Fertility Preservation Techniques Research Articles

Balancing Fertility Preservation and Treatment Efficacy in (Neo)adjuvant Therapy for Adolescent and Young Adult Breast Cancer Patients: a Narrative Review.

Adolescent and young adult (AYA) breast cancer survivors face a significant risk of infertility due to the gonadotoxic effects of (neo)adjuvant therapy, which complicates their ability to conceive post-treatment. While (neo)adjuvant therapy primarily aims to improve recurrence-free and overall survival, fertility preservation strategies should also be considered for young patients. This narrative review explores recent advancements in fertility preservation techniques, such as oocyte, embryo, and ovarian tissue cryopreservation, and evaluates the feasibility of modifying breast cancer (neo)adjuvant therapy to preserve fertility without compromising survival outcomes. Our review highlights that clinical trials with co-primary endpoints of oncological safety and fertility preservation are limited, and substituting standard treatment regimens solely for fertility preservation is currently not recommended. Nevertheless, new clinical studies have emerged that either exclude highly ovarian-toxic agents, such as cyclophosphamide, or omit adjuvant therapy altogether, even if fertility preservation is not their primary endpoint. Unfortunately, many of these trials have not evaluated ovarian toxicity. Notably, since 2020, major oncology organizations, including the American Society of Clinical Oncology (ASCO), the European Society of Medical Oncology (ESMO) have advocated for the routine assessment of ovarian toxicity in all clinical trials. The review underscores the importance of incorporating ovarian toxicity as a standard endpoint in future trials involving premenopausal breast cancer patients to identify treatment regimens that can effectively balance fertility preservation with treatment efficacy.

In-depth analysis of transcriptomes in ovarian cortical follicles from children and adults reveals interfollicular heterogeneity

The ovarian cortical reserve of follicles is vital for fertility. Some medical treatments are toxic to follicles, leading to premature ovarian insufficiency. Ovarian tissue cryopreservation is an established method to preserve fertility in adults and even applied in prepuberty despite unproven efficacy. Here, we analyze transcriptomes of 120 cortical follicles from children and adults for detailed comparison. We discover heterogeneity with two main types of follicles in both age groups: one with expected oocyte-granulosa profiles and another with predicted role in signaling. Transcriptional changes during growth to the secondary stage are similar overall in children and adults, but variations related to extracellular matrix, theca cells, and miRNA profiles are found. Notably, cyclophosphamide dose correlates with interferon signaling in child follicles. Additionally, morphology alone is insufficient for follicle categorization suggesting a need for additional markers. Marker genes for early follicle activation are determined. These findings will help refine follicular classification and fertility preservation techniques across critical ages.

In Vitro Maturation of Oocytes Obtained from Ovarian Cortex Among Postpubertal Hematological Cancer Patients Undergoing Fertility Preservation.

Purpose: In vitro maturation (IVM) of oocytes obtained from ovarian tissue during ovarian tissue cryopreservation (OTC) is a technique for fertility preservation in patients with cancer obviating the need to postpone chemotherapy initiation. Little is known about IVM outcomes in hematological malignancies, especially post-chemotherapy. The purpose of this study was to evaluate the effect of cytotoxic treatment on the potential to retrieve immature oocytes and mature them in vitro and examine the association between serum inflammatory markers and these results. Methods: In this retrospective study, we evaluated inflammation markers, including B symptoms and IVM outcomes of 78 chemotherapy-naive and exposed patients diagnosed with Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), or acute myeloid leukemia (AML). Results: The mean number of oocytes found was 7.2 ± 7.2. The average number of oocytes matured by IVM was 2.8 ± 3.5, and a mean IVM rate was 32.1 ± 27.7%. All patients in the ALL and AML groups had previous exposure to chemotherapy before OTC, compared with 50.0% (7/14) and 31.9% (15/47) in the NHL and HL groups, respectively. Among patients with lymphoma, chemotherapy exposure was associated with the reduced number of retrieved oocytes (9.8 ± 7.7 vs. 5.3 ± 5.7 oocytes, p = 0.049) in the HL group but not with the number of mature oocytes or IVM rate. B symptoms were not associated with IVM outcomes. Lymphocyte count (ß = 1.584; p = 0.038) and lactate dehydrogenase (ß = 0.009; p = 0.043) were the only significant parameters associated with the number of matured oocytes in a linear regression model. Conclusion: IVM is a promising assisted reproductive technology, which holds great potential for patients in need of urgent fertility preservation or those who cannot receive hormonal stimulation. Our results demonstrate the feasibility of the technique even in the presence of B symptoms and elevated inflammation markers and in patients with previous exposure to chemotherapy.

O-086 Risk of serious adverse event after fertility preservation procedures: a comparison of cancer and non-cancer patients

Abstract Study question Do cancer patients have a higher risk of serious adverse event associated to fertility preservation procedures compared to non-cancer patients ? Summary answer No increased risk of adverse event after fertility preservation procedures was identified in cancer patients compared to non-cancer patients undergoing fertility preservation for other indications. What is known already Current recommendations encourage a prompt and exhaustive discussion on the different techniques of fertility preservation that can be performed in cancer patients of reproductive age prior to cancer treatments. Although cryopreservation of mature oocytes and/or embryos is the technique of reference in the absence of contraindication, ovarian stimulation and subsequent oocyte retrieval are associated to complications. Cancer patients might present an additional risk given tumoral hypervascularity and proinflammatory environment, as well as possible immune or coagulation disorders. However, whether cancer patients have an increased risk of serious adverse event associated to fertility preservation procedures compared to non-cancer patients remains unknown. Study design, size, duration A bicentric, retrospective study between January 1st, 2014 and December 31st, 2021. Participants/materials, setting, methods All women undergoing fertility preservation procedures by oocyte and/or embryo cryopreservation after controlled ovarian stimulation or in vitro maturation.The main endpoint was the occurrence of a serious adverse event (hospitalization for ovarian hyperstimulation syndrome, hemorrhage, infection, thromboembolic event, ovarian torsion, acute urine retention or death) in cancer patients compared to non-cancer patients undergoing fertility procedures. Main results and the role of chance A total of 4476 cycles (n = 3180 patients) were included, of which 3761 after controlled ovarian stimulation and 715 in vitro maturation cycles. Among the 4476 cycles, 1678 were performed in an oncological context (n = 1546 cancer patients) and 2798 were fertility preservation cycles for an indication other than cancer (n = 1634 patients). A total of 29 serious adverse events associated to fertility preservation procedures were registered, of which 17 intraperitoneal hemorrhages, 8 cases of ovarian hyperstimulation syndrome, 3 cases of infection and 1 case of acute urine retention. The risk of serious adverse event associated to fertility preservation procedures was not significantly different between cancer patients and non-cancer patients (0.36% vs. 0.82%, respectively, P = 0.06). Young age (P = 0.002), a higher number of oocytes retrieved (P = 0.006) and a higher number of oocytes vitrified (P = 0.002) were significantly associated to the risk of presenting a serious adverse event after fertility preservation. Limitations, reasons for caution Although rates of serious adverse events in our study are similar to that reported in previous literature and that the declaration and registration of any serious adverse event is mandatory according to French legislation, it is possible that not all serious adverse events were declared and registered. Wider implications of the findings Given the trend of delaying parenthood and the improved survival rates after cancer treatments, these findings are of particular importance, emphasizing the safety of performing fertility preservation procedures for cancer patients of reproductive age who might have a pregnancy desire after cancer treatment. Trial registration number not applicable

O-234 Indication for fertility preservation in patients with endometriosis

Abstract Endometriosis is a complex gynecological condition that not only causes debilitating symptoms but also significantly impacts fertility. As the disease affects approximately 10% of women of reproductive age, addressing fertility preservation strategies becomes paramount. The conventional treatments for endometriosis, such as medical therapy and surgery, often fail to fully address its adverse effects on ovarian reserve and reproductive potential. Consequently, there is a growing interest in exploring fertility preservation options, particularly oocyte cryopreservation (OOC), for endometriosis patients. Despite the prevalence and impact of endometriosis on fertility, comprehensive data and guidelines specifically tailored to fertility preservation in this population remain scarce. The available evidence suggests that endometriosis, particularly when it involves ovarian endometriomas, is associated with a significant reduction in ovarian reserve, as indicated by lower levels of anti-Müllerian hormone (AMH). Surgical interventions, often necessary for managing endometriosis-related complications, can further compromise ovarian function and diminish fertility prospects. However, recent studies have shed light on the potential benefits of OOC in preserving fertility for endometriosis patients. OOC offers a minimally invasive approach with no impact on ovarian reserve compared to other fertility preservation techniques. Despite the lack of randomized controlled trials, our retrospective data have demonstrated promising outcomes, with a notable number needed to treat (NNT) of 16 for one successful pregnancy. This underscores the significance of discussing and considering OOC as part of the treatment plan for endometriosis patients, especially those at risk of ovarian compromise due to the disease or its management. The decision to pursue fertility preservation through OOC should be made on a case-by-case basis, taking into account various factors such as disease severity, patient age, ovarian reserve, and treatment history. French guidelines recommend considering OOC for endometriosis patients with bilateral ovarian endometriomas larger than 3 cm or those with endometriomas on a single ovary. Initiating fertility preservation discussions early, preferably before surgical intervention, allows patients to make informed decisions regarding their reproductive future. It is crucial to acknowledge the challenges and uncertainties associated with fertility preservation in endometriosis patients. Socio-economic factors, patient preferences, and the lack of clear criteria for selecting candidates for OOC pose significant hurdles. Furthermore, the effectiveness and cost-effectiveness of OOC in this population warrant further investigation. In addition to OOC, alternative fertility preservation options, such as ovarian tissue preservation, could be considered, particularly in cases where ovarian stimulation is not feasible or declined by the patient. However, data on the efficacy and safety of ovarian tissue preservation specifically in endometriosis patients are limited, highlighting the need for further research in this area. In conclusion, fertility preservation, particularly through OOC, holds promise for mitigating the adverse effects of endometriosis on ovarian function and fertility. While uncertainties persist, integrating fertility preservation discussions into the comprehensive management of endometriosis is essential. This ensures that patients are empowered to make informed decisions about their reproductive health and maximizes their chances of achieving desired fertility outcomes despite the challenges posed by endometriosis.

P-359 Ten years’ experience using cryopreserved oocytes from In Vitro Maturation (IVM) or Controlled Ovarian Hyperstimulation (COH) cycles for fertility preservation in oncologic indications

Abstract Study question Is IVM a relevant option for fertility preservation in cancer patients, considering biological/clinical outcomes post-thawing, compared to COH? Summary answer This study shows that despite a significantly altered embryo morphology within the IVM group, the clinical outcomes remain comparable to those of COH. What is known already Fertility Preservation (FP) techniques are proposed to patients with cancer to provide the possibility of childbearing using their own gametes. Currently, oocyte vitrification after COH is the standard option. IVM serves as an alternative when COH is contraindicated, urgent cancer therapy is required, or in conjunction with ovarian cortex cryopreservation. Limited live births have been reported from frozen-thawed oocytes in IVM cycles of cancer survivors. Scarce data are available for comparing biological/clinical outcomes of frozen-thawed oocytes from IVM versus COH cycles in cancer survivors. Study design, size, duration This bicentric retrospective cohort study aimed to analyze the outcomes of all oocyte warming cycles in 73 cancer survivors having undergone oocyte vitrification for FP after COH and/or IVM. All of them had oocyte retrieval before the administration of gonadotoxic treatment and returned after being cured, with their oncologist agreement, for assisted reproduction treatments, between November 2012 and January 2024. Participants/materials, setting, methods Seventy-seven warming attempts followed by ICSI respectively from 37 COH and 40 IVM cycles were analyzed. Four patients benefited from an IVM and COH cycle. Survival, fertilization, top and good-quality embryos, defined at day-2 respectively as 4 and 3-5 adequate-sized blastomeres, without multinucleation with < 20% of cytoplasmic fragments, implantation, biochemical (hCG>100 UI/mL), clinical (intrauterine sac with fetal heartbeat) and live birth rates were compared using appropriate statistical tests. Main results and the role of chance The mean age and antral follicle count at the time of FP was similar in both groups. The indications for FP were breast cancer (n = 61), hematologic malignancies (n = 7), ovarian cancer (n = 3), other (n = 2). The number of cryopreserved oocytes tended to be higher in the COH group, when compared to the IVM group (8.5±7.3 vs 5.9±4.04; p = 0.16). The mean oocyte maturation rate after IVM was 68.6±23.1%. Oocyte survival, and fertilization rates were similar in COH and IVM groups, respectively (76.4±27.0% vs 76.1±22.0%; p = 0.76) and (67.1±34.3% vs 65.3±25.4%; p = 0.36). We reported a significantly better embryo quality at day-2 in the COH group when compared to the IVM group, with respectively top-quality embryos (44.0±34.2% vs 26.1±33.4%, p = 0,04) and good-quality embryos (62.2±38.0% vs 42.8±40.8%, p = 0.049), and also a significantly higher number of useful embryo in the COH group (2.7±2.6 vs 1.5±1.2, p = 0.03). Regarding clinical outcomes, the results were similar in COH and IVM groups, in terms of implantation rates (12.2±30.4% vs 15.5±35.6%; p = 0.86), biochemical (32.3% (10/31) vs 17.9% (6/28); p = 0.39), clinical pregnancies (25.8% (8/31) vs 17.9% (4/28); p = 0.54), live birth rates ( 25.8% (8/31) vs 14.3% (4/28); p = 0.34). Limitations, reasons for caution Statistical power to compare IVF outcomes after COH and IVM is limited by the few women who returned to use their frozen oocytes. The subjective nature of embryo morphology assessment. Wider implications of the findings This study is the largest evaluating frozen-warmed oocytes from IVM cycles in cancer patients, with 5 live births newly reported. A higher oocyte-yield may be necessary in IVM as the number of useful embryos is significantly lower. Novel approaches are being developed to improve maturation rates following IVM. Trial registration number Not applicable

P-141 Elevating human oocyte vitrification and warming to a new level: fast, efficient, and effective

Abstract Study question Due to the rising trend for oocyte cryopreservation and increasing demand, there is an urgency to make oocyte vitrification and warming protocols more efficient. Summary answer Oocyte vitrification and warming can be done successfully in 4 minutes, reducing the time of commonly used current protocols by up to 25 minutes. What is known already Vitrification and warming of oocytes is widely used in many IVF clinics worldwide and routinely utilized as a dominant technique for fertility preservation and freezing of donor as well as autologous oocytes in many clinical settings. Outcome data using cryopreserved oocytes is comparable to fresh oocytes. However, vitrification and warming of human oocytes can be time consuming. Usually, vitrification of oocytes is done in about 11-16 minutes, and warming requires another 11 minutes. Also, it is a common practice to load not more than 2 oocytes per carrier at time of vitrification. Study design, size, duration From November 2022 to November 2023, 504 germinal vesicles (GV) and 207 metaphase I (MI) oocytes, which did not convert into mature oocytes at day of oocyte retrieval, were vitrified in Vit Kit Freeze (FujiFilm Irvine Scientific, USA), and RapidVit Oocyte (Vitrolife, Sweden). Their survival rates were compared, and as an additional viability indicator, post-warming developmental capabilities were evaluated after 24 and 48hrs of culture in Global High Protein (LifeGlobal, USA). Participants/materials, setting, methods A group of 4 GV or MI oocytes was vitrified at room temperature for 1 minute in Equilibration solution (ES) and 1 minute in Vitrification solution (VS), loaded on a S-Cryolock (Biotech, USA) and then plunged into liquid nitrogen. Warming was done at 37ºC in 0.5M sucrose for 1 minute and Wash solution (WS) for another minute. Post warming, GV and MI oocytes were cultured for developmental evaluation. Statistical significance was defined as P < 0.05. Main results and the role of chance There was no statistically significant difference in the survival rate of GV oocytes between Irvine (209/219; 95.4%), and Vitrolife media (270/285; 94.7%; P = 0.72). The survival of MI oocytes was also comparable and not significantly different between both media; Irvine: 103/106; 97.2%, vs Vitrolife: 96/101; 95.0%; P = 0.43). Because of the similar survival rates of oocytes in both groups, for the developmental potential and conversion rates, oocytes of both groups were combined. Of the 504 GV, 479 survived (95.0%) and after 24hrs of culture, 441 converted to MI (92.1%). After a culture of 48hrs, 56.5% (249/441) converted to metaphase II (MII) oocytes. Combining the vitrified and warmed MI oocytes from both groups, 96.1% (199/207) survived the warming, and after 24hrs of culture, 168 (84.4%) converted to MII oocytes. Vitrification and warming of oocytes at different developmental stages can be done with a short exposure time to hypertonic (ES/VS) and hypotonic (0.5M sucrose) solutions in a total of 4 minutes. Limitations, reasons for caution Immature oocytes were used as study material to evaluate a new protocol with significantly reduced vitrification and warming times. At this moment we cannot provide data on fertilization, embryo development, and blastocyst formation. Wider implications of the findings Oocytes are exposed to less suboptimal temperatures during dehydration and rehydration and help to maintain their developmental potential. Loading 4 oocytes per carrier combined with the decrease in time resulted in increased efficiency. Warming in 0.5M instead of 1M sucrose contributes positively to survival and allows earlier resumption of functionality. Trial registration number not applicable

O-307 Decrease of human sperm hypercondensed chromatin volume after slow freezing revealed by three-dimensional (3D) nuclear morphometry

Abstract Study question Are the 3D morphometry parameters of the human sperm nucleus affected by slow freezing? Summary answer The slow freezing-thawing cycle induces significant alterations on hypercondensed nucleus zone by reducing its volume and splits it into several small zones. What is known already Sperm cryopreservation is an essential technique for infertility care, but it seems to highly affect the genetic and epigenetic integrity of sperm nuclei with poorly identified mechanisms. Moreover, it is known that sperm nuclear alterations may be involved in pregnancy failures. Therefore, sperm nuclear biomarkers are an essential issue to assess the outcome of ART procedures when frozen sperm is used. Thereby, 3D visualization of chromatin is a good way to understand modifications in the organization and composition of sperm chromatin after a slow freezing procedure. Study design, size, duration Ten semen of patients were analyzed (Germetheque biobank) after informed consent. Standard semen parameters, DNA fragmentation, chromatin decondensation, sperm telomere length (STL) and 3D nuclear morphometry were performed before and after slow freezing. Morphometric measurements were performed from a digital representation of the sperm nucleus in 3 dimensions that allow us to measure the volume, flatness and elongation of each sperm nucleus and characterize hypercondensed zones, with live/dead spermatozoa distinction. Participants/materials, setting, methods After addition of cryoprotective medium v/v (Cryosperm®), sperm was frozen with a programmable freezer (NanoDigitcool®). Standards sperm parameters were measured in accordance with WHO guidelines 2021, DNA fragmentation by flow cytometry TUNEL assay, chromatin decondensation by epifluorescent microscopy with Chromomycin A3 and STL using qPCR. 3D nuclear representation was performed by a z-axis image acquisition series of DAPI/PI stained slides with optigrid epifluorescent microscopy. Analyses were carried out using the NucleusJ2.0 software with NODeJ plugin. Main results and the role of chance Freezing induces an alteration of sperm vitality (p < 0.0001) and progressive and total motility (p < 0.001 and p < 0.0001 respectively) and an increase in the percentage of sperm with DNA fragmentation (18.30% fresh vs 31.6% frozen, p < 0.05). We did not observe a modification of the median volume of the sperm nucleus before and after freezing (37.15 [IC = 36.5;38.14] and 37.10 [33.27;37.78] µm3 respectively), as the same for flatness and elongation (2.48 vs. 2.50 a.u. and 2.04 vs. 2.04 a.u. respectively). Nevertheless, five samples showed significant alterations of nucleus volume (p < 0.0001), due to diminution of flatness and more or less elongated. A significant decrease of the total volume of the hypercondensed chromatin zone was observed after freezing (0.94 [0.84;0.99] before vs. 0.61 [0.53;0.69] µm3 after freezing-thawing, p < 0.0001), with an effect size of -1.48 [-2.10; -0.86]. Decrease of total volume of hypercondensed region was measured homogeny in all the samples tested, particularly on live (1.00 vs. 0.68 µm3 respectively, p < 0.0001) compared with dead spermatozoa (0.72 vs. 0.57 µm3, p < 0.05). We showed also a significant increase of the number of hypercondensed zones in each nucleus (p < 0.001), reflecting a split into several parts of the hypercondensed chromatin. Limitations, reasons for caution A 3D-FISH analysis would allow to characterize the hypercondensed chromatin portion, probably as heterochromatin and which we suspect to be the nucleus ring. Moreover, a chromosomes specific marking would allow for the identification of whether whole chromosomes or specific parts of chromosomes (centromeres or telomeres) are affected by this decompaction. Wider implications of the findings This study is the first to make exacts measurements of human sperm nucleus because of a non-decondensing method. We demonstrate that slow freezing affects hypercondensed chromatin probably through a decondensation and modification of the nucleus-specific organization. This new assessment will allow a better proficiency of men fertility preservation techniques. Trial registration number NCT04715828

P-379 Fertility outcomes several years after fertility preservation for endometriosis

Abstract Study question To study the fertility outcomes of women who tried to conceive at least 2 years after fertility preservation (FP) for endometriosis. Summary answer To advise patients with endometriosis on the benefit of FP, particulary on the utilization rates of frozen oocytes and the actual chances of pregnancy What is known already Endometriosis is found in 25-40% of infertile patients. Due to the multiple and recurrent nature of lesions and the significant incidence of repeated ovarian surgery, endometriosis increase the risk of damaging the ovarian follicular stockpile. Since the revision of the French bioethics law (2014), women with endometriosis can be offered FP techniques. However, there is currently little data available in this population, limiting the possibility to establish formal recommendations Study design, size, duration A retrospective observational, bicentric cohort study conducted at Antoine Beclère and Jean Verdier University Hospitals.Inclusion criteria were: i) patients with confirmed endometriosis using imaging (pelvic MRI or ultrasound scan); ii) controlled ovarian hyperstimulation for FP between from July 1st 2013, and December 31st, 2019 (n = 200). The endpoint date was February 15, 2023, with data collected retrospectively. Participants/materials, setting, methods Cumulative incidences of pregnancy and live birth were calculated. Time to conception, time to utilization of oocytes, and predictive factors for pregnancy and live birth were assessed using logistic regression Cox models. Main results and the role of chance Among the 184 patients with available data after FP for endometriosis, 76 attempted to conceive (41%). The mean number of oocytes vitrified per patient were 14.7 ± 7.6 [8-20]. Patients attempting conception at least 2 years post-FP were more likely to have a partner at the first consultation (70.7% vs. 25.7%, p < 0.0001). Overall, 48 patients (43%) achieved a pregnancy, predominantly through spontaneous conception (50%), frozen-thawed oocytes (37.5%), or a new IVF attempt using fresh eggs (12.5%). Among those attempting conception, 31 (39%) reported a live birth. Cumulative chances of pregnancy at 4 years post-FP were estimated at 52% CI 95% [41% - 65%]. Utilization rates for frozen oocyteswere 7% CI 95% [4% - 12%] and 18% CI 95% [13% - 26%], respectively, 2 and 5 years post-freezing. Nulliparity was the only factor significantly associated with an increased probability of oocyte utilization (RR = 1.43 [1.0 - 2.06]). Limitations, reasons for caution The result should be interpreted with caution due to the small sample size of our study. Data were collected retrospectively and some information, concerning obstetrical and neonatal information where missing. Furthermore, the duration of the follow up time was too short to evaluate long-term fertility. Wider implications of the findings Despite endometriosis affecting fertility, our study revealed that half of pregnancies occurred spontaneously, irrespective of the endometriosis phenotype. These findings provide valuable insights into advising women on the utilization rates of frozen oocytes (7% to 18%) and the relatively high chances of natural conception after FP for endometriosis. Trial registration number NA

Global status of research on fertility preservation in male patients with cancer: A bibliometric and visual analysis

BackgroundRecently, male fertility preservation before cancer treatment has become more prevalent. The research in this field has progressed over time, with some studies having a major impact and providing guidance for further research. However, the trends and hotspots of research on fertility preservation in male cancer patients may have changed; exploring them is essential for relevant research progress. DesignWe extracted relevant studies from the Web of Science Core Collection database, capturing information on the countries of study, affiliations, authors, keywords, as well as co-citations of references and journals. To identify publication trends, research strengths, key subjects, prominent topics, and emerging areas, we conducted a bibliometric analysis using CiteSpace. ResultsWe included 3201 articles on fertility preservation in male cancer patients published over January 1999 to December 2023 were included. Although the relevant research growth rate was slow initially, the number of publications increased annually. Of all study countries, the United States, Germany, and Japan reported the earliest studies; the United States published the highest number of relevant studies. The US institutions remained at the forefront for all 25 years, and the US researcher Ashok Agarwal published the most articles. Literature co-citation analyses indicated a transformation in the study participants; they comprised a younger demographic (i.e., a large number of adolescent male patients underwent fertility preservation); moreover, fertility preservation techniques evolved from sperm cryopreservation to testicular tissue cryopreservation. Research on reproductive outcomes of sperm cryopreservation was the recent hotspot in male fertility preservation research, and the impact of immunotherapy and checkpoint inhibitors on male fertility requires further research. ConclusionsMale fertility preservation will be a major future research focus, with closer connections and collaborations between countries and organizations. Our results present the historical data on the development of research on male fertility preservation in cancer patients, providing relevant insights for future research and development in this study area.

FMR1 allelic complexity in premutation carriers provides no evidence for a correlation with age at amenorrhea

BackgroundPremutations in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene, defined as between 55 and 200 CGGs, have been implicated in fragile X-associated primary ovarian insufficiency (FXPOI). Only 20% of female premutation carriers develop early ovulatory dysfunction, the reason for this incomplete penetrance is unknown. This study validated the mathematical model in premutation alleles, after assigning each allele a score representing allelic complexity. Subsequently, allelic scores were used to investigate the impact of allele complexity on age at amenorrhea for 58 premutation cases (116 alleles) previously published.MethodsThe allelic score was determined using a formula previously described by our group. The impact of each allelic score on age at amenorrhea was analyzed using Pearson’s test and a contour plot generated to visualize the effect.ResultsCorrelation of allelic score revealed two distinct complexity behaviors in premutation alleles. No significant correlation was observed between the allelic score of premutation alleles and age at amenorrhea. The same lack of significant correlation was observed regarding normal-sized alleles, despite a nearly significant trend.ConclusionsOur results suggest that the use of allelic scores combination have the potential to explain female infertility, namely the development of FXPOI, or ovarian dysfunction, despite the lack of correlation with age at amenorrhea. Such a finding is of great clinical significance for early identification of females at risk of ovulatory dysfunction, enhancement of fertility preservation techniques, and increasing the probability for a successful pregnancy in females with premutations. Additional investigation is necessary to validate this hypothesis.

Fertility Preservation and Ovarian Hyperstimulation Syndrome Management in Cancer Care: A Pathophysiological Perspective on Gonadotropin-Releasing Hormone Agonists and Antagonists.

This narrative review delves into the evolving landscape of fertility preservation techniques, with a particular focus on their use in patients undergoing oncology treatment that carries a risk of ovarian insufficiency. Advances in established methods such as cryopreservation of oocytes and embryos are highlighted, and the increasing use of gonadotropin-releasing hormone (GnRH) agonists is discussed. The review also addresses the complexities and controversies associated with these approaches, such as the 'flare-up' effect associated with GnRH agonists and the potential of GnRH antagonists to reduce the risk of ovarian hyperstimulation syndrome. Despite advances in fertility preservation, the report highlights the challenges we face, including the need for personalized treatment protocols and the management of associated risks. It calls for continued research and collaboration between healthcare professionals to refine these techniques and ultimately improve reproductive outcomes for patients facing the prospect of fertility-impairing treatment.

Three-dimensional analysis of partial restoration of spermatogenesis in vitamin A-deficient mice.

An animal model of the partial restoration of spermatogenesis may be useful in the field of reproductive biology and medicine. Vitamin A deficiency (VAD) induces the restorable arrest of spermatogenesis at the level of spermatogonia and is used as a mouse model of spermatogenesis disorder. We aimed to establish an animal model in which spermatogenesis is partially restored by switching a vitamin A deficiency diet to a normal vitamin A-containing diet and conduct a comprehensive analysis to identify vulnerable sites in the seminiferous tubules that affect the efficient restoration of spermatogenesis in this model. Mice fed a vitamin A deficiency diet until 12weeks old and then reared with a normal diet for 15weeks served as the restoration model. We performed three-dimensional reconstructions of the seminiferous tubules and analyzed the three-dimensional distribution of restored spermatogenesis throughout the testis. Fifteen weeks after the switch to the normal diet, spermatogenesis was restored in 78% of the length of seminiferous tubules. The percentage of restored spermatogenesis was lower in longer seminiferous tubules. An analysis of the distribution of spermatogenesis throughout the testis in this model revealed that it was restored less in portions of seminiferous tubules near the rete testis and hairpin curves and also in those located in the caudal region of the testis. These sites tended to correspond to sites with fewer spermatogonia in the vitamin A deficiency testis. We established an animal model of the partial restoration of spermatogenesis and examined the three-dimensional distribution of restored spermatogenesis in seminiferous tubules. The results obtained provide insights into the mechanisms underlying spermatogenesis disorders and may contribute to better clinical practices, such as the screening of drugs or therapeutic interventions for human male infertility and improvements in fertility preservation techniques for individuals undergoing chemotherapy.

Fertility preservation through natural and artificial ovaries: a review

Ovarian tissue cryopreservation (OTC) is currently the exclusive choice for preserving fertility in both young girls before reaching puberty and young women who require immediate chemotherapy. Ovarian tissue transplantation has proven to be effective in restoring hormonal cycles and fertility. However, in certain cancer cases, there is a potential risk of inadvertently reintroducing malignant cells when transplanting cryopreserved ovarian tissue. Therefore, the use of an artificial ovary as an innovative and complementary approach allows for the development of isolated follicles, facilitates oocyte maturation and ovulation, and can partially restore endocrine function. This paper presents a comprehensive overview of techniques used to preserve fertility in natural ovarian tissues, including slow freezing, vitrification and hydrogel encapsulation methods. Additionally, it reviews fertility preservation techniques for artificial ovarian tissues, such as strategies involving hydrogel-encapsulated follicle, scaffolding for constructing ovarian microtissues, and 3D printing engineering. Lastly, this article explores current challenges and difficulties encountered in preserving ovarian tissue fertility, while also anticipating future trends in development, making it a valuable reference for the implementation of ovarian tissue fertility preservation.

Fertility preservation before cancer treatment: the dilemma of saying 'no' as the price of glory.

A great deal of work has been carried out by professionals in reproductive medicine in order to raise awareness about fertility preservation (FP) techniques, particularly for women, and to ensure that FP is included in the care of young adults treated for cancer or a pathology requiring gonadotoxic treatment. If the importance of the development of our discipline is obvious, our militancy in favour of FP and our emotional projections must not make us forget that medical thinking must be carried out not only on a case-by-case basis, weighing up the benefit-risk balance, but also without losing sight that conceiving a child with one's own gametes is not a vital issue. The cultural importance given to the genetic link with offspring may bias patients' and physicians' decisions, while other ways of achieving parenthood exist, and are often more effective. Systematic information should be provided on the existence of FP techniques, but this should not lead to their systematic implementation, nor should it obscure that early information will also allow patients to begin projecting themselves in alternative options to become parents.

Ovarian Tissue Oocyte-In Vitro Maturation for Fertility Preservation.

Mature oocyte vitrification is the standard of care to preserve fertility in women at risk of infertility. However, ovarian tissue cryopreservation (OTC) is still the only option to preserve fertility in women who need to start gonadotoxic treatment urgently or in prepubertal children. During ovarian cortex preparation for cryopreservation, medullar tissue is removed. Growing antral follicles reside at the border of the cortex-medullar interface of the ovary and are broken during this process, releasing their cumulus-oocyte complex (COC). By thoroughly inspecting the medium and fragmented medullar tissue, these immature cumulus-oocyte complexes can be identified without interfering with the OTC procedure. The ovarian tissue-derived immature oocytes can be successfully matured in vitro, creating an additional source of gametes for fertility preservation. If OTC is performed within or near a medical assisted reproduction laboratory, all necessary in vitro maturation (IVM) and oocyte vitrification tools can be at hand. Furthermore, upon remission and child wish, the patient has multiple options for fertility restoration: ovarian tissue transplantation or embryo transfer after the insemination of vitrified/warmed oocytes. Hence, ovarian tissue oocyte-in vitro maturation (OTO-IVM) can be a valuable adjunct fertility preservation technique.

Practices and the Interest of Practitioners Regarding Female Fertility in Morocco

Treatment regimens for cancer patients are known for their toxicity and pose a threat to their fertility. This study takes the form of a survey aimed to analyzing the current knowledge and motivation of physicians involved in cancer care. The majority of surveyed physicians believe that fertility is a concern for women cured of cancer. A significant portion of physicians do not offer preservation methods to their patients, either due to the unavailability of an oncofertility center or due to the severity of the type of cancer. The main challenge in the coming years will be to improve access to fertility preservation techniques for patients whose treatments could affect their ovarian reserve.

Successful pregnancy using immature oocytes retrieved from resected borderline ovarian tumor: a case report and literature review

BackgroundDespite the recent progress of fertility preservation technique, achievement of pregnancy in women with ovarian tumor is still challenging. Here, we report a case of OTO-IVM (ovarian tissue oocyte in-vitro maturation) resulting in a successful delivery.Case presentationThe patient, a 33-year-old woman with a history of left borderline ovarian tumor (BOT) who underwent left salpingo-oophorectomy three years ago, presented with an enlarged right ovary during infertility treatment, indicating the recurrence of BOT. Because the patient disagreed with curative surgery and normal part-preservation surgery, we eventually performed OTO-IVM. A right salpingo-oophorectomy was first performed. Eight immature oocytes were immediately aspirated not only from visible follicles, but also from entire cortex for invisible follicles, of the removed ovary. In addition, IVM procedure generated six mature oocytes, and were subjected to intracytoplasmic sperm injection (ICSI). Accordingly, three embryos were obtained and cryopreserved. Three months after surgery, hormone replacement therapy was initiated, and a frozen-thawed embryo was transferred, resulting in a successful pregnancy. Although a cesarean section was performed at 36 weeks due to maternal ileus, the baby was delivered without complications.ConclusionsThis report indicates this treatment to be an effective approach for fertility preservation in BOT patients, especially, the importance of collecting oocytes from the entire ovarian cortex was suggested.

Role of NR5A1 Gene Mutations in Disorders of Sex Development: Molecular and Clinical Features.

Disorders/differences of sex development (DSDs) are defined as broad, heterogenous groups of congenital conditions characterized by atypical development of genetic, gonadal, or phenotypic sex accompanied by abnormal development of internal and/or external genitalia. NR5A1 gene mutation is one of the principal genetic alterations implicated in causing DSD. This review outlines the role of NR5A1 gene during the process of gonadal development in humans, provides an overview of the molecular and functional characteristics of NR5A1 gene, and discusses potential clinical phenotypes and additional organ diseases due to NR5A1 mutations. NR5A1 mutations were analyzed in patients with 46,XY DSD and 46,XX DSD both during the neonatal and pubertal periods. Loss of function of the NR5A1 gene causes several different phenotypes, including some associated with disease in additional organs. Clinical phenotypes may vary, even among patients carrying the same NR5A1 variant, indicating that there is no specific genotype-phenotype correlation. Genetic tests are crucial diagnostic tools that should be used early in the diagnostic pathway, as early as the neonatal period, when gonadal dysgenesis is the main manifestation of NR5A1 mutation. NR5A1 gene mutations could be mainly associated with amenorrhea, ovarian failure, hypogonadism, and infertility during puberty. Fertility preservation techniques should be considered as early as possible.

Fertility outcomes several years after urgent fertility preservation for patients with breast cancer

To study the fertility outcomes of women who tried to conceive after breast cancer (BC) treatment and fertility preservation. Retrospective observational, bicentric cohort study. University hospital. Patients with BC. All patients who had undergone fertility preservation before BC treatment between January 2013 and July 2019 were included (n = 844). The endpoint date was March 1, 2022. Patients with missing data on pregnancy attempts after a cancer diagnosis (n = 195) were excluded from the pregnancy analysis. Cumulative incidences of pregnancy and live birth (LB) were calculated. For women who became pregnant, the time to conception was calculated between the first fertility preservation consultation and the estimated day of conception. For those who did not conceive, we considered the time between the first fertility preservation consultation and the endpoint date, or the date of patient death. A Cox regression model was used to study the predictive factors for pregnancy and LB. Among the 649 patients with available data on pregnancy attempts after BC diagnosis, 255 (39.3% [35.5-43.2]) tried to conceive (median follow-up of 6.5 years). Overall, 135 (52.9% [46.6-59.2]) of these patients achieved a pregnancy, mainly through unassisted conception (79.3% [72.8-84.8]), and 99 reported an LB (representing 38.8% of patients who attempted conception). In our cohort, 48 months after the first fertility preservation consultation, the cumulative incidence of pregnancy was 33.1% ([27.6-37.9]). After adjustment for age, parity, type of chemotherapy administration, and endocrine therapy, only multiparity at diagnosis and absence of chemotherapy were positive predictive factors of pregnancy after cancer. Of the 793 patients who had vitrified oocytes and embryos, 68 used them (27% [21.3-32.5] of the patients who tried to conceive), resulting in 8 LBs (11.8% [5.2-21.9]). Women who used their cryopreserved oocytes and embryos were older at the first consultation of fertility preservation (hazard ratio 1.71 [1.42-2.21]), and chose more often to vitrify embryos (hazard ratio 1.76 [1.28-2.23]). Although pregnancy rates after fertility preservation for patients with BC are low, most conceptions are achieved without medical assistance. Our findings provide useful information to advise women on the different techniques of fertility preservation, their efficacy, and safety, as well as the relatively high chances of unassisted conception.