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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-0648
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 3 1173-1177
Copyright © 2006 by The Endocrine Society

BRIEF REPORT

Increased Circulating Levels of Matrix Metalloproteinase-2 and -9 in Women with the Polycystic Ovary Syndrome

K. C. Lewandowski, J. Komorowski, C. J. O’Callaghan, B. K. Tan, J. Chen, G. M. Prelevic and H. S. Randeva

Department of Biological Sciences (K.C.L., B.K.T., J.C., H.S.R.), Molecular Medicine Research Group, The University of Warwick, Coventry CV4 7AL, United Kingdom; Department of Endocrinology and Metabolic Diseases (K.C.L., J.K.), The Medical University of Lodz, 90-419 Lodz, Poland; Department of Community Health and Epidemiology (C.J.O.), Queen’s University, Kingston, Ontario, Canada K7L 3N6; and Department of Medicine (G.M.P.), Royal Free and University College Medical School, London NW3 2PF, United Kingdom

Address all correspondence and requests for reprints to: Dr. Harpal S. Randeva, M.B.Ch.B., F.R.C.P., Ph.D., Molecular Medicine Group, Department of Biological Sciences, The University of Warwick, Coventry CV4 7AL, United Kingdom. E-mail: hrandeva{at}bio.warwick.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Introduction: Matrix metalloproteinases (MMPs) have been implicated in various pathological processes including inflammatory response, cardiovascular disease, and recently also in ovarian dysfunction. Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age and is characterized by chronic anovulation, insulin resistance, and increased prevalence of cardiovascular risk factors. Circulating levels of MMPs and their tissue inhibitors (TIMPs) so far have not been assessed in the PCOS.

Materials and Methods: Serum levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 were measured in 23 women with PCOS [age (mean ± SD), 30.5 ± 6.7 yr; body mass index, 35.8 ± 7.5 kg/m2] and 22 healthy, regularly menstruating women (age, 29.4 ± 5.6; body mass index, 31.7 ± 9.2 kg/m2).

Results: Women with PCOS had significantly higher concentrations of MMP-2 (999.8 ± 155 vs. 521.8 ± 242 ng/ml; P < 0.001), MMP-9 (592.4 ± 279 vs. 345 ± 309; P = 0.007), and TIMP-1 levels (823.8 ± 145 vs. 692 ± 210 ng/ml; P = 0.02) than control healthy women. There was no difference in TIMP-2 levels (47.3 ± 30 vs. 44.4 ± 39.7 ng/ml; P = 0.21) between women with PCOS and controls.

Conclusions: Obese women with PCOS have elevated serum concentrations of MMP-2 and -9. It might be hypothesized that elevated MMP concentrations may be related to increased cardiovascular risk in PCOS and/or menstrual irregularities associated with this syndrome.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
MATRIX METALLOPROTEINASES (MMPS) are a family of zinc-binding proteolytic enzymes that normally remodel the extracellular matrix. Increased activity of MMPs has been reported in numerous disease processes including atherosclerosis and cardiovascular disease (1, 2, 3, 4, 5, 6). The regulation of MMP activity is complex and occurs at multiple levels, including interactions of secreted MMPs with tissue inhibitors of metalloproteinases (TIMPs) (7). In its inactive form, MMP-9 is complexed to TIMP-1, whereas proMMP-2/MMP-2 is complexed to TIMP-2, and the balance between MMPs and TIMPs determines the degree of matrix degradation. The gelatinases (MMP-2 and -9), along with MMP-1 (interstitial collagenase) and Mt1-MMP, are the major MMP species in the vasculature; the gelatinases specifically attack type IV collagen, laminin, and fibronectin (8).

MMP-2 and MMP-9 play a major role in vascular matrix remodeling (9). Increased expression of MMP-9 has been demonstrated in the vulnerable regions of human atherosclerotic plaques (2, 5). Circulatory levels of MMP-2 and MMP-9 are raised in patients with acute coronary syndromes (6) and cerebral ischemia (10, 11). MMPs and TIMPs have also been implicated in ovarian physiology and pathophysiology (12). For example, MMP-2 and -9 and TIMP-1 and -2 are also expressed in human ovary (13), and their function is necessary for follicular rupture and oocyte release. These observations may be particularly relevant to women with polycystic ovary syndrome (PCOS).

PCOS, the most common endocrinopathy in women of reproductive age, is characterized by hyperandrogenism, chronic anovulation, and hyperinsulinemia (14). The syndrome is also a multifaceted metabolic disease with insulin resistance, dyslipidemia, impaired glucose tolerance, overt type 2 diabetes mellitus, and elevated systolic blood pressure being more prevalent in obese young women with PCOS than weight-matched controls (15, 16, 17, 18). A significantly higher incidence of type 2 diabetes mellitus and hypertension, compared with age-matched controls, has been reported in PCOS women (19), although not all studies are consistent with these findings (20, 21).

In view of the role of MMPs in cardiovascular disease and also ovarian physiology, we decided to assess plasma levels of MMPs and TIMPs in women with PCOS.


   Subjects and Methods
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 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The study group consisted of 23 women with the PCOS [age 30.5 ± 6.7 yr, body mass index (BMI) 35.8 ± 7.5 kg/m2] and 22 healthy, regularly menstruating women, who acted as controls (age 29.4 ± 5.6 yr, BMI 31.7 ± 9.2 kg/m2). Thirty-five consecutive patients who presented with ovulatory dysfunction (oligo-/amenorrhea) and features of hyperandrogenism and who had polycystic ovaries on pelvic ultrasound (22) were offered to participate in this study. Those who accepted to take part in our study (PCOS; n = 23) were recruited from our Reproductive Endocrine Clinic. All had ovulatory dysfunction and polycystic ovaries on scan. Eighteen (78%) had mild to moderate hirsutism, and 12 (52%) had acanthosis nigricans. All women with PCOS had raised either total testosterone or free androgen index and decreased SHBG levels. None of these subjects were on any medications for at least 6 months before the study. The presence of other endocrinopathies were ruled out by measuring basal serum 17-hydroxyprogesterone, prolactin, and 0800–0900 h cortisol after 1.0 mg (2300 h) overnight dexamethasone suppression (value < 30 nmol/liter was considered to rule out Cushing’s syndrome). Women from the control group (n = 22) were volunteers from the medical school and the staff of the University of Lodz. All volunteers had medical examination for the purpose of the study; normal findings on pelvic ultrasound scan, regular periods, and no hirsutism/acne and were not taking any medications. Exclusion criteria for the study included age over 40 yr, known cardiovascular disease, thyroid disease, current smoking, diabetes mellitus, hypertension (blood pressure > 140/90 mm Hg), and renal impairment (serum creatinine > 150 µmol/liter). All subjects gave informed consent for participation in the study, which was approved by the Ethics Committees of the University College of London and the Medical University of Lodz.

Biochemical analyses

In control subjects, who had regular menses, and PCOS women with oligomenorrhea, blood samples were taken during the early follicular phase (d 2–5 from the first day of spontaneous bleeding episode), whereas there was no special timing in amenorrheic women. In amenorrheic PCOS women (n = 4), serum progesterone levels were measured to ascertain the stage of the menstrual cycle.

After an overnight fast, blood samples were collected on ice and stored at –70 C. MMP-2, MMP-9, TIMP-1, and TIMP-2 were measured by ELISAs [MMP-2: human, Biotrak ELISA system; Amersham Biosciences, Buckinghamshire, UK; intraassay precision coefficient of variation (CV) 6.3%; MMP-9 (total): R & D Systems, Minneapolis, MN, CV 2.9%; TIMP-1: Amersham Pharmacia Biotech UK Ltd., Little Chalfont, UK, CV 9.4%; TIMP-2: Amersham Pharmacia Biotech, CV 5.2%].

Statistical analysis

Simple descriptive statistics and tests of differences between groups and associations between covariates within groups were performed using SAS software (version 8.2; SAS Institute, Inc., Cary, NC). Univariate tests of differences between study groups were supplemented with multiple variable models for main outcome parameters controlling for the potential effects of other cofactors. In all analyses, statistical significance was considered achieved for P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Given that controls (Caucasians) were volunteers from University of Lodz and PCOS women (Caucasians) from the reproductive clinic, University of London, we analyzed and compared MMPs and TIMPs from normal volunteers (Caucasians) from both countries (European Union Grant QLK3-CT-2002-30326) to study potential differences in MMPs between populations in Poland and the United Kingdom. Matched women from Poland [n = 78; age 40 ± 7.8 yr (range 21–46), BMI 28.6 ± 5.6 kg/m2 (range 22–40)] and those from the United Kingdom [n = 82; age 39 ± 9.1 yr (range 23–44), BMI 29.9 ± 8.5 kg/m2(range 24–43)] had no significant differences in MMPs and TIMPs [Poland (mean ± SD; ng/ml): MMP-2 560 ± 201; MMP-9 465 ± 193; TIMP-1 590 ± 224; TIMP-2 90 ± 42; United Kingdom: MMP-2 541 ± 229; MMP-9 487 ± 221; TIMP-1 572 ± 201; TIMP-2 101 ± 53; P = NS].

Serum progesterone levels in the amenorrheic PCOS women (n = 4) corresponded to values in the follicular phase of the menstrual cycle [1.6 ± 1.1 nmol/liter; (follicular < 6 nmol/liter; luteal 6–64 nmol/liter)]. Descriptive demographics and contrasts of covariates of interest between control women and women with PCOS are presented in Table 1Go. There was no significant difference in mean age and BMI difference between the two groups. Women with PCOS had higher waist to hip ratio (WHR; P = 0.03) and fasting insulin (P = 0.004). In addition, women with PCOS had higher total testosterone (P = 0.0008), lower mean SHBG (P = 0.0002), resulting in a higher free androgen index (P < 0.001). With respect to the main outcome variables of interest, MMP-2 (P < 0.0001), MMP-9 (P = 0.007), and TIMP-1 (P = 0.02) levels were all significantly higher in women with PCOS than observed in controls, except for TIMP-2 (P = 0.21). When the potential effects of age, BMI, WHR, and hormonal indices were controlled for by inclusion in a multiple variable regression model for each outcome (MMP-2, MMP-9, and TIMP-2), the differences observed between women with PCOS and controls were preserved (Table 1Go), but the difference ceased to be significant for TIMP-1 (P = 0.1; Table 1Go). Moreover, the ratio of MMP-9 to TIMP-1 and that of MMP-2 to TIMP-2 was significantly greater in women with PCOS [0.59 ± 0.24 (SD) vs. 0.36 ± 0.23, P < 0.01; and 19.2 ± 10.42 vs. 9.40 ± 6.4, P = 0.008, respectively].


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  		TABLE 1. Descriptive demographics and univariate and multiple variable contrasts of covariates between control women (n = 22) and women with PCOS (n = 23)

 
Table 2Go illustrates the bivariate assessments of association between covariates of interest for each study group. There was a negative correlation between MMP-2 and WHR in the PCOS group (r = –0.50, P = 0.017), a finding that failed to reach significance in the control group (r = –0.47, P = 0.07).). In the control group, there was a negative correlation between MMP-2 and BMI (r = –0.50, P < 0.05). MMP-9 levels correlated positively with both age (r = 0.46; P < 0.05) and BMI (r = 0.60; P < 0.05) in controls. There was no correlation between MMP-9 and age or BMI in women with PCOS (r = 0.30, P = 0.16 and r = 0.09, P = 0.70, respectively). In both groups, there was no significant correlation between fasting insulin and MMPs or TIMPs.


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  		TABLE 2. Bivariate assessments of association between covariates of interest for each study group expressed as Pearson correlation coefficients

 

   Discussion
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The most important and novel finding of this study is that women with PCOS, a patient group at increased risk of cardiovascular disease, have raised circulating concentrations of MMP-2 and MMP-9. To date, data on the levels of MMP-2 and MMP-9 measured in ovarian follicular fluid appear to be conflicting. Lahav-Baratz et al. (23) report similar activities of follicular fluid MMP-2 and MMP-9 in PCOS women, compared with controls. Another study, however, reported higher follicular fluid concentrations of MMP-2 and MMP-9 in 16 women with PCOS in comparison with 16 controls (24). However, both studies did not assess circulating levels of MMPs and TIMPs. The present study is the first to assess circulating MMPs/TIMPs in PCOS women.

Raised circulating concentrations of MMPs might be, however, potentially related to the pathophysiology of PCOS, in which follicular atresia and increased ovarian stroma may be associated with alterations of extracellular matrix remodeling (12, 25, 26) and increased MMP-2 and -9 levels (27). Proteolytic enzymes that degrade collagen type IV, which maintains the tensile strength of the follicular wall (28), include MMP-2 and MMP-9, and MMP-3; the latter however, has not been detected within the ovarian follicles (29). One can therefore only speculate that increased circulating concentrations of MMP-2 and MMP-9 in women with PCOS may be related to abnormal basement membrane rupture or follicular atresia. It has yet to be clarified whether increased MMP-2 and MMP-9 concentrations are the cause or the consequence of follicular atresia.

In the vasculature, MMP-2 is synthesized predominantly by mesenchymal cells (smooth muscle and fibroblasts), whereas MMP-9 by endothelial cells, macrophages, and infiltrating inflammatory cells. MMPs are known acute phase reactants that increase inflammation, and factors that stimulate their production including oxidative stress and inflammatory cytokines (5, 30) are raised in PCOS (15, 16, 17, 18). Our finding of raised circulating MMP-2 and MMP-9 in women with PCOS is important because these women have an increased risk of developing early-onset atherosclerosis (31). Furthermore, in male subjects, angiographically documented early-onset atherosclerosis is associated with raised MMP-2 and MMP-9 levels (32). Epidemiological data also demonstrate, in both sexes, an increased risk of cardiovascular events in subjects with increased quartiles of MMP-9 concentrations (33, 34). MMP-9 also has been shown to impair cardiac contraction and depress systolic function (35), a phenotype also observed in women with PCOS (36). On the strength of the available evidence, it could be hypothesized that elevated serum concentrations of MMPs, found in women with PCOS, might potentially reflect their higher cardiovascular risk. Because TIMP-1 forms a specific complex mainly with proMMP-9 (7), then significantly raised MMP-9 levels and MMP-9 to TIMP-1 ratio in women with PCOS, as documented in this study, might result in higher free MMP-9 concentrations, thus further contributing to the increased cardiovascular risk in this group, such as early-onset atherosclerosis (31) and cardiac dysfunction (36). Similarly, given that proMMP-2 forms a specific complex mainly with TIMP-2 (7), the higher total MMP-2 concentrations and MMP-2 to TIMP-2 ratio in women with PCOS would suggest higher free MMP-2 concentrations in these subjects.

Although women with PCOS have a tendency to obesity, it is of interest to note that the increased MMP-2 and MMP-9 levels in women with PCOS do not seem to be related to their BMI or WHR, even when accounting for these variables and other hormonal indices in a multiple variable regression model. The lack of correlation between the MMPs and fasting insulin and between TIMPs and fasting insulin, with a negative correlation between MMP-2 and WHR in the PCOS group, would suggest against a significant relationship between the concentrations of MMPs and insulin resistance. Interestingly, Laimer et al. (37) have recently shown that weight loss, through gastric banding, decreased serum MMP-9 levels.

Finally, we also provide data comparing blood levels of MMPs and TIMPs among healthy European women of Caucasian origin and found no differences between Polish women and those women from the United Kingdom. The only available data on population differences in MMP/TIMP levels pertain to interracial differences, with no racial differences in MMP-2, TIMP-1, or TIMP-2 but lower MMP-9 in those from the Far East (38). A limitation of our study was related to the fact that current assays do not allow us to determine the exact origin of the measured MMPs (and TIMPs). The extent of the ovarian contribution to the serum pool of MMP-2 and MMP-9 as well as TIMP-1 and TIMP-2 remains, however, unclear and would require the invasive procedure of selective ovarian vein catheterization.

In conclusion, our study demonstrates elevated serum concentrations of MMP-2 and MMP-9 in women with PCOS. The clinical relevance of our findings remains to be established. Elevated MMP concentrations might be related to either increased cardiovascular risk or abnormalities of ovarian extracellular matrix remodeling, multiple cyst formation, and chronic anovulation noted in women with the PCOS.


   Acknowledgments
 
H.S.R. thanks S. Waheguru and Jaspal Kaur (University of Warwick, Coventry, UK) for their incessant support.


   Footnotes
 
First Published Online December 6, 2005

Abbreviations: BMI, Body mass index; CV, coefficient of variation; MMP, matrix metalloproteinase; PCOS, polycystic ovary syndrome; TIMP, and their tissue inhibitors of MMP; WHR, waist to hip ratio.

This work was partially supported by a European Union grant (Center of Excellence in Molecular Medicine QLK3-CT-2002-30326).

Received March 24, 2005.

Accepted November 30, 2005.


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 Introduction
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Raised Matrix Metalloproteinases in Women with Polycystic Ovary Syndrome
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