Whether hormone replacement therapy has beneficial metabolic effects in postmenopausal women remains controversial because of between-study differences in menopausal duration, estrogen formulations, and diet. Additionally, animal studies have not reflected the typical human obesogenic, Western-style diet (WSD). In this study, we determined the effects of immediate 17bestradiol (ImE) or delayed 17b-estradiol treatment on weight and metabolism parameters in old ovo-hysterectomized rhesus macaques consuming a WSD over a 30-month period. The placebo and ImE groups exhibited progressive gains in weight and fat mass, which ImE initially attenuated but did not prevent. Progression of insulin resistance (IR) was lessened by ImE compared with placebo under both fasting and IV glucose-stimulated conditions, plateauing in all groups between 24 and 30 months. Consequently, relative euglycemia was maintained through lower stimulated insulin levels with ImE than with placebo. Bone mineral density decreased in the placebo group but was maintained in the ImE group, whereas bone mineral content was unaffected by placebo and increased with ImE. Daily activity was reduced while macaques consumed a WSD and was not affected by ImE. Over time, total cholesterol, triglyceride, very-low-density cholesterol, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and IL-8 levels increased or trended upward in all animals, with only the change in HDL-C affected by ImE. Delayed estrogen treatment (months 24 to 30) had no significant impact on body composition or glucometabolic parameters. In summary, detrimental WSD-induced changes in body composition and metabolism were only temporarily ameliorated by ImE, with the important exception of glucose homeostasis, which benefited from E replacement even as body composition worsened.
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