|Year : 2018 | Volume
| Issue : 7 | Page : 151-155
Effect of six-month use of oral contraceptive pills on plasminogen activator inhibitor-1 & factor VIII among women with polycystic ovary syndrome: An observational pilot study
Syed Douhath Yousuf1, Mohammad Ashraf Ganie2, Samoon Jeelani3, Syed Mudassar4, Zaffar Amin Shah5, Mohammad Afzal Zargar1, Shajrul Amin1, Imtiyaz Ahmad Wani2, Fouzia Rashid1
1 Department of Clinical Biochemistry/Biochemistry, University of Kashmir, Srinagar, India
2 Department of Endocrinology & Metabolism, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, India
3 Department of Haematology, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, India
4 Department of Clinical Biochemistry, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, India
5 Department of Immunology & Molecular Medicine, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, India
|Date of Submission||29-Nov-2017|
|Date of Web Publication||3-Apr-2019|
Dr Fouzia Rashid
Department of Clinical Biochemistry, University of Kashmir, Srinagar 190 006, Jammu & Kashmir
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background & objectives: Polycystic ovary syndrome (PCOS) is an endocrinopathy warranting lifelong individualized management by lifestyle and pharmacological agents mainly oral contraceptive pills (OCPs). This study was aimed to report the impact of six-month OCP use on plasminogen activator inhibitor-1 (PAI-1) and factor VIII (FVIII) in women with PCOS.
Methods: PCOS women diagnosed on the basis of Rotterdam 2003 criteria, either treated with OCPs (ethinyl estradiol-0.03 mg, levonorgestrel-0.15 mg) for a period of six months (n=40) or drug-naïve (n=42), were enrolled in this study. Blood was drawn to estimate glucose, insulin levels and lipid profile. Chemiluminescence immunoassays were used to measure hormones (LH, FSH, PRL, T4). Plasma levels of PAI-I and FVIII were measured by commercially available kits.
Results: Menstrual regularity, Ferriman-Gallwey score and serum total testosterone significantly improved in the OCP group compared to drug-naïve group (P<0.01). No significant difference was observed in PAI-1 levels of the two groups; however, significant decrease in FVIII levels was observed in OCP group as compared to drug-naïve group. PAI-1 levels of OCP group correlated positively with blood glucose two hours, triglycerides and insulin two hours, while FVIII levels of OCP group correlated negatively with fasting insulin and homoeostatic model assessment-insulin resistance.
Interpretation & conclusions: OCPs use has differential effect on pro-coagulant markers among women with PCOS. Well-designed, long-term, prospective, large-scale studies are prerequisite to elucidate the efficacy and safety of OCP in the treatment of PCOS.
Keywords: Factor VIII - oral contraceptive pills - plasminogen activator inhibitor-1 - polycystic ovary syndrome - pro-coagulant markers
|How to cite this article:|
Yousuf SD, Ganie MA, Jeelani S, Mudassar S, Shah ZA, Zargar MA, Amin S, Wani IA, Rashid F. Effect of six-month use of oral contraceptive pills on plasminogen activator inhibitor-1 & factor VIII among women with polycystic ovary syndrome: An observational pilot study. Indian J Med Res 2018;148, Suppl S1:151-5
|How to cite this URL:|
Yousuf SD, Ganie MA, Jeelani S, Mudassar S, Shah ZA, Zargar MA, Amin S, Wani IA, Rashid F. Effect of six-month use of oral contraceptive pills on plasminogen activator inhibitor-1 & factor VIII among women with polycystic ovary syndrome: An observational pilot study. Indian J Med Res [serial online] 2018 [cited 2019 Apr 23];148, Suppl S1:151-5. Available from: http://www.ijmr.org.in/text.asp?2018/148/7/151/255400
Polycystic ovary syndrome (PCOS), is a common endocrine disorder of reproductive age women globally  and in India also . Besides the various reproductive abnormalities (chronic anovulation and hyperandrogenism), these women are prone to develop insulin resistance (IR), compensatory hyperinsulinaemia, dyslipidaemia, hypertension, obesity , metabolic syndrome (MS), type 2 diabetes mellitus (T2DM) and higher risk of cardiovascular diseases (CVD). Several reports have shown dysregulation of the haemostatic system pointing towards pro-thrombotic state, including hypofibrinolysis, hypercoagulability , and endothelial and platelet dysfunction ,.
Plasminogen activator inhibitor-1 (PAI-1), a key regulator of fibrinolysis, is a marker of IR as plasma PAI-1 antigen levels and activity are frequently elevated in IR states, such as abdominal obesity, MS and T2DM . Given the increased prevalence of IR in women with PCOS, plasma PAI-1 levels have been assessed in women with PCOS ,, and in some elevated levels of PAI-1 have been reported. Factor VIII (FVIII) is a vitamin K dependent coagulation factor primarily synthesized in the liver and circulates in the plasma in a non-covalent complex with von Willebrand factor. FVIII is reported as a common risk factor for venous thrombosis, coronary artery disease and stroke ,, with its elevated levels being linked to higher body mass index (BMI), plasma glucose, insulin, fibrinogen and triglycerides levels . There are scarce data on FVIII; it has not been extensively investigated among women with PCOS.
Oral contraceptive pills (OCPs) are considered the treatment of choice for PCOS as these agents are useful in regulating menstrual cycles and ameliorating androgenic symptoms . However, OCPs have been linked to derangement in lipid and glucose metabolism in addition to venous thrombosis ,. This pilot study was undertaken to compare plasma levels of PAI-I and FVIII among women with PCOS receiving OCP at least for six months with drug-naïve PCOS women.
| Material & Methods|| |
This single-contact, observational pilot study was conducted from January 2014 to March 2015 in the department of Endocrinology of Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, India. The women were required to qualify Rotterdam 2003 criteria  for diagnosis of PCOS before enrolling into the study; therefore, of the 200 women screened during this period, only those fulfilling the inclusion criteria were selected for this study. The women were divided into two groups: OCP group (n=40); women who had received OCP (ethinyl estradiol-0.03 mg, levonorgestrel-0.15 mg) at least for 24±2 wk after the diagnosis and drug-naïve group (n=42) which included women with PCOS and were not taking any drug. The study protocol was approved by the Institutional Ethics Committee of SKIMS, Srinagar (IEC No: SIMS 131/IEC-SKIMS/2013-6479).
Clinical assessment: Consecutive women attending the clinics with complaints of oligomenorrhoea, unwanted hair growth or acne vulgaris were informed about the study and those who volunteered to be part of the study were asked to sign informed consent. Details regarding menstrual history, weight gain, unwanted hair growth, acne vulgaris, etc. were noted. Oligomenorrhoea was defined as number of cycles less than eight per year or interval of >35 days while amenorrhoea as cessation of menstrual cycle for six months. Anthropometry (measurement of height, weight, waist-hip ratio and blood pressure) and detailed systemic examination were done in all women. Hirsutism score was done using Ferriman-Gallwey score  by counting nine specified body areas. A score of >8 was taken as significant. Exclusion criteria included those with known diabetes or hypertension, Cushing's syndrome, hypothyroidism, hyperprolactinaemia and androgen-secreting tumours.
Laboratory evaluation: Blood samples for glucose and insulin were collected at 0 (4 ml), 60 (3 ml) and 120 min (2 ml) after the glucose load [oral glucose tolerance test (OGTT)] performed after 10-12 h of an overnight fasting. A fasting sample was taken for hormones [luteinizing hormone (LH), follicular-stimulating hormone (FSH), T4, thyroid-stimulating hormone (TSH), prolactin (PRL), cortisol, 17-OHP and total testosterone], lipid profile and liver and kidney function tests. The hormone estimation included 17-OHP (to rule out non-classical congenital adrenal hyperplasia), TSH and T4 (to rule out hypothyroidism), PRL (to rule out prolactinoma), cortisol (to rule out Cushing's syndrome) and total testosterone (to diagnose hyperandrogenism and to rule out androgen-secreting ovarian or adrenal tumours).
Assays: Glucose (mg/dl) was measured by glucose oxidase peroxidise method (DiaSys Diagnostic Systems, Germany). Plasma insulin was measured by electrochemiluminescence (Cobase411, Roche Diagnostics Limited, Germany), using commercially available kits. Lipid parameters such as cholesterol, triglycerides, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) were measured by colorimetric method (DiaSys Diagnostic Systems, Germany). Chemiluminescence immunoassay (ECLIA, Meditron, USA) was used to analyze LH, FSH, PRL, T4, TSH, cortisol and total testosterone using commercial kits (BECKMAN COULTER uicel DXI 800, USA) in duplicate. ELISA was used to analyse 17-OHP using commercial kits (Diagnostics Biochem, Canada). Plasma levels of PAI were measured in duplicate using ELISA kit (SYMANSIS, New Zealand). FVIII in the plasma was estimated by coagulometric method using commercially available kit (SIEMENS, USA).
IR was estimated using homoeostatic model assessment-IR (HOMA-IR) which was calculated as product of fasting insulin value (μIU/ml) and the fasting plasma glucose value (mg/dl) divided by 405. Quantitative insulin sensitivity check index (QUICKI) was used to estimate insulin sensitivity and was calculated as 1/log fasting insulin (μIU/ml)+log fasting glucose (mg/dl). Fasting glucose and insulin ratio (FGIR) was calculated as fasting plasma glucose (mg/dl)/fasting insulin (μIU/ml).
Statistical analysis: Statistical analysis was done using SPSS 20 software (SPSS 20, IBM, Armonk, NY, USA). Various parameters such as anthropometry, basic biochemical, hormonal and insulin measures were compared between cases and controls using two-sampled t test. Pearson correlation coefficient (r) was used to analyze the association between study variables.
| Results & Discussion|| |
Baseline characteristics of the study groups are summarized in [Table 1] and [Table 2]. The characters such as mean age (years) and BMI (kg/m 2) were comparable among the two groups. However, significant difference was observed between number of cycles per year and serum total testosterone levels (P<0.01) between OCP and drug-naïve group. Serum total cholesterol, LDL cholesterol, insulin two hours (P<0.01) and QUICKI (P<0.05) were significantly higher in the OCP group compared to drug-naïve group. The difference in plasma PAI-1 levels was insignificant between the OCP-treated and drug-naïve participants. However, plasma FVIII level was significantly lower in the OCP-treated group compared to drug-naïve women (P<0.01). PAI-1 in OCP group showed significant positive correlation with blood glucose two hours (r=0.26, P=0.02), insulin two hours (r=0.28, P=0.03) and serum triglyceride level (r=0.24, P=0.01). However, FVIII levels showed significant negative correlation with fasting insulin (r=−0.34, P=0.02) and HOMA-IR (r=−0.32, P=0.030).
|Table 1: Comparison of various clinical and biochemical parameters of drug-naïve group and oral contraceptive pill group|
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|Table 2: Comparison of oral glucose tolerance test derived insulin resistance parameters, gonadotropins, total testosterone and pro-coagulant markers between drug-naive group and oral contraceptive pill group|
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Women with PCOS are characterized by increased levels of pro-coagulant markers such as fibrinogen and PAI-1, which promote atherogenic processes and increase the risk of CVD in these women . Several studies have reported higher PAI-1 levels in women with PCOS which correlated positively with components of IR ,. Furthermore, evidence suggests that OCP use may further worsen coagulation state and risk for CVD ,.
There are limited studies evaluating the effect of OCPs on plasma PAI-1 levels, and the results remain controversial rather than conclusive ,,. In the current study, an insignificant increase in plasma PAI-1 levels was observed with six months of OCP use. However, PAI-1 levels of OCP group correlated positively with markers of MS and IR. Previous data suggest that OCP use may decrease , or have no effect  on PAI-1 levels. Teede et al reported that additional decrease in PAI-1 levels occurred with the use of OCP containing cytoproterone acetate in women with PCOS. Similar to our results, Küçük et al reported an insignificant difference in PAI-1 levels between women taking OCPs containing levonorgestrel and control women who had not received OCPs although this study was conducted among non-PCOS women.
FVIII level is known to increase the pro-coagulant activity and use of OCPs further elevates FVIII levels . A significant decrease in plasma FVIII levels was observed with the use of OCP containing ethinyl estradiol and levonorgestrel compared to drug-naïve PCOS patients and FVIII of OCP group correlated negatively with markers of IR in the present study. A study has reported that OCPs seem to have no effect on FVIII levels . Women with OCP intake showed increase in fibrinogen and FX and a reduction in anti-thrombin III levels when compared with their control values . This group also reported small but significant increases in triglycerides and triglyceride-rich lipoproteins .
In conclusion, results of this pilot study may not be conclusive owing to several limitations such as lack of baseline data in the OCP group, smaller number of subjects and no control group with longitudinal follow up. Despite these limitations, the data may pave way for well-designed, randomized, longitudinal studies with large cohort among women with PCOS.
Financial support & sponsorship: None.
Conflicts of Interest: None.
| References|| |
Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO, et al
. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab
Joshi B, Mukherjee S, Patil A, Purandare A, Chauhan S, Vaidya R, et al.
A cross-sectional study of polycystic ovarian syndrome among adolescent and young girls in Mumbai, India. Indian J Endocrinol Metab
Teede HJ, Hutchison S, Zoungas S, Meyer C. Insulin resistance, the metabolic syndrome, diabetes, and cardiovascular disease risk in women with PCOS. Endocrine
Lo JC, Feigenbaum SL, Yang J, Pressman AR, Selby JV, Go AS, et al.
Epidemiology and adverse cardiovascular risk profile of diagnosed polycystic ovary syndrome. J Clin Endocrinol Metab
Moran LJ, Hutchison SK, Meyer C, Zoungas S, Teede HJ. A comprehensive assessment of endothelial function in overweight women with and without polycystic ovary syndrome. Clin Sci (Lond)
Mannerås-Holm L, Baghaei F, Holm G, Janson PO, Ohlsson C, Lönn M, et al
. Coagulation and fibrinolytic disturbances in women with polycystic ovary syndrome. J Clin Endocrinol Metab
Rajendran S, Willoughby SR, Chan WP, Liberts EA, Heresztyn T, Saha M, et al
. Polycystic ovary syndrome is associated with severe platelet and endothelial dysfunction in both obese and lean subjects. Atherosclerosis
Cesari M, Pahor M, Incalzi RA. Plasminogen activator inhibitor-1 (PAI-1): A key factor linking fibrinolysis and age-related subclinical and clinical conditions. Cardiovasc Ther
Meigs JB, O'donnell CJ, Tofler GH, Benjamin EJ, Fox CS, Lipinska I, et al.
Hemostatic markers of endothelial dysfunction and risk of incident type 2 diabetes: The Framingham offspring study. Diabetes
Orio F Jr., Palomba S, Cascella T, Tauchmanovà L, Nardo LG, Di Biase S, et al.
Is plasminogen activator inhibitor-1 a cardiovascular risk factor in young women with polycystic ovary syndrome? Reprod Biomed Online
Tarkun I, Cantürk Z, Arslan BC, Türemen E, Tarkun P. The plasminogen activator system in young and lean women with polycystic ovary syndrome. Endocr J
Zhao JV, Schooling CM. Coagulation factors and the risk of ischemic heart disease: A Mendelian randomization study. Circ Genom Precis Med
Samai AA, Boehme AK, Shaban A, George AJ, Dowell L, Monlezun DJ, et al.
A model for predicting persistent elevation of factor VIII among patients with acute ischemic stroke. J Stroke Cerebrovasc Dis
Cushman M, Yanez D, Psaty BM, Fried LP, Heiss G, Lee M, et al.
Association of fibrinogen and coagulation factors VII and VIII with cardiovascular risk factors in the elderly: The Cardiovascular Health Study. Cardiovascular Health Study Investigators. Am J Epidemiol
Badawy A, Elnashar A. Treatment options for polycystic ovary syndrome. Int J Womens Health
Bounhoure JP, Galinier M, Roncalli J, Assoun B, Puel J. Myocardial infarction and oral contraceptives. Bull Acad Natl Med
Tanis BC. Oral contraceptives and the risk of myocardial infarction. Eur Heart J
Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril
Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia
Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, et al
. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab
Legro RS, Castracane VD, Kauffman RP. Detecting insulin resistance in polycystic ovary syndrome: purposes and pitfalls. Obstet Gynecol Surv
Nieuwdorp M, Stroes ES, Meijers JC, Büller H. Hypercoagulability in the metabolic syndrome. Curr Opin Pharmacol
Tanis BC, van den Bosch MA, Kemmeren JM, Cats VM, Helmerhorst FM, Algra A, et al.
Oral contraceptives and the risk of myocardial infarction. N Engl J Med
Döring A, Fröhlich M, Löwel H, Koenig W. Third generation oral contraceptive use and cardiovascular risk factors. Atherosclerosis
Teede HJ, Meyer C, Hutchison SK, Zoungas S, McGrath BP, Moran LJ, et al.
Endothelial function and insulin resistance in polycystic ovary syndrome: The effects of medical therapy. Fertil Steril
Scarabin PY, Plu-Bureau G, Zitoun D, Bara L, Guize L, Samama MM, et al.
Changes in haemostatic variables induced by oral contraceptives containing 50 micrograms or 30 micrograms oestrogen: Absence of dose-dependent effect on PAI-1 activity. Thromb Haemost
Akhter QS, Akhter N, Begum USN, Rahman F. Assessment of coagulation disorder in women taking oral contraceptives. J Bangladesh Soc Physiol
Küçük M, Sezer SD, Odabaşi AR, Güner Z, Yuksel H, Serter M, et al
. The effect of low-dose combined oral contraceptive containing 100 ug levonorgestrel on plasma plasminogen activator inhibitor-1 concentrations. Clin Exp Obstet Gynecol
Patole S, Ramya I. Bilateral renal vein thrombosis due to elevated factor VIII levels. J Assoc Physicians India
Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, Koster T, Bertina RM, Vandenbroucke JP, et al.
Hemostatic effects of oral contraceptives in women who developed deep-vein thrombosis while using oral contraceptives. Thromb Haemost
[Table 1], [Table 2]