Longitudinal changes in mammographic density and reproductive hormones during the menopausal transition in middle-aged Korean women: effect modification by obesity

Background: Breast cancer, strongly associated with female hormones, peaks around perimenopause in Asia, versus post-menopause in Western countries. This study aims to investigate longitudinal changes in reproductive hormones and mammographic density (MD) through the menopausal transition (MT), as MD serves as both a strong breast cancer risk factor and a proxy marker of cumulative hormone exposure. Methods: This longitudinal study included 4,737 Korean women who were in the premenopausal stage at baseline. MD was measured using digital mammography and analyzed with LIBRA software. Mean of craniocaudal views from both breasts were used for density assessments. A subset of 255 women with samples collected at four visits was assayed for hormone measurements across menopausal stages. Linear mixed-effects models were used to analyze longitudinal changes in reproductive hormones, including follicle-stimulating hormone (FSH), estradiol (E2), and anti-Müllerian hormone (AMH), and MD to evaluate potential interaction by obesity status. Results: For MD analyses, the mean age of participants was 41.0 (± 3.3) years, with a median follow-up of 7.0 years (IQR 4.1–9.1). For hormone analyses, the mean age was 45.9 (± 2.4) years, with a median follow-up of 6.1 years (IQR 5.8–6.9). As menopausal stage advanced, FSH increased, whereas AMH and E2 decreased. The association between E2 and menopausal stages differed by obesity (P for interaction = 0.016); in early transition, E2 increased in the non-obese group (14.53 [95% CI: −15.68, 44.75]) but decreased in the obese group (− 86.02 [95% CI: −151.05, − 21.00]). Similarly, MD changes across the MT varied by BMI category (P for interaction < 0.001); overall, mean MD decreased with advancing stages, but an increasing MD pattern was observed during early transition in the underweight group (1.69 [95% CI: −0.08, 3.46]). Conclusions: In Korean women undergoing MT, transient increases in MD paralleled E2 elevations, particularly in non-obese women. These findings align with the peak breast cancer incidence in Korean women in their 40s, preceding menopause, and the importance of considering hormonal and MD dynamics, as well as BMI, in breast cancer risk assessment and screening strategies for Asian women.