Women’s Midlife: A Nexus of Depression,Insulin Resistance,and Opportunity for Lifestyle Intervention

Insulin resistance (IR) is a critical risk factor for type 2 diabetes,^1,2 cardiovascular disease (CVD), ³ and some cancers.^4,5 The menopause transition (i.e., perimenopause) is associated with hormonal shifts and intra-abdominal fat mass gains that contribute to significant increases in the prevalence of IR, greater than that attributable to chronological ageing.^6–9 Perhaps in part owing to this, women after perimenopause, compared with before, display a twofold increased risk of CVD independent of age. ¹⁰ As such, there is an eminent need to address these menopause-specific risk factors to improve health outcomes for women. The menopause transition is also associated with a 40% greater risk of depression compared premenopause. ¹¹ Intriguingly, emerging evidence suggests a potential link between depression and IR specific to peri- and postmenopause. ¹² If substantiated, understanding this relationship could open new avenues for researchers and clinicians to better identify and manage both conditions, thereby improving health outcomes and quality of life for women navigating the menopause transition.

The historic underrepresentation of women in research has skewed medical research and practice toward male-centric approaches and left an enormous “hill to climb” for researchers aiming to improve health outcomes in women throughout the lifespan. Since the 1980s, this climb has been gaining momentum.^13–15 The Study of Women’s health Across the Nation (SWAN) is one such study that has been instrumental in leading the way. Established in 1996, this large-scale study enrolled a multi-ethnic sample of 3,302 females with the aim of defining the menopause transition and documenting its associated “antecedents and consequences.” ¹⁶ To-date, SWAN continues to generate novel insights on the physical and mental health changes women experience throughout the menopause transition.

In this issue of the Journal of Women’s Health, Chen and colleagues (2025) leverage longitudinal data from the SWAN cohort to characterize the relationship between IR and depressive symptoms among a multi-ethnic sample of nearly 3000 midlife (age 42–52) females, followed for an average of 20 years, and 15 follow-up assessments. ¹⁷ After adjustment for physical activity, waist circumference, and age, the authors report a significant positive association between depression and IR, as measured by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). They also evaluated the temporality of this relationship, finding that the association was present only concurrently. Specifically, current, but not prior, risk for clinical depression, defined as a score of ≥16 on the Center for Epidemiological Studies Depression Scale (CES-D), was associated with IR. For clinicians, this finding may be actionable in that midlife women presenting with signs of depression could also be screened for IR, a high-risk yet often underdiagnosed condition. Intriguingly, in stratified analyses based on race/ethnicity, this relationship was strong among Hispanic females and was not significant among White, Black, Chinese, and Japanese females. This study provides some of the first longitudinal, repeated-measures analyses exploring the link between depression and IR in women. Further, the diversity of the sample enabled ethnicity/race stratified analyses that produced a potentially meaningful relationship in an understudied racial minority group of Hispanic women.

While these findings have clinical application, the use of HOMA-IR as a measure of IR has some noteworthy limitations. HOMA-IR is a mathematical calculation using fasting glucose and insulin concentrations that has been validated as a measure of IR. ¹⁸ Yet its reliance upon a single fasting blood sample results in HOMA-IR being particularly reflective of the liver’s response to insulin. Postprandial (i.e., after a meal) glucose and insulin responses, which can be evaluated clinically through an oral glucose tolerance test, can capture earlier signs of metabolic dysfunction that may be missed by HOMA-IR. Indeed, in many cases, postprandial hyperglycemia precedes elevations in fasting glucose. ¹⁹ For these reasons, future research would be strengthened by utilizing postprandial measures of IR (such as those derived from an oral glucose tolerance test, like Matsuda Index) which reflect systemic IR. Using measures that capture earlier signs of IR would deepen our understanding of the magnitude and temporality of the relationship between depression and IR.

Another avenue for future directions that build upon this research is different measures of depression and improved characterization of menopausal status. Chen and colleagues assessed the potential role of pre-, peri-, versus postmenopausal status. ¹⁷ Contrary to their hypothesis, the authors report no effect of menopausal stage on the relationship between IR and depression (Interaction term, p = 0.25), which suggests that screening for this multi-morbidity pattern could be valuable throughout the adult female lifespan. It is nevertheless noteworthy that “perimenopausal depression,” has a distinct symptom profile and etiology ²⁰ that was likely not captured by the CES-D. Given the high prevalence of menopause-related depression, ¹¹ future research in midlife women should consider complementary tools like the Meno-D questionnaire to determine whether this unique form of depression is also related to metabolic dysfunction, helping to inform the most effective screening practices and interventions for women across each life stage. Further, this SWAN analysis did not apply the most up-to-date and gold standard criteria for menopausal staging, the Stages of Reproductive Ageing Workshop +10, which could be an important consideration for future studies. ²¹ Nonetheless, even if the magnitude of the relationship between depression and IR did not vary by menopause status in the current sample, depression and IR have been reported to occur more frequently during and after perimenopause, ¹¹ highlighting the importance of considering their co-occurrence in these life stages. In composite, Chen and colleagues’ work has laid a foundation for several lines of further research on the interactions between menopausal status, depression and IR, as well as risk factor modification over the lifespan.

One of the most significant implications of this new knowledge of temporality of co-occurrence of two health conditions in women’s midlife is that it presents a potential key window of opportunity for intervention. Previous findings from the SWAN and other research suggest that lifestyle interventions provide multifaceted benefits for addressing depression, IR and other cardiometabolic health concerns. For instance, sleep has been shown to be a powerful predictor of both depressive symptoms ²² and metabolic health,^23,24 raising the possibility that sleep could serve as a common, modifiable strategy to reduce the co-occurrence of IR and depression. Similarly, lifestyle factors such as physical activity (PA) and diet have been shown to positively impact both depression and IR. ²⁵ In this regard, it was valuable that Chen et al. adjusted for PA in their analysis, yet it would be insightful for future studies to describe the modifying or therapeutic effects of PA, sleep, and diet on the interaction between depression and IR.

In conclusion, the study by Chen et al. and overall results of SWAN, provide important new knowledge specific to the unique experiences and health risks of midlife women. Chen and colleagues’ work suggests that assessing for presence, rather than history of depression, particularly in patients of Hispanic background, could hold clinical utility for early intervention and management strategies, including through sleep, PA, and diet, to improve metabolic health outcomes in midlife women. This work continues to advance women’s health research by opening new avenues to explore the role of depression in identifying metabolic health risk and thereby opening a window of opportunity for lifestyle intervention among women across the lifespan. The outcomes of this work also serve as a reminder of the importance of research in underrepresented groups by highlighting a potential difference in depression and IR interactions in Hispanic women.