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Az oestrogen-pótló terápia hatása a glükóz metabolizmus inzulin szenzitivitására, valamint az érfunkció prerezisztenciája és rezisztenciája egészséges postmenopauzás nőkbenAz oestrogen-pótló terápia hatása a glükóz metabolizmus inzulin szenzitivitására,
valamint az érfunkció prerezisztenciája és rezisztenciája egészséges postmenopauzás
Jelen tanulmányunkban feltételezzük, hogy az oestradiol, endothelium-függő módon a vazodilatációt okozó képességének köszönhetően, megnövelheti az inzulin vasculáris hatását. A bazális és az inzulin-stimulált perifériás véráramlást és rezisztenciát, az artériás érfalmerevséget és glükóz metabolizmust vizsgáltuk 27 egészséges postmenopauzás nőnél 12 héttel a trandermalis vagy orális oestradiollal vagy placebo készítményekkel végzett kezelés előtt és után. A teljes test inzulin szenzitivitást meghatároztuk az euglikémiás inzulin clamp technika segítségével (a folyamatos inzulin infúzió mértéke 1mU/kg x min volt), az alkar véráramlását strain-gauge pletizmográfiával, az artériás érfalmerevséget pedig pulzushullám analízissel állapítottuk meg. Az oestradiol terápia megnövelte a bazális perifériás véráramot (1,5±0,1 vs. 1,9±0,1 mL/dL x min, 0 vs. 12 hét; p<0,01), csökkentette a perifériás vasculáris rezisztenciát ( 65±3 vs. 52±3 mm Hg/mL/dL x min; p<0,01), valamint a diastolés vérnyomást (78±2 vs. 75±2 Hgmm; p<0,05), de nem volt hatással a nagy artériák érfalmerevségére. Az inzulin infúzió akutan nem változtatta meg a perifériás véráramlást, de szignifikánsan lecsökkentette a nagy artériák érfalmerevségét mind a 12 hetes oestradiol terápia előtt, mind pedig utána. Az oestradiol és a placebo készítmények sem okoztak mérhető változást az akut inzulin akció során (glükóz metabolizmus, véráramlás, vagy a nagy artériák Ezen adatok azt demonstrálják, hogy az inzulinnak és az oestradiolnak pontosan meghatározott hemodinamikai hatásai vannak. Az oestradiol fiziológiai adagban növeli a perifériás véráramlást, de nem hat a nagy artériák érfalmerevségére, míg az inzulin fiziológiai koncentrációban akutan csökkenti az érfalmerevséget a perifériás véráramlás megváltoztatása nélkül. Az oestradiol vasculoprotektív hatása feltételezhető, így nem kapcsolható össze az artériás érfalmerevségben és az inzulin szenzitivitásban előforduló módosulásokkal. (J Clin
Endocrinol Metab 2000; 85:4663-4670)
Effect of Estrogen Replacement Therapy on Insulin
Sensitivity of Glucose Metabolism and Preresistance
and Resistance Vessel Function in Healthy
SATU VEHKAVAARA, JUKKA WESTERBACKA, TIINA HAKALA-ALA-PIETILA¨ ,
ANTTI VIRKAMA¨ KI, OUTI HOVATTA, AND HANNELE YKI-JA¨ RVINEN
Department of Medicine (S.V., J.W., A.V., H.Y.-J.), University of Helsinki, 00029 HUCH, Helsinki,
Finland; Minerva Foundation Institute for Medical Research (A.V.), 00250 Helsinki, Finland; Family
Federation of Finland (T.H.-A.-P.), 00100 Helsinki, Finland; and Karolinska Institut, Department of
Obstetrics and Gynaecology (O.H.), Huddinge University Hospital, S-14186 Huddinge, Sweden
In the present study, we hypothesized that estradiol, via its ability
to vasodilate in an endothelium-dependent manner, might enhance
vascular effects of insulin. Basal and insulin-stimulated peripheral
blood flow and resistance, arterial stiffness, and glucose metabolism
were determined in 27 healthy postmenopausal women before and
after 12 weeks of treatment with either transdermal or oral estradiol
or corresponding placebo preparations. Whole body insulin sensitivity
was determined using the euglycemic insulin clamp technique (rate
of continuous insulin infusion 1 mU/kgzmin), forearm blood flow with
a strain-gauge plethysmography, and arterial stiffness using pulse
wave analysis. Estradiol therapy increased basal peripheral blood
flow (1.5 6 0.1 vs. 1.9 6 0.1 mL/dLzmin, 0 vs. 12 weeks; P , 0.01),
decreased peripheral vascular resistance (65 6 3 vs. 52 6 3 mm
Hg/mL/dLzmin, respectively; P , 0.01), and diastolic blood pressure
(78 6 2 vs. 75 6 2 mm Hg, respectively; P , 0.05) but had no effect
on large artery stiffness. Infusion of insulin did not acutely alter
peripheral blood flow but diminished large artery stiffness significantly
both before and after the 12-week period of estradiol therapy.
No measure of acute insulin action (glucose metabolism, blood flow,
or large artery stiffness) was altered by estradiol or placebo treatment.
These data demonstrate that insulin and estradiol have distinct
hemodynamic effects. Physiological doses of estradiol increase peripheral
blood flow but have no effects on large artery stiffness,
whereas physiological concentrations of insulin acutely decrease stiffness
without changing peripheral blood flow. Putative vasculoprotection
by estradiol is, thus, not mediated via alterations in arterial
stiffness or insulin sensitivity. (J Clin Endocrinol Metab 85: 4663–
INSULIN RESISTANCE and its accompanying features
form a cluster that is associated with an increased risk ofcardiovascular morbidity and mortality (1–3). Recent studieshave also demonstrated insulin to have direct vascular actions,which include the ability of insulin to acutely decreasevascular stiffness (4, 5), as measured from a decrease incentral aortic pressure augmentation using pulse wave analysis,and an increase in peripheral blood flow (6). The lattereffect can be blocked by inhibiting nitric oxide synthesis (6,7). Defects in the vascular actions of insulin have been suggestedto provide a novel mechanistic link between insulinresistance and macrovascular disease (8).
Hormone replacement therapy (HRT) seems to have favorableeffects on some aspects of vascular function. Severalstudies have reported improvements in in vivo endothelialfunction, as measured from an increase in flow-mediatedbrachial artery diameter by ultrasound techniques (9 –13). Asthose of insulin, the favorable vascular effects of estradiolmay be mediated via increased synthesis of nitric oxide (14).
Cross-sectional studies (15–17) have also suggested that largeartery stiffness, measured using Doppler techniques (17) orpulse wave analysis (15, 16), is greater in women using HRTthan in nonusers. Withdrawal of HRT has been suggested to increase arterial stiffness (18, 19), but no placebo-controlled
studies have hitherto examined effects of estradiol or HRT on
arterial stiffness. No studies have examined whether estradiol
or HRT alters the sensitivity of blood flow or arterial
stiffness to insulin.
Regarding effects of sex steroids on insulin action on glucose
metabolism, data are complex. Whereas women seem to
be more insulin sensitive than equally fit men (20, 21), effects
of HRT on insulin sensitivity have more often been neutral
or negative than positive. In three studies in which the euglycemic
insulin clamp technique, the golden standard for
measuring whole body insulin sensitivity (22), was used,
insulin sensitivity remained either unchanged (23–25) or
even decreased (25). The decrease was observed in a study
where a high dose of oral estradiol (2 mg) combined with
norethisterone acetate was used as HRT (25). Similarly, in
most other studies that used techniques such as the oral or
the iv glucose tolerance test, or the iv insulin tolerance test,
insulin sensitivity either remained unchanged (23–30) or decreased
(25, 27, 31, 32). In these studies, estradiol was used
Received March 3, 2000. Revision received July 18, 2000. Accepted
August 25, 2000.
Address correspondence and requests for reprints to: Hannele Yki-
Ja¨rvinen, M.D., Department of Medicine, University of Helsinki, P.O.
Box 340, 00029 HUCH, Helsinki, Finland. E-mail: email@example.com.
* Supported by grants from the Academy of Finland (to H.Y.-J. and
S.V.), Novo-Nordisk (to H.Y.-J.), Sigrid Juselius Foundations (to H.Y.-J.),
and Liv och Ha¨lsa (to A.V.).
0021-972X/00/$03.00/0 Vol. 85, No. 12
The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A.
Copyright 2000 by The Endocrine Society
either alone (24, 26, 28–31) or in combination with progestin
(23, 25, 27, 31, 32) and was administered either via the transdermal
(23, 24, 27, 30) or the oral (24 –29) route. There are,
however, also studies that reported improvements in indirect
measures of insulin sensitivity, using both transdermal (30,
31, 33, 34) and oral (32, 33, 35) estrogen preparations.
In the present study, we hypothesized, given the consisted
reports of effects of estradiol on endothelium-dependent
vasodilatation, that it might enhance vascular effects of insulin.
We, therefore, measured actions of insulin on peripheral
blood flow and resistance, arterial stiffness, and glucose
metabolism in 27 postmenopausal women before and after 12
weeks of treatment with either transdermal or oral estradiol
or corresponding placebo preparations.
Subjects and Study Design
Screening visit I (internist). Postmenopausal women were recruited
using a newspaper advertisement and were first
screened for eligibility by an internist (S.V.). To be acceptable
for the study, the subjects had to fulfill the following inclusion
criteria: 1) natural amenorrhea for at least 12 months or
age greater than 52 yr; 2) FSH greater than 30 U/I; 3) no
gynecological or other contraindications for estrogen treatment;
and 4) no evidence of acute or chronic disease based
on history and physical examination and standard laboratory
tests (blood counts, serum creatinine, electrolyte concentrations,
liver function tests, and electrocardiogram).
None of the women used any medications, including vitamins
Screening visit II (gynecologist). A total of 36 women visited a
gynecologist (T.H-A.-P.). A gynecological history was obtained,
and a gynecological examination including transvaginal
ultrasound scan was performed. The size of the uterus
and ovaries and the thickness of the endometrium were
measured, and possible tumors were registered.APap smear
was taken in case it had not been examined or had been
abnormal during the past 12 months or the past 5 yr in case
of hysterectomy. An endometrial biopsy was taken, and
breasts were examined. To be included in the study, the
subjects had to fulfill the following criteria: 1) no suspicion
of gynaecological malignancy; 2) no submucous myomas or
other myomas greater than 4 cm; 3) no endometrial pathology;
4) endometrial thickness less than 6 mm; 5) normal
ovaries (no simple cysts .1.5 cm, no other tumors); and 6)
Of the 36 women attending the first gynecological examination
4 had had a bleeding after the first screening visit.
Two of these women had an endometrial thickness greater
than 6 mm, and two women had a suspicion of an endometrial
polyp. These women were excluded from the study.
Another three subjects were excluded from the study because
of myomas. Two of the subjects did not wish to continue the
study after the first gynecological visit. Thus, the remaining
number of subjects after this visit was 27. All subjects were
amenorrheic. The subjects gave written informed consent to
participate in the study. The experimental protocol was designed
and performed according to the principles of Helsinki
Declaration and was approved by the Ethics Committee of
the Helsinki University Central Hospital.
Randomization and metabolic studies. Subjects considered eligible
to participate in the study were randomly assigned into
three groups by using minimization of differences (calculated
for the variables listed below) between the treatment
groups as the method of randomization (36). The following
variables (relative weight of each variable is given in parentheses)
were included: age (23), body mass index (23), total
cholesterol (1.53), total triglycerides (13), and smoking status
(13). The first group used an oral estradiol tablet of 2 mg
(Estrofem; Novo Nordisk, Bagsværd, Denmark) and a placebo
patch; the second group transdermal estradiol (50 mg/
day) (Menorest; Noven Pharmaceuticals Inc., Miami, FL) and
a placebo tablet; and the third group a placebo patch and a
placebo tablet for 12 weeks. Measurements of insulin sensitivity,
blood flow, and arterial stiffness were performed at 0
and 12 weeks. Because results regarding insulin sensitivity,
blood flow, or arterial stiffness were not dependent on the
route of estradiol administration, results from the transdermal
and oral estradiol groups were pooled, and the combined
group is referred to as estradiol group.
Materials and Methods
Whole body insulin sensitivity and insulin action on forearm blood flow and
arterial stiffness. Whole body insulin sensitivity of glucose metabolism
(the M-value) was determined using the euglycemic insulin clamp technique
(22). The study was performed after an overnight fast starting at
0730 h. Two 18-gauge catheters (Venflon; Viggo-Spectramed, Helsingborg,
Sweden) were inserted as described previously (37). Insulin (rate
of continuous infusion 1 mU/kgzmin) and 20% glucose were infused in
a catheter inserted in the left antecubital vein. The left hand was kept in
a heated chamber (65 C), and arterialized venous blood was withdrawn
from a heated dorsal hand vein. Before and during the 120-min insulin
infusion, metabolic and hemodynamic measurements (pulse wave analysis,
heart rate, blood flow, and vascular resistance) were performed at
30-min intervals, as detailed below. We did not perform a time control
study because we have previously shown that there are no changes in
these hemodynamic or metabolic parameters during a 6-h saline infusion
Pulse wave analysis. The technique of pulse wave analysis was used to
determine central aortic pressure and the augmentation index, a measure
of large artery stiffness (38). All measurements were made from the
radial artery by applanation tonometry using a Millar tonometer (SPC-
301; Millar Instruments, Houston, TX), as described previously (4). Data
were collected directly into a desktop computer and processed withSphygmoCor Blood Pressure Analysis System (BPAS-1; PWV Medical,Sydney, Australia), which allows continuous on-line recording of theradial artery pressure waveform. The radial waveform was assessedvisually to ensure that artifacts from movement and respiration wereminimized. Pulse wave analyses were made basally and every 30 minduring insulin infusion. The mean of three measurements, each consistingof 15–20 sequentially recorded radial artery waveforms, was usedto calculate augmentation and the augmentation index, as well as otherparameters at a given time point. The integral system software was usedto calculate an average radial artery waveform and to generate thecorresponding ascending aortic pressure waveform using a previouslyvalidated transfer factor (39, 40). The aortic waveform was then subjectto further analysis for calculation of aortic augmentation, the augmentationindex, and central blood pressure. The augmentation index iscalculated by dividing augmentation with pulse pressure (38, 41). Assuggested by O’Rourke and Gallagher (38), the radial blood pressurewas calibrated against the sphygmomanometrically determined brachialpressure, ignoring the small degree of amplification between thebrachial and radial sites. All measurements were made by a single4664 VEHKAVAARA ET AL. JCE & M² 2000Vol. 85 ² No. 12operator (S.V.). The measurement of the augmentation index with applanationtonometry has shown to be highly reproducible (42, 43). Thistransfer function is not influenced by gender (44, 45).
Forearm blood flow and peripheral vascular resistance. Forearm blood flowwas measured every 30 min with venous occlusion plethysmographyusing a mercury in silastic rubber strain-gauge apparatus (Model EC-4;Hokanson, Bellevue, WA), a rapid cuff inflator (Rapid Cuff Inflatormodel E20; Hokanson), and computerized analysis of flow curves(MacLab/4e; AD Instruments, Castle Hill, Australia), as described previously(37). Peripheral vascular resistance was calculated by dividingmean arterial pressure in the brachial artery by forearm blood flow.
Other measurements. Fat free mass and the percentage of body fat weredetermined using bioelectrical impedance analysis (BioElectrical ImpedanceAnalyzer System model BIA-101A; RJL Systems, Detroit, MI)(46). Serum free insulin was measured before and at 30-min intervalsduring the insulin infusion by double antibody RIA (Pharmacia InsulinRIA kit; Pharmacia, Uppsala, Sweden) after precipitation with polyethyleneglycol (47). The plasma glucose concentration was measured induplicate with the glucose oxidase method (48) using a Beckman GlucoseAnalyzer II (Beckman Coulter, Inc., Fullerton, CA). Glycosylatedhemoglobin (HbA1c) was measured by high-performance liquid chromatographyusing a fully automated Glycosylated Hemoglobin AnalyzerSystem (Bio-Rad Laboratories, Inc., Richmond, CA). Serum totalcholesterol and triglycerides and high-density lipoprotein cholesterolconcentrations were measured as described previously (49, 50). Lowdensitylipoprotein cholesterol concentration was calculated by the formulaof Friedewald. Serum concentrations of FSH and sex hormonebindingglobulin (SHBG) (AutoDELFIA SHBG; Wallac, Inc., Turku,Finland) were measured by fluoroimmunometric assays (51). Serumestradiol (Estradiol-2; Sorin Biomedica, Saluggia, Italy), estrone (Estrone-RIA; Bu¨ hlman, Scho¨nenbuch, Switzerland), and serum testosterone(Spectria; Orion Diagnostica, Espoo, Finland) concentrations weremeasured by RIA (52). Because estradiol is bound to SHBG and oral, butnot transdermal, estradiol increases SHBG concentrations (53), free estradiolconcentrations were calculated based on serum estradiol, estrone,SHBG, and testosterone concentrations as described by Dunn et al. (54).
Final visit at the gynecologist. After the second insulin sensitivity study,the patients underwent a gynecological examination, including transvaginalultrasound scan. This visit revealed pathology in three patients;one had an endometrial polyp, one a submucous myoma, and one asimple ovarian cyst. All these women were referred for further treatment.
Immediately after stopping the study medication, the women whohad been randomized to either of the hormone treatment groups andwere not hysterectomized received 2mg estradiol (Progynova; ScheringAG, Berlin, Germany) and 15 mg norethisteroneacetate (Primolut N;Schering AG) daily for 12 days to induce bleeding.
Statistical analysisAnalysis of group, time, and group 3 time effects between studygroups were made using ANOVA for repeated measures, followed bythe Bonferroni test. Correlation analyses were performed using Spearman’snonparametric correlation coefficient. The results are expressedas means 6 sem. P values less than 0.05 were considered statisticallysignificant.
Baseline characteristics of the study groups
At baseline the estradiol and placebo groups were comparable
with respect to biological and menopausal ages,
body weight, blood pressure, and circulating concentrations
of glucose, insulin, lipids, and FSH (Table 1). Body weight
remained unchanged in the estradiol (68.562.1 kg vs. 69.16
2.2 kg, 0 vs. 12 weeks) and placebo (67.8 6 2.5 kg vs. 68.3 6
2.6 kg, respectively) groups. Also, waist to hip ratio remained
unchanged in both groups (0.82 6 0.01 vs. 0.82 6 0.01 and
0.83 6 0.02 vs. 0.83 6 0.02, respectively).
Serum estradiol, SHBG, and testosterone concentrations
Serum estradiol concentrations were below the limit of
detection in the placebo group (,20 pmol/L) at 0 and 12
weeks. In the estradiol group, serum total estradiol concentrations
increased from undetectable at baseline to 310 6 40
pmol/L at 12 weeks (P,0.001). Serum SHBG concentrations
remained unchanged in the placebo group (49 6 10 vs. 48 6
9 pmol/L, 0 vs. 12 weeks) but increased in the estradiol group
by 84% from 65 6 6 to 112 6 13 pmol/L at 12 weeks (P ,
0.001). This increase was due to an increase in the oral estradiol
(72 6 11 vs. 168 6 11 nmol/L, 0 vs. 12 weeks, P ,
0.001) group, whereas the concentrations remained unchanged
in the transdermal group (58 6 4 vs. 65 6 7 nmol/L,
0 vs. 12 weeks). Serum free estradiol concentrations increased
from undetectable to 3.160.4 pmol/L in the estradiol group.
Because of the increase in serum SHBG concentrations, serum
free estradiol concentrations were similar in the oral
(3.2 6 0.4 pmol/L) and transdermal (3.1 6 0.5 pmol/L)
groups at 12 weeks. Serum testosterone concentrations remained
unchanged in the estradiol (1.0760.10 vs. 1.0160.09
nmol/L, 0 vs. 12 weeks) and placebo (1.07 6 0.12 vs. 1.01 6
0.09 nmol/L, 0 vs. 12 weeks) groups.
Basal hemodynamic parameters
Peripheral blood flow and vascular resistance (Fig. 1). Basal (measured
before insulin infusion) forearm blood flow (1.5 6 0.1
vs. 1.9 6 0.1 mL/dLzmin, 0 vs. 12 weeks, P , 0.01) increased
significantly in the estradiol group but not in the placebo
group (Fig. 1). In the estradiol group, brachial diastolic blood
pressure also decreased slightly (78 6 2 vs. 75 6 2 mm Hg,
0 vs. 12 weeks, P , 0.05). Consequently, peripheral vascular
resistance decreased significantly (65 6 3 vs. 52 6 3 mm
Hg/(mL/dLzmin), 0 vs. 12 weeks, P , 0.01) in the estradiol
group but not in the placebo group (Fig. 1). Forearm blood
flow increased similarly in the women using oral (1.4 6 0.1
vs. 1.8 6 0.2 mL/dLzmin, 0 vs. 12 weeks, P , 0.05) and
transdermal (1.6 6 0.1 vs. 1.9 6 0.1 mL/dLzmin, 0 vs. 12
weeks, P , 0.05) estradiol. Also, peripheral vascular resis-
TABLE 1. Baseline characteristics of the groups
(n 5 20)
(n 5 7)
Age (yr) 56 61 55 6 1
Weight (kg) 68 62 68 6 2
BMI (kg/m2) 25.1 6 0.6 25.9 6 0.9
Waist/hip ratio 0.82 6 0.01 0.83 6 0.02
SBP (mm Hg) 132 6 4 131 6 7
DBP (mm Hg) 78 62 79 6 4
Smoking (1/ex/2) 11/2/7 4/0/3
Fasting plasma glucose (mmol/L) 5.5 6 0.1 5.3 6 0.1
Fasting serum insulin (mU/L) 5 61 46 1
HbA1C (%) 5.8 6 0.1 5.7 6 0.1
Serum cholesterol (mmol/L) 5.9 6 0.2 5.8 6 0.3
Serum HDL cholesterol (mmol/L) 1.6 6 0.1 1.4 6 0.1
Serum LDL cholesterol (mmol/L) 3.9 6 0.2 3.8 6 0.3
Serum triglycerides (mmol/L) 1.2 6 0.1 1.3 6 0.2
Menopausal age (yr) 51 (48–53) 52 (50-56)Serum FSH (IU/L) 70 65 64 6 9BMI, Body mass index; SBP, systolic blood pressure; DPB, diastolicblood pressure; 1, current smoker; ex, ex-smoker; 2, never smoked.
Data are shown as mean 6 SEM.
ESTRADIOL AND INSULIN SENSITIVITY 4665tance decreased similarly in the women using oral (6365 vs.
50 6 3 mm Hg/(mL/dLzmin), 0 vs. 12 weeks, P , 0.05) andtransdermal (68 6 4 vs. 55 6 6 mm Hg/(mL/dLzmin), 0 vs.
12 weeks, P , 0.05) estradiol. Basal brachial systolic bloodpressure did not decrease in the estradiol group [129 6 4 vs.
12565mmHg,0 vs. 12 weeks; not significant (NS)]. The basalbrachial pulse pressures did not change in the estradiol(50.5 6 3.1 mm Hg vs. 52.6 6 3.3 mm Hg, 0 vs. 12 weeks, NS)or placebo (49.4 6 3.5 mm Hg vs. 50.3 6 4.8 mm Hg, respectively)groups.
Central hemodynamic parametersAortic diastolic blood pressure decreased significantly(79 6 2 vs. 76 6 2 mm Hg, 0 vs. 12 weeks, P , 0.05) in theestradiol group but not in the placebo group (81 6 4 vs. 79 63 mm Hg, 0 vs. 12 weeks, NS). Augmentation (14.6 6 1.7 vs.
13.1 6 1.1 mm Hg, NS, 0 vs. 12 weeks) and aortic systolicblood pressure (data not shown) remained unchanged in theestradiol group. The basal augmentation index (31.261.7 vs.
29.9 6 1.5%, 0 vs. 12 weeks, NS) also remained unchanged inthe estradiol group. Basal aortic systolic and diastolic bloodpressure, augmentation, and the augmentation index remainedunchanged in the placebo group (data not shown).
Insulin action on glucose metabolismFasting plasma glucose concentrations were 5.5 6 0.1 and5.4 6 0.1 mmol/L at 0 and 12 weeks (NS) in the estradiolgroup and 5.3 6 0.1 and 5.6 6 0.1 mmol/L, respectively (NS)in the placebo group. Glycosylated hemoglobin (HbA1C) concentrationsaveraged 5.860.1 and 5.660.1% in the estradiolgroup (0 and 12 weeks) and 5.7 6 0.1 and 5.7 6 0.1% in theplacebo group, respectively (NS for changes betweengroups). Serum free insulin concentrations were 29 6 3 and25 6 3 pmol/L (0 and 12 weeks, NS) in the estradiol groupand 26 6 6 and 28 6 4 pmol/L in the placebo group, respectively(NS). During the insulin infusion, serum free insulinconcentrations averaged at 0 weeks 439 6 12 (30–120min) and at 12 weeks 407617 pmol/L in the estradiol group(NS), and 447 6 22 and 435 6 26 pmol/L in the placebogroup, respectively (NS). During hyperinsulinemia plasmaglucose concentrations were maintained at 4.860.3 mmol/L(30–120 min) at 0 weeks and 5.1 6 0.1 mmol/L at 12 weeksin the estradiol group and at 5.1 6 0.1 and 5.1 6 0.1 mmol/Lin the placebo group, respectively (NS). Whole body insulinsensitivity averaged 4.99 6 0.35 vs. 4.61 6 0.32 mg/kgBWzmin in the estradiol group (0 vs. 12 weeks, NS) and 5.1060.59 vs. 4.80 6 0.56 mg/kg BWzmin in the placebo group,respectively, NS) (Fig. 1).
Insulin action on vascular functionInsulin action on central hemodynamic parameters (Fig. 2). Augmentationwas significantly acutely decreased by insulinwithin 30 min in the estradiol group both at 0 and 12 weeks(Fig. 2). The decrease in augmentation by insulin was notaltered by estradiol treatment (Fig. 2). The augmentationindex was also significantly decreased by insulin within 30min both at 0 and 12 weeks (Fig. 2). The ability of insulin todecrease the augmentation index was not altered by estradioltreatment in the estradiol group (Fig. 2). The response of theaugmentation and augmentation index to insulin were identicalin the placebo group at 0 and 12 weeks (data not shown).
Acute hyperinsulinemia did not change heart rate (62 6 2
vs. 64 6 1 beats/min, basal vs. 30–120 at 0 weeks and 60 6
1 vs. 61 6 1 beats/min, basal vs. 30–120 min at 12 weeks) or
ejection duration (33864 vs. 33763 ms, basal vs. 30–120 min
at 0 weeks and 349 6 4 vs. 340 6 3 ms, basal vs. 30–120 min
FIG. 1. Basal brachial diastolic blood
pressure, basal forearm blood flow,
whole body insulin sensitivity (M-value),
and basal peripheral vascular resistance
in the estradiol and placebo
groups at 0 and 12 weeks. *, P , 0.05;
**, P , 0.01. BW, Body weight.
4666 VEHKAVAARA ET AL. JCE & M² 2000
Vol. 85 ² No. 12
at 12 weeks) in the estradiol or placebo groups (data not
shown). Estradiol therapy also did not change heart rate
(6461 and 6161 beats/min, 0 and 12 weeks, NS) or ejection
duration (337 6 3 and 340 6 3 ms, respectively, NS) during
hyperinsulinemia. These parameters also remained unchanged
in the placebo group (data not shown).
Insulin action on peripheral hemodynamic parameters
Estradiol therapy did not change insulin action on peripheral
blood flow (1.5 6 0.1 vs. 1.5 6 0.1 mL/dLzmin, basal vs.
30–120 min at 0 weeks and 1.960.1 vs. 1.860.1 mL/dLzmin,
basal vs. 30–120 min at 12 weeks) or peripheral vascular
resistance [65 6 6 vs. 65 6 4 mm Hg/(mL/dLzmin), basal vs.
30–120 min at 0 weeks and 52 6 3 vs. 53 6 4 mm Hg/(mL/
dLzmin), basal vs. 30–120 min at 12 weeks] in the estradiol or
placebo groups (data not shown).
In the present study, we determined whether 12 weeks of
estradiol therapy changes basal arterial stiffness, peripheral
vascular resistance, or the effects of insulin on these measures
of vascular function in healthy postmenopausal women. Basally,
estradiol decreased peripheral vascular resistance by
increasing peripheral blood flow, and diastolic blood pressure
also decreased significantly. Estradiol had, however, no
effect on either basal arterial stiffness or on the actions of
insulin on glucose metabolism, peripheral blood flow, or
arterial stiffness. Insulin did not change peripheral blood
flow but did diminish arterial stiffness. These data demonstrate
that physiological concentrations of estradiol and insulin
have different vascular effects and that any putative
cardiovascular benefit of estradiol is not mediated via
changes in insulin sensitivity.
The increase in peripheral blood flow by estradiol in the
present study is consistent with a recent cross-sectional report,
which suggested postmenopausal women to have
lower forearm blood flow and vasodilator reserve than premenopausal
women (55). Acute administration of estradiol
has also been shown to decrease peripheral vascular resistance
via an increase in peripheral blood flow (56). However,
the peak estradiol concentrations were ;10-fold higher than
those observed during chronic therapy. Regarding previous
intervention studies, HRT has repeatedly been shown to
improve endothelium-dependent vasodilatation (9 –13). Because
30–40% of basal forearm blood flow is endotheliumdependent
(57, 58), one would expect HRT to increase not
only blood flow responses to various endothelium-dependent
stimuli but also to increase basal blood flow. In previous
endothelial function studies, basal flow tended to increase in
two studies (10, 11) and was not reported in four studies (12,
13, 59, 60). As an expected consequence of the increase in
blood flow, peripheral vascular resistance and diastolic
blood pressure decreased significantly. This finding is in
keeping with other data according to which estradiol and itsactive metabolite estrone, have either a small depressor (61–64) or no (10, 65) effect on blood pressure.
The present study is the first placebo-controlled study toexamine effects of estradiol on arterial stiffness, as measuredusing the augmentation index (38). Changes in the augmentationindex reflect changes in stiffness provided peripheralvascular resistance, heart rate, and ejection duration all remainunchanged (38, 66). Basally, before the insulin infusion,peripheral blood flow increased and vascular resistance decreasedsignificantly by the 12 weeks of estradiol therapy.
This could be predicted to slightly decrease both augmentationand the augmentation index independent of stiffness,although it is well established that wave reflection mainlyoccurs at reflection points along the arterial tree before resistancevessels (38). The small nonsignificant decrease inaugmentation and the augmentation index support this viewof the anatomical location of reflection sites. Regarding heartrate and ejection duration, both heart rate and ejection durationremained unchanged by estradiol and, thus, did notconfound interpretation of the augmentation index.
In previous cross-sectional studies, postmenopausal estrogenreplacement therapy has been associated with higherFIG. 2. Augmentation and the augmentation index (augmentation/pulse pressure) before and during insulin infusion in the estradiolgroup at 0 and 12 weeks. Euglycemia was maintained with the use ofthe insulin clamp technique. *, P , 0.05; **, P , 0.01; and ***, P ,0.001 for change in augmentation or augmentation index at a giventime point vs. 0 min.
ESTRADIOL AND INSULIN SENSITIVITY 4667common carotid artery distensibility (67– 69) and loweraorto-femoral and leg pulse-wave velocity (19), with no differencesin brachial pulse-wave velocity (16) and commoncarotid artery distensibility (68). In another cross-sectionalstudy, central arterial compliance was similar in nonsmokingwomen using HRT and in those not using HRT. However,among smoking women, users of HRT had higher compliancethan nonusers (68). The present study does not excludethe possibility that estradiol has beneficial effects on arterialstiffness in postmenopausal women with elevated cardiovascularrisk. Also, the effects of progestins were not examinedin this study. Regarding intervention studies, Waddellet al. (18) measured systemic arterial compliance and pulsewave velocity in postmenopausal women on and 4 weeks offHRT. Systemic arterial compliance decreased after discontinuationof HRT. This decrease did not seem to be due to achange in large artery compliance because the aorto-femoralpulse wave velocity remained unchanged while pulse wavevelocity in the femoral-dorsalis pedis region increased significantlyin response to cessation of HRT. In view of thepresent data, the latter might have been due to an increasein peripheral vascular resistance.
During insulin infusion, peripheral blood flow and vascularresistance remained unchanged. This finding is consistentwith previous data demonstrating insulin to be a slowand relatively weak vasodilatator compared with classic endothelium-dependent vasodilatators (70, 71). Even so, theblood flow response to the classic agents such as acetylcholineis markedly enhanced by low concentrations of insulin(72). Given that both insulin (7, 73) and estradiol (74 –77)vasodilate via an endothelium-dependent mechanism, itseemed reasonable to hypothesize that estradiol and insulinhave additive or even synergistic effects on peripheral bloodflow. An additive effect was observed because blood flow was higher during hyperinsulinemia after than before insulintherapy. This effect could, however, be entirely attributedto the estradiol induced increase in basal blood flow.
We have previously demonstrated temporal dissociationbetween the effect of insulin on wave reflection and its effecton peripheral blood flow (4), and also that these actions ofinsulin are blunted in insulin-resistant obese subjects (5). Inboth of these studies, which were performed in younghealthy volunteers, insulin markedly reduced wave reflectionwithin 1 h whereas peripheral blood flow did not changesignificantly until after 2 h at an insulin infusion rate, whichwas twice that used in the present study (4). In keeping withstiffening of arteries by aging (78), the effect of insulin on theaugmentation index was much smaller in the postmenopausalwomen than in the young volunteers studied previously(4). The ability of insulin to acutely diminish stiffnessremained, however, unchanged during estradiol therapy.
Although, and as discussed above, acute administration oflarge doses of estradiol diminishes stiffness, the present datasuggest that this does not happen with physiological dosesof estradiol and also that such doses also do not potentiatethe ability of insulin to diminish stiffness.
A recent analysis of the European Group for the Study ofInsulin Resistance of the relationship between age and insulinsensitivity of glucose metabolism in 320 women foundno difference in insulin sensitivity, measured using the euglycemicinsulin clamp technique, between women with amean age of 45 yr (n 5 76) and those aged 65 yr (n 5 88) (79).
Although no information of use of HRT was available, thesedata suggest that no abrupt change in insulin sensitivityoccurs at menopause. Most (80, 81), although not all (32),studies directly comparing insulin sensitivity between preandpostmenopausal women are compatible with thisconclusion. Effects of HRT on insulin sensitivity of glucosemetabolism have previously been examined in three placebocontrolledstudies using the clamp technique. The presentnegative findings of effects of 2 mg oral estradiol or 50 mgtransdermal estradiol on insulin stimulated glucose uptakeadd to the list of other negative studies which used either 100mg transdermal estradiol or 1.25 mg oral conjugated estrogen(24), 50mg transdermal estradiol and oral norethisterone (23),or continuous combined oral estradiol/norethisterone acetate(25). A limitation of our study is the relatively smallnumber of subjects studied, although when subdivided intosubjects using transdermal and oral estradiol similar to theprevious clamp-studies (23, 24). If we assume that the size ofdata groups is doubled (40 1 14 subjects) and that in subsequentclamps insulin sensitivity improves in each estradiol-treated subject by 25% and that in the placebo groupM-values either increase or decrease by 5%, which is thereproducibility of the clamp technique (82), we would still beunable to detect a significant difference in the change ininsulin sensitivity between the estradiol and placebo groups.
In conclusion, physiological doses of estradiol increaseperipheral blood flow, decrease peripheral vascular resistanceand diastolic blood pressure, but have no effect onarterial stiffness. Insulin at a dose of 1 mU/kgzmin did notalter peripheral blood flow, but diminished large artery stiffnesssignificantly. Estradiol does not change either insulinsensitivity of glucose metabolism or the vascular effects ofinsulin, indicating that cardioprotective effects of estradiolare not mediated via changes in insulin sensitivity or arterialstiffness.
Wegratefully acknowledge Ms. Kati Tuomola and Ms. Sari Haapanen
for excellent technical assistance.
1. Pyora¨la¨ M, Miettinen H, Laakso M, Pyora¨la¨ K. 1998 Hyperinsulinemia and
the risk of stroke in healthy middle-aged men: the 22-year follow-up results
of the Helsinki Policemen Study. Stroke. 29:1860 –1866.
2. Balkau B, Bertrais S, Ducimetiere P, Eschwege E. 1999 Is there a glycemic
threshold for mortality risk? Diabetes Care. 22:696–699.
3. Ruige JB, Assendelft WJ, Dekker JM, Kostense PJ, Heine RJ, Bouter LM. 1998
Insulin and risk of cardiovascular disease: a meta-analysis. Circulation.
4. Westerbacka J, Wilkinson I, Cockcroft J, Utriainen T, Vehkavaara S, Yki-
Ja¨rvinen H. 1999 Diminished wave reflection in the aorta. A novel physiological
action of insulin on large blood vessels. Hypertension. 33:1118 –1122.
5. Westerbacka J, Vehkavaara S, Bergholm R, Wilkinson I, Cockcroft J, Yki-
Ja¨rvinen H. 1999 Marked resistance of the ability of insulin to decrease arterial
stiffness characterizes human obesity. Diabetes. 48:821– 827.
6. Laakso M, Edelman SV, Brechtel G, Baron AD. 1990 Decreased effect of
insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism
for insulin resistance. J Clin Invest. 85:1844 –1852.
7. Scherrer U, Randin D, Vollenweider P, Vollenweider L, Nicod P. 1994 Nitric
oxide release accounts for insulin’s vascular effects in humans. J Clin Invest.
8. Jiang ZY, Lin YW, Clemont A, et al. 1999 Characterization of selective resis-
4668 VEHKAVAARA ET AL. JCE & M² 2000
Vol. 85 ² No. 12
tance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin
Invest. 104:447– 457.
9. Bush DE, Jones CE, Bass KM, Walters GK, Bruza JM, Ouyang P. 1998
Estrogen replacement reverses endothelial dysfunction in postmenopausal
women. Am J Med. 104:552–558.
10. Lieberman EH, Gerhard MD, Uehata A, et al. 1994 Estrogen improves endothelium-
dependent, flow-mediated vasodilatation in postmenopausal
women. Ann Intern Med. 121:936 –941.
11. Koh KK, Cardillo C, Bui MN, et al. 1999 Vascular effects of estrogen and
cholesterol-lowering therapies in hypercholesterolemic postmenopausal
women. Circulation. 99:354 –360.
12. Herrington DM, Werbel BL, Riley WA, Pusser BE, Morgan TM. 1999 Individual
and combined effects of estrogen/progestin therapy and lovastatin on
lipids and flow-mediated vasodilation in postmenopausal women with coronary
artery disease. J Am Coll Cardiol. 33:2030 –2037.
13. Gerhard M, Walsh BW, Takawol A, et al. 1998 Estrogen therapy combined
with progesterone and endothelium-dependent vasodilatation in postmenopausal
women. Circulation. 98:1158 –1163.
14. Guetta V, Quyyumi AA, Prasad A, Panza JA, Waclawiw M. 1997 The role of
nitric oxide in coronary vascular effects of estrogen in postmenopausal women.
15. Teede HJ, Liang YL, Shiel LM, McNeil JJ, McGrath BP. 1999 Hormone
replacement therapy in postmenopausal women protects against smokinginduced
changes in vascular structure and function. J Am Coll Cardiol.
16. Hayward CS, Knight DC, Wren BG, Kelly RP. 1997 Effect of hormone replacement
therapy on non-invasive cardiovascular haemodynamics. J Hypertens.
17. Penotti M, Farina M, Castiglioni E, et al. 1996 Alteration in the pulsatility
index values of the internal carotid and middle cerebral arteries after suspension
of postmenopausal hormone replacement therapy: a randomized crossover
study. Am J Obstet Gynecol. 175:606–611.
18. Waddell TK, Rajkumar C, Cameron JD, Jennings GL, Dart AM, Kingwell
BA. 1999 Withdrawal of hormonal therapy for 4 weeks decreases arterial
compliance in postmenopausal women. J Hypertens. 17:413– 418.
19. Rajkumar C, Kingwell BA, Cameron JD, et al. 1997 Hormonal therapy increases
arterial compliance in postmenopausal women. J Am Coll Cardiol.
20. Yki-Ja¨rvinen H. 1984 Sex and insulin sensitivity. Metabolism. 33:1011–1015.
21. Nuutila P, Knuuti MJ, Ma¨ki M, et al. 1995 Gender and insulin sensitivity in
the heart and in skeletal muscles. Studies using positron emission tomography.
22. DeFronzo RA, Tobin JD, Andres R. 1979 Glucose clamp technique: a method
for quantifying insulin secretion and resistance. Am J Physiol. 237:E214–E223.
23. Duncan AC, Lyall H, Roberts RN, et al. 1999 The effect of estradiol and a
combined estradiol/progestagen preparation on insulin sensitivity in healthy
postmenopausal women. J Clin Endocrinol Metab. 84:2402–2407.
24. O’Sullivan AJ, Ho KK. 1995 A comparison of the effects of oral and transdermal
estrogen replacement on insulin sensitivity in postmenopausal women.
J Clin Endocrinol Metab. 80:1783–1788.
25. Kimmerle R, Heinemann L, Heise T, et al. 1999 Influence of continuous
combined estradiol-norethisterone acetate preparations on insulin sensitivity
in postmenopausal nondiabetic women. Menopause. 6:36–42.
26. Brussaard HE, Gevers Leuven JA, Fro¨ lich M, Kluft C, Krans HMJ. 1997
Short-term oestrogen replacement therapy improves insulin resistance, lipids
and fibrinolysis in postmenopausal women with NIDDM. Diabetologia.
27. Godsland IF, Gangar K, Walton C, et al. 1993 Insulin resistance, secretion, and
elimination in postmenopausal women receiving oral or transdermal hormone
replacement therapy. Metabolism. 42:846–853.
28. Andersson B, Mattsson L-Å, Hahn L, et al. 1997 Estrogen replacement therapy
decreases hyperandrogenicity and improves glucose homeostasis and plasma
lipids in postmenopausal women with noninsulin-dependent diabetes mellitus.
J Clin Endocrinol Metab. 82:638–643.
29. Cagnacci A, Tuveri F, Cirillo R, Setteneri AM, Melis GB, Volpe A. 1997 The
effect of transdermal 17-beta-estradiol on glucose metabolism of postmenopausal
women is evident during the oral but not the intravenous glucose
administration. Maturitas. 28:163–167.
30. Cagnacci A, Soldano R, Carriero PL, Paoletti AM, Fioretti P, Melis GB. 1992
Effects of low doses of transdermal 17-b-estradiol on cardohydrate metabolism
in postmenopausal women. J Clin Endocrinol Metab. 74:1396 –1400.
31. Lindheim SR, Duffy DM, Kojima T, Vijod MA, Stanczyk FZ, Lobo RA. 1994
The route of administration influences the effect of estrogen on insulin sensitivity
in postmenopausal women. Fertil Steril. 62:1176 –1180.
32. Lindheim SR, Presser SC, Ditkoff EC, Vijod MA, Stanczyk FZ, Lobo RA.
1993 A possible bimodal effect of estrogen on insulin sensitivity in postmenopausal
women and the attenuating effect of added progestin. Fertil Steril.
33. Colacurci N, Zarcone R, Mollo A, et al. 1998 Effects of hormone replacement
therapy on glucose metabolism. Panminerva Med. 40:18 –21.
34. Raudaskoski T, Tomas C, Laatikainen T. 1999 Insulin sensitivity during
postmenopausal hormone replacement with transdermal estradiol and intrauterine
levonorgestrel. Acta Obstet Gynecol Scand. 78:540 –545.
35. Lindheim SR, Buchanan TA, Duffy DM, et al. 1994 Comparison of estimates
of insulin sensitivity in pre- and postmenopausal women using the insulin
tolerance test and the frequently sampled intravenous glucose tolerance test.
J Soc Gynecol Investig. 1:150 –154.
36. Taves DR. 1974 Minimization: a new method of assigning patients to treatment
and control groups. Clin Pharmacol Ther. 15:443– 453.
37. Utriainen T, Malmstrom R, Ma¨kimattila S, Yki-Ja¨rvinen H. 1995 Methodological
aspects, dose-response characteristics and causes of interindividual
variation in insulin stimulation of limb blood flow in normal subjects. Diabetologia.
38. O’Rourke MF, Gallagher DE. 1996 Pulse wave analysis. J Hypertens Suppl.
39. Karamanoglu M, O’Rourke MF, Avolio AP, Kelly RP. 1993 An analysis of the
relationship between central aortic and peripheral upper limb pressure waves
in man. Eur Heart J. 14:160 –167.
40. Chen CH, Nevo E, Fetics B, et al. 1997 Estimation of central aortic pressure
waveform by mathematical transformation of radial tonometry pressure. Validation
of generalized transfer function. Circulation. 95:1827–1836.
41. Kelly R, Hayward C, Avolio A, O’Rourke M. 1989 Noninvasive determination
of age-related changes in the human arterial pulse. Circulation. 80:1652–1659.
42. Wilkinson IB, Fuchs SA, Jansen IM, et al. 1998 Reproducibility of pulse wave
velocity and augmentation index measured by pulse wave analysis. J Hypertens.
43. Liang YL, Teede H, Kotsopoulos D, et al. 1998 Non-invasive measurements
of arterial structure and function: repeatability, interrelationships and trial
sample size. Clin Sci. 95:669–679.
44. Nichols WW, O’Rourke M. 1998 McDonald’s blood flow in arteries. Theoretical,
experimental and clinical principles. London: Arnold; 461–466.
45. Gallagher DE. 1993 Analysis of Pressure Wave Propagation in the Human
Upper Limb: Physical Determinants and Clinical Applications, Ph.D. Thesis,
University of New South Wales, Australia.
46. Lukaski HC, Johnson PE, Bolonchuk WW, Lykken GI. 1985 Assessment of
fat-free mass using bioelectrical impedance measurements of the human body.
Am J Clin Nutr. 41:810–817.
47. Desbuquois B, Aurbach GD. 1971 Use of polyethylene glycol to separate free
and antibody-bound peptide hormones in radioimmunoassay. J Clin Endocrinol
48. Kadish AH, Little RL, Sternberg JC. 1968 A new and rapid method for the
determination of glucose by measurement of rate of oxygen consumption. Clin
Chem. 14:116 –131.
49. Yki-Ja¨rvinen H, Ryysy L, Kauppila M, et al. 1997 Effect of obesity on the
response to insulin therapy in noninsulin-dependent diabetes mellitus. J Clin
Endocrinol Metab. 82:4037– 4043.
50. Gidez LJ, Miller GJ, Burstein M, Eder HA. 1998 Analysis of plasma high
density lipoprotein subclasses by a precipitation procedure: correlation with
preparative and analytical ultracentrifugation. In: Lippel K, ed. Report of the
high density lipoprotein methodology workshop. Bethesda, MD: NIH publication
no. 79-661; 328–340.
51. Hemmila¨ I, Dakubu S, Mukkala V-M, Siitari H, Lo¨vgren T. 1984 Europium
as a label in time-resolved immunofluorometric assays. Atherosclerosis.
52. Mertens R, Liedke RJ, Batjer JD. 1983 Evaluation of radioimmunoassay for
estradiol in unextracted serum. Clin Chem. 31:359 –370.
53. Campagnoli C, Biglia N, Altare F, et al. 1993 Differential effects of oral
conjugated estrogens and transdermal estradiol on insulin-like growth factor
1, growth hormone and sex hormone binding globulin serum levels. Gynecol
54. Dunn JF, Nisula BC, Rodbard D. 1981 Transport of steroid hormones: binding
of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-
binding globulin in human plasma. J Clin Endocrinol Metab. 53:58–68.
55. Mercuro G, Longu G, Zoncu S, Cherchi A. 1999 Impaired forearm blood flow
and vasodilator reserve in healthy postmenopausal women. Am Heart J.
56. Volterrani M, Rosano G, Coats A, Beale C, Collins P. 1995 Estrogen acutely
increases peripheral blood flow in postmenopausal women. Am J Med.
57. Vallance P, Collier J, Moncada S. 1989 Effects of endothelium derived nitric
oxide on peripheral arterial tone in man. Lancet. 997–1000.
58. Calver A, Collier J, Moncada S, Vallance P. 1992 Effect of local intra-arterial
NG-monomethyl-l-arginine in patients with hypertension: the nitric oxide
dilator mechanism appears abnormal. J Hypertens. 10:1025–1031.
59. Gilligan DM, Badar DM, Panza JA, Quyyumi AA, Cannon III RO. 1995
Effects of estrogen replacement therapy on peripheral vasomotor function in
postmenopausal women. Am J Cardiol. 75:264 –268.
60. Cagnacci A, Modena MG, Malmusi S, Muia N, Volpe A. 1999 Effect of
prolonged administration of transdermal estradiol on flow-mediated endothelium-
dependent and endothelium-independent vasodilation in healthy
postmenopausal women. Am J Cardiol. 84:367–370.
61. Lind T, Cameron EC, Hunter WM, et al. 1979 A prospective, controlled trial
ESTRADIOL AND INSULIN SENSITIVITY 4669
of six forms of hormone replacement therapy given to postmenopausal
women. Br J Obstet Gynaecol. 86(Suppl 3):1–29.
62. Wren BG, Routledge AD. 1983 The effect of type and dose of oestrogen on the
blood pressure of postmenopausal women. Maturitas. 5:135–142.
63. Luotola H. 1983 Blood pressure and hemodynamics in postmenopausal
women during estradiol-17b substitution. Ann Clin Res. 15(Suppl 38):1–121.
64. Akkad AA, Halligan AW, Abrams K, al-Azzawi F. 1997 Differing responses
in blood pressure over 24 hours in normotensive women receiving oral or
transdermal estrogen replacement therapy. Obstet Gynecol. 89:97–103.
65. Hassager C, Christiansen C. 1988 Blood pressure during oestrogen/progestogen
substitution therapy in healthy post-menopausal women. Maturitas.
66. Nichols WW, O’Rourke MF. 1998 McDonald’s blood flow in arteries: Theoretical,
experimental and clinical principles. London: Arnold; 215–219.
67. Liang YL, Teede H, Shiel LM, et al. 1997 Effects of oestrogen and progesterone
on age-related changes in arteries of postmenopausal women. Clin Exp Pharmacol
Physiol. 24:457– 459.
68. McGrath BP, Liang YL, Teede H, Shiel LM, Cameron JD, Dart A. 1998
Age-related deterioration in arterial structure and function in postmenopausal
women: impact of hormone replacement therapy. Arterioscler Thromb Vasc
Biol. 18:1149 –1156.
69. Nagai Y, Earley CJ, Kemper MK, Bacal CS, Metter EJ. 1999 Influence of age
and postmenopausal estrogen replacement therapy on carotid arterial stiffness
in women. Cardiovasc Res. 41:307–311.
70. Ma¨kimattila S, Virkama¨ki A, Groop P-H, et al. 1996 Chronic hyperglycemia
impairs endothelial function and insulin sensitivity via different mechanisms
in insulin-dependent diabetes mellitus. Circulation. 94:1276 –1282.
71. Yki-Ja¨rvinen H, Utriainen T. 1998 Insulin-induced vasodilatation: physiology
or pharmacology? Diabetologia. 41:369 –379.
72. Taddei S, Virdis A, Mattei P, Natali A, Ferrannini E, Salvetti A. 1995 Effect
of insulin on acetylcholine-induced vasodilatation in normotensive subjects
and patients with essential hypertension. Circulation. 92:2911–2918.
73. Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD.
1996 Obesity/insulin resistance in associated with endothelial dysfunction.
Implications for the syndrome of insulin resistance. J Clin Invest.
74. Reis SE, Gloth ST, Blumenthal RS, et al. 1994 Ethinyl estradiol acutely
attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal
women. Circulation. 89:52– 60.
75. Gilligan DM, Quyyumi AA, Cannon III RO, Johnson GB, Schenke WH. 1994
Effects of physiological levels of estrogen on coronary vasomotor function in
postmenopausal women. Circulation. 89:2545–2551.
76. Collins P, Rosano GMC, Sarrel PM, et al. 1995 17b-estradiol attenuates acetylcholine-
induced coronary arterial constriction in women but not men with
coronary heart disease. Circulation. 92:24 –30.
77. GilliganDM,BadarDM,Panza JA, Quyyumi AA, Cannon III RO. 1994 Acute
vascular effects of estrogen in postmenopausal women. Circulation.
78. Kelly R, Hayward C, Avolio A, O’Rourke M. 1989 Noninvasive determination
of age-related changes in the human arterial pulse. Circulation.
79. Iozzo P, Beck-Nielsen H, Laakso M, Smith U, Yki-Ja¨rvinen H, Ferrannini E.
1999 Independent influence of age on basal insulin secretion in nondiabetic
humans. European Group for the Study of Insulin Resistance J Clin Endocrinol
Metab. 84:863– 868.
80. O’Shaughnessy IM, Kasdorf GM, Hoffmann RG, Kalkhoff RK. 1992 Does
aging intensify the insulin resistance of human obesity? J Clin Endocrinol
81. Walton C, Godsland IF, Proudler AJ, Wynn V, Stevenson JC. 1993 The effects
of the menopause on insulin sensitivity, secretion and elimination in nonobese,
healthy women. Eur J Clin Invest. 23:466–473.
82. Yki-Ja¨rvinen H. 1984 Insulin sensitivity during the menstrual cycle. J Clin
Endocrinol Metab. 59:350 –353.
4670 VEHKAVAARA ET AL. JCE & M² 2000
Vol. 85 ² No. 12
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