Menstrual Recovery and Premature Ovarian Insufficiency Following Fertility-Sparing Surgery and Platinum-Based Chemotherapy in Children, Adolescents and Young Adults (≤25 Years) With Malignant Ovarian Germ Cell Tumours: A Systematic Review and Meta-Analysis

Abstract

Background and Rationale Malignant ovarian germ cell tumours (MOGCTs) are uncommon ovarian malignancies that predominantly affect children, adolescents, and young adults. Fertility-sparing surgery combined with platinum-based chemotherapy is an important treatment approach for eligible patients, aiming to achieve oncological control while preserving reproductive potential. Although many patients are young and may have a long reproductive lifespan ahead, the effects of cancer treatment on menstrual function and ovarian reserve remain clinically important concerns. Platinum-based chemotherapy can potentially affect ovarian function, while surgical intervention may also influence reproductive outcomes depending on the extent of ovarian tissue preservation and the patient's pretreatment ovarian status. Menstrual recovery following treatment is a clinically relevant indicator of reproductive recovery, but the resumption of menstruation does not necessarily establish normal ovarian reserve or exclude premature ovarian insufficiency (POI). Conversely, the absence of reported menstrual recovery may reflect insufficient follow-up or incomplete outcome assessment rather than permanent ovarian dysfunction. The available evidence on menstrual recovery and POI following fertility-sparing surgery and platinum-based chemotherapy in young patients with MOGCTs is likely to be limited by the rarity of these tumours, relatively small study populations, differences in treatment protocols, variable follow-up durations, and inconsistent definitions of reproductive outcomes. A systematic synthesis of the available evidence is therefore needed to quantify reported outcomes, characterise the uncertainty surrounding these estimates, and identify important gaps in the literature. Aim The aim of this systematic review and meta-analysis is to estimate the proportions of children, adolescents, and young adults aged 25 years or younger with MOGCTs who experience menstrual recovery and develop POI following fertility-sparing surgery and platinum-based chemotherapy. Objectives The primary objectives are: To estimate the pooled proportion of patients experiencing spontaneous menstrual recovery or menarche following treatment, where these outcomes are applicable and reported. To estimate the pooled proportion of patients developing POI following treatment, using the definitions and diagnostic criteria reported in the eligible studies and assessing their comparability. The secondary objectives are: To describe the timing of menstrual recovery and the duration of follow-up, where reported. To examine differences in reproductive outcomes according to chemotherapy regimen, age at diagnosis, surgical approach, and other clinically relevant characteristics when sufficient comparable data are available. To summarise the definitions and methods used to assess menstrual function and POI across studies. To evaluate the methodological quality or risk of bias of included studies using appropriate tools. To identify evidence gaps that may inform future research, reproductive counselling, and long-term follow-up of young patients treated for MOGCTs. Methods Overview The review will be conducted using a prespecified protocol and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidance, as applicable. The protocol will be registered prospectively on the Open Science Framework (OSF). Relevant bibliographic databases will be searched using a comprehensive strategy combining controlled vocabulary and free-text terms for MOGCTs, fertility-sparing surgery, platinum-based chemotherapy, menstrual recovery, ovarian function, and POI. Reference lists of eligible publications and relevant reviews may also be examined to identify additional studies. Eligible studies will include children, adolescents, and young adults aged 25 years or younger with MOGCTs who received fertility-sparing surgery and platinum-based chemotherapy and for whom relevant menstrual or ovarian-function outcomes are reported. Study selection will involve title and abstract screening followed by full-text assessment against predefined eligibility criteria. Data will be extracted using a structured form covering study characteristics, participant demographics, tumour characteristics, surgical procedures, chemotherapy regimens, follow-up duration, outcome definitions, and outcome-specific event counts and denominators. Risk of bias will be assessed using a tool appropriate to the designs of the included studies. Where clinically and methodologically appropriate, random-effects meta-analysis will be used to pool proportions with corresponding 95% confidence intervals. Statistical heterogeneity will be assessed, and prespecified subgroup or sensitivity analyses will be undertaken when supported by the available evidence. If pooling is inappropriate because of substantial clinical or methodological differences or insufficient data, findings will be synthesised narratively. Menstrual recovery and POI will be analysed as distinct outcomes. Differences in outcome definitions, follow-up periods, and diagnostic criteria will be considered during interpretation. Menstrual recovery will not be treated as equivalent to normal ovarian reserve, fertility, or the absence of POI. Similarly, amenorrhoea alone will not automatically be considered diagnostic of POI. Expected Outcomes and Significance The review is expected to provide pooled estimates of menstrual recovery and POI following fertility-sparing surgery and platinum-based chemotherapy in young patients with MOGCTs, provided that sufficient comparable evidence is available. It will also describe the variability in reported outcomes, identify potential sources of heterogeneity, and clarify the extent to which current evidence supports comparisons between treatment regimens or patient subgroups. The findings may help clinicians provide more evidence-informed counselling about menstrual function and potential ovarian complications following treatment. They may also support the development of more consistent approaches to reproductive outcome reporting and follow-up in this population. By identifying uncertainties in the existing literature, the review may guide future prospective studies and research priorities in oncofertility. The review will not establish individual-level causal effects of chemotherapy or surgery unless the available study designs and data support such conclusions. The certainty and generalisability of the findings will depend on the quantity, quality, and comparability of the included evidence.