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Clinical Studies |
rin,
Leif Lapidus,
Göran Holm,
Bengt-Åke Bengtsson and
Per Björntorp
Department of Internal Medicine (B.A., P.M., B.B.) and Heart and Lung Diseases (G.H., P.B.), Sahlgren’s Hospital, S-413 45 Göteborg; and Department of Obstetrics and Gynaecology (L.-A.M., L.H.), Östra Hospital, University of Göteborg, S-416 85 Göteborg, Sweden.
Address all correspondence and requests for reprints to: Dr. Björn Andersson, Department of Medicine, Sahlgren’s Hospital, S-413 45 Göteborg, Sweden.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Blood glucose, glycosylated hemoglobin, insulin, c-peptide, lipoprotein profile, sex steroid hormones, GH, and insulin-like growth factor I (IGF-I) were measured, and insulin sensitivity was determined by the euglycemic hyperinsulinemic clamp method. All metabolic measurements were taken at baseline and after 68 days of active or placebo treatment.
Estradiol treatment, compared with the placebo period, was followed by a marked increase of sex hormone-binding globulin and a decrease of free testosterone. Blood glucose, glycosylated hemoglobin, c-peptide, total cholesterol, low-density lipoprotein cholesterol, and IGF-1 decreased significantly (P < 0.01–P < 0.001), whereas high-density lipoprotein cholesterol rose (P < 0.001).
In conclusion, estrogen replacement therapy in postmenopausal women with NIDDM ameliorated hyperandrogenicity, and this was accompanied by marked improvements in glucose homeostasis and lipoprotein profile.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Apart from plasma lipids, hyperinsulinemia and insulin resistance also are strong and independent risk factors for cardiovascular disease (9), but the effects of estrogens on carbohydrate metabolism and insulin resistance are more controversial. However, in two large population studies, the use of conjugated estrogens recently has been reported to be associated with lower fasting insulin levels than in nonusers (10, 11), and Manson (12) has shown that the use of estrogen replacement therapy (ERT) was not associated with a higher incidence of noninsulin-dependent diabetes mellitus (NIDDM).
Recent investigations have demonstrated an association between hyperandrogenicity, as indicated by low levels of sex hormone-binding globulin (SHBG), and elevated free testosterone on the one hand, and insulin resistance on the other, in both pre- and postmenopausal women (13, 14, 15). Furthermore, a low level of SHBG is a strong and independent risk factor for development of NIDDM in women (16, 17), and postmenopausal women with manifest NIDDM seem to be relatively hyperandrogenic in comparison with healthy women of similar age and body mass index (18).
With this background, we hypothesized that hormone replacement therapy with estradiol might alleviate hyperandrogenicity and insulin resistance in postmenopausal women with NIDDM. The present study was therefore performed to test this possibility.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Twenty-five naturally (n = 21) or surgically (n = 4) postmenopausal women, 45–65 yr old, with NIDDM were recruited from outpatient diabetes clinics or through advertisement in a local newspaper.
Their diabetes was diagnosed according to criteria of the World Health Organization (19) at least 12 months before entering the study. They were on dietary management alone or taking oral hyperglycemic agents for control of their NIDDM, and they all had a glycosylated hemoglobin (HbA1c) of 7.0% or more and an SHBG less than 60 nmol/L. Women with insulin therapy were excluded.
The postmenopausal status was defined as 1 yr or more of amenorrhea or hysterectomy and concentrations of FSH more than 50 IU/L and concentrations of estradiol less than 0.1 nmol/L.
Exclusion criteria were cardiac dysfunction, thromboembolic disorders, acute or chronic liver disease, known or suspected estrogen-dependent neoplasia, known or past history of carcinoma of the breast, regular smoking (>10 cigarettes/day), alcohol abuse, uncontrolled hypertension, or use of steroid hormones less than 12 weeks before entering the study.
All women reported a stable body weight (<3 kg change) within 3 months preceding the study. All patients gave their informed consent to the study, which was approved by the Ethics Committee of the University of Göteborg.
Study design
The study was conducted in a randomized, double-blind, cross-over design with an active drug and placebo. Each treatment period was 3 months, with an 8-week wash-out period between treatments.
Active treatment consisted of 2 cycles (2 x 28 days) of 2 mg 17-ß-estradiol (Estrofem, Novo Nordisk A/S, Copenhagen, Denmark) and 1 cycle of Trisequens (Novo Nordisk), which comprised 12 days of 2 mg 17-ß-estradiol, 10 days of 2 mg 17-ß-estradiol and 1 mg of norethisterone acetate, and 6 days of 1 mg 17-ß-estradiol.
Placebo tablets were supplied for the trial in a 28-day calendar dial pack and were of similar appearance as active treatment. Throughout the study, each subject received 3 calendar dial packs of placebo tablets for one treatment period and 2 calendar packs of Estrofem and 1 calendar pack of Trisequens for the other treatment period. After each treatment period, all calendar packs were returned to the investigator, and any lost or forgotten tablet was noted.
All metabolic and anthropometric examinations were performed in the fasting state at day 1 (baseline) and at days 60–68 (before the addition of norethisterone acetate) during each treatment period.
Gynecological examination
A clinical gynecological examination was performed in all women before the start of the study. A cervical smear was taken from the fornix and cervical canal. A transvaginal ultrasound examination was performed (Siemens Sonoline A.C., Issaquah, WA). An endometrial thickness of 5 mm or below was considered normal, but when exceeding 5 mm, an endometrial biopsy was taken by means of a pipelle curette. Gynecological bleeding was registered. Furthermore, mammography was carried out in all women.
The ultrasound examination was repeated three times during the study. The mammography was repeated only after cessation of the study.
Anthropometric examinations and blood pressure
Before (at baseline) and after each treatment period, a general physical examination was performed. The participants were weighed in their underwear to the nearest 0.1 kg and height was recorded to the nearest centimeter. Body mass index was calculated as weight (kg)/height (m2). Waist circumference was assessed midway between the lower rib margin and the iliac crest by an ordinary measuring tape with the subject standing in a normally respiratory position. Hip circumference was recorded over the widest part of the hip region, and the waist-to-hip ratio was calculated (20).
Total body potassium was determined in a whole-body counter (Nuclear Enterprise, Edingburgh, UK), which detects naturally occurring 40K (21). Lean body mass (LBM) was calculated according to the method of Forbes et al. (22), assuming that LBM has a potassium content of 68.1 mmol/kg. Body fat was obtained by subtracting LBM from body weight.
Blood pressure was measured with a mercury sphygmometer on the right arm with the cuff size adjusted for arm circumference after a 5-min rest period in the supine position. This measurement was repeated after 1 min. The mean value was used. Korotkoff phases I and V sounds were taken as the systolic and diastolic readings, respectively.
Metabolic measurements
Blood glucose was determined with a commercial glucose oxidase method (Merck, Kabi, Stockholm, Sweden) and HbA1c by high-pressure liquid chromatography (Waters Millipore AB, Göteborg, Sweden). Insulin and c-peptides were assessed by RIA methods (Insulin RIA 100, Pharmacia, Uppsala, Sweden and Sangtec Diagnostica, Dietzenbach, Germany, respectively). Hemoglobin, serum creatinine, alanine aminotransferase, and alkaline phosphatase were analyzed by routine hospital methods.
Triglycerides and total cholesterol were measured by enzymatic, semiautomated methods (Boehringer, Ingelheim, Germany). HDL-cholesterol was assessed as previously described (23). LDL cholesterol was calculated according to the formula of Friedewald: LDL cholesterol = total cholesterol - (triglycerides/2.2 + HDL - cholesterol) (24).
Growth hormone was analyzed in 24-hr urine samples by an immunoradiometric method (BioMerieux, Marcy-Le Étoile, France) with a coefficient of variation of 6%. Serum IGF-1 was determined by an RIA method (Nichols Diagnostics, San Juan) with a coefficient of variation of 4%.
FSH was measured by an RIA method (Diagnostic Products Corp, Los Angeles, CA; coefficient of variation 5%) and SHBG by an immunoradiometric method (Pharmos, Åbo, Finland; coefficient of variation 5%). Total testosterone was analyzed by an RIA method (ICN, Biomedical, Costa Mesa, CA; coefficient of variation 15%) and 17-ß-estradiol by an RIA from Sorin Biomedica, Milano, Italy, with a coefficient of variation of 15%. Free testosterone was calculated as the molar ratio of total testosterone/SHBG.
All laboratory tests were performed on fresh samples.
Euglycemic hyperinsulinemic glucose clamp
After an overnight fast, an euglycemic, hyperinsulinemic glucose clamp examination was performed as previously described (25). Insulin and glucose were infused through a catheter inserted into an antecubital vein. Arterialized blood samples were collected after heating from a dorsal vein on the contralateral hand. Insulin (Actrapid MC, Novo, Copenhagen, Denmark) was infused at a concentration of 500 mU/mL in isotonic saline, containing 2 mL plasma from the subject to prevent losses of insulin.
A 20% glucose (1.1 mol/L) solution was infused at varying rates in the same catheter as the insulin. A primed insulin infusion for 10 min was followed by a constant infusion of 0.12 U x kg BW-1 x min-1 for 120 min. Blood was analyzed for glucose concentration before, and every 10 min during, infusion. The rate of glucose infusion was adjusted to maintain a glucose level of 5.0 mmol/L. Samples for plasma insulin were taken before and after 80, 90, 100, 110, and 120 min of insulin infusion.
Glucose infusion rate during the clamp was assumed to be equal to the tissue glucose uptake rate during the last 20 min, when steady state was reached. Insulin concentrations during this period were 188 ± 8 mU/L before and 172 ± 4 mU/L (mean ± SEM, P < 0.05) after treatment.
Statistics
Results are given as mean ± SEM. Student’s t test for paired samples was used for comparisons between the treatment periods. Linear regression analyses were used, as available, in the Statview program of the Macintosh system. The data were verified also with nonparametric methods (Wilcoxon’s signed rank test and Spearman), showing the same results. P-values less than 0.05 (two-tailed) were regarded as indicating statistical significance.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. Twenty-four subjects completed the study. One
woman was excluded after the first treatment period because of
development of a thrombosis in her left calf. All her accessible
results have, however, been used in the analyses of the study data. The
most frequent adverse effects seen with estradiol treatment were
abdominal pain (16%), breast tenderness (8%), and emesis and nausea
(8%). These side-effects disappeared after 1–2 weeks of
treatment.
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These results are found in Table 2. There was a
slight increase in BW (82.1 ± 3.1 kg vs. 83.4 ±
3.2 kg, P < 0.001 mean ± SEM) and
body fat (38.0 ± 2.0 kg vs. 38.4 ± 2.0 kg,
P < 0.05) after estradiol substitution.
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These results are presented in Table 3. SHBG
increased from 16 ± 1 nmol/L at baseline to 61 ± 5 nmol/L
after estradiol substitution (P < 0.001), and free
testosterone decreased from 6.73 ± 0.85% at baseline to
1.52 ± 0.27% after estradiol treatment (P <
0.001).
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Glucose metabolism
Changes in glucose metabolism are shown in Table 4.
During treatment with estradiol, fasting blood glucose decreased from
12.1 ± 0.4 mmol/L at baseline to 9.5 ± 0.4 mmol/L
(P < 0.001) after treatment. HbA1c was reduced from
8.7 ± 0.2% before estrogen substitution to 7.5 ± 0.2%
after substitution (P < 0.001). During the placebo
period, HbA1c increased significantly from 8.5 ± 0.2% to
9.0 ± 0.3% (P < 0.001).
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Lipid metabolism
Cholesterol was reduced from 5.7 ± 0.2 mmol/L to 5.2 ±
0.1 mmol/L after estradiol treatment (P < 0.01, Table 5). HDL cholesterol increased from 1.10 ± 0.05
mmol/L at baseline to 1.33 ± 0.06 mmol/L (P <
0.001, Table 5). LDL cholesterol decreased from 3.74 ± 0.17
mmol/L to 2.86 ± 0.14 mmol/L after estradiol treatment
(P < 0.001, Table 5).
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SHBG at baseline seemed to be correlated to changes in glucose disappearance rate (GDR) during estradiol treatment (r = 0.36, P = 0.08 borderline significance, not shown). There were no significant correlations between changes in SHBG and changes in GDR or HbA1c in the whole group.
However, after subdivision of the women, according to the median of
SHBG, into one group with low SHBG (<15, n = 12) and one group
with high SHBG (
15, n = 13), a correlation was found between
changes in SHBG and changes in HbA1c during estradiol treatment (r
= -0.64, P < 0.05, Fig. 1), in the
group with low SHBG.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Estradiol treatment brought about a slight increase in body weight and body fat, whereas LBM and waist-to-hip ratio remained unchanged. Thus, the improved glucose homeostasis probably was not related to a reduction in body weight or body fat.
Data on estradiol substitution in postmenopausal women with NIDDM are scarce. Luotola (26) and Mosnier-Pudar (27) found no change in glucose homeostasis after 6 months of ERT in such patients. The results reported here are thus contradictory, which might be because of differences in sample or route of administration.
In previous studies, the coupling between hyperandrogenicity and insulin resistance does not seem to have been considered. Several recent epidemiological cross-sectional studies have demonstrated this relationship in both pre- and postmenopausal, nondiabetic and diabetic women (13, 14, 15, 28). Hyperandrogenicity, as indicated by low SHBG values, also is a powerful independent risk factor for the development of NIDDM (16, 17), hypertension (29), and cardiovascular disease and overall mortality (30).
Furthermore, a low SHBG level is associated closely with visceral obesity. Women with central body fat distribution have low levels of SHBG and increased free testosterone in parallel with insulin resistance (31). Visceral obesity is a risk factor for cardiovascular disease, stroke, and NIDDM (32, 33). Low SHBG concentrations and visceral obesity may have additive effects on insulin resistance and risk to develop NIDDM, hypertension, and cardiovascular disease.
The direction of causality between hyperandrogenism and insulin resistance in women is not fully clarified. Both types of causal associations have been postulated. Studies of anabolic steroids (34, 35), PCO women (36, 37), androgen treatment of female to male transsexuals (38), oral contraceptive administration (39), and studies of the effect of testosterone on insulin sensitivity in female rats (40) suggest that increased androgenicity in women may cause insulin resistance.
On the other hand, there are several pieces of evidence that insulin resistance, or rather hyperinsulinemia, may lead to hyperandrogenism. It has been shown that hyperinsulinemia increases androgen output from the ovary (41, 42, 43) and may suppress SHBG production in the liver, shown in vitro (44) and indirectly in clinical studies (45, 46).
Furthermore, several previous studies in women with hyperandrogenism have shown that suppression of androgens into normal levels did not result in improvements in insulin resistance (47, 48, 49). However, Moghetti (50) and Shoupe (51) have demonstrated recently that antiandrogen treatment resulted in partially reversed insulin resistance.
The potential cause-effect sequence, implying that hyperandrogenicity induces insulin resistance and glucose intolerance, seems to be in agreement with the results reported here because elevated SHBG levels induced by estrogen administration alleviating hyperandrogenicity was followed, at least partly, by an improved glucose tolerance.
In the present study, there also was a correlation between baseline SHBG and changes in GDR during treatment, although of borderline significance, and an inverse relationship between changes in SHBG and changes in HbA1c during treatment, which was found in the most androgenic group of women. These observations indicate that improvement of glucose tolerance was more pronounced in those women with most marked hyperandrogenicity.
Previously it has been suggested that insulin sensitivity is preserved in the liver but reduced in the periphery in hyperandrogenic women or female-to-male transsexuals treated with androgens (38, 52). The diminished peripheral insulin sensitivity may be mediated via a direct effect of androgens on skeletal muscle (53, 54, 55).
In addition to alleviating androgen effects on muscle, estrogens alone also may have direct effects on skeletal muscle. Estrogens regulate insulin-induced glucose transport (56) via translocation of glucose transporter 4 (57).
Another possible mechanism for the improvement of glucose homeostasis may be an increased estrogen mediated basal and insulin-mediated suppression of hepatic glucose production because patients with NIDDM have both hepatic and extrahepatic insulin resistance (58). Estradiol has been reported to depress hepatic glucose output (59). In support of this possibility, a recent report published while this work was in progress has shown that estradiol treatment of postmenopausal women with NIDDM was followed by increased suppression of hepatic glucose production and improvement in HbA1c and HDL cholesterol concentrations (60).
HDL cholesterol was increased significantly after estradiol treatment, and total cholesterol and LDL cholesterol were markedly decreased. These findings are in agreement with previous observations in subjects without NIDDM (6, 7, 8). A rise in total cholesterol and LDL cholesterol levels generally occurs around the menopause in women, whereas HDL cholesterol seems to be unaffected (7). These untoward metabolic changes may partly provide background factors for the gradual and progressive increase in the incidence of coronary heart disease in menopausal women.
There is some evidence that estrogens may induce the formation of LDL cholesterol receptors and subsequently remove cholesterol from the circulation (61), and animal and autopsy studies suggest that estrogen may inhibit the development of atherosclerotic lesions (62).
HDL cholesterol plays a major role in reverse cholesterol transport, or the collection of excessive cholesterol. In the liver, hepatic lipase removes HDL cholesterol, counteracted by estrogen, which may, at least partly, explain the increase of HDL cholesterol levels with estrogen administration (6).
A rise in triglycerides after administration of conjugated estrogens has been reported (7, 8). Elevated triglycerides are associated with an increased risk for cardiovascular disease in women (63). In the present study, no significant treatment effect on triglycerides by estradiol was found.
The observed alteration in GH/IGF-1 axis during active therapy with estrogen might be an effect of the route of administration of estrogen. Weissberger et al. (64) recently observed that, during oral administration of estrogens in postmenopausal women, GH secretion rose to levels in excess of those seen in premenopausal women. Oral estrogen administration inhibits hepatic IGF-1 synthesis and increases GH secretion through reduced feedback inhibition. Such changes would be expected to deteriorate insulin sensitivity, which was not the case in the present study, suggesting that other effects of estrogens, such as a decrease in hyperandrogenicity, were more important.
In summary, administration of estradiol to postmenopausal women with NIDDM markedly alleviated hyperandrogenicity and tentatively improved glucose homeostasis, lipid profile, and, seemingly, also insulin resistance. These findings may implicate a favorable impact of ERT on cardiovascular risk factors and NIDDM. However, the present examination was conducted as a short-term study with a small sample, and more long-term studies with larger samples are warranted.
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Footnotes |
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Received July 8, 1996.
Revised September 26, 1996.
Accepted October 14, 1996.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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rin P, Lissner L, Vermeulen A,
Björntorp P. 1994 Testosterone concentrations in women and
men with NIDDM. Diabetes Care. 17:405–411.[Abstract]
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