BACKGROUND: Despite sex differences in type 2 diabetes (T2D), few studies have examined the role of sex hormones. We sought to assess the impact of weight loss, the cornerstone of T2D management, on sex hormone levels. METHODS: This was an ancillary study to the Look AHEAD (Action for Health In Diabetes) Study [n = 850 postmenopausal females, n = 890 males, with T2D and body mass index (BMI) ≥25 kg/m2]. We measured total testosterone (T), estradiol (E2), and SHBG and calculated bioavailable T (bioT). We examined the effect of the intensive lifestyle intervention (ILI) on hormone changes and whether changes were mediated by waist circumference and sex differences in treatment effect. RESULTS: The baseline mean age was 60 years with a higher proportion of Black females (21%) vs males (9%) and higher mean BMI in females vs males (36.3 vs 34.8 kg/m2). At year 1 in females, ILI decreased E2 by 15% and bioT by 13% and increased SHBG by 21%. At year 1 in males, ILI did not change E2 levels but increased T by 14% and increased SHBG by 18%. The effect was attenuated over 4 years
there were statistically significant sex differences in treatment effect and change in waist circumference due to ILI at year 1 was a significant mediator of sex hormone changes. CONCLUSION: Weight loss in T2D resulted in sex hormone changes, which varied by sex and were mediated by changes in waist circumference. Changes in sex hormones due to weight loss in T2D should be considered in the context of an individual's health risks, including cardiovascular conditions, bone health, menopausal symptoms, and cognitive function.