Hormone Replacement Therapy and Its Relationship to Lipid and Glucose Metabolism in Diabetic and Nondiabetic Postmenopausal Women

Carlos J. Crespo, DrPH, MS, Ellen Smit, PHD, RD, Anastacia Snelling, PHD, Christopher T. Sempos, PHD and Ross E. Andersen, PHD


Diabetes Care. 2002;25(10) 

In This Article


We examined lipid profiles and indicators of glucose metabolism in a nationally representative sample of postmenopausal diabetic and nondiabetic women from NHANES III. Although HDL was found to be significantly higher among nondiabetic women who were currently taking HRT than among never or previous users of HRT, this finding was not observed among diabetic women. Total cholesterol and non-HDL levels, however, were significantly lower among diabetic women currently on HRT than among never or previous users of HRT. Furthermore, these findings were not observed in nondiabetic women. This divergent result may be indicative of a different effect of HRT on lipid metabolism in diabetic compared with nondiabetic women.

Our findings confirm that glucose metabolism among diabetic women who were currently taking HRT as evidenced by lower fasting glucose, fasting insulin, and GHb is superior to those who were not on HRT. This may indicate that women who take HRT are also in better control of their diabetes and may be indicative of other favorable health behaviors among women who use HRT. Not only were fasting glucose and GHb lower among diabetic current users of HRT compared with never or previous users of HRT, but also among nondiabetic women users of HRT compared with nonusers.

Current users of HRT in both diabetic and nondiabetic postmenopausal women also had significantly higher levels of apoA levels than never users of HRT. ApoA is the major protein component of HDL and an important coenzyme for the enzyme lecithin:cholesterol acyltransferase, which attaches a free fatty acid on the cholesterol molecule, forming a cholesterol ester that will later remove cholesterol via the bile acids.[23] Therefore, higher levels of apoA are considered to be beneficial. ApoB is an atherogenic component of the lipoproteins and is more closely linked to non-HDL cholesterol. ApoB levels in both diabetic and nondiabetic postmenopausal women appear to be lower in current users of HRT when compared with women who previously or never used HRT, but it only approached statistical significance because the 95% CIs overlapped slightly. Other researchers have found that HRT reduced apoB in postmenopausal women with type 2 diabetes.[11,24] The difference may be due to the smaller sample size in our study or the cross-sectional design of our study.[11]

We found no significant differences in Lp(a) among the groups studied. Lp(a) is a complex of an LDL-like particle and apoA. Elevations in Lp(a) have been associated with coronary heart disease and thrombotic stroke.[25,26,27] The mechanism of this relationship is not known, but it is thought that because apoA and plasminogen are homologous, elevated levels of Lp(a) may interfere with fibronolysis and therefore promote thrombosis.[2]

Fibrinogen is an important component in platelet aggregation and is also a risk indicator for cardiovascular disease, including coronary heart disease, stroke, and peripheral artery disease, and has been closely linked to smoking, hypertension, and total cholesterol.[28] We found fibrinogen to be significantly lower among current HRT users than women who never used HRT for both diabetic and nondiabetic women. Similar findings were observed in a group of postmenopausal women aged 52-65 years (n = 300), where HRT usage was associated with significantly lower fibrinogen concentration (232 vs. 268 mg/dl) and decreased plasma viscosity.[29] Results from this study, however, were not provided separately for diabetic and nondiabetic women.

C-reactive protein is an important inflammatory biomarker that has been suggested to have an intermediary role in the pathogenesis of cardiovascular disease in individuals with type 2 diabetes.[14] Our results indeed confirm higher levels of C-reactive protein among postmenopausal diabetic women. Both diabetic and nondiabetic women currently using HRT had higher levels of C-reactive protein than previous or never users, but these only approached statistical significance.

We found lower fasting glucose and GHb among diabetic women currently using HRT than among never or previous users of HRT. This may be due to higher compliance in using glucose-controlling medication among diabetic women currently using HRT than among with previous or never users of HRT and is not necessarily an effect of HRT. However, several studies support our findings using prospective, observational, or randomized controlled trials.[7,9,11] Also, the fact that we observed a similar finding in nondiabetic women confirms the possible hypoglycemic effect of HRT or the fact that women on HRT may have healthier habits. Adjustment for smoking, BMI, physical activity, education, and race/ethnicity did not alter the lower fasting glucose levels observed, especially among diabetic women (data not shown).

One of the strengths of this analysis is the inclusion of emerging cardiovascular disease risk factors such as Lp(a), fibrinogen, apoA, and apoB in a national sample of postmenopausal women according to HRT use. Some of these measurements were obtained during phase 1 (apoA and apoB), while another [Lp(a)] was collected during phase 2. One of the limitations of this study was that to further subdivide the analytic sample among diabetic and nondiabetic subjects by HRT use, we reduced the sample size considerably for some of these components, and because of these smaller sample sizes, we may have failed to see a difference when there was one. We did, however, observe statistically significantly different levels of apoA between current HRT users compared with never or previous HRT users in both diabetic and nondiabetic women.

A possible limitation of this analysis is that it is based on cross-sectional data. However, this is a descriptive epidemiological analysis based on a national representative sample of the civilian noninstitutionalized population of postmenopausal women 40-74 years of age who underwent a rigorous lipid and glucose metabolism assessment. Our findings serve to confirm previous smaller studies that have examined the relationship of HRT with glucose and lipid metabolism in diabetic and nondiabetic postmenopausal women.

Our definition of diabetes is not a clinical definition of diabetes, but rather an epidemiological definition based on clinical measurements, self-reported use of medications to control glucose levels, and previous diagnosis of diabetes by a health professional. The prevalence of diabetes in the U.S. among individuals aged 40-74 years falls between 12 and 14%. Since the prevalence of undiagnosed diabetes (5-7%) can be as great as the prevalence of diagnosed diabetes (7%), our definition of diabetes allowed us to more clearly separate postmenopausal women without diabetes from those with diabetes.

Although favorable lipid and glucose profiles were observed among HRT users, we caution that our findings are observational and may not be adequate to guide lipid-altering therapy in postmenopausal diabetic women. Nevertheless, our findings at the population level suggest that HRT use may be associated with increased apoA and lower fasting glucose, GHb, total cholesterol, and non-HDL in this group of diabetic postmenopausal women. To what extent these differences are explained by the fact that women who use HRT are more health conscious is not entirely clear. In our analyses we controlled for BMI, education, race/ethnicity, smoking, and age and the results did not change substantively. A large and more rigorous clinical trial is necessary to better assess if the potential cardiovascular risk- reducing benefits of HRT observed in nondiabetic women are applicable to women with diabetes.


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