The changes in lipid metabolism that occur with the menopause, including increased total and LDLC, triglycerides and Lp(a), and decreased HDL-C, resemble those of type 2 diabetes and the metabolic syndrome (12). Adverse changes in carbohydrate metabolism also emerge with the menopause including decreased insulin sensitivity and insulin secretion (128). These together with increased central adiposity contribute to the increased risk of CVD in postmenopausal women.
The effects of estrogen on lipid parameters are discussed in detail in the first part of this chapter. A number of observational studies have also reported that estrogen improves insulin resistance in postmenopausal women, a factor that is predictive for the development of type 2 diabetes (125,129). Estrogen therapy also appears to prevent central fat distribution, a factor that is strongly associated with insulin resistance (126). Thus, estrogen can potentially prevent the insulin resistance associated with central obesity in postmenopausal women.
Another characteristic of postmenopausal women is androgenicity associated with low SHBG levels, which is also considered an important risk factor for insulin resistance and type 2 diabetes (120). In the Rancho Bernardo Study, SHBG was found to be inversely correlated with type 2 diabetes and impaired glucose tolerance (IGT) in postmenopausal women (130). In this regard, Andersson and associates (131) also reported that low SHBG levels were associated with type 2 diabetes in both men and women. Furthermore, they also reported that serum testosterone levels were positively correlated with the degree of insulin resistance in women. Estrogen, in contrast to androgens may increase SHBG levels. These increases in SHBG were associated with improved glucose homeostasis (132). In this context, it is also interesting that the incidence of diabetes is higher in men than in women until women reach menopause (133).
Given the evidence from the observational studies that estrogen improves insulin resistance and the other adverse factors associated with it, and the fact that insulin resistance is predictive for the development of type 2 diabetes one would expect a protective role of estrogen against the development of type 2 diabetes in postmenopausal women. In this regard, the Nurses' Health Cohort Study of 21,028 postmenopausal women aged 30 to 55 years showed that the use of HRT reduced slightly the relative risk (0.88, CI,
0.67-0.96) of developing type 2 diabetes after adjusting for age, body mass index and other confounding factors, although the duration of estrogen use was not associated with a decreased risk (134). The Rancho Berdardo Study reported a linear trend toward a lower incidence of type 2 diabetes with current use of estrogen therapy (0.88, CI, 0.48-1.62), but the trend was reversed after adjusting for confounding factors (135).
A recently published post hoc analysis from the HERS trial reported a lower risk for new-onset type 2 diabetes in postmenopausal women with heart disease receiving HRT (136). At the start of the study the participants had fasting glucose levels measured and were categorized as having normal or impaired fasting glucose or having diabetes. Participants were followed up for the development of new cases of type 2 diabetes over 4 years. Daily treatment with 0.625 ng CEE plus 2.5 mg MPA resulted in a 35% lower risk for type 2 diabetes during the follow-up period. This reduction in risk was primarily as a result of the fact that women in the HRT group maintained a lower fasting glucose level than women in the placebo group. Thus, HRT prevented the increase in fasting glucose levels that was seen in the placebo group over time in this high-risk study population.
These data are encouraging and suggest important metabolic effects of hormone therapy. However, the results of this posthoc analysis of the HERS study are not definitive and require confirmation in a formal clinical trial. The authors do not recommend the use of HRT for diabetes prevention but encourage further study of the issue.
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