Biomedical Review-Journal of Basic and Applied Medical Science

The most common classification system was used, which is in line with biological properties per group and is reflected in their effects on levels of sex hormone binding globulin.

Classification of hormonal contraceptive

Usually, COC classification includes estrogen dose or molecule, type of progestin and route of administration. While the first pills contained high doses of synthetic estrogen (150 mg of ethinylestradiol or mestranol), current COCs now deliver 50 to 15 mg per day of ethinylestradiol. New formulations delivering natural estradiol (E2) have recently been marketed. A quadriphasic COC combining E2 valerate and dienogest has recently been approved in Europe and the USA, and a second monophasic COC that combines E2 with nomegestrol acetate, a progesterone-derived progestin, is now available in several European countries. COCs can also be classified into generations (first, second, third and other) depending upon the type of progestin and their introduction into market. The so-called first generation pills that contained either norethisterone acetate, lynestrenol, ethnodiol acetate or norethynodrel are currently no longer used [5]. COCs also include non orally administered drugs, such as the combined ethinyl-estradiol/norelgestromin transdermal patch and ethinylestradiol/etonogestrel vaginal ring. These two new methods provide continuous hormone dosing and simplify obedient.

The presently available oral contraceptives are both second and third generation pills; second generation pills containing norgestrel or levonorgestrel, and third generation containing desogestrel, norgestimate or gestodene. Pills with other type of progestins are classified as other generation pills and contain either progesterone or testosterone-derived progestins including cyproterone acetate, drospirenone, dienogest, chlormadinone acetate or nomegestrol acetate. Drospirenone, an aldosterone antagonist, and cyproterone acetate are molecules introducing high anti androgenic effects. Using progestin only products as a contraceptive method may be an attractive option for women with contraindications for the consumption of COCs. Four types of progestin only contraceptives are currently available in Europe and in the United States:

 -Progestin only pill that deliver low daily doses of progestin (norethindrone, levonorgestrel or desogestrel)

In other category, combined oral contraceptives have only one strogen, ethinyl estradiol (EE), in various doses formulated with a progestin. Progestins can be grouped chronologically. First generation progestins, commonly referred to as estranges include norethindrone acetate and ethynodiol diacetate. Second generation progestins, called gonanes, are more potent and norgentral and levonorgestrel (LNG). Third generation progestins also called gonanes have reduced androgenic and metabolic effects and include novestimate desogestrel and gestodene (not available in the united state). Finally a newer miscellaneous category in the form of: drospirenone an antimineralocorticoide with progestogen and antiandrogenic activity was introduced [8]. In other formulation oral contraceptive pills come in two types of formulations. In monophasic oral contraception, all the “active”

pills contain the same amount of ethinyl estradiol and progestin (traditional pack: 21 days active/7 days

placebo). The ‘active’ pills in triphasic formulations vary in the amount of ethinyl estradiol and/or the

progestin (traditional pack: 21 days active/7 days placebo). Some newer formulations of extended

monophasic forumulations include cycles of 84 active pills/7 days placebo or 24 active pills/4 days placebo.

Use of Oral Contraceptives in Women with Migraine

Susan Hutchinson, MD

Family Medicine, Women’s Medical Group of Irvine, Irvine, CA

American Headache Society • 19 Mantua Road, Mt. Royal, NJ, 08061 • 856.423.0043 • www.AmericanHeadacheSociety.org

COCs and Antioxidants alterations:

Antioxidant Enzymes

The pool data of the study about the effect of low dose contraceptive pills (LD) OCPs on the activities of the erythrocyte antioxidant enzymes glutathione peroxidase (GPX) and superoxide dismutase (SOD) of OCP consumers in our previous study [9] identified that erythrocyte GPX activity in OCP was significantly higher than controls but the same comparison for SOD activity between control group

48 years from the ELAN study in the province of Liege, Belgium was investigated. It was concluded that intake of OC significantly increases the lipid peroxidation in women aged 40-48 years. This may represent the OC as a potential cardiovascular risk factor for these women [14]. In a prospective case-control study the serum zinc status of rural women taking combined OC are examined. Their mean serum zinc of women taking OC was reduced significantly in comparison with controls (p<0.001) [15-16]. Antioxidants, in particular carotenoids, may influence the risk for cardiovascular disease. In a study by Berg G. et al. [17] the influence of oral contraceptives (OC) on the serum concentration of beta-carotene, which may in turn affect the risk of cardiovascular diseases due to its antioxidative impact was investigated. A negative association was found between OC taking and serum beta-carotene concentration via bi- and multivariable analyses, after adjustment for age, smoking, alcohol consumption, dietary intake of beta-carotene, use of vitamin supplements, body mass index, pregnancies, and total triglyceride and cholesterol levels. A strong interaction was observed between OC use and age on beta-carotene concentration. While no relationship was seen between OC taking and serum beta-carotene in the youngest age-group (18-24 years), there was a modest but significant negative association between OC use and beta-carotene levels among 25-34 years old women. It was identified that OC consumption was associated with a strong decrease in beta-carotene levels among 35-44 years old women. The interaction between OC use and age could partly be explained by age dependent OC taking with higher estrogen content [16]. Changes in metabolic processes and trace element profiles are governed by genetic disposition as well as environmental factors. Alterations in lifestyle, dietary habits environmental factors, and active ingredients of hormonal agents have been known to affect status of micronutrients in humans. Some of these micronutrients eg. manganese, vitamin B12 and magnesium are co-factors and co-enzymes which are involved in important metabolic pathways. Changes in the tissue level or bioavailability of these elements could play a significant role in health risk and the pathogenesis of some disorders such as cardiovascular complications; the aging process and certain cancers have been associated with the contraceptives use. Some of these trace elements for example, selenium and manganese are potent

that such Cu increase could be implicated in oxidative pathophysiological processes in the body. Further research on safety of COCs use, including oxidative-stress-related effects, was warranted.

High serum copper concentration in women using oral contraceptives is well known. In a bi- and multivariable linear regression models with log-transformed it was shown that oral contraceptives consumption was positively associated with copper levels. The amount of copper was introduced as dependent variable whereas the oral contraceptive preparations and potential confounding variables were introduced as independent variables. It was shown that copper levels in women using oral contraceptives varied more strongly by different progestin compounds than by estrogen contents. Although increased serum copper concentration was found in users of all types of oral contraceptives, but this increase was more impressive among women taking oral contraceptives with antiandrogen effective progestins like antiandrogens or third generation oral contraceptives containing desogestrel. The highest increase of serum copper was seen in women using oral contraceptives containing antiandrogen progestins (55%; 95% CI: 37-76%), followed by desogestrel (46%; 95% CI: 36-56%), norethisteron/lynestrenol (42%; 95% CI: 29-57%), and levonorgestrel (34%; 95% CI: 24-45%) [19]. In prior study the serum copper and zinc levels of combined estrogen-progestogen contraceptives users and users of injectable progestogen were investigated. Consumption of combined estrogen-progestogen contraceptives resulted in a significant decline in serum zinc levels within 3 days and an increase in serum copper levels within 10 days. It was observed that amplitude and occurrence time of zinc levels decrease and copper levels increase were not changed by chemical composition, dosage, administration route and duration of use beyond 3 month in combined estrogen-progestogen contraceptives users. A significant decline was found in zinc levels within 24 hours after injection of progestogen (norethindrone enanthate, 20 mg/month) while serum copper concentration was not changed. In case of injectable progestogen the type of drug, dosage and duration of taking beyond 1si month had no effect on the magnitude of the decrease in serum zinc levels [20].

A study designed by Prema et al to investigate the association of the long-term

levels of sex hormones and their declining activity with increasing age. So, for example in elder men, the relatively lower Cu levels could be related to the testosterone level decline with age. The relationship between Zn and Se levels did also has no alteration tendency in Contraception user. It was found that hormonal contraception did not influence concentrations of Se and Zn in the blood. It has been thought that the decrease in serum zinc could be reflected in a reduction of tissue zinc status due to changes in zinc absorption, excretion or tissue turnover. If these changes occur, the dietary zinc requirement would be greater in women using OCP. Circulating zinc level may be reduced while some tissue level may be increased. Also, the release of zinc from tissues may be depressed in OCP user, OCP therapy may alter the postabsorptive utilizationof zinc [23]. These findings may be important because selenium is currently believed to offer protective benefits against carcinogenesis. Previous investigation showed that progestational agents alone have no effect on serum copper, whereas estrogen alone has a considerable effect on elevating copper and copper binding proteins levels. Apparently increase in copper levels was proportional to the administrated estrogen dose [24]. It has been demonstrated that plasma iron and TIBC increased during contraceptive therapy. However this elevation of iron and TIBC levels did not prevent of the hemoglobin decrease after phlebotomy and no reticulocyte alteration was also observed. These finding may be able to interpret in part the observation that oral COC users who develop iron deficiency anemia show a minor reduction in iron levels. It was concluded that progestogens therapy failed to affects the transferrin levels and substances such as medroxyprogestrone, which are not metabolized to estrogen was observed to be ineffective in changing the transferrin levels. It was suggested that there may be separate mechanisms affecting iron levels and iron binding capacities. Most of the changes observed on iron and TIBC have been attributed to hormone effects on transferring increase. According to these considerations, it was suggested that contraceptive pill may be a protective device for women and may have a beneficial effect in conserving in iron stores. In this connection, mechanisms that were proposed include reduction of menstrual loss, which associated with the pill taking and the possible alteration in TIBC percent saturation may affect increasing iron absorption [25].

results suggested a slightly increased risk of death among women having an MI associated with exposure to second generation OC, but the absolute risk is very low. Pooled OR of MI among first generation consumers and second generation users were not significantly different (p ¼0.09); Pooled OR of MI among first generation users and third generation users were significantly different (p <0.01); Pooled OR of MI among second generation users and third generation users were not significantly different (p ¼0.23). Recent data shows that use of these pills could be associated with an increased risk of myocardial infarction, especially in women with cardiovascular risk factor such as smoking or hypertension .The studies performed on women receiving HRT indicate that adverse cardiovascular effects may depend on the type, dosage, form and route of administration of hormones [39].

A Population-based cohort study with linkage of 4 national registries between 1995 and 2009 setting 1 626 158 women participants from 15 to 49 years of age showed that of Oral hormonal contraceptives containing ethinyl estradiol were associated with increased risk myocardial infarction (p<0.00i) [40]. Based on the method of administration, many data are available regarding the risk of cardiovascular disease. The relative risk of MI [2.08 (95% CI: 0.67–6.48)] among women who used vaginal ring and no transdermal patch user experienced MI was reported. It is noteworthy to bold that for some specific contraceptives, the number of women who suffering from MI was too small to provide reliable estimates [41]. The MI risk among users of transdermal contraceptive systems and the same component norgestimate containing oral contraceptives was compared by another small study and no difference in MI risk (RR: 1.2; 95% CI:0.3–4.7) among women who used vaginal ring and no transdermal patch user experienced MI was showed. Overall, the relative risk of MI was not significantly elevated for any of the progestin only contraceptives [41].

The cardiovascular safety of oral contraceptives (OCs) containing less than 50 mcg of estrogen and second or third generation progestins was reviewed in a research literature and suggests that these formulations are safer than earlier OCs. Although some recent studies detected an increased risk of venous thromboembolism of 1.5-2.0 in users of OCs containing desogestrel or gestodene

hepatic CRP and homocysteine synthesis. Previous studies have shown that OCPs may directly modulate hepatic synthesis of several factors at the transcriptional level and may also have various immune modulatory effects, therefore predispose to thromboembolic events by stimulating inflammatory mechanism. CRP and homocysteine levels seem to be sensitive to hormonal changes in oral contraceptive users. It was suggested that even a small amount of steroid compounds in OCP could be converted to peroxide and is sufficient to induce synthesis a new molecules of homocysteine and CRP. It has been suggested that decreased bioavailability of nitric oxide (NO may result in abnormal reactions between the vessel wall and platelets and is thus involved in the initiation and progression of atherosclerosis. NO leads to vasodilatation and inhibits platelet aggregation and migration. Reduced bioavailability of NO has been implicated to be involved in the initiation and progression of atherosclerosis. There is evidence for endothelial dysfunction and specific defects in NO mediated vasodilatation in patients with hypertension, smokers, and individuals with elevated concentration of HCY. Several studies have defined that female sex steroids may affect NO and HCY [42-43]. The results of the studies by Ridker et al. [44] conducted on healthy postmenopausal women indicate that cardiovascular risk is increased more than twice in women with moderately increased HCY concentration ,irrespective of the conventional risk factors. HCY level is higher in post-menopausal women in comparison with those in the premenopausal period. This might be due to the effect of OCP on decreasing the availability of group B vitamins for HCY metabolic pathways. HCY metabolic pathways strongly depend on folate, VB12 and B6 vitamins and deficiency of one or more of these vitamins has been implicated as the most common cause of moderately elevated HCY levels among adults. The results of the reports on the effects of OCPs on HCY levels are not consistent. For example, in a study, Merki-Feld et al. [45] showed that long- term (3cycles) treatment with two OCPs of EE/LKG (30 μg ethyinylestrsdiol/150 μg levonorgestrel) and EE/GSD (30 μgethynylestradiol/75μggestodene) increased HCY levels. But, Hanna et al. [46] reported that consumption of the three forms of HRT in three groups of women in the early postmenopausal stage with normal initial concentration of HCY, had no influence on the

adverse conditions in young women. In another study we [49] indicated that LD COC uptake results in a significant decrease in serum adiponectin concentration, nosignificant increase in leptin levels and a more atherogenic lipid profiles by significantly increasing LDL and no significantly decreasing HDL concentrations. These findings suggested that COC may reduce or stimulate the adiponectin and leptin concentrations, respectively. This might be due to an effect of these pills on adipocyte maturation via inhibition or stimulation of the synthesis of new adiponectin and leptin molecules or may be are result of the increased frequency of a particular allele of the adiponectin and leptin. It was suggested that these alterations in adiponectin and leptin concentrations and lipid profiles may be related to their probable effects in response to various pathological and physiological properties of COC or its metabolites. It has been suggested that probably free radicals produced during metabolism of COCs change the amounts of adipokines, leptin and atherogenic lipids. The effects of lipid metabolism on 98 women who received 2 different types of progestin-only pills, desogestrel 75 mcg/d vs LNG 30 mcg/d were evaluated. There were minimal changes in the lipid profile except for decreasing trends in levels of HDL, its subfractions, and apolipoprotein-I and -II. No differences were observed between the 2 formulations, including LDL and apolipoprotein-B, despite the higher progestin dose found in desogestrel. Third-generation progestins with “lesser androgenicity” may allow more expression” of the effects of estrogen on lipids. A prospective study of 66 women over 9 months comparing either desogestrel (50/100/150 mcg) and EE (35/30/30 mcg) with LNG (50/100/ 150 mcg) and EE (30/40/30 mcg) showed that the desogestrel formulation increased HDL, whereas LNG decreased HDL. Another study compared monophasic desogestrel/EE with triphasic LNG/EE in 37 healthy young women. While both preparations led to an increase in total cholesterol, the desogestrel formulation led to a reduction in the LDL. A 1995 study of DRSP compared with LNG for 6 months showed that HDL increased in the DRSP group (P<.05) but triglyceride levels showed a greater increase in the DRSP group (P<.05). It was suggested that use of OCs in the absence of risk factors dose not promote coronary heart disease (CAD), and OCs should not be withheld from dislipidemic women [50].

venous thromboembolism for use of third-generation OCs is approximately equal to that previously reported for second generation products. Generally, evidence has shown that the risk of venous thromboembolism and the impact on hemostatic parameters are reduced with decreasing estrogen dose. In addition, there is no evidence of a clinically significant effect of the OC progestogen doses on hemostatic parameters. The results of a meta-analysis of eight observational studies [57], did not show an association between progestin-only contraception consumption and an increase risk of venous thromboembolism when compared with nonusers of hormonal contraception. On contrast, four additional epidemiologic studies have revealed a two-fold increased risk of non-fatal venous thromboembolism for OCs containing desogestrel or gestodene compared to levonorgestrel; the excess risk is about 15 per 100,000 events per year. It is noteworthy that association of thromboembolism risk in third-generation OCs users should be took a biologic explanation. It was believed that until there is a biologic interpretation of the greater thromboembolism risk in the third-generation OCs users, this association should not be considered as causal and no change in OC advising practices is warranted for either current or new acceptors. However, smokers over 35 years of age should not use any combination OCs [58]. A systematic review of studies published between January 1995 and April 2010 aimed at determining the effect of combined hormonal contraceptives (CHCs), administered orally, transdermally or vaginally, on the risk of venous thromboembolism (VTE). It was suggested the safest CHCs in terms of VTE are those containing levonorgestrel or norgestimate. The risk of VTE, which associated with desogestrel, drospirenone or cyproterone acetate-containing CHCs is greater than those associated with CHCs containing levonorgestrel regardless of how to get. An increased risk of VTE was found for CHCs with gestodene in comparison with CHCs with levonorgestrel. They showed no differences in VTE risk between oral and transdermal CHCs containing norgestimate or norelgestromin, respectively [59]. Two recent studies, a cohort study from Denmark, and a case-control study from the Netherlands, have reported increased risks of venous thromboembolism (VTE) among users of oral contraceptives (OCs) containing desogestrel, gestodene, drospirenone and cyproterone, relative to levonorgestrel consumption. The evidences

disease related to oral contraceptive use in young women. However, smokers more than 35 years of age should use a nonestrogen contraceptive [61]. Combined hormonal contraceptives, menopause hormone treatment and surgery/cast in orthopedic patients are important risk factors for venous thromboembolism (VTE) in women. Women with a positive family history and combined hormonal contraceptive or menopause hormone treatment had an OR of 15.3 (95% CI 6.1-38) and 5.9 (95% CI 3.3-11) respectively compared to women without hormones or family history [62]. Bhargava et al. [63] showed that Oral contraceptive causing renal artery thrombosis. They identified that the of renal artery thrombosis leading to acute renal infarction associated with oral contraceptive use. They showed that after stopping the oral contraceptive consumption in a young female with a haematuria and elevated serum creatine, fever, leucocytosis, elevated lactate dehydrogenase and acute left lower quadrant pain followed by nausea, the fever and leucocytosis was stopped in following 3 days. Extensive thrombophilic work-up was negative and no recurrence of thrombosis was found during a 6-month follow-up period [63]. In systematic review and meta-analysis was adjusted with Peragallo Urrutia R et al., to estimate the risk of venous thromboembolism, stroke, or myocardial infarction (MI) associated with the use of oral contraceptive pills (OCPs) and to describe how these risks vary by dose or formulation, showed that current use of combined OCPs is associated with increased odds of venous thromboembolism and ischemic stroke but not hemorrhagic stroke or MI [64]. In a study by Josse AR et al [65], the effect of Hormonal Contraceptives on emerging cardiometabolic and other disease risk factors was investigated and this result was achieved that HC use was associated with different concentrations of plasma proteins along various disease-related pathways, and these differences were present across different ethnicities. Aside from the known effect of HC on traditional biomarkers of cardiometabolic risk, HC use also affects numerous proteins that may be biomarkers of dysregulation in inflammation, coagulation and blood pressure. In order to compare the effect of combined oral contraceptive (COC) and combined vaginal contraceptive (CVC) methods on the inflammation and procoagulation,. female participants were recruited in 3 groups: control participants, COC users, and CVC users. Different blood biomarkers were measured. The users

of PGE2, as an immune activator is influenced with hormones. For example, a study conducted on dysmenorrheal adolescents who were treated with the oral contraceptive Lyndiol2.5mg (R) for one cycle, the levels of PGF2a, PGE2, PGI2 metabolites, TXA2, 6- Keto- -PGF1a and TXB2 were tested before, during and after treatment. All PG levels during the treatment cycle (TC) and post treatment cycle (PoTC) were found significantly lower, compared to those of the pretreatment cycle (PrTC). The results of a study by Sato et al [69] investigating the effect of progesterone and17-estradiolon the PGE2 production of the rabbit uterine cervical fibroblasts showed that the progesterone and 17-estradiol prevent the initiation of labor through inhibiting PGE2 production after the suppression of COX-2 production during pregnancy. In our previous study [70], we showed a significant increase in PGE2,LDL-C, cholesterol concentrations, systolic and diastolic blood pressure.

The univariante and multivariate analysis of achieved data showed that COC taking and age together affect the blood pressure significantly. It is noteworthy the results indicated that effect of OCP taking is more remarkable than age. It was suggested that the increase of Prostaglandin E2 and atherogenic lipid levels may be related to their probable effects in response to various pathological and physiological properties of COCs. According to this fact that PGE2 is a principle mediator in inflammation pathway, it was hypothesized that the COCs and their metabolites probably could result in many inflammatory pathological statues. We also showed that these alterations were also accompanied by the finding of a strong and statistically significant elevation of serum LDL-C and cholesterol concentrations and a considerable decrease (no significant) in HDL-C levels of women treated with LD COCs. It was proposed that COC consumption probably leads to an alteration in serum hormonal balance, which might cause a disturbance in lipid metabolism and their profiles. In a study, Barreiros et. al [71] showed that after 1 year of continuous contraceptive consumption, there was a significant increase in triglyceride, total cholesterol (TC), and HDL-C levels. It has been found that the contraceptive induced dyslipidemia has a pro-atherogenic nature, whereas the TC/ HDL-C ratio was unchanged. It was suggested that oral contraceptives with estrogen

COC could be converted to peroxide and is sufficient to induce synthesis of new molecules of lipids and PGE2. The role of PGE2 and its receptors on development of cardiovascular and inflammatory diseases were also demonstrated [72-73]

Glintborg D et al. [74] designed the study where ninety patients with PCOS were randomized to 12-month treatment with metformin (M) (2 g/day), M + OCP (150 mg desogestrel + 30 microgram ethinylestradiol) or OCP. Adiponectin, IL-6, MCP-1 and clinical evaluations were performed before and after the intervention period in the 65 study completers. Their results show that Adiponectin, IL-6, and monocyte chemo attractant protein (MCP-1) levels were unchanged during the three types of medical intervention. They concluded that Long-term treatment with M alone or in combination with OCP was associated with improved body composition compared to OCP, whereas inflammatory markers were unchanged. OCP was not associated with increased inflammatory markers despite a small but significant weight gain [74]. The influence of OC on the production of thermoregulatory cytokines, i.e. interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), soluble glycoprotein 130 (s-gp130) and leptin, and that OC-induced changes in oral temperature (T(oral)) are associated with changes in plasma concentrations of these cytokines was investigated by Salkeld BD et al [75]. They showed that (a) leptin implication in basal thermoregulation; (b) progestins have a significant influence on circulating IL-6 concentrations, and (c) plasma CRP concentrations depend upon combined influences of progestins and bioavailable IL-6.

COCs and Systemic High Blood Pressure

Hormonal contraceptives use in Women with hypertension might increases the cardiovascular events risk. Several studies have been shown an increased prevalence of acute myocardial infarction (AMI) and stroke among hypertensive women who use combined oral contraceptives (COCs) when compared with normotensive and hypertensive nonusers. According to the US Medical. Eligibility Criteria for Contraceptive Use (US MEC), women with adequately controlled hypertension or moderately elevated blood pressure (140–159/90–99 mmHg) generally should not use combined hormonal contraceptives (CHCs) (US MEC 3). Women with severely elevated blood

taking OC for more than 8 years showed higher age-adjusted blood pressure levels than women using OC for shorter periods. Patients using OC had poor blood pressure control (p for trend = 0.046) and a higher proportion of them presented moderate-severe hypertension. These results were independent of antihypertensive drug use. In a logistic regression model, they found that current OC use was independently and significantly (P=0.000) associated with prevalence of uncontrolled hypertension. It was concluded that hypertensive women using OC present a significant increase in both DBP and SBD and poor blood pressure control, independent of age, weight and antihypertensive drug treatment. Consistently, we also showed [49, 70] that OCP taking for at least 3 month cause a significant increase in both DBP and SBD as comparison controls (P=0.000). In a prospective study [78], the association of oral contraceptive consumption before pregnancy and the risk of gestational hypertension and preeclampsia was investigated .It was identified that recent use of oral contraceptives was associated with a reduced risk for developing gestational hypertension. In contrast, there was a suggestion that recent use of OCP was associated with an increased risk of developing preeclampsia, but only among women who had used these agents for ≥ 8 years. The effect of COCs containing estradiol (E2) on the 24-h ambulatory BP and heart rate (HR) in 18 normotensive and normal-weight women with mean age 32.50±7.49 years and body mass index 22.87±4.08 every 30 min with an ambulatory BP device in 18 normotensive healthy non-smoking women prior to (Days 3-6 of menstrual cycle) and after 6 months of use (Days 20-24 of cycle 6) of a COC containing either a quadriphasic combination of E2 valerate plus dienogest (n=11) or a monophasic association of micronized E2 plus nomegestrol acetate (n=7). was investigated by Grandi et al. The achived data suggestd that estradiol-based COCs has a neutral effect on independent risk factors for cardiovascular diseases such as BP or HR [79].

COCs and Cancer: Data based on the impact of COC tanking on cancer is contradictory. Quote from Mr. DAN HELLBERG and ULF STENDAHL in their review article the consequences of OC use in cervical neoplasia have still not been established.a slight but apparent increased risk with long-, but not short-term use of OCs has been found in most,

An observational study, showed an increased breast cancer risk in users of estrogens combined with either medroxy progesterone acetate (MPA), norethisterone, or norgestrel. It is unclear and questionable to what extent these results might be extrapolated to other HRT regimens, that differ in their doses, compositions and administration routes, and that were not assessed in the WHI trial and the MWS [83].

The results of a study conducted by Faber [84] showed that use of combined oral contraceptives only and the mixed use of combined and progestin-only pills decreased the risk of ovarian cancer, while no association was found with exclusive use of progestin-only pills. They showed that no major differences in risk were found for users of combined oral contraceptives with high- and low-potency estrogen and progestin. There was no effect of cumulative progestin intake, but decreased risk of ovarian cancer with increasing cumulative intake of estrogen (OR = 0.82; 95 % CI 0.67-0.99, per 100 mg estrogen) and increasing duration of oral contraceptive use (OR = 0.95; 95 % CI 0.92-0.98, per year of use) were found. No effect of cumulative estrogen intake was found. I a study by Park et al. [85] the outcomes of second round of fertility-sparing management using progestin was surveyed in patients with recurrent endometrial cancer after successful fertility-sparing management. Progestin re-treatment in patients with recurrent endometrial cancer was effective and safe. Therefore, this can be recommended for young women who still want to preserve fertility at recurrence after complete response to progestin. It has been identified that risk of colorectal cancer is reduced among users of oral contraceptives or menopausal hormone therapy. To help understand possible mechanisms through which exogenous and endogenous hormonal exposures are involved in colorectal cancer, they evaluated the risk of these malignancies according to tumor expression of estrogen receptor-β (ESR2). In a population-based study of postmenopausal women (503 cases and 721 controls matched for sex and age), the incidence of the colorectal cancer was determined in 445 cases via immunohistochemical assay of the ESR2 expression. Unconditional logistic regression in case-case analyses were used to evaluate the heterogeneity between risk associations according to ESR2 status. They showed that, colorectal cancer risk significantly decreased with duration

The first case reports regarding deep vein thrombosis (DVT) in women consuming OCs were published shortly after their first prescription. The main cause of these problems was the strong dose of estrogens. The development of OCs with lower estrogen doses dramatically reduced the risk. However, when third-generation pills were developed, different initial studies suggested that those preparations increased DVT risk. In 1995, publications of the WHO cardiovascular disease group of experts, followed by various other studies, suggested that third-generation pills induced a two to four fold relative risk of DVT compared with levonorgestrel-containing OCs. On the other hand, three other studies were unable to find any increase in the risk for DVT in third-generation pill users. The DVT risk returned to baseline after stopping of OCs taking. OCs elevates prothrombin, Factors VII, VIII and X, fibrinogen and prothrombin fragment levels and decline Factor V levels. Those alterations seem to be more important with third than second generation OCs and are associated with an increased risk of DVT. In addition, OCs induce a resistance to activated protein C, also observed in Factor V Leiden mutation carriers, resulting in a decreased sensitivity to the anticoagulant action of activated protein C. It was demonstrated that third generation OCs caused a more impressive resistance. The molecular basis of this achieved resistance is unknown, but it can be in part explained by the decreased level of cofactors of the activated protein C. Additionally, different fibrinolytic variables are changed by OCs (plasminogen, tissue plasminogen activator, plasminogen activator inhibitor type I and plasmin-antiplasmin complexes), which theoretically result in increased fibrinoloytic activity. The clinical implications of these changes are unknown. Finally, prothombotic effects of third-generation pills could be explained on the one hand by the increase in procoagulant effect, and on the other hand by the decrease in anticoagulant effects. These effects appear to be more important with third-generation pills than with second-generation ones. This is probably an example of the complexity of the pharmacological effects of steroids. Although estrogen doses are lower, third-generation progestagens may potentiate the estrogenic effects on clotting factors, thus resulting in a procoagulant effect [88]. In the a case-control study designed by Heinemann[89] , conclude that high doses of EE (≥ 50 mcg) were associated with increased risk of

or drospirenone. With regard to the contraceptive patch, the available data suggest that the risk of VTE is similar to that observed with COCs. The greatest risk of COC-associated VTE occurs during the first year of use, thus suggesting the existence of a predisposing condition, such as being a carrier of a thrombogenic mutation with which the COCs would exert a synergistic effect. Routine screening for such conditions is not justified. Changes in haemostatic variables produced by COCs, for example, acquired resistance to protein C, could be linked to VTE, although it has yet to be demonstrated that such alterations are related to a clinical risk of VTE among COC users [92].
However, four additional epidemiologic studies have revealed a two-fold increased risk of non-fatal venous thromboembolism for OCs containing desogestrel or gestodene compared to levonorgestrel; the excess risk is about 15 per 100,000 events per year. Until there is a biologic explanation of the greater thromboembolism risk in users of third-generation OCs, this association should not be viewed as causal and no change in OC prescribing practices is warranted for either current or new acceptors. However, smokers over 35 years of age should not use any combination OCs [93].

In a study, which conducted by Susan et al [94] the risk of non-fatal venous thromboembolism in women receiving oral contraceptives containing drospirenone with that in women receiving oral contraceptives containing levonorgestrel was compared? It was found that risk of non-fatal venous thromboembolism among users of oral contraceptives containing drospirenone was found to be around twice that of users of oral contraceptives containing levonorgestrel.

In a study on 85 women who were diagnosed with VTE ceriteria, two of whom were users of progestagen-only OCs. Of the 83 cases of VTE associated with use of combined OCs, 43 were recorded as deep-vein thrombosis, 35 as pulmonary thrombosis, and five as venous thrombosis not otherwise specified. The crude rate of VTE per 10,000 women was 4.10 in current users of any OC, 3.10 in users of second-generation OCs, and 4.96 in users of third-generation preparations. After adjustment for age, the rate ratio of VTE in users of third-generation relative to second-generation OCs was 1.68 (95% CI 1.04-2.75). Logistic regression showed no significant difference

oral contraceptives, which investigated in this analysis were associated with an increased risk of venous thrombosis.It was suggested that effect size depended both on the progestogen used and the dose of ethinylestradiol. They observed that all generations of progestogens were associated with an increased risk of venous thrombosis and that third generation users had a slight increased risk compared with second generation users. All individual types of combined oral contraceptives increased thrombosis risk compared with non-use more than two-fold. The highest risk of venous thrombosis was found among 50LNG users, and the risk was similar in 30DRSP, 35CPA, and 30DSG users. Users of 30LNG, 20LNG, and 20GSD had the lowest thrombosis risk [7]. Despite the low incidence of venous thrombosis about three per 10000 woman years among women of reproductive age, the effect of combined oral contraceptives on venous thrombosis is large. Because the oestrogen compound (ethinylestradiol) in combined oral contraceptives probably cause the increased risk in thrombosis. There was an association between declined dose of ethinylestradiol and decrease in the risk of venous thrombosis. Apart from adjustments in the dose of ethinylestradiol, the progestogen compound was also altered in an effort to reduce side effects. However, the combined oral contraceptives users with third generation progestogens show a higher risk of venous thrombosis than those using second generation progestogens. Other progestogens have been developed after the introduction of third generation progestogens that is, drospirenone (introduced in 2001). The thrombosis risk for contraceptives with drospirenone was found to be higher than for combined oral contraceptives with second generation progestogens. The thrombosis risk for contraceptives with drospirenone was found to be higher than for combined oral contraceptives with second generation progestogens [7].

Overall, despite the low incidence of venous thrombosis, the risk in women using combined oral contraceptives could be a real concern because of the widespread use of these contraceptives. Risk of venous thrombosis for combined oral contraceptives with 30-35 μg ethinylestradiol and gestodene, desogestrel, cyproterone acetate and drospirenone were identified to be similar, and about 50-80% higher than with levonorgestrel. The combined of 30 μg ethinylestradiol with levonorgestrel as

aura if aura symptoms appear. The newest combined oral contraceptive formulations are generally well tolerated in migraine without aura, and the majority of migraine without aura sufferers do not show any problems with their use; nevertheless, at least two evidences related to the combined oral contraceptives consumption: exogenous hormone-induced headache and estrogen-withdrawal headache are identified by the last International Classification of Headache Disorders. As regards the safety, even if both migraine and combined oral contraceptive intake are associated with an increased risk of ischemic stroke, migraine without aura per se is not a contraindication for combined oral contraceptive use. When prescribing combined oral contraceptives in migraine without aura patients, in particular in women aged over 35 years, other risk factors (tobacco use, hypertension, hyperlipidemia, obesity and diabetes) must be carefully considered. Furthermore, the exclusion of a hereditary thrombophilia and of alterations of coagulative parameters should precede any decision of combined oral contraceptive prescription in migraine patients [99].

Combination OC use increases a woman’s risk for VTE and ischemic stroke. Observational studies found 1-3 additional cases of VTE among 10,000 women taking combination contraceptives for one year. Taking into account a baseline 10-year ischemic stroke rate of 2.7 per 10,000 young women (ages 25-29) years, OC usage increases the risk to 4.0. The risk increases to 11.0 for women who have migraine with aura, and to 23.0 for women with migraine with aura using OC [99]. In 2003, WHO convened an Expert Working Group to review medical eligibility criteria for contraceptive use. After reviewing the evidence provided above the group determined that women with nonmigrainous headaches can use COCs (WHO Category 1), women having migraine without aura who are less than age 35 can generally use COCs (WHO Category 2), women having migraine without aura who are 35 years or older generally should not use COCs (WHO Category 3) and women having migraine with aura, at any age, should not use COCs (WHO Category 4). In addition, WHO made recommendations regarding continued use of COCs among women with headaches and noted that any new headaches or marked changes in headaches while using COCs should be evaluated.

side effect of hormonal contraception and may cause women to avoid or discontinue contraceptive methods. Prior studies have shown weight gain and changes in body composition among users of depot medroxyprogesterone acetate (DMPA). DMPA as an aqueous suspension of 17-acetoxy 6-methyl progestin is administered by intramuscular injection for long-term contraception [101]. Weight change was variable among women using progestin-only contraceptives. Black race was a significant predictor of weight gain among contraceptive users. A previous36-months longitudinal study of 703 women taking contraceptive found that DMPA users had a 5.1-kg weight gain compared to 1.5-kg gain among oral contraceptive users (pb.001) and 2.1kg gain among non-hormonal contraceptives users (pb.001). In addition, DMPA users had a greater increase in total body fat and percent body fat. The perception of weight gain is clinically important, because it may affect a woman’s satisfaction with her contraceptive method or influence a woman’s decision to continue use of the method. Due to several adverse physical and mental health effects that commonly is associated with obesity, it is important for clinicians to be aware of their patients’ weight gains. Understanding that some contraceptive methods have higher rates of perceived weight gain could prove helpful to clinicians when counseling their patients [102].

It was shown that risk of venous thromboembolism is increased with obesity, and this risk may be additive when using a combined hormonal method. According to The World Health Organization (WHO) report ~56.7% of reproductive-age women in the United States are overweight (body mass index [BMI] between 25 and 29.9 kg/m²) and >30% are obese (BMI >30 kg/m²). There are increasing proportions of overweight and obese females in other developed nations as well. In the United Kingdom, >24% of reproductive age women are obese; in Australia 20% of women are also obese. On the other hand, obesity may also impact the efficacy of combined hormonal contraception (CHC), particularly the oral contraceptive (OC) [103].

One possible mechanism of this effect is dilution; steroids may have declined the availability due to increased circulating blood volume or fat sequestration. Obese women may also have different metabolism of steroids than normal weight women. A recent study looking at the impact of obesity on the pharmacokinetics

The effect of a long–acting injectable progestin, depomedroxyprogesterone acetate (DMPA) on diabetes risk in Latino women with prior gestational diabetes mellitus (GDM) was studied. Diabetes prevalence rate of the DMPA group was found (19%) more than COC group (12%). The weight gain of the DMPA group during consumption was identified higher (Average 1.8 Kg) significantly (P=0.0001) than COC group. They concluded that DMPA consumption is associated with an increased diabetes risk that could be explained by three factors: 1) use in women with increased baseline diabetes risk, 2) weight gain during taking, and 3) use with high baseline triglycerides and/or during breast-feeding [107].

Serum adiponectin, resistin and markers of adipocyte development (DLK-1) levels in reproductive-age female rhesus macaques monkeys of normal (n=5, mean=5.76kg) and inherently obese (n=5, mean=8.11kg) weight were determined before, during and 2 months after stop taking COC of 8 months of continuous treatment with COCs. The obese group alone showed a significant decrease (p<.01) in weight with COC use, which returned to baseline after COC cessation. In the obese group, the baseline adiponectin levels prior to COC treatment were lower (p<.05). Adiponectin levels elevated from baseline in both groups, but was higher in the obese group (p<.05). Resistin levels was similar at baseline, with an increase in both groups following treatment. Circulating resistin remained increased above baseline levels after stop taking COC, particularly in the obese group (p<.05). While DLK-1 levels did not change significantly in either group, a tendency for higher levels was observed in obese animals. It was suggested that COC taking may change metabolic processes via direct (resistin) or indirect (adiponectin) means, while unchanging DLK1 levels suggest that COC do not affect adipocyte development. It was suggested that COCs may directly increase the resistin levels, as observed in both groups. It was also concluded that as adiponectin levels is inversely related to adipocyte mass, therefore increased levels in the obese group are likely attributed to weight loss [108]. A cross-sectional associations between 1) current use of oral contraceptives (OCs) and 2) glucose levels, insulin levels, and diabetes in young adult, who were in the Coronary Artery Risk Development in Young Adults (CARDIA) was investigated

Table 1: Oral contraceptives; A review of the options

Oral cotraceptives: A review of the options (continued)

Adapted from: Oral contraceptives: Does formulation matter? Kathryn A. Szabo, MD; Eric A. Schaff, MD. Vol 62, No 10 | october 2013 | The Journal of Family Practice. 

Table 2- Relative risk of myocardial infarction among current users of hormonal contraceptives from studies in women after 1990.

Table 3- Relative risk of myocardial infarction among current users of hormonal contraceptives according to the type of progestincombined with ethinylestradiol.

Pooled OR 1.8 (1.2–2.8)

11. Massafra C., Buonocre G., Berni S., Gioia D.n Giuk\liani A., Vezzosi P. Antioxidant erythrocyte enzyme activities during oral contraception. Contraception .1993 Jun; 47(6):590-6.)

12. Akinloye O, Adebayo TO, Oguntibeju OO, Oparinde DP, Ogunyemi EO. Effects of contraceptives on serum traceelements, calcium and phosphorus levels. Med J. 2011; 60(3):308-15.

13. Groote D., Hauterive P.S., Pintiaux A., Balteau B., Gerday C., Claesen J., Claesen J., Foidart JM. Effects of oral contraception with ethinylestradiol and drospirenone on oxidative stress in women 18-35 years old. Contraception. Aug; 80(2):187-93. doi: 10.1016/j.contraception.2009.02.015. Epub 2009 Apr 22.

14. Pincemail J., Vabelle S, Gaspard U, Collette G., Haleng J., cheramy B, et al. Effect of different contraceptive methods on the oxidative stress status in women aged 40 48 years from the ELAN study in the province of Liege, Belgium. Hum reprod. 2007 Aug; 22(8):2335-43.

15. Akhter S., Shamsuzzaman AK. Siddiqui NI., Banerhee M., Deb K., Hossain MZ., Serum zinc status of rural women taking combined OC. Mymensingh Med J. 2005 Jul;14(2):128-32.

16. Akhtar S., Shamszaman AK., Banarjee M., Sema Sa., Deb K. Serum zinc status of rural women taking combined OC. Mymensingh Med J. 2006 Jan;15(1):25-92.

17. Berg G., Kohlmeier L. Use of oral contraceptives and serum beta-carotene. Eur J Clin Nutr . 1997 Mar; 51(3):181-7.

18. Akinlove O., Adebayo T., Oguntibeju O., Oparinde E. Effects of contraceptives on serum trace elements, calcium and phosphorus levels.West Indian Med J. 2011 Jun;60(3):308-15.

19. Babic Z., Tariba B., Kovacic J., Pizent A., Varnai V., Macan J. Relevance of serum copper elevation induced by oral contraceptives: a meta-analysis. Contraception. 2013 Jun; 87(6):790-800. doi: 10.1016/j.contraception.2012.10.006. Epub 2012 Nov 13.

20. Berg G.,Kohlmeier L., Bernner H. Effect of oral contraceptive progestins on serum copper concentration. Eur J. Clin Nutr 1998 Oct; 52(10):711-5.

Regulation. Comparative study of the effects of two once-a-month injectable contraceptives (Cyclofem® and Mesigyna®) and one oral contraceptive (Ortho-Novum 1/35®) on coagulation and fibrinolysis.Contraception.2003; 68 (3): 159-76.

31. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Cardiovascular disease and use of oral and injectable progestogen only contraceptives.Contraception.1998; 57 (5): 315-24.

32. Sartorelli DS, Franco LJ. Tendências do diabetes mellitus no Brasil: o papel da transição nutricional. Cad SaúdePública.2003; 19 (1): S29-S36.

33. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone. Acute myocardial infarction and combined oral contraceptives: results of an international multicentre case-control study. Lancet.1997; 349 (9060): 1202-9.

34. 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. 2001; 345 (25):1787–93.

35. Kemmeren JM, Tanis BC, van den Bosch MA, Bollen EL, Helmerhorst FM, van der Graaf Y, et al. Risk of arterial thrombosis in relation to oral contraceptives (RATIO) study: oral contraceptives and the risk of ischemic stroke. Stroke.2002; 33: 1202-8

36. Shufelt CL, BaireyMerz CN. Contraceptive hormone use and cardiovascular disease. J Am CollCardiol. 2009; 53 (3): 221-31.

37. Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan . postmenoposal hormone replace therapy. JAMA, 2002; 288 (7): 872-881

38. Preshaw P. Contraceptives and the periodontium.. Periodontal 2000. 2013; 61(1):125-59. doi: 10.1111/j.1600-0757.2011.00399.x(

39. Norouzi V., Seifi M. Fallah F., Korani M., Samadikuchaksaraei A. Anadolu Kardiyol Derg, . Effect of oral contraceptive therapy on cysteine and C-reactive protein levels in women: an observational study. 2011; 11: 698-702

40. Lidegaard Ø., Løkkegaard, E., Jensen A., Wessel C. Skovlund, and Keiding N. Thrombotic Stroke and Myocardial Infarction with Hormonal Contraception. The New England journal of medicin. 2012; 366; 24: 2257-2266

51. Kathryn A. Szabo, Eric A. Schaff, Oral contraceptives: Does formulation matter? The Journal of Family Practice Page E1-E12. 2013; 62(10) E1-E12.

52. Sidney S, Petitti DB, Quesenberry CP Jr, Klatsky AL, Ziel. Heart. Nov 1999; 82(5): 581–583

53. Petitti D. , Sidney S., Bernstein A., Wolf S., Quesenberry C., Ziel H. Stroke in users of low-dose oral contraceptives. N Engl Jed. 1996; 335(1):8-15.

54. Geneviève P., Justine H., Rodin, Lorraine M., Marianne C. Hormonal contraceptives and arterial disease. Best Practice & Research Clinical Endocrinology & Metabolism. 2013; 27: 35–45

55. The Women's Health Initiative Study Group. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288:321-33

56. Valerie Beral. Breast cancer and hormone-replacement therapy in the million women study. Lancet 2003; 362:419-27.

57. Rekers H., Norpoth T., Michael M. Oral contraceptive use and venous thromboembolism: a consideration of the impact of bias and confounding factors on epidemiological studies. Eur J Contracept Reporod Health Care. 1996; 1(1):21-30.

58. Mantha, Karp R., Terrin N., Bauer K., Zwicker J. Assessing the risk of venous thromboembolic events in women taking progestin-only contraception: a meta-analysis. BMJ. 2012; 345: e4944.

59. Carr B., Ory H. Estrogen and progestin components of oral contraceptives: relationship to vascular disease. Contraception. 1997 55(5):267-72.

60. Martinez F., Ramirez I., Perez C.E., Latorre K., Lete I. Venous and pulmonary thromboembolism and combined hormonal contraceptives. Systematic review and meta-analysis. Eur J Contracept Reprod. 2012 Feb; 17(1):7-29. doi: 10.3109/13625187.2011.643836.

61. Samuel S. and Jügen D. Risk of venous thromboembolism among users of oral contraceptives: a review of two recently published studies. J Fam Plann Reprod Health Care 2010 36: 33-38. doi: 10.1783/147118910790291037.

62. Schwing P., Ory H.W, Visness CM. Estimates of the risk of cardiovascular death attributable to

Arch Gynecol Obstet. 2013; 287:1031–1037. DOI 10.1007/s00404-012-2661.

72. Barreiros FA., Guazzelli CA, Babosa R., Torloni MR., Barbieri M., Araujo Ff. Extended regimens of the combined contraceptive vaginal ring containing etonogestrel and ethynyl estradiol effects on lipid metabolism. Contraception. 2010; 84: 155-159. Doi; 10.1016/j.contraception.2010.11.002.

73. Shimizu Y., Mita S., Takeuchi T., Notsu T., Mizuguchi K., Kyo S. Dienogest a synthetic progestin, inhibits prostaglandin E2 production and aromatase expression by human endometrial epithelial cells in a spheroid culture system. Steroids. 2011, 76: 60-67. Doi: 10.1016/j. steroids.2010.08010.

74. Lai TY., Chen LM., Lin, JY., Tzang BS., Lin JA., Tsai CH et al. 17 beta –estradiol inhibits prostaglandin E2 –induced COX-2 expression and cell migration by by suppressing Akt and ERK1/2 signaling pathways in human Loco colon cancer. Mol Cell. 2010, 342: 63-70. Doi: 10.1007/s110-010-0469-7.

75. Glintborg D, Mumm H, Altinok ML, Richelsen B, Bruun JM, Andersen M. Adiponectin, interleukin-6, monocyte chemoattractant protein-1, and regional fat mass during 12-month randomized treatment with metformin and/or oral contraceptives in polycystic ovary syndrome. J Endocrinol Invest. 2014 Jun 7. [Epub ahead of print])

76. Salkeld BD, MacAulay JC, Ball RW, Cannon JG. Modulation of body temperature, interleukin-6 and leptin by oral contraceptive use.Neuroimmunomodulation. 2001; 9(6):319-25).

77. Naomi K.T., Kathryn M.C , Maria W. S., Polly A.M. Blood pressure measurement prior to initiating hormonal contraception: a systematic review. Contraception 87; 2013; 87:631–638

78. Lubianca JN, Faccin CS, Fuchs FD. Oral contraceptives: a risk factor for uncontrolled blood pressure among hypertensive women. Contraception. 2003; 67 (1): 19-24.

79. Thadhani R., Stampefer MJ, Chasan T.L., Willett W.C., Curhan GC. A prospective study of pregravid oral contraceptive use and risk of hypertensive disorders of pregnancy. 1999; 60(3):145-50.

80. Grandi G., Xholli A., Napolitano A., Piacenti I., Bellafront M., Cagnacci A. Prospective measurement

L., Buffet C. Third -Generation Oral Contraceptives: Future Implicationa of current Use. Expert Rev of Obstet Gynecol. 2008; 3(2):189-201

90. Heinemann LA, Lewis MA, Thorogood M, Spitzer WO, Guggenmoos- Holzmann I, Bruppacher R. Case-control study of oral contraceptives and risk of thromboembolic stroke: results from international study on oral contraceptives and health of young women. BMJ.1997; 315 (7121): 1502-4.

91. Kemmeren JM, Tanis BC, van den Bosch MA, Bollen EL, Helmerhorst FM, van der Graaf Y, et al. Risk of arterial thrombosis in relation to oral contraceptives (RATIO) study: oral contraceptives and the risk of ischemic stroke. Stroke.2002; 33: 1202-8.

92. Chan WS, Ray J, Wai EK, Ginsburg S, Hannah ME, Corey PN, et al. Risk of stroke in women exposed to low-dose oral contraceptives: a criticalevaluation of the evidence. Arch Intern Med. 2004; 164 (7): 741-7. DOI: 10.1161/01.STR.0000015345.61324.3F

93 Francisa M. and The European Journal of Contraception and Reproductive Health Care d Avecilla A. Combined hormonal contraception and venous thromboembolism.. 2007; 12(2): 97-106 (doi: 10.1080/13625180701300194)

94. Carr BR. and Ory H. Estrogen and progestin components of oral contraceptives: relationship to vascular disease. Contraception. 1997; 55(5):267-72.

95. Jick S., Hernandez R.K. Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data. BMJ 2011; 340:d2151 (1-8) doi:10.1136/bmj.d2151.

96. Farmer RD., Lawrenson RA., Thompson CR., Kennedy JG. And Hambleton IR. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet. 1997 Jan 11; 349(9045):83-8.

97. Jick S., James A., Kaye, Russmann S., and Hershel J. Risk of nonfatal venous thromboembolism with oral contraceptives containing norgestimate or desogestrel compared with oral contraceptives containing levonorgestrel. Contraception. 2006; 73: 566-570.

of a combined estrogen and progesterone oral contraceptive on circulating adipocytokines adiponectin, resistin and DLK-1 in normal and obese female rhesus monkeys. Contraception. 2013; 88(1):177-82. doi: 10.1016/j.

110. Kim C., Siscovick D.S., Sidney. S., Lewis C.F., Kiefe K., Koepsell,T.D. Oral Contraceptive Use and Association With Glucose, Insulin, and Diabetes in Young Adult Women: The CARDIA Study .Diabetes Care. 2002; 25(6):1-6