patients with malignant tumors, in order to achieve a balance between life extension and fertility preservation.
The rapid development of assisted reproductive technology (ART) has provided additional options for fertility preservation in cancer patients. Many emerging technologies offer hope for most patients with tumor diseases. This article reviews the methods of fertility preservation in male and female cancer patients to provide a comprehensive set of reference data for clinical treatment.
| Male Cancer Patients|| |
Fertility preservation in adult males and pubertal males
Cryopreservation of sperms is the best choice for fertility preservation in male patients with a tumor. However, in cases in which semen or sperms cannot be obtained, cryopreservation of testicular tissue is also an important strategy. The beginning of puberty is a key time point for successful fertility cryopreservation. Sperm collection before tumor treatment is recommended because a single treatment modality may impair semen quality and sperm DNA integrity, leading to a potentially higher risk of genetic damage. Testicular tissue is extremely sensitive to radiotherapy, with an apparent dose correlation. A single radiation dose of as low as 0.1 Gy can cause morphologic and numeric changes in spermatogonial cells; a single radiation dose of >4 Gy can reduce sperm concentration and germ cell number to levels that would require >5 years to recover; and a single radiation dose of >6 Gy can lead to permanent azoospermia. The damaging effects of chemotherapy on male gonads largely depend on the drugs, dose, and course of treatment, and the drugs that commonly affect gonadal function are alkylating agents, platinum, antimetabolites, vinblastine, and topoisomerase inhibitors. Except for those used to target radioisotopes or toxins to cells, most of the newer biologic targeted therapies have fewer adverse effects on male gonads; however, their effects when combined with cytotoxic agents are unclear.
Malignant tumors have several negative effects on normal sperm production before diagnosis, and sperm quantity and quality may have already decreased before treatment. Studies have shown that the sperm quality of cancer patients is lower than that of healthy sperm donors, and the sperm quality of patients with a testicular tumor is lower than that of patients with other tumors. In one study, 20.72% (29/140) of patients with a tumor had oligospermia at the first visit and 10.00% (14/140) had occasional motile sperms, among whom seven patients had no sperm detected in the semen. The DNA fragmentation index (DFI) of sperms is an important indicator of sperm quality, and the sperm DFI of patients with a tumor is higher than that of fertile male controls. Various factors affect sperm production and motility in patients with malignant tumors. The hypothalamic-pituitary-gonadal (HPG) axis is essential for regulating the production of hormones necessary for normal sperm formation. Tumors that directly invade the hypothalamus, pituitary gland, or testis affect fertility. Human chorionic gonadotropin (hCG) and/or alpha-fetoprotein secreted by prolactinomas, paraneoplastic syndrome lesions, and testicular tumors can disrupt the HPG axis. Malignant tumors can also directly damage reproductive epithelial cells by causing systemic inflammation induced by cytokines.
Various factors have led to an increase in fertility problems in recent years, with male infertility accounting for approximately 50% of fertility-related problems. In addition to the negative effects of malignant tumors, infertility caused by severe oligospermia or azoospermia is more common in male cancer patients. Because the number of live sperms is highly reduced, traditional cryopreservation techniques are difficult to implement in these patients. The continuous optimization of freezing carriers, cryopreservation procedures, and cryopreservation protectant formulations has yielded new cryopreservation techniques that can preserve fertility in patients with a small number of spermatozoa or even severe oligospermia and obstructive azoospermia.,,, Berkovitz et al. used a novel sperm vitrification device (SpermVD) to successfully freeze a single sperm. In their study, the fertilization and pregnancy rates after thawing and intracytoplasmic sperm injection (ICSI) were 59% and 55%, respectively, with a delivery rate of at least 32%. The device can be directly used on ICSI dishes under heating conditions, thereby reducing the postthaw search time from hours to minutes. The study was considered valid because it consisted of preclinical validation and subsequent clinical results. Further studies using SpermVD as the freezing carrier showed that 8 min was the best time for freezing protectants, and the highest motility rate could be obtained after sperm reheating. The single-sperm cryopreservation technique that was introduced in 1997 has been continuously optimized. In particular, the development of cryopreservation carriers directly improves the technology of single-sperm cryopreservation, increases the recovery and activity of the sperm after cryopreservation, and can preserve fertility in patients with severe oligospermia and non-obstructive azoospermia.
In summary, spermatozoa cryopreservation is the best choice for fertility preservation in postpubertal male patients with a tumor, and the development of this technology provides technical conditions for fertility preservation in more patients.
Fertility preservation in prepubertal males
The current methods of fertility preservation require the acquisition of mature sperms for use in ART after tumor recovery. For prepubertal males with immature sperms, fertility preservation techniques are still underdeveloped.
The first unequivocal evidence for fertility preservation in prepubertal males was provided by a 2012 study that showed that cryopreserved testicular tissue from prepubertal primates maintained its function and produced sperms after grafting. In a recent study, by reducing the concentration of dimethyl sulfoxide, increasing the volume of frozen testicular tissue, and suturing the subcutaneous tissue slice for transplantation, the cryopreserved testicle of prepubescent rhesus monkey was successfully autologously transplanted, producing functional sperms and obtaining healthy offspring. However, in cancer patients, especially those with childhood leukemia, lymphoma, and testicular tumors, testicular tissue collected before cancer treatment may contain malignant cells; thus, there is a potential risk of reintroducing malignant cells during cryopreservation and transplantation. Cell sorting cannot completely rule out the possibility of the existence of cancer cells. Autologous testicular tissue transplantation is more suitable for patients with bone marrow transplant for nonmalignant diseases (e.g., thalassemia and sickle cell tumors) and patients with solid tumors (e.g., sarcoma and neuroblastoma). At present, cryopreservation and replantation or transplantation of testicular tissue is still in the experimental stages and should only be performed as part of clinical trials or approved experimental protocols.
Yokonishi et al. froze the testicular tissue of newborn mice. After thawing, the sperms were cultured in agarose gel, and healthy offspring were obtained through microfertilization. This indicates the possibility that freezing testicular tissue before puberty could be used as a method for preserving male fertility in future. Zhou et al. differentiated mouse embryonic stem cells in vitro to produce primitive germ cell-like cells, co-cultured them with neonatal testicular somatic cells, and allowed the cells to differentiate and complete meiosis to obtain functional sperms. Thereafter, they performed ICSI and eventually obtained vital offspring with fertility. This is the first time that meiosis of stem cells in vitro and acquisition of functional sperm cells were achieved. This experiment was a breakthrough in the in vitro culture of spermatogonial stem cells and laid the foundation for the induction and differentiation of human spermatogonial stem cells into functional sperm cells in vitro. At present, the culture conditions for human spermatogonial stem cell amplification have yet to be determined, and the viability of frozen spermatogonial stem cells has yet to be confirmed.
In summary, testicular tissue containing spermatogonial stem cells should be frozen before cancer treatment in prepubertal males, with a view of potentially benefiting from safer and more effective treatments in future [Figure 1].
| Female Cancer Patients|| |
After chemoradiotherapy, female patients experience premature ovarian failure (POF), characterized by ovarian atrophy, follicular atresia, and oocyte apoptosis. Fertility preservation in female cancer patients is attempted by taking various measures before anticancer treatment.
Assisted reproductive technology
Cryopreservation of mature oocytes and embryos
For the preservation of fertility in female cancer patients, mature oocytes need to be obtained through controlled ovarian stimulation (COS) in advance, followed by cryopreservation of mature oocytes or embryos after in vitro fertilization. However, the safety and effectiveness of COS must be ensured before its implementation.
Cancer patients need to be treated as early as possible, whereas traditional COS is performed during the follicular phase. The procedure normally requires 2–6 weeks, depending on the patients' menstrual cycle. Therefore, traditional COS is disadvantageous for patients who need urgent treatment. Studies on freeze-all in vitro fertilization cycles have suggested that the early follicular cycle phase is the preferred starting point for ovarian stimulation, although luteal cycles can also be acceptable if necessary. A prospective multicenter study has shown that random-start protocols can yield oocytes, frozen oocytes, and frozen embryos in the same numbers as conventional stimulation. In a previous study, no significant statistical difference was observed between the random-start protocol and ovarian stimulation in the follicular stage, in terms of demographics and cycle-related outcomes such as peak E2, stimulation days, number of retrieved oocytes, and number of cryopreserved oocytes and embryos. A randomized controlled trial confirmed that follicular growth is not disturbed by the presence of dominant follicles or luteum, which supported the effectiveness of random-start protocols. Random-start protocols allow patients to start ovarian stimulation immediately and shorten the time to embryo or oocyte storage. Oocytes or embryos can be gained within 2 weeks in most patients, which can minimize delays in cancer treatment.
Conventional COS can increase the overall estradiol concentration several times than normal, which may have negative effects on estrogen-dependent tumors (e.g., breast cancer and endometrial cancer [EC]). For estrogen-sensitive women with breast cancer, protocols with co-administration of letrozole, an aromatase inhibitor, have been shown to significantly reduce the mean estradiol concentration on triggering day. The use of gonadotropin-releasing hormone analog (GnRHa), rather than hCG, as a trigger further reduces estradiol concentrations and minimizes the risk of ovarian hyperstimulation. In fact, the risk of severe ovarian hyperstimulation syndrome may remain low in breast cancer patients undergoing COS, especially when GnRHa is used clinically. The addition of letrozole did not significantly affect the yield of oocytes in either a systematic review study or in a prospective controlled trial., In the COS group with the co-administration of letrozole, GnRHa also obtained more mature oocytes and frozen embryos than hCG as the trigger,, which represents an additional benefit for patients.
A study that compared the long-term outcomes of fertility preservation and nonpreservation of fertility showed no difference in cancer mortality. The changes in the concentrations of other hormones (e.g., androgen, progesterone, or vascular endothelial growth factor), caused by controlled ovarian hyperstimulation in patients with breast cancer, have not been quantified. However, a long-term follow-up study showed that the all-cause survival was similar between women who underwent COS and those who did not. Moreover, there was no difference in the 5-year survival of women undergoing COS treatment with or without letrozole. A systematic review of randomized controlled trials showed that breast cancer patients treated with COS protocols with letrozole co-administration did not have reduced disease-free survival compared with those who were not enrolled in a fertility preservation program.
Because the number of patients using their preserved oocytes or embryos after completing cancer treatment is currently low, data on reproductive outcomes are limited. Thawing oocytes and/or embryos after the cure of cancer has achieved live births in some women. Cancer patients at the same center had similar rates of achieving a live birth with embryos from cryopreserved oocytes after receiving the same treatment as noncancer patients, with slightly higher rates of embryo implantation per embryo transfer.
In summary, the addition of letrozole and the random-start protocol using GnRHa as the trigger have significantly reduced delays in tumor therapy and resulted in satisfactory oocyte production at reduced estradiol concentrations. The flexible use of COS protocols makes the fertility preservation strategy of freezing mature oocytes or embryos suitable for most postadolescent female patients.
Cryopreservation of immature oocytes
Immature oocytes can be obtained through ultrasound-guided puncture or during tumor surgery, and cryopreservation of immature oocytes can be performed at any time during the menstrual cycle. Immature oocytes are more tolerant to temperature changes during freezing than mature oocytes. Cryopreservation of immature oocytes combined with in vitro maturation (IVM) culture is a safer method for fertility preservation. However, the immature oocyte IVM technique is still underdeveloped and has not been widely implemented.
In recent years, some studies have been published on the improvement and optimization of IVM. Oocytes were precultured in medium containing C-type natriuretic peptide and subsequently cultured in normal IVM. Animal experiments demonstrated that such an improved IVM system enhanced the viability of immature goat oocytes and improved the cumulus function and oocyte quality in minimally stimulated mice. In women with polycystic ovarian syndrome, this method, when applied to oocytes from small sinus follicles (<6 mm), had the best effect in promoting maturity and improving embryo quality, indicating that its optimization effect is not limited to the laboratory but is feasible in the clinical population. Other studies have also confirmed that this IVM system improves the oocyte maturation rate and day 3 cleavage embryo availability, resulting in high-quality blastocysts, significantly improved clinical pregnancy rates, and healthy live births. Epigenetic studies have shown that blastocyst obtained in this manner showed similar rates of methylation, genomic DNA gene expression, and expression of major epigenetic regulators.
Melatonin is an effective antioxidant, and its addition in appropriate concentrations is beneficial in IVM of human oocytes. Compared with conventional COS in women with polycystic ovarian syndrome, the mechanism of IVM with melatonin may be enhancing clathrin-mediated endocytosis and decreasing intra-oocyte cAMP concentrations, as well as alleviating oxidative stress in human oocytes by improving mitochondrial function. During controlled ovarian hyperstimulation in a previous study, when immature oocytes were retrieved for IVM, the rate of high-quality blastocyst formation in the melatonin group was significantly higher than that in the nonmelatonin group (28.4% vs. 2.0%), and the incidence of high-quality blastocyst aneuploidy in the melatonin group was very low (15.8%). Healthy live births were achieved in this clinical experiment.
At present, there are still very few reports of babies born from cryopreservation and rewarming of immature oocytes, and the clinical pregnancy rate is much lower than that of mature oocyte cryopreservation. Cryopreservation of immature oocytes combined with IVM has the advantage of reducing ovarian stimulation and eliminating the risk of reintroducing malignant cells during autologous transplantation of ovarian tissue. The combination of immature oocyte cryopreservation and in vitro culture systems (including IVM) is expected to benefit fertility preservation in patients, especially in preadolescent women.
In summary, cryopreservation of immature oocytes can be applied to preadolescent women and is an alternative method for patients who need urgent fertility preservation or patients with hormone-dependent tumors who do not wish to undergo ovarian hormone stimulation.
Cryopreservation of ovarian tissue
Cryopreservation of ovarian tissue and autotransplantation
Ovarian cortical tissue or complete ovaries are often obtained via laparoscopy. After cancer recovery, ovarian tissue autotransplantation can restore the ovarian endocrine function. In 2004, Donnez et al. reported the first successful pregnancy and delivery after the transplantation of cryopreserved ovarian cortical tissue. Five months after replantation, recovery of the normal ovulatory cycle was achieved, as shown by the patient's basal body temperature, menstrual cycle, transvaginal ultrasound findings, and hormone concentrations. Eleven months after replantation, hCG and transvaginal sonography revealed intrauterine pregnancy, resulting in a single live birth. Another study has shown that even if ovarian failure occurs during chemoradiotherapy, autologous transplantation of ovarian tissue frozen before chemoradiotherapy can result in sufficient secretion of estradiol to induce pubertal development in prepubertal girls. To date, >140 live births have been achieved through cryopreservation and retransplantation of ovarian tissue worldwide.
The optimal thickness of ovarian tissue for cryopreservation, which can maximize the preservation of the primary follicles while allowing the cryopreservation agent to fully enter the ovarian tissue, is approximately 1 mm. There are two types of ovarian tissue transplantation according to the transplantation site: orthotopic and heterotopic. After the resuscitation of frozen ovarian tissue, retransplantation to the pelvic area is referred to as orthotopic transplantation, and transplantation to another site outside of the pelvic area (e.g., subcutaneous portion of the abdominal wall and subcutaneous portion of the forearm) is referred to as heterotopic transplantation. The most common site of orthotopic transplantation after thawing the ovarian cortex is the surface of the ovarian medulla (after peeling atrophic ovarian tissue). Transplantation to the ovary is more likely to achieve natural conception, as the local environment of the ovary and its vascularization facilitate the functional recovery of the transplanted tissue. The original follicles should be present in the transplanted ovarian tissue to allow a 100% recovery rate of ovarian activity. According to studies published to date, follicular development recovery and increase in estradiol secretion can be achieved approximately 4–6 months after ovarian cortical transplantation, with the ovarian function lasting for approximately 5 years on an average. If the transplanted ovarian cortical tissue is not functional, the remaining ovarian tissue can be thawed and ovarian activity can be restored for >11 years. If follicular density is high, the recovery of ovarian activity depends on age. As follicular density is higher in children than that in adults, cryopreservation of the ovarian cortex during childhood and its subsequent implantation may be more successful, at a rate inversely proportional to age.
Ovarian tissue cryopreservation as a means of preserving fertility still has some deficiencies. Surgery is invasive and requires general anesthesia, which may pose an unacceptable risk in some children with cancer. As cancer patients may have immune deficiency and pancytopenia, they have an increased risk of bleeding and infection. Moreover, there is a risk of reintroducing malignant cells during autologous transplantation of cryopreserved ovarian tissue, including malignant ovarian tumor cells or ovarian metastasis, as well as the possibility of malignant transformation of the transplanted ovarian tissue. A systematic review revealed that in 422 patients subjected to testing for malignant cells using various methods, 31 (7%) were suspected to have malignant cell infiltration in ovarian tissue. Transplantation is prohibited if ovarian cancer cells are detected in the cryopreserved tissue. It is crucial to identify minimal residual lesions before ovarian tissue transplantation in patients with hematologic malignancies. Because leukemia and Burkitt's lymphoma often metastasize to the ovaries, transplants are highly risky. The safety of autologous transplantation in patients with gastrointestinal cancers or endometrial cancers is also a concern. Breast cancer, osteosarcoma and other connective tissue sarcomas, other gynecologic tumors, Hodgkin's lymphoma, and non-Hodgkin's lymphoma have a lower risk of introducing malignant cells in autologous transplantation. The risk of metastasis to the ovary is not only related to the classification of the primary tumor but also closely related to the tumor stage at the time of ovarian tissue removal. In addition, rapid changes in temperature during cryopreservation and exposure to cryoprotectants may increase the risk of malignant transformation of ovarian tissue. Therefore, thorough examination of ovarian tissue is crucial before cryopreservation and transplantation. In ovarian tissue studies in patients with leukemia, despite the detection of malignant cells in xenograft ovarian tissue and digested ovarian suspension liquid, no leukemia cells were detected in all separated and cleaned follicular suspension liquids. This result demonstrates the potential application of follicular separation techniques in restoring fertility in leukemia patients.
Cryopreservation of ovarian tissue combined with in vitro maturation
Cryopreservation of ovarian tissue may be combined with the removal of small antral follicles via puncture, making it possible to freeze both ovarian tissue and isolated immature oocytes. In 2014, the first live birth achieved through this approach was reported. The young patient in the study had Stage IIIC ovarian tumor and underwent fertility preservation through the removal of immature oocytes from the ovaries, IVM of the immature oocytes, and cryopreservation and transfer of the obtained embryo. For patients at a high risk of reimplantation of malignant tumors, isolation of individual follicles from ovarian tissue, then subjecting the immature oocytes to IVM and fertilization, may be considered. Another method of fertility preservation was reported in 2008, in which immature oocytes were obtained from the removed ovarian tissue and subjected to IVM and vitrification, while the ovarian tissue was cryopreserved. This strategy was subsequently adopted at some centers to maximize fertility preservation., Combining IVM of immature oocytes with ovarian tissue cryopreservation is applicable to young and even prepubescent cancer patients with a high risk of recurrence after ovarian tissue thawing and retransplantation. A study reported that a higher average number of oocytes and a higher proportion of degenerated oocytes were retrieved from young girls than in adult women [Figure 2].
|Figure 2: Cryopreservation of ovarian tissue combined with in vitro maturation|
Click here to view
In summary, ovarian tissue autotransplantation has unique advantages as a method of fertility preservation in cancer patients, as follows: it can be immediately performed without ovarian stimulation; it can restore ovarian function; and it does not require sexual maturity, making it the only feasible method for children. Future studies should address how to avoid the reintroduction of malignant cells, how to prolong the life of transplanted ovaries as much as possible, and how to improve the effect of artificial ovaries [Figure 3].
Gonadotropin-releasing hormone agonist
By inhibiting the HPG axis, GnRHa can prevent the transformation of primitive follicles to mature follicles and reduce the damage caused by chemotherapy drugs.
GnRHa has been shown to have beneficial effects for patients with blood disorders (primarily Hodgkin's lymphoma) and in young patients with breast cancer; however, these preliminary results need to be confirmed in a larger group of patients and in prospective randomized studies. In a previous review, the incidence of POF in patients treated with GnRHa was lower than that in the control group; however, the statistical evidence was insufficient, and a definitive conclusion about the reduction of POF by GnRHa was not reached owing to the retrospective and nonrandomized nature of most studies. Other studies reached an opposite conclusion. Prospective studies involving patients with lymphoma could not prove that GnRHa is effective in preventing POF. Another prospective randomized trial demonstrated that GnRHa was ineffective in preventing chemotherapy-induced POF in young patients with lymphoma, and no evidence was found for its benefits in preserving ovarian function and fertility in lymphoma survivors who received chemotherapy.
A major limitation in GnRHa trials is the reliance on menstrual status and estradiol or follicle-stimulating hormone assessments to determine fertility. The long-term live birth rate is the most appropriate fertility indicator; however, studies evaluating long-term live birth rates are scarce and often lack effective follow-up duration or sufficient patient numbers to draw accurate conclusions. Trials with the number of pregnancies as the study end point showed that premenopausal patients with hormone receptor-negative breast cancer who received chemotherapy and goserelin had higher pregnancy rates than patients who received chemotherapy alone, and this combined treatment improved disease-free survival and overall survival. However, another randomized trial showed the opposite result: no significant difference in pregnancy rates was observed between the treatment groups. Of four systematic reviews, two studies showed that the pregnancy rate of patients receiving chemotherapy plus GnRHa was significantly higher than that of patients receiving chemotherapy alone., However, the other two studies did not reach a similar conclusion: they reported that GnRHa does not protect the ovaries from toxicity during chemotherapy and concluded that the utility of GnRHa in fertility preservation remains uncertain., Because of the unreliability of this treatment, its use is not recommended, except in clinical trials.,
GnRHa may have other potential medical benefits. A study has shown that the incidence of vaginal bleeding during chemotherapy is lower in patients treated with GnRHa than that in controls. In young women with thrombocytopenia caused by chemotherapy, GnRHa combined with medication can more effectively prevent menorrhagia. GnRHa is also an effective agent for preventing uterine bleeding due to hematologic malignancies.
In summary, based on the conflicting results of studies on the role of GnRHa in reducing the risk of ovarian dysfunction, especially when considering all types of cancers, GnRHa cannot replace proven methods of fertility preservation.
AMH is produced by granulosa cells that grow in follicles. By measuring serum AMH concentrations, ovarian damage caused by toxic interventions such as chemotherapy and radiotherapy can be quantitatively assessed. AMH is a negative regulator of primordial follicular activation. It can be used to prevent chemotherapy-related ovarian dysfunction by blocking the activation of primitive follicles. In mice administered with carboplatin, doxorubicin, or cyclophosphamide, the AMH-treated group had more primary follicles than that of the control group.
The protective effect of AMH on human ovaries needs further studies; however, its action mechanism broadens the idea of chemotherapy-related ovarian protection.
S1P is an inhibitor of sphingolipid hydrolysis that induces cell apoptosis. Chemotherapeutic drugs accelerate the apoptosis of germ cells by activating the apoptosis pathway, and inhibition of apoptosis can protect the ovarian function. Mice pretreated with S1P were protected from follicular cell death that can be caused by intravenous chemotherapy with dacarbazine, thereby protecting their fertility. In mice with human ovarian xenograft tumors treated with cyclophosphamide or doxorubicin, S1P was shown to significantly reduce the apoptosis of primitive follicles, indicating the protective effect of S1P on primitive follicles in vivo in a chemotherapy environment. In addition, S1P has been shown to protect rhesus monkey ovaries from being damaged by 15-Gy targeted radiotherapy. In one study, offspring conceived and delivered by S1P-protected females developed normally with no signs of genomic instability. These experiments indicate that S1P and its analogs have potential clinical applications as therapeutic agents that can protect the ovarian function and fertility of female cancer patients who receive cytotoxic therapy.
However, the mechanism by which S1P protects primate ovaries from cytotoxic treatment-induced damage in vivo remains to be determined. In addition, because S1P must be directly injected into the ovary, the clinical application of this treatment is challenging. Further drug studies are needed to develop more effective protective agents to ensure ovarian function preservation.
Ovarian transposition and fertility preservation therapy
The ovary is a therapy-sensitive tissue. Radiotherapy accelerates oocyte atresia and results in POF and ovarian dysfunction. Before radiotherapy, the ovary should be moved and fixed to a different position via laparoscopy or laparotomy to prevent it from being irradiated, while preserving its blood supply. Ovarian translocation not only can protect the ovarian endocrine function but also can enable ultrasound-guided oocyte retrieval to achieve pregnancy through ART.
As primordial oocytes are more resistant to the effects of radiation than mature oocytes, the effects may vary at different stages of oocyte development. Wallace et al. proposed, through mathematical modeling, that the higher the patient's age, the lower the dose of effective radiation needed to cause immediate ovarian failure. Multicentric retrospective cohort studies have shown that ovarian failure is associated with radiation dose and patient age.
However, there is a risk that the displaced ovary will self-migrate to the original position in the pelvis. Additionally, ovarian displacement will not thoroughly protect the ovary from scattered radiation. In addition to changes to the blood supply into the ovaries, the effect of this procedure on fertility protection is limited.
In summary, ovarian transposition as a means of fertility preservation is mainly used for young cancer patients undergoing pelvic radiotherapy, and its protective effect is limited.
Fertility preservation therapy
Fertility-sparing surgery for cervical cancer
Cervical cancer has a high incidence in women of childbearing age. Fertility-sparing surgery (FSS) is mainly applicable to patients with Stage IA1–IB1 cervical cancer, no obvious parauterine or uterine body infiltration, no pelvic lymph node or para-aortic lymph node metastasis, and maximum lesion diameter of ≤2 cm. Among patients aged ≤40 years with Stage IA1 cervical cancer, no significant difference in the 5-year survival rate was observed between those treated with hysterectomy and those treated with conization. Other studies have confirmed the oncologic safety of radical cervicectomy; however, subsequent complete surveys of reproductive data have shown that radical vaginal cervicectomy requires extensive fertility treatment, mainly due to cervical factors or stenosis.
Fertility-sparing surgery for ovarian tumors
For patients with borderline ovarian tumors or low-grade ovarian malignancies who require fertility preservation, unilateral salpingo-oophorectomy is feasible. In this treatment, the healthy ovarian tissue is retained, biopsies of the omentum and peritoneum are performed, and pelvic lavage is employed. A retrospective analysis of 240 patients with epithelial ovarian cancer showed that FSS had a negative effect on prognosis only in Grade 3 patients and was significantly associated with extra-ovarian recurrence. Other studies on FSS for early epithelial ovarian cancer have shown that preserving the uterus and at least some ovarian tissue does not lead to a high risk of recurrence. According to the new International Federation of Gynecology and Obstetrics staging system, conservative treatment is safe for Stage IA and IC Grade 1 and 2 disease and Stage IC1 disease. As the number of patients with Grade 2 disease is small, the safety of FSS for this subgroup cannot be determined. Because stage and histologic characteristics (tumor type and grade) are crucial to the patient's choice, surgical staging needs to be carefully and thoroughly completed, and the tumor needs to be pathologically analyzed or reviewed by a professional pathologist. Proper conservative surgery can maintain organ function, allowing patients of childbearing age to maintain fertility and improving their quality of life.
Oncofertility therapy in endometrial cancer
EC is one of the most common malignant gynecologic tumors, and the 5-year survival rate of patients with Stage IA EC is >93%. For patients desiring fertility preservation, conservative treatment that retains fertility function should be offered, after genetic counseling and satisfying all of the following conditions: well-differentiated (Grade 1) endometrioid adenocarcinoma, disease limited to the endometrium on magnetic resonance imaging or transvaginal ultrasound, and absence of suspicious or metastatic disease on imaging.
Two kinds of conservative treatments are available: progesterone therapy and progesterone therapy combined with hysteroscopy. Patients with Stage Ia, Grade 2, EC who received oral progestin therapy had achieved a high rate of complete remission (CR) and an acceptable pregnancy rate. The levonorgestrel intrauterine sustained release system (LNG-IUS) also resulted in a high regression rate and good fertility outcomes in patients with EC. A prospective Phase II multicentric study showed that oral medroxyprogesterone acetate (MPA)/LNG-IUS as a combined treatment for early EC provided a CR rate of 37.1% after 6 months, and a higher CR rate after 9 or 12 months of continued treatment. Therefore, the combination of MPA and LNG-IUS is a viable treatment option.
The other treatment modality is comprehensive hysteroscopic evaluation and lesion resection combined with progesterone therapy, which is a safe and effective conservation method. It provides similar response and live birth rates, but a significantly lower recurrence rate than progesterone therapy alone. Therefore, it is recommended that the lesion be resected before drug therapy as a preliminary operation to achieve tumor cell reduction and detailed histopathologic diagnosis.
In addition to the above two treatments, the combined application of metformin has also achieved a certain therapeutic effect. MPA combined with metformin has been shown to be effective in terms of relapse-free survival and posttreatment conception. Moreover, metformin may be more effective in patients with a body mass index of ≥25 kg/m2. A recent randomized, single-center, open-label, controlled trial conducted by Chinese researchers showed a higher CR in patients treated with megestrol acetate with metformin than in those treated with megestrol acetate alone within 16 weeks.
Longer treatment is associated with a higher CR rate in EC patients receiving fertility-preserving treatment. A retrospective analysis of the MPA/LNG-IUS combination treatment showed that a lower grade may be a positive factor for future pregnancy and a successful pregnancy may be a factor in preventing recurrence. Patients can also choose ART after achieving CR. Studies have revealed that the cumulative pregnancy rate of early EC patients receiving conservative treatment followed by in vitro fertilization is acceptable. Moreover, ART is positively correlated with a higher pregnancy rate and better chances of having a live birth. A 15-year retrospective study showed that in patients with EC recurrence who initially received fertility-preserving treatment, repeated fertility-preserving treatment could still achieve a better curative effect and achieving a live birth remains likely.
In summary, fertility preservation in young patients with early EC should be performed only if all criteria are met. After CR, pregnancy is encouraged and endometrial biopsy every 6 months is required. Patients also need to be closely monitored after ART. Patients with no pregnancy plans in the near future are treated with progesterone-based therapy and must undergo regular biopsies. For patients with persistent lesions after treatment, hysterectomy is recommended.
With the continuous improvements of various cryopreservation technologies and incessant optimization of drug interventions and surgical procedures, fertility preservation in cancer patients has greatly improved. This paper discussed the conventional methods of fertility preservation, the applicable population, and the possible risks. Some controversial methods and the potential benefits of various emerging technologies for more cancer patients were also considered. Although the current cryopreservation technology is becoming increasingly better, there is still room for improvement. Performing more fundamental scientific research is the only means to further benefit cancer patients, and to realize the safety, effectiveness, and feasibility of fertility preservation in these patients.
Financial support and sponsorship
Gansu Province Science Foundation for Distinguished Young Scholars (Grant No. 18JR3RA262).
Conflicts of interest
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[Figure 1], [Figure 2], [Figure 3]