ABSTRACT. The effect of tibolone, a new therapeutic agent for menopause, on glucose and lipid metabolism was investigated in 11 healthy post- menopausal ...
0021-972X/97/$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1997 by The Endocrine Society
Vol. 82, No. 1 Printed in U.S.A.
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 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. (J Clin Endocrinol Metab 82: 251–253, 1997)
ABSTRACT 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
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IBOLONE is a synthetic steroid [(7a, 17a)-17 hydroxy7-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 (12–14). On the other hand, it induces a transient decrease in apoprotein-A (Apo-A) (11) and high-density lipoprotein (HDL)-cholesterol (12–14), 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.
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 230, 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 215, 210, 25, 21, 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 225 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, pro-
Materials and Methods 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 Received June 17, 1996. Revision received July 25, 1996. Accepted August 22, 1996. Address all correspondence and requests for reprints to: Angelo Cagnacci, M.D., Istituto di Fisiopatologia della Riproduzione Umana, Universita` di Modena, via del Pozzo 71, 41100 Modena, Italy.
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gesterone, 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 3 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 3 1024/min 3 mU/mL, and Sg in units 3 1024/min. Statistical analysis of the results was performed by the t test for paired data. Two-way ANOVA for repeated measures (treatment 3 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 6 se.
Results
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 6 0.7 vs. 23.2 6 0.6). The levels of HDLcholesterol (1.18 6 0.1 mmol/L vs. 1.11 6 0.1 mmol/L), total cholesterol (4.62 6 0.34 mmol/L vs. 4.28 6 0.32 mmol/L), and the HDL-cholesterol/total cholesterol ratio (0.27 6 0.04 mmol/L vs. 0.28 6 0.04 mmol/L) were not modified by tibolone administration, as well as the levels of Apo-A (247.6 6 18.9 mg/dL vs. 208.2 6 19.0 mg/dL), Apo-B (78.9 6 9.27 mg/dL vs. 79.4 6 9.9 mg/dL) and the Apo-A/Apo-B ratio (3.59 6 0.76 mg/dL vs. 2.91 6 0.37 mg/dL). By contrast, triglyceride levels were significantly decreased from 0.9 6 0.07 mmol/L to 0.65 6 0.06 mmol/L (227.3 6 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 6 0.18 mmol/L vs. 4.16 6 0.19 mmol/L; P , 0.025) but did not influence the fasting levels of insulin (58.9 6 10.7 pmol/L vs. 56.6 6 7.3 pmol/L) and C-peptide (287.6 6 33.3 pmol/L vs. 258.7 6 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. Si, but not Sg, evaluated by FSIGT, was inversely correlated with BMI (r 5 0.803; P , 0.01) and independent of BMI, was significantly increased during tibolone administration from 4.8 6 0.6 to 7.4 6 3.5 (162.8 6 15.7%; P , 0.01). By contrast, Sg values remained unmodified (0.031 6 0.004 vs. 0.032 6 0.005). Discussion
FIG. 1. Mean (6 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.
The present data confirm previous reports on the effect of tibolone on lipid metabolism (11–14). Although we were unable to document a negative influence of tibolone on HDLcholesterol/total cholesterol ratio (12, 13), the observed reduction in triglyceride levels confirms previous reports (12– 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
TABLE 1. Integrated values (units 3 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) OGTT
Glucose Insulin C-peptide C-peptide/insulin
FSIGT
Before
During
Before
During
1060 6 67 49719 6 5584 88479 6 21970 1.90 6 0.4
1114 6 72 61382 6 9680 89102 6 18173 1.72 6 0.4
218.2 6 13.8 4882 6 770 10089 6 1835 2.1 6 0.2
172.2 6 13.6 4522 6 1000 9373 6 2820 2.8 6 0.9
TIBOLONE AND GLUCOSE METABOLISM
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). References 1. van der Vies J. 1987 Pharmacological studies with ((7a, 17a)-17 hydroxy-7methyl-19-norpregn-5(10)-en-20-yn-3-one) (Org OD14). Maturitas. [Suppl]1: 15–24. 2. Tax L, Goorisen EM, Kicovic PM. 1987 Clinical profile of ORG OD 14. Maturitas. [Suppl]1:3–13. 3. Crona N, Samsioe G, Lindberg U-B, Silfverstolpe G. 1988 Treatment of climacteric complaints with ORG OD 14: a comparative study with oestradiol valerate and placebo. Maturitas. 9:303–308. 4. Rymer J, Chapman MG, Fogelman I, Wilson POG. 1994 A study of the effect of tibolone on the vagina in postmenopausal women. Maturitas. 18:127–133. 5. Lindsay R, McK Hart D, Krazewski A. 1980 Prospective double-blind trial of synthetic steroid (Org OD 14) for preventing postmenopausal osteoporosis. Br Med J. 280:1207–1209. 6. Geusens P, Dequeker J, Gielen J, Schot LPC. 1991 Non-linear increase in vertebral density induced by a synthetic steroid (Org OD 14) in women with established osteoporosis. Maturitas. 13:155–162.
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