Note** This is a summary/review of the article "Shufelt, C. L., & Noel Bairey Merz, C. (2009). Contraceptive Hormone Use and Cardiovascular Disease. Journal of the American College of Cardiology, 53(3), 221–231. References are below. For study purpose only.
Birth Control Use
Internationally, cardiovascular disease (CVD) is the leading cause of mortality and morbidity among women - vulnerable women. You might ask, what defines a woman as vulnerable and why should a woman be labelled as vulnerable in a scientific text? The word vulnerable, generally, is pointed at someone that is completely open, unguarded with their heart, mind, and soul. But in this context, a woman that is vulnerable is often categorized as socially and economically disadvantaged or maybe even so elderly and neglected. Social factors that can contribute a woman to be placed in this category can vary from low income, race, health and emotional/physical ability. With the increase of women with socioeconomic stress, some women find themselves controlling their need to have children. We often hear the following, “It is too expensive to have children… I can’t afford to have another child, I need to go on birth control... Children ruin careers, birth controls prevent that.” Thus, we live in an era of changing preferences for fertility control, family size, timing of establishing a family, and choice of occupation. Nowadays, Canadians and their health care providers are involved in fertility related decisions that will fundamentally influence individual lives and society well into the future (1). The 2006 Canadian Contraception Survey found that sexually active women in between the ages of 15-49, who were not attempting to conceive, 14.9% were not using contraceptives but 20% were using them orally (1). Observational studies have stated that young women have a naturally low risk of CVD compared with men, but after menopause their risk of CVD rises. This suggests that the hormonal changes, such as the endogenous reproductive hormones, may play a protective role as women get older. In the article, Cardiovascular Hormone Use and Cardiovascular Disease, the authors demonstrated that the disruption of the ovulatory cycling, indicated by estrogen deficiency and hypothalamic dysfunction, or irregular menstrual cycling in pre-menopausal women is associated with a risk in cardiovascular disease (8). Parallel to this, recently published data on the mortality and morbidity from cardiovascular disease has represented that mortality rates increased in women on OC in women between the ages of 35 to 44 compared with other age groups (8). While it is safe to say, that Oral contraceptives are safe and effective, and most women do not really - or maybe ignorantly do not complain of any symptoms - there has not been any current specific research dedicated to correlating cardiovascular disease and oral contraceptives use. Since there has been an increasing demand for OC in the market, there is no current data indicating what specific doses and type of OC pills women should be taking in respective with their age, weight, history of vascular disease, pregnancy outcomes, diabetes, and smoking habits. This review’s aim is to provide data on cardiovascular metabolic and clinical complications found in women on oral contraceptive pills.
A closer look at the physiology of estrogen and progesterone
What are oral contraceptive pills anyway and how do they work? Often known as birth control, these hormonal contraceptive pills are made up of a combination of estrogen, usually ethinyl estradiol (EE) and a synthetic progesterone and less commonly used, a progesterone only pill. In estrogen's’ most abundant form, 17B- estradiol produced by the ovaries, binds equally on two receptors known as ER-β and ER-α. The binding of estrogen to the receptors can occur through pathways: genomic and nongenomic. The genomic pathway takes place through ligand binding, here, estrogen as a steroid makes its way through the lipid membrane and binds the receptors located in the nucleus. This, then either activates or inhibits gene transcriptions. The non-genomic pathway is more direct, in which there is a rapid activation of the receptor located at the cell membrane and causes a release of intracellular messengers such as nitric oxide, calcium, or kinase. An example of a non genomic pathway is the activation of nitric oxide synthase to cause arterial vasodilation.
Endogenous PR blood levels rise each month from the corpus luteum after ovulation occurs and increase during luteal menstruation phase to top ovulation, and eventually decrease at the time of menstruation. Progestins are hormones used by both men and women for different purposes. For women, they are usually used to regulate their menstrual cycle and treat abrupt stopping of periods. Progestins work by altering the uterus; after the level of progestin drops in the blood, the lining of the uterus starts to come off producing vaginal bleeding. There are many types of progestins but they each differ by their potency and affinity to bind to the progesterone, estrogen and androgen receptors. The newest type of contraceptive and hormonal pills includes a combination of estrogen and drospirenone.
The Evolution of Contraceptive Hormones
Contraceptive pills were first introduced in the 1960’s as oral contraceptive. Their aim was to stimulate a “state of pregnancy” by increasing levels of hormonal blood levels that directly suppressed ovulation and implantation. Often referred to as the “pill”, these OC’s were developed to be cyclical, with a 28-day cycle of 3-week combination of a fixed dose of estrogen and progestins followed by a week of placebos. The week of sham pills, consequently, induced hormonal withdrawal bleeding which reassured women of the absence of pregnancy.
Contraceptive hormone formulation and dosing also vary. For example, monophasic dosing has consistent doses that do not change during the month, while in tricyclic, the progestin percentage of the contraceptive hormones, increase each week to mimic the natural hormonal cycling in women. Thirdly, contraceptive hormones also vary according to their delivery method and nowadays include non-oral routes such as the combined estrogen/progestin through the trans dermal patch or vaginal ring. The trans dermal patch and vaginal ring is continuously worn for 21 days stimulating an estrogen and progestin formulation and taken off for 7 days. Both methods are simple methods to provide hormone dosing and are beneficial as they avoid first pass metabolism in the liver as a pose to OC’s (8). However, those on OCs may suffer from many pro thrombotic effects, such as increasing circulating levels of prothrombin and decreasing antithrombin III due to estrogen's’ first-pass effect on the liver. The extent in which the delivery method is associated with an increase in cardiovascular disease risk is uncertain and this review aims to highlight this problem.8
There have been three main developments of OC’s: (1) The dose and types of hormones used, (2) The formulation timing and dosing, and (3) The delivery method. The dose percentage of OC has decreased significantly since the 1960’s, with a history of OC’s containing a high dose of combined estrogen and progestins. First generation estrogen OCs contained 150ug, and current doses now range from 20-35ug of ethinyl estradiol (EE) (8).
Mechanism of Estrogen and Progestin on Cardiovascular Disease
The most abundant and circulating estrogen in the body is 17-β-estradiol (E2). E2 binds equally to the receptors: ERα and ERβ. E2 is strongly identified among other types of estrogen (e.g., estrone, estriol). E2 is produced because of testosterone converting by the enzyme aromatase. The enzyme aromatase is found in several extragonadal tissues including the brain, heart, bones and vasculature in both sexes. There has been a correlation between the increase level of aromatase conversion of androgen and estrogen in adipose tissue that has resulted in significant increase in circulating E2. Sex hormones and their activated receptors include the AR, ERα, ERβ, and the G protein-coupled receptor GPR30. These receptors, both at the cellular and sex specific level, affect both genomic and non-genomic pathways. Specific pathways to the cardiovascular system include activation of the ERα on endothelial cells and myocardial cells. ERs in the cardiovascular system play a role in modulating a vasodilatory response via nitric oxide and possess long term effects via the genomic pathway by increasing endothelial growth cell and inhibiting smooth muscle cell proliferation. Estrogen reduces low-density lipoprotein cholesterol (LDL-C) oxidation, binding and platelet aggregation, and increases high density lipoprotein cholesterol, facilitating nitric oxide mediated vasodilation, and inhibiting the response of blood vessels to injury.
Through the genomic pathway, estrogen affects the cardiovascular system indirectly through cardiovascular risk factors such as the lipid profile.
The alternations of ER affect the hepatic apolipoprotein up-regulation. Previous studies on OC’s and pre-menopausal women have shown a dose related response in lipid profile. For example, women using 20ug EE/100 ug Levonorgestrel (LNG) OC resulted in reductions in high density lipoprotein cholesterol (HDL-C) and a small increase in LDL-C in contrast to a 30 ug of EE/150ug LNG OC (8). A recent study conducted a randomized, double-blind study that evaluated the effect of lipid metabolism on 98 women. The women received 2 different types of progestin-only pills, desogestrel 75 ug/day or LNG 30ug a day (8). They saw minimal changes to the individual’s lipid profile except for a decrease in the levels of HDL-C. There were no significant differences observed between the 2 formulations of OCs, despite the higher dose of progestin found in desogestrel (8).
A significant amount of studies on blood pressure in normal sensitive women have shown an increase in blood pressure associated with OC use. One of the studies showed an increase of systolic blood pressure by 7-8 mm Hg compared with systolic blood pressure in those not using OCs. However, the newer progestins such as drospirenone, produced lower blood pressure. Another study took 80 healthy women and randomized them into groups of 3 mg of drospirenone combined with a 15,20, or 30 ug dose of EEs and found that the systolic blood pressure at 6 months fell by a range 1-4 mm Hg across all the groups, compared with an increase of blood pressure of 4 mm Hg in the control group of women taking LNG/EEs. In addition, the body weight of the groups receiving the drospirenone fell by a range of 0.8 - 1.7 kg compared with an increase of body weight in those receiving LNG/EE by 0.7 kg.
Moreover, oral contraceptives can also impact glucose tolerance and diabetes mellitus. A recent study on glucose levels in 80 healthy women was conducted. The women were assigned to 4 groups and received 3 mg of drospirenone combined with 30, 20 and 15 ug of doses of EE or LNG/30-ug EE (7). The woman performed oral glucose tolerance at pre-treatment and at the end of 6 months use of the OCs. When evaluated on treatment, fasting glucose was unchanged for all the groups, however, the area under the curve (this is mainly evaluated during an oral glucose tolerance test) increased for all formulations. Moreover, evidence suggests that there is no link between worsening conditions of diabetes mellitus and early generation of OCs (7).
Pradhan et al. have demonstrated that the effect of estrogen on the vasculature depend on whether atherosclerosis has been established (7). For example, estrogen receptor expression is decreased in atherosclerotic arteries, but this may have different outcomes depending on the state of health of the underlying vessel. For example, the upregulation of estrogen on specific members of the matrix metalloproteinase (MMP) family such as MMP-9 degrade the extracellular matrix with the arterial wall (7). Thus, in an artery that is non-diseased, an estrogen-induced increase in MMP-9 has little consequences. In contrast, in an atherosclerotic artery, where MMP-9 is expressed in the shoulder region of an atherosclerotic plaque, an increase in MMP-9 expression is associated with an increased risk of plaque rupture and thus acute coronary syndromes. Figure 1 summarizes some of the thrombogenic effects caused by estrogen.
Figure 1: Estrogen: beneficial and thrombogenic effects. Retrieved from Mendelsohn and Karas
To expand more on the risk of thrombogenic effects, estrogen has also been known to have prothrombotic effects and increases cardiovascular nervous thromboembolism (VTE) by elevating prothrombin. Sidney et al. conducted a matched case control study and found that OC use with more than 50 ug EE correlated with a 4 times higher risk of VTE compared with that seen in nonusers. It was also noted that there is a
n increased risk of thrombosis with the newer formulation of OCs in women that used OCs for more than 6 months compared with those that used the OCs for longer periods of time (5).
Women face a higher risk of sudden cardiac death associated with electrocardiograph QT prolongation compared with men. Androgen has been demonstrated to “blunt QT prolongation in response to quinidine (quinidine is a pharmaceutical agent that acts as a class I anti arrhythmic agent in the heart), in contrast to estrogen that alter the expression of potassium channels. In healthy postmenopausal women, hormone replacement therapy alongside estrogen has demonstrated prolongation of the QT interval, while estrogen and progesterone combine produce no significant effects on the QT interval. Figure 2 shows known mechanisms in which contraceptive hormones impact the cardiovascular system including a summary of effects on atherosclerosis, thrombosis, vasomotion, and arrhythmogenesis.
Figure 2:Estrogen and Progestins effect on atherosclerosis, thrombosis, vasomotion, and arrhythmogenesis. This is dependent on the delivery method and dose of estrogen and type of progestins. Cox-2: cyclooxygenase (isoenzymes that catalyzes the formation of prostaglandins), HDL: high density lipoprotein, LDL: low density lipoprotein; VSMC: Vascular smooth muscle cell. (Retrieved from Shufelt and Bairey Merz)
Clinical Studies: current/past contraceptive use in young and midlife women
A prospective study conducted by the Nurses' Health Study (U.S) initiated an 8-year self-report assessing the risk of Myocardial Infarction (MI) and the use of OC use in midlife women (ages 30-55 years) (3). They found no significant increase in the risk of MI among past users of OCs for cardiovascular disease, nonfatal MI, or fatal coronary disease when they compared it to women that have never used OCs. Moreover, there was no duration indicating the use of OCs and cardiovascular disease - women that has used OCs for 10 years had no risk of MI. However, among current users of OCs, there was a 2.5 relative increased risk of adverse cardiovascular events, including cardiovascular death, nonfatal MI, and stroke.3 The risk of cardiovascular events associated with current users was believed to be a consequence of pro-thrombotic effects, and 7/10 of the events occurred in cigarette smokers. Another prospective study showed an increase risk of acute MI among women who take other medications along with OCs and smoke. To date, no studies have shown the risk of CVD with the fourth-generation OCs, as well as non-OC hormone formulations compared to current and past use (3).
A prospective study from Sweden followed 48,321 women age 30-49 years over 11 years. The study was meant to determine the risk of MI with women on OCs. When the researchers followed up, there was a total of 190 nonfatal MIs and 25 deaths due to MI.9 When the study was narrowed down to age, cardiac risk factors such as hypertension, smoking status, and diabetes, there were no increased results of MI in both past and present users.
Post-menopausal Women: Long term use in contraceptive hormones
We see an increased risk in MI in women taking OCs, however there is no sufficient data to have existed regarding long term past OC users and subsequent cardiovascular disease in post-menopausal women. The data available is scarce due to the short time of availability of OC (they have only been present since the 1960s ), the decades needed to perform clinical event studies and the follow up time needed to since most of cardiovascular disease events are occurring later in life among women. Since some human and animal data in the literature find a correlation between OCs and anti atherosclerosis effects, it is safe to hypothesize that, compared with non-users, women with a history of OC in their menopausal years may be protected against atherosclerosis which in return results in a lower cardiovascular disease event during post-menopause (9). One study explored this hypothesis by quantitatively measuring the atherosclerosis. The study assessed past OC use and evidence of atherosclerotic coronary artery disease in 672 postmenopausal women with coronary risk factors that were undergoing coronary angiography for suspected ischemia in the WISE (Women’s Ischemia Syndrome Evaluation) study. Past OC use resulted in a 2.4% reduced risk of atherosclerosis coronary heart disease measured by quantitative coronary analysis (9).
Discussion and Recommendations
Several of the human and animal data collected from these studies have correlated contraceptive hormones with anti atherosclerosis effects, however it is not known is OCs do have an impact on thrombosis, vasomotion, arrhythmogenesis and mechanistic pathways that may contribute to cardiovascular risk. To summarize, recent data with first and second generation high dose OC formulations show a small but significantly increased risk of MI and VTE among women that currently use OC and smoke. While, the use of third generation formulation is associated with a reduction in MI. The highest risk thrombosis is seen in women with in the first year of using high dose estrogen OCs. The current, newer formulations used indicate no risk of MI, but an increased risk of VTE that may increase with time and age. To date, there is no cardiovascular data available for the newest type of OCs, including the progestins that lower blood pressure and body weight. Specific study is needed to evaluate the risk these new formulations might have on the body. A future goal would be to assess the newest contraceptive formulations by weighing risks according to an individual patient by taking account age, history of CVD, and current health state.
References
(1). Canadian Contraception Consensus Chapter 1 Contraception in Canada. Journal of Obstetrics and Gynecology Canada, Volume 37, Issue 10, S5 - S12
(2). Chasen-Taber L, Willet W, Stampfer M, Hunter D, Colditz G, Spiegelman D. A Prospective Study of Oral Contraceptives and NIDDM Among U.S. Women. 1997. Diabetes Care. Mar; 20(3): 330-35.
(3). Dunn et al. Oral contraceptives and myocardial infarction: results of the MICA case-control study Commentary: Oral contraceptives and myocardial infarction: reassuring new findings. BMJ 1999 Jun;318(1):1579-83.
(4). ESHRE Capri Workshop Group. Hormones and Cardiovascular Health in Women. Human Reproduction Update 2006 Sept;12(5):483–97.
(5). Mendelsohn Me, Karas RH. Molecular and cellular basis of cardiovascular gender differences. Science 2005 Jun;308(5728):1583-7.
(6). Ouyang P, Michos ED, Karas RH. Hormone replacement therapy and the cardiovascular system lessons learned and unanswered questions. J Am Coll Cardiol 2006 May 2;47(9):1741-53.
(7). Pradhan et al. Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women's Health Initiative observational study. JAMA 2002 Aug 28;288(8):980-7.
(8). Shufelt, C. L., & Noel Bairey Merz, C. (2009). Contraceptive Hormone Use and Cardiovascular Disease. Journal of the American College of Cardiology, 53(3), 221–231. http://doi.org/10.1016/j.jacc.2008.09.042
(9). Stampfer M, Willet W, Colditz G, Speizer F, Hennekens C. A Prospective Study of Past Use of Oral Contraceptive Agents and Risk of Cardiovascular Diseases. N Eng J Med Nov 1988;319(1):1313-17.