The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 1 251-253
Copyright © 1997 by The Endocrine Society
Effect of Tibolone on Glucose and Lipid Metabolism in Postmenopausal Women
Angelo Cagnacci,
Elisabetta Mallus,
Federica Tuveri,
Rocco Cirillo,
Anna Maria Setteneri and
Gian Benedetto Melis
Institute of Obstetrics and Gynecology (A.C., E.M., F.T., G.B.M.),
Institute of Internal Medicine (R.C., A.M.S.), University of Cagliari,
09124 Cagliari, Italy
Address all correspondence and requests for reprints to: Angelo Cagnacci, M.D., Istituto di Fisiopatologia della Riproduzione Umana, Università di Modena, via del Pozzo 71, 41100 Modena, Italy.
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Abstract
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The effect of tibolone, a new therapeutic agent for menopause, on
glucose and lipid metabolism was investigated in 11 healthy
postmenopausal women. At baseline and after 3 months of tibolone
administration (2.5 mg/day), glucose metabolism was evaluated in each
subject using both an oral glucose tolerance test (75 g) and the
minimal model method of a frequently sampled intravenous glucose
tolerance test. Frequently sampled intravenous glucose tolerance test
allows the calculation of insulin sensitivity and peripheral glucose
use independent of insulin. High-density lipoprotein-cholesterol, total
cholesterol, apoprotein-A, and apoprotein-B measured in fasting
conditions were not modified by tibolone, whereas triglycerides were
reduced significantly (P < 0.01). Fasting levels
of glucose were reduced significantly (P < 0.025),
whereas those of insulin, C-peptide, and the C-peptide/insulin ratio
were not modified. Glucose, insulin, C-peptide, and the
C-peptide/insulin ratio responses to oral or iv glucose were not
modified. Insulin sensitivity was inversely correlated to body mass
index, and independent on that body mass index was significantly
enhanced (P < 0.01). Glucose utilization
independent of insulin was not modified. The present data indicate that
tibolone does not negatively influence glucose metabolism and may
indeed improve both the peripheral tissue sensitivity to insulin and
the lipid profile.
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Introduction
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TIBOLONE is a synthetic steroid
[(7
, 17)-17
hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one]
with estrogenic, and to a lesser extent, progestogenic and androgenic
properties (1). In postmenopausal women, administration of tibolone
reduces gonadotropin secretion (2), improves climacteric complaints (3, 4), and prevents the decline (5) (and even increases) bone mineral
density (6) without inducing the recurrence of menstrual bleedings (2, 7, 8). Tibolone does not negatively influence blood pressure (8, 9) or
coagulation (2, 10) and decreases serum levels of Lipoprotein (a) (11)
and triglycerides (12, 13, 14). On the other hand, it induces a transient
decrease in apoprotein-A (Apo-A) (11) and high-density lipoprotein
(HDL)-cholesterol (12, 13, 14), and it has been reported to deteriorate the
glucose response to an oral load of glucose (12). Because alterations
in glucose metabolism, with an elevation in insulin levels, represent
an independent risk factor for cardiovascular diseases (15),
particularly in women (16), the effect of tibolone on glucose
metabolism and on lipid profile was further investigated.
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Materials and Methods
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Eleven healthy women, 52–57 yr of age, gave their informed
consent to the study, which was previously approved by our local
ethical committee. All women were in natural menopause for at least 1
yr and with FSH and estradiol E2 levels higher than 50 IU/L and lower
than 73.4 pmol/L (20 pg/mL), respectively. All women were free from
medications, including hormones, for at least 3 months. None of the
subjects had a family or personal history of glucose or lipid
alterations. All women were instructed to consume more than 200 g/day
carbohydrate in their diet for the 3 days before testing. After an
overnight fast of 12 h, each woman was admitted to the hospital at
0700 h on 2 consecutive days. Glucose metabolism was investigated
by both an oral glucose tolerance test (OGTT) and the minimal model
method (of a frequently sampled intravenous glucose tolerance test)
(17) performed on 2 consecutive days in a randomized order.
For the OGTT, a polyethylene catheter inserted in an antecubital vein
was kept patent by a slow infusion of saline solution. A glucose load
of 75 g was given orally at 0900 h. Samples of arterialized
blood, obtained by forearm warming, were collected at times -30, 0,
15, 30, 60, 90, 120, and 180 min after glucose administration.
For the FSIGT, two polyethylene catheters placed in two antecubital
veins were kept patent by a slow infusion of saline solution. One
catheter was used for iv glucose or insulin administration and the
other for blood collection. At 0900 h, glucose (0.3 g/kg) was
injected over 1 min iv and was followed 20 min later by an iv insulin
bolus (0.03 U/kg). Samples of arterialized blood were collected at
times -15, -10, -5, -1, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 20,
22, 23, 24, 25, 27, 30, 40, 60, 70, 80, 90, 100, 120, 160, and 180 min
after glucose loading.
Each woman was assigned to receive 2.5 mg/day tibolone orally and,
after 3 months of treatment, was submitted to the same investigation
procedures.
Blood samples, collected on ice into heparinized glass tubes, were
centrifuged immediately. An aliquot of plasma was tested immediately
for glucose levels, whereas another aliquot was frozen immediately to
-25 C until assayed. Glucose was determined by the glucose oxidase
method. Insulin levels were assayed in duplicate in all samples by a
RIA using commercial kits (Biodata, Guidonia Montecelio, Roma, Italy)
with intra- and interassay coefficients of variation of 6.2% and 7%,
respectively, and sensitivity of 14.35 pmol/L. C-peptide levels were
analyzed in duplicate in all OGTT samples, and, in the samples
collected in the first 20 min of FSIGT, by commercial RIA kits
(Biodata, Guidonia Montecelio, Roma, Italy) with intra- and interassay
coefficients of variation of 3.2% and 8.5%, respectively, and
sensitivity of 33.1 pmol/L. Circulating levels of total cholesterol and
triglycerides were measured by enzymatic methods (Olympus),
HDL-cholesterol was determined after precipitation with Peg 6000, and
Apo-A and Apo-B were determined by immunonephelometry on a Behring
Nephelometer Analyser (Behringwerke Marburg). To avoid interassay
variability, samples of each subject were analyzed in the same assay.
Circulating levels of estradiol, progesterone, androstenedione,
testosterone, and DHEAS also were analyzed in baseline samples by
RIA.
Responses of glucose, insulin, and C-peptide observed during OGTT and
in the first 20 min of FSIGT were reported as absolute values and as
area under the curve, calculated by the trapezoid method and expressed
in arbitrary units (pmol/L x min). To have an index of hepatic
insulin clearance, the C-peptide/insulin ratio of absolute and
integrated values also was calculated (18). Glucose and insulin values
obtained during FSIGT were used to calculate a computerized algorithm
(MINMOD) the sensitivity of glucose elimination to insulin (Si), which
is inversely related to insulin resistance and glucose-dependent
glucose elimination (Sg). Si was expressed in units x
10-4/min x µU/mL, and Sg in units x
10-4/min.
Statistical analysis of the results was performed by the t
test for paired data. Two-way ANOVA for repeated measures
(treatment x time, with subjects as replicates) also was used to
evaluate differences in glucose or hormone responses to OGTT in first
20 min of FSIGT. The relationship of Si values to body mass index (BMI;
Kg/m2) were statistically compared using linear regression
analysis. All the results are expressed as the mean ±
SE.
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Results
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Circulating levels of estradiol, progesterone, testosterone,
androstenedione, and DHEAS were in the normal range for postmenopausal
women and were not modified by treatment (data not shown). BMI did not
vary during tibolone administration (23.1 ± 0.7 vs.
23.2 ± 0.6). The levels of HDL-cholesterol (1.18 ± 0.1
mmol/L vs. 1.11 ± 0.1 mmol/L), total cholesterol
(4.62 ± 0.34 mmol/L vs. 4.28 ± 0.32 mmol/L), and
the HDL-cholesterol/total cholesterol ratio (0.27 ± 0.04 mmol/L
vs. 0.28 ± 0.04 mmol/L) were not modified by tibolone
administration, as well as the levels of Apo-A (247.6 ± 18.9
mg/dL vs. 208.2 ± 19.0 mg/dL), Apo-B (78.9 ±
9.27 mg/dL vs. 79.4 ± 9.9 mg/dL) and the Apo-A/Apo-B
ratio (3.59 ± 0.76 mg/dL vs. 2.91 ± 0.37 mg/dL).
By contrast, triglyceride levels were significantly decreased from
0.9 ± 0.07 mmol/L to 0.65 ± 0.06 mmol/L (-27.3 ±
4.7%; P < 0.01).
In all subjects, at baseline, the glucose response to OGTT was within
the normal range. Tibolone significantly reduced fasting levels of
glucose (4.49 ± 0.18 mmol/L vs. 4.16 ± 0.19
mmol/L; P < 0.025) but did not influence the fasting
levels of insulin (58.9 ± 10.7 pmol/L vs. 56.6 ±
7.3 pmol/L) and C-peptide (287.6 ± 33.3 pmol/L vs.
258.7 ± 17.9 pmol/L). Absolute levels (Fig. 1
)
or integrated values (Table 1) of
glucose, insulin, C-peptide, and the C-peptide/insulin ratio (evaluated
during OGTT or the first 20 min of FSIGT) were not modified by tibolone
administration.
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Figure 1. Mean (± SE) glucose, insulin,
C-peptide, C-peptide/insulin responses to an OGTT (on the
left) or to the iv administration of glucose (30 mg/kg) in
the first 20 min of FSIGT (on the right), observed in 11
postmenopausal women at baseline (open circles) and after 3
months of treatment with tibolone (2.5 mg/day; closed
circles). Arrows indicate time of glucose
administration.
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View this table:
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Table 1. Integrated values (units x min; AUC) of
glucose, insulin, C-peptide, and C-peptide/insulin ratio during OGTT
(75 g) or first 20 min of FSIGT observed in 11 postmenopausal women
before and after 3 months of tibolone administration (2.5 mg/day)
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Si, but not Sg, evaluated by FSIGT, was inversely correlated with BMI
(r = 0.803; P < 0.01) and independent of BMI,
was significantly increased during tibolone administration from
4.8 ± 0.6 to 7.4 ± 3.5 (+62.8 ± 15.7%;
P < 0.01). By contrast, Sg values remained
unmodified (0.031 ± 0.004 vs. 0.032 ±
0.005).
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Discussion
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The present data confirm previous reports on the effect of
tibolone on lipid metabolism (11, 12, 13, 14). Although we were unable to
document a negative influence of tibolone on HDL-cholesterol/total
cholesterol ratio (12, 13), the observed reduction in triglyceride
levels confirms previous reports (12, 13, 14). Elevated triglycerides may
represent a risk factor for cardiovascular diseases (19), and their
tibolone-induced decline might be beneficial. Oral estrogens increase
triglycerides along with an increase in HDL-cholesterol and a decrease
in total cholesterol levels (18, 20), and all these actions are
antagonized by progestogens (20, 21). The effect of tibolone on lipid
metabolism is in agreement with its mixed estrogenic-progestogenic
properties and a prevalence of the latter on the former.
In a previous double-blind cross-over study, a slight deterioration of
glucose response to OGTT was reported in women treated with tibolone in
comparison with those treated with placebo (12). However, posttreatment
data were not compared with a baseline investigation, and both insulin
and C-peptide levels were not measured. In the present study, we were
not able to show any negative effect of tibolone on glucose metabolism.
Because progestogens (22, 23) reduce peripheral insulin sensitivity,
the observed improvement induced by tibolone was somewhat unexpected.
It is possible that the progestogenic effect is mainly exerted in
tissues, such as the endometrium or the liver (24), where tibolone is
locally metabolized in potent progestogenic derivatives. In peripheral
tissues devoid of this capability, tibolone may act predominantly as an
estrogen. Indeed, the administration of 0.625 mg/day of conjugated
estrogens (like tibolone) to postmenopausal women decreases fasting
glucose levels (18) and improves peripheral tissue sensitivity to
insulin (22). The capability of tibolone to reduce triglyceride levels
may represent an additional mechanism of action on glucose metabolism,
because triglycerides have been reported to negatively influence
peripheral tissue sensitivity to insulin (25).
Good compliance, because of the absence of menstrual bleedings,
clinical efficacy, and the herein demonstrated metabolic safety, make
tibolone an important therapeutic tool to be used in postmenopausal
women, including those with alterations in glucose metabolism (26).
Received June 17, 1996.
Revised July 25, 1996.
Accepted August 22, 1996.
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Abstract
Introduction
