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. 2004 Aug 18;130(11):687–693. doi: 10.1007/s00432-004-0587-2

Insulin resistance, its consequences for the clinical course of the disease, and possibilities of correction in endometrial cancer

L M Berstein 1,✉, J O Kvatchevskaya 2, T E Poroshina 1, I G Kovalenko 1, E V Tsyrlina 1, T S Zimarina 1, A F Ourmantcheeva 2, L Ashrafian 3, J H H Thijssen 4
PMCID: PMC12161792  PMID: 15322863

Abstract

Objectives

To study the frequency of insulin resistance (IR) in endometrial cancer patients, its relation to the clinical course of the disease and DNA damage, and to evaluate possible approaches to the pharmacological correction of IR in the patients studied.

Methods

The signs of insulin resistance syndrome and its association with the clinical and pathological features of the disease and DNA damage in somatic cells (micronucleus frequency in peripheral blood lymphocytes) and endometrial normal and tumor tissue (alkaline unwinding) were determined in 99 endometrial cancer patients.

Results

The frequency of insulin resistance syndrome counted on the basis of fasting plasma glucose and insulin concentrations according to Duncan et al. is equal to 0.35 (95% CI 0.24–0.46), or 35%, in endometrial cancer patients who do not have a history of diabetes mellitus. Patients with well- or moderately differentiated endometrial adenocarcinomas (mostly type I) had statistically significantly higher basal and stimulated plasma insulin and C-peptide concentrations than patients with poorly differentiated endometrial adenocarcinomas or rarely encountered tumors of the endometrium (primarily type II). Interestingly, the level of fasting insulinemia positively correlates with disease stage and with local and regional tumor dissemination only in the group of patients with well- or moderately differentiated endometrial adenocarcinomas. On the other hand, hyperinsulinemia and other hormonal-metabolic disturbances typical of insulin resistance syndrome do not increase the probability of DNA damage of somatic cells (according to the data of micronucleus test). In addition, no association between hormonal-metabolic disturbances and the degree of DNA unwinding in tumor and visually unchanged endometrium was found.

Conclusion

Thus, insulin resistance/hyperinsulinemia is associated with a more aggressive course of the disease in certain groups of the patients but—in contrast to excessive estrogenic stimulation—does not result in increased genotoxic damage in tumor and normal tissues. The data obtained once more confirm the need for treatment and prevention measures aimed at correcting hormonal-metabolic disturbances in endometrial cancer patients and groups at risk of this disease. Such an approach might include use of antidiabetic biguanides, thiazolidinediones (glitazones), and statins.

Keywords: Insulin, Insulin resistance, Endometrial cancer, Types, Clinical course, DNA damage, Pharmacological correction

Introduction

According to existing epidemiological data, endometrial cancer (EC) ranks fourth in developed countries among cancers in women and first among gynecological cancers. It is significant that at least in 60–70% of the cases EC develops against a background of endocrine-metabolic disturbances (Bokhman 1983; Berstein 2000; Sherman 2000). The effects of the known EC risk factors (obesity, anovulation, sterility, late menopause, etc.) are considered to be mediated through a single hormonal mechanism; that is, relatively high estrogen levels along with absolute or relative progesterone insufficiency affecting the endometrium. In fact, it has been shown that obesity is one of the leading EC risk factors which increases the risk of disease development due to boosted extragonadal androstendione-to-estrone conversion. However, some researchers discredit the fact that obesity’s influence in regard to EC is determined only by estrogen. For example, a point of view exists that obesity in EC patients is just a long-term hyperinsulinemia marker (Troisi et al. 1997). The value of insulinemia as an increased cancer risk factor and a modulator of the clinical course of the disease is worthy of additional study.

It should be mentioned that most of the signs of insulin resistance syndrome, or X-syndrome—which include insulin resistance, hyperinsulinemia, impaired carbohydrate tolerance, dyslipidemia, hypertension, abdominal obesity, etc., (Reaven 1988; Facchini et al. 2001)—coincide with the description of cancrophilia syndrome (Dilman 1987; Dilman 1994) and with a premorbid status in patients with the so-called hormone-dependent EC variant (Bokhman 1983; Emons et al. 2000; Sherman 2000). A connection between hyperinsulinemia and increased EC risk was confirmed in several case-control studies (Nagamani et al. 1988; Gamajunova et al. 1997). Although other studies have rejected the existence of such an association (Troisi et al. 1997; Weiderpass et al. 2003), as was demonstrated in a very recent prospective investigation, chronic hyperinsulinemia is related to increased endometrial cancer risk (Lukanova et al. 2004). One cannot exclude the possibiity that the mechanisms mediating the influence of insulin on endometrial cancer development, except for its metabolic and, to a lesser degree, mitogenic activity, are also insulin’s capability to inhibit expression of IGF-binding (insulin-like growth factors) proteins in endometrium, modify aromatase activity, enhance steroidogenesis in ovaries, decrease sex steroid-binding globulin production in liver, alter sensitivity of target tissue to sex hormones, etc. (Randolph et al. 1987; Nestler 1993; Rutanen et al. 1994; Vishnevsky et al. 1993; Troisi et al. 1997; Facchini et al. 2001).

The same mechanisms probably facilitate hyperinsulinemia-determined modification of the course of the disease in EC patients. However, there is practically no data on insulin resistance/hyperinsulinemia and the clinical-morphological features of endometrial cancer, including separation of this disease into types I and II (Bokhman 1983; Emons et al. 2000; Sherman 2000). One of our objectives was to study this issue. Besides this, the concept of the presence of two hormonal carcinogenesis types, promoter and genotoxic ones (Liehr 1997; Berstein 2000; Cavalieri et al. 2000), as well as data on increased DNA damage in endometrial cancer tissue in patients with abdominal fat accumulation (indirect hyperinsulinemia sign) (Berstein et al. 1999) were the basis to collate metabolic disturbances characteristic for insulin resistance syndrome with DNA unwinding in cancer and normal endometrial tissue, and chromosome alterations in peripheral blood lymphocytes (micronuclear test) in EC patients.

Materials and methods

Ninety-nine primary endometrial cancer patients were examined in total. They were admitted for surgical treatment to the gynecological departments of St. Petersburg Municipal Cancer Dispensary and Prof. N.N.Petrov Research Institute of Oncology. The patients were randomly selected. Exclusion criteria were as follows: 1) diabetes mellitus (since the study program utilized a load assay—peroral glucose tolerance test/PGTT/); 2) any other decompensated concomitant disorder; 3) primary-multiple tumors.

Laboratory tests were performed 2–3 days prior to surgery. At the same time, anthropometric parameters were measured. A standardized patient history was also compiled. This included data on main disease development, menstrual and reproductive functions, and concomitant diseases. Patient age varied from 37 years to 82 years. Its median, upper, and lower quartiles were 59, 64, and 52 years, respectively. There were 76 post-menopausal patients and 23 of the patients still had menstruations.

Only patients with endometrial cancer after histological verification were enrolled. Ninety-one percent of the cases (90 patients) were endometrioid adenocarcinoma. Nine percent were rare variants of endometrial cancer (seven patients with serous-papillary adenocarcinoma, one clear cell adenocarcinoma, and one patient with mesonephroid cancer). Endometriod adenocarcinomas were distributed according to the degree of histologic differentiation as follows: 18 patients out of 90 with well-differentiated adenocarcinoma, 53 patients with moderate-differentiated adenocarcinoma, and 19 patients with poor-differentiated adenocarcinoma.

The disease was staged according to the International Federation of Gynecologists and Obstetricians (FIGO) Surgical staging system and TNM system based on intraoperational findings, removed macrospecimens (with tumor size measurement), and on the conlusions of detailed morphological examination. There was a majority of localized tumors (Т1а-3bNoMo) in 94 patients, while regional spread was found in four patients, and signs of generalized disease in one patient only.

Anthropometric data were used to calculate: a) body mass index (Quetelet index): weight, kg/(growth, m)2; and b) waist circumference/hip circumference ratio [the upper (android) fat distribution type was defined as such in patients with a value of this index higher than 0.85]. Percentage of fat in the body was determined with a bioimpedance method using special software.

To assess carbohydrate metabolism, a standard 2-h peroral glucose tolerance test (40 g of glucose per 1 m2 of body surface) was applied. Prior to glucose application,and 2 h afterwards, vein blood samples were taken. In both serum samples glucose content was determined by enzyme-colorimetric methods using Boehringer Mannheim (Germany) kits. The following parameters were determined in fasting blood samples: triglycerides and total cholesterol by enzyme-colorimetric methods and total lipoproteins by colorimetric method.

In the blood samples obtained from the patients before and during the glucose-tolerance test, the following parameters were determined: a) insulin level by radio-immune method using HOP IBOH (Belorus) kits; and b) C-protein concentration by radioimmunological method using Immunotech (Czech Republic) kits.

The insulin resistance index was calculated according to the formula of Duncan et al. (Duncan et al. 1995): (glucose 0×insulin 0)/25, where glucose 0 means fasting glucose concentration in blood, mmol/l; insulin 0—fasting insulin concentration, μU/l; and 25—empirical coefficient. As a criterion of the insulin resistance state an index value of 4.8 and more was used (Duncan et al. 1995).

The DNA damage (unwinding) rate in normal and malignant endometrium was determined with a fluorimetric method based on alkaline processing of samples (Birnboim and Jevcak 1981). Peripheral blood lymphocytes of the EC patients were used for the micronucleus test to determine genotoxicity (clastogenicity) (Fenech and Morley 1986). To standardize the method, citohalasin B was added to the PHA-stimulated lymphocyte culture (Kolubaeva et al. 1989). The following indices were calculated: 1) number of micronuclei in 1,000 cells; 2) number of cells with micronuclei per 1,000 cells. Micronuclei were examined at a magnification of ×900 and only in live cells with normal-looking cytoplasm.

The following major objectives were set for statistical processing of the obtained data: a) description of the studied parameters in groups; b) pair group comparison; c) study of parameters characterizing, on the one hand, insulin resistance syndrome, and, on the other hand, clinical-morphological features of endometrial cancer or genotoxic damage severity with an assessment of the associations in the entire studied population as well as in selected subgroups. Since a large number of comparisons should be performed for collating similar data to overcome multiple comparison effects, statistical significance was set at <0.01.

The absence of a normal distribution in the indices studied required the use of non-parametrical statistical methods. To describe central trends, we used a median, and for the description of observation dispersion, minimum and maximum values of interquartile amplitude were used. Correlation coefficients according to Kendall were also calculated when needed. Statistical processing was performed with STATISTICA software, version 5.5a.

Results and Discussion

There are various approaches to diagnosing insulin resistance syndrome. We have selected as a main index the combination of basal insulinemia and glycemia assessed by the insulin resistance index of Duncan et al. (Duncan et al. 1995) which is quite close to the so-called HOMA index (Hrebicek et al. 2002). Insulin resistance frequency in the studied cohort with such a methodical approach was 0.35 (35/99). Based on this data, insulin resistance incidence in endometrial cancer patients was 24–46% (with a 95% probability rate). In assessing the results, it should be taken into account that at least two methodological assumptions were made while enrolling the patients: first, patients with overt diabetes mellitus diagnosed prior to the performed laboratory examination were excluded from the study; second, only patients planned for surgery were enrolled (this excluded patients who were not eligible for surgery due to concomitant disorder severity and/or cancer spread). Unfortunately, it seems to be impossible to compare the obtained data with the insulin resistance syndrome incidence in the general population for various reasons. However, the index found in the EC cohort was quite high.

When studying anthropometric parameters in EC patients as well as particular features of insulinemia, lipid and carbohydrate metabolism (Table 1, Table 2), it was found that, as one would expect, some of the parameters notably depend on enrolled patient age, for instance,the “waist/hip” ratio or glucose blood level (120 min.). Nevertheless, the age factor can hardly explain hormonal-metabolic status differences in EC patients with an insulin resistance index below or above 4.8, and what is most important, there were no significant differences for this index mean value in the reproductive and menopausal age patients.

Table.

 [CE1] 1 Absolute values of the studied hormonal-metabolic parameters in endometrial cancer patients

Parameter All patients (n=99) Patients in reproductive period (n=23) Postmenopausal patients (n=76) Significance level, Pb
Age, years 59a (52; 64) 48 (37; 56) 61 (51; 82) <0,00001
Body mass index kg/m2 28,4 (25,3; 32,8) 27,5 (17,9; 53,4) 28,8 (18,3; 46,8) 0,35014
Waist/hip ratio 0,85 (0,80; 0,92) 0,82 (0,61; 0,95) 0,88 (0,70; 10,2) 0,02741
Glucose, 0 min mmol/l 5,22 (4,66; 5,99) 5,05 (3,33; 7,16) 5,43 (3,94;14,82) 0,07966
Glucose, 120 min mmol/l 6,94 (5,55; 8,60) 5,77 (4,11; 13,1) 7,35 (3,66;16,98) 0,01071
Insulin, 0 min μU/l 11,9 (7,9; 18,8) 12,9 (1,0; 30,6) 11,7 (4,8; 69,3) 0,99356
Insulin, 120 min μU/l 54,9 (32,3; 95,4) 44,4 (5,0; 200,0) 59,0 (7,0; 251,4) 0,14823
Insulin resistance index 2,9 (1,8; 4,5) 2,64 (0,3; 8,0) 2,9 (0,9; 18,8) 0,50126
Total cholesterol, mmol/l 5,62 (4,64; 6,60) 4,95 (3,46; 7,71) 5,78 (3,72; 10,42) 0,18118
Triglycerides, mmol/l 2,48 (1,11; 2,62) 1,23 (0,98; 1,57) 1,59 (1,23; 2,16) 0,0061
Total lipoproteins, cond. units 389 (314; 493) 336 (247; 550) 432 (222; 915) 0,00339
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a Data are presented as medians and 25- and 75-percentiles (in brackets)

b According to Mann Whitney U-criterion (patients in reproductive period vs postmenopausal patients)

Table 2.

Hormonal-metabolic status of endometrial cancer patients with a different value of insulin resistance index

Parameter Insulin resistance index <4,8 Insulin resistance index ≥4,8 Significance level, Pb
Age, years 58a (52; 62) 59 (51;66) 0,49553
Body mass index kg/m2 27,1 (23,8; 30,5) 32,7 (28,4;34,8) <0,00001
Waist/hip ratio 0,83 (0,8; 0,92) 0,89 (0,84; 0,94) 0,03386
Body fat, % 25,49 (21,08; 30,16) 33,41 (25,285; 40,85) 0,01153
Glucose, 0 min mmol/l 5,11 (4,61; 5,61) 5,99 (5,16; 7,16) <0,00001
Glucose, 120 min mmol/l 6,54 (5,41; 7,85) 8,58 (6,44; 10,43) 0,00061
Insulin, 0 min μU/l 9,0 (5,0; 11,9) 20,1 (18,0; 26,6) <0,00001
Insulin, 120 min μU/l 40,1 (24,7; 66,8) 101,9 (67,5;135,0) <0,00001
Insulin resistance index 2,11 (1,19; 4,41) 5,44 (5,0; 7,46) <0,00001
C-peptide 0 min, pmol/l 623,5 (407;679) 900,0 (756,0; 1230,5) <0,00001
C-peptide 120 min, pmol/l 2246,5 ( 1767,0; 3134,0) 3154,0 (2645,5; 4306,5) 0,00354
Total cholesterol, mmol/l 5,62 (4,64; 6,60) 5,57 (4,59; 6,63) 0,86629
Triglycerides, mmol/l 1,46 (1,00; 2,04) 1,55 (1.27; 2,09) 0,04985
Total lipoproteins, cond. units 363,0 (304,0; 474,0) 473,5 (378,0; 584,0) 0,00451
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a Data are presented as medians and 25- and 75-percentiles (in brackets)

b According to Mann Whitney U-criterion (patients in reproductive period vs postmenopausal patients)

To compare insulin resistance syndrome signs with the clinical-morphological parameters of endometrial cancer, we performed correlation analysis to determine the relationships among the studied parameters. Both the entire group and its subgroups were appropriately assessed. The subgroups were determined based on the following signs: 1) cancer grade (high- and moderate grade vs low grade); 2) obesity (body mass index < or ≥30; fat content < or ≥38%; “waist/hip” ratio < or ≥0.85 orientated to median value); 3) insulinemia [insulin (0 min)< or ≥14.2 μmol/l]; 4) reproductive status (postmenopausal period vs retained menstrual cycle).

Significant positive correlations were found only between fasting insulin indices and cancer spread in the patients with highly and moderately differentiated endometrial adenocarcinomas which, as mentioned earlier, are mainly type I (Table 3). The association noted is most probably not an accidental coincidence due to the following reasons: 1) quite solid statistical significance was reached regarding the correlation analysis results; 2) the association of hyperinsulinemia with cancer progression is biologically explainable (there are several mechanisms capable of mediating the insulin growth-promoting effect in endometrium); 3) similar results were obtained when studying hyperinsulinemia’s impact on the course of breast and prostate cancer (Goodwin et al. 2002; Lehrer et al. 2002). As a whole, this allows us to consider the data obtained to be regular and reproducible.

Table 3.

Association level of basal insulinemia with some clinical-morphological parameters in the group of patients (n=71) with well- or moderately differentiated endometrial adenocarcinomas

Parameters Kendall correlation coefficient Significance level
Insulin (0 min) & stage of disease (FIGO) 0,226207 0,005268
Insulin (0 min) & local tumor dissemination (Т) 0,264695 0,001095
Insulin (0 min) & regional tumor dissemination (N) 0,24941 0,002095
Insulin (0 min) & tumor size 0,091842 0,257283
Insulin (0 min) & tumor differentiation grade -0,02399 0,767276
Insulin (0 min) & myometrial invasion 0,15329 0,05865
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As was already mentioned, there are virtually no publications on the association of increased insulin blood concentrations with clinical-morphological endometrial cancer features (contrary to assessing hyperinsulinemia as a risk factor for the disease). The article of Troisi et al. (Troisi et al. 1997) presented the following rationale for this. According to the author, a systematic error caused by excluding the properties of the tumor from consideration is insignificant since the course of endometrial cancer is usually slow and favorable. The disease is diagnosed in its early stages and can be treated radically. Thus, hyperinsulinemia’s impact on the course of disease and its prognosis should be of no real importance.

Our results contradict this point of view and do not share a common notion that metabolic abnormalities (obesity, dyslipidemia, etc.) are markers for a more favorable course and prognosis in such patients (Bokhman 1983; Bokhman 1989; Anderson et al. 1996). The obtained data specifically indicate a stimulating activity of insulin resistance/hyperinsulinemia on cancer spread in high- and moderate-grade tumors, that is, “within” this group. Undoubtedly, there are many questions to be addressed, such as: what are the particular mechanisms responsible for stimulatory insulin effects on cancer growth? Why is this activity exhibited only in highly and moderately differentiated neoplasms? How can one explain insulin’s capacity both to participate in hormone-dependent tumor development and, simultaneously, to stimulate its growth? Although it can be assumed that the mentioned associations are related to the biological features of the disease, the issue regarding hyperinsulinemia’s prognostic value in the case of endometrial cancer is still open to debate. It is clear that to draw well-founded and final conclusions in regard to hyperinsulinemia’s impact on prognosis in EC patients it is necessary to conduct prospective studies similar to the investigations made in the area of breast cancer (Goodwin et al. 2002).

It should be noted that a special study performed in our laboratory showed that estradiol content in endometrial tumor tissue correlates positively with DNA unwinding (a predisposition to DNA damage) mainly in patients with upper (android) fat distribution (Berstein et al. 1999; Berstein et al. 2003). This was one of the reasons to assess the correlation of various insulin resistance syndrome constituents with the DNA unwinding rate. With this aim we studied 11 normal endometrium samples and 26 tumor tissue samples in total. However, contrary to the data obtained earlier in regard to tissue estrogen content, Spearman and Kendall correlation coefficients did not exhibit statistically significant associations between the degree of DNA unwinding in tumor tissue and normal endometrium with signs of severe insulin resistance.

Furthermore, the micronucleus test is a widely used method to determine the clastogenicity (genotoxicity) of external and internal factors. The method is based on the determination of the number of micronuclei in interphase somatic cells. Peripheral blood lymphocytes are the cells which are the easiest to obtain to study micronuclei. Damage sites in lymphocytes are retained for a long time (Fenech and Morley 1986; Kolubaeva et al. 1989). An increase in the number of structural chromosome aberrations in lymphocytes of endometrial cancer patients in comparison with healthy women and patients with precancer disorders in endometrium was found earlier. Alterations in lymphocyte karyotypes are considered as chromosome instability of somatic cells in cancer patients. These abnormalities, as was assumed along with other reasons, could be caused by the modification of organism regulatory systems (Ganina et al. 1999). On the basis of these data, and those mentioned above, it seemed reasonable to evaluate an assumption on the possible increase in the number of chromosome aberrations detected with the micronucleus test in endometrial cancer patients depending on the severity of various insulin resistance signs.

Comparing the number of cells with micronuclei and the amount of micronuclei per 1,000 lymphocytes in the EC patient group vs the healthy women group (comparable in regard to age and anthropometric indices), no significant differences were found in these parameters (data not shown). In addition, statistically significant correlations in the number of micronuclei were not noted between patient groups with high- and low-grade tumors. The data obtained do not show statistically significant associations regarding micronucleus test parameters (the number of cells with micronuclei and the number of micronuclei per 1,000 lymphocytes) with signs of severe insulin resistance. The only consistent pattern deduced in the groups studied was a positive correlation between the number of cells with micronuclei and the number of micronuclei, on the one hand, and patient age, on the other (for cells with micronuclei r=0.5581, P<0.01 in the EC patients and 0.3824, P<0.01 in healthy women). Such a phenomenon is usually explained by an age-dependent increase in spontaneous micronuclei formation (Fenech and Morley 1986; Wojda and Witt 2003). Although this alteration was found in parallel to an augmentation in insulin resistance signs peculiar to aging in healthy people (Dilman 1987; Dilman 1994; Facchini et al. 2001), the present study was unable to show the dependence of cytogenetic damage in somatic cells (lymphocytes) of EC patients on the abovementioned hormonal-metabolic abnormalities.

In conclusion, hyperinsulinemia, unlike excessive stimulation by estrogens and their catechol derivatives (Liehr 1997; Cavalieri et al. 2000; Berstein et al. 2003), does not yield in the case of uterine cancer any increase of genotoxic alterations either in normal somatic cells or tumor tissue. Therefore, considering the data regarding the stimulating impact of insulin resistance/hyperinsulinemia on endometrial cancer development, and taking into account the results obtained in the present study, it may be assumed that hyperinsulinemia/insulin resistance primarily affects the stages of cancer promotion and progression but not the initiation stage. For all practical purposes, data on the impact of excessive insulin concentrations and insulin resistance on the course of EC confirm once again the need for treatment designed to control hormonal-metabolic alterations in patients with hormonal-dependent neoplasms, or to perform so-called metabolic rehabilitation (Dilman et al. 1982; Dilman 1994; Berstein 2000). Such an approach should be applied in EC patients previously treated by surgery and characterized with the “retained” set of hormonal-metabolic abnormalities considered in the present article. Besides the use of antidiabetic biguanides (such as metformin) which we previously recommended with this aim (Dilman et al. 1982; Berstein et al. 1992), the use of thiazolidinediones (glitazones) and statins possessing the capability to correct insulin resistance, diminish hyperlipidemia, and inhibit—according to some observations—tumor growth (Schneider et al. 2001; Cauley et al. 2003; Jakobisiak and Golab 2003; Tsujie et al. 2003) is recommended. The same pharmacologic measures are under evaluation now in polycystic ovarian disease patients who form a risk group for EC development (Costello and Eden 2003).

Acknowledgements

This study was partly supported by grants from INTAS (01–434) and RFBR (03–04–49282)

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