Researchers and clinicians are debating the value of endoplasmic reticulum aminopeptidase 2, known as ERAP2, as a biomarker reflecting biological ageing in women with premature ovarian insufficiency (POI), following a letter in BJOG that highlights both potential and uncertainties in interpretation.
Biomarkers and ovarian ageing
Premature ovarian insufficiency is defined by early loss of ovarian function before age 40, with impaired hormone production, irregular cycles, and reduced fertility. It represents an accelerated form of reproductive ageing, distinct from normal menopause.
Clinicians and researchers have long sought reliable biomarkers that can track biological rather than chronological ovarian ageing, both to improve understanding of POI mechanisms and to refine clinical prognosis. Traditional markers such as anti-Müllerian hormone and antral follicle count provide indirect estimates of ovarian reserve, but do not fully capture molecular ageing processes.
ERAP2’s proposed role
Endoplasmic reticulum aminopeptidase 2 (ERAP2) is a protein involved in peptide processing with roles in immune regulation and cellular function. Recent primary research has suggested that serum ERAP2 levels are elevated in women with POI and may be predictive of intermittent recovery of ovarian function and clinical pregnancy outcomes when integrated into predictive models.
These findings support the notion that ERAP2 may reflect underlying ovarian ageing biology beyond standard clinical markers, offering a potential tool for personalised reproductive assessment.
Interpreting the data
In a letter published in BJOG, authors emphasised that caution is needed when interpreting ERAP2 as an ageing-derived biomarker for POI. They noted that while associations between ERAP2 and ovarian ageing have been reported, the evidence base is still emerging and may be influenced by study design, population differences, and analytical methods.
The letter underscored that biomarkers must be validated in larger and more diverse populations, and that clear standards are required to distinguish whether elevated ERAP2 truly reflects biological ageing processes or other systemic factors.
Clinical and research implications
Accurate biomarkers of ovarian ageing could transform reproductive counselling and management for women with POI, enabling clinicians to estimate the likelihood of intermittent ovarian function return or response to fertility interventions more precisely. However, expert commentary stresses that premature adoption of unvalidated markers may lead to misinterpretation and inappropriate clinical decisions.
Future research must not only replicate initial findings on ERAP2’s predictive value but also compare it with existing clinical measures in longitudinal settings to determine its added predictive utility.
Future directions
The ongoing debate highlights the need for collaborative research efforts to establish rigorous validation frameworks for biomarkers in reproductive ageing. Prospective cohort studies and standardised analytical pipelines will be essential for determining whether ERAP2 or similar molecular markers can be integrated into clinical practice for women with POI and other forms of ovarian ageing.
Reference
Interpreting ERAP2 as an Ageing-Derived Biomarker for Premature Ovarian Insufficiency. BJOG. 2026;DOI:10.1111/1471-0528.70148.
