Journal of Human Reproductive Science
Home Ahead of Print Current Issue Archives
   Bookmark this page Print this page Email this page Small font sizeDefault font size Increase font size    Users online: 859


 
   Table of Contents     
ORIGINAL ARTICLE  
Year : 2019  |  Volume : 12  |  Issue : 4  |  Page : 299-302
 

There is no association between premature ovarian insufficiency and levels of fetuin-A/α2-Heremans-Schmid glycoprotein


Ankara Dr. Zekai Tahir Burak Health Practice Research Center, University of Health Sciences, Ankara, Turkey

Date of Submission19-Jul-2019
Date of Acceptance01-Nov-2019
Date of Web Publication17-Dec-2019

Correspondence Address:
Dr. A Seval Ozgu-Erdinc
Ankara Dr. Zekai Tahir Burak Health Practice Research Center, University of Health Sciences, Ankara
Turkey
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jhrs.JHRS_104_19

Rights and Permissions

 

   Abstract 


Objective: Fetuin-A is a well-known negative acute-phase protein and has been used liberally to predict vascular disease. The aim of this study was to evaluate the association between serum human fetuin-A/alpha2-Heremans–Schmid glycoprotein levels and idiopathic premature ovarian insufficiency (POI). Methods: A total of 75 women were included in this case–control study between January 2013 and December 2013. Serum fetuin-A concentrations were measured in 36 women with idiopathic POI and 39 healthy women with regular cycles. Blood samples were drawn after a 12-h overnight fast and were kept at −80°C for subsequent assay. The serum levels of fetuin-A were assessed by commercial ELISA kits (BioVendor Laboratory Medicine Inc., Brno, Czech Republic) and serum concentration values were expressed as μg/ml. Results: The mean serum fetuin-A levels of idiopathic POI and control women were 229.02 ± 27.79 and 232.37 ± 65.56, respectively, with P = 0.771 (independent samples t-test). Our results showed no statistically significant difference between serum fetuin-A levels of idiopathic POI women and controls. Conclusion: The mean values of serum fetuin-A in idiopathic POI women were not significantly different from controls, which implies that there is no significant association between serum fetuin-A levels and idiopathic POI.


Keywords: Fetuin-A, inflammation, premature ovarian insufficiency


How to cite this article:
Ozgu-Erdinc A S, Oskovi Kaplan ZA, Engin-Ustun Y, Yilmaz N, Yildirim G, Tokmak A, Erkenekli K, Erkaya S, Uygur D. There is no association between premature ovarian insufficiency and levels of fetuin-A/α2-Heremans-Schmid glycoprotein. J Hum Reprod Sci 2019;12:299-302

How to cite this URL:
Ozgu-Erdinc A S, Oskovi Kaplan ZA, Engin-Ustun Y, Yilmaz N, Yildirim G, Tokmak A, Erkenekli K, Erkaya S, Uygur D. There is no association between premature ovarian insufficiency and levels of fetuin-A/α2-Heremans-Schmid glycoprotein. J Hum Reprod Sci [serial online] 2019 [cited 2020 Jul 13];12:299-302. Available from: http://www.jhrsonline.org/text.asp?2019/12/4/299/273107





   Introduction Top


Premature ovarian insufficiency (POI) is hypergonadotropic hypoestrogenic amenorrhea seen in 0.3%–1.2% of women before the age of 40 years.[1],[2],[3],[4] There is not a clear consensus on the definition of POI and follicle-stimulating hormone (FSH) levels; according to the European Society of Human Reproduction and Embryology, POI is defined as the loss of ovarian activity before the age of 40 years, characterized with menstrual disturbance (amenorrhea and oligomenorrhea), raised gonadotropins and low estradiol.[1] Guideline development group recommends the diagnostic criteria as: women under 40 years of age experiencing symptoms of amenorrhea/oligomenorrhea for 4–6 months and FSH levels >25 mIU/ml measured >4 weeks apart are confirmed for the diagnosis of POI.[1] There are three presumable mechanisms involved in the development of POI; apoptosis acceleration, follicular maturation blocking, and premature follicle activation.[5] POI has a multifactorial etiology: familial history, genetic abnormalities, autoimmune conditions, iatrogenic damage of ovaries, and idiopathic causes.[6],[7],[8],[9] Recent studies showed that some inflammatory markers may serve as a diagnostic marker in POI.[10]

Fetuin-A, which is also known as α-2-Heremans–Schmid protein, is a well-known negative acute-phase protein (APP), mainly produced by the liver and to a lesser extent by the placenta and tongue.[11],[12] Fetuin-A takes part in insulin signaling pathways, vascular calcification, metabolic disorders, central nervous system, cardiovascular system, and pro-inflammatory pathways.[13],[14] Fetuin-A was reported to take part in molecular pathways of oocyte maturation and existed in human follicular fluid.[15]

The aim of this study was to evaluate the association between human fetuin-A/α-2-HS glycoprotein levels and idiopathic POI considering the mechanism that is possibly related with inflammation.


   Methods Top


Seventy-five women who were referred to our reproductive endocrinology outpatient clinic between January 2013 and December 2013 were enrolled in this prospective cohort study. The institutional review board (9/23/2013 #15) approved the study and written informed consent for participation in the study was obtained from all the participants. Serum fetuin-A concentrations were measured in 36 women diagnosed with idiopathic POI and 39 healthy women with regular menstrual cycles. The idiopathic POI group selection criteria were determined as women between the ages of 20–40 years, experiencing amenorrhea within the past 4 months, and with FSH levels higher than 40 mlU/Ml recorded two times during measurements within at least 1 month apart. Patients having hormone therapy, history of pelvic surgery, exposure to radiotherapy and chemotherapy, abnormal karyotype analysis in participants younger than 30 years of age, and any systemic disease such as thyroid disorders or hyperprolactinemia were excluded from the study. Women aged 20–40 years with regular menstrual cycles who were not using hormonal contraception and without a history systemic disease or drug use were included in the control group. Blood samples were drawn after 12-h overnight fasting and were kept at −80°C for subsequent assay. The serum levels of fetuin-A were assessed by commercial ELISA kits (BioVendor Laboratory Medicine Inc., Brno, Czech Republic) and serum concentration values were expressed as μg/ml. Complete blood count, fasting plasma glucose (FPG), FSH, luteinizing hormone, estradiol, prolactin, and thyroid-stimulating hormone (TSH) levels were evaluated in all participants.

Demographic variables and fetuin-A results were presented as mean with standard deviation or median with range for continuous variables. The univariate analyses were investigated using the Student's (independent samples) t-test or the Mann–Whitney U-test to compare continuous variables as appropriate. Pearson correlation coefficients were calculated for continuous variables with normal distribution, and Spearman rank correlation coefficients were calculated for non-normally distributed continuous variables. A two-tailed P < 0.05 was considered statistically significant. The statistical software package SPSS 23.0 (SPSS Inc., Chicago, Ill., USA) was used for the data analyses.


   Results Top


Patients were statistically similar in terms of age, body mass index, FPG, TSH, prolactin and hemoglobin levels, leukocyte (white blood cell [WBC]) count, and neutrophil-to-lymphocyte ratio (NLR) (P > 0.05) [Table 1].
Table 1: Demographic variables and serum fetuin-A levels of premature ovarian insufficiency and control group

Click here to view


The mean serum fetuin-A levels of POI and control women were 229.02 ± 27.79 μg/mL and 232.37 ± 65.56 μg/mL, respectively, with P = 0.771 (independent samples t-test) [Figure 1]. There was no correlation between fetuin-A and age, body mass index, FPG, TSH, prolactin and hemoglobin levels, leukocyte (WBC) count, and NLR (P > 0.05). Our results showed no statistically significant difference and correlation between serum fetuin-A levels of POI women and controls.
Figure 1: Serum fetuin-A levels in premature ovarian insufficiency and control group

Click here to view



   Discussion Top


This is the first study investigating the association between POI and fetuin-A. Fetuin is defined as a multifunctional protein which was first isolated from bovine in 1944.[16] Intensive researches on this liver-synthesized protein unveiled that fetuin-A had various functions on metabolism, central nervous system, cardiovascular system, and bone and mineral metabolism.[17] Fetuin-A acts as a negative APP in infection and as a positive APP in injury.[11]

The inflammation-associated pathogenesis of POI is investigated by several studies. Since the mechanism that induces ovarian autoimmunity and inflammation is still unknown, some of the findings by these studies supported this inflammation hypothesis. Lymphoplasmacellular infiltration around steroid-producing cells in POI patients in association with adrenal autoimmunity may be an evidence for autoimmune oophoritis which is set forth to common autoantigens.[18] Ovarian tissue damage due to the viral infection may be another cause of inflammatory pathogenesis.

Yildirim et al. studied inflammatory biomarkers in POI patients and found a decreased NLR, whereas C-reactive protein and serum amyloid-A protein had no significant difference between the women with normal menstrual cycles and POI patients.[10]

In the literature, a respectable amount of studies have been reported on a possible relationship of fetuin-A with obesity, polycystic ovary syndrome, metabolic syndrome, fatty liver disease, diabetes mellitus, and atherosclerosis.[19],[20],[21] When metabolic profile was studied in patients with POI, POI was found to have increased risk of metabolic syndrome independent of age and obesity.[22] In terms of fetuin-A, although a relationship with pathophysiology of metabolic disorders existed in literature, the results were heterogeneous about its significance. Moreover, our results showed no relation with increased risk of metabolic syndrome in patients with premature menopause.

It was shown that fetuin-A was present in human follicular fluid and had inhibitory effects on oocyte maturation[23] and had a role in mitogenic pathways through insulin receptors in hamster ovary cells.[15] When serum and follicular fluid fetuin-A levels were analyzed in patients undergoing in vitro fertilization (IVF) treatment, both the levels were found higher in the IVF group[24] which also suggested the relationship of fetuin-A with infertility.

Mathur et al. studied fetuin-A in patients with endometriosis and concluded that the increased fetuin-A levels in serum and peritoneal fluid samples of the patients with endometriosis may have a role in autoimmune pathophysiology of the disease, which lead to decreased ovarian reserve and infertility.[25],[26],[27]

Høyer et al. showed fetuin mRNA and protein in granulosa cells; however, the pattern of staining differed between growing healthy follicles and atretic follicles. Depending on the macrophage-like behavior of granulosa cells in follicular atresia, they hypothesized that fetuin may have a role in the regulation of follicular growth, differentiation, and atresia.[28],[29],[30],[31] Recent studies have been made, but a clear evidence has not been reported on a possible relation between fetuin-A and infertility. Bódis et al. compared serum and follicular fluid fetuin-A levels of patients receiving IVF treatment and healthy controls and found that fetuin-A was markedly elevated in serums of IVF patients; however, they reported that fetuin-A could not be used as a direct marker for the estimation of fertilization success.[24] Fetuin-A was assessed in blood samples of patients undergoing IVF treatment in a study by Yen et al. and was found significantly higher in the pregnant group, which would propose a possible predictive value for achieving live birth in IVF treatment in future.[32]

Taking into consideration of this studies that reported the role of fetuin-A in inflammation and autoimmunity in endometriosis and the presence of fetuin in granulosa cells in follicles which may have a role in atresia, we hypothesized that the levels of plasma fetuin-A might have a difference between the women with normal menstrual cycles and patients with POI. However, our results did not have a significant difference between the study and control groups. Further studies are needed to define the pathogenesis of early follicular atresia and the role of fetuin-A in follicular physiology which is not yet explained by the existing literature.


   Conclusion Top


The mean values of serum fetuin-A in idiopathic POI women were not significantly different from controls, which implies that there is no significant association between serum fetuin-A levels and idiopathic POI.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI, Webber L, Davies M, Anderson R, Bartlett J, Braat D, et al. ESHRE guideline: Management of women with premature ovarian insufficiency. Hum Reprod 2016;31:926-37.  Back to cited text no. 1
    
2.
Cox L, Liu JH. Primary ovarian insufficiency: An update. Int J Womens Health 2014;6:235-43.  Back to cited text no. 2
    
3.
Torrealday S, Pal L. Premature menopause. Endocrinol Metab Clin North Am 2015;44:543-57.  Back to cited text no. 3
    
4.
Nippita TA, Baber RJ. Premature ovarian failure: A review. Climacteric 2007;10:11-22.  Back to cited text no. 4
    
5.
Persani L, Rossetti R, Cacciatore C. Genes involved in human premature ovarian failure. J Mol Endocrinol 2010;45:257-79.  Back to cited text no. 5
    
6.
Michalakis K, Coppack SW. Primary ovarian insufficiency: Relation to changes in body composition and adiposity. Maturitas 2012;71:320-5.  Back to cited text no. 6
    
7.
Gowri V, Al Shukri M, Al-Farsi FA, Al-Busaidi NA, Dennison D, Al Kindi S, et al. Aetiological profile of women presenting with premature ovarian failure to a single tertiary care center in oman. Post Reprod Health 2015;21:63-8.  Back to cited text no. 7
    
8.
Shelling AN. Premature ovarian failure. Reproduction 2010;140:633-41.  Back to cited text no. 8
    
9.
Cordts EB, Christofolini DM, Dos Santos AA, Bianco B, Barbosa CP. Genetic aspects of premature ovarian failure: A literature review. Arch Gynecol Obstet 2011;283:635-43.  Back to cited text no. 9
    
10.
Yildirim G, Tokmak A, Kokanal MK, Sarkaya E, Züngün C, İnal HA, et al. Association between some inflammatory markers and primary ovarian insufficiency. Menopause 2015;22:1000-5.  Back to cited text no. 10
    
11.
Wang H, Sama AE. Anti-inflammatory role of fetuin-A in injury and infection. Curr Mol Med 2012;12:625-33.  Back to cited text no. 11
    
12.
Dziegielewska KM, Andersen NA, Lovell D, Nicol SC, Müller-Esterl W, Saunders NR. Fetuin – A new acute phase protein in the adult and in the fetus. Folia Histochem Cytobiol 1992;30:187-9.  Back to cited text no. 12
    
13.
Siegel-Axel DI, Ullrich S, Stefan N, Rittig K, Gerst F, Klingler C, et al. Fetuin-A influences vascular cell growth and production of proinflammatory and angiogenic proteins by human perivascular fat cells. Diabetologia 2014;57:1057-66.  Back to cited text no. 13
    
14.
Nasri H, Mayel Y, Sheikhvatan M, Forood A. Premature menopause and severity of coronary artery disease. J Res Med Sci 2011;16:1026-31.  Back to cited text no. 14
    
15.
Srinivas PR, Deutsch DD, Mathews ST, Goustin AS, Leon MA, Grunberger G. Recombinant human alpha 2-HS glycoprotein inhibits insulin-stimulated mitogenic pathway without affecting metabolic signalling in Chinese hamster ovary cells overexpressing the human insulin receptor. Cell Signal 1996;8:567-73.  Back to cited text no. 15
    
16.
Pederson K. Fetuin, a new globulin isolated from serum. Nature 1944;154:575.  Back to cited text no. 16
    
17.
Mori K, Emoto M, Inaba M. Fetuin-A: A multifunctional protein. Recent Pat Endocr Metab Immune Drug Discov 2011;5:124-46.  Back to cited text no. 17
    
18.
Hoek A, Schoemaker J, Drexhage HA. Premature ovarian failure and ovarian autoimmunity. Endocr Rev 1997;18:107-34.  Back to cited text no. 18
    
19.
Mukhopadhyay S, Mondal SA, Kumar M, Dutta D. Proinflammatory and antiinflammatory attributes of fetuin-A: A novel hepatokine modulating cardiovascular and glycemic outcomes in metabolic syndrome. Endocr Pract 2014;20:1345-51.  Back to cited text no. 19
    
20.
Gulhan I, Bozkaya G, Oztekin D, Uyar I, Kebapcilar AG, Pamuk B. Serum fetuin-A levels in women with polycystic ovary syndrome. Arch Gynecol Obstet 2012;286:1473-6.  Back to cited text no. 20
    
21.
Schultes B, Frick J, Ernst B, Stefan N, Fritsche A. The effect of 6-weeks of aerobic exercise training on serum fetuin-A levels in non-diabetic obese women. Exp Clin Endocrinol Diabetes 2010;118:754-6.  Back to cited text no. 21
    
22.
Ates S, Yesil G, Sevket O, Molla T, Yildiz S. Comparison of metabolic profile and abdominal fat distribution between karyotypically normal women with premature ovarian insufficiency and age matched controls. Maturitas 2014;79:306-10.  Back to cited text no. 22
    
23.
Kalab P, Schultz RM, Kopf GS. Modifications of the mouse zona pellucida during oocyte maturation: Inhibitory effects of follicular fluid, fetuin, and alpha 2HS-glycoprotein. Biol Reprod 1993;49:561-7.  Back to cited text no. 23
    
24.
Bódis J, Peti AM, Sulyok E, Kovács GL, Várnagy A. Serum and follicular fluid fetuin-A in women undergoing in vitro fertilization. Clin Chem Lab Med 2014;52:1313-8.  Back to cited text no. 24
    
25.
Mathur SP, Lee JH, Jiang H, Arnaud P, Rust PF. Levels of transferrin and alpha 2-HS glycoprotein in women with and without endometriosis. Autoimmunity 1999;29:121-7.  Back to cited text no. 25
    
26.
Pillai S, Zhou GX, Arnaud P, Jiang H, Butler WJ, Zhang H. Antibodies to endometrial transferrin and alpha 2-heremans schmidt (HS) glycoprotein in patients with endometriosis. Am J Reprod Immunol 1996;35:483-94.  Back to cited text no. 26
    
27.
Mathur SP. Autoimmunity in endometriosis: Relevance to infertility. Am J Reprod Immunol 2000;44:89-95.  Back to cited text no. 27
    
28.
Byskov AG. Cell kinetic studies of follicular atresia in the mouse ovary. J Reprod Fertil 1974;37:277-85.  Back to cited text no. 28
    
29.
Kasuya K. Elimination of apoptotic granulosa cells by intact granulosa cells and macrophages in atretic mature follicles of the guinea pig ovary. Arch Histol Cytol 1997;60:175-84.  Back to cited text no. 29
    
30.
van Wezel IL, Dharmarajan AM, Lavranos TC, Rodgers RJ. Evidence for alternative pathways of granulosa cell death in healthy and slightly atretic bovine antral follicles. Endocrinology 1999;140:2602-12.  Back to cited text no. 30
    
31.
Høyer PE, Terkelsen OB, Grete Byskov A, Nielsen H. Fetuin and fetuin messenger RNA in granulosa cells of the rat ovary. Biol Reprod 2001;65:1655-62.  Back to cited text no. 31
    
32.
Yen M, Donma O, Yildizfer F, Ekmekci O, Asli Karatas Kul Z, Esat Imal A, et al. Association of fetuin A, adiponectin, interleukin 10 and total antioxidant capacity with IVF outcomes. Iran J Reprod Med 2014;12:747-54.  Back to cited text no. 32
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1]



 

Top
Print this article  Email this article
             

    

 
   Search
 
  
    Similar in PUBMED
    Search Pubmed for
    Search in Google Scholar for
  Related articles
    Article in PDF (630 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  


    Abstract
   Introduction
   Methods
   Results
   Discussion
   Conclusion
    References
    Article Figures
    Article Tables

 Article Access Statistics
    Viewed474    
    Printed29    
    Emailed0    
    PDF Downloaded32    
    Comments [Add]    

Recommend this journal