Fertility Preservation in Women With Malignancy: FutureEndeavors

Fertility preservation in men and women: Where are we in 2021? Are we rising to the challenge?

Study question What are the return rates and reproductive outcome after fertility preservation (FP) in women with cervical cancer (CC)? Summary answer Return rates after FP in women with CC seem to be comparable with those after FP for other indications. What is known already Cervical cancer is the fourth most common cancer among women. Approximately 42% of the affected women are under the age of 45, and many of them wish to preserve fertility at the time of diagnosis. Fertility sparing treatment modalities and FP with cryopreservation of oocytes, embryos or/and ovarian tissue can be offered for this purpose to carefully selected patients. These treatments are offered at Swedish academic centers within the health insurance coverage available to all citizens. To date, data on return rates, reproductive outcome and survival in women with cervical cancer undergoing FP are scarce. Study design, size, duration Prospective, single center study aiming to report long-term outcomes in women with CC who have versus have not undergone FP at Karolinska University Hospital between January 1st 1999 and September 30th 2018. Participants/materials, setting, methods During the study period, 74 women with CC received FP counseling at Karolinska University Hospital, and 52 of them women proceeded to FP. Data on return rates, reproductive outcomes and overall survival were extracted using the clinical registries. Main results and the role of chance By January 15th, 2023, 22 of 52 women with FP returned for a new fertility counselling or treatment, mean time between FP and return was 4 years (1-7 years). Among women with cryopreserved ovarian tissue (n = 40), 17 have been in contact with the clinic with fertility wish, 3 of them had re-transplantation of the tissue, but none of them achieved oocyte retrieval yet. Additionally, one woman is planned for re-transplantation in February 2023, and one woman is awaiting the decision. In two cases the decision not to re-transplant ovarian tissue was based on absence of endometrial growth following attempts of hormonal substitutive therapy. Among women with cryopreserved oocytes (n = 5), 1 returned for thawing but no pregnancy has been achieved. Among women with cryopreserved embryos (n = 5), 3 returned during follow-up, 2 proceeded to thawing and transfer, 1 got pregnant and gave birth to a child. Of two women with combination of oocytes and ovarian tissue cryopreserved, one returned for fertility treatment, but no pregnancy has been achieved after thawing and re-transplantation. Eight women died during follow-up because of recurrence of their cancer, 4 of 22 in the group without FP and 4 of 52 in the group with FP. Limitations, reasons for caution This study provides much needed data on real-world outcome in women with FP indicated by diagnosis of CC, but it has the limitations related to its descriptive character. The use of gestational carriers is not permitted in Sweden and FP program may differ from those in other countries. Wider implications of the findings The study results provide much needed data on real-world reproductive and oncologic outcome following FP in women with CC. Trial registration number NTC04602962

IntroductionOur objective was to assess the feasibility of fertility preservation (FP) in women referred for cervix cancer, the long‐term reproductive outcome, and overall survival.Material and MethodsProspective cohort study of patients referred for FP counseling between 1999 and 2021 to the FP program of Karolinska University Hospital, Stockholm, Sweden. Baseline data included age, parity, disease stage, treatment characteristics, and FP methods applied. Data on reproductive outcomes and overall survival (by October 19, 2023) were retrieved from clinical registries and a population‐based register. Trial registration number: ClinicalTrials.gov NTC04602962.ResultsIn total, 91 women were referred, 67% with stage I cancers and 25%, 7%, and 1% with stages II, III, and IV, respectively. Cancers were diagnosed during pregnancy or postpartum in six cases. Cancer treatments included fertility‐sparing surgery in 14%, hysterectomy in 30%, and radiochemotherapy in 79% of cases. The treatment modality did not rule out the possibility to undergo FP, and following counseling, 68 patients elected to undergo FP by cryopreservation of embryos or oocytes (N = 11), ovarian tissue (N = 54), or both (N = 3). After a mean follow‐up of 8.1 years, 25 women (37%) returned to the center, five women achieved conception either spontaneously or through assisted reproduction, and 11 women became mothers through adoption or surrogacy. In the group of women receiving radical surgery or chemo/radiotherapy, no live births using cryopreserved specimens have yet been achieved. During follow‐up, 7 women (10%) in the FP group and 5 women (24%) in the group without FP had died of their disease. Cancer recurrence was documented in 19 patients.ConclusionsOur findings underscore the complexity and challenges associated with FP in the context of cervix cancer. Results of this study demonstrate that many women diagnosed with cervix cancer at reproductive age desire to achieve parenthood. While fertility‐sparing surgery can allow pregnancy, those who undergo a hysterectomy are limited to adoption, surrogacy, or the emerging possibility of uterus transplantation.

Ovarian protection and fertility preservation in women with cancer: A French national registry analysis between 2005 and 2014

Sarcomas frequently affect adolescent girls and young women, for whom future fertility is a critical concern. The urgency of initiating treatment—due to rapid tumor progression and the need for extensive diagnostic evaluation—often limits the window for fertility preservation prior to chemotherapy. However, emerging evidence indicates that gonadotoxicity is variable, and ovarian function may be preserved in a substantial number of cases. This observational cohort study evaluates the feasibility, timing, and clinical relevance of fertility preservation in young women treated for high‐grade sarcomas or desmoid tumors at Cochin Hospital, AP‐HP (Paris, France), with a focus on long‐term ovarian function and reproductive outcomes. Among 59 patients (median age at first oncology consultation, 24.3 years), 13 underwent oocyte or ovarian tissue cryopreservation before or early during treatment. Therapy regimens included alkylating and non‐alkylating chemotherapies, radiotherapy, or combinations thereof. At last follow‐up, 49 women were alive, and 27 had experienced relapse or progression. Among 26 patients assessed for post‐treatment ovarian function (median follow‐up 62 months), 77% resumed menstruation, 27% conceived naturally, 78% of those actively attempting pregnancy were naturally successful, and 19% gave birth. No patient used cryopreserved oocytes or ovarian tissue. One patient underwent fertility preservation after therapy. These results suggest that systematic fertility preservation may not be mandatory for all patients and that spontaneous ovarian function recovery is common. The observed pregnancy outcomes underscore the importance of personalized, patient‐centered fertility counseling based on tumor characteristics and treatment modalities.

Vitrification of immature mouse oocyte using stepwise equilibration before or after in vitro maturation

In vitro maturation of oocytes: uncommon indications

Efficacy and safety of ovarian stimulation before chemotherapy in 205 cases

There is increasing interest and experience in the options available to preserve fertility in those about to undergo potentially gonadotoxic chemotherapy or radiation therapy, usually related to treatment for cancer. Recent years have seen the development of methods for prepubertal girls, female adolescents and adult women, although these remain less established than sperm cryopreservation for men. At present, the options for prepubertal boys remain experimental. Embryo cryopreservation following ovarian stimulation and IVF is a routine procedure technically and its success in the management of infertility is established. However, there are no data on uptake or success rates in the context of fertility preservation in women with cancer. Oocyte cryopreservation is technically challenging and requires ovarian stimulation, thus potentially resulting in a delay in cancer treatment. Oocyte vitrification offers increased success rates in comparison with slow freezing; however, this approach is also limited by the number of oocytes that can be obtained. The third possibility, ovarian tissue cryopreservation, can be performed without significant delay and is the only option for prepubertal girls. Worldwide, a small number of children have been born following reimplantation of frozen/thawed ovarian tissue. It is clear that fertility preservation is important for some girls and young women facing treatments that will compromise their fertility, but the availability of all approaches varies widely. Effective approaches for prepubertal boys are also required.

Fertility Preservation for Pediatric Patients: Current State and Future Possibilities

Fertility preservation in women with Turner syndrome is highly controversial. Some strongly recommend freezing of ovarian tissue at a young age, others do not. The controversy is partly due to different perspectives and professions. Biologists prefer to freeze young ovaries with high follicle density, reproductive physicians want to avoid risky operations and iatrogenic infertility by removing one ovary, and cardiologists and obstetricians warn against the risks of later pregnancies. Accordingly, fertility preservation in young women with Turner syndrome is more than just the freezing of ovarian tissue or oocytes. Fertility preservation requires a balanced decision considering the conservation of fertility, the protection of reproductive health, and future health consequences. Therefore, fertility preservation strategies should be based not only on the individual ovarian reserve but also on the genotype and the expected cardiac health status to decide what is the best option: to freeze tissue or alternatively to wait and see.

Emergency IVF versus ovarian tissue cryopreservation: decision making in fertility preservation for female cancer patients

In women, ∼10% of cancers occur in those <45 years old. Chemotherapy, radiotherapy and bone marrow transplantation can cure >90% of girls and young women with diseases that require such treatments. However, these treatments can result in premature ovarian failure, depending on the follicular reserve, the age of the patient and the type and dose of drugs used. This article discusses the different fertility preservation strategies: medical therapy before chemotherapy; ovarian transposition; embryo cryopreservation; oocyte vitrification; and ovarian tissue cryopreservation. The indications, results and risks of these options are discussed. Whether medical therapy should be used to protect the gonads during chemotherapy remains a source of debate. Fertility preservation needs to be completed before chemotherapy and/or irradiation is started and might take 2-3 weeks with established techniques such as embryo or oocyte cryopreservation. Further studies are needed in patients with cancer to confirm the excellent outcomes obtained in patients without cancer or in egg donation programmes. For prepubertal girls or cases where immediate therapy is required, cryopreservation of ovarian tissue is the only available option. Finally, possible future approaches are reviewed, including in vitro maturation of nonantral follicles, the artificial ovary, oogonial stem cells and drugs to prevent follicle loss.

With the increasing survival rates of cancer patients, the demand for fertility preservation in women has become increasingly prominent. Ovarian tissue cryopreservation and transplantation (OTCT) is an emerging fertility preservation technique that offers a unique advantage over embryo or oocyte cryopreservation, as it does not require ovarian stimulation. This makes it particularly suitable for prepubertal girls requiring urgent gonadotoxic therapy and reproductive-age women who cannot delay cancer treatment. Clinical evidence confirms that OTCT can effectively restore female fertility-especially the potential for natural conception-and restore ovarian endocrine function. The OTCT process involves key steps such as patient evaluation, tissue processing, cryopreservation, and transplantation. The patient's age at cryopreservation, ovarian reserve status, and prior exposure to gonadotoxic therapy significantly influence the outcomes of fertility preserva-tion. Optimal tissue preparation and the choice of cryopreservation method are critical for preserving ovarian tissue viability. During processing, the size of ovarian tissue fragments must be carefully controlled to balance freezing efficiency and post-transplantation viability, with adjustments based on individual patient factors. Slow freezing remains the mainstream clinical method, while vitrification is still considered experimental, with its efficacy and safety under ongoing investigation. The number, size, and transplantation site of ovarian tissue grafts impact their biological activity and functional outcomes. Both orthotopic and heterotopic transplantation can restore endocrine function, but orthotopic sites are superior for restoring fertility. A major safety concern in OTCT is the potential risk of reintroducing malignant or premalignant cells upon reimplantation. Innovative techniques such as in vitro maturation of oocytes and artificial ovaries are being explored to mitigate this risk. This review summarizes recent clinical advances in OTCT, with a focus on its indications, efficacy, implementation strategies, and safety profile, aiming to provide a reference for further research and clinical practice in this field.

Cancer may be detected at any age and could affect children, and reproductive age women as well. In recent years, cancer treatment has become less destructive and more specific. As a result, survival rates and quality of life following successful treatment have continuously improved. Cancer treatment typically involves surgery, chemo- or radiation therapy, or the combinations of these. These interventions often adversely affect the function of the reproductive organs. Chemo- and radiation therapy are known to be gonadotoxic. Survivors of oncologic therapy are typically rendered infertile primarily due to the loss of ovarian function. There are, however, several medical, surgical, and assisted reproductive technology options that could be and should be offered to those diagnosed with cancer and wish to maintain their fertility. Embryo cryopreservation has been available for decades and has been successfully applied for fertility preservation in women diagnosed with cancer. Recent advances in cryobiology have increased the efficacy of not just embryo but even oocyte and ovarian tissue freezing-thawing. Oocyte vitrification just like embryo cryopreservation requires the use of stimulation but does not require the patient to be in a stable relationship or accept the use of donor sperm. Ovarian tissue cryopreservation does not require stimulation and, following successful transplantation, provides the patient with the most eggs but is currently still considered experimental. This paper summarizes the various fertility-sparing medical, surgical and assisted reproductive technology options. It reviews the current status of embryo, oocyte, and ovarian tissue cryopreservation and discusses their risks and benefits.