Endogenous dehydroepiandrosterone levels and its derivatives modifies the association between total estradiol and type 2 diabetes risk in postmenopausal women: The Rotterdam Study
Ina Zaimi1,2, Eralda Asllanaj1, Marija Glisic1, M. Arfan Ikram1,3,4, Joop S.E. Laven5, Maryam Kavousi1, Taulant Muka1, Oscar H. Franco1
[email protected]
Objectives
Conclusions
We aimed to investigate: 1. the association between endogenous estradiol levels with Type 2 Diabetes in postmenopausal women 2. to examine whether this association was modified by the levels of the endogenous DHEA steroid hormone and its derivatives
1. These findings suggest that high levels of endogenous estradiol increase T2D risk in postmenopausal women, but this risk may be reduced by high levels of DHEA, DHEAS or androstenedione. 2. It is unclear whether Lifestyle factors and medications targeting DHEA metabolism, as well as hormone replacement therapy containing DHEA and estradiol might contribute in maintaining an optimal metabolic health
Background
Results
Recent evidence indicates that higher levels of endogenous estradiol might be associated with increased risk of type 2 diabetes (T2D) in postmenopausal women. Dehydroepiandrosterone (DHEA) may influence the levels of estrogen in the body, and higher levels of DHEA are associated with lower risk of developing T2D. However, it is not known whether DHEA levels may modify the effect of estradiol on T2D.
The association between total estradiol and Type 2 Diabetes
Methods Data of 3,148 participants of The Rotterdam Study, a prospective population based cohort, were available (median follow-up, 11.15 years). » Blood samples were drawn fasting in the morning (≤11:00 am). » At baseline, total estradiol, DHEA, DHEAS and androstenedione levels were measured. » Type 2 Diabetes Mellitus events were diagnosed on the basis of medical records and glucose measurements from Rotterdam Study visits. » Multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression models. All associations were corrected for age, body mass index, cohort, smoking status, alcohol consumption, prevalent cardiovascular disease, systolic blood pressure, anti-hypertensive medications intake, serum total cholesterol, statin usage, hormone replacement therapy, age of menopause, sex hormone binding globulin and testosterone levels.
During a median follow-up of 11.15 years, we identified 390 incident cases of T2D. » Total estradiol was associated with increased risk of developing T2D (3rd tertile vs. 1st tertile: RR: 1.40; 95%CIs=1.02 -1.92, P-trend=0.045). Effect modification by DHEA, DHEAS and androstenedione
» Significant interaction terms were found between total estradiol, DHEA (Pinteraction=0.02) and androstenedione (P-interaction=0.03), but not with DHEAS (P-interaction=0.13). » An increased risk of T2D was observed for total estradiol in subjects with levels lower than the respective median of DHEA (3rd tertile vs.1st tertile: HR = 1.77, 95% CI=1.11-2.82, P-trend=0.02), DHEAS (3rd tertile vs.1st tertile: HR = 1.91, 95% CI=1.20-3.03, P-trend=0.008) or androstenedione (3rd tertile vs.1st tertile: HR = 2.25, 95% CI=1.42-3.56, P-trend=0.001). » No association was observed between total estradiol levels and risk of T2D in subjects with levels of DHEA, DHEAS or androstenedione. Table 1 The association between serum Estradiol and the risk of Type 2 Diabetes Mellitus in postmenopausal women, The Rotterdam Study (N=3148) Estradiol 1st tertile 2nd tertile 3rd tertile P-Trend HR, 95% CI 1 1.068 (0.820; 1.392) 1.396 (1.017; 1.917) 0.045
Figure 1 The association between serum total estradiol levels and risk of Type 2 Diabetes by levels of DHEA, DHEAS, and androstenedione*.
*Multivariable HRs (95% CIs) for the association of total estradiol and type 2 diabetes by levels of dehydroepiandrosterone, dehydroepiandrosterone sulfate and androstenedione among 3148 postmenopausal women participant of the Rotterdam Study. HRs (95% CIs) were estimated by using Cox’s proportional hazard model adjusted for confounding factors. Tests for trend were carried out by entering the categorical variables as continuous variables in multivariable Cox’s proportional hazard models. P-interaction estradiol x DHEA: 0.02; estradiol x DHEAS: 0.13; estradiol x androstenedione: 0.03. HR, hazard ratio; CI, confidence interval
Author affiliations 1 Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands. 2 Department of Surgery, Erasmus MC, Rotterdam, the Netherlands. 3 Department of Neurology, Erasmus MC, Rotterdam, the Netherlands 4 Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands. 5 Department of Obstetrics and Gynaecology, Erasmus MC, Rotterdam, the Netherlands. *Authors contributed equally
Funding Taulant Muka and Oscar H Franco work in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.); Metagenics Inc.; and AXA.These funding sources had no role in design and conduct of this manuscript; collection, management, analyses, and interpretation of the data; and preparation, review or approval of this manuscript.
