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Oral Contraceptives
Monophasic, Biphasic, and Triphasic Preparations


Oral contraceptives (OCs) reduce serum magnesium levels by shifting circulating magnesium from serum to tissues (Olatunbosun et al. 1974; Seelig 1990; Seelig 1993; Stanton and Lowenstein 1987). This may deplete magnesium levels and increase dietary requirements.

Significance of Depletion

Magnesium deficiency affects calcium and vitamin D metabolism and is primarily associated with hypocalcemia (Cashman and Flynn 1999). Clinically, neuromuscular hyperexcitability may be the first symptom manifested in patients with hypomagnesemia (reflected in a serum concentration of 17 mg/L or less). Recent evidence supports a possible connection between chronically low magnesium levels and various illnesses such as cardiovascular disease, hypertension, diabetes, and osteoporosis.

Replacement Therapy

The current recommended dietary allowance (RDA) for magnesium ranges from 30 to 420 mg/day, depending upon age and gender (Cashman and Flynn 1999). For replacement therapy, doses should be tailored to the patient's clinical condition, taking into account serum magnesium levels, dietary habits, and medication regimen.

Vitamin B2 (Riboflavin)

Oral contraceptives interfere with riboflavin metabolism and may cause deficiency in women with already compromised riboflavin status (Ahmed et al. 1975; Matsui and Rozovski 1982; Newman et al. 1978; Webb 1980).

Significance of Depletion

Riboflavin deficiency usually occurs as a result of deficiencies in dietary protein and is associated with other B vitamin deficiencies (Covington 1999). Depleted levels of riboflavin affect carbohydrate and amino acid metabolism by interfering with enzyme systems involved in the production of ATP. Lack of an adequate supply of riboflavin disturbs several physiological and biochemical processes and results in retarded growth in infants and children (Covington 1999; Powers 1999). Symptoms include corneal vascularization, glossitis, cheilosis, seborrheic dermatitis, and impaired wound healing (Covington 1999).

Replacement Therapy

Doses of 5 to 25 mg/day are recommended for the treatment of riboflavin deficiency (Covington 1999). For replacement therapy, doses should be based upon the patient's individual needs, considering the clinical presentation, serum riboflavin levels, age, gender, dietary habits, and medication regimen.

Vitamin B6 (Pyridoxine)

Oral contraceptives deplete vitamin B6 levels, possibly through induction of tryptophan oxidase (Bermond 1982; Prasad et al. 1976; Slap 1981). Side effects such as depression may be due to altered metabolism of vitamin B6, folate, and B12 (Kane 1976).

Significance of Depletion

Usually, vitamin B6 deficiency is accompanied by depletions of other B vitamins (National Research Council 1989). Signs and symptoms of low levels of this vitamin include epileptiform convulsions with abnormal EEG findings, dermatitis, anemia, weakness, mental confusion, irritability, nervousness, insomnia, and abnormal tryptophan metabolism (Covington 1999; National Research Council 1989; Wilson 1998). Depleted levels may increase the risk of colon and prostate cancers, heart disease, brain dysfunction, and birth defects (Ames 2000).

Replacement Therapy

In one study, vitamin B6 supplements (150 mg/day) reduced the severity of headache and dizziness but had no effect on nausea, vomiting, depression, or irritability (Villegas-Salas et al. 1997). Other researchers have also reported clinical improvement with doses of 40 mg/day of vitamin B6 (Bermond 1982). Neuropathology resulting from vitamin B6 deficiency should be treated with doses of 50 to 200 mg/day (Covington 1999). Dietary deficiency usually responds to doses of 10 to 20 mg/day. Doses should be tailored to account for the patient's age, gender, clinical presentation, serum vitamin B6 levels, dietary habits, and medication regimen.

Vitamin B9 (Folic Acid)

Oral contraceptives can lower serum folate levels and reduce folate stores in the body (Li et al. 1995; Prasad et al. 1976; Shojania 1982). However, a recent study with 229 adolescent females on OCs (age 14 to 20 years) reported that oral contraceptive use was not associated with significantly lower serum or RBC folate levels (Green et al. 1998).

Significance of Depletion

Women who stop taking oral contraceptives to conceive should be assessed to ensure they have adequate folate stores before becoming pregnant (Shojania 1982). Low levels of folate have been linked to colon cancer, heart disease, cognitive deficits, and birth defects, specifically neural tube defects (Ames 2000; Covington 1999). Deficiency increases chromosome breakage and elevates serum homocysteine. Vitamin B9 deficiency may also lead to megaloblastic anemia.

Replacement Therapy

The recommended dietary allowance (RDA) for adults is 300 to 600 mcg/day (Covington 1999). However, recommendations of doses of folic acid as high as 2000 mcg/day have been reported in the literature (Mayer et al. 1996). For replacement therapy, doses should be based upon the patient's individual needs, considering the clinical presentation, serum folate levels, age, gender, dietary habits, and medication regimen.

Vitamin B12 (Cobalamin)

Studies have shown that oral contraceptives have either a minor impact or no impact on serum vitamin B12 levels; it is probably not significant enough to cause a deficiency (Kornberg et al. 1989; Seelig 1990; Shojania 1982). Several studies have found no significant effect of OCs on vitamin B12 status (Hjelt et al. 1985; Prasad et al. 1976).

Significance of Depletion

Symptomatic vitamin B12 deficiency is rare because complications may appear only after the deficiency has existed for 10 to 15 years (Berger 1985; Carpentier et al. 1976). Low vitamin B12 levels could increase the risk of colon cancer, heart disease, brain dysfunction, birth defects, and irreversible neuropathy (Ames 2000; Covington 1999). Irritability, weakness, numbness, fatigue, glossitis, anorexia, headache, palpitations, and altered mental status, including personality and behavioral changes, are some of the signs and symptoms of vitamin B12 depletion (Covington 1999). Prolonged deficiency leads to pernicious or megaloblastic anemia that may be associated with leukopenia and thrombocytopenia.

Replacement Therapy

Doses of 25 to 250 mcg/day of vitamin B12 have been used to correct nutritional deficiency (Covington 1999). Oral doses between 500 to 1000 mcg/day have been recommended for the treatment of pernicious anemia (Carmel 2000). Replacement therapy should be based on the patient's individual needs, considering the clinical presentation, serum B12 levels, age, gender, dietary habits, and medication regimen.

Vitamin C (Ascorbic Acid)

Oral contraceptives reduce plasma, leukocyte, and platelet ascorbic acid levels (Nash et al. 1979; Rivers 1975; Webb 1980). This reduction may be due to increased ascorbic acid turnover in tissues (Weininger and King 1982).

Significance of Depletion

Patients with depleted levels of vitamin C may present with anemia, icterus, edema, lethargy, fatigue, fever, ecchymoses, hypotension, convulsions, gum disorders, tooth loss, emotional changes, and perifollicular hyperkeratotic papules (Carr and Frei 1999; Covington 1999; National Research Council 1989; Wilson 1998). In addition, they may exhibit signs of poor wound healing, increased susceptibility to infection, and markedly defective collagen synthesis. Severe deficiency results in scurvy, which is potentially fatal (Carr and Frei 1999; National Research Council 1989; Wilson 1998). Scurvy involves degenerative changes in capillaries, bone, and connective tissue, resulting in clinical symptoms that include weakness, joint tenderness and swelling, and spontaneous hemorrhages (Carr and Frei 1999; Covington 1999; National Research Council 1989; Wilson 1998). Patients with vitamin C deficiency may also be at increased risk of developing cataracts and heart disease (Ames 2000).

Replacement Therapy

Treatment of scurvy requires doses between 300 and 1000 mg/day for adults (Covington 1999). Other recommendations range from the recommended dietary allowance (RDA) of 60 mg to 2000 mg/day for adults (Carr and Frei 1999; Wilson 1998). One study proposes that no adult receive more than 1000 mg/day because higher doses could cause nausea and diarrhea (Ausman 1999). To minimize the possibility of gastric upset, buffered and sustained-release vitamin C preparations are recommended. Specific doses account for the patient's age, gender, overall health status, dietary habits, and medication regimen. Smokers must consume 2 to 3 times more vitamin C than non-smokers (Ames 2000).


Oral contraceptives reduce serum zinc levels (Dorea et al. 1982; Tyrer 1984).

Significance of Depletion

Clinically, signs and symptoms of zinc deficiency include alopecia, dermatitis, diarrhea, growth retardation, increased susceptibility to infection, and loss of appetite or sense of taste (Ames 2000; Falchuk 1998). Severe zinc deficiency further impacts dermatologic, gastrointestinal, immune, nervous, reproductive, respiratory, and skeletal systems (Ames 2000; Hambidge 2000).

Replacement Therapy

Doses of zinc up to 50 mg/day may be recommended (Hambidge 2000). This upper limit includes an adult's total daily intake, which may be higher than anticipated because of the increasing trend to fortify foods with zinc. It is important to be mindful of this limit, even if decisions are deliberately made to temporarily exceed this level for anticipated pharmacological benefits.

Editorial Note

This information is intended to serve as a concise reference for healthcare professionals to identify substances that may be depleted by many commonly prescribed medications. Depletion of these substances depends upon a number of factors including medical history, lifestyle, dietary habits, and duration of treatment with a particular medication. The signs and symptoms associated with deficiency may be nonspecific and could be indicative of clinical conditions other than deficiency. The material presented in these monographs should not in any event be construed as specific instructions for individual patients.


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Copyright © 2000 Integrative Medicine Communications

This publication contains information relating to general principles of medical care that should not in any event be construed as specific instructions for individual patients. The publisher does not accept any responsibility for the accuracy of the information or the consequences arising from the application, use, or misuse of any of the information contained herein, including any injury and/or damage to any person or property as a matter of product liability, negligence, or otherwise. No warranty, expressed or implied, is made in regard to the contents of this material. No claims or endorsements are made for any drugs or compounds currently marketed or in investigative use. The reader is advised to check product information (including package inserts) for changes and new information regarding dosage, precautions, warnings, interactions, and contraindications before administering any drug, herb, or supplement discussed herein.