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Cite this article: Manzoor S, Gania AM, Yusuf SD, Amin S, Habib R, et al. (2017) Metabolic Derangements and Possible CVD Risk in PCOS Women Owing to Use of OCP’s as a Treatment Mode – Pros and Cons. J Endocrinol Diabetes Obes 5(3): 1109.

*Corresponding authorFouzia Rashid, Department of Clinical Biochemistry, University of Kashmir, India, Tel: 9469042001; E-mail:

Submitted: 23 May 2017

Accepted: 25 June 2017

Published: 27 June 2017

ISSN: 2333-6692

Copyright© 2017 Rashid et al.

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Keywords•Polycystic ovary syndrome•Oral contraceptive pills•Type 2 diabetes mellitus•Cardiovascular disease•Hyperandrogenism•Insulin resistance; Treatment

Review Article

Metabolic Derangements and Possible CVD Risk in PCOS Women Owing to Use of OCP’s as a Treatment Mode – Pros and Cons.Saika Manzoor1, Ashraf M. Gania2, Syed Douhath Yusuf3, Shajrul Amin3, Rizwana Habib4, and Fouzia Rashid1*1Department of Clinical Biochemistry, University of Kashmir, India2Department of Endocrinology and Metabolism, Sher-i-Kashmir Institute of Medical Sciences, India3Department of Biochemistry, University of Kashmir, India4Department of Obstetrics and Gynaecology, Government Medical College, India

Abstract

Polycystic Ovary Syndrome (PCOS) is one of the most common endocrinopathies of clinical importance, affecting the women of reproductive age. Women with PCOS are clinically diagnosed by the presence of menstrual irregularities, hirsutism, acne which are commonly occurring symptoms while as acanthosis nigricans and alopecia are rarely occurring symptoms in these women. PCOS is a vicious cycle with absence of any particular pathway regarding its pathogenesis. Various co-morbidities have been found associated with PCOS. Likewise disturbance in normal metabolic pathways like endocrine system, reproductive system, glucose metabolism, lipid metabolism, coagulation system and inflammation system are usually predictors of various diseases like Coronary Vascular Diseases (CVD), atherosclerosis, obesity, Venous Thrombo Embolism (VTE), Type 2 Diabetes Mellitus (T2DM), Insulin resistance (IR), pregnancy complications, infertility, cancers etc. in PCOS women. Thus, PCOS is not just a disease but is considered to be a syndrome. Various options are available regarding the management and the treatment of PCOS .Life style modifications: including weight reduction by increasing physical activity and reduction of high calorific diet being first choice regarding PCOS management. Moreover, Oral Contraceptive Pills(OCPs) along with life style modifications are being used as first line of treatment in women with PCOS. OCPs seem to be drug of choice in case of adolescent girls where the pregnancy is not main concern. They help to reduce various hyper androgenic symptoms like acne, hirsutism, alopecia, acanthosis nigricans and help to regularize the menstrual cyclicity. But, the use of high dose OCPs for longer duration of time puts the OCP-user at various future health risks which include: further metabolic derangements, hyper-coagulation and hyper-inflammation, cancer risk etc. Thus, women with PCOS need to be assessed carefully regarding the various complications associated with the syndrome which can otherwise get further worsened due to various risk factors involved with the use of OCPs mode of treatment. This review mainly deals with the use of OCPs in PCOS women as a treatment mode and will high light positive and negative influences of OCP use in these cases in light of various research articles that have been reported in these areas of study.

ABBREVIATIONS ACTH: Adrenocorticotropin Hormone; AES: Androgen Excess

Society; Cocs: Combined Oral Contraceptives; DHEA/DHEAS: Dehydroepiandro Sterone Sulphate; EE: Ethinyl Estradiol; FSH: Follicle Stimulating Hormone; IR: Insulin Resistance; LDL: Low Density Lipoproteins; LH: Luteinizing Hormone; MBS: Metabolic Syndrome; MNC: Mononuclear Cells; MI: Myocardial Infarction; NCAH: Non Classic Adrenal Hyperplasia; NF-КB: Necrosis Factor Kappa B; NHS: Nurses’ Health Study; NIH: National Institute Of Health; OA: Oligo Anovulation; PCOS: Polycystic Ovary Syndrome; Ocps: Oral Contraceptive Pills; VTE: Venous Thromboembolism; CVD: Cardiovascular Diseases; IGT: Impaired Glucose Tolerance; SHBG: Sex Hormonal Binding Globulin; T2DM: Type 2 Diabetes Mellitus; TG: Triglyceride; TNF-Α: Tissue Necrosis Factor Alpha; TSH: Thyroid Stimulating Hormone; WHO: World Health Organization

INTRODUCTIONPolycystic ovary syndrome is a most common endocrine

disorder in women of reproductive age. It is also called as Stein-Leventhal syndrome because they in 1935 first time presented a case study of seven women presented with amenorrhea, infertility and enlarged ovaries. Polson et al., later on in 1988, showed that the presence of polycystic ovaries is not an essential criteria for diagnosis of PCOS because several patients were clinically diagnosed to be PCOS but did not have cystic ovaries [1].

In clinical practice, PCOS women are typically characterised by menstrual irregularity, hirsutism, acne, alopecia, or infertility. Overall, PCOS has been considered to be the leading cause of anovulatory infertility [2].

Although,various diagnostic criteria are available to detect the presence of PCOS. But the Rotterdam criteria, is more inclusive than other two criteria, of NIH (National Institute of Health) and AES (Androgen Excess Society).

• Clinical manifestation of hyperandrogenism includes

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hirsutism, acne & alopecia. Biochemical hyperandrogenia includes increased levels of male–sex hormone testosterone, increased levels of luteinizing hormone (LH) relative to follicle stimulating hormone (FSH), i.e., the circulating LH to FSH ratio is elevated [3,4]. In summary, the characteristic endocrine picture of PCOS women of fertile age is that of increased LH [5,6] normal to low FSH [7], increased androgens [8] normal to low SHBG and normal to increased estradiol levels [1,8]. Ultrasonographic description for establishment of PCO must fulfill the criteria like presence of 12 or more of follicles measuring 2-9 mm and/or increased ovarian volume (>10 cm3) in at least one ovary. It is important to distinguish the clinical features of various other diseases similar to PCOS which includes :

• Cushing’s syndrome

• Non classic adrenal hyperplasia (NCAH)

• Androgen-secreting tumors

• Thyroid dysfunction and

• Hyperprolactinaemia.

Hormonal analysis which needs to be done to rule out the various diseases includes:

• 17-hydroxy progesterone (17-OHP) excludes NCAH

• Testosterone excludes androgen-secreting neoplasms

• Thyroid stimulating hormone (TSH) excludes thyroid dysfunction

• Prolactin excludes hyperprolactinaemia.

PREVALENCEThe estimated prevalence of PCOS was 8.7% according to NIH

criteria, 11.9% according to the Rotterdam criteria and 10.2% according to AE-PCOS criteria: with the inclusion of imputed data, the prevalence rate increased to 17.8% for Rotterdam and to 12.0% for the AE-PCOS criteria. A recent community-based study from Sri Lanka [9] reports 6.3% of women of childbearing age have PCOS, according to the 2003 Rotterdam Criteria

Diagnostic criteria

It is difficult to determine the exact prevalence of PCOS for a variety of reasons. One issue is that healthcare providers do not always use the same criteria to identify PCOS. There are

various criteria which are in use like National Institute of Health, Rotterdam, and Androgen Excess Society. A second problem associated with determining the prevalence of PCOS is that it remains a highly undiagnosed disease (Table 1). Although, various diagnostic criteria are available to detect the presence of PCOS. But the Rotterdam criteria, is more inclusive than other two criteria, of NIH (National Institute of Health) and AES (Androgen Excess Society).

VARIOUS PROPOSED THEORIES REGARDING PCOS PATHOGENESIS ARE AS FOLLOWSHypothalamus-pituitary-ovarian axis dysfunctions

Most of the women with PCOS have increased level of LH [5,6] and normal to low level of FSH [7] resulting in the increased LH/FSH ratio. Due to neuroendocrine disorders, there is an increased frequency of hypothalamic Gonadotropin releasing hormone(GnRH) [6] leading to increased pulsatile frequency of Luteinizing hormone (LH) which results in increased production of β subunit of LH over the β subunit of FSH [10]. With the increased production of LH, there occurs increased production of ovarian androgens by stimulated theca cells of the ovaries. Theca cells of the ovaries produces androstenedione from various steroid precursors, androstenedione diffuses from the basal cells of the ovaries to the granulosa cells where it gets aromatized to either estradiol or testosterone. Androstenedione gets further metabolized to estradiol by increasing the expression of various enzyme involved in the process by FSH [11]. Moreover, insulin increases the sensitivity of theca cells to LH and thus resulting in the increased androgen production [12,13]. Thus, the androgen excess in women with PCOS leads to the stimulation of pilosebaceous glands which increases sebum production resulting in terminal hair differentiation. Rarely, it leads to pilosebaceous unit atresia resulting in androgenic alopecia.

Adrenal androgen excess

Besides ovaries, adrenal cortex is the major site for the production of androgen hormones in female – dehydroepiandro sterone sulphate (DHEA/DHEAS), androstenedione and testosterone. Almost 97-99% of DHEAS is produced by adrenal gland exclusively and is considered as an androgen marker of adrenal gland function. While as androstenedione is produced in both adrenal gland and in ovaries as well. Almost 50% of testosterone is produced in peripheral organs like skin, liver and adipose tissues by conversion of androstenedione to testosterone. While as, 50% testosterone is produced by the adrenal glands and ovaries. It has been reported that 60-80%

Table 1: The various diagnostic criteria available regarding PCOS diagnosis are given in table.

Definition Diagnostic criteria

NIH1990

Requires the presence of1) Hyperandrogenism (HA)2) Chronic Anovulation

Rotterdam2003

Requires the presence of at least two of1) Hyperandrogenism2) Oligo- and/or anovulation (OA)3) PCO morphology (PCO)

AES 2006Requires the presence of1) Hyperandrogensim 2) Ovarian dysfunction (OA or PCO)

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of PCOS women have higher concentrations of testosterone [14]. Reports suggested 20-30% of adrenal hyperandrogenism in women with PCOS. It is proposed that adrenal excess may be resulting by the increased metabolism of cortisol which could lead to decreased negative feedback on ACTH secretion [15] but overall the adrenal androgen excess in PCOS is yet to be evaluated. Thus, the disturbed steroidogenesis is mostly found to be associated with PCOS women.

Liver dysfunctions

Sex hormonal binding globulin (SHBG) is produced in liver and is known to bind circulating free testosterones. Women with PCOS have multiple disturbances in insulin action and insulin is having inhibitory effect on SHBG production [16]. Hyperinsulinemia up regulates lipogenesis, free fatty acid production and also drives androgen production and thus reduces Sex Hormone-Binding Globulin (SHBG) [16] resulting in increased biologically active androgens [17].

Insulin dysfunctions

It is hypothesized that the majority of women with PCOS have a genetic predisposition exacerbated by adverse lifestyle and obesity, causing IR (insulin resistance). IR is a condition where inspite of having normal insulin concentrations in the body, it does not produce normal insulin response in various target tissues. IR results in the impaired stimulation of glycogen formation in the skeletal muscles, liver, kidney and adipose tissues and is further exacerbated by obesity [18]. As a result, IR causes compensatory hyperinsulinemia which further contributes to hyperandrogenism and gonadotropin aberrations. High insulin level causes LH stimulation of the theca cells of the ovaries and results in the increased production of androgens [12,13]. IR causes effect on adrenal glands as well to produce ACTH-mediated androgen production [19]. Circulating SHBG is reduced by high insulin levels which results in the increased free bioavailability of testosterone [16,20]. Hyperinsulinemia also affects granulosa cells in small follicles (follicular arrest at about 4mm in diameter). The follicular arrest may be caused by premature activation of LH-mediated terminal differentiation of granulosa cells [21]. It results in the induction of early response to LH on granulosa cells of small follicles. The premature activation of granulosa cells to LH induces terminal differentiation causing the arrest of follicular growth which eventually results in anovulation [22].

PCOS AND ASSOCIATED RISK FACTORSPCOS and T2DM risk

From last two decades, numerous studies have reported a link

between PCOS and T2DM, particularly in obese individuals .One of the studies shows prevalence of glucose intolerance in PCOS women was 31.1% as Impaired Glucose Tolerance (IGT) and 7.5% as Diabetes Mellitus where as in non-obese PCOS women, 10.3% IGT and 1.5% diabetes was found [23]. Overall, women with PCOS are known to have higher prevalence and greater degree of hyperinsulinemia and IR [18, 24-27] as compared to weight matched control subjects. Apart from the risk of familial history of T2DM, impaired insulin action is considered as the major risk for developing T2DM in women with PCOS. Moreover, women with PCOS are reported to have altered lipid profile and increased visceral obesity which is associated with the hyperandrogenism and hyperinsulinemia [28-31] and thus the risk of T2DM is further increased in such cases. There are evidences from epidemiologic data [32] that PCOS is associated with increased risk of impaired glucose tolerance (IGT) and T2DM [33,34]. By reducing hyperinsulinemia or IR, various symptoms associated with PCOS are found to be improved. The molecular mechanism that lie behind the development of T2DM in PCOS subjects is the presence of IR in the skeletal muscles. In case of normal healthy subjects, almost one-third of the ingested glucose is taken up by the liver and two-third of it is taken up the skeletal muscle cells. With the increase in the concentration of plasma glucose levels, increased secretion of insulin from the beta cells of the pancreas takes place which leads to suppression of lipolysis [35]. Glucose uptake by the skeletal cells require membrane transporters and there is a family of membrane transporters in humans called as GLUT. GLUT-4 belongs to GLUT family and is considered as the major membrane transporter in skeletal muscles which gets activated in response to insulin and exercise. Thus, GLUT-4 translocation takes place by insulin in skeletal muscle cells [36-38]. But, in case of PCOS subjects there is a defect in insulin activation and beta cells dysfunctions [39] which leads to impairment in the normal functioning of GLUT-4 translocation and therefore, IR results in T2DM in PCOS women [40].

PCOS and CVD risk

Both the hyperandrogenism and hyperinsulinemia are considered as the PCOS associated conditions and are known to have adverse impact on the lipid profile which further exaggerates the CVD risk in women with PCOS. Cardiovascular diseases include myocardial infarction (MI), angina, stroke and peripheral vascular disease. IR is known to suppress lipolysis which results in the mobilization of fat storage in the adipose tissues. Excessive fat storage in turn exacerbate IR [34]. Thus, a similar lipid pattern found in atherogenic and T2DM subjects indicates the link between IR and dyslipidemia [41]. Altered

Table 2: Summarize the actions of estrogen and progestin components of oral contraceptive pills (OCPs):

Action of estrogen component of OCPs Action of progestin component of OCPsHelps to increase hepatic production of SHBG which inturn reduces the availability of free androgen levels.

Suppression of LH which inturn reduces ovarian androgen production and thus acts as anti-androgenic in action.

Potentiates the action of progestin component of OCPs Act as an androgen blockadeSuppression of FSH by providing the negative feedback on anterior pituitary gland.

Prevents endometrial hyperplasia and thus helps to reduce the chances of endometrial carcinomas aswell.

Suppression of overall androgenlevels . Inhibition of LH surge which prevent anovulation.

Suppression of 5-α-reductase

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lipid profile in women with PCOS which is characterized by increased triglyceride and cholesterol levels predisposes them to the increased risk of developing early atherosclerosis [42-44]. Moreover, abnormalities in lipid profile has been reported to activate platelet adhesion, coagulation pathways and inhibit fibrinolysis, which may lead to development of CVD in PCOS women [45,46]. Thus, the various factors which leads to increased risk of CVD in PCOS women includes: obesity, T2DM, IR, dyslipidemia and clotting disorders.

Evidence-based guidelines for women provided by the American Heart Association (AHA) classify women for CVD risk as:

1) Optimal risk;

2) At risk; or

3) At high risk.

1. At risk—PCOS women with any following risk factors:

• Obesity (especially increased abdominal adiposity)

• Cigarette smoking

• Hypertension

• Dyslipidemia (increased LDL-C and/or non-HDL-C)

• Subclinical vascular disease

• Impaired Glucose Tolerance (IGT)

• Family history of premature CVD (55 yr of age in male relative, 65 yr of age in female relative)

2. At high risk—PCOS women with:

• Metabolic Syndrome (MBS)

• Type 2 Diabetes Mellitus (T2DM)

• Overt vascular or renal disease

Because adolescent PCOS women acquire IRas an antecedent to T2DM and CVD, lifetime CVD prevention strategies are of more greater value to younger than older women .Therefore, all women with PCOS should be assessed for CVD risks.

PCOS, obesity and inflammation

Obesity increases the risk of T2DM, IR, CVD and IGT in general population and the same are exacerbated in obese PCOS individuals. Thus, the obesity is known to increase the various PCOS linked complications like hyperandrogenism, infertility and the pregnancy complications [47]. Weight gain results in the elevation of both lipogenesis and adipogenesis inside the fatty depositions and the secretion of various proinflammatory cytokines and chemokines into the plasma. In response to such cytokine and chemokine stimuli, there occurs the recruitment of MNC from the peripheral blood circulation into fat tissue deposits which further results in the increased number of resident macrophages. Increased population of macrophages results in the increased inflammatory response by the production of different type of cytokines like TNF-α, interleukins, and NF-КB. Progressively, this cascade transcends to a chronic low-grade inflammation. And the whole inflammation scenario

affects the various peripheral tissues like liver, skeletal and endothelial tissues resulting in IR, hypertension, atherosclerosis and hypercoagulability. Thus, the inflammation is likely to be associated with other prominent aspects of PCOS including insulin resistance and cardiovascular disease (CVD) risk factors. Low grade chronic inflammation is considered to be at the basis of PCOS. It is yet to be cleared that chronic inflammation is cause of PCOS or it is secondary to obesity and insulin resistance, which are often associated with the syndrome.

PCOS and metabolic syndrome

Obesity and insulin resistance are associated with PCOS and the secretion of various adipokines are assumed to play a role in pathogenesis of PCOS .According to NCEP nearly 70% of PCOS women have abnormal serum lipid levels [48]. Abdominal obesity has been found to be associated with insulin resistance and T2DM, hypertension, dyslipidemia and CVD [49-52]. The link between central obesity and subsequent risk of CVD may be mediated through increased production of inflammatory markers in adipose tissue. Number of pro-inflammatory markers is known to have active participation in the development of insulin resistance and the increased risk of CVD associated with obesity. Insulin resistance, T2DM, hyperinsulinemia, dyslipidemia and, possibly CVD are considered as the metabolic abnormalities associated with PCOS women. Thus, PCOS is not considered just a gynecological or endocrine disorder but a sex linked manifestation of metabolic syndrome (Figure 1,2).

The various targets regarding the management of PCOS including menstrual dysfunctions, androgen excess, metabolic and infertility related issues are discussed as under:

Treatment of menstrual dysfunctions: Chronic anovulation leads to increased risk of endometrial hyperplasia and endometrial carcinomas [53]. OCPs are considered as the first line of treatment in women with PCOS after weight reduction and life style modifications. OCPs contains estrogen and progestin combination and helps to regularize the menstrual cyclicity. Thus, OCPs helps to reduce the risk of endometrial hyperplasia and carcinomas.

Treatment of androgen excess: The clinical symptoms of hyperandrogenism found in women with PCOS include hirsutism, acne and alopecia. Hyper androgenic symptoms can be reduced by administrating anti-androgens. Anti-androgens act by competitive inhibition of androgen-binding receptors or by decreasing androgen production [54]. Anti-androgens, such as cyproterone acetate, spironolactone or flutamide have been used in women with PCOS mainly for the treatment of hirsutism. Spironolactone, is an aldosterone antagonist and posses an anti-androgenic effects aswell. It has got demonstrable effects on hirsutism and is well tolerated but it can occasionally cause fatigue, dizziness and hypertension. When it is administered in high doses, it may causes menstrual irregularity and possesses the risk of feminizing the male fetus in pregnant PCOS women .So as to minimize the various risks associated with the use of spirnolactone, it is usually administered in combination with OC. The combination therapy is very effective in treatment of hirsutism and acne [55].

Finasteride is a type 2 (5-α-reductase) activity inhibitor that

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Figure 1 PCOS is a multi-factorial disorder and there is not any single specific mechanism suggested regarding its pathogenesis. It is a vicious cycle which can be initiated at any specific point.

Figure 1 PCOS is a multi-factorial disorder and there is not any single specific mechanism suggested regarding its pathogenesis. It is a vicious cycle which can be initiated at any specific point.

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inhibits the conversion of testosterone to dihydrotestosterone by reducing 5-α-reductaseproduction [56]. Finasteride has got a low side effect profile comparatively [57]. In PCOS, the observed beneficial effects on some of metabolic aberra tions with antiandrogen treatment may be attrib uted to the blockade of androgen receptor and reduction of androgen excess.

Metabolic dysfunctions: There is a strong pathophysiological connection of insulin resistance with PCOS which might increases the risk of CVD and T2DM in such cases. The therapeutic use of insulin sensitizers helps to reduce aberrations in PCOS cases. The extensive literature has shown that reduction in insulin levels pharmacologically ameliorates the sequel of hyperinsulinemia and hyperandrogenemia. Commonly used insulin sensitizers are metformin and thiazolinediones, which can effectively manage the established metabolic derangements in PCOS.

Treatment of infertility: Clomiphene citrate is a drug of choice for the women who have got fertility issues. It is an estrogen antagonist which helps to restore the ovulation in PCOS women. The molecular mechanism behind this drug is folliculogenesis and prevention of anovulation which increases the chances of pregnancy in women with PCOS.

Other drugs of choice for inducing fertility are aromatase inhibitor which inhibit estrogen production and stimulate FSH production [58] such as Letrozole and thus induce ovulation and increases the chances of pregnancy.

SAFETY OF USE OF OCP’S AS THE DRUG OF CHOICE FOR TREATMENT IN PCOS WOMEN

OCPs are considered as the first line of treatment for PCOS.OCP’s are the combination of estrogen and progestin component. OCP’s play a great role in the reduction of LH levels without surges. Estrogen part helps to stimulate the hepatic production of SHBG [59]. Thus, estrogen part helps to reduce bioavailability of free androgen. So, the various symptoms associated with androgen excess like hirsutism, acne and alopecia are reduced. While as, the progestin component acts as an antagonistic to androgen at its receptors. Thus, reducing the action of male steroid hormone namely testosterone at the target organ. The progestin component protects endometrium from hyperplasia and can reduce the risk of endometrial cancer [53]. Effective treatment for about 3- 6 months results in decreased production of free androgens. Thus, the growth of new hair and growth of terminal hair is reduced. OCP’s are also beneficial in the reduction of ovarian volume and ovarian cysts. Higher estrogen doses are required in the preparation of OCP’s so as to attain significant protection against ovarian cysts [60]. Overall clinical benefits of OCP treatment are as under.

OCP’S AND VARIOUS RISK FACTORS ASSOCIATED WITH ITS USE

Besides, all the beneficial effects of OCP treatment, there are various adverse effects of OCP treatment on metabolic, cardio vascular, BMI and HOMA IR [61-63]. COC (Combined Oral Contraceptive) treatment of PCOS also has been shown to cause an increase in total cholesterol, triglycerides, HDL and LDL cholesterol [64,65,28]. Some studies indicate increased risk for T2DM in OCP treated PCOS women [29] (Table 2).

ORAL CONTRACEPTIVES AND CARBOHYDRATE METABOLISM

The first ever study which was conducted regarding the impact of OCPs on the glucose tolerance dates back to 1960s and was reported to have deleterious effect on glucose metabolism with the use of high dose COCs [30,31]. While as the other study carried by Gaspard et al., did not report any harmful effect of using low dose COCs when were administered for a period of 13 months to almost 27 OCP users. Moreover, two cohort studies of NHS (Nurses Health study) in population of healthy women were carried out in order to evaluate the risk regarding T2DM with the use of COC. In one of the two studies, total number of 2276 healthy subjects were followed for 12 years and the 10% risk of T2DM was found to be associated with COC users as compared to non-users [66]. In the second cohort study, cases were followed up for about 4 years so as to assess the risk of developing T2DM with the use of low dose COCs. And it was found there is relatively high risk in OCP users as compared to non-users [67]. Thus, it became evident from the reports obtained from numerous studies that low dose EE containing OCPs (<50µg) have advantage as compared to high dose OCPs with regard to carbohydrate metabolism and the risk to develop T2DM. According to the recommendations in the eligibility criteria of the World Health Organization (WHO), COCs can be used by PCOS and diabetes subjects but progesterone only contraceptives are to be recommended to be used in the presence of associated vasculopathy.

OCPS AND DYSLIPIDEMIA Dyslipidemia is one of the most common derangement

seen in women with PCOS [65]. It is characterized by increased TG, increased LDL-cholesterol, increased total cholesterol and decreased HDL-cholesterol levels .Estrogen component of OCPs are known to have interference with the lipid metabolism causing increased levels of TG and HDL-cholesterol. While as progesterone component is known to have least interference in the lipid metabolism but when it is used in combination with estrogen, it results in the potentiation of estrogen action on lipid profile [68,69]. Thus, COCs should be avoided in subjects with the history of hyperglyceridemia.

EFFECT OF OCPS ON INFLAMMATORY AND COAGULATORYSTATUS OF PCOS WOMEN

OCPs are considered as the first line of treatment for PCOS women as it inhibit free androgen levels in such cases. The main goal of OCP treatment is overall decrease in gonadotrophin activity, by decreased production of both 5-α reductase and dihydrotestosterone [70-72].

However as has been reported oral contraceptives put even young PCOS women, (18-24 years of age) at risk for VTE (venous thromoembolism) and this is further amplified by obesity [73,74]. Also, estrogen component of OCPs brings number of prothrombotic alterations in proteins involved in coagulation [75]. Although estrogen was initially thought to be only contributor to COC induced thrombosis but it has now been found that certain progestins also have their influence on thrombosis [75].

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Available data suggested that the risk of myocardial infarction being the higher with the use of second generation oral contraceptives while as the risk of venous thromboembolism being higher with the use of third generation oral contraceptives [76]. A study by Steven Bird reported 2-fold increase of VTE among women with PCOS compared with matched controls. Increased risk of both arterial and venous thrombosis associated with the use of hormonal contraception is clearly evident from the large population-based studies [76-79]. Hypercoagulability state in OCP users have been reported in epidemiological studies and is evident by the elevated coagulation proteins [80]. Coagulation proteins are sensitive to estrogen component of OCPs and get modulated by it [81]. Estrogen leads to increased production of pro-coagulant factors like VII, X and XIII in the liver and decreased production of anti-coagulant factors [82-85]. Thus OCP are also known to increase the risk of CVD by altering the thrombotic mechanism .But, there is not any specific mechanism involved in the development of prothrombotic and pro-inflammatory status seen in OCPs user PCOS women. The possible mechanism which could explain the impact of OCPs on inflammatory status and thrombosis is linked to the alteration in lipid profile of OCP users. Estrogen component of OCPs causes dyslipidemia by increasing levels of total cholesterol, LDL–cholesterol, triglycerides and causes increased secretion of apolipoproteins, all these factors contributes to the stimulation of inflammatory status .Inflammation is known to play a key role in the pathogenesis of CVD and the elevated levels of various inflammatory markers could serve as the strongest predictor of the disease process. Moreover, there are various reports regarding the elevated levels of inflammatory markers in general population and in OCP user PCOS women [86,87]. Thus, the various metabolic risk factors like obesity, deranged state of proinflammatory and procoagulant factors seen to be associated with PCOS individuals need to be taken into consideration while prescribing OCP’ s as mode of treatment.

CONCLUSIONPCOS is not just a gynecological or dermatological disorder

but a sex limited manifestation of metabolic syndrome that involves multiple body systems.

Although, treatment with OCP’s helps to regularize the menstrual cyclicity, also helps to improve hyperandrogenism reduces various clinical symptoms like hirsutism and acne, but at the same time, use of OCP’s does contribute to the worsening of disease process. Obesity, increased lipid profile, insulin resistance, increased pro inflammatory and pro-coagulatoy markers were reported in various studies regarding OCPs mode of treatment. Increased insulin levels confer an increased risk for glucose intolerance that may enhance the risk for type 2 Diabetes. Increased lipid profile can increase the risk of various metabolic and cardiovascular diseases. Dyslipidemia may results in the activation of inflammatory signaling pathway and thus may results in the progression of various diseases associated with metabolic syndrome like atherosclerosis, heart failure and type 2 Diabetes Mellitus. Thus OCP treatment increases the risk of CVD (cardiovascular disease) and type 2 Diabetes Mellitus and the deranged metabolic parameters gives a clear indication of various risks associated with the use of OCP treatment in PCOS

women.

ACKNOWLEDGEMENTSAuthors acknowledge the financial assistance provided by

the J&K, DST.

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Manzoor S, Gania AM, Yusuf SD, Amin S, Habib R, et al. (2017) Metabolic Derangements and Possible CVD Risk in PCOS Women Owing to Use of OCP’s as a Treatment Mode – Pros and Cons. J Endocrinol Diabetes Obes 5(3): 1109.

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