|Year : 2019 | Volume
| Issue : 11 | Page : 1463-1466
Can clomiphene citrate resistance be predicted by RDW-CV levels in infertile women with PCOS?
Nurullah Peker1, Serhat Ege2, Muhammet Hanifi Bademkiran2, Edip Aydin2, Talip Karacor3, Mehmet Obut2, Esref Arac4, Elif Agacayak1, Talip Gul1
1 Department of Obstetrics and Gynecology, Dicle University, Faculty of Medicine, Diyarbakir, Turkey
2 Department of Obstetrics and Gynecology, Health Sciences University, Gazi Yasargil Training and Research Hospital, Diyarbakir, Turkey
3 Department of Obstetrics and Gynecology, Adıyaman University, Faculty of Medicine, Adıyaman, Turkey
4 Department of Internal Medicine, Health Sciences University, Gazi Yasargil Training and Research Hospital, Diyarbakir, Turkey
|Date of Submission||26-Dec-2018|
|Date of Acceptance||29-May-2019|
|Date of Web Publication||13-Nov-2019|
Assist. Prof. Nurullah Peker
Department of Obstetrics and Gynecology, Dicle University, Faculty of Medicine, Diyarbakir 21070
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objective: To identify whether red blood cell distribution width coefficient of variation (RDW-CV) and mean platelet volume (MPV) levels can predict clomiphene citrate resistance (CC-R) in infertile, anovulatory females with polycystic ovarian syndrome (PCOS). Methods: A total of 89 infertile patients who were admitted to a tertiary center diagnosed with non-obese PCOS were included in this study. The patients were divided into two groups: the first group comprised 53 non-obese patients with PCOS and CC-R, and the second group included 36 non-obese patients with PCOS and CC-S. RDW-CV, RDW-SD, and MPV values, along with routine whole blood count parameters were compared between the groups. Results: RDW-CV values were found to be significantly higher in the patients with CC-R compared to those with CC-S (P < 0.05). The sensitivity, specificity, positive, and negative predictive values were found to be 69%, 58.1%, 34.5%, and 12.5%, respectively, at an RDW-CV level of 12.85. The odds ratio was calculated as 3.077 (95% CI 1.245–7.603) in terms of the cut-off point. Conclusion: We think that RDW-CV which is a marker of inflammation is a simple, cheap, and accessible marker for the prediction of CC resistance.
Keywords: Clomiphene citrate resistance, inflammation, polycystic ovarian syndrome, red blood cell distribution width
|How to cite this article:|
Peker N, Ege S, Bademkiran MH, Aydin E, Karacor T, Obut M, Arac E, Agacayak E, Gul T. Can clomiphene citrate resistance be predicted by RDW-CV levels in infertile women with PCOS?. Niger J Clin Pract 2019;22:1463-6
|How to cite this URL:|
Peker N, Ege S, Bademkiran MH, Aydin E, Karacor T, Obut M, Arac E, Agacayak E, Gul T. Can clomiphene citrate resistance be predicted by RDW-CV levels in infertile women with PCOS?. Niger J Clin Pract [serial online] 2019 [cited 2020 Feb 26];22:1463-6. Available from: http://www.njcponline.com/text.asp?2019/22/11/1463/270869
| Introduction|| |
Polycystic ovarian syndrome (PCOS) is one of the major causes of anovulatory infertility in women of reproductive age. The prevalence is approximately 10% of reproductive-aged women. A woman with PCOS may display various abnormalities that require attention, such as oligomenorrhoea, hyperandrogenism, anovulatory infertility or metabolic risk factors including obesity, insulin resistance, dyslipidaemia, or impaired glucose tolerance. The etiology of PCOS is not known. On the other hand, no single etiologic factor is completely responsible for the spectrum of abnormalities in this syndrome. PCOS is associated with a high prevalence of chronic low-grade inflammation, dyslipidemia, hypertension, obesity, impaired glucose tolerance, metabolic syndrome, diabetes, and cardiovascular risk factors.,,,,
For patients with PCOS, clomiphene citrate (CC) is the widely preferred treatment to induce ovulation. However, clomiphene citrate resistance (CC-R) is seen in 15-40% of women with PCOS. CC-R is defined as the inability to ovulate after receiving up to 150 mg of CC daily for 5 days, beginning on the second day of the menstrual cycle, for at least 3 menstrual cycles.
Red blood cell distribution width (RDW) is a measure of heterogeneity in the sizes of the circulating erythrocytes. Moreover, it is typically included in the complete blood count (CBC) at no extra cost. The two RDW measurements currently used are the red blood cell distribution width coefficient of variation (RDW-CV) and the red blood cell distribution width standard deviation (RDW-SD). RDW plays a significant role in terms of the differential diagnosis of anaemia. Furthermore, increased RDW has been found to be related to cardiovascular disease and metabolic syndrome., Despite these associations, the mechanisms underlying elevated RDW remain unknown, although chronic inflammation may be a possible cause.,
Moreover, because platelets of a larger size indicate greater haemostatic function, mean platelet volume (MPV) is a significant indicator of platelet activation. Previous research has noted that MPV increases in coronary artery disease, diabetes mellitus, atherosclerosis and PCOS.,
No research related to RDW and MPV levels in clomiphene citrate sensitive (CC-S) and CC-R PCOS patients was found in the relevant literature. Therefore, the aim of this study was to analyse the RDW and MPV values of CC-S and CC-R PCOS patients having normal body mass indexes (BMI). We aimed to predict the clomiphene citrate resistance of PCOS patients planning to undergo ovulation induction with CC via CBC, which is a simple and cheap test available in every hospital.
| Methods|| |
This study was carried out by examining the files of infertile patients with PCOS who were admitted to the infertility outpatient clinic of the Gazi Yaşargil Diyarbakır Training and Research Hospital between January 15, 2018 and May 15, 2018. Ethics committee approval (Ethics Committee No. 96) was obtained. The study was designed in accordance with the provisions of the Declaration of Helsinki.
Amongst 1,803 patients admitted to the infertility outpatient clinic during the study period, 89 (4.93%) non-obese patients with PCOS who met the Rotterdam Criteria were selected for the study. According to the World Health Organization's (WHO) criteria, patients desired to have children, had open Fallopian tube More Detailss as determined via hysterosalpingography or hysteroscopic diagnosis, and had normal semen analyses. The patients were divided into two groups: the first group comprised 53 non-obese patients with PCOS and CC-R, and the second group included 36 non-obese patients with PCOS and CC-S. All patients received continuous CC treatment for 3 consecutive months, with dosage being administered for 5 days starting on the second day of menstruation at a maximum dose of 150 mg/day. The CC-R group was defined as those who failed to ovulate in response to CC treatment after 3 cycles. The exclusion criteria consisted of patients under 18 years of age, over 40 years of age, with male infertility, infertility due to endometriosis, decreased ovarian reserve, tubal factor, planned in vitro fertilisation treatment, PCOS patients with a BMI below 20 or above 25, and in patients with chronic systemic diseases or a history of chronic drug use.
The ages of the patients and their hormone levels (i.e. serum FSH, LH, E2 and prolactin), RDW-CV, RDW-SD, and MPV values, along with routine whole blood count parameters, were compared between the groups.
The Statistical Package for the Social Sciences (SPSS) version 16 for Windows (SPSS Inc., Chicago, IL, USA) was used to analyse the data. According to our study, results for RDW-CV levels, sample size of the study population was calculated to be 89 patients (α = 0.05 and the study power = 80%). The Shapiro-Wilk and Kolmogorov-Smirnov tests were used to examine normal distribution. All parameters were found to be abnormally distributed. Nonparametric data were analysed using the Mann-Whitney U test. Receiver Operating Characteristic (ROC) curve analysis was used to identify the cut-off point of RDW-CV measurements according to the presence of ovulation. Then the results were evaluated with a 95% confidence interval and a significance level of P < 0.05.
| Results|| |
Of the 1,803 patients who were admitted to our outpatient clinic with infertility, 89 (4.93%) were non-obese PCOS patients, 36 (40.4%) of whom had CC-S and 53 (59.6%) of whom had CC-R. RDW-CV values were found to be higher in the CC-R patients. This difference was statistically significant (P < 0.05) [Table 1].
|Table 1: Comparison of age and laboratory parameters between CC-R and CC-S patients|
Click here to view
The cut-off of RDW-CV was higher than 12.85, which correlated with the CC resistance in ovulation induction. The sensitivity, specificity, positive, and negative predictive values were found to be 69%, 58.1%, 34.5%, and 12.5%, respectively, at an RDW-CV level of 12.85. The area below the curve was 63.2%, with a standard error of 0.06% in the ROC curve [Table 2]. The odds ratio was calculated as 3.077 (95% CI: 1.245–7.603) for the cut-off [Figure 1] and [Figure 2].
| Discussion|| |
In this study, RDW and MPV, two whole blood count parameters determined through a simple and cheap technique, were investigated to predict clomiphene resistance in patients with PCOS. The literature review found publications that showed an association between RDW and MPV with PCOS on the basis of chronic inflammation.,,, CC being the first choice for ovulation induction in PCOS, although many studies have investigated CC resistance, and none of the literature evaluated RDW and MPV for the prediction of clomiphene resistance.
In a study examining pro-inflammatory cytokine high sensitivity C-reactive protein (hsCRP) for the prediction of CC resistance, hsCRP was found to be higher in patients with CC-R than in patients with CC-S. In the same study, circulating cytokines were also evaluated, and it was found that decreased angiopoietin-2 levels and increased chemokine CXCL-16 levels were significantly associated with the presence of CC resistance. As a result, it was thought that inflammation may be related to CC response. In another study evaluating vaspin, which is a mediator of inflammation, it was found that high vaspin levels (≥ 3.74 ng/mL) correlated with PCOS patients with CC-R. A study that investigated CC resistance with tumour necrosis factor alpha (TNF-α) found that TNF-α levels were elevated in all PCOS patients, whilst even more elevated in patients with CC-R. Similar results were obtained in this study with RDW-CV, which is another indicator of inflammation. We believe that CC resistance can be predicted in patients with RDW-CW values of 12.85 and above before ovulation induction is commenced.
In a study that evaluated anti-Müllerian hormone (AMH), serum AMH concentration was found to be a useful predictor of CC resistance. Furthermore, it has been reported that in PCOS patients with higher levels of AMH, the CC response is lower. However, AMH has the disadvantages of being an expensive examination method with limited availability in hospitals. We believe that RDW-CV is a potential option in the absence of AMH for predicting CC resistance, both because it is less expensive and since it can be studied in every hospital.
While some studies have indicated that high MPV is associated with PCOS,, other studies have reported no association between MPV and PCOS. However, no previous study evaluated MPV for predicting CC resistance in PCOS patients undergoing ovulation induction with CC. Although we evaluated MPV in this study, we found no statistically significant difference between the CC-R and CC-S patients.
In conclusion, many mediators affect ovulation induction with CC in infertile patients with PCOS. However, defining these parameters involves costly tests that are not available in every hospital. In this study, RDW-CV, which is a marker of inflammation, was studied for the first time to predict CC resistance in PCOS. RDW-CV is a simple, inexpensive and accessible marker. Our aim was to determine CC resistance at an early stage through RDW-CV elevation, thereby reducing the financial burden for the patient. However, because our study was conducted with a limited number of patients, more extensive studies are required on this subject.
We would like to thank Ayhan Aktas and Bilge Karaaslan their assistance with the statistics used in this report.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Norman RJ, Dewailly D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet (London, England). 2007;370:685-97.
Legro RS, Arslanian SA, Ehrmann DA, Hoeger KM, Murad MH, Pasquali R, et al.
Diagnosis and treatment of polycystic ovary syndrome: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2013;98:4565-92.
Li W, Li Q. Dysregulation of glucose metabolism even in Chinese PCOS women with normal glucose tolerance. Endocr J 2012;59:765-70.
Dahlgren E, Janson PO, Johansson S, Lapidus L, Odén A. Polycystic ovary syndrome and risk for myocardial infarction: Evaluated from a risk factor model based on a prospective population study of women. Acta Obstet Gynecol Scand 1992;71:591-604.
Wild S, Pierpoint T, McKeigue P, Jacobs H. Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: A retrospective cohort study. Clin Endocrinol (Oxf) 2000;52:595-600.
Delibas IB, Yapca OE, Laloglu E. Does endocan level increase in women with polycystic ovary syndrome ? A case — control study. Ginekol Pol 2018;89:500-5.
Temur M, Calan M, Akşit M, Yılmaz Ö, Çift T, Akselim B, et al.
Increased serum neuregulin 4 levels in women with polycystic ovary syndrome : A case-control study. Ginekol Pol 2017;88:517-22.
Homburg R. Clomiphene citrate--end of an era? A mini-review. Hum Reprod 2005;20:2043-51.
Brown J, Farquhar C, Beck J, Boothroyd C, Hughes E. Clomiphene and anti-oestrogens for ovulation induction in PCOS. Cochrane Database Syst Rev 2009:CD002249. doi: 10.1002/14651858.CD002249.pub4.
Lappé JM, Horne BD, Shah SH, May HT, Muhlestein JB, Lappé DL, et al.
Red cell distribution width, C-reactive protein, the complete blood count, and mortality in patients with coronary disease and a normal comparison population. Clin Chim Acta 2011;412:2094-9.
Sánchez-Chaparro MA, Calvo-Bonacho E, González-Quintela A, Cabrera M, Sáinz JC, Fernández-Labandera C, et al.
Higher red blood cell distribution width is associated with the metabolic syndrome: Results of the ibermutuamur cardiovascular risk assessment study. Diabetes Care 2010;33:e40.
Vayá A, Carmona P, Badia N, Hernandez-Mijares A, Bautista D. Association between high red blood cell distribution width and metabolic syndrome. Influence of abdominal obesity. Clin Hemorheol Microcirc 2011;47:75-7.
Kosus N, Kosus A, Turhan NO. Relationship of ovarian volume with mean platelet volume and lipid profile in patients with polycystic ovary syndrome. Exp Ther Med 2011;2:1141-4.
Schneider DJ. Abnormalities of coagulation, platelet function, and fibrinolysis associated with syndromes of insulin resistance. Coron Artery Dis 2005;16:473-6.
Wang L, Qi H, Baker PN, Zhen Q, Zeng Q, Shi R, et al.
Altered circulating ınflammatory cytokines are associated with anovulatory polycystic ovary syndrome (PCOS) women resistant to clomiphene citrate treatment. Med Sci Monit 2017;23:1083-9.
Dogan K, Ekin M, Helvacioğlu Ç, Yaşar L. Can serum vaspin levels predict clomiphene resistance in infertile women with PCOS? Eur J Obstet Gynecol Reprod Biol 2017;217:6-11.
Seyam E, Hasan M, Khalifa EM, Ramadan A, Hefzy E. Evaluation of tumor necrosis factor alpha serum level in obese and lean women with clomiphene citrate resistant polycystic ovary disease. Gynecol Endocrinol 2017;33:892-8.
Gülşen MS, Ulu İ, Yıldırım Köpük Ş, Kıran G. The role of anti-Müllerian hormone in predicting clomiphene citrate resistance in women with polycystic ovarian syndrome. Gynecol Endocrinol 2019;35:86-9.
Silfeler DB, Kurt RK, Yengil E, Un B, Arica S, Baloglu A. Evaluation of mean platelet volume values in lean women with polycystic ovary syndrome. Pak J Med Sci 2014;30:589-92.
[Figure 1], [Figure 2]
[Table 1], [Table 2]