Hormonal Changes Associated with Reproduction in Females with Type 2 Diabetes Mellitus and Prediabetes: Protocol for A Systematic Review and Meta-Analysis (Preprint)

<sec> <title>BACKGROUND</title> Reproductive hormones play a crucial role in regulating the menstrual cycle, ovulation, and fertility in females. Hormonal imbalances, particularly involving estradiol, progesterone, luteinizing hormone LH, FSH, and testosterone, can significantly affect reproductive health. T2DM is a chronic metabolic disorder characterized by insulin resistance and hyperglycemia, both of which have been associated with disruptions in the HPO axis and altered ovarian steroidogenesis. Prediabetes is an intermediate metabolic state between normoglycemia and diabetes, with a high risk of progression to T2DM. Emerging evidence suggests that even in the prediabetic state, changes in reproductive hormone concentrations may occur, potentially leading to menstrual irregularities, anovulation, and infertility. </sec> <sec> <title>OBJECTIVE</title> This systematic review protocol outlines the planned synthesis and analysis of existing literature investigating hormonal changes associated with reproduction in females with T2DM and prediabetes. </sec> <sec> <title>METHODS</title> This protocol is prepared in accordance with the PRISMA-P 2020 guidelines. Electronic databases including PubMed, Google Scholar, Scopus, and EBSCO will be systematically searched for published observational, case-control, and cross-sectional studies reporting on reproductive hormone changes in females with T2DM and/or prediabetes. Eligible participants will be females in their reproductive age diagnosed with T2DM or prediabetes. Studies involving pregnant women, those with type 1 diabetes mellitus, known endocrine disorders unrelated to diabetes, or those receiving hormonal therapy will be excluded. The control group will consist of non-diabetic females without known reproductive endocrine disorders. Data on changes in estradiol, progesterone, LH, FSH, and testosterone will be extracted. A second reviewer will verify extracted data, with disagreements resolved by a third reviewer. The risk of bias will be assessed using the Downs and Black checklist. Where sufficient data are available, Review Manager (RevMan) v5.4 will be used to perform a meta-analysis, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach will be used to assess evidence quality. </sec> <sec> <title>RESULTS</title> This review will use only publicly available published data, which will be collected after protocol publication. </sec> <sec> <title>CONCLUSIONS</title> The findings will provide a comprehensive synthesis of current evidence regarding reproductive hormonal changes in females with T2DM and prediabetes, highlighting knowledge gaps and informing future clinical and epidemiological research. These results may guide early detection and intervention strategies to preserve reproductive health in at-risk women. As the review will be based solely on published literature, ethical approval is not required. </sec> <sec> <title>CLINICALTRIAL</title> International Prospective Register of Systematic Reviews (PROSPERO) CRD420251078685, https://www.crd.york.ac.uk/PROSPERO/view/CRD420251078685. </sec>