Small leucine-rich proteoglycans (SLRPs) in the endometrium of polycystic ovary syndrome women: a pilot study

Ricardo Santos Simões, José Maria Soares Jr, Manuel J Simões, Helena B Nader, Maria Cândida P Baracat, Gustavo Arantes R Maciel, Paulo C Serafini, Ricardo Azziz, Edmund C Baracat, Ricardo Santos Simões, José Maria Soares Jr, Manuel J Simões, Helena B Nader, Maria Cândida P Baracat, Gustavo Arantes R Maciel, Paulo C Serafini, Ricardo Azziz, Edmund C Baracat

Abstract

Background: Small leucine-rich proteoglycans (SLRPs) play an important role in tissue homeostasis and cell proliferation since these proteoglycans sequester multiple growth factors. However, the content of SLRPs in the endometrium of polycystic ovary syndrome (PCOS) women is unknown. Our purpose was to test the hypothesis that excessive endometrial proliferation in PCOS may be partly related to abnormalities in SLRPs.

Methods: In a cross section study a total of 20 endometrial samples were collected from 10 patients with PCOS and 10 ovulatory women during their proliferative (pre-ovulatory) phase. The study subjects were matched for age, body mass index and race. The age range was 20 to 35 years. All volunteers were evaluated in reproductive endocrinology clinic, Gynecology Division, Clinics Hospital, University of São Paulo Medical School Profile and concentration of small leucine-rich proteoglycans (decorin, lumican, fibromodulin and biglycan) were determined by immunohistochemical testing and Western blotting.

Results: Decorin and lumican demonstrated higher immunoreactivity and relative expression in the endometrium of women with PCOS compared to that of women with regular menstrual cycles.

Conclusion: Our data suggests that the endometrium of PCOS women demonstrate a greater content of SLRP than controls; decorin and lumican, in particular, were found in higher concentrations in the endometrium of PCOS women during the proliferative phase. These differences may, in part, explain the excess of endometrial proliferation frequently observed in PCOS. Further studies are warranted.

Keywords: Endometrium; Polycystic ovary syndrome; Proliferative phase; Small leucine-rich proteoglycans.

Conflict of interest statement

Authors’ information

Not applicable.

Ethics approval and consent to participate

The study was approved by the Research Ethics Committee of the Clinics Hospital, University of São Paulo School of Medicine (CEP 0164/09) and informed written consent was obtained from all subjects.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Photomicrographs of the endometrium in the proliferative phase (a, b, and c) of the CONTROL and PCOS women (d, e, and f). Note thicker surface epithelium (EP) and gland (GL) as well as a higher concentration of leukocytes within the lamina propria of the endometrium of PCOS patients in d and e compared to a and b (thin arrows). Also note typical apoptosis in d and e (thick arrows) (* mitotic figure). Staining with H.E. d = 200X, b and e = 400X, and c and f = 100X
Fig. 2
Fig. 2
Photomicrographs of the endometrium in the proliferative phase of CONTROL and PCOS women. Endometrial fragments subjected to immunohistochemical methods for identification of decorin, biglycan, lumican, and fibromodulin. Bar = 20 μm
Fig. 3
Fig. 3
Western blotting results for decorin, lumican, biglycan, and fibromodulin expression in the endometrium of CONTROL and PCOS women

References

    1. Azziz R. Introduction: Determinants of polycystic ovary syndrome. Fertil Steril. 2016;106:4–5. doi: 10.1016/j.fertnstert.2016.05.009.
    1. Hull MG. Epidemiology of infertility and polycystic ovarian disease: endocrinological and demographic studies. Gynecol Endocrinol. 1987;1:235–245. doi: 10.3109/09513598709023610.
    1. Lopes IM, Maganhin CC, Oliveira-Filho RM, Simões RS, Simões MJ, Iwata MC, et al. Histomorphometric Analysis and Markers of Endometrial Receptivity Embryonic Implantation in Women With Polycystic Ovary Syndrome During the Treatment With Progesterone. Reprod Sci. 2014;21:930–938. doi: 10.1177/1933719113519169.
    1. Balen AH, Conway GS, Kaltsas G, Techatrasak K, Manning PJ, West C, Jacobs HS. Polycystic ovary syndrome: the spectrum of the disorder in 1741 patients. Hum Reprod. 1995;10:2107–2111. doi: 10.1093/oxfordjournals.humrep.a136243.
    1. Barry JA, Azizia MM, Hardiman PJ. Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2014;20:748–758. doi: 10.1093/humupd/dmu012.
    1. Gadducci A, Gargini A, Palla E, Fanucchi A, Genazzani AR. Polycystic ovary syndrome and gynecological cancers: is there a link? Gynecol Endocrinol. 2005;20:200–208. doi: 10.1080/09513590400021201.
    1. Pillay OC, Te Fong LF, Crow JC, Benjamin E, Mould T, Atiomo W, Menon PA, Leonard AJ, Hardiman P. The association between polycystic ovaries and endometrial cancer. Hum Reprod. 2006;21:924–929. doi: 10.1093/humrep/dei420.
    1. Roemer KL, Young SL, Savaris RF. Characterization of GAB1 expression over the menstrual cycle in women with and without polycystic ovarian syndrome provides a new insight into its pathophysiology. J Clin Endocrinol Metab. 2014;99:E2162–E2168. doi: 10.1210/jc.2014-2128.
    1. Lopes IM, Baracat MC, Simões Mde J, Simões RS, Baracat EC, Soares JM., Jr Endometrium in women with polycystic ovary syndrome during the window of implantation. Rev Assoc Med Bras. 2011;57:702–709. doi: 10.1590/S0104-42302011000600020.
    1. Baracat MC, Serafini PC, Simões Rdos S, Maciel GA, Soares JM, Jr, Baracat EC. Systematic review of cell adhesion molecules and estrogen receptor expression in the endometrium of patients with polycystic ovary syndrome. Int J Gynaecol Obstet. 2015;129(1):1–4. doi: 10.1016/j.ijgo.2014.10.022.
    1. Mauviel A, Santra M, Chen YQ, Uitto J, Iozzo RV. Transcriptional regulation of decorin gene expression. Induction by quiescence and repression by tumor necrosis factor-alpha. J Biol Chem. 1995;270:11692–11700. doi: 10.1074/jbc.270.19.11692.
    1. Seidler DG, Dreier R. Decorin and its galactosaminoglycan chain: extracellular regulator of cellular function? IUBMB Life. 2008;60:729–733. doi: 10.1002/iub.115.
    1. Iozzo RV. The family of the small leucine-rich proteoglycans: key regulators of matrix assembly and cellular growth. Crit Rev Biochem Mol Biol. 1997;32:141–174. doi: 10.3109/10409239709108551.
    1. Iozzo RV, Sanderson RD. Proteoglycans in cancer biology, tumour microenvironment and angiogenesis. J Cell Mol Med. 2011;15:1013–1031. doi: 10.1111/j.1582-4934.2010.01236.x.
    1. Ono YJ, Terai Y, Tanabe A, Hayashi A, Hayashi M, Yamashita Y, Kyo S, Ohmichi M. Decorin induced by progesterone plays a crucial role in suppressing endometriosis. J Endocrinol. 2014;223:203–216. doi: 10.1530/JOE-14-0393.
    1. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS) Hum Reprod. 2004;19:41–47. doi: 10.1093/humrep/deh098.
    1. Lizneva D, Suturina L, Walker W, Brakta S, Gavrilova-Jordan L, Azziz R. Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertil Steril. 2016;106:6–15. doi: 10.1016/j.fertnstert.2016.05.003.
    1. Fraser IS, Critchley HO, Broder M, Munro MG. The FIGO recommendations on terminologies and definitions for normal and abnormal uterine bleeding. Semin Reprod Med. 2011;29(5):383–390. doi: 10.1055/s-0031-1287662.
    1. Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Am J Obstet Gynecol. 1975;122:262–263. doi: 10.1016/S0002-9378(16)33500-1.
    1. Andrade PM, Baracat EC, Simões MJ, Rodrigues de Lima G. Histomorphometric aspects of adult castrated rat endometrium after the use of estrogen, progesterone and tamoxifen. Clin Exp Obstet Gynecol. 2000;27:138–141.
    1. Cheung AP. Ultrasound and menstrual history in predicting endometrial hyperplasia in polycystic ovary syndrome. Obstet Gynecol. 2001;98:325–331.
    1. Apparao KBC, Lovely LP, Gui Y, Lininger RA, Lessey BA. Elevated endometrial androgen receptor expression in women with polycystic ovarian syndrome. Biol Reprod. 2002;66:297–304. doi: 10.1095/biolreprod66.2.297.
    1. San Martin S, Soto-Suazo M, Ferreira de Oliveira S, Aplin JD, Abrahamsohn P, TMT Z. Small leucine-rich proteoglycans (SLRPs) in uterine tissues during pregnancy in mice. Reproduction. 2003;125:585–595. doi: 10.1530/rep.0.1250585.
    1. Giudice LC. Endometrium in PCOS: Implantation and predisposition to endocrine CA. Best Pract Res Clin Endocrinol Metab. 2006;20:235–244. doi: 10.1016/j.beem.2006.03.005.
    1. Iatrakis G, Tsionis C, Adonakis G, Stoikidou M, Anthouli-Anagnostopoulou F, Parava M, et al. Polycystic ovarian syndrome, insulin resistance and thickness of the endometrium. Eur J Obstet Gynecol Reprod Biol. 2006;127:218–221. doi: 10.1016/j.ejogrb.2006.01.023.
    1. Rutanen EM. Insulin-like growth factors in endometrial function. Gynecol Endocrinol. 1998;12(6):399–406. doi: 10.3109/09513599809012842.
    1. Kaaks R. Plasma insulin, IGF-I and breast cancer. Gynecol Obstet Fertil. 2001;29(3):185–191. doi: 10.1016/S1297-9589(00)00047-3.
    1. Randolph JF, Jr, Kipersztok S, Ayers JW, Ansbacher R, Peegel H, Menon KM. The effect of insulin on aromatase activity in isolated human endometrial glands and stroma. Am J Obstet Gynecol. 1987;157(6):1534–1539. doi: 10.1016/S0002-9378(87)80258-2.
    1. Kitaya K, Yasuo T. Dermatan sulfate proteoglycan biglycan as a potential selectin L/CD44 ligand involved in selective recruitment of peripheral blood CD16(−) natural killer cells into human endometrium. J Leukoc Biol. 2009;85:391–400. doi: 10.1189/jlb.0908535.
    1. Salgado RM, Favaro RR, Zorn TM. Modulation of small leucine-rich proteoglycans (SLRPs) expression in the mouse uterus by estradiol and progesterone. Reprod Biol Endocrinol. 2011;9:22. doi: 10.1186/1477-7827-9-22.
    1. Yamaguchi Y, Ruoslahti E. Expression of human proteoglycan in Chinese hamster ovary cells inhibits cell proliferation. Nature. 1988;336:244–246. doi: 10.1038/336244a0.
    1. Vij N, Roberts L, Joyce S, Chakravarti S. Lumican suppresses cell proliferation and aids Fas - Fas ligand mediated apoptosis: implications in the cornea. Exp Eye Res. 2004;78:957–971. doi: 10.1016/j.exer.2003.12.006.
    1. Niu C, Liang C, Guo J, Cheng L, Zhang H, Qin X, Zhang Q, Ding L, Yuan B, Xu X, et al. Downregulation and growth inhibitory role of FHL1 in lung cancer. Int J Cancer. 2012;130:2549–2556. doi: 10.1002/ijc.26259.
    1. Coulson-Thomas VJ, Coulson-Thomas YM, Gesteira TF, Andrade de Paula CA, Carneiro CR, Ortiz V, et al. Lumican expression, localization and antitumor activity in prostate cancer. Exp Cell Res. 2013;319:967–981. doi: 10.1016/j.yexcr.2013.01.023.
    1. Hildebrand A, Romarís M, Rasmussen LM, Heinegård D, Twardzik DR, Border WA, Ruoslahti E. Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor beta. Biochem J. 1994;302:527–534. doi: 10.1042/bj3020527.
    1. Lala PK, Nandi P. Mechanisms of trophoblast migration, endometrial angiogenesis in preeclampsia: The role of decorin. Cell Adhes Migr. 2016;10:111–125. doi: 10.1080/19336918.2015.1106669.
    1. Vogel KG, Paulsson M, Heinegard D. Specific inhibition of type I and type II collagen fibrilogenesis by the small proteoglycan of tendon. Biochem J. 1984;222:587–597. doi: 10.1042/bj2230587.
    1. Vogel KG, Trotter JA. The effect of proteoglycan on the morphology of collagen fibrils formed in vitro. Coll Relat Res. 1987;7:105–114. doi: 10.1016/S0174-173X(87)80002-X.
    1. Rada JA, Cornuet PK, Hassell JR. Regulation of corneal collagen fibrillogenesis in vitro by corneal proteoglycan (lumican and decorin) core proteins. Exp Eye Res. 1993;56:635–648. doi: 10.1006/exer.1993.1081.
    1. Giordano MV, Giordano LA, Gomes RC, Simões RS, Nader HB, Giordano MG, et al. The evaluation of endometrial sulfate glycosaminoglycans in women with polycystic ovary syndrome. Gynecol Endocrinol. 2015;31(4):278–281. doi: 10.3109/09513590.2014.989980.
    1. Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab. 2006;91:4237–4245. doi: 10.1210/jc.2006-0178.
    1. Christ JP, Willis AD, Brooks ED, Vanden Brink H, Jarrett BY, Pierson RA, Chizen DR, Lujan ME. Follicle number, not assessments of the ovarian stroma, represents the best ultrasonographic marker of polycystic ovary syndrome. Fertil Steril. 2014;101:280–287. doi: 10.1016/j.fertnstert.2013.10.001.

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