Early Menopause Linked to Increased Type 2 Diabetes Risk

Early menopause before age 45 years is linked to an increased risk of type 2 diabetes, regardless of a variety of confounding factors, according to a study published online July 18 in Diabetologia.

"In this large population-based study of postmenopausal women free of type 2 diabetes at baseline, we showed that early onset of natural menopause is associated with an increased risk of type 2 diabetes, independent of potential intermediate risk factors for type 2 diabetes (including body mass index [BMI], glucose, and insulin levels) and levels of endogenous sex hormones and SHBG [sex hormone-binding globulin]," write Taulant Muka, MD, PhD, of Erasmus University Medical Center, Rotterdam, the Netherlands, and colleagues.

"We also showed that shared genetic factors could not explain the association between age at natural menopause and risk of type 2 diabetes," they add.

The study is one of few to look at the associations between age at menopause and risk for type 2 diabetes. Past studies of links between menopause and cardiometabolic disease have focused more on cardiovascular disease (CVD), pointing to a link between early menopause and increased risk for CVD.

Declining levels of estrogen and other adverse effects of menopause may play a role; for example, menopause is associated with weight gain, increased visceral fat, and impaired glucose metabolism. All of these may increase the risk for type 2 diabetes, which in turn increases the risk for CVD.

But whether age at menopause is associated with type 2 diabetes risk has remained unclear, and prior cross-sectional studies examining the association between the two have yielded contradictory results. And no prior studies have examined the role of postmenopausal hormone levels in the association between age of menopause and risk of type 2 diabetes.

Late Menopause Linked to Lower Risk of Type 2 Diabetes

To evaluate the issue, researchers studied 3639 postmenopausal women (mean age 66.9 years) from the Rotterdam study, a prospective cohort study that began in the Ommoord district of Rotterdam between 1990 to 1993. The study excluded women who already had diabetes, had undergone non-natural menopause (such as after surgery), or were not postmenopausal at first assessment.

Women self-reported age at natural menopause on questionnaires. Researchers then categorized women's menopausal status as premature (< 40 years), early (40–44 years), normal (45–55 years), or late (> 55 years). Data on incident type 2 diabetes came from medical records and blood glucose measurements taken at clinical visits about every 4 years.

The authors also performed an extensive medical record review for potential confounders, such as BMI, smoking, alcohol consumption, reproductive factors, lifestyle, and cardiometabolic risk factors. Laboratory tests included thyroid stimulating hormone, cholesterol, inflammatory markers (such as C-reactive protein), insulin, estrogen, and other sex hormone levels.

Finally, they calculated genetic risk using genes associated with age at natural menopause identified in past studies.

Over a median followed-up of 9.2 years, 348 women developed type 2 diabetes. Results adjusted for age, time of study entry, hormone replacement therapy, and reproductive factors (age at menarche, pregnancies), showed that women with late menopause had a significantly lower risk of type 2 diabetes than other women.

Compared with late menopause, the risk for type 2 diabetes was almost four times higher with premature menopause (hazard ratio [HR], 3.65), twice as high with early menopause (HR, 2.36), and 60% higher with normal menopause (HR, 1.62; P for trend < .001).

For each 1-year delay in the onset of menopause, the risk of type 2 diabetes decreased by 4% (HR, 0.96).

Adjusting for a variety of confounding factors, including glucose levels, insulin levels, and genetic risk, did not change the results.

The authors mention that age at natural menopause may be associated with genetic pathways associated with aging. So menopause may be a marker of aging in general, not just aging of the reproductive system. Women who have a genetic tendency to age faster, perhaps related to less efficient DNA repair mechanisms, may be more likely to go through early menopause. That, in turn, may serve as a marker of general health, including risk of type 2 diabetes.

For now, though, the underling pathophysiology remains unclear.

"Early onset of natural menopause is an independent market for type 2 diabetes in postmenopausal women. Future studies are needed to examine the mechanisms behind this association and explore whether the timing of natural menopause can add value to diabetes prediction and prevention," they conclude.

The study was funded by Metagenics, ERAWEB, and ZonMw (The Netherlands Organization for Health Research and Development). Dr Muka is an employee of ErasmusAGE, a center for ageing research funded by Nestlé Nutrition (Nestec), Metagenics, and AXA. Disclosures for the other authors are listed in the article.

Diabetologia. Published online July 18, 2017. Full article

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