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The effects of oral contraceptive induced nutrition depletions and its consequences.


Medications are prescribed to treat patients for a wide variety of conditions. They have very positive effects on health and disease. However, some medications have detrimental side effects. Some of the side effects can be explained by nutrient deficiencies. Although the administration of these drugs is aimed at improving a patient's quality of life, they can act as nutrient interfering agents and deprive the body of vitamins and minerals vital for the maintenance of optimal health.

Oral contraceptives are medications that can deplete nutrients in the body by disrupting their digestion and absorption in the gastrointestinal tract or inhibiting the synthesis of nutrients in various body tissues. Therefore, nutritional supplementation becomes essential for maintaining optimal health, both while taking medications and for a period after the drug is ingested. We will address the negative effects of oral contraceptives on the body.


Many different forms of oral contraceptives are available today. The different brands vary chemically, but they possess many similar properties. There are two main groups of oral contraceptives. The first is a compound that combines both estrogen and progesterone and the second is the administration of continuous progesterone therapy in an oral form. These preparations are designed to be readily absorbed without altering their pharmacokinetic and pharmacodynamic properties. The pill is administered each day for 21 consecutive days. During the final week of the cycle, it may be beneficial for the patient to supplement with iron containing vitamins despite the fact that no oral contraceptives will be consumed based upon the information presented in this paper. Oral contraceptives can be monophasic, biphasic or triphasic. Monophasic compounds release a fixed amount of estrogen and progesterone while biphasic and triphasic formulations contain different ratios of these hormones. All oral contraceptives release hormones that mimic the physiologic activity of estrogen and progesterone produced naturally by the body. The higher levels of progesterone and estrogen that are introduced to the body through administration of the oral contraceptive inhibits the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH). (1)

FSH is released at the beginning of the menstrual cycle. This hormone activates the receptors on the follicles for FSH, enhancing their development. Although all of these will develop to a certain degree, only one of the follicles will undergo enough development to become the dominant follicle for that month's menstrual cycle. Growth of the follicle initiates the production of estrogen from specific cells. The different estrogens that are produced are estrodial, estrone and estriol. These estrogenic hormones promote the growth and development of the endometrium and mammary glands in order to prepare the uterus for pregnancy. Sufficient growth of the follicle occurs in 14 days. After this time ovulation occurs. This stage is characterized by the rupturing of the follicle. The ruptured follicle releases an ovum that enters the fallopian tube in order to be fertilized. Although the initiation of ovulation occurs independent of estrogen, normal endogenous amounts of estrogen affect the motility of the fallopian tubes and create a favorable environment for the sperm to transverse the endometrium. (1)

The ruptured follicle remains in the ovary and is transformed into the corpus luteum by luteinizing hormone. In addition to producing estrogen, the corpus luteum initiates the synthesis of progesterone. Normal amounts of this hormone enhance the development of the uterine lining and the mammary duct system. Upon completion of their development, the uterus and mammary system are prepared for fertilization and lactation (1).

If fertilization has not occurred by the end of the ovarian cycle, progesterone and estrogen secretion drastically diminishes. This results in menstruation. Menstruation is characterized by the degeneration of the corpus luteum, constriction of the uterine vasculature and tissue death causing sloughing off of the uterine lining resulting in vaginal bleeding (1). Upon the completion of menstruation, the vaginal bleeding ceases and a new follicle begins to grow in the ovary (1).

Oral contraceptives containing exogenous amounts of estrogen and progesterone provide a very effective method of preventing fertilization by enhancing the effects of FSH and LH. Thus inhibiting ovulation and reducing the possible permeability of sperm. However, it increases the risk of developing several different types of thromboembolic vascular diseases (2), including a pulmonary embolism, cerebrovascular accident (CVA), thrombophlebitis, cardiovascular disease (CVD) and myocardial infarction. The duration and the strength of the dose are highly correlated to the development of these conditions. Other factors that can influence the progression of thromboembolic disease are smoking, hypertension (HTN), obesity, diabetes, hyperhomocysteinemia and hypercholesterolemia (2). Evidence suggests the concurrent administration of oral contraceptives and smoking increases the risk of CVD by increasing the hypoxic damage to the vasculature contributing to the development of atherosclerosis (3).

The increased risk of thromboembolic vascular diseases in women taking oral contraceptives may be caused by the depletion of certain nutrients. The mechanism that is responsible for the deficiency of these nutrients can be explained by the effects that estrogen has on the body. Estrogen causes an increase in prostaglandin synthesis producing a systemic inflammatory response. In order to compensate for the inflammatory activity, the body recruits B-vitamins, which are water soluble and are stored for short periods in the vascular system. Since B-vitamins are only stored for short periods, they must be continuously replenished. The anti-inflammatory activity of B-vitamins helps to reduce the concentration of prostaglandins. However, this diverts the concentration of B-vitamins that can be used for other processes in the body especially the metabolism of other biochemical substances, which interferes with the ability of the gastrointestinal tract to absorb nutrients.

The depletion of B-vitamins from the body is further exacerbated by estrogen and progesterone metabolism in the liver. Vitamin B12 is stored in the liver and assists in the catabolic process of these hormones. The nutrients that are depleted by Ovral, Lo/Ovral and Low-Ogestrel (4) are magnesium, folic acid, vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B6 (pyridoxine), B12 (cobalamin) and C, tryptophan, tyrosine and zinc (4, 5). Interference of the absorption of these nutrients can alter physiologic processes in the body and can, in turn, reduce the function of certain organ systems. Although pharmaceutical companies are producing oral contraceptives with lower concentrations of estrogen and progesterone in an attempt to prevent complications and while the lower dosages may help to reduce the risk of developing chronic diseases, nutrient depletion and deficiency is still a major concern.

Biological Actions of Vitamins

Magnesium is essential for a wide variety of biologic processes in the body. It is used on the cellular level for the maintenance of the integrity and the electrical stability of the cell as well as assisting with nerve conduction. It also regulates glucose by enhancing the sensitivity of insulin GLUT4 receptors. Magnesium often works in combination with calcium to generate adenosinetriphosphate (ATP) for cellular energy and these minerals are also involved in the synthesis of proteins and nucleic acids. They are found in the bone matrix and promote the maintenance of healthy bones. Magnesium has earned the name of "nature's calcium channel blocker" due to its ability to regulate the flow of intracellular calcium. The regulation of calcium flow allows magnesium to influence muscular contraction and vasodilation (6). Magnesium is also a cofactor in homocysteine metabolism.

Folic acid is a member of the B-vitamin family. It is important for the synthesis and replication of DNA for tissue growth. It is necessary for the maintenance of the genome and gene expression. This vitamin is essential for RNA and protein synthesis. Another very important function of folic acid is the conversion of homocysteine to L-methionine. This process is vital for the formation of nucleic acids, phospholipids, epinephrine, melatonin, creatine and proteins, which are very important for the developing fetus and may be deficient in an individual taking oral contraceptives (6).

Vitamin B2 or riboflavin functions as a precursor for flavin compounds. The two most notable flavin compounds are flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). These compounds act as cofactors for flavoenzymes that are biologically available for several processes in the body. Important processes in which these cofactors are active in are oxidative phosphylation and the electron transport chain. Oxidative phosphylation and the electron transport chain contribute to energy production through the synthesis of ATP, which is responsible for increasing energy in the body and the formation of cytochrome complexes. Vitamin B2 also acts as a cofactor for the production of the antioxidant reduced glutathione and it indirectly functions to reduce plasma homocysteine levels (6).

The most common use of vitamin B3 or niacin is as an antihyperlipidemic agent. However, vitamin B3 is utilized in the body as a coenzyme and substrate known as nicotinamide adenine dinucleotide (NAD+) and its reduced form nicotiamide dinucleotide (NADH). These enzymes participate in redox reactions for the metabolism of stored carbohydrates, lipids and proteins. Thus this compound is used as a cofactor contributing to the metabolism of the intermediate byproducts of carbohydrates, lipids and proteins eventually leading to an increase in the production of ATP. Along with the metabolism of compounds, nicotinamide adenine dinucleotide phosphate (NADP+) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) are involved with the synthesis of fatty acids, cholesterol and steroids (6).

Other molecules that NAD+ synthesizes are involved with signal transduction. These signaling molecules are involved with mobilization of intracellular calcium. As a substrate, NAD+ transfers its ADP-ribose to proteins to create poly-ADP-ribose. This enzyme, whose function is not completely understood, is abundant in the nucleus and is believed to be involved with DNA repair, regulation of gene expression and maintaining the integrity of the genome. These processes are involved with cellular differentiation, replication and apoptosis (6). Vitamin B3 acts as an antioxidant by preserving glutathione in its reduced form (6).

Vitamin B6 or pyridoxine is used to describe a group of compounds that are B-vitamin derivatives. These compounds include pyridoxine, pyridoxal, pyridoxamine and their phosphorylated counterparts. Vitamin B6 is capable of forming a Schiff base, which is formed from the reaction of an aldehyde and amino group. Schiff bases are highly reactive and allows for vitamin B6 to participate as a coenzyme in a variety of different reactions. A majority of the enzymes are found in the metabolism of amino acids and glycogen. Vitamin B6 is essential for the synthesis of the blood forming elements. It acts as a coenzyme in the initial step of porphyrin synthesis including porphyrin IX, which is the precursor to the heme element of hemoglobin, myoglobin and cytochromes (6). Vitamin B6 also aids in the catabolism of homocysteine and is involved with the formation and regulation of epinephrine, norepinephrine, dopamine and serotonin. Vitamin B6 is used for is the synthesis of purine nucleotides and thymidylate for the production of DNA and RNA (6).

Vitamin B12 or cobalamin is a member of the B-vitamin family. There are four principal forms of cobalamin. The form that is found in nutritional supplements and food most often is known as cyanocobalamin. Vitamin B12 cooperates with folate in the synthesis of DNA and RNA and in maintaining the integrity of the genome (6).

With the assistance of other B-vitamins, vitamin B12 can be converted to coenzymes by the body to form two other biologically active compounds known as methylcobalamin and 5'deoxyadenosylcobalamin. These coenzymes in collaboration with folate participate in the metabolism of homocysteine. Vitamin B12 is also required for the metabolism of nutrients. Other functions of vitamin B12 are the synthesis of fatty acids, production of energy and maintenance of the integrity of the nervous system (6).

Vitamin C or ascorbic acid is a hexose molecule that structurally resembles glucose. In 1970, Linus Pauling described it as an essential nutrient. It has been referred to as the most important water-soluble antioxidant in the body. It may also have anti-hypertensive and anti-atherogenic effects. This vitamin is required for the formation of collagen fibers and other connective tissue components such as elastin, fibronectin, proteoglycans, the bone matrix and elastin-associated fibrillin (6). It is used for the biosynthesis of corticosteroids and aldosterone. It also functions in the conversion of cholesterol to bile acids. Vitamin C regulates iron absorption, storage and transport (6).

Tryptophan is an essential amino acid that is absorbed by the body and transported to the liver. In the liver, tryptophan is converted into nicotinic acid, which is used to form vitamin B3. Tryptophan can also be converted into other important neurotransmitters such as serotonin or melatonin. Serotonin is the precursor to melatonin. Melatonin is most notably responsible for regulating the circadian rhythm. Melatonin also acts as an antioxidant (3).

Tyrosine is also an amino acid that is used for the proper function of the endocrine and nervous system and as a regulator of metabolism. In the endocrine system, tyrosine interacts with the thyroid, pituitary and adrenal glands. Tyrosine is combined with iodine to form the thyroid hormones for the maintenance of the thyroid function. A role of tyrosine that affects the adrenals and the central nervous system is the use of this amino acid as a precursor for neurotransmitters (7).

Zinc is a mineral that is biologically active as a component of numerous metalloenzymes. These enzymes assist in the metabolism of nucleic acids, proteins and lipids for energy production. Structurally zinc fingers help to stabilize DNA, RNA, proteins and the plasma membrane. As a component of the cell membrane, zinc fingers promote extracellular communication. Zinc is required for growth, development, sexual maturation and reproduction. It promotes a healthy immune function, acts as an antioxidant and regulates insulin (6).


The use of magnesium as a potent vasodilator is seen in the treatment of migraines, HTN and CVD. Studies have shown that low levels of magnesium in the diet can increase blood pressure, which can eventually result in HTN (8). This is believed to be attributed to the ability of magnesium to regulate the flow of calcium by acting as a calcium channel blocker (8). As a calcium channel blocker, magnesium induces a vasodilatory effect, which can assist in lowering blood pressure by decreasing peripheral resistance. During HTN or a myocardial infarction, there is an increase in the peripheral resistance in the vasculature. Increasing the peripheral resistance requires an increase in the force of contraction of the cardiac musculature to ensure that a sufficient amount of blood is transported to the rest of the body, which contributes to the risk of developing CVD.

Other studies have shown that magnesium deficiency may be associated with diabetes (9). There have been reports of altered glucose tolerance resulting in insulin resistance and impairment of the secretion of insulin. There are several theories to explain the association between magnesium deficiency and diabetes, but no studies have confirmed the exact mechanism. There are two theories, which attempt to explain the relationship between the two. The first attributes poor glucose regulation to insufficient cofactor production resulting in inadequate oxidative phosphorylation, while the second theory states that there is an alteration in insulin receptor binding and signal transduction. The inability to control blood glucose levels increases the risk of developing atherosclerosis through the process of glycosylation of the hemoglobin. The extent of glycosylation can be measure by HBAlc levels. Levels that are above 7% are poorly controlled and increase the risk of damage to the vasculature and may progress to arteriosclerosis and CVD.

Magnesium and folic acid deficiency are associated with increased risk of CVA and CVD. The reason for the increased risk of CVA and CVD is because magnesium and folic acid are necessary for the reduction of homocysteine levels. Homocysteine acts as a free radical causing damage to the lining of the vasculature and cardiovascular system. This can be demonstrated through the conversion of the free radical homocysteine into L-methionine. Folic acid as well as vitamin B12 cooperate in this reaction. This is accomplished by 5-methyltetrahydrofolate transferring a methyl group to homocysteine. L-methionine is then converted into S-adenosyl-L-methionine or SAMe. SAMe is a potent antioxidant and methyl donor. A methyl donor helps to increase the metabolism of important neurotransmitters such as epinephrine and norepinephrine, which assists in maintaining cardiovascular function. It promotes emotional well being and has been used to reduce oxidative stress.

High amounts of oxidative stress in the body increase the release of cortisol by the adrenal glands. Overtime from chronic stimulation, the adrenal glands become fatigued and the body's ability to manage stress is reduced. The inability of the body to manage stress contributes to an immunocompromised state of the individual and the development of chronic diseases such as CVD and CVA. B-vitamins are sometimes referred to as stress B-vitamins due to their cardioprotective and adrenal enhancing activities during times of stress.

In a study performed in 2010 (10), they found that there was a positive correlation between high serum homocysteine levels and CVA. The proposed mechanism of action was that high levels of plasma homocysteine increased peripheral resistance narrowing the lumen of the arteries by causing an accumulation of phosphates, cholesterol and triglycerides to the area damaged by homocysteine. The lumen narrows further due to high levels of homocysteine increasing the adhesiveness of platelets, macrophages and white blood cells and contributing to oxidative stress leading to stenosis and occlusion of the internal carotid artery.

This proposed mechanism of action can also explain the increase in CVD that is observed in patients with high plasma homocysteine levels. High plasma homocysteine levels increase the peripheral resistance and narrow the lumen of the arteries, which contributes to damage to the endothelial cells and the formation of platelet plugs. Over time, this can lead to atherosclerosis, arteriosclerosis and the progression to CVD as previously described.

Several studies have shown that supplementing with up to 250 mcg of folic acid can significantly reduce the levels of homocysteine (11). Other studies showed that 200 mcg of folic acid a day reduce the levels of low-density lipoproteins in the blood, which may positively correlate with a reduction in atherosclerosis leading to a reduced the risk of CVD and CVA (12). A study published in November of 2010, evaluated the effects of folic acid in CVD. It concluded that supplementation with folic acid for two years reduced the risk of CVD by 15% and homocysteine levels by 20% without increasing the dosage (13).

Another important vitamin to reduce the risk of CVD and CVA is vitamin B2. Clinically, vitamin B2 is used as a result of its antioxidant activity and metabolic enhancement of biochemical processes and pathways by acting as a cofactor for reduced glutathione and as a precursor for FAD. Reduced glutathione is an important cofactor for the selenium-containing enzyme glutathione peroxidase, which has antioxidant properties. Decreasing the levels of reduced glutathione leads to a reduction in the activity of glutathione peroxidase, which allows more oxidative damage to occur and causes an increase in lipid peroxidation increasing the concentration of oxidized plasma low-density lipoproteins. This contributes to the development of CVD and CVA.

Other enzymes that utilize vitamin B2 that may be compromised by the use of oral contraceptives are NADPH-cytocrhome P450 reductase and NADPH-cytochrome b reductsae. This can be attributed to the role of vitamin B2 in cellular respiration. In cellular respiration, cofactors of vitamin B2 accept hydrogen ions in the mitochondrial electron transport chain and convey them to the cytochrome system. These enzymes are active in liver detoxification and helps protect the body from oxidative damage. Deficiency in these enzymes can result in the oxidation of the hemeproteins. The oxidation of hemeproteins is responsible for ischemic reperfusion injuries of the brain resulting in transient ischemic attacks or mini-strokes. Vitamin B2 significantly decreases the amounts of oxidative hemeproteins allowing for a higher oxygen carrying capacity.

Studies have shown that deficiency of vitamin B2 is associated with hyperhomocysteinemia. One study found that the group with the lowest dosage of vitamin B2, (1.4 micromol/L) increased the plasma homocysteine levels (14). This may be due to the fact that vitamin B2 helps to metabolize vitamin B6 and B12 and folic acid. FAD and FMN act as cofactors for the metabolism of these vitamins. By assisting in the metabolism of these vitamins, vitamin B2 indirectly assists in the metabolism of homocysteine reducing the risk of CVD and CVA.

The major effects that are observed due to the deficiency of vitamin B3 by oral contraceptives that contribute to CVD and CVA are an increase in hyperlipidemic and oxidative activity contributing to oxidative stress. Vitamin B3 increases the levels of high-density lipoprotein (HDL) while reducing total cholesterol, low-density lipoproteins (LDL), very low-density lipoprotein (VLDL) and triglycerides (6). HDL cholesterol is synthesized in the liver and excreted into the vasculature, where in a reverse transport system they attract to free fatty acids, triglycerides and LDL and VLDL cholesterol. After extracting these compounds from the cell, HDL is converted into HDL3, which transports the above mentioned fatty acid structures to the liver for degradation and excretion from the body and/or reuse through the cholesterol synthesis mechanism. This reduces the risk of arterial damage. VLDLs are synthesized by the liver and released into circulation. In the vasculature, VLDLs are converted into LDL cholesterol, which is stored in the cell as unesterified cholesterol. Unesterfied cholesterol contributes to the risk of arterial damage and the development of atherosclerosis. The LDL cholesterol may contribute to atherosclerosis by binding at the site of free radical damage in the intima lining of the arteries (15).

There are two hypotheses to explain the mechanism of action. The first claims that vitamin B3 lowers the amount of free fatty acids that are released from adipose tissue, which reduces the number of free fatty acids that enter the liver. This leads to a reduction in hepatic reesterification activity and lowers the concentration of VLDLs in the blood. The second hypothesis involves apolipoprotein B-100, which is the protein carrier of LDLs. Vitamin B3 is believed to inhibit the synthesis or secretion of this substance by the liver. Studies have found a positive correlation between the antihyperlipidemic activity of vitamin B3 and a significant reduction in the risk of CVD and CVA (16).

Another vitamin that is affected by oral contraceptive medication is vitamin B6. A review article written by Miller, stated that studies have shown that oral contraceptive medications reduce the level of vitamin B6 in the body. The review of the studies performed by Roepke and Kirksey found that women that became pregnant after long-term use of oral contraceptives had significantly lower concentrations of vitamin B6, when compared with women that didn't utilize oral contraceptives or only took them for a short period. However, this study also demonstrated that the concentration of vitamin B6 in the breast milk during lactation was reduced in both short and long term women compared to women that had never used oral contraceptives, which resulted in a lower concentration of infant vitamin B6 levels. These studies suggest a need for vitamin B6 supplementation in women that are taking oral contraceptives even after administration of the drug has ceased (17).

A deficiency of vitamin B6 also plays are role in cardiovascular health. Although vitamin B6 may not be as important as folic acid or vitamin B12, it does help to regulate homocysteine metabolism and prevent hyperhomocysteinemia. There are two enzymes that are required for the conversion of homocysteine to L-cysteine. Both of the enzymes are dependent on pyridoxal 5'-phosphate activity to perform their function. The negative effects of hyperhomocysteinemia have been mentioned previously.

Another positive effect of vitamin B6 is the prevention of atherosclerosis and CVD. This is accomplished through a variety of the functions of vitamin B6. The first function of this vitamin is the regulation of blood pressure. Vitamin B6 has the ability to lower both systolic and diastolic blood pressure in hypertensive patients by reducing peripheral resistance (6). This mechanism involves the conversion of arginine into nitric oxide, which is a potent vasodilator (18). This mechanism is attenuated in the absence of vitamin B6 resulting in an increase in blood pressure. The second function is the regulation of cholesterol. Vitamin B6 lowers total cholesterol and raises HDL. This is accomplished by its ability to prevent the degradation of tryptophan (19).

Studies indicate that the use of oral contraceptives alter tryptophan metabolism (5). As previously mentioned, tryptophan has anti-atherogenic and antioxidant activities and is active in serotonin synthesis, which can reduce the risk of developing CVD and CVA. Although the mechanism is unknown, evidence suggests that supplementation with vitamin B6 spares tryptophan from degradation during administration of oral contraceptives containing progesterone. This can be explained by progesterones ability to increase the activity of tryptophan pyrrolase. Tryptophan pyrrolase catabolizes tryptophan causing a reduction in the total levels of serum, albumin and liver tryptophan.

The third function of vitamin B6 is the inhibition of epinephrine-induced platelet aggregation. During periods of stress, the sympathetic nervous system induces the secretion of epinephrine and norepinephrine. These hormones increase blood flow resulting in an elevation of the blood pressure. Elevated blood pressure for prolonged periods increases the amount of peripheral resistance and the potential for arterial damage. Vitamin B6 has the ability to adjust the amounts of these hormones by acting as cofactors in their metabolism. Therefore, epinephrine and norepinephrine undergo a decarboxylation reaction dependent upon vitamin B6, which is a cofactor for pyridoxal 5'-phosphate enzymes. These enzymes possess the ability to downregulate steroid activity by interacting with the glucocorticoid recaptors, which helps prevent an elevation in blood pressure for prolonged periods of time (6).

Studies have shown that vitamin B6 protects vascular endothelial cells from damage by platelets and oxidative stress (20). A possible explanation of this is the ability of vitamin B6 to maintain the integrity of the cell. This reduces the damage to the endothelial cells by limiting the amount of cholesterol and platelets that can aggregate. This minimizes the damage to the vasculature and effectively reduces the risk of atherosclerosis.

A deficiency of vitamin B12 can also contribute to the development of CVD or CVA. Reductions in vitamin B12 as well as folic acid can lead to artherosclerosis and CVD or CVA in two separate ways. The first way occurs through the formation of dysfunctional erythrocytes. The second mechanism involves the conversion of methionine to homocysteine in the absence of vitamin B12 and folic acid leading to endothelial dysfunction.

A deficiency of either vitamin B12 or folic acid can inhibit the formation of DNA resulting in pernicious anemia. However, a deficiency in vitamin B12 alone leads to a reduction in the concentration of tetrahydrofolate (THF). A lower concentration of THF reduces the amount of methionine and SAMe produced, leading to a lower amount of nucleotide base pairs for the formation of DNA. In erythrocytes and leukocytes, this results in a failure of maturation of the cells due to a reduction in DNA replication and cellular division. In erythrocytes, unsuccessful cellular division causes the cells to be macrocytic and hyperchromic, while the nucleus of the leukocytes increases the number of lobes becoming hypersegmented and dysfunctional.

Reduction in the maturation of erythrocytes reduces the number of cells that are capable of transporting oxygen rich blood to the tissues. In order to prevent an ischemic event, the cardiac musculature must increase the force of contraction. Maintaining the force of contraction at higher than normal intensities for prolonged periods of time can lead to hypertrophy of the cardiac musculature and progress to arteriosclerosis or CVD. Studies have found a positive correlation between pernicious anemia and the development of CVD or occurrence of a CVA (21).

Vitamin B12 further demonstrates its cardioprotective function by assisting with the metabolism of homocysteine. As previously mentioned, homocysteine increases peripheral resistance and contributes to atherosclerosis. In homocysteine metabolism, the coenzymes of vitamin B12 and folic acid contribute to the synthesis of methionine synthase, which is required for the conversion of homocysteine to methionine. A deficiency in vitamin B12, therefore, contributes to elevated levels of homocysteine and an increased risk of CVD. However, it must be noted that a deficiency in vitamin B12 induces a reduction in THF, which further contributes to elevated levels of homocysteine in the body. It is important to screen for both vitamin B12 and folic acid deficiency, since folic acid can mask a vitamin B12 deficiency.

Although symbiotic microflora in the gastrointestinal tract synthesizes and secretes vitamin B12 (22), the amount necessary to overcome the effects of the oral contraceptive induced vitamin B12 deficiency is insufficient. Vitamin B12 is necessary to ensure the degradation of carbohydrates, proteins and fats. Reducing the amount of vitamin B12 interferes with the absorption of these nutrients. This can contribute to further deprivation of the body of essential vitamins and minerals negatively impacting a wide variety of biological processes. The impairment of the biological processes can potentially reduce the function of organs and organ systems increasing the risk of developing a multitude of chronic diseases including CVD.

The depletion of vitamin C by oral contraceptives increases the risk of CVD or CVA. As previously mentioned, vitamin C is required for the formation of collagen. Vitamin C acts as a cofactor for prolyl and lysl hydroxylase. These enzymes synthesize hydroxylproline and hydroxylysine, which are components found in collagen23. A vitamin C deficiency impairs the formation of collagen resulting in fragility of the tissues that collagen composes. This can result in the endothelial wall of vasculature becoming compromised leading to atherosclerosis.

Oxidation of low density lipoproteins and platelet aggregation are key components in the development of atherosclerosis. As an antioxidant, vitamin C scavenges both reactive oxygen and nitrogen compounds thereby preventing tissue damage, which prevents oxidative damage to lipids, DNA and protein. Some studies report that vitamin C may even raise HDL cholesterol (24) as well as a reducing platelet aggregation (25). The ability of vitamin C to preserve and restore alpha-tocopherol levels further illustrates its cardioprotective activity (6). Alpha-tocopherol, a component of vitamin E, possesses anti-atherogenic effects by aiding in the absorption of lipids and reducing cholesterol and triglycerides as well as being an antioxidant against peroxides.

Another way vitamin C helps to prevent CVD is through the regulation of prostaglandin synthesis. This is accomplished by promoting and inhibiting the production of eicosanoids. Vitamin C promotes the production of prostaglandin 1 (PGE1), which has some anti-inflammatory potential (6) and inhibits platelet aggregation. At the same time, it inhibits the synthesis of prostaglandin 2 (PGE2), which is a proinflammatory prostaglandin (26).

A deficiency of vitamin C due to the administration of oral contraceptives can result in a reduction in the amount of PGE1 and an elevation of PGE2. Both of these actions contribute to systemic inflammation, increased incidence of platelet aggregation and clot formation and an increased risk of CVA and CVD. The vasodilatory effects of PGE1 assist in lowering blood pressure and preventing hypercholesterolemia and congestive heart failure.

The antioxidant effects of vitamin C are demonstrated through the preservation of reduced glutathione in the cells. Sparing glutathione helps to promote the synthesis and maintenance of adequate levels of nitric oxide. Nitric oxide helps to vasodilate the vasculature. This promotes the function of the endothelial cells in the blood vessels and reduces the peripheral resistance. Studies show that individuals with low levels of vitamin C are more susceptible to hypertension and CVD and have an increased risk of CVA. In a double blind controlled trial on three groups of hypertensive patients receiving 500 mg, 1,000 mg and 2,000 mg of vitamin C for 8 months, each of the groups experienced a 4.5 mmhg reduction in systolic and a 1.5 mmhg reduction in diastolic blood pressure. The effects were observed one month after administration without an additional reduction in blood pressure. However, the lower blood pressure was maintained for the entire 8 month period (27).

Another consideration relative to the deficiency of vitamin C is the activity of this vitamin in iron absorption, transport and storage. Vitamin C accomplishes this by reducing ferric to ferrous iron (6). Iron is incorporated into erythrocytes, where it binds to oxygen. Deficiency of vitamin C can disrupt this process leading to iron deficiency anemia. Lower levels of iron in hemoglobin lower the number of oxygen molecules that can be transported in the vasculature, which increases the incidence of hypoxia. Hypoxia causes oxygen deprivation in the tissue leading to a reduction in the synthesis of ATP and contraction of the cardiac mechanism. This results in a decrease in the force of contraction of the cardiac musculature. A decrease in the force of contraction can result in hypertrophy of the cardiac muscle by increasing the rate of contraction to compensate for the low levels of oxygen in the brain. Over time this can lead to congestive heart failure (28).

Tryptophan deficiency has been linked to anxiety, depression, obesity and CVD (3). This can be explained by its ability to be converted into a variety of different substances that are used for different physiological processes. One process that is disrupted is the regulation of cholesterol. Tryptophan is the precursor to vitamin B3. Therefore, a deficiency of tryptophan reduces the amount of vitamin B3 synthesized. Consequently, administration of oral contraceptives already lowers the levels of vitamin B3, so a deficiency in tryptophan further reduces the amount of vitamin B3 available. The various negative effects associated with vitamin B3 deficiency and the development of CVD and CVA has been previously discussed.

Another important consideration is the indirect role of tryptophan in the prevention of oxidative stress. A deficiency of tryptophan can reduce the amount of serotonin that is synthesized. Tryptophan is metabolized into 5-hydroxytryptophan (5-HTP), which is metabolized into serotonin. A reduction in the levels of serotonin has been linked to anxiety and depression3. Anxious and depressive states can lead to end organ dysfunction as the result of the release of corticosteroids during stress. This has the potential to increase the level of oxidative stress on the body. An increase in oxidative stress may lead to a variety of health care conditions such as weight gain, insomnia, sedentary lifestyle and fatigue3. Many of the previously described conditions have been associated with the development of atherosclerosis and the progression to CVD or CVA.

There is also a positive correlation between low levels of serotonin in the body and weight gain in the absence of depression (3). Evidence suggests that the brain interprets low levels of serotonin as a hypoglycemic state (3). This stimulates the hypothalamus producing a craving for carbohydrates. The craving for carbohydrates can result in binge eating, which may contribute to the development of obesity or bulimia. Both obesity and bulimia have been associated with the development of CVD.

A tryptophan deficiency interferes with the synthesis of melatonin. After serotonin is synthesized, it is converted to melatonin. Low levels of melatonin can cause a disturbance of the circadian rhythm. The circadian rhythm is regulated by the suprachiasmatic nucleus (SCN) in the hypothalamus. The SCN is a 24 hour clock that responds to changes in light and dark cycles using information transmitted by the optic nerve. Periods of natural light stimulate the SCN to activate the sympathetic nervous system to produce norepinephrine and epinephrine to promote wakefulness. Periods of darkness stimulate the pineal gland to synthesize and secrete melatonin (6).

Proper regulation of the circadian rhythm is essential to allow for an adequate amount of sleep. Melatonin acts as a suppressant to the sympathetic nervous system allowing for stage 3 and 4 sleep to occur (3). Individuals with low levels of serotonin and melatonin have an increase in sympathetic activity, which increases the amount of epinephrine and norepinephrine in the body. Higher levels of these neurotransmitters not only interfere with achieving restful sleep, but they promote the absorption of LDL cholesterol into the vasculature contributing to arterial damage and the development of atherosclerosis (3). Another positive effect of melatonin is the inhibition of platelet aggregation3. The inability to inhibit platelet aggregation increases the risk of atherosclerosis, CVD and CVA.

Another important factor is that a low level of melatonin significantly increases oxidative stress on the body. This occurs by two different mechanisms. The first mechanism is the disruption of the sleep-wake cycles resulting in difficulty initiating sleep and the possibility of insomnia. Lack of sleep or insomnia prevents the stage 3 and 4 sleep that is necessary to rejuvenate our physical and mental state and regenerate the different tissues in the body. Failure to achieve restful sleep can increase oxidative stress on our bodies. The second mechanism is the interference with the antioxidant effect of melatonin, which has been previously linked to CVD and CVA.

Another amino acid deficiency that may contribute to the development of CVD or CVA is tyrosine. A deficiency of tyrosine interferes with a variety of systems in the body. The endocrine system is one of the primary systems affected. In the endocrine system, a tyrosine deficiency has the potential to reduce the effectiveness of the thyroid and the adrenal glands function. The thyroid gland affects every cell in the body to promote homeostasis. Low levels of tyrosine are positively correlated with hypothyroidism (29). As previously mentioned, this is due to the fact that tyrosine is incorporated into the formation of thyroid hormones such as thyroxine (T4). Low levels of thyroid hormones slow down the metabolism of proteins, carbohydrates and fats. This results in an increase in circulating cholesterol and triglycerides concentrations, which as previously noted is related to CVD and CVA. Other conditions associated with a reduced metabolism from hypothyroidism that can contribute to CVD and CVA are weight gain, fatigue and depression (27).

As previously mentioned, tyrosine is a precursor for neurotransmitters. A deficiency interferes with the production of neurotransmitters, which can alter the adrenal function as well as the activity of the nervous system. The neurotransmitters that are produced from tyrosine are norepinephrine, epinephrine and dopamine. Norepinephrine and epinephrine are also known as noradrenaline and adrenaline. During periods of stress, the adrenal glands are activated by the sympathetic nervous system, which is an extension of the autonomic nervous system. Stress induces the adrenal glands to increase the secretion of cortisol from the adrenal cortex and the release of noradrenaline and adrenaline from the adrenal medulla. These neurotransmitters help our bodies to cope with stress.

A deficiency of tyrosine lowers the amount of norepinephrine and epinephrine available to the adrenal gland for secretion reducing our ability to respond to stressful situations. The inability to cope with stress leads to psychosocial and behavioral consequences (3). Norepinephrine is also associated with regulating a person's disposition, which can result in mood alterations and the possibility of developing depression, which further contributes to an increase risk of CVD and CVA (3).

Tyrosine also plays a role in the regulation of the metabolism. This is accomplished by tyrosine being converted into norepinephrine, which acts as an appetite suppressant (29). Reducing the appetite can help prevent individuals from overindulging and consuming excess amounts of carbohydrates and fats that will be stored as adipose tissue. Impairment of this function leads to an increase in appetite and potential weight gain contributing to obesity, atherosclerosis and an increased risk of developing CVD and CVA.

Evidence suggests that zinc deficiency is positively correlated with CVD (30). This may be due to the fact that zinc fingers are involved in the maintenance of the integrity of proteins and the plasma membrane. Zinc fingers are proteins that incorporate zinc ions into their structure to stabilize their folds. These proteins are structural components of DNA, RNA and other amino acids, which act as cofactors to mediate biochemical reactions responsible for activating or inactivating genes (23).

Studies show that zinc fingers mediate protein-lipid interactions (30). Impairment of protein-lipid interactions results in a cascade of adverse reactions. This impairment alters the transportation of LDLs. The altered transportation of LDLs disrupts lipid metabolism in the liver resulting in a subsequent increase in circulatory LDLs, total cholesterol and circulating triglycerides and may lead to a higher tendency for dietary lipids to be converted into LDLs as opposed to HDLs. The effects of elevated levels of cholesterol, CVD and CVA have been previously noted.

Another positive correlation is found with zinc deficiency and diabetes (3l). Studies have shown that zinc is involved with synthesis, storage and secretion of insulin (31). It has also been found to assist in the maintenance of the integrity of the conformational shape of insulin. Therefore, deficiencies of zinc can contribute to the inability to produce insulin resulting in Type I diabetes. Impairment of zinc related cellular receptors can cause a disruption of cellular signaling (30). This has the potential to induce insulin resistance resulting in hyperglycemia. Prolonged periods of a hyperglycemic state can contribute to weight gain, obesity and the potential development of Type II diabetes, which are all predisposing factors to CVD and CVA.

The immune boosting potential and antioxidant effects of zinc are found to reduce the levels of oxidative stress. Zinc promotes T-lymphocyte, natural killer cells, macrophage and neutrophil activity as well as the production of antibodies (6). Zinc deficiency may compromise the immune system function and increase the susceptibility to infection. Chronic diseases associated with infections can lead to an overall attenuation of the immunes system, which can contribute to oxidative stress. This oxidative stress resulting from chronic debilitation further compromises the immune system and cardiovascular function through endothelial dysfunction increasing the risk of CVD (18).

The antioxidant action of zinc can largely be demonstrated through lipid metabolism. Evidence has shown that an alteration of LDL metabolism and an increase in LDL concentration results in a higher level of lipid oxidation (33). A higher level of lipid oxidation increases the levels of oxidative stress in the body increasing the risk of CVD and CVA.


Oral contraceptives are very useful pharmaceutical products to prevent fertilization of the ovum as well as to regulate the menstrual cycle. However, it should be noted that these contraceptive agents can deplete essential vitamins and nutrients that the body requires for normal functioning. Discontinuation of oral contraceptives for the purpose of becoming pregnant or for various other reasons may result in devastating effects to the fetus due to the previously mentioned deficiencies. Deficiency or depletion of these vitamins can result in an increased risk CVD and CVA. These cardiovascular events may be due to the long-term depletion of these vitamins and nutrients as well as the negative effects on metabolism of proteins, carbo-hydrates and fats due to the deficiency and lack of function of their cofactors. These deficiencies may further complicate cardiovascular events that may have occurred prior to administration of oral contraceptives. These authors suggest supplementation of these nutrients may be important both during and following oral contraceptives treatment. Choosing the appropriate product, dosage and route of administration is important, since deficiencies can be overcome with proper supplementation.


(1) Hitner, Henry. Nagle, Barbara. Pharmacology An Introduction. New York: McGraw-Hill, 2005. 428-430, 435-437

(2) Zhang, Y. Nutrition, Metabolism and Cardiovascular Disease. Cardiovascular Diseases in American Women. June 2009. Vol. 20(6): 386-393

(3) Murray, Michael. Pizzorno, Joseph. Textbook of Natural Medicine. St. Louis: Churchill Livingstone Elsevier, 2006. 1021-1029, 1057-1062, 1429, 1573, 1953

(4) Fox, Barry. Vagnini, Frederic. Life Extension. Preventing Pharmaceutical-Induced Nutritional Deficiencies. March 2006.

(5) Bano, S. Saeed, S. Journal of College Physicians and Surgeons Pakistan. Inhibition of Tyrptophan Pyrrolase Activity in Restraint Female Rats following Medroxyprogesteron Administration. February 2007. Volume 17(2):63-8

(6) Physician Desk Reference. Montvale: Medical Economics Thomson Healthcare, 2001. 157-161, 288-291, 318-323, 401-404, 469-474, 477-483, 486-491, 534-537

(7) Balch, Phyllis. Prescription for Nutritional Healing. New York: Avery a Member of Penguin Group, 2000. 51-52

(8) Altura, BM. Altura BT. Alcohol Clin Exp Res. Role of Magnesium and Calcium in Alcohol-induced Hypertenstion and Strokes as Probed by in vivo television microscopy, digital image microscopy, optical spectroscopy, 31P-NMR, spectroscopy and a unique magnesium ion-selective electrode. 1994. Vol 18:1057

(9) Folsom, AR. Kao, WHL. Nieto, J. Arch. Int Med. Serum and Dietary Magnesium and the Risk for Type 2 Diabetes Mellitus (editorial). 1999. 159:2151-2159

(10) da Chunha, AA. da Chunha, MJ. Kolling, J. Scherer, EB. Wyse, AT. Cardiovascular Toxicology. Homocysteine Induces Oxidative-Nitrative Stress in Heart of Rats: Prevention by Folic Acid. 2010. Epub ahead of print.

(11) Aarsand, AK. Carlsen, SM. Journal of Internal Medicine. Folate Administration Reduces Circulating Homocysteine Levels in NIDDM patients on Longterm Metformin Treatment. 1998. Vol. 244:169-174

(12) Boushey, CJ. Beresford, SA. Motulsky, AG. Omenn, GS. JAMA. A Quantitative Assessment of Plasma Homocysteine as a Risk Factor for Vascular Disease. Probable Benefits of Increasing Folic Acid Intake. 1995. Vol. 274:1049-1057

(13) Chen, Y. Huo, Y, Langman, CB. Matossian, Du. Qin, X. Wang, X. Xu, X. Clinical Journal of the American Society of Nephrology. Folic Acid Therapy and Cardiovascular Disease in ESRD or Advanced Chronic Kidney Disease: A Meta-Analysis. November 2010.

(14) Hustad, S. Ueland, PM. Vollset, SE. Clinical Chemistry. Riboflavin as a Determinant of Plasma Total Homocysteine: Effect Modifiation by Methylenetetrahydrofolate Reductase C677T Polymorphism. 2000. Vol. 468:1065-1071

(15) Ovine, P.T. European Heart Journal. Atheroma Formation: Defective Control in the Intimal Round-Trip of Cholesterol. 1990. Vol. 11:238-246

(16) Chapman, MJ. Giral, P. McGovern, ME. Redfern, JS. Pharmacology and Therapeutics. Niacin and Fibrates in Atherogenic Dyslipidemia: Pharmacotherapy to Reduce Cardiovascular Disease. June 2010. Vol. 126 (6): 314-345

(17) Miller, Lorraine. Journal of Clinical Nutrition. Do Oral Contraceptive Agents Affect Nutrient Requirements-Vitamin B-6?. 1986. Vol. 116:1344-1345

(18) Flechas, Jorge. The Original Internist. Endothelial Dysfunction, an Endocrine Metabolic Disorder. 2011.

(19) Al-Sayegh, A. Ebadi, M. Gessert, CF. Q Rev Drug Metab Drug Interact. Drug-Pyridoxal Phosphate Interactions. 1982. Vol. 4:289-331

(20) Chang, SJ. Nutrition Research. Vitamin B6 Protects Vascular Endothelial Injury by Activated Platelets. 1999. Vol. 19:1613-1624

(21) Eikelboom, John. Lonn, Eva. Yusuf, Salim. Annals of Internal Medicine. Homocysteine and Cardiovascular Disease. 2004. 132:676

(22) Lehne, Richard. Pharmacology for Nursing Care. St. Louis: Elsevier Saunders, 2004. 579

(23) Berg, Jeremy. Stryer, Lubert. Tymoczko, John. Biochemistry. W.H. Freeman and Company, 2002. 217-218,880-881

(24) Bingham, S. Day, NE. Khaw, KT. Ness, AR. European Journal of Clinical Nutrition. Vitamin C Status and Serum Lipids. 1996. Vol. 50:724-729

(25) Cockcroft, JR. MacCallum, H. Megson, IL. Journal of Cardiovascular Pharmacology. Oral Vitamin C Reduces Arterial Stiffness and Platelet Aggregation in Humans. 1999. Vol. 34:690-693

(26) Akundi, Ravi. Appel, Kurt. Candelario-Jalil, Eduardo. Journal of Neuroimmunology. Ascorbic Acid Enhances the Inhibitory Effect of Aspirin on Neuronal Cyclooxygenase-2-Mediated Prostaglandin E2 Production. 2006. Vol. 174(l-2):39-51

(27) George, V. Hajjar, IM. Kochar, MS. American Journal of Therapeutics. A Randomized, Double-Blind, Controlled Trial of Vitamin C in the Management of Hypertension and Lipids. 2002. Vol. 9:289-293

(28) Gayomali, Charina. Hegde, Nikita. Rich, Michael. Texas Heart Institute Journal. The Cardiomyopathy of Iron Deficiency. 2006. Vol. 33(3):340-344

(29) Murray, Michael. Pizzorno, Joseph. Encyclopedia of Natural Medicine. Rocklin: Prima Health, 1998. 394-395, 558-561

(30) Bruemmer, Dennis. Daugherty, Alan. Hennig, Bernhard. MacDonald, Ruth. Shen, Huiyun. Stromberg, Arnold. Toborek, Michal. The Journal of Nutrition. Zinc deficiency alters lipid metabolism in LDL receptor deficient mice treated with rosiglitazone. November 2007. Vol. 137: 2339-2345

(31) Chausmer, Arthur. Journal of the American College of Nutrition. Zinc, Insulin and Diabetes. 1998. Vol. 17 (2): 109-115

(32) Bodiga, S. Krishnapillai, MN. World Journal of Gastroenterology. Concurrent Repletion of Iron and Zinc Reduces Intestinal Oxidative Damage in Iron and Zinc Deficient Rats. 2007. Vol. 13(43):5707-5717

by: Brett R. Martin DC and Daniel L. Richardson Ms, PhD, DAANC
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Date:Jun 1, 2011
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