JMIR Publications

Background:

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterised by insulin resistance and persistent hyperglycaemia, which can disrupt the hypothalamic–pituitary–ovarian (HPO) axis and impair ovarian steroidogenesis. These metabolic disturbances are associated with alterations in key reproductive hormones, including estradiol, progesterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone, contributing to menstrual irregularities, anovulation, and infertility. However, before the onset of T2DM, individuals often experience a transitional phase of prediabetes; a metabolic state preceding T2DM and is increasingly prevalent worldwide. Emerging evidence suggests that reproductive hormonal disturbances may begin during prediabetes; however, existing findings are inconsistent and have not been systematically synthesised.

Objective:

This systematic review aims to identify, evaluate, and synthesise available evidence on changes in reproductive hormone concentrations (estradiol, progesterone, LH, FSH, and testosterone) in females of reproductive age with T2DM and prediabetes, compared with non-diabetic controls.

Methods:

This protocol was developed in accordance with the PRISMA-P 2020 guidelines. A systematic search will be conducted in PubMed, Scopus, Google Scholar, and EBSCOhost MEDLINE for observational and case control studies published up to the date of the final search (June/2025). Eligible studies will include females of reproductive age diagnosed with T2DM or prediabetes and reporting circulating concentrations of at least one reproductive hormone of interest. Studies involving pregnant women, individuals with type 1 diabetes mellitus, known non-diabetic endocrine disorders, or those receiving hormonal therapy will be excluded. Non-diabetic females without reproductive endocrine disorders will serve as controls. Risk of bias will be assessed using the Downs and Black checklist. Where data are sufficiently homogeneous, quantitative synthesis will be performed using Review Manager (RevMan) version 5.4. The certainty of evidence will be evaluated using the GRADE approach.

Results:

At the time of manuscript submission, database searches have not yet been completed. Data collection is expected to commence in May 2025 and conclude in June 2025. The review will report the number and characteristics of included studies, summarize hormone-specific findings, and, where possible, present pooled estimates of hormonal differences between metabolic groups. Results are anticipated to be finalised and submitted for publication in August 2025. The study will be funded by CHS scholarship in 2025.

Conclusions:

This systematic review will provide a comprehensive synthesis of current evidence on reproductive hormonal alterations in females with T2DM and prediabetes. By identifying consistent patterns, gaps, and limitations in the existing literature, the findings will inform future research directions and support early identification of reproductive endocrine disturbances associated with metabolic dysfunction.

ClinicalTrial:

International Prospective Register of Systematic Reviews (PROSPERO) CRD420251078685, https://www.crd.york.ac.uk/PROSPERO/view/CRD420251078685.