| It is well accepted that administration of hormone replacement therapy (HRT) to postmenopausal women alters insulin sensitivity and glucose tolerance; however, whether or not those effects are beneficial is controversial, and the mechanisms for these alterations are poorly characterized. Thus, the hypothesis of this series of studies was that treatment of ovariectomized cynomolgus monkeys with estrogen (conjugated equine estrogens, CEE) improves insulin sensitivity and increases expression and activity of the insulin receptor and associated downstream proteins. Furthermore, the addition of the progestin, medroxyprogesterone acetate (MPA), to CEE negates these beneficial effects.; It was found that the HRT regimen containing CEE alone did not affect whole body measures of insulin sensitivity, glucose tolerance, body weight, or body composition. CEE treatment was associated with smaller-sized adipocytes and improved insulin metabolism (lower insulin AUC). The HRT regimen containing CEE+MPA impaired whole body insulin sensitivity, but did not affect glucose tolerance. It also caused gains in body weight, attributable to increases in soft tissue mass, and a trend for increased fat mass. CEE+MPA impaired insulin sensitivity in subcutaneous adipocytes to a greater degree than cells from either control or CEE-treated animals. Combined HRT was associated with impairments in insulin signaling in skeletal muscle, evident by decreased glucose transporter 4 content, and a trend for decreased insulin receptor expression and activity.; In conclusion, the decreased glucose uptake in fat tissue and altered insulin signaling in skeletal muscle likely contributed to the impairments seen in whole body insulin sensitivity with CEE+MPA-treatment. These factors should be taken into account when prescribing HRT to postmenopausal women with type 2 diabetes or those at risk for developing diabetes, and a less detrimental progestogen should be considered. |
