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Divisions of Endocrinology, Diabetes, and Clinical Nutrition (J.J.P., S.V., M.K., U.K., B.M.) and Gynecological Endocrinology and Reproductive Medicine (C.D.G.), University Hospital, CH-4031 Basel, Switzerland
Address all correspondence and requests for reprints to: Jardena J. Puder, Division of Endocrinology, Diabetes, and Clinical Nutrition, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland. E-mail: Puderj{at}uhbs.ch.
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Abstract |
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Methods: Blood was drawn from 20 patients with PCOS and compared with 15 controls, matched for body mass index and age. Regional fat distribution was assessed using dual x-ray absorptiometry.
Results: Compared with controls, patients with PCOS had a higher trunk to extremity fat ratio (T/E fat), were more insulin resistant (higher homeostasis model assessment of insulin resistance and lower SHBG concentrations), and had higher levels of highly sensitive C-reactive protein, TNF-
, procalcitonin, and white blood cell count (all P 
0.04), even after adjusting for total body fat. However, additional adjusting for T/E fat eliminated or attenuated the effect of PCOS status on estimates of insulin resistance, on inflammatory mediators, and on white blood cell count but not on circulating sex hormones. Independently of each other, total body fat as well as T/E fat correlated with estimates of insulin resistance and most inflammatory mediators (P 0.04). However, the correlations between T/E fat and circulating sex hormones (P 0.02) were greatly reduced after adjustment for the presence of PCOS.
Conclusion: The increase in low-grade chronic inflammation and in insulin resistance in women with PCOS is primarily associated with increased central fat excess rather than PCOS status per se. Procalcitonin represents a novel marker of the inflammatory activity of body fat and of PCOS.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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, IL-6, and procalcitonin (ProCT) (7, 8, 9). It is also the origin of the antiinflammatory IL-1 receptor antagonist (IL-1Ra) (10, 11). In patients with PCOS, circulating levels of TNF-, IL-6, and hs-CRP as well as white blood cell count (WBC) and neutrophil count have been found to be elevated compared with age- and/or body mass index (BMI)-matched controls (12, 13, 14, 15, 16, 17, 18, 19). In contrast, recent reports found that obesity and not PCOS status per se was a major determinant of the circulating inflammatory markers TNF-, soluble type 2 TNF receptor, IL-6, and hs-CRP (4, 5). Although control women have previously been investigated in the early to midfollicular phase, women with PCOS have been studied randomly, either during prolonged amenorrhea and/or after progestin-induced or spontaneous withdrawal bleeding in most studies. Recent data suggest, however, that menstruation itself is an inflammatory process (20) and thus might also modulate serum concentrations of inflammatory markers. Furthermore, these markers are also influenced by circulating sex hormones (21, 22, 23, 24, 25). We showed, for example, that hs-CRP serum concentrations change during the menstrual cycle. They are highest in the early follicular phase and decrease again in the midfollicular phase (26). Thus, the exact timing (early follicular vs. midfollicular phase) of blood sampling in control subjects can be crucial.
When comparing patients with PCOS with controls, most previous studies adjusted differences in serum inflammatory markers for BMI or total fat mass. However, the impact of body fat distribution, i.e. the central accumulation of body fat, on these markers has never been assessed previously.
Therefore, the present study investigated inflammatory markers and estimates of insulin resistance in patients with PCOS on d 3 and 6 after progestin-induced withdrawal bleeding. These were compared with the values of control women on d 3 and 5 after spontaneous bleeding and to their respective mean concentrations during the menstrual cycle, respectively. We were specifically interested whether differences in inflammatory markers and in estimates of insulin resistance between patients with PCOS and controls are associated with total body fat, the central accumulation of body fat, or the presence of PCOS status per se. Because sex hormones have a strong influence on body fat distribution (27, 28), we also studied the relationship between circulating sex hormones and central fat accumulation in these young women.
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Subjects and Methods |
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We consecutively recruited 20 patients diagnosed with PCOS who presented to our clinic and met the inclusion criteria. Fifteen control women with regular menses were simultaneously recruited, with an attempt to match for BMI and age.
The diagnosis of PCOS was based on a history of oligomenorrhea. In the two patients who had more than eight menstrual cycles per year, oligoovulation was confirmed by serum progesterone less than 9 nmol/liter between d 22 and 24 of the menstrual cycle (29). In addition, patients presented with either hirsutism, as defined by a modified Ferriman-Gallwey score above 7, acne, and/or circulating total testosterone or free androgen index, androstenedione, or dehydroepiandrosterone sulfate levels above the 95th percentile of levels observed in controls (30). Hyperprolactinemia, abnormal thyroid function and androgen-secreting tumors, and nonclassical 21-hydroxylase deficiency were ruled out in all of the patients. Fifteen of the 20 patients underwent transvaginal ultrasound, and all of them showed a polycystic appearance of their ovaries. None of the subjects had diabetes or evidence of cardiovascular disease, and blood pressure was less than 140/90 mm Hg in all participants on screening examination. None of the controls and three patients with PCOS smoked occasionally (all less than 10 cigarettes/d), and they were asked to abstain from smoking during the 2 wk of the study. Body weight had to be stable for at least 3 months before study. None of the subjects were taking drugs affecting metabolism, reproduction, or inflammation at the start of the study and during the preceding 6 months (sexual steroids) or during the last month (antiinflammatory drugs). There was no concurrent minor infection reported during the study or during the month preceding the study. Subjects were screened by medical history and examination. Blood was drawn in controls on d 21 of their preceding menstrual cycle to confirm ovulation by assessing progesterone levels. As a part of the screening, a blood cell count and chemistry including lipid levels were obtained to exclude major illnesses in all subjects. Asymptomatic urinary tract infection was excluded by routine urinalysis. All subjects were on an unrestricted diet and were instructed not to modify their usual eating patterns during the period of sampling. Participants were instructed not to exercise vigorously more than 3 h/wk and to refrain from exercise on the day before and on the morning of blood sampling. Some of the results of the controls have been previously reported (26). The study was approved by the local Ethics Committee of the University of Basel, Switzerland, and all subjects signed and received a copy of a written informed consent form.
Protocol
Clinical and anthropometric variables were evaluated by a single investigator in all subjects. Controls and one patient with PCOS were studied after spontaneous menstrual bleeding had begun. The other patients with PCOS received 20 mg dydrogesterone for 10 d to induce withdrawal bleeding. After an overnight fast of at least 10 h, fasting blood samples were drawn between 0730 and 0930 h on d 3 and 5 after the beginning of spontaneous menstrual bleeding in controls and on d 3 and 6 after withdrawal bleeding in patients with PCOS. Then, a 75-g oral glucose tolerance test was performed in patients with PCOS, and samples were obtained for measurement of plasma glucose at 0, 30, 60, 90, and 120 min. Insulin resistance (IR) was estimated by calculating homeostasis model assessment (HOMA-IR) index [fasting serum insulin (µU/ml) x fasting plasma glucose (mmol/liter)/22.5] (31).
In women with regular menstrual cycles, fasting morning blood samples were further drawn on d 8–16, 18, 21, 24, and 27 of their menstrual cycle.
Assays
Blood samples were immediately centrifuged, and serum was aliquoted and stored at –70 C until batch analyzed. Fasting samples were assayed for progesterone, estradiol, LH, hs-CRP and TNF-, ProCT, IL-1Ra, SHBG, and fasting and poststimulation samples for insulin using a electrochemiluminescence assay (Roche-Diagnostics, Rotkreuz, Switzerland) with a reference range of 17.8–173 pmol/liter (2.6–24.9 µU/ml), intraassay coefficient of variation (CV) of 1.9%, and interassay CV of 2.6%. The insulin assay was highly specific without known cross-reaction with proinsulin. Plasma glucose was measured by the hexokinase method.
LH, progesterone, and estradiol were measured by electrochemiluminescence immunoassays (Roche-Diagnostics). The intraassay CVs were 1.8, 2.4, and 3.3%, respectively. The interassay CVs were 5.2, 5.5, and 4.7%, respectively. SHBG was measured by electrochemiluminescence immunoassay (Roche-Diagnostics). The reference range for women was 20–130 nmol/liter. The intraassay CV was 2.7%, and the interassay CV was 5.6%.
Hs-CRP was measured automatically by a nephelometric latex immunoassay (Roche-Diagnostics), and TNF- and IL-1Ra were measured by a manual ELISA (R&D Systems, Minneapolis, MN). The sensitivity of hs-CRP was 0.11 mg/liter, and the reference range was less than 0.5–4.71 pg/ml. The intraassay CVs of hs-CRP, TNF-, and IL-1Ra were 1.3, 8.8, and 6.2%, respectively, and their interassay CVs were 5.7, 16.7, and 6.7% at the respective cutoffs of the reference range, respectively.
ProCT was measured by an ultrasensitive immunoluminometric assay (ProCa-S; BRAHMS, Hennigsdorf, Germany). The functional assay sensitivity was 6.0 ng/liter, and the normal reference range was 30 ± 20 ng/liter (32). At the limit of the functional sensitivity, the intraassay CV was less than 15%, and the interassay CV was less than 20%. Samples for each subject were run in the same assay, and duplicate measurements for TNF- and ProCT were performed for each subject.
Body composition and fat distribution
On d 3 of the menstrual cycle, dual-energy x-ray absorptiometry (DXA) was performed to determine total and regional body fat mass using a Lunar Expert densitometer (Lunar, Madison, WI). Regions of interest (including arms, legs, and trunk) were standardized. Percent body fat and percent lean body mass were calculated. Percent trunk fat was calculated as the ratio of trunk fat tot total fat x 100. Percent extremity fat was calculated as the ratio of total extremity fat (right and left arm fat and right and left leg fat) to total fat x 100. Trunk to extremity fat ratio was determined by dividing percent trunk fat by percent extremity fat (26, 33, 34).
Statistical analysis
Data are shown as means ± SD for normally distributed variables and as median and interquartile ranges for not normally distributed variables, respectively, unless stated differently. Variables with a skewed distribution were log transformed for all analyses. The mean values of both test days (d 3 and 5 for controls and d 3 and 6 for patients with PCOS, respectively) were used for all analyses unless stated otherwise. For the serum hs-CRP and estradiol concentrations, the mean values of 15 measurements taken throughout the menstrual cycle were generally used for the controls and mean values of d 3 and 6 for the patients with PCOS, unless stated differently. Laboratory and anthropometric parameters of patients with PCOS and controls were compared by Student’s t test or Mann-Whitney U test. The effects of PCOS status on laboratory and anthropometric parameters were assessed using multiple linear regression models adjusting for age, total fat mass, and central fat accumulation. Correlation analysis and partial correlation analysis adjusting for age, total fat mass, central fat accumulation, or PCOS status were applied to define the relationship between laboratory and anthropometric parameters.
Based on the data from Kelly et al. (12), who had studied 17 patients with PCOS and 15 controls, we estimated a mean difference in log CRP between patients and controls to be 0.5 log mg/liter. Assuming a SD of 0.6 log mg/liter for log CRP, a type I error rate of 5% and a type II error rate of 10% (i.e. 90% power), the sample size calculated to 32 subjects in both groups together. Post hoc power analysis, assuming a type I error rate of 5% and a type II error rate of 20% (i.e. 80% power), revealed a sample size of 24–42 subjects in both groups together for the different inflammatory mediators and metabolic hormones.
Statistical analyses were done by Statistica for Windows, version 6 (StatSoft, Inc., Tulsa, OK) or by Intercooled STATA (version 8; StataCorp LP, College Station, TX).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Serum inflammatory markers, WBC, neutrophil count, and estimates of insulin resistance were higher in patients with PCOS compared with controls despite similar total fat mass (Table 1
and Fig. 1). Patients with PCOS were characterized by higher triglyceride and lower high-density lipoprotein (HDL) serum concentrations. For comparisons of the serum concentrations of hs-CRP and estradiol, both the mean concentrations of d 3 and 5 and the mean concentrations during the whole menstrual cycle were used in the controls.
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, IL-1Ra, WBC, and neutrophil count as well as HOMA-IR and SHBG were higher in the 16 obese participants (patients and controls) compared with the lean participants (all P 0.03). All of the controls had normal fasting glucose levels, whereas one patient with PCOS had impaired fasting glucose, one had impaired glucose tolerance, and three had both impaired fasting glucose and impaired glucose tolerance.
Anthropometric and laboratory parameters were progressively adjusted for age (because patients with PCOS were slightly older), fat mass, and body fat distribution. Even after adjustment for age and total fat mass, PCOS status was still associated with increased central fat accumulation and increased serum concentrations of mean hs-CRP, ProCT, leukocytes, and estimates of insulin resistance, whereas this association remained only borderline significant for the TNF- serum concentrations (Table 2). However, after additional adjustment for central accumulation of body fat (trunk to extremity fat ratio), the impact of PCOS status per se on inflammatory markers and estimates of insulin resistance lost statistical significance (hs-CRP, TNF-, WBC, neutrophil count, HOMA-IR, triglycerides, and HDL). In contrast, the impact of PCOS status per se on circulating sex hormones (estradiol, LH, testosterone, and the free androgen index) remained unchanged or changed only minimally after adjustment for age, total fat mass, and central accumulation of body fat. Very similar results were obtained if the trunk fat mass was used instead of the trunk to extremity fat ratio as a marker of central fat accumulation (data not shown).
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Total fat mass correlated significantly to the estimates of insulin resistance and to the serum levels of most inflammatory markers (hs-CRP, ProCT, and IL-1Ra) except TNF- after adjusting for age and central fat accumulation (data not shown). Even after additional adjustment for PCOS status, there was still a significant correlation between fat mass and HOMA-IR (r2 = 0.35; P < 0.0001) as well as the serum concentrations of SHBG (r2 = 0.16; P = 0.02), hs-CRP (r2 = 0.36; P = 0.001), ProCT (r2 = 0.29; P < 0.0001), and IL-1Ra (r2 = 0.58; P < 0.0001).
Central fat accumulation (trunk to extremity fat ratio) correlated significantly to the estimates of insulin resistance and to the serum levels of most inflammatory markers (hs-CRP, ProCT, and IL-1Ra) except TNF-, independently of age and total fat mass (data not shown). After additional adjustment for PCOS status, there was still a significant correlation between the trunk to extremity fat ratio and HOMA-IR (r2 = 0.35; P < 0.0001), as well as the serum concentrations of SHBG (r2 = 0.31; P = 0.04), hs-CRP (r2 = 0.27; P = 0.003), and IL-1Ra (r2 = 0.20; P = 0.009).
The trunk to extremity fat ratio correlated significantly to the serum ProCT concentrations after adjusting for age and fat mass but not after additional adjustment for PCOS status (partial correlation analysis before adjustment for PCOS status, r2 = 0.07 and P = 0.02; after additional adjustment for PCOS status, r2 = 0.01 and P = 0.4). Using the trunk fat mass instead of the trunk to extremity fat ratio as a marker of central fat accumulation did not significantly alter the results (data not shown).
Relationship between circulating sex hormones and central fat accumulation in all women (PCOS and controls)
Because the serum estradiol concentrations change during the menstrual cycle, the integral exposure of estrogen in cycling controls was used to assess its effect on body fat distribution. Thus, the mean estradiol concentrations during the total menstrual cycle were used in controls, and the mean estradiol concentrations on d 3 and 6 in the oligoovulatory patients with PCOS. In all participants, serum estradiol concentrations correlated positively to the percent extremity fat (r2 = 0.15; P = 0.02) and negatively to both the percent trunk fat (r2 = 0.15; P = 0.02) and the trunk to extremity fat ratio (r2 = 0.15; P = 0.02). In contrast, the free androgen index correlated negatively to the percent extremity fat (r2 = 0.22; P = 0.005) and positively to both the percent trunk fat (r2 = 0.25; P = 0.002) and the trunk to extremity fat ratio (r2 = 0.24; P = 0.003). Adjusting for total fat and age did not alter these correlations. However, adjusting for other parameters that are associated with central accumulation of body fat greatly reduced or eliminated the correlations between circulating sex hormones and body fat distribution. For example, after adjusting for HOMA-IR, hs-CRP serum concentrations, or PCOS status, the inverse correlation between the serum estradiol concentrations and the trunk to extremity ratio was reduced to r2 = 0.08 (P = 0.09), 0.08 (P = 0.1), and –0.01 (P = 0.5), respectively. Similarly, after adjusting for HOMA-IR, hs-CRP serum concentrations, or PCOS status, the correlation between the free androgen index and the trunk to extremity ratio diminished to r2 = 0.07 (P = 0.1), 0.08 (P = 0.1), and 0.15 (P = 0.09), respectively.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In agreement with previous studies (2, 3), we found that patients with PCOS had an excess of central fat independent of total fat mass. Central fat excess is usually associated with an increase in serum inflammatory markers and in insulin resistance (27). On the other side, sex hormones affect body fat distribution and thereby might in part explain the gender-specific differences in body fat distribution (27, 28). In our present study as well as in other studies, the free androgen index correlated to the central fat accumulation (37, 38). Also, estrogens have been shown to influence body fat distribution (27, 39). We found that estradiol serum concentrations correlated negatively to central accumulation of body fat and positively to extremity fat. This supports the hypothesis that physiological concentrations of estrogens have a protective effect on central fat accumulation in young women. However, the role of sex hormones on the central fat excess in patients with PCOS is most likely minor. For example, the relationship between circulating sex hormones and central fat accumulation in our study was greatly reduced or even lost after adjustment for other factors that are associated with central fat excess. Furthermore, the impact of PCOS on circulating sex hormones was independent of body fat or body fat distribution. These observations are important for an improved understanding of the complex relationships between circulating sex hormones and features of the metabolic syndrome in PCOS. Alterations in plasma levels of sex hormones, i.e. an increase in free androgens, could be an entity in PCOS that is independent of a second entity that consists of central fat, insulin resistance, and hs-CRP. This concept may contribute to the striking efficacy of combining insulin-sensitizing (metformin) and antiandrogen (flutamide) therapy to attenuate both the central fat excess, assessed by DXA, and the proinflammatory state in women with PCOS (3, 38, 40). Thereby, metformin had a more normalizing effect (40). These intervention studies point to a causal relationship between insulin resistance, inflammation, and central fat excess in women with PCOS. Thus, central fat excess might lead to increased insulin resistance and inflammation or, as demonstrated in the above studies, increased insulin resistance (and inflammation) might lead to central fat excess (41). However, one limitation of our study is that the needed sample size for many variables is just around or above our actual sample size. Therefore, the borderline lack of association between some of the inflammatory mediators such as TNF- and the PCOS status after adjustment for central fat accumulation could potentially also be a result of the power limitation of the study.
Our study might also be limited by the fact that we used DXA measurements. DXA can assess only total trunk mass or trunk to extremity fat ratio and cannot differentiate between visceral vs. sc central fat. However, it is also debated whether central visceral, central sc fat, or both have a predominant impact on insulin resistance (42). Using the trunk to extremity fat ratio as calculated by DXA, we found a good correlation to the HOMA-IR or the hs-CRP serum concentrations in young, regularly menstruating women (26). Furthermore, more recent studies show parallel changes in the trunk fat (in kilograms or in percentage of total fat) as calculated by DXA and visceral adipose fat measured by magnetic resonance imaging or computed tomography (43, 44).
Both obesity and central fat excess are closely linked to low-grade chronic inflammation (6, 7, 45). In adipose tissues, many proinflammatory markers (IL-1, IL-6, TNF-, and ProCT) as well as antiinflammatory markers (IL-1Ra) are secreted (7, 8, 9, 10, 11, 45). CRP is produced in the liver, primarily upon IL-6 stimulation (46). The present study reported for the first time an increase in serum ProCT concentrations in women with obesity and PCOS. ProCT levels correlated significantly to both body fat and body fat distribution. Several clinical and experimental data indeed suggest that ProCT is ubiquitously produced upon infectious and (to a lesser extent also) by inflammatory stimulation (9, 47, 48). Thus, ProCT represents a novel marker of the more chronic inflammatory activity of body fat and of PCOS.
Serum levels of inflammatory markers such as TNF-, IL-6, and hs-CRP have been found to be elevated in patients with PCOS compared with age- and/or BMI-matched controls in several studies (12, 13, 14, 15, 16, 17, 18). In addition, in young women with PCOS, changes in serum concentrations of IL-6 paralleled the changes of both total and abdominal fat mass (3). Accordingly, common polymorphisms in the genes encoding TNF-, soluble type 2 TNF receptor, IL-6, and the IL-6 signaling molecule gp130 were associated with PCOS (49). In contrast, two recent studies found that the increase in the inflammatory markers TNF-, IL-6, and hs-CRP in PCOS was solely caused by obesity, i.e. that PCOS status per se had no effect in these patients (4, 5). Thus, although it is indisputable that patients with PCOS are more insulin resistant, at least in part because of central fat excess (2, 4, 5), the impact of PCOS status or of body fat distribution in addition to obesity on inflammatory markers is controversial. In our study, the obese group of patients and controls together had higher concentrations of inflammatory markers and higher estimates of insulin resistance compared with nonobese subjects, even after adjusting for age and central body fat accumulation. On the other side, also PCOS status, most likely a result of central fat excess, was a major predictor for low-grade chronic inflammation and insulin resistance, independently of age and total body fat.
The controversy regarding the impact of PCOS status on low-grade chronic inflammation in addition to total fat could have several explanations: differential expression of inflammatory markers in the various tissue compartments, e.g. visceral vs. sc tissues (11), variability of their serum concentrations (35), a predominant local activity of some of the inflammatory markers (e.g. TNF-) (4), and influence of sex hormones or the inflammatory process of menstruation itself on the serum concentrations of some inflammatory markers (20, 21, 22, 23, 24, 25). We showed, for example, that the serum concentrations of hs-CRP change during the menstrual cycle and are highest in the early follicular phase compared with all other menstrual cycle phases (26). This can explain why comparing the hs-CRP serum concentrations of patients with PCOS to those of controls drawn in the early follicular phase did not show any differences in our and some other studies (4, 5) but were higher when compared with the mean hs-CRP concentrations of controls during the menstrual cycle.
In summary, we demonstrated that the increase in low-grade chronic inflammation and in insulin resistance in women with PCOS is associated with central fat excess. Independently of each other, both total body fat as well as central fat excess have a major impact on serum levels of inflammatory mediators, on the WBC, and on estimates of insulin resistance. In our population of young women, serum ProCT, in low levels, represents a novel inflammatory marker of body fat. In contrast to low-grade chronic inflammation and insulin resistance, the differences in circulating sex hormones, especially the androgen excess, in women with PCOS are independent of body fat distribution. Although we can demonstrate a relationship between central body fat accumulation and sex hormones, this relationship is greatly reduced or even lost after adjustments for other factors that are associated with central fat accumulation. Our findings underline the important links between total and regional body fat, insulin resistance, low-grade chronic inflammation, and circulating sex hormones.
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Acknowledgments |
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Footnotes |
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First Published Online August 16, 2005
1 J.J.P. and S.V. contributed equally to this study. 
Abbreviations: BMI, Body mass index; CV, coefficient of variation; DXA, dual-energy x-ray absorptiometry; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment of insulin resistance; hs-CRP, highly sensitive serum C-reactive protein; IL-1Ra, IL-1 receptor antagonist; PCOS, polycystic ovary syndrome; ProCT, procalcitonin; WBC, white blood cell count.
Received May 5, 2005.
Accepted August 4, 2005.
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References |
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levels in normal-weight women with polycystic ovaries or the polycystic ovary syndrome. J Reprod Med 48:165–170[Medline]
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