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From the Clinical Research Centers |
Department of Medicine (K.E.F., C.D.) and General Clinical Research Center (R.U.F.), Tulane University Health Sciences Center, New Orleans, Louisiana 70112
Address all correspondence and requests for reprints to: Karen E. Friday, M.D., 1430 Tulane Avenue, SL53, New Orleans, Louisiana 70112. E-mail: fridayk{at}tulane.edu
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Abstract |
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When compared with 8 weeks of placebo, estrogen reduced fasting serum glucose (7.2 ± 0.3 vs. 8.4 ± 0.4 mmol/L, P = 0.0003), glycated hemoglobin (8.7 ± 0.4% vs. 9.3 ± 0.4%, P = 0.04), total cholesterol (5.27 ± 0.20 vs. 5.50 ± 0.21 mmol/L, P = 0.04), low-density lipoprotein cholesterol (2.47 ± 0.13 vs. 2.69 ± 0.14 mmol/L, P = 0.02), serum apolipoprotein B (114 ± 6 vs. 121 ± 5 mg/dL, P = 0.03), and postprandial glucose area under the curve (by 12%, P = 0.015). Estrogen replacement therapy also increased high-density lipoprotein (HDL) cholesterol (1.27 ± 0.08 vs. 1.1 ± 0.07 mmol/L, P = 0.0002), high-density lipoprotein2 cholesterol (0.41 ± 0.04 vs. 0.30 ± 0.03 mmol/L, P = 0.0001), and fasting triglyceride (2.17 ± 0.21 vs. 1.94 ± 0.16 mg/dL , P = 0.02) concentrations but not postprandial triglyceride area under the curve (P = not significant).
We conclude that estrogen replacement therapy improves glycemic control, blood lipoproteins, and apolipoprotein B concentrations while modestly increasing triglyceride levels in postmenopausal, type 2 diabetic women.
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Introduction |
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Estrogen replacement therapy has been shown to improve blood lipoproteins and apolipoproteins (6, 7), enhance vascular relaxation (8), and reduce the incidence of cardiovascular disease (9, 10) in women. However, the majority of these findings were demonstrated in Caucasian, healthy, postmenopausal women. Because of concerns about the safety of estrogen replacement therapy in diabetic women, they were excluded from early prospective trials of estrogen replacement therapy (11). As a result, little is known about the effects of estrogen replacement on glucose and lipid metabolism in diabetic women. Thus, metabolic studies of lipid and glucose metabolism were performed during a blinded, placebo-controlled study of estrogen replacement in postmenopausal, type 2 diabetic women.
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Subjects and Methods |
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The study was approved by the Committee on Use of Human
Subjects. Forty-six women with type 2 diabetes were screened for
inclusion criteria at the General Clinical Research Center (GCRC).
Women were considered postmenopausal with absent menstrual periods
1 yr and an elevated FSH level, or bilateral oophorectomy and
elevated FSH. Women were recruited with fasting glucose concentrations
between 70–200 mg/dL (3.9–11.1 mmol/L), glycosylated hemoglobin of
7–11%, and fasting serum triglyceride concentrations less than 400
mg/dL (<4.5 mmol/L). Subjects with untreated hypothyroidism
(TSH > 5 µIU/mL), any history of pancreatitis,
angina, myocardial infarction, stroke, general surgery, drug or alcohol
abuse within the past 6 months were excluded. Subjects taking thiazide
diuretics, corticosteroids, ß-adrenergic blocking agents, or anabolic
steroids and subjects with a history of breast or uterine cancer were
excluded. Twenty-seven subjects were randomized to estrogen or placebo
treatment arms and completed at least 1 treatment arm. No subjects
discontinued the study during a treatment arm. Twenty-five diabetic
women, 50–77 yr old, completed the entire cross-over protocol. Two
subjects completed only the estrogen phase of the study but not the
placebo treatment, because of the diagnosis of a fatal brain cancer in
1 subject and personal, nonmedical reasons in the other subject. This
paper will include results obtained from the 25 subjects that completed
both the placebo and estrogen treatment arms. Of these women, 11 were
initially randomized to placebo and 14 to conjugated equine estrogen.
Women taking estrogen replacement before recruitment to the study
discontinued estrogen on study admission and remained off estrogen for
a minimum of 8 weeks during the lead-in period described below. All
subjects had a benign mammogram and breast exam before randomization to
estrogen or placebo. Every attempt was made to continue the same
diabetes, hypertension, and other medications at constant doses
throughout the study. There were no changes in diabetes medications in
22 out of the 25 subjects studied. In 1 subject, the total daily
insulin dose was increased from 25 U during the estrogen phase to 26 U
during the placebo phase by her primary physician. Another subject was
taking 2500 mg/day metformin during the placebo phase but only 1000
mg/day during the estrogen arm of the protocol. A third subject had
glipizide (5 mg twice daily ) added by her diabetes clinic
physician during the estrogen, but not placebo, arm of the study.
Dietary protocol
Each subject was instructed to consume an American Diabetes Association diet with less than 30% of total calories as fat, up to 10% saturated fat, 10% monounsaturated fat, and up to 10% n-6 polyunsaturated fats.
Initial lead-in phase
Each subject began with an 8-week lead-in period, during which time the subjects continued their prescribed diabetic therapies and diet.
Estrogen replacement therapy
At the end of the lead-in phase, subjects were randomized to conjugated equine estrogen, 0.625 mg/day (Wyeth-Ayerst Laboratories, Inc., Philadelphia, PA), placed in lactose-filled blue capsules or blue placebo capsules filled with powdered lactose (Gallipot Inc., St. Paul, MN), in a single blinded fashion, for a duration of 8 weeks. After completing metabolic studies on their original treatment, 25 subjects then crossed over to the opposite treatment, separated by a 4-week washout period. The subjects reported to the GCRC monthly for monitoring and to pick up study medication.
Study measurements
At the end of the estrogen and placebo phases (8 weeks), each subject was admitted to the GCRC for 2 nights of metabolic studies. All of the subjects continued their usual medications during metabolic studies in the GCRC. Fasting blood (12-h fast) was analyzed in duplicate for glucose, glycated hemoglobin, plasma lipids, lipoproteins, apolipoprotein B, and fasting insulin. Postprandial measurements of serum glucose and triglyceride were performed hourly, for 5 h, after standardized research breakfasts and lunches, respectively. The whole-food research diets contained 485 calories, 13 g fat, 28 g protein, and 57 g carbohydrate at breakfast and 613 calories, 16 g fat, 28 g protein, and 81 g carbohydrate at lunch. In addition, height and fasting weight were measured during each admission, in duplicate, in the fasting state.
Laboratory determinations
Total cholesterol and cholesterol lipoprotein fractions were measured at Atherotech (Birmingham, AL) using the vertical autoprofile (11A ) during the study. Mean results obtained at the end of the estrogen treatment phase were compared with results at the end of the placebo phase, using the paired t test. Most results were considered significant with a two-tailed P less than 0.05. Postprandial glucose and triglyceride results were analyzed for time and treatment interactions using a repeated-measures ANOVA. When significant time and treatment interactions were identified, hourly glucose and triglyceride measurements during the estrogen and placebo treatment phases were compared using paired t tests, and results were considered significant with a Bonferroni corrected P value less than 0.005.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. Diabetes treatment
regimens included diet alone, insulin only, oral agents
(glimepiride, glipizide,
metformin, troglitazone alone, or multiple
oral agents combined), and insulin plus oral agents. Surprisingly, 80%
of these diabetic women had a history of surgical hysterectomy. There
were no thrombotic or cardiovascular events detected in any of the
participating women.
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). Estrogen
replacement therapy was also associated with significant increases
in fasting triglyceride, along with high- density lipoprotein (HDL)
and HDL2 cholesterol concentrations. There were
no significant differences in very-low-density-ipoprotein cholesterol,
intermediate-density lipoprotein cholesterol,
HDL3 cholesterol, or fasting [n =
25, P = not significant (NS)] and 2-h postprandial
insulin (n = 23, P = NS) concentrations during
estrogen vs. placebo phases. There was also no effect of
treatment order on any of the observed results.
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), after a standardized breakfast and
lunch, was significantly reduced from 112.5 ± 5.2 mmol/L·h
during placebo therapy to 99.2 ± 3.9 mmol/L·h during estrogen
therapy (P = 0.015, n = 24). The postprandial
incremental glucose AUC was not significantly different during estrogen
(17.3 ± 3.4 mmol/L·h) and placebo (15.8 ± 3.7 mmol/L·h)
treatments (P = NS, n = 24). Repeated-measures
ANOVA testing showed significant time and treatment interactions for
both absolute and incremental glucose values (both P =
0.0001). However, comparisons of hourly absolute and incremental
glucose measurements showed only the fasting glucose value to be
significantly lower during estrogen than the placebo treatment phases
(6.8 ± 0.3 vs. 8.0 ± 0.4 mmol/L or 123 ± 5
vs. 145 ± 7 mg/dL, n = 24, P <
0.005) after Bonferroni correction.
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) were not significantly affected by
estrogen replacement therapy. The postprandial triglyceride AUC was
similar (P = NS, n = 24) during estrogen
(28.53 ± 2.74 mmol/L·h) and placebo (27.67 ± 2.17
mmol/L·h) treatments. Incremental postprandial triglyceride
excursions (Fig. 2B), however, were significantly greater during
placebo therapy than estrogen therapy (estrogen triglyceride AUC of
3.22 ± 1.13 mmol/L·h vs. placebo triglyceride AUC of
4.75 ± 0.94 mmol/L·h, n = 23, P = 0.03).
There were significant time and treatment interactions with both the
absolute and incremental postprandial triglyceride values when analyzed
by ANOVA (P = 0.0001). However, there were no
significant differences in absolute fasting and postprandial
triglyceride concentrations after Bonferroni adjustment. Significant
reductions in postprandial incremental triglyceride values were noted
during estrogen treatment, compared with placebo, at 5 h
(0.39 ± 0.11 vs. 0.63 ± 0.12 mmol/L, n =
23, P < 0.005) and 6 h (0.56 ± 0.11
vs. 0.81 ± 0.11 mg/dL, n = 23, P
< 0.005).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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There are a few additional small, short-term, human studies that have
demonstrated improved glucose metabolism in diabetic women treated with
17-ß estradiol (12, 13, 14). Treatment with 2 mg/day
of oral 17-ß estradiol for 60–68 days significantly improved blood
glucose control, compared with placebo treatment, in 25 hyperandrogenic
women with noninsulin-dependent diabetes mellitus, in a blinded,
cross-over study (12). Brussaard et al.
(13, 14) also demonstrated improvements in HbA1c during a
6-week dual-arm placebo-controlled trial of 2 mg micronized 17-ß
estradiol per day (n = 20) vs. placebo (n = 20) in
postmenopausal diabetic women with noninsulin-dependent diabetes
mellitus. In this study, hepatic glucose production, during a
euglycemic hyperinsulinemic clamp, was significantly reduced with
estradiol treatment in normotriglyceridemic women (fasting
triglyceride 
2.0 mmol/L) but not women with fasting
hypertriglyceridemia (>2.0 mmol/L). More recently, a randomized,
prospective, but nonplacebo-controlled trial (15) with 2
months of conjugated equine estrogen (0.625 mg/day) followed by 4
months of CEE/MPA (0.625 mg/5 mg) in a small group of diabetic
women (n = 14) showed that hormone replacement significantly
improved HgbA1c and reduced the waist-to-hip ratio and central fat
mass, compared with 6 months of control observation.
There are also a limited number of animal studies that have examined the impact of estrogen replacement or estrogen deficiency on glucose metabolism. Matute et al. (16) demonstrated that a 3-week course of either estradiol benzoate injections alone or estradiol plus progesterone significantly reduced hepatic gluconeogenesis in female rats. Estrogen loss through ovariectomy has been shown to decrease whole-body insulin-mediated glucose uptake in female rats (17), decrease glycogen synthase protein expression in rat muscle, and block an insulin-stimulated increase in the plasma membrane glucose transporter GLUT4 content of soleus muscle, which could explain a reduced insulin-stimulated glucose uptake (17). Therefore, it is unclear at this time whether estrogen improves glucose control by improving whole-body glucose uptake, by reducing hepatic glucose output, or by some combination of mechanisms.
The effects of estrogens on glycemic control in nondiabetic women have shown variable results. In nondiabetic women, estrogen replacement has been shown to decrease fasting blood glucose and fasting insulin concentrations (18, 19, 20). Transdermal estradiol, but not conjugated equine estrogen, has been shown to increase C-peptide responses to an oral glucose tolerance test and reduce fasting and postglucose insulin concentrations (19). Elkind-Hirsch et al. (21), however, demonstrated a trend toward decreased insulin sensitivity in women taking estradiol (2 mg/days 1–25·month) alone, with a tolbutamide-modified iv glucose tolerance test, and a significant reduction in insulin sensitivity in women taking estradiol plus medroxyprogesterone acetate (5 mg/days 15–25·month). Therefore, controversy exists concerning the effects of estrogenic and progesterogenic compounds on glucose and insulin metabolism in nondiabetic women.
Several case-control and prospective, epidemiological studies have shown that postmenopausal women treated with estrogen or estrogen plus progesterone have a lower incidence of cardiovascular disease than women not receiving estrogen (9, 10). Limited epidemiologic data are available in diabetic women, but one article suggests that the risk of myocardial infarction in postmenopausal diabetic women is only reduced in current estrogen users with a cumulative duration of use greater than 6 yr (22). Furthermore, the Heart and Estrogen/Progestin Replacement Trial, which included 18–19% women with diabetes mellitus and coronary artery disease in the study population, only showed a worsening in cardiovascular events in the first year of study but cardiovascular benefits in women taking conjugated equine estrogen plus medroxyprogesterone after 4 and 5 yr of use (23). More recently, however, Herrington et al. have reported that neither conjugated equine estrogen (0.625 mg/day) nor conjugated equine estrogen (0.625 mg/day) plus medroxyprogesterone acetate (2.5 mg/day), for a mean duration of 3.2 yr, reduced the progression of coronary atherosclerosis in women with at least one coronary artery stenosis greater than 30%, as measured by quantitative angiography (24). Therefore, it is difficult to determine, at this time, whether estrogen therapy will actually reduce the incidence of clinically significant cardiovascular disease in diabetic women. The results from additional prospective randomized clinical trials will be necessary to determine whether estrogen and/or hormone replacement therapy benefit women at high risk for cardiovascular disease.
Hypertriglyceridemia has consistently been shown to be a risk factor for cardiovascular disease among diabetic individuals in cross-sectional studies (3). In our study, mild elevations in fasting triglyceride of 12% were observed in these diabetic women, which is less than the triglyceride elevations frequently observed in nondiabetic women (6). However, incremental postprandial triglyceride concentrations throughout the day were significantly improved during estrogen treatment, which may negate any increase in fasting triglyceride. Other published work has also shown improvements in postprandial plasma retinyl palmitate AUC during treatment with 17ß-estradiol therapy in nondiabetic women (25). These changes in postprandial triglyceride suggest that lipoprotein lipase activity is increased in these diabetic women during estrogen treatment; estradiol administration to nondiabetic male rats has also been shown to increase muscle lipoprotein lipase activity and reduce plasma triglyceride (26). In contrast, there were no statistically significant triglyceride elevations detected during 17-ß estradiol therapy in diabetic women (12, 13, 14). Several prospective studies of estrogen replacement in diabetic women, thus far, have demonstrated significant reductions in LDL cholesterol and significant elevations in HDL cholesterol (12, 13, 14, 15). Brussard has also shown that 17-ß estradiol also increases HDL2 cholesterol and apolipoprotein A-1 and reduces apolipoprotein B in diabetic women (14). Thus, estrogen replacement in diabetic women produces lipid and lipoprotein changes fairly similar to those observed in nondiabetic women.
In summary, our data show that short-term estrogen replacement therapy improves glycemic control and cholesterol lipoprotein and apolipoprotein B concentrations but slightly increases fasting triglyceride concentrations in postmenopausal diabetic women. Additional research will be necessary to determine whether a longer period of estrogen replacement will further improve glucose control and to determine the mechanism by which estrogen replacement improves glycemic control.
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Acknowledgments |
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Footnotes |
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2 Present address: Department of Medicine, Louisiana State
University, Shreveport, Louisiana 71105.
Received July 26, 2000.
Revised September 18, 2000.
Accepted September 25, 2000.
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