0021-972X/99/$03.00/0 The Journal of Clinical Endocrinology & Metabolism Copyright © 1999 by The Endocrine Society
Vol. 84, No. 7 Printed in U.S.A.
The Effect of Estradiol and a Combined Estradiol/Progestagen Preparation on Insulin Sensitivity in Healthy Postmenopausal Women A. C. DUNCAN, H. LYALL, R.N. ROBERTS, J. R. PETRIE, M. J. PERERA, S. MONAGHAN, D. M. HART, J. M. C. CONNELL, AND M. A. LUMSDEN Department of Obstetrics and Gynecology, Queen Mother’s Hospital (A.C.D., H.L., R.N.R., M.J.P., S.M., D.M.H., M.A.L.), Yorkhill, Glasgow, United Kingdom G3 8SJ; and the Department of Medicine and Therapeutics, Western Infirmary (J.R.P., J.M.C.C.), Glasgow, United Kingdom G11 8NT ABSTRACT Abnormalities of carbohydrate metabolism and insulin sensitivity have been reported in estrogen deficiency. Estrogen replacement appears to result in an improvement in these parameters, although progestagens may antagonize these effects. We have examined the effects of transdermal estradiol and oral norethisterone on insulin sensitivity using the hyperinsulinemic euglycemic clamp method by performing a randomized, double blind, placebo-controlled study in 22 healthy women after a surgically induced menopause. After baseline measurements, subjects were randomized to receive either transdermal 17b-estradiol (50 mg) or matching placebo patches for 6 weeks. The subjects were then further randomized to receive either estradiol in combination with oral norethisterone (1 mg) or a matching oral placebo preparation, crossing over after 6 weeks, with assessment of
C
ORONARY heart disease (CHD) is well recognized as the commonest cause of morbidity in men. It is less well appreciated that this is also the case in women (1), although a temporal association between loss of ovarian function at the time of the menopause and increased risk of cardiovascular disease in women has now been established (2, 3). Loss of ovarian function leads to a range of potentially unfavorable and interrelated metabolic alterations in women (4), including changes in lipids and lipoproteins (5), glucose and insulin metabolism (6, 7), body fat distribution (8), coagulation and fibrinolysis (9), and increased arterial resistance to flow (10). Postmenopausal women have reduced glucose tolerance and impaired insulin sensitivity and secretion, and although these changes may in part be attributable to aging, postmenopausal hypoestrogenism may also contribute (6). Impaired glucose tolerance resulting from reduced sensitivity of target tissues to insulin-mediated glucose uptake is associated with an approximate doubling of the risk of ischemic heart disease (11, 12), and it has been proposed that insulin resistance and hyperinsulinemia are pivotal disturbances in the etiology of CHD in nondiabetic subjects (13). Many observational studies have found that postmeno-
Received May 29, 1998. Revision received January 4, 1999. Rerevision received March 12, 1999. Accepted March 24, 1999. Address all correspondence and requests for reprints to: Dr. M. A. Lumsden, Department of Obstetrics and Gynecology, The Queen Mother’s Hospital, Yorkhill, Glasgow, United Kingdom G3 8SJ.
insulin sensitivity at the end of each treatment. No significant increase in insulin sensitivity was observed after 6 weeks of transdermal 17b-estradiol treatment (95% confidence interval, 20.54, 1.86; P 5 0.27). Addition of norethisterone for a further 6 weeks had no detectable effect on insulin sensitivity (95% confidence interval, 21.65, 1.10; P 5 0.65). The results of this study using transdermal estradiol do not support previous reports that unopposed estrogens exert potentially beneficial effects on insulin sensitivity and suggest that the addition of an oral progestagen confers no clinically important risk or benefit. It is therefore unlikely that effects on insulin sensitivity contribute appreciably to the cardioprotective benefits attributed to hormone replacement therapy. (J Clin Endocrinol Metab 84: 2402–2407, 1999)
pausal women who are estrogen users are at lower risk of coronary disease than those who are not (14), although most data are for estrogen alone (15). The addition of progestagens to prevent endometrial cancer in women who have not had a hysterectomy (16) may diminish the apparent cardioprotective effect of hormone replacement therapy (HRT) (17), but information about the risk of cardiovascular disease associated with combined therapy is sparse. To date there have been relatively few studies of the effects of hormone replacement therapy on carbohydrate metabolism, and the role of postmenopausal replacement with ovarian steroids in the modification of insulin sensitivity remains unclear. Here we report the first study examining the effects of estradiol and a combined estradiol/progestagen preparation on insulin sensitivity using the gold standard methodology: the hyperinsulinemic euglycemic clamp (18). Our aim was to determine whether initiation of transdermal estrogen-based HRT in postmenopausal women has a beneficial effect on insulin sensitivity, and whether the addition of a progestagen antagonizes any such effect. Materials and Methods Subjects Women undergoing total abdominal hysterectomy and bilateral salpingo-oopherectomy for benign gynecological disease were recruited from the gynecological out-patient clinics of the Western Infirmary and Stobhill Hospital (Glasgow, Scotland) and gave written informed consent to participate in the study, which was approved by the ethics committee of the West Glasgow Hospitals University National Health Service Trust. The women, aged 35–50 yr, were nonobese, had no sig-
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nificant medical history, and were deemed to be healthy on physical examination and routine screening investigations. The study protocol was timed to start at 3– 6 weeks postoperatively to allow time for stabilization of gonadotropins and other metabolic processes.
m2) were recorded. On each study morning subjects attended at 0800 h after an overnight fast from 2200 h..
Study protocol
Glucose concentrations were measured at the bedside using a Beckman Coulter, Inc. II Glucose Analyzer (Beckman Coulter, Inc., Fullerton, CA). All blood samples for hormone concentrations were collected in chilled tubes and separated for storage at 220 C until assay. Serum insulin concentrations were measured in batches by RIA (INCSTAR Corp., Stillwater, MN). Serum lipids were measured on a Roche Lobas centrifugal analyzer (Roche Diagnostics, Welyn, UK) in the local biochemistry laboratory.
A randomized, double blind, placebo-controlled study protocol was adopted (Fig. 1). In phase 1, after baseline measurements (visit 1), subjects were randomized to either placebo or 50 mg transdermal 17bestradiol for 6 weeks, after which a second assessment was performed (visit 2). In phase 2, subjects were then further randomized to receive transdermal estradiol in combination with either 1 mg oral norethisterone or placebo for an additional 6 weeks, and a third assessment was performed (visit 3). The two groups were then crossed over, and a final assessment (visit 4) was performed after a further 6 weeks. Insulin sensitivity was measured using a modification of the hyperinsulinemic euglycemic clamp method of De Fronzo et al., as previously described (19 –21). Briefly, plasma insulin was raised acutely to a steady state level using a constant rate infusion of soluble insulin (Actrapid, 1.5 mU/kgzmin) in a 10% (vol/vol) solution of the subject’s own blood in 0.9% saline. The arterialized serum glucose concentration was measured at the bedside every 5 min. Variable rate 20% dextrose was infused from 0 –180 min to maintain euglycemia (5.2 mmol/L). Blood pressure and heart rate were recorded at 15-min intervals throughout the procedure. Baseline blood samples were taken for glucose, insulin, estradiol, cholesterol, and triglycerides determinations. Serum insulin concentrations were monitored hourly throughout the study. At each visit, weight (kilograms), height (meters), and body mass index (BMI; kilograms per
Laboratory methods
Power A power calculation based on previous euglycemic clamp studies conducted on healthy male volunteer and hypertensive subjects in our laboratory (22) indicated that a sample size of 20 in phase 2 (cross-over) of the study would give an 80% power to detect a 12% change in insulin sensitivity at a 5 0.05.
Statistical analysis Results are expressed as the mean 6 sd unless otherwise indicated. The distribution of all data (parametric vs. nonparametric) was assessed using the Anderson-Darling test (Minitab Statistical Package, Minitab, Inc., State College, PA). Insulin sensitivity (M-value) in milligrams per kg/min was calculated as previously described (19, 20). The insulin sensitivity index (SIP 3 105 dL/minzkg per mU/L) was calculated from the glucose infusion rate and ambient glucose and insulin concentrations (22). For the primary end points of the study (M-value and SIP), two main comparisons were made: 1) phase 1, placebo vs. estradiol; and 2) phase 2, estradiol with placebo vs. estradiol with norethisterone. In phase 1, comparisons between estradiol and placebo conditions were made after subtraction of baseline values using unpaired t tests; 95% confidence intervals (CI) are shown. In the cross-over phase of the study, comparisons between estradiol with placebo and estradiol with norethisterone were made using paired t tests; 95% CI are again quoted. The reproducibility of the M-value was estimated by calculating the intrasubject coefficient of variation from the phase 1 placebo data.
Results
Twenty-two healthy Caucasian women (age, 43.7 6 5.94 yr; BMI, 24.8 6 1.33; mean 6 sd) participated in phase 1 of the study. Seventeen women then agreed to continue to phase 2 of the study. In total, 78 clamps were performed, all of which were well tolerated. The coefficient of variation for insulin sensitivity (M-value) was 6.6%. BMI
Most subjects reported that they had gained weight during the course of the study (Fig. 2, a and b). The 9 women randomized to placebo treatment in phase 1 had a BMI of 26 6 4.2 at baseline and 27 6 3.9 after 6 weeks of treatment (P 5 0.76; 95% CI, 23.5, 4.7). Similarly, the mean BMI for the 13 women randomized to estradiol in phase 1 was 23 6 2.6 at baseline and 24 6 3.2 after treatment (P 5 0.63; 95% CI, 21.81, 2.92). Estradiol
FIG. 1. Study design.
Circulating estradiol levels at baseline indicated biochemical postmenopausal status (i.e. , 50 pmol/L) in all subjects except 1, in whom an estradiol level of 80 pmol/L was measured. This subject was randomized to the placebo arm of the study in phase 1, and at the end of phase 1 had an estradiol level of 53 pmol/L. An FSH level above 40 IU/L is considered
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to indicate postmenopausal status; in this woman, the FSH level was 60.8 IU/L, which is consistent with postmenopausal status. The mean circulating estradiol level during treatment cycles was 141.5 6 122.2 pmol/L. In one subject the circulating estradiol level remained below 50 pmol/L throughout the study, probably indicating either poor absorption or noncompliance with treatment. The women who received the placebo patches had a mean circulating estradiol level of 53.7 6 10.6 at baseline compared with 51.2 6 2.7 after the placebo patches (P 5 0.53; 95% CI, 26.6, 11.6). The mean circulating estradiol levels in the women who received estradiol patches was 50.0 6 0.003 at baseline compared with 144.0 6 89.8 after the estradiol patches (P 5 0.009; 95% CI, 2158.4, 230.0). Comparing the estradiol levels in the women who continued into the second phase of the study who had initially been given the placebo patches with those women who had received estradiol, we did not observe any significant dif-
ference in the final circulating estradiol levels. The mean estradiol level at the end of the study in the women who received placebo patches in phase 1 was 119.6 6 53.5 compared with 114.5 6 59.6 in the group who received transdermal estrogen (P 5 0.87). Insulin sensitivity (M-value)
No statistically significant differences were observed between treatments for steady state insulin concentrations (Table 1). In phase 1, insulin sensitivity (M-value) changed from 7.0 6 1.42 to 7.6 6 1.72 mg/kgzmin after placebo and from 8.9 6 1.73 to 8.8 6 2.27 mg/kgzmin after estradiol treatment (P 5 0.27; 95% CI, 20.54, 1.86; Figs. 3 and 4). In phase 2, insulin sensitivity was 8.3 6 2.07 mg/kgzmin during estradiol with placebo compared with 8.0 6 1.86 mg/kgzmin during estradiol with norethisterone (P 5 0.41; 95% CI, 21.65, 1.10; Fig. 5). To correct for small variations in the insulin stimulus resulting from error in serial weight measurements, SIP values were calculated (see Materials and Methods). In phase 1, SIP changed from 36 6 4.5 to 33 6 3.5 after placebo and from 52 6 3.0 to 52 6 4.3 after estradiol (P 5 0.78; 95% CI, 212.8, 9.8). In phase 2, SIP was 46 6 3.7 during estradiol with placebo and 41 6 3.1 during estradiol with norethisterone (P 5 0.27; 95% CI, 215.5, 4.4). Fasting glucose and insulin
With one exception, no significant differences were observed in fasting glucose and insulin in either phase of the study (Table 2). The exception (fasting insulin in phase 1 of the study) resulted from an artifact of baseline subtraction when higher fasting serum insulin concentrations were observed in some women assigned to placebo at the end of phase 1. Lipids
Mean fasting serum cholesterol and triglyceride levels are summarized in Table 2. Fasting cholesterol and triglycerides did not change significantly with either treatment regimen. Discussion
FIG. 2. A, BMI placebo group. B, BMI estradiol group.
To our knowledge, this is the first and largest study using a double blind, placebo-controlled protocol to examine the effect of estradiol and combined HRT on insulin sensitivity using the hyperinsulinemic euglycemic clamp technique. Because previous open uncontrolled studies, using less reliable methods of measuring insulin sensitivity, have reported that unopposed transdermal estradiol alters insulin sensitivity (23), we employed an experimental design that addressed the
TABLE 1. Steady state insulin concentrations Phase 1
Steady state insulin conc.
Clamp 1 (B)
Clamp 2 (P/E)
B 113 6 18 B 101 6 18
P 133 6 29 E 103 6 21
Phase 2 P value
Clamp 3 (E 1 P)
Clamp 4 (E 1 N)
P value
0.16
112 6 22
122 6 30
0.29
ESTRADIOL AND PROGESTAGEN AFFECT INSULIN SENSITIVITY
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FIG. 5. M-value (estradiol plus placebo vs. estradiol vs. norethisterone). FIG. 3. M-value (baseline vs. placebo).
FIG. 4. M-value (baseline vs. estradiol).
question of whether addition of a widely used progestagen to transdermal estradiol therapy would blunt the expected improvement in insulin sensitivity seen with unopposed estrogen. However, our results did not demonstrate a detectable effect of estradiol (either alone or combined with progestagen) on insulin sensitivity. Studies of insulin resistance are complicated by the use of different methods of measurement and experimental designs. We chose the hyperinsulinemic euglycemic clamp as a reproducible and reliable method that, with a larger group size than is usually found in studies using clamp methodology, was powered to detect a clinically important difference. The use of other less precise methods and open, uncontrolled study designs may in part explain the different results reported in the literature. The women in our study were carefully selected in terms
of age and general characteristics. Studying a homogeneous group of women who had undergone a surgical menopause had the advantage of controlling for hypoestrogenism, a time-dependent effect, but may limit the generalizability of our results to older women who have undergone a natural menopause. We chose an interval of 3– 6 weeks postoperation for the first clamp, as metabolic processes have usually normalized by this point (24), and it would be unethical to withhold estrogen from some women for more than 3 months. This interval has also been used in other studies measuring lipid and carbohydrate metabolism (25). Women randomized to receive estradiol in phase 1 tended to be lighter and less insulin resistant than those randomized to placebo, but this did not compromise our results because of the experimental design. Other studies have measured insulin sensitivity in postmenopausal women during HRT, but their conclusions are not uniform. Some of the discrepancies may be due to the route of administration. Oral estrogen passes directly from the gut to the liver via the portal vein, giving a high local concentration that profoundly affects hepatic metabolism. In contrast, transdermal estrogen avoids first pass metabolism, and it would therefore not be surprising to find different effects of oral and transdermal estrogen. Previous studies with transdermal estrogen have reported a neutral or beneficial effect (26) and in one smaller study there was no significant change (22). Conversely, oral administration of estradiol, particularly at high doses, is frequently associated with a decrease in insulin sensitivity (28). The circulating concentration of estradiol clearly varies with the dose administered. Subcutaneous hormone implants containing up to 100 mg estradiol lead to midfollicular phase levels of estradiol that are significantly higher than those achieved using other modes of administration and have been associated with improved insulin sensitivity in a group of recently hysterectomized women (25). This illustrates the importance of dosage and concentration of estradiol in interpreting discrepancies between studies. In all but one woman in our study, levels of estradiol comparable with
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TABLE 2. Fasting insulin, glucose, and lipids Phase 1 Clamp 1 (B)
Clamp 2 (P/E)
Fasting insulin
B 5.2 6 2.23 B 6.7 6 3.21
P 7.5 6 2.90 E 6.4 6 4.21
Fasting glucose
B 5.0 6 0.28 B 5.1 6 0.30
Fasting cholesterol Fasting triglycerides
Phase 2 P value
Clamp 3 (E 1 P)
Clamp 4 (E 1 N)
P
0.33
7.5 6 5.3
8.4 6 6.5
0.68
P 5.0 6 0.32 E 5.0 6 0.19
0.50
4.9 6 0.46
5.1 6 0.35
0.28
B 5.6 6 1.00 B 5.5 6 1.02
P 5.5 6 1.10 E 5.6 6 0.68
0.42
5.5 6 0.84
5.0 6 1.01
0.21
B 1.0 6 0.34 B 1.3 6 0.76
P 1.2 6 0.54 E 1.0 6 0.47
0.29
1.2 6 0.73
1.0 6 0.40
0.19
P, Placebo; E, estradiol; N, norethisterone. In phase 1, P value compares placebo and estradiol after baseline subtraction; in phase 2, the P value compares estradiol with placebo or norethisterone, as described in the text.
the early follicular phase were observed, but no correlation with insulin sensitivity was demonstrated. Most women receive combined HRT, and the effect of progestagen must be taken into account. Estrogen is administered to restore a lack of hormone rather than to impose an excess; therefore, the effect of the progestagen may dominate. The use of conjugated equine estrogens in combination with medroxyprogesterone acetate (29) or levonorgestrel (30) is associated with a deterioration in glucose tolerance, possibly by an impairment of the initial insulin secretory response. Medroxyprogesterone acetate and levonorgestrel may be independently associated with insulin resistance (28, 29). In contrast, norethisterone in combination with estradiol may be relatively neutral (30, 31), as in the present study. The latest generation of progestagens has also been reported to have neutral or even beneficial effects in combination with low dose conjugated equine estrogens (32) or estradiol (33). Beneficial effects of HRT on lipids and lipoprotein metabolism, particularly high density lipoprotein cholesterol, are widely reported throughout the literature and are thought to account at least in part for the reported cardioprotective effect. In this study we did not measure high density lipoprotein cholesterol, but no significant differences attributable to either treatment regimen were noted in either fasting triglycerides or total cholesterol. A larger sample size would have been required to make formal comparisons of the effects on these end points, but other studies of similar size have shown no effect or a slight improvement in lipids after transdermal estrogen treatment (27, 34, 35). In summary, the results of the present study do not support previous reports that unopposed transdermal estrogen exerts beneficial effects on insulin sensitivity. The addition of the oral progestagen norethisterone appears to confer no additional risk or benefit. We conclude, therefore, that it is unlikely that beneficial effects on insulin sensitivity contribute appreciably to the cardioprotective benefits attributed to HRT. Acknowledgments The authors thank Solvay Healthcare Ltd. for providing the estradiol patches, and Dr. L. S. Murray for guidance with statistical analysis.
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