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Serum Adiponectin Concentration and Cardiovascular Risk Factors in Climacteric Women

Posted on: Thursday, 26 May 2005, 03:00 CDT

Abstract

Objective Adiponectin plays a significant role in the modulation of glucose tolerance and insulin sensitivity. We attempted to evaluate the relationship between adiponectin level and parameters of the menopausal metabolic syndrome: body mass index, waist-to-hip ratio, lipid profile and insulin resistance indices.

Subjects and methods Thirty-two women and ten men aged 40-63 years were included. The percentage of body fat and of abdominal fat deposits were measured with dual-energy X-ray absorptiometry. Serum adiponectin, tumour necrosis factor-α (TNFα) and leptin were measured with commercially available radioimmunoassay kits. To exclude the influence of nutritional factors on adiponectin secretion, diet content was analysed in the preceding three days.

Results Postmenopausal non-obese women had a non-significantly lower level of adiponectin compared with premenopausal women of corresponding body mass. Serum adiponectin level was significantly lower in postmenopausal obese women than in non-obese women (p = 0.0023). Men with similar age and body mass to the women had the lowest level of adiponectin (p = 0.06). Three months of estrogen replacement therapy in women with surgical menopause did not significantly change the serum level of adiponectin. We found a negative correlation of adiponectin with leptin, insulin resistance index and total cholesterol, and a positive correlation with high- density lipoprotein cholesterol. Adiponectin level was negatively correlated with free testosterone, but we did not find such a relationship with estradiol. There was no correlation of adiponectin level with TNFa; however, serum TNFα correlated positively with leptin. The dietary analysis showed no differences between the diets of obese and non-obese women over the preceding three days. Moreover, mean diastolic and systolic blood pressures were noted to be significantly lower in premenopausal women than in postmenopausal non-obese women (p = 0.05).

Conclusions Our results suggest that adiponectin could be a marker of risk for developing menopausal metabolic syndrome. Moreover, it is possible that sex steroids have an influence on adiponectin secretion.

Keywords: Adiponectin, menopause

Introduction

Adiponectin (adipocyte complement-related protein of 30 kDa, Acrp30), an adipocyte-specific molecule belonging to the group of collectins, is a protein of 244 amino acids, induced by peroxisome proliferator-activated receptor-γ ligands. This protein is a product of the adipose most abundant transcript 1 gene (apMl), which is expressed exclusively and in large quantities in white adipose tissue [1-3].

Several recent reports from experimental studies on animals indicate that adiponectin plays a significant role in modulation of glucose tolerance and tissue insulin sensitivity [4-6]. A significant suppression of serum adiponectin level was observed in obese subjects with type 2 diabetes [7]. Moreover, it was suggested that adiponectin extends atheroprotective properties by limiting the secretion and antagonizing the activity of tumour necrosis factor- α (TNFα) in peripheral tissues [8].

With the progress of climacterium, women suffer increased morbidity and mortality from cardiovascular disease. The primary cause for this phenomenon seems to be a menopausal metabolic syndrome, observed in 40% of climacteric women. This syndrome is characterized by visceral obesity (caused by the redistribution of adipose tissue, i.e., an increase in visceral fat deposits at the expense of gynoid fat), hyperinsulinaemia, insulin resistance, hypertension and impairment of coagulation and lipid metabolism (increased concentrations of triglycrides with a reduction in the high-density lipoprotein (HDL)-cholesterol fraction) [9-11]. Results of experimental and clinical studies suggest that adiponectin concentration is closely related to tissue insulin sensitivity [4, 7]. However, there is paucity of data on the relationship between serum adiponectin level and endo- or exogenous estrogens, as well as androgens and sex hormone-binding globulin (SHBG), in relation to cardiovascular risk factors such as obesity, visceral fat deposits, glucose tolerance, serum insulin, lipid metabolism and hypertension.

The aim of the present study was to assess the relationship between serum adiponectin concentrations with diet and the progress of climacterium with respect to cardiovascular risk factors associated with the development of menopausal metabolic syndrome. Moreover, the relationship between serum adiponectin concentration and sex hormones was studied.

Materials and methods

Subjects

Among the 32 healthy women included in the study, ten were premenopausal (aged 34-41 years, with body mass index (BMI) 23.4 + 3.3 kg/m^sup 2^ and waistto-hip ratio (WHR) 0.76 0.05) and 22 were postmenopausal, of which 11 were non-obese (aged 45-62 years, BMI 22.8 2.2 kg/m^sup 2^ and WHR 0.79 0.04) and 11 were obese (aged 44- 63 years, BMI 36.6 4.9 kg/m^sup 2^ and WHR 0.86 0.06). Ten women had a history of hysterectomy and ovariectomy (aged 47-52 years, BMI 27.0 5.5 kg/m^sup 2^ and WHR 0.88 0.02). Furthermore, to assess the influence of gender on adiponectin serum concentration, ten men (aged 40-63 years, BMI 26.7 3.0 kg/m^sup 2^ and WHR 0.98 0.02) were included in the study. Blood pressure was measured in all of the women.

Assessment of body fat and tissue fat distribution

Total body fat was measured by dual-energy X-ray absorptiometry (DPX; Lunar Radiation Corporation, Madison, WI, USA). The percentage of abdominal fat deposits was determined as a quotient of the total fat tissue (in grams) included in a rectangle in which the upper limit was the upper surface of vertebra L2, the lower limit was the lower surface of L4 and lateral was the body outline.

Assessment of nutritional habits and diet

To exclude the influence of nutritional factors on adiponectin secretion, diet was analysed over the preceding three days. Intakes of nutrients and foods were assessed by use of a single dietary questionnaire prepared by ourselves. The questionnaire comprised two parts: in the first were questions regarding the intake of recommended food products as well as of elements like cereals, fruits, vegetables, diary products and fat; in the second part, the 24-h dietary recall was administered by an interviewer. An album showing portions of products and meals (Institute of Food and Nutrition, Warsaw, Poland) was used to estimate consumed amounts. Data were collected from each person only once. From the 24-h dietary recall, the nutrient content of the daily food rations was calculated using the Nutritionist IV(TM) computer program (First DataBank Inc., San Bruno, CA, USA), based on its own database. We determined total calories, carbohydrates, proteins, fat, fibre and the following nutrients: cholesterol, fatty acids (saturated, monounsaturated and polyunsaturated), potassium, zinc, copper, magnesium and vitamins A, E, B1, B^sub 2^, B^sub 3^, B6 and C.

Biochemical studies

Blood samples were drawn from the ulnar vein in each subject before breakfast, early in the morning (at 08.00), after overnight bed-rest with last meal in the preceding day at 18.00. Concentrations of glucose and lipids (total cholesterol, HDL- cholesterol, lowdensity lipoprotein (LDL)-cholesterol and triglycrides) in serum were estimated by routine colorimetric methods using commercial assays. Serum estradiol (E^sub 2^), follicle-stimulating hormone (FSH), free testosterone (FT), SHBG, dehydroepiandrosterone sulfate (DHEA-S) and insulin were measured with commercially available radioimmunoassay (RIA) kits. Serum adiponectin, TNFα and leptin were measured also with RIA, using assays from LINGO Research Inc. (St. Charles, MI, USA).

Assessment of insulin sensitivity

Fasting insulin resistance index (FIRI) and quantitative insulin sensitivity check index (QUICKI) were calculated using the following formulas [12]:

To assess the effect of exogenous estrogens on serum adiponectin level in women with surgical menopause (after hysterectomy with ovariectomy), transdermal estrogen replacement therapy (ERT) was carried out (Systen 50 g every 3 days; Janssen-Cilag, Poland). Adiponectin levels were evaluated before and after 3 months of therapy.

Statistical analysis

Data were analysed with Statistica for Windows version 5.1 (StatSoft Inc., Tulsa, OK, USA) and are presented as mean standard deviation. To assess differences between groups, means were compared using the Student r-test. To determine the correlations between analysed data, Pearson's linear correlation analysis was carried out. The level of statistical significance was set at p < 0.05.

Results

Premenopausal women did not differ in BMI, WHR and percentage body fat from postmenopausal nonobese women (percentage body fat: 33.8 5.0 vs. 31.1 6.4, respectively). In postmenopausal obese women percentage body fat was 44.7 4.6 being significantly higher (p < 0.05) than in the other two groups.

The dietary analysis showed no differences in mean diet between obese and non-obese women (protein 67.3 28.7 vs 68.6 + 18.3 g/24 h, carbohydrates 238.7 106.7 vs. 269.6 99.4 g/24 h and fat 84.3 37.8 vs. 83.0 26.4 g/24 h, respectively), or between pre- and postmenopausal non-obese women.

Mean systolic \and diastolic blood pressures noted in premenopausal women were respectively 110.7 17.9 and 75.8 8.6 mmHg. In postmenopausal non-obese women they were 137A 24.9 and 87.2 9.3 mmHg, respectively, which is significantly higher compared with the other groups (p = 0.05).

Hormonal profile of the pre- and postmenopausal obese and non- obese women is illustrated in Table I. Mean FSH and E^sub 2^ levels in premenopausal women differed significantly from those in obese and nonobese postmenopausal women (p = 0.0001). Furthermore, SHBG concentrations were lower (p = 0.02) and FT concentrations higher (p = 0.04) in obese postmenopausal women than in non-obese postmenopausal and premenopausal women. Mean DHEAS level was lower in obese than in non-obese and in premenopausal women; however, the difference was significant only between postmenopausal obese and premenopausal women (p = 0.04). The ratio E^sub 2^/FT attained higher values in premenopausal subjects, compared with the other groups.

Table I. Hormonal parameters in pre- and postmenopausal women.

Table II. Serum insulin levels and insulin sensitivity/ resistance indices in pre- and postmenopausal women.

Table II depicts mean serum concentrations of insulin and glucose, and mean values of QUICKI and FIRI, in the investigated groups of women. Insulin level in both groups of postmenopausal women was significantly higher (p = 0.002) than in premenopausal women. Fasting glucose level did not differ significantly between these three groups. QUICKI was significantly higher (p = 0.003) in the group of premenopausal women than in the obese postmenopausal women, yet showed no difference with reference to non-obese postmenopausal women. In accordance with expectations, FIRI value was significantly lower in the premenopausal women (p = 0.007) compared with the postmenopausal obese women; however, it did not differ from that of postmenopausal non-obese women. In postmenopausal non-obese women, QUICKI values and FIRI were significantly higher (both = 0.03) in comparison with obese women.

Table III presents serum lipid levels (total cholesterol, HDL- cholesterol, LDL-cholesterol and triglycerides) in the groups of premenopausal women and postmenopausal women, non-obese and obese. Total cholesterol level and its HDL and LDL fraction, as well as triglycerides, were not significantly different between the groups of women studied, but we noticed a tendency to increased triglycerides and reduced HDL-cholesterol levels in obese women.

Serum adiponectin level in obese postmenopausal women was significantly lower than in postmenopausal non-obese women (p = 0.02) (Figure 1). Moreover, postmenopausal non-obese women had a non- significantly lower level of this peptide than premenopausal women with corresponding body mass. Postmenopausal obese women had a significantly lower (p = 0.0007) level of adiponectin than premenopausal women. Men, of similar age and body mass to the women, had the lowest level of adiponectin (Figure 1). Moreover, in women with surgical menopause, this peptide did not change significantly after estrogen replacement therapy (27.4 10.4 vs. 31.7 11.5 ng/ ml).

Table III. Serum concentrations of total cholesterol, high- density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)- cholesterol and triglycerides in pre- and postmenopausal women.

Figure 1. Serum adiponectin concentrations in pre- and postmenopausal women and men. SD, standard deviation; mean values with unlike superscript letters are significantly different at p = 0.0007 (a-c), p < 0.0001 (a-cd), p = 0.02 (ab-c) and p = 0.08 (ab- cd).

Serum TNFα was significantly lower (p = 0.0003) in premenopausal women compared with both obese and non-obese postmenopausal women (Figure 2). However, serum concentration of this cytokine in postmenopausal obese women was non-significantly higher than in non-obese women. Leptin level was significantly lower in premenopausal compared with postmenopausal non-obese women (p = 0.03). Moreover, in postmenopausal obese women, the leptin level was significantly higher than in both premenopausal (p = 0.0001) and postmenopausal non-obese women (p = 0.003) (Figure 3).

Linear correlations of serum adiponectin levels in the total group were studied with available anthropomtrie and biochemical parameters. In all women investigated, serum adiponectin level correlated negatively with FT level (r= -0.65;p = 0.017) andFIRI (r= -0.49; p = 0.015), total cholesterol (r = -0.46; P = 0.02) and leptin (r=-0.41; p = 0.016), and positively with QUICKI (r = 0.52; p = 0.001) and HDL-cholesterol (r=0.68; p = 0.001). There was no correlation of adiponectin level with TNFα; however, serum TNFα correlated positively with leptin (r= 0.25; p = 0.03).

Discussion

The physiological role of adiponectin is still not well known. Experimental animal studies showed its atheroprotective and anti- inflammatory properties. In humans, low levels of this peptide were noted in subjects with type 2 diabetes and ischaemic heart disease [5-8].

Our results showed that adiponectin levels in preand postmenopausal women with comparable diet, BMI, WHR, percentage body fat and percentage abdominal fat were not different; merely we saw a downward tendency with progress of climacterium. We observed an insignificant increase of adiponectin level in women with surgical menopause after 3 months of estrogen therapy, suggesting no effect of exogenous estrogens on adiponectin level; however, the relatively short period of therapy might be also the cause.

Figure 2. Scrum tumour necrosis factor-&945;) concentrations in pre- and postmenopausal women. SD, standard deviation; mean values with unlike superscript letters are significantly different at p = 0.0003 (a-b).

Figure 3. Serum leptin concentrations in pre- and postmenopausal women and men. SD, standard deviation; mean values with unlike superscript letters are significantly different at p = 0.03 (a-b), p = 0.0001 (a-c) and p = 0.03 (b-c).

Matsubara and colleagues [13] showed weak correlation of adiponectin with biological age and E^sub 2^ in 252 Japanese women aged 16-86 years, and that relationship was even weaker after adjustment for BMI and percentage body fat. We did not find any correlations between adiponectin level and FSH, E^sub 2^ or biological age. This might be caused by the smaller number of subjects in our study, especially premenopausal women.

Our observation of significantly lower serum adiponectin levels in men than in women, and negative correlation of adiponectin concentration with FT level, support the suggestion of Arita and associates [14] that adiponectin level depends on the profile of sex hormones. However, further studies are needed to definitely confirm this relationship. It could be hypothesized that similar adiponectin concentration in obese postmenopausal women and men is associated with a high risk of cardiovascular disease in both groups [U].

In accordance with other studies, we observed significantly lower adiponectin levels in obese than in non-obese women who were similar in relation to the progress of climacterium (FSH and E^sub 2^) and diet [7,13,14]. Both groups differed in QUICKI, FIRI and blood pressure. In contrast to the Japanese study [13], in our study lower adiponectin levels in obese postmenopausal women were not accompanied by severe serum lipid disturbances, but associated with only minor proatherosclerotic modifications in the obese women. This difference could be caused by the lower number of subjects in our group and mediocre degree of obesity and minor expression of the metabolic syndrome in our postmenopausal obese women.

Simultaneously, in the total group of women, we proved the existence of a negative correlation of adiponectin with total cholesterol and a positive correlation with HDL-cholesterol, which suggests a relationship of adiponectin with lipid metabolism that is independent of obesity. This was also found in a study by hotta and co-workers, who reported a negative correlation of adiponectin with triglycerides and a positive correlation with HDL-cholesterol in subjects with type 2 diabetes [15].

In our study adiponectin levels were not correlated with glycaemia and insulinaemia, but only with insulin sensitivity/ resistance indices, showing a significant positive correlation with QUICKI and a negative correlation with FIRI. This fact, in addition to the previously described relationship of adiponectin to lipid metabolism, indicates the important connection of this peptide with disturbances leading to the metabolic syndrome [7,13]. However, Stefan and colleagues showed in children that adiponectin level could not be a mediator of insulin resistance induced by obesity [16].

It has been shown that adiponectin decreases the secretion of and antagonizes TNFα by influencing the expression of many adhesive molecules and the adhesion of monocytes to endothelial cells (early stage of atheromatosis) [8,9]. In our study, TNFα level depended on progress of climacterium and to a lesser extent on obesity. Those premenopausal women with the highest adiponectin levels showed simultaneously the lowest TNFα, in comparison with other groups. Postmenopausal non-obese women had non- significantly lower TNFα levels compared with postmenopausal obese women. However, we did not observe any correlation between serum adiponectin and TNFα in the study women. TNFa correlated positively with leptin in the studied group. These results, i.e., a significant negative correlation between adiponectin and leptin, confirm earlier observations of hotta and associates in animal models [17].

In summary, the negative correlation of serum adiponectin level with FT and the significantly lower concentration of this peptide in men suggest a relationship between sex hormones and adiponectin concentrations that requires further study. We also demonstrated a significant asso\ciation of adiponectin levels with markers of the metabolic syndrome, i.e., obesity, insulin resistance and lipid disorders. Our results suggest that adiponectin could be a marker of insulin resistance for distinguishing those women at risk of developing menopausal metabolic syndrome.

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ANDRZEJ MILEWICZ1, KATARZYNA ZATONSKA1, MAREK DEMISSIE1, DIANA JDRZEJUK1, KATARZYNA DUNAJSKA1, RAFAL ILOW2, & FELICJA LWOW3

1 Department of Endocrinology and Diabetology, Wroclaw Medical University, Wroclaw, Poland, 2 Department of Bromatology, Wroclaw Medical University, Wroclaw, Poland, and 3 Department of Promotion of Health and Hygiene, Wroclaw University of Physical Education, Wroclaw, Poland

Correspondence: A. Milewicz, Department of Endocrinology and Diabetology, Wroclaw Medical University, Wybrzeze L. Pasteura 4, 50- 367 Wroclaw, Poland. Tel/Fax: 48 71 7840957. E-mail: milewicziaiendo.am.wroc.nl

Copyright CRC Press Feb 2005

Source: Gynecological Endocrinology

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