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Background With the increase in the number of long-term survivors, interest is shifting from cancer survival to life and quality of life after cancer. These include consequences of long-term side effects of treatment, such as gonadotoxicity. Fertility preservation is becoming increasingly important in cancer management. International recommendations agree on the need to inform patients prior to treatments about the risk of fertility impairment and refer them to specialized centers to discuss fertility preservation. However, the literature reveals suboptimal access to fertility preservation on an international scale, and particularly in France, making information for patients and oncologists a potential lever for action. Our overall goal is to improve access to fertility preservation consultations for women with breast cancer through the development and evaluation of a combined intervention targeting the access and diffusion of information for these patients and brief training for oncologists. Methods Firstly, we will improve existing information tools and create brief training content for oncologists using a qualitative, iterative, user-centred and participatory approach (objective 1). We will then use these tools in a combined intervention to conduct a stepped-wedge cluster randomized trial (objective 2) including 750 women aged 18 to 40 newly treated with chemotherapy for breast cancer at one of the 6 participating centers. As the primary outcome of the trial will be the access to fertility preservation counselling before and after using the combined intervention (brochures and brief training for oncologists), we will compare the rate of fertility preservation consultations between the usual care and intervention phases using linear regression models. Finally, we will analyse our approach using a context-sensitive implementation analysis and provide key elements for transferability to other contexts in France (objective 3). Discussion We expect to observe an increase in access to fertility preservation consultations as a result of the combined intervention. Particular attention will be paid to the effect of this intervention on socially disadvantaged women, who are known to be at greater risk of inappropriate treatment. The user-centred design principles and participatory approaches used to optimize the acceptability, usability and feasibility of the combined intervention will likely enhance its impact, diffusion and sustainability. Trial registration Registry: ClinicalTrials.gov. Trial registration number: NCT05989776. Date of registration: 7 th September 2023. URL: https://classic.clinicaltrials.gov/ct2/show/NCT05989776 . Protocol version Manuscript based on study protocol version 2.0, 21st may 2023.

Currently, the only fertility preservation option of prepubertal patients is ovarian tissue cryopreservation followed by autotransplantation (OTCTP). Once in remission and patients desire to conceive, autotransplantation of frozen/thawed tissue is performed. A major issue of this technique is follicular loss directly after transplantation, mainly due to follicle activation. Our previous research showed that adding rapamycin to the freezing medium counteracted follicle proliferation and activation induced by OTCTP in heterotopic autotransplantation of ovaries in mice. Our current study aimed to test the potential of this approach to improve fertility restoration in mice. Forty 4-week-old female C57BL/6 mice underwent unilateral oophorectomy followed by slow-freezing of ovaries with or without rapamycin. After chemically disabling the remaining ovary, orthotopic autotransplantation was performed. After recovery, estrous cycle analysis was conducted using daily vaginal smears. The mice were mated with males for 4 months, and pregnancy outcomes were recorded. After mating, half the females were super-ovulated for oocyte quantification and ovarian analysis, while the others had their ovaries collected for analysis of remaining primordial follicles using immunohistochemistry. Female mice whose ovaries were cryopreserved with rapamycin prior to chemically disabling the remaining ovary and orthotopic autotransplantation, gave birth to more pups (102 rapamycin, 48 control). The live birth rate was also higher ( P  = 0.0025) when ovaries were cryopreserved in rapamycin compared to control medium. Additionally, more mice in the rapamycin group gave birth (13 rapamycin, 8 control) with a higher average litter size ( P  = 0.0837). More mice had primordial follicles left at the end of the experiment in the rapamycin group ( P  = 0.0397). Superovulation showed a similar number of oocytes collected ( P  = 0.4462). While rapamycin did not influence cyst formation after autotransplantation, mice that developed ovarian cysts gave birth to fewer pups per dam ( P  = 0.0119) with a lower live birth rate compared to mice without ovarian cysts ( P  = 0.0032). The use of rapamycin improved fertility restoration in mice. Using rapamycin during OTCTP in humans could potentially resolve the massive follicular loss directly after grafting, and thus eventually lead to better opportunities for women to become pregnant.

Oocytes can be effectively cryopreserved and stored for future use in in-vitro fertilisation. Oocyte cryopreservation (OC) can therefore mitigate different threats to female fertility, but attitudes and policies often seem more favourable in medical rather than age-related fertility preservation scenarios. The value of OC for potential candidates may be perceived differently depending on the indications, although relevant empirical data are lacking. An adequately powered sample of Swedish female university students (n = 270; median age 25; range 19–35) were randomly delivered a medical (n = 130) or age-related (n = 140) fertility preservation scenario within an online survey. Sociodemographic factors, reproductive experiences, and awareness about OC were not significantly different between the groups. Differences in four outcomes were studied: proportions of respondents (1) positive to the use of OC, (2) positive to public funding for OC, or (3) open to considering OC; and (4) willingness-to-pay (WTP) for OC, measured in thousand Swedish krona (K SEK) through contingent valuation. There were no significant differences in the proportions of respondents positive to the use of OC (medical: 96%; age-related: 93%) or open to consider it (medical: 90%; age-related: 88%) in each scenario. However, public funding had significantly greater support in the medical scenario (85%) than in the age-related one (64%). The median WTP (45 K SEK ≈ 4.15 K EUR) approximated the current Swedish market price for a single elective cycle and was not significantly different between the scenarios (Cliff’s delta − 0.009; 95%CI − 0.146, 0.128). These findings suggest that it may be inappropriate to justify counselling and priority policies only on the assumption that fertility preservation with OC for medical indications is more beneficial to women than when the same technique is used for age-related reasons. However, it would be interesting to investigate further why public funding appears more debatable than the treatment itself.

There are limited data regarding the optimal management of pre-menopausal women with cervical lesions measuring 2–4 cm who desire to preserve fertility. To evaluate the feasibility of preserving fertility. Neo-adjuvant chemotherapy will be effective in reducing the size of the tumor and will enable fertility-sparing surgery without compromising oncologic outcome. Pre-menopausal women diagnosed with stage International Federation of Gynecology and Obstetrics (FIGO) IB2, 2–4 cm cervical cancer who wish to preserve fertility will receive three cycles of platinum/paclitaxel chemotherapy. Patients with complete/partial response will undergo fertility-sparing surgery. Patients will be followed for 3 years to monitor outcome. Patients with suboptimal response (residual lesion ≥2 cm) will receive definitive radical hysterectomy and/or chemoradiation. Patients must have histologically confirmed invasive cervical cancer, 2–4 cm lesion, by clinical examination and magnetic resonance imaging (MRI), negative node, and pre-menopausal (≤40 years old). Following three cycles of neo-adjuvant chemotherapy, patients must achieve a complete/partial response (residual lesion <2 cm). Exclusion criteria include high-risk histology, tumor extension to uterine corpus/isthmus (as per MRI), and suboptimal response/progression following neo-adjuvant chemotherapy. Assess the rate of functional uterus defined as successful fertility-sparing surgery and no adjuvant therapy. A total of 90 evaluable patients will be needed to complete the study. Expected complete accrual in 2022 with presentation of results by 2025. Pending ethics submission.

Background Diagnosis of breast cancer in young women has been shown to affect their decision‐making with regard to fertility and family planning. Limited data are available from populations across the U.S. regarding this issue; thus, we sought to describe fertility concerns and efforts to preserve fertility in a national clinical trial population of young breast cancer patients. Methods The young and strong study was a cluster‐randomized controlled trial testing an intervention program for young women with breast cancer. Patients were surveyed within 3 months after diagnosis and at 3, 6, and 12 months after. Surveys asked about sociodemographics, psychosocial domains, fertility concerns, and fertility preservation strategies. Univariable and multivariable models were used to investigate sociodemographic, clinical, and psychosocial predictors of fertility concerns. Results Of 467 women from 54 clinical sites across the U.S. (14 academic, 40 community), 419 were evaluable regarding fertility concerns. Median age was 40 years (range 22–45), 11% were Black, 6% Hispanic, and 75% had children. Tumor stage was I (35%), II (51%), or III (14%); 82% received chemotherapy. At time of the treatment decision, 133 (32%) participants had fertility concerns, among whom 47% indicated this affected their treatment decisions. Sixty percent of participants reported having discussed fertility with their physician. Twenty percent of those with fertility concerns used fertility preservation strategies. History of difficulty becoming pregnant and younger age were associated with higher odds of fertility concerns in multivariable modeling. Conclusion Many young women with newly diagnosed breast cancer are concerned about fertility in a way that impacts their treatment decisions. Concerns were discussed, but few used fertility preservation strategies. These findings have implications for counseling young patients.

PurposeTo investigate the differences concerning post-thawing/warming follicle survival, DNA damage and apoptosis in human ovarian tissues cryopreserved by slow freezing, open, or closed vitrification methods.MethodsA total of 50 pieces of 5 × 5 × 1 mm ovarian cortical pieces were harvested (5 donor ovaries; mean age 31 ± 6.62 years). From each donor, one cortical piece was used as baseline; the remaining were randomly assigned to slow freezing (SF), vitrification using open device (VF-open), or closed device (VF-closed) groups. After 8–10 weeks of cryostorage, tissues were evaluated 4 h after thawing/warming. Histological analysis was evaluated for follicle survival (primordial and primary follicle densities) by H&E staining. The percentages of primordial and primary follicles with DNA double-strand breaks (γH2AX) and apoptotic cell death pathway activation (AC3) were immunohistochemically assessed. Data were analysed using one-way ANOVA and LSD post hoc comparison.ResultsCompared to the baseline, primordial follicle (pdf) densities significantly declined in all cryopreserved groups (SF, VF-open, and VF-closed, P < 0.05). However, the total and non-apoptotic pdf densities were similar among SF, VF-open, and VF-closed. SF and VF with either open or closed devices did not increase the percentages of primordial or primary follicles with DNA double-strand breaks (DSBs) or apoptosis compared to the baseline or among the freezing methods in the present study.ConclusionBased on the intact primordial follicle survival, DNA damage, and apoptosis rates after thawing/warming, SF vs VF with either open or newly developed closed devices appear to be comparable.

PurposeThe objective of the trial was to compare the regression rate of atypical endometrial hyperplasia (AEH) in patients treated with megestrol acetate (MA) vs. levonorgestrel-intrauterine device (LNG-IUS). We also aimed to assess the fertility and pregnancy outcomes in these patients.MethodsThe study was a phase II multi-centre randomised controlled trial on the use of MA compared to LNG-IUS in the treatment of AEH conducted from January 2020 to January 2024 in Singapore. Women who were diagnosed with AEH and between 21 and 40 years old were included. The patients were randomised to receive either MA (160 mg orally daily) or LNG-IUS. The primary outcomes assessed were the regression rates at 3 months, 6 months and 9 months of treatment. The secondary outcomes assessed were the side effects, patient acceptability and fertility outcomes.ResultsThirty-six patients completed the trial. The overall regression rate was 88.9% by 9 months. There was no statistically significant difference in the 9-month complete regression rate between MA vs. LNG-IUS. There was also no significant difference in side effects and weight change between both arms. Nineteen patients were actively pursuing fertility after complete regression. There were 8 pregnancies achieved, with resultant 4 live births and 4 miscarriages.ConclusionOur study confirms a high regression rate of AH with medical treatment. LNG-IUS is a non-inferior treatment compared to megestrol acetate. Successful pregnancy outcomes can be achieved after regression of AEH. Long-term studies of sufficient sample-size are needed to assess for fertility and pregnancy outcomes, risk of recurrence and long-term risk of malignancy.Trial registration numberThe study was registered with the Health Science Authority (HSA) (License No.: CTA1900087) on September 5, 2019: https://eservice.hsa.gov.sg/prism/ct_r/enquiry.do?action=loadSpecificDetail.The trial was registered retrospectively on ClinicalTrials.gov (ID: NCT05492487) on April 7, 2022: https://clinicaltrials.gov/study/NCT05492487.

Background Around 4% of women receive an endometrial cancer diagnosis before turning 40, mainly those without prior childbirth experience and a strong desire to preserve their ability to conceive. Consequently, for young patients diagnosed with atypical endometrial hyperplasia (AEH) or early endometrial carcinoma (EC), a fertility-preserving approach employing high-dose oral progesterone has been adopted. However, previous research has shown a notable relapse rate. Furthermore, the extended use of substantial oral progesterone doses may hinder ovarian function and raise the risk of weight gain, liver issues, blood clotting, and breast cancer. We previously assessed the clinical effectiveness and pregnancy outcomes of gonadotropin-releasing hormone agonist (GnRH-a) based re-treatment for women with EC and AEH who did not respond to oral progestin therapy but achieved favorable treatment results and reproductive outcomes. Methods This study will be an open-label, two-armed, randomized, investigator-initiated multicenter trial evaluating the combination of GnRH-a with the levonorgestrel-releasing intrauterine system or the combination of GnRH-a with an aromatase inhibitor (comprising a subcutaneous GnRH-a injection every 4 weeks and daily oral letrozole 2.5 mg). A total of 226 participants will be randomly allocated to one of the two treatment groups in a 1:1 ratio. The primary objective is to determine the effectiveness of GnRH-a-based re-treatment in achieving a complete response (CR) at 24 weeks for patients with AEH or EC. Secondary objectives include assessing the pregnancy rate 12 weeks after treatment, as well as post-treatment pregnancy outcomes and the rate of recurrence. Ethics and dissemination The protocol received approval from the Institutional Review Board of Peking Union Medical College Hospital and from boards at five other institutions. The trial will adhere to the principles outlined in the World Medical Association’s Declaration of Helsinki and follow Good Clinical Practice standards. The trial results will be disseminated through publication in a peer-reviewed journal. Conclusions Prospective evidence supporting conservative treatment for EC and AEH is limited. There is a need for new approaches that can achieve higher CR rates with fewer side effects. This trial will assess the effectiveness of GnRH-a-based fertility-sparing treatment in obese women and recurrent patients, offering a promising alternative for patients with EC and AEH. Trial registration number Chinese Clinical Trial Registry ChiCTR2200067099. Registered on December 27, 2022.

IntroductionMultimodal anticancer therapies greatly damage the fertility of breast cancer patients, which raises urgent demand for fertility preservation. The standard options for fertility preservation are oocyte and embryo cryopreservation; both require controlled ovarian hyperstimulation (COH). However, there are safety concerns regarding breast cancer relapse due to the elevated serum estradiol levels during COH. Serum estradiol levels can be effectively decreased with the highly specific aromatase inhibitor letrozole. Letrozole is still uncommonly used during COH for fertility preservation, which has only been reported in a few studies, and the evidence of oocyte retrieval during ovarian stimulation and short-term safety from the perspective study is insufficient. As a result, this study will compare the efficacy of ovarian stimulation and the short-term safety of letrozole COH and non-letrozole COH protocols for preserving fertility in patients with breast cancer.Methods and analysisThis is an open-label, multicentre RCT being conducted in five Chinese reproductive medical centres. 64 eligible patients diagnosed with breast cancer will be randomly assigned (1:1) to the letrozole or non-letrozole group during their COH cycles. The primary outcome is the number of mature oocytes. The secondary outcomes are the number of high-quality embryos, incidence of ovarian hyperstimulation syndrome(OHSS) and recurrence rate of breast cancer.Ethics and disseminationEthical approval was obtained from the Ethics Review Committee of Guangdong Provincial People’s Hospital (KY-Q-2023-840-02). Written informed consent will be obtained from each participant. Findings will be disseminated to patients, clinicians and commissioning groups through peer-reviewed publications.Trial registration numberChiCTR2300078625

IntroductionProgestin therapy is the only fertility-sparing treatment option for patients with atypical endometrial hyperplasia (AEH) and endometrial cancer (EC). However, the results of three meta-analyses revealed a high remission rate, as well as an association with a high rate of relapse. We previously conducted a phase II of medroxyprogesterone acetate (MPA) plus metformin as a fertility-sparing treatment for AEH and EC patients, and reported that metformin inhibited disease relapse after remission.Methods and analysisA randomised, open, blinded-endpoint design phase IIb dose response trial was planned to commence in July 2019. The trial aims to identify the appropriate dose of metformin to be combined with MPA therapy for fertility-sparing treatment of patients with AEH and EC. The primary endpoint of the trial is the 3-year relapse-free survival (RFS) rate. The secondary endpoints are RFS rate, the overall rate of response to MPA therapy, the conception rate after treatment, the outcome of pregnancy, toxicity evaluation and changes in insulin resistance and body mass index. A total of 120 patients will be enrolled from 15 Japanese institutions within a 2.5-year period and followed up for at least 3 years.Ethics and disseminationThe protocol was approved by the institutional review board at Chiba University Hospital and boards at 14 other institutions. The trial will be conducted according to the principles of the World Medical Association’s Declaration of Helsinki and in accordance with Good Clinical Practice (GCP) standards. The trial findings will be published in a peer-reviewed journal.Trial registration numberJapan Registry of Clinical Trials (jRCT2031190065).