Prior research from Metagenics collaborators at Erasmus MC in Rotterdam, published in JAMA and JAMA Cardiology, gave evidence of the link between early menopause (before age 45 years) and increased risk for cardiovascular disease (CVD) and mortality. In those publications, the authors suggested that increased risk was due to the adverse effect of menopause on CVD risk factors—and the actual effects of age on the various risk factors was still uncertain.

While type 2 diabetes (T2D) is a known risk factor for CVD, it is not known if age at natural menopause (ANM) is also a risk factor.  In this analysis, the researchers assessed the effect that ANM had on risk for developing type 2 diabetes (T2D) along with the consequences of possible intermediate risk factors.

Study design
The authors used data from the Rotterdam Study — a population-based, prospective cohort study carried out in the Netherlands. The postmenopausal women were categorized according to age at menopause: Premature (<40 years), Early (40–44 years), Normal (45–55 years), and Late menopause (>55 years) as a reference group and followed every 3 to 5 years. Of a total of 6816 participants, 3969 women were included in this analysis — some were excluded due to not reaching menopause, already diagnosed with T2D or who had surgical or ‘non-natural’ menopause.

Menopausal status was assessed by questionnaire; post-menopausal women were defined as not having had a menstrual period for at least 12 months. ANM was self-reported age at last period.  At baseline visits and during follow up, cases of T2D were determined by HCP records, hospital discharge notes and glucose measurements from visits. All potential cases of T2D were independently adjudicated by study physicians. Additional variables assessed included:  current health status, medical history, medication use, smoking, socioeconomic status, educational status, age at menarche (first period), number of pregnancies of at least 6 months, alcohol intake, history of CVD, BP  and use of antihypertensives. Biochemical parameters were also measured — thyroid-stimulating hormone, cholesterol, triacylglycerol, and C-reactive protein. Physical activity was also assessed.

Measurements taken during baseline visits included height, weight, BMI; fasting insulin and glucose, estradiol levels and levels of sex hormones. Genotyping was also conducted, to allow calculation of a weighted genetic risk score using a selection of 54 SNPs (single nucleotide polymorphisms), previously reported to have an association with ANP taken from a GWAS (Genome-Wide Association Study) of 70,000 women.

Results showed:

  • Of 3639 women without diabetes at baseline, 348 developed incident T2D over a median follow up of 9.2 years
  • Compared with women having late menopause (55 years or later), those with the earliest menopause (age under 40 years) were almost 4 times more likely to have developed T2D
    • Those with menopause at 40-44 years were 2.4 times more likely to develop T2D
    • Those with menopause at 45-55 years were 60% more likely than those with late menopause to develop T2D
  • Overall risk of developing T2D reduced by 4% per year older that a woman experienced menopause

Why is this Clinically Relevant?

Menopause can be a sign of advanced aging. Women equipped with less efficient DNA repair and maintenance genes might age faster compared to women with the more efficient repair and maintenance genes. Therefore, early menopause might be a good predictor of upcoming health problems related to this less efficient DNA repair. The authors explain: “Our findings might suggest that the risk of diabetes related to menopause is already there before menopause begins. This could explain why other risk factors for diabetes do not explain the link between menopause and T2D — early menopause is an independent marker for T2D, indicating that something else is the driving force behind this observation, possibly defective DNA repair and maintenance.”

The authors further note, Epigenetic modifications might constitute an additional pathway leading to menopause onset and T2D and future studies should explore epigenetic markers related to menopause onset and whether epigenetic signatures can explain the association between ANM and T2D.”

This study suggests that early onset of natural menopause potentially could be an independent marker for T2D in postmenopausal women. Clinicians should evaluate their patients, who undergo natural menopause at a younger age, for signs of prediabetes or diabetes and implement management plans in particularly at-risk patients that include appropriate nutrition and lifestyle behaviors to prevent progression to T2D.

View the Open Access Article

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