Steroid Sex Hormones, Sex Hormone-Binding Globulin, and Diabetes Incidence in the Diabetes Prevention Program

Abstract

Context: Steroid sex hormones and SHBG may modify metabolism and diabetes risk, with implications for sex-specific diabetes risk and effects of prevention interventions.

Objective: This study aimed to evaluate the relationships of steroid sex hormones, SHBG and SHBG single-nucleotide polymorphisms (SNPs) with diabetes risk factors and with progression to diabetes in the Diabetes Prevention Program (DPP).

Design and setting: This was a secondary analysis of a multicenter randomized clinical trial involving 27 U.S. academic institutions.

Participants: The study included 2898 DPP participants: 969 men, 948 premenopausal women not taking exogenous sex hormones, 550 postmenopausal women not taking exogenous sex hormones, and 431 postmenopausal women taking exogenous sex hormones.

Interventions: Participants were randomized to receive intensive lifestyle intervention, metformin, or placebo.

Main outcomes: Associations of steroid sex hormones, SHBG, and SHBG SNPs with glycemia and diabetes risk factors, and with incident diabetes over median 3.0 years (maximum, 5.0 y).

Results: T and DHT were inversely associated with fasting glucose in men, and estrone sulfate was directly associated with 2-hour post-challenge glucose in men and premenopausal women. SHBG was associated with fasting glucose in premenopausal women not taking exogenous sex hormones, and in postmenopausal women taking exogenous sex hormones, but not in the other groups. Diabetes incidence was directly associated with estrone and estradiol and inversely with T in men; the association with T was lost after adjustment for waist circumference. Sex steroids were not associated with diabetes outcomes in women. SHBG and SHBG SNPs did not predict incident diabetes in the DPP population.

Conclusions: Estrogens and T predicted diabetes risk in men but not in women. SHBG and its polymorphisms did not predict risk in men or women. Diabetes risk is more potently determined by obesity and glycemia than by sex hormones.

Trial registration: ClinicalTrials.gov NCT00004992.

Figure 1.

Consort diagram representing participants with available data for the current analyses. Premenopausal women taking exogenous hormones were excluded from the current analyses due to the small sample size (n = 72; exclusion indicated by diagonal line). One postmenopausal woman reporting no hormone use was found to have elevated estradiol levels, and was excluded from analysis.

Figure 2.

Cox proportional hazards modeling of the relationships between sex hormones and diabetes incidence in the DPP. Model 1 is adjusted for treatment arm, without adjustment for demographic, anthropometric, or metabolic factors. Model 2 is adjusted for age, race/ethnicity, smoking, alcohol consumption, and leisure activity. Model 3 is further adjusted for waist circumference. Model 4 is further adjusted for inverse fasting insulin and the insulinogenic index. For each model, the midpoint symbol indicates the HR point estimate, and the line extends to the lower and upper 95% CIs for the estimate. Lines that do not cross the line of unity achieve statistical significance. HRs are expressed per SD difference of each variable within the treatment group.