Treatment-induced ovarian function loss is a significant concern for many young patients with breast cancer. Accurately predicting this risk is crucial for counselling young patients and informing their fertility-related decision-making. However, current risk prediction models for treatment-related ovarian function loss have limitations. To provide a broader representation of patient cohorts and improve feature selection, we combined retrospective data from six datasets within the FoRECAsT (Infertility after Cancer Predictor) databank, including 2679 pre-menopausal women diagnosed with breast cancer. This combined dataset presented notable missingness, prompting us to employ cross imputation using the k-nearest neighbours (KNN) machine learning (ML) algorithm. Employing Lasso regression, we developed an ML model to forecast the risk of treatment-related amenorrhea as a surrogate marker of ovarian function loss at 12 months after starting chemotherapy. Our model identified 20 variables significantly associated with risk of developing amenorrhea. Internal validation resulted in an area under the receiver operating characteristic curve (AUC) of 0.820 (95% CI: 0.817-0.823), while external validation with another dataset demonstrated an AUC of 0.743 (95% CI: 0.666-0.818). A cutoff of 0.20 was chosen to achieve higher sensitivity in validation, as false negatives-patients incorrectly classified as likely to regain menses-could miss timely opportunities for fertility preservation if desired. At this threshold, internal validation yielded sensitivity and precision rates of 91.3% and 61.7%, respectively, while external validation showed 92.9% and 60.0%. Leveraging ML methodologies, we not only devised a model for personalised risk prediction of amenorrhea, demonstrating substantial enhancements over existing models but also showcased a robust framework for maximally harnessing available data sources.

BACKGROUND: Ovarian tissue cryopreservation is an increasingly utilized fertility preservation method in young women, with this technique being largely implemented across Europe and Australia. Australia is a pioneer of ovarian tissue cryopreservation, but the clinical perinatal outcomes are currently unknown for the Australian population. These outcomes are important as they contribute to the global understanding of which patients can benefit from this fertility preservation option. OBJECTIVE: To examine the pregnancy and mortality outcomes of patients who have undergone ovarian tissue cryopreservation and/or ovarian tissue transplantation in Victoria, Australia, and investigate predictors of success. STUDY DESIGN: A retrospective cohort study was conducted including patients who underwent ovarian tissue cryopreservation from July 1995-July 2022 at the largest ovarian tissue cryopreservation center in Victoria, Australia. Patients over the age of 18 at the time of the study were included in the study. Perinatal and mortality data were obtained through data linkage from the Victorian Perinatal Data Collection and Births Deaths and Marriages databases. RESULTS: Overall, 593 patients had undergone ovarian tissue cryopreservation between July 1995 and July 2022 in Victoria, Australia. All 593 patients were successfully linked to the perinatal and mortality databases, of whom 6 (1.0%) had pregnancies lacking perinatal data, and 17 had mortality data not reflected in the linkage but next of kin reported their deaths to the ovarian tissue cryopreservation providing clinic. Of this cohort, 48 (8.1%) underwent ovarian tissue transplantation and 106 (17.9%) died from complications of their medical indication for tissue freezing. A total of 192 neonates from 114 women were reported from both transplant (n=12/48, 25.0%) and nontransplant (n=102/545, 18.7%) cohorts. Most women had reported pregnancies by 15 years after ovarian tissue cryopreservation, with transplant cases having a similar overall pregnancy rate as per the time-to-event analysis (adjusted sub-distribution hazard ratio 1.378, 95% confidence interval 0.755-2.515, P=.296). CONCLUSION: This is a large single-center cohort study within the southern hemisphere that investigates patients who have undergone ovarian tissue cryopreservation, with one in 5 women achieving a pregnancy, emphasizing the clinical feasibility of ovarian tissue cryopreservation as a fertility preservation option for future fertility counseling.

AbstractChemotherapeutic agents result in the loss of growing follicles, which can manifest as amenorrhoea. Alkylating chemotherapy (AC) is known to be more gonadotoxic than non-alkylating chemotherapy (NAC). Anti-Müllerian hormone (AMH), an indirect marker of ovarian reserve, and age have been investigated as predictors of ovarian function after chemotherapy; however, little is known about the time to return of menses. This study aimed to assess how patient age and baseline serum AMH levels at cancer diagnosis affect the time to return of menses post-chemotherapy. This retrospective cohort study examined oncology patients (n = 67) who underwent chemotherapy and were treated through the Reproductive Services Unit of two institutions in Melbourne, Australia. Primary outcomes included the correlation between age and baseline AMH with time to return of menses after chemotherapy. Secondary outcomes include the change in AMH levels at 6- and 12-months post-completion of chemotherapy. Pairwise correlation of the pre-chemotherapy AMH level and time to return of menses demonstrated statistical significance (Spearman’s coefficient, ρ = −0.40) for patients who underwent AC. This analysis in breast cancer patients who underwent AC displayed a negative correlation but was not statistically significant. No association was found between age and time to return of menses for all cancer (NAC or AC) or breast cancer patients who underwent AC. Higher AMH levels prior to AC were associated with an earlier return of menses after chemotherapy. Age at the commencement of chemotherapy was not associated with return of menses. Further prospective research is required to assess post-chemotherapy recovery of AMH.Lay summaryChemotherapy, used to treat cancer, is known to damage women’s ovaries, with certain types having a more toxic effect than others. This may result in a temporary loss of periods while undergoing chemotherapy. AMH is a hormone produced by the ovaries and gives an indication of their level of function. This study looks at whether an individual's AMH or age when beginning chemotherapy can predict the time before the resumption of periods after completing chemotherapy. This study found that for cancer patients who underwent the chemotherapy type known to be more toxic to ovaries, the higher their AMH level was before beginning chemotherapy, the more rapidly their periods would return after completing chemotherapy. Age was not found to accurately predict how rapidly periods would return after completing chemotherapy. This information can be used to inform patients before treatment of the chances of periods returning and, consequentially, pregnancy after the completion of their chemotherapy.

Abstract As the prevalence of cancer in young people rises, and with improved survival rates such that over 80% of young cancer patients can expect to recover, future fertility and having their own family has become an important consideration which needs to be addressed. Best-practice oncofertility management includes initial discussion, assessment of fertility risk and medical risk, and consideration of preservation strategies prior to commencement of potentially gonadotoxic therapy, where possible, as well as post cancer-treatment fertility care. The window of opportunity for oocyte cryopreservation and/or ovarian tissue cryopreservation may be very limited. Therefore it is of paramount importance that a patient’s medical condition, gonadotoxicity risk, and current reproductive health and potential are considered when planning fertility preservation. Antimullerian hormone (AMH) is one of a group of tests performed which can assist with planning treatment and with counselling regarding the likely yield of a cycle. Knowledge regarding pre-treatment AMH, along with a patient’s age and the type of cancer treatment, may also assist with counselling regarding the likelihood of recovery of fertility after completion of this treatment. However, there are many factors which affect AMH levels, and it is well-known that the results of stimulation can be very variable, as can be the long-term impact of the potentially gonadotoxic treatment. Hence an AMH test, while useful, needs to be contextualized as being only one of many factors to be considered when planning optimal (in terms of yield and safety) fertility preservation treatment and advising re future fertility.

BackgroundThe presence of different breast cancer receptor status may impact ovarian stimulation outcomes. AimTo study the association between oestrogen receptor (ER) status in breast cancer patients and fertility preservation outcomes in a major tertiary referral centre. Materials and MethodsWomen who underwent fertility preservation following the diagnosis of breast cancer from 2008 to 2018 were included in the study. Patient age, ovarian stimulation parameters and laboratory outcomes were recorded and compared between the ER positive and negative groups. The primary outcome was total number of oocytes frozen. Secondary outcomes included total number of oocytes collected, mature oocytes, and embryos frozen. ResultsThe women included in the study (n = 214) were analysed in the following groups based on their fertility preservation method: oocyte freezing (n = 131), embryo freezing (n = 70), and both embryo and oocyte freezing (n = 13). There was an increase in the mean (but not mature) number of oocytes frozen (12.4 and 9.2, P-value = 0.03) favouring the ER positive group, even though the women in this group were older (35.0 and 33.4, P-value of 0.03). There is no difference in the starting follicle-stimulating hormone dose, duration of stimulation, mature oocytes collected, and embryos frozen in both groups. ConclusionPatients with ER positive breast cancer may have more positive ovarian stimulation outcomes.

To review elective oocyte vitrification at a single IVF unit over a 10-year period to facilitate the management of patient expectations. Retrospective analysis of 3280 elective oocyte vitrification cycles. Oocytes vitrified using Rapid I device in 15% ethylene glycol, 15% dimethyl sulfoxide and 0.5M sucrose. From January 2013 through December 2022, 3280 elective oocyte vitrification cycles were performed with 32621 oocytes vitrified. For oocytes vitrified between January 2013 and June 2017 the survival rate was 81.6% (701/859). In June 2017, an audit of the procedure indicated that some embryologists had been under filling the Rapid-I hole. Subsequent retraining and education on filling the Rapid-I resulted in a significant increase in survival to 91.5% (829/906) p<0.05. The outcomes of these warmed oocytes (vitrified post July 2017) were divided into age groups <38 and ≥38 (at the time of vitrification) and compared to age groups, from the same time, with fresh oocytes only. For vitrified oocytes from <38 patients, survival was 91.0% (454/499) with an average number of oocytes available for ICSI 11.4 vs 10.1 fresh (p=0.2); fertilisation was 64.8% vs 64.0% fresh (p=0.6) and foetal heart (FH) pregnancy rate was 42.3% (11/26) vs 41.0% (1801/4388) fresh (p=0.5). Similar survival was achieved with oocytes from the ≥38 patients; 92.1% (375/407) with an average number of oocytes for ICSI of 8.3 vs 6.7 fresh (p=0.04); fertilisation was 68.5% vs 60.3% fresh (p=0.9) and foetal heart (FH) pregnancy rate was 35.3% (12/34) vs 23.3% (954/4092) fresh (p=0.9). When vitrifying oocytes with the Rapid-I device, it is important to correctly fill the hole with solution. Patients undergoing oocyte vitrification should understand that not all their oocytes are likely to survive (loss rate of approximately 8.5%). Of the oocytes which do survive warming, fertilisation and pregnancy rates are similar to those of patients who did not vitrify oocytes.

BACKGROUND Most couples in Australia want to have children but some might not attain their reproductive goals, experiencing involuntary childlessness or not reaching their desired family size. There is increased focus on helping couples achieve their reproductive goals. Identifying existing barriers, such as those related to social and societal factors, access to treatment and treatment success, is crucial to optimising outcomes. OBJECTIVE This article discusses existing barriers to reproduction to help general practitioners (GPs) raise the topic of future fertility with patients, care for those presenting with fertility concerns and support those undergoing fertility treatment. DISCUSSION Recognition of the impact of barriers such as age to achieving reproductive goals remains the highest priority for GPs. This will help them to broach this topic with patients, carry out a timely evaluation or provide referral, as well as discuss opportunities such as elective egg freezing. Other barriers can be mitigated by educating patients, informing them about available resources and supporting those undergoing fertility treatment as part of a multidisciplinary reproductive team.

BACKGROUND Conception difficulties are a common reason for presentation to general practitioners (GPs), who play an integral part in advising couples regarding optimisation of trying to conceive, timely and relevant investigations, as well as referral to non-GP specialist care. Lifestyle modification to optimise reproductive and offspring health is a crucial, though sometimes overlooked, component of pre-pregnancy counselling. OBJECTIVE This article provides an update on fertility assistance and reproductive technologies to help GPs care for patients presenting with fertility concerns as well as those who require donor gametes to conceive or are carrying genetic conditions that may affect the chance of having a healthy baby. DISCUSSION Recognition of the impact of a woman's (and, to a slightly lesser degree, man's) age remains the highest priority for primary care physicians to allow thorough and timely evaluation/referral. Advising patients about lifestyle modification, such as diet, physical activity and mental health, prior to conception is crucial for overall and reproductive health outcomes. Various treatment options exist to provide personalised and evidence-based care for patients for infertility. Other indications for using assisted reproductive technology include preimplantation genetic testing of embryos to avoid transmission of serious genetic conditions, elective oocyte freezing and fertility preservation.

Background Fertility preservation is an important healthcare focus in the paediatric and adolescent population when gonadotoxic treatments are required. Ovarian stimulation (OS) resulting in oocyte cryopreservation is a well-established fertility preservation option in the adult population. It’s utility, however, is little known in young patients. The purpose of this review was to synthesise the available literature on OS in patients ≤18 years old, to identify gaps in current research and provide suggestions for future research directions. Methods Using PRISMA guidelines, a systematic review of the literature was performed for all relevant full-text articles published in English in Medline, Embase, the Cochrane Library and Google Scholar databases. The search strategy used a combination of subject headings and generic terms related to the study topic and population. Two reviewers independently screened studies for eligibility, extracted data and assessed the risk of bias. Characteristics of the studies, objectives and key findings were extracted and summarised in a narrative synthesis. Results Database search and manual review identified 922 studies, 899 were eliminated based on defined exclusion criteria. Twenty-three studies were included and comprised 468 participants aged ≤18 years who underwent OS (median 15.2, range 7-18 years old). Only three patients were premenarchal, and four patients were on treatment to suppress puberty. Patients had OS for a broad range of indications including oncology treatment, transgender care and Turner syndrome. A total of 488 cycles of OS were completed, with all but 18 of these cycles (96.3%) successfully resulting in cryopreserved mature oocytes (median 10 oocytes, range 0-35). Fifty-three cycles (9.8%) were cancelled. Complications were rare (<1%). One pregnancy was reported from a female who had OS aged 17 years old. Conclusion This systematic review demonstrates that OS and oocyte cryopreservation is achievable in young females however there are only a few cases in the literature describing OS in premenarcheal children or those who have suppressed puberty. There is little proof that OS can lead to pregnancy in adolescents, and no proof that this can be achieved in premenarchal girls. Therefore it should be regarded as an innovative procedure for adolescents and experimental for premenarcheal girls. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=265705 , identifier CRD42021265705.

Background: There has been much debate and concern about whether the dose of exogenous gonadotrophins used for controlled ovarian stimulation (COS) adversely affects the selection of leading follicles and potentially impacts the quality of the eggs retrieved and the embryos created. The ploidy status of the embryo, as assessed by pre-implantation genetic testing (PGT), is used as a measure of embryo quality.

Background: Recognised female fertility preservation strategies include oocyte and embryo cryopreservation. Ovarian tissue cryopreservation is no longer experimental, and the only option for children and pre-pubertal girls. Although testicular cryopreservation remains experimental for boys, it has the potential to evolve and provide a realistic opportunity for fertility in the future. The RWH/MIVF fertility preservation service has been preserving ovarian tissue since 1995. This service has been available to children, adolescent young adults (AYA) and adults about to receive gonadotoxic treatment for malignant and non-malignant conditions. In 2013, this service was extended to freezing testicular tissue for pre-pubertal and peri-pubertal males. Until 2019 these fertility preservation options have only been available to those undergoing procedures at Melbourne metropolitan hospitals. Young cancer patients seeking fertility preservation in regional or interstate areas, did not have this opportunity due to lack of access and resources. One approach to increasing patient access to Gonadal Tissue Cryopreservation (GTC), was to establish a national tissue retrieval and transport service. Aim: This paper describes the uptake of a GTC transport program at RWH, allowing rural and interstate oncology referral for transport, processing and storage of gonadal tissue in an acknowledged centre of excellence. Method: An information/education/instruction resource package was developed for fertility units Australia-wide, supported by a centralised GTC program coordinator. Referrals are fast tracked to eliminate any delay in treatment. Gonadal tissue is harvested at the referring hospital and transported to RWH for cryopreservation and storage, following methods established in other countries with a centralised service 1 – 3 . Results: To date, 40 ovarian and testicular tissue has been transported from all Australian states, and Northern Territory to RWH, including semen transported from a regional hospital where no fertility service was available. This service was made possible, and free of charge to those patients 13–30 yo with a cancer diagnosis, through a generous donation by Sony Foundation. Conclusion: Provision of a comprehensive fertility preservation service, including GTC, for young people, was not widely available until 2019. Gonadal tissue transport facilitates engagement and upskilling in oncofertility with extensive support from a centre of excellence, allowing expansion of patient and provider access to best-practice fertility preservation options, regardless of their geographic location and socio-economic status.

Ovarian tissue cryopreservation (OTC) and transplantation is an innovative procedure increasingly utilized to help preserve fertility after gonadotoxic treatments especially in cancer patients. Approximately 30% of autotransplanted patients are able to achieve live birth, typically with the help of in-vitro fertilization. Numerous techniques and grafting sites have been described to continue to increase this figure. In the field of plastic surgery, tissue grafting has been successful performed for thousands of years and knowledge in this area has been significantly refined. A qualitative review of the literature using PubMed, Cochrane, SCOPUS and Medline databases was performed to look for articles relating to ovarian tissue transplantation (OTT) and comparisons made to plastic surgery tissue grafting. Many parallels were found between the principles of grafting in plastic surgery and the principles of OTT, including pre-operative patient optimization, suitable donor site selection, tissue harvest and preparation, graft site choice, immobilization of the graft and post-operative care. Consideration of the benefits and risks of using orthotopic versus heterotopic recipient sites is also highly important with regards to graft take, morbidity and ease of access of oocyte collection. We believe that ongoing discussion between disciplines can have the potential to improve knowledge, surgical techniques and patient outcomes.

STUDY QUESTIONIs a sub-peritoneal abdominal site a suitable site for cryopreserved ovarian tissue transplantation?SUMMARY ANSWERLive births have resulted from oocytes aspirated from follicles within cryopreserved ovarian tissue transplanted in a sub-peritoneal abdominal site with similar outcomes observed in terms of number of mature oocytes recovered and embryo development from tissue transplanted to sub-peritoneal abdominal, ovarian, and pelvic sites in our clinic.WHAT IS KNOWN ALREADYOver 130 live births have been reported from cryopreservation of ovarian tissue and subsequent transplantation. In the majority of these, tissue was transplanted onto the remaining ovary. Although grafting to a non-ovarian, non-pelvic, sub-peritoneal abdominal site has resulted in births, it has been suggested that compromised outcomes may be expected from a non-pelvic site.STUDY DESIGN, SIZE, DURATIONThe aim of the study was to assess the outcome from cryopreserved ovarian tissue transplanted to a site out of the pelvic area; a sub-peritoneal abdominal site. These outcomes were compared to transplantation to the ovary and peritoneal pelvic area in a cohort of 17 fertility preservation women where the individual sites of follicle aspiration were known and subsequent outcomes tracked. Ovarian tissue was slow frozen using the cryoprotectants propanediol and sucrose (n = 16 women) or using dimethyl sulfoxide and sucrose (n = 1 woman). Tissue was kept at 4°C overnight prior to freezing for 1 case. Tissue was thawed appropriately and prepared on 6.0 vicryl sutures for transplantation. Tissue was placed laparoscopically into a sub-peritoneal abdominal site, a pelvic side wall peritoneal pocket and the ovary.PARTICIPANTS/MATERIALS, SETTING, METHODSFollowing resumption of cycling, gonadotrophin stimulation commenced with FSH, LH and antagonist and a trigger was given when one follicle was >13 mm in diameter. Abdominal follicles were aspirated under ultrasound guidance trans-abdominally; ovarian and pelvic follicles were aspirated trans-vaginally. Due to an inability to differentiate pelvic from ovarian follicles at the time of ultrasound-guided oocyte retrieval, both were classified as ovarian on the side where both were present. However, on the side, where no ovary was present, outcomes from pelvic follicles were reported.MAIN RESULTS AND THE ROLE OF CHANCEAverage time lapse between ovarian tissue harvest and graft was 6 years. Resumption of cycling occurred on average 4.2 months post first graft, regardless of graft site. Mean follicle diameter on the day of oocyte aspiration was 14 mm for all sites. Aspiration failed to retrieve an oocyte in 30% (36/120) of abdominal follicles which was similar to the other sites; ovarian 24% (21/87), pelvic 32% (31/97). A similar proportion of retrieved oocytes was mature from all sites (67% (50/75) abdominal, 68% (42/62) ovarian, 59% (34/58) pelvic). The proportion of embryos which developed on Day 2 from those fertilized was also similar in all groups (90% (34/38) abdominal, 76% (22/29) ovarian, 96% (22/23) pelvic). To our knowledge, this is the first report of outcomes from cryopreserved ovarian tissue transplanted to a sub-peritoneal abdominal site and the subsequent comparison to outcomes from the ovary and a sub-peritoneal pelvic graft, within the same cohort of patients, where tissue was slow frozen predominantly with the cryoprotectant propanediol and sucrose.LIMITATIONS, REASONS FOR CAUTIONThe study reports outcomes from a small number of women following ovarian tissue transplantation. Follicle density is an estimate only and the amount of tissue grafted varied between patients.WIDER IMPLICATIONS OF THE FINDINGSThe demonstration of successful outcomes from cryopreserved ovarian tissue grafted to a sub-peritoneal abdominal site has significant implications for the management of women in which grafting to pelvic sites is contraindicated although it appears to be important to trigger follicle maturation at a lower than normal follicular diameter. The relative ease of oocyte retrieval at the sub-peritoneal abdominal site also has positive implications for the introduction of this approach into clinical practice.STUDY FUNDING/COMPETING INTEREST(S)No specific funding was used. All authors have no conflict of interest.TRIAL REGISTRATION NUMBERN/A.

Introduction As cancer treatments may impact on fertility, a high priority for young patients with breast cancer is access to evidence-based, personalised information for them and their healthcare providers to guide treatment and fertility-related decisions prior to cancer treatment. Current tools to predict fertility outcomes after breast cancer treatments are imprecise and do not offer individualised prediction. To address the gap, we are developing a novel personalised infertility risk prediction tool (FoRECAsT) for premenopausal patients with breast cancer that considers current reproductive status, planned chemotherapy and adjuvant endocrine therapy to determine likely post-treatment infertility. The aim of this study is to explore the feasibility of implementing this FoRECAsT tool into clinical practice by exploring the barriers and facilitators of its use among patients and healthcare providers. Methods and analysis A cross-sectional exploratory study is being conducted using semistructured in-depth telephone interviews with 15–20 participants each from the following groups: (1) premenopausal patients with breast cancer younger than 40, diagnosed within last 5 years, (2) breast surgeons, (3) breast medical oncologists, (4) breast care nurses (5) fertility specialists and (6) fertility preservation nurses. Patients with breast cancer are being recruited from the joint Breast Service of three affiliated institutions of Victorian Comprehensive Cancer Centre in Melbourne, Australia—Peter MacCallum Cancer Centre, Royal Melbourne Hospital and Royal Women’s Hospital, and clinicians are being recruited from across Australia. Interviews are being audio recorded, transcribed verbatim and imported into qualitative data analysis software to facilitate data management and analyses. Ethics and dissemination The study protocol has been approved by Melbourne Health Human Research Ethics Committee, Australia (HREC number: 2017.163). Confidentiality and privacy are maintained at every stage of the study. Findings will be disseminated through peer-reviewed scholarly and scientific journals, national and international conference presentations, social media, broadcast media, print media, internet and various community/stakeholder engagement activities.