Skip to main content

Advertisement

SpringerLink
Log in

The role of ADAMTS4 and ADAMTS9 in cardiovascular disease in premature ovarian insufficiency and idiopathic hypogonadotropic hypogonadism

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Purpose

We aimed to determine the relation of a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS4), and a disintegrin and metalloproteinase with thrombospondin motifs-9 (ADAMTS9) with cardiovascular disease (CVD) risk, in ovarian dysfunction patients with premature ovarian insufficiency (POI), and idiopathic hypogonadotropic hypogonadism (IHH).

Methods

43 IHH and 44 POI patients were enrolled to this case–control study. Serum hormonal parameters, lipid profiles, ADAMTS4 and ADAMTS9 levels were measured. Lipid accumulation product (LAP) index, visceral adiposity index (VAI), and homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. The patients with at least two out of the four following criteria were accepted to have increased CVD risk; waist-to-hip ratio (WHR) ≥ 0.8, waist circumference (WC) ≥ 79 cm, triglycerides (TG) ≥ 150 mg/dL, high-density lipoprotein cholesterol (HDL-C) < 50 mg/dL. Serum ADAMTS4 and ADAMTS9 levels were measured by enzyme-linked immunosorbent assay (ELISA).

Results

ADAMTS4 and ADAMTS9 levels were significantly higher in the IHH group than the POI group (p = 0.002, and p = 0.013, respectively). IHH group had significantly higher levels of insulin, HOMA-IR index, and LAP index (p = 0.006, p = 0.005, and p = 0.013, respectively). The mean age of patients in the IHH group (23.60 ± 5.64 years) was significantly lower than the POI group (31.05 ± 6.03 years), (p < 0.001). Odds ratios (OR) were 1.236 (95% CI 1.055–1.447) and 1.002 (95% CI 1.000–1.004) for LAP index and ADAMTS4, respectively, in the IHH group. These two parameters found to have high predictivity for CVD risk in the IHH group (p = 0.009 and p = 0.028, respectively).

Conclusion

The lower levels of ADAMTS4 in the POI group, when compared with the IHH patients pointed out that even limited hormone secretion and ovulation in the POI group, may have protective effect on cardiovascular system. The higher levels of ADAMTS4 and LAP index in the IHH group demonstrated the increased risk of these patients for CVD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. The ESHRE Guideline Group on POI, Webber L, Davies M, Anderson R, Bartlett J, Braat D, Cartwright B, Cifkova R, de MuinckKeizer-Schrama S, Hogervorst E et al (2016) ESHRE guideline: management of women with premature ovarian insufficiency. Hum Reprod 31(5):926–937

    Article  Google Scholar 

  2. Podfigurna-Stopa A, Czyzyk A, Grymowicz M, Smolarczyk R, Katulski K, Czajkowski K, Meczekalski B (2016) Premature ovarian insufficiency: the context of long-term effects. J Endocrinol Invest 39(9):983–990

    Article  CAS  Google Scholar 

  3. Seminara SB, Hayes FJ, Crowley WF (1998) Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann’s syndrome): pathophysiological and genetic considerations. Endocr Rev 19:521–539

    CAS  PubMed  Google Scholar 

  4. Roetersvan Lennep JE, Heida KY, Bots ML, Hoek A, Collaborators of the Dutch Multidisciplinary Guideline Development Group on Cardiovascular Risk Management after Reproductive Disorders (2016) Cardiovascular disease risk in women with premature ovarian insufficiency: a systematic review and meta-analysis. Eur J Prev Cardiol 23(2):178–186

    Article  Google Scholar 

  5. Tao XY, Zuo AZ, Wang JQ, Tao FB (2016) Effect of primary ovarian insufficiency and early natural menopause on mortality: a meta-analysis. Climacteric 19(1):27–36

    Article  Google Scholar 

  6. Yialamas MA, Dwyer AA, Hanley E, Lee H, Pitteloud N, Hayes FJ (2007) Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 92:4254–4259

    Article  CAS  Google Scholar 

  7. Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L et al (2015) Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment. Nat Rev Endocrinol 11(9):547–564

    Article  Google Scholar 

  8. Russell DL, Brown HM, Dunning KR (2015) ADAMTS proteases in fertility. MatrixBiol 44–46:54–63

    Google Scholar 

  9. Porter S, Clark I, Keveorkian L, Edwards DR (2005) The ADAMTS metalloproteinases. Biochem J 386:15–27

    Article  CAS  Google Scholar 

  10. Kelwick R, Desanlis I, Wheeler GN, Edwards DR (2015) The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family. Genome Biol 16(1):113

    Article  Google Scholar 

  11. Richards JS, Hernandez-Gonzalez I, Gonzalez-Robayna I et al (2005) Regulated expression of ADAMTS family members in follicles and cumulus oocyte complexes: evidence for specific and redundant patterns during ovulation. Biol Reprod 72(5):1241–1255

    Article  CAS  Google Scholar 

  12. Huang X, Hao C, Shen X, Zhang Y, Liu X (2013) RUNX2, GPX3 and PTX3 gene expression profiling in cumulus cells are reflective oocyte/embryo competence and potentially reliable predictors of embryo developmental competence in PCOS patients. Reprod Biol Endocrinol 11:109

    Article  Google Scholar 

  13. Pyun JA, Kim S, Cho NH, Koh I, Lee JY, Shin C, Kwack K (2013) Genome-wide association studies and epistasis analyses of candidate genes related to age at menarche and age at natural menopause in a Korean population. Menopause J N Am Menopause Soc 21(5):522–529

    Article  Google Scholar 

  14. Wight T, Merrilees M (2004) Proteoglycans in atherosclerosis and restenosis: key roles for versican. Circ Res 94:1158–1167

    Article  CAS  Google Scholar 

  15. Koo BH, Coe DM, Dixon LJ et al (2010) ADAMTS9 is a cell-autonomously acting, anti-angiogenic metalloprotease expressed by microvascular endothelial cells. Am J Pathol 176:1494–1504

    Article  CAS  Google Scholar 

  16. Karakose M, Caliskan M, Arslan MS, Demirci T, Karakose S, Tutal E, Cakal E (2017) Association of ADAMTS4 and ADAMTS9 levels with cardiovascular risk in patients with primary hyperparathyroidism. Endocr Res 22:1–6

    Google Scholar 

  17. Ulucay S, Cam FS, Batır MB, Sutcu R, Bayturan O, Demircan K (2015) A novel association between TGFb1 and ADAMTS4 in coronary artery disease: a new potential mechanism in the progression of atherosclerosis and diabetes. Anatol J Cardiol 15(10):823–829

    Article  CAS  Google Scholar 

  18. Dong H, Du T, Premaratne S, Zhao CX, Tian Q, Li Y, San Y, Zhang WW (2018) Relationship between ADAMTS4 and carotid atherosclerotic plaque vulnerability in humans. J Vasc Surg 67(4):1120–1126

    Article  Google Scholar 

  19. Nelson LM (2009) Clinical practice primary ovarian insufficiency. N Engl J Med 360(6):606–614

    Article  CAS  Google Scholar 

  20. Rossouw JE, Cushman M, Greenland P et al (2008) Inflammatory, lipid, thrombotic, and genetic markers of coronary heart disease risk in the women’shealth initiative trials of hormone therapy. Arch Intern Med 168(20):2245–2253

    Article  CAS  Google Scholar 

  21. Burgues S, The Spanish Collaborative Group on Female Hypogonadotrophic Hypogonadism (2001) The effectiveness and safety of recombinant human LH to support follicular development induced by recombinant human FSH in WHO group I anovulation: evidence from a multicentre study in Spain. Hum Reprod 16(12):2525–2532

    Article  CAS  Google Scholar 

  22. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419

    Article  CAS  Google Scholar 

  23. Kahn HS (2005) The “lipid accumulation product” performs better than the body mass index for recognizing cardiovascular risk: a population-based comparison. BMC Cardiovasc Disord 5:26

    Article  Google Scholar 

  24. Amato MC, Giordano C, Galia M et al (2010) Visceral adiposity index: a reliable indicator of visceral fat function associated with cardiometabolic risk. Diabetes Care 33:920–922

    Article  Google Scholar 

  25. Andrus B, Lacaille D (2014) 2013 ACC/AHA guideline on the assessment of cardiovascular risk. J Am Coll Cardiol 63(25 Pt A):2886

    Article  Google Scholar 

  26. Glueck CJ, Morrison JA, Friedman LA, Goldenberg N, Stroop DM, Wang P (2006) Obesity, free testosterone, and cardiovascular risk factors in adolescents with polycystic ovary syndrome and regularly cycling adolescents. Metabolism 55(4):508–514

    Article  CAS  Google Scholar 

  27. Mendelsohn ME, Karas RH (2005) Molecular and cellular basis of cardiovascular gender differences. Science 308:1583–1587

    Article  CAS  Google Scholar 

  28. Stuenkel CA, Davis SR, Gompel A et al (2015) Treatment of symptoms of the menopause: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 100:3975

    Article  CAS  Google Scholar 

  29. Kern CB, Wessels A, Mc Garity J et al (2010) Reduced versican cleavage due to Adamts9 haploinsufficiency is associated with cardiac and aortic anomalies. Matrix Biol 29(4):304–316

    Article  CAS  Google Scholar 

  30. Zha Y, Chen Y, Xu F, Zhang J, Li T, Zhao C, Cui L (2010) Elevated level of ADAMTS4 in plasma and peripheral monocytes from patients with acute coronary syndrome. Clin Res Cardiol 99(12):781–786

    Article  CAS  Google Scholar 

  31. Xie X, Li Q, Zhang L, Ren W (2018) Lipid accumulation product, visceral adiposity index, and chinese visceral adiposity index as markers of cardiometabolic risk in adult growth hormone deficiency patients: a cross-sectional study. Endocr Pract 24(1):33–39

    Article  Google Scholar 

  32. Ates S, Yesil G, Sevket O, Molla T, Yildiz S (2014) Comparison of metabolic profile and abdominal fat distribution between karyotypically normal women with premature ovarian insufficiency and age matched controls. Maturitas 79(3):306–310

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the staff at Zekai Tahir Burak Women’s Health Care Training and Research Hospital and to all women who participated in the study.

Author information

Authors and Affiliations

  1. Department of Perinatology, Konya Education and Research Hospital, Konya, Turkey

    S. Ozler

  2. Department of Gynecological Oncology, Gazi University, Ankara, Turkey

    E. Isci Bostanci

  3. Department of Perinatology, Eskisehir State Hospital, Eskisehir, Turkey

    E. Oztas

  4. Department of Gynecology and Obstetrics, Zekai Tahir Burak Women’s Health Education and Research Hospital, Ankara, Turkey

    M. Kuru Pekcan

  5. Department of Gynecology and Obstetrics, Istinye University, Ankara, Turkey

    B. Gumus Guler

  6. Department of Reproductive Endocrinology, Zekai Tahir Burak Women’s Health Education and Research Hospital, Ankara, Turkey

    N. Yilmaz

Authors
  1. S. Ozler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Isci Bostanci
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. Oztas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Kuru Pekcan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B. Gumus Guler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N. Yilmaz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. Ozler.

Ethics declarations

Conflict of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Ethical approval

The study protocol was approved by the local institutional Review Board (Zekai Tahir Burak Women’s Health Care Training and Research Hospital, Ankara, Turkey).

Informed consent

Informed consent forms were obtained from all the patients who participated in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ozler, S., Isci Bostanci, E., Oztas, E. et al. The role of ADAMTS4 and ADAMTS9 in cardiovascular disease in premature ovarian insufficiency and idiopathic hypogonadotropic hypogonadism. J Endocrinol Invest 41, 1477–1483 (2018). https://doi.org/10.1007/s40618-018-0948-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-018-0948-3

Keywords

Search

Navigation