Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
1 To whom correspondence should be addressed. E-mail: yutakaos-tky{at}umin.ac.jp
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: adiponectin/endometriosis
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
It is well known that the development of endometriosis is estrogen dependent. Estrogen also functions as a promoting factor for gynaecological tumours such as breast cancer, endometrial cancer and uterine leiomyoma. Notably, several recent studies demonstrated that circulating adiponectin concentrations are decreased in women with breast cancer (Miyoshi et al., 2003; Mantzoros et al., 2004
), endometrial cancer (Dal Maso et al., 2004
) and uterine leiomyomas (Chen et al., 2004
), suggesting possible roles of adiponectin in these diseases.
Adiponectin is an 30 kDa polypeptide containing an N-terminal signal sequence, a variable domain, a collagen-like domain, and a C-terminal globular domain. It is highly and specifically expressed in differentiated adipocytes and circulates at high levels in the blood stream (Scherer et al., 1995
; Hu et al., 1996
; Maeda et al., 1996
; Nakano et al., 1996
; Kadowaki and Yamauchi, 2005
). Both adiponectin concentrations in adipose tissue and in the circulation are reduced in obesity (Hu et al., 1996
; Arita et al., 1999
). Adiponectin was first discovered as a regulator of insulin sensitivity and metabolism; later studies manifested its pleiotropic activities such as anti-inflammatory, anti-angiogenic and anti-atherosclerotic effects (Yokota et al., 2000
; Brakenhielm et al., 2004
; Goldstein and Scalia, 2004
).
In view of the possible implication of adiponectin in the estrogen-related tumours, we set out to examine whether serum adiponectin concentrations are aberrant in women with endometriosis.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The distribution of the stage of endometriosis was as follows: stage I, n = 10; stage II, n = 6; stage III, n = 10; stage IV, n = 22. The non-endometriosis (control) group consisted of women with infertility (n = 13), ovarian dermoid cysts (n = 14), and ovarian serous cysts (n = 3), and none of these women had uterine leiomyoma. In the non-endometriosis group, 15 women were in the proliferative phase and 15 were in the secretory phase. Eight women were in each phase in stage I/II endometriosis, and 16 were in each phase in stage III/IV endometriosis.
Fasting morning blood samples were taken for measurement of adiponectin before laparoscopy. The blood was immediately separated by centrifugation at 400¥g for 10 min, and the serum was stored at 80°C until use.
Concentrations of adiponectin in the serum were measured using a specific enzyme-linked immunosorbent assay (ELISA; Genzyme/Techne, Minneapolis, MN, USA) according to the manufacturers protocol. The sensitivity of the assay was 62.5 pg/ml for adiponectin. The intra- and inter-assay coefficients of variation were 3.2 and 7.4% respectively.
Statistical analysis was conducted using MannWhitney U-test and linear regression analysis. P < 0.05 was considered significant.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
As shown in Figure 1, adiponectin concentrations in the serum with endometriosis (median, 13.1 µg/ml; IQR, 10.216.7) were significantly lower than those without endometriosis (15.9 µg/ml, 13.519.5; P = 0.008). The women with endometriosis were then subdivided into those with stage I/II and those with stage III/V for further analysis. The concentrations of adiponectin in stage III/IV endometriosis (12.8 µg/ml, 10.616.6) were significantly lower than those in non-endometriosis (P = 0.004), while those in stage I/II endometriosis (15.1 µg/ml, 9.317.0) appeared to be intermediate. No remarkable difference was observed between the proliferative phase and the secretory phase in each stage (data not shown).
|
The correlations between serum adiponectin concentrations and endometriosis scores or adhesion scores are shown in Figure 2. A significant negative correlation was found between serum adiponectin concentrations and both endometriosis scores (R = 0.307, P = 0.006) and adhesion scores (R = 0.254, P = 0.026). As demonstrated in Figure 3, the women with obliteration of cul-de-sac had significantly lower adiponectin concentrations (12.8 µg/ml, 7.816.6) than those without obliteration (14.8 µg/ml, 12.818.3; P = 0.026).
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
It is well known that the circulating levels of adiponectin are inversely related to body mass index (BMI) (Arita et al., 1999; Hotta et al., 2000
; Yang et al., 2002
). However, BMI is substantially the same in women with endometriosis and in those without the disease in this study. Therefore, the low serum adiponectin concentrations observed in women with endometriosis is not due to the difference of BMI but related to the disease per se.
Estrogen is known to stimulate the development of endometriosis. Together with the findings that circulating adiponectin concentrations are decreased in women with estrogen-related tumours, such as breast cancer (Miyoshi et al., 2003; Mantzoros et al., 2004
), endometrial cancer (Dal Maso et al., 2004
) and uterine leiomyomas (Chen et al., 2004
), it is speculated that the decrease in adiponectin concentrations observed in the present study may facilitate the growth-promoting effect of estrogen on endometriosis. A possibility is that insulin resistance induced by low adiponectin is associated with low SHBG levels (Jayagopal et al., 2004
), and may potentiate the effect of estrogen.
Another possible reason why low adiponectin levels may be associated with the development of endometriosis could be explained with an anti-angiogenic property of adiponectin. Adiponectin has been shown to inhibit angiogenesis both in vitro and in vivo (Brakenhielm et al., 2004). Furthermore, adiponectin suppressed tumour growth with decreased neovascularization in a mouse model (Brakenhielm et al., 2004
). These findings support the notion that low adiponectin concentrations may permit angiogenesis required for the development of endometriosis. Similarly, circulating and peritoneal fluid levels of angiogenic factors, such as angiogenin (Steff et al., 2004
; Suzumori et al., 2004
), hepatocyte growth factor (Osuga et al., 1999
; Zong et al., 2003
) and vascular endothelial growth factor (Matalliotakis et al., 2003
), are increased in women with endometriosis.
Low circulating adiponectin concentrations have been shown to be associated with increased plasma insulin levels (Yamamoto et al., 2002). Circulating insulin levels are inversely correlated with levels of serum insulin-like growth factor-binding protein 1 (IGFBP-1) (Suikkari et al., 1989
), which binds to insulin-like growth factor (IGF-I) and regulates its biological effect. Accordingly, low adiponectin concentrations may enhance effects of IGF-I, which has been shown to stimulate the growth of endometriosis (Giudice et al., 1994
).
It is well established that peritoneal inflammation is involved in the pathogenesis of endometriosis. In accordance with the notion, many proinflammatory cytokines are elevated in serum and peritoneal fluid of women with endometriosis (Wu and Ho, 2003; Yang et al., 2004
). Adiponectin has been shown to suppress macrophage activities (Yokota et al., 2000
). In addition, circulating adiponectin concentrations negatively correlate with C-reactive protein (Krakoff et al., 2003
; Ouchi et al., 2003
). Given the anti-inflammatory potential of adiponectin, it is feasible that low adiponectin concentrations are related to proinflammatory status associated with endometriosis.
A remarkable finding in the present study is that serum adiponectin concentrations are negatively correlated with adhesion scores as well as endometriosis scores. It is also noted that women with cul-de-sac obliteration had lower adiponectin concentrations than those without the obliteration. Anti-fibrotic characteristics of adiponectin were recently reported with the findings that adiponectin prevents liver fibrosis and suppresses the gene expression of transforming growth factor (TGF) , an inducer of fibrosis, in hepatic cells (Kamada et al., 2003
). Considering that fibrosis often accompanies adhesions in endometriosis, low adiponectin concentrations might also be related to pelvic adhesions associated with endometriosis.
Due to limitations of an observational study, it is difficult to determine whether the present findings are a cause or consequence of the endometriotic condition. Nevertheless, many biological features of adiponectin fit well for possible causes of the disease. Further studies are needed to settle the issue.
In summary, the present study demonstrated that serum adiponectin concentrations are decreased in women with endometriosis. In view of its pleiotropic functions, adiponectin may be involved in the pathophysiology of endometriosis.
![]() |
Acknowledgements |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K et al (1999) Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257,7983.[CrossRef][ISI][Medline]
Brakenhielm E, Veitonmaki N, Cao R, Kihara S, Matsuzawa Y, Zhivotovsky B, Funahashi T and Cao Y (2004) Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci USA 101,24762481.
Chen HS, Chan TF, Chung YF, Su JH and Yuan SS (2004) Aberrant serum adiponectin levels in women with uterine leiomyomas. Gynecol Obstet Invest 58,160163.[CrossRef][ISI][Medline]
Dal Maso L, Augustin LS, Karalis A, Talamini R, Franceschi S, Trichopoulos D, Mantzoros CS and La Vecchia C (2004) Circulating adiponectin and endometrial cancer risk. J Clin Endocrinol Metab 89, 11601163.
Giudice LC, Dsupin BA, Gargosky SE, Rosenfeld RG and Irwin JC (1994) The insulin-like growth factor system in human peritoneal fluid: its effects on endometrial stromal cells and its potential relevance to endometriosis. J Clin Endocrinol Metab 79,12841293.[Abstract]
Goldstein BJ and Scalia R (2004) Adiponectin: a novel adipokine linking adipocytes and vascular function. J Clin Endocrinol Metab 89,25632568.
Halme J, Hammond MG, Hulka JF, Raj SG and Talbert LM (1984) Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol 64,151154.[Abstract]
Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K et al (2000) Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20,15951599.
Hu E, Liang P and Spiegelman BM (1996) AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem 271,1069710703.
Jayagopal V, Kilpatrick ES, Jennings PE, Holding S, Hepburn DA and Atkin SL (2004) The biological variation of sex hormone-binding globulin in type 2 diabetes: implications for sex hormone-binding globulin as a surrogate marker of insulin resistance. Diabetes Care 27,278280.
Kadowaki T and Yamauchi T (2005) Adiponectin and adiponectin receptors. Endocr Rev 26,439451.
Kamada Y, Tamura S, Kiso S, Matsumoto H, Saji Y, Yoshida Y, Fukui K, Maeda N, Nishizawa H, Nagaretani H et al (2003) Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin. Gastroenterology 125,17961807.[ISI][Medline]
Krakoff J, Funahashi T, Stehouwer CD, Schalkwijk CG, Tanaka S, Matsuzawa Y, Kobes S, Tataranni PA, Hanson RL, Knowler WC et al (2003) Inflammatory markers, adiponectin, and risk of type 2 diabetes in the Pima Indian. Diabetes Care 26,17451751.
Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y and Matsubara K (1996) cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun 221,286289.[CrossRef][ISI][Medline]
Mantzoros C, Petridou E, Dessypris N, Chavelas C, Dalamaga M, Alexe DM, Papadiamantis Y, Markopoulos C, Spanos E, Chrousos G et al (2004) Adiponectin and breast cancer risk. J Clin Endocrinol Metab 89,11021107.
Matalliotakis IM, Goumenou AG, Koumantakis GE, Neonaki MA, Koumantakis EE, Dionyssopoulou E, Athanassakis I and Vassiliadis S (2003) Serum concentrations of growth factors in women with and without endometriosis: the action of anti-endometriosis medicines. Int Immunopharmacol 3,8189.[CrossRef][ISI][Medline]
Miyoshi Y, Funahashi T, Kihara S, Taguchi T, Tamaki Y, Matsuzawa Y and Noguchi S (2003) Association of serum adiponectin levels with breast cancer risk. Clin Cancer Res 9,56995704.
Momoeda M, Taketani Y, Terakawa N, Hoshiai H, Tanaka K, Tsutsumi O, Osuga Y, Maruyama M, Harada T, Obata K et al (2002) Is endometriosis really associated with pain? Gynecol Obstet Invest 54(Suppl 1),1821.
Nakano Y, Tobe T, Choi-Miura NH, Mazda T and Tomita M (1996) Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. J Biochem (Tokyo) 120,803812.[Abstract]
Osuga Y, Tsutsumi O, Okagaki R, Takai Y, Fujimoto A, Suenaga A, Maruyama M, Momoeda M, Yano T and Taketani Y (1999) Hepatocyte growth factor concentrations are elevated in peritoneal fluid of women with endometriosis. Hum Reprod 14,16111613.
Osuga Y, Koga K, Tsutsumi O, Yano T, Maruyama M, Kugu K, Momoeda M and Taketani Y (2002) Role of laparoscopy in the treatment of endometriosis-associated infertility. Gynecol Obstet Invest 53(Suppl 1),3339.
Ouchi N, Kihara S, Funahashi T, Nakamura T, Nishida M, Kumada M, Okamoto Y, Ohashi K, Nagaretani H, Kishida K et al (2003) Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue. Circulation 107,671674.
Scherer PE, Williams S, Fogliano M, Baldini G and Lodish HF (1995) A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 270,2674626749.
Steff AM, Gagne D, Page M, Rioux A, Hugo P and Gosselin D (2004) Serum concentrations of insulin-like growth factor-1, soluble tumor necrosis factor receptor-1 and angiogenin in endometriosis patients. Am J Reprod Immunol 51,166173.[CrossRef][ISI][Medline]
Suikkari AM, Koivisto VA, Koistinen R, Seppala M and Yki-Jarvinen H (1989) Doseresponse characteristics for suppression of low molecular weight plasma insulin-like growth factor-binding protein by insulin. J Clin Endocrinol Metab 68,135140.[Abstract]
Suzumori N, Zhao XX and Suzumori K (2004) Elevated angiogenin levels in the peritoneal fluid of women with endometriosis correlate with the extent of the disorder. Fertil Steril 82,9396.[CrossRef][ISI][Medline]
Wu MY and Ho HN (2003) The role of cytokines in endometriosis. Am J Reprod Immunol 49,285296.[CrossRef][ISI][Medline]
Yamamoto Y, Hirose H, Saito I, Tomita M, Taniyama M, Matsubara K, Okazaki Y, Ishii T, Nishikai K and Saruta T (2002) Correlation of the adipocyte-derived protein adiponectin with insulin resistance index and serum high-density lipoprotein-cholesterol, independent of body mass index, in the Japanese population. Clin Sci (Lond) 103,137142.[Medline]
Yang WC, Chen HW, Au HK, Chang CW, Huang CT, Yen YH and Tzeng CR (2004) Serum and endometrial markers. Best Pract Res Clin Obstet Gynaecol 18,305318.[CrossRef][ISI][Medline]
Yang WS, Lee WJ, Funahashi T, Tanaka S, Matsuzawa Y, Chao CL, Chen CL, Tai TY and Chuang LM (2002) Plasma adiponectin levels in overweight and obese Asians. Obes Res 10,11041110.
Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner AJ, Tomiyama Y et al (2000) Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 96,17231732.
Zong LL, Li YL and Ha XQ (2003) Determination of HGF concentration in serum and peritoneal fluid in women with endometriosis. Di Yi Jun Yi Da Xue Xue Bao 23,757760.[Medline]
Submitted on May 24, 2005; resubmitted on June 26, 2005; accepted on July 5, 2005.
|