Type 2 diabetes is among the most consequential public health challenges of the twenty-first century, ranking as the eighth leading cause of death and disability worldwide. The burden is unevenly distributed, not only between countries but between the sexes, and the reasons are deeply tied to biology. Before menopause, women tend to enjoy a metabolic advantage that men do not, largely because estrogen enhances insulin sensitivity, supports glucose-stimulated insulin secretion, and protects insulin-producing beta cells from apoptosis. After menopause, that advantage erodes. Estrogen levels fall, insulin resistance rises, and body fat shifts toward the abdomen in an androgenic pattern, all of which converge to raise diabetes risk in older women above that of men in the same age groups. Epidemiological evidence reinforces this picture: women who reach menopause before the age of forty, or who lose their ovaries surgically, face markedly higher diabetes rates than those who reach menopause after fifty, a pattern attributed primarily to prolonged estrogen deficiency.

While the influence of individual reproductive factors, such as breastfeeding, parity, age at menarche, and age at menopause, has been studied extensively, the results have often been contradictory. Breastfeeding appears protective, abortion may raise risk, and findings on menarche and menopause timing conflict across studies. What researchers behind the new study argued was missing was a unified metric: the total duration over which a woman is exposed to estradiol-dominant menstrual cycles across her reproductive life. To their knowledge, no prior investigation had examined how this cumulative exposure relates to the incidence of type 2 diabetes, despite earlier work by the same group linking estrogen exposure duration to fractures, chronic kidney disease, cardiovascular outcomes, and hypertension.

To address the gap, the team turned to the Tehran Lipid and Glucose Study, a population-based cohort launched in 1998 with 15,005 participants aged three and older, selected through multistage cluster sampling and followed at three-year intervals across seven completed study phases. From this resource, the researchers identified 6,273 postmenarchal women aged twenty or older who had at least one follow-up visit. After excluding women with prevalent diabetes, insufficient follow-up, hormone replacement therapy use, surgical menopause, or incomplete data, the analytic sample comprised 3,411 women, of whom 1,053 developed type 2 diabetes over a median follow-up of approximately 17.6 years. Diabetes was defined rigorously according to American Diabetes Association criteria, using fasting plasma glucose of 126 mg/dL or higher, two-hour plasma glucose of 200 mg/dL or higher during an oral glucose tolerance test, or the use of antidiabetic medication.

The study’s central methodological innovation lay in how exposure was quantified. Endogenous estrogen exposure duration was defined as the interval between menarche and whichever came first: natural menopause, the onset of diabetes, or the end of follow-up. Critically, the investigators subtracted periods during which the estradiol-dominant follicular phase was absent, including pregnancies calculated at forty weeks per birth and twenty weeks per abortion, hormonal contraceptive use, months of breastfeeding per child, and the roughly two-week progesterone-dominant luteal phase of each menstrual cycle. This refinement aimed to isolate the estrogen-dominant portions of reproductive life, producing a z-score that could be entered into Cox proportional hazards regression models, adjusted first for age and body mass index and then for a fuller set of covariates including cholesterol fractions, triglycerides, physical activity, prediabetes, family history of diabetes, and gestational diabetes history.

The results were consistent across both models. In the fully adjusted analysis, each one-standard-deviation increase in the estrogen exposure z-score was associated with a 10 percent lower hazard of developing type 2 diabetes, a highly significant effect. The relationship was most pronounced among premenopausal women, who made up nearly 81 percent of the sample. In that subgroup, the age- and BMI-adjusted hazard ratio indicated a 16 percent risk reduction per standard deviation of longer exposure, and the fully adjusted estimate of 0.87 remained significant. Among the 657 postmenopausal women, the association was directionally similar and of comparable magnitude, with a fully adjusted hazard ratio of 0.88, but the wider confidence interval that touched 1.0 meant the finding fell just short of conventional statistical significance, likely reflecting the smaller subgroup size.

The baseline data contextualize these findings. Women who went on to develop diabetes were older, heavier, and had a less favorable lipid profile, with higher total cholesterol and triglycerides and lower HDL cholesterol. They also carried a substantially higher burden of prediabetes, affecting 39.5 percent of future cases compared with 11.7 percent of those who remained diabetes-free, along with more frequent histories of gestational diabetes and family history of the disease. Yet the protective association between estrogen exposure and diabetes incidence persisted after adjustment for all of these factors, suggesting the relationship was not merely an artifact of baseline metabolic differences. Adjusted survival curves also revealed that postmenopausal women showed consistently lower cumulative diabetes-free survival than premenopausal women, with the gap widening over time.

The biology underlying the association is increasingly well understood. Oestrogen receptors are expressed in the brain, liver, skeletal muscle, adipose tissue, and pancreatic beta cells, and activation of these receptors modulates glucose balance across multiple tissues simultaneously. Estrogen suppresses hepatic gluconeogenesis through transcriptional mechanisms involving Foxo1, curbs low-grade inflammation linked to insulin resistance, and influences energy equilibrium and body composition, with menopausal loss of these effects promoting visceral fat accumulation and further insulin resistance. Interestingly, the authors caution that estrogen’s metabolic actions are not universally beneficial: evidence from type 1 diabetes and insulin-deficient animal models suggests that in autoimmune, insulin-deficient contexts, estrogen can worsen vascular and metabolic instability. The protective association observed in this cohort, they argue, likely reflects estrogen’s favorable role in the insulin-resistant physiology that defines type 2 diabetes, a fundamentally different metabolic environment.

The study’s strengths are considerable: its long follow-up, large sample size, objective laboratory-based diabetes ascertainment repeated across seven phases, and careful statistical modeling of confounders. Limitations remain, however. Reproductive histories, including ages at menarche and menopause and durations of breastfeeding and contraceptive use, were self-reported and therefore vulnerable to recall bias, although three-yearly reassessment in the cohort supports consistency. The subtraction of a uniform two-week luteal phase is an approximation, fasting insulin data were unavailable precluding HOMA-IR analysis, the cohort was urban, and the observational design means the findings establish association rather than causation.

Even so, the implications are striking. If cumulative estrogen exposure can be incorporated into diabetes screening tools, clinicians may be able to identify women with short reproductive life spans, early menopause, or surgically induced menopause as candidates for intensified monitoring and personalized prevention. With Iranian diabetes prevalence at 15.14 percent among adults aged 25 and older and projections approaching 9.2 million cases without effective intervention, and with women worldwide shouldering rising risk after menopause while often receiving less guideline-recommended treatment than men, the study underscores the need for sex-specific approaches to diabetes prevention. Future research, the authors conclude, should clarify precisely how estrogen exposure duration shapes metabolic trajectories and translate that knowledge into targeted primary prevention strategies for the women at greatest risk.

Subject of Research: The association between cumulative endogenous estrogen exposure duration and the incidence of type 2 diabetes in women

Article Title: Diabetes Type 2 in Women: The Impact of EndogenousOestrogen, A Population‐Based Study With About 2 Decades of Follow‐Up

Article References: Ramezani Tehrani, F., Mousavi, M., Farhadi‐Azar, M., Mahboobifard, F., Azizi, F., & Farahmand, M. (2026). Diabetes Type 2 in Women: The Impact of EndogenousOestrogen, A Population‐Based Study With About 2 Decades of Follow‐Up. Endocrinology, Diabetes & Metabolism, 9(5), Article e70267. https://doi.org/10.1002/edm2.70267

Image Credits: AI Generated

DOI: 10.1002/edm2.70267

Keywords: type 2 diabetes, endogenous estrogen exposure, menopause, women's health, insulin resistance, reproductive factors, cohort study, Tehran Lipid and Glucose Study, estrogen, diabetes risk, hormonal exposure, epidemiology