Oral Contraceptives

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References

Adams PW, Rose DP, Folkard J, Wynn V, Seed M, Strong R. Effect of pyridoxine hydrochloride (vitamin B6) upon depression associated with oral contraception. Lancet 1973 Apr 28;1(7809):899-904.

Adams PW, Wynn V, Folkard J, Seed M. Influence of oral contraceptives, pyridoxine (vitamin B6), and tryptophan on carbohydrate metabolism. Lancet 1976 Apr 10;1(7963):759-764.
Abstract: Carbohydrate metabolism and vitamin-B6 status were assessed before and after pyridoxine administration in 46 women taking combined oestrogen-progestagen oral contraceptives (O.C.). 18 women had evidence of tissue depletion of vitamin B6, although all the women had abnormal tryptophan metabolism, including increased urinary xanthurenic acid (X.A.) excretion. In the women with vitamin B6 deficiency, administration of this vitamin caused elevation of fasting blood-pyruvate levels, and reduction in plasma glucose, insulin, and blood-pyruvate responses after an oral glucose load. These changes in carbohydrate metabolism were not found in the 28 non-vitamin-B6-deficient women. These results indicate that carbohydrate intolerance in women on O.C. is unlikely to be mediated by the formation of a complex of X.A. with insulin, as has formerly been proposed. Since the synthesis of the tryptophan metabolite quinolinic acid, an inhibitor of the heptaic enzyme phosphoenolpyruvate carboxykinase, may be enhanced by the administration of pyridoxine, it is suggested that this metabolite might be the important factor in the improvement of glucose tolerance in the vitamin-B6-deficient women. This conclusion is supported by the improvement in glucose tolerance observed in 6 women on O.C. and in 4 patients with glucocorticoid excess who were not vitamin-B6 deficient, when they were given tryptophan to augment the synthesis of quinolinic acid.

Ahmed F, Bamji MS. Vitamin supplements to women using oral contraceptives (studies of vitamins B1, B2, B6 and A). Contraception 1976 Sep;14(3):309-318.

Back DJ, Orme ML. Pharmacokinetic drug interactions with oral contraceptives. Clin Pharmacokinet 1990 Jun;18(6):472-484.
Abstract: Oral contraceptive steroids are used by an estimated 60 to 70 million women world-wide. Over the past 20 years there have been both case reports and clinical studies on the topic of drug interactions with these agents. Some of the interactions are of definite therapeutic relevance, whereas others can be discounted as being of no clinical significance. Pharmacological interactions between oral contraceptive steroids and other compounds may be of 2 kinds: (a) drugs may impair the efficacy of oral contraceptive steroids, leading to breakthrough bleeding and pregnancy (in a few cases, the activity of the contraceptive is enhanced); (b) oral contraceptive steroids may interfere with the metabolism of other drugs. A number of anticonvulsants (phenobarbital, phenytoin, carbamazepine) are enzyme-inducing agents and thereby increase the clearance of the oral contraceptive steroids. Valproic acid has no enzyme-inducing properties, and thus women on this anticonvulsant can rely on their low dose oral contraceptive steroids for contraceptive protection. Researchers are now beginning to unravel the molecular basis of this interaction, with evidence of specific forms of cytochrome P450 (P450IIC and IIIA gene families) being induced by phenobarbital. Rifampicin, the antituberculous drug, also induces a cytochrome P450 which is a product of the P450IIIA gene subfamily. This isozyme is one of the major forms involved in 2-hydroxylation of ethinylestradiol. Broad spectrum antibiotics have been implicated in causing pill failure; case reports document the interaction, and general practitioners are convinced that it is real. The problem remains that there is still no firm clinical pharmacokinetic evidence which indicates that blood concentrations of oral contraceptive steroids are altered by antibiotics. However, perhaps this should not be a surprise, given that the incidence of the interaction may be very low. It is suggested that an individual at risk will have a low bioavailability of ethinylestradiol, a large enterohepatic recirculation and gut flora particularly susceptible to the antibiotic being used. Two drugs, ascorbic acid (vitamin C) and paracetamol (acetaminophen), give rise to increased blood concentrations of ethinylestradiol due to competition for sulphation. The interactions could have some significance to women on oral contraceptive steroids who regularly take high doses of either drug. Although on theoretical grounds adsorbents (e.g. magnesium trisilicate, aLuminium hydroxide, activated charcoal and kaolin) could be expected to interfere with oral contraceptive efficacy, there is no firm evidence that this is the case. Similarly, there is no evidence that smoking alters the pharmacokinetics of oral contraceptive steroids. These agents are now well documented as being able to alter the pharmacokinetics of other concomitantly administered drugs.

Bamji MS, Safaya S, Prema K. Low dose injectable contraceptive norethisterone enanthate 20mg monthly - II. Metabolic side effects. Contraception 1981 Jan;23(1):23-36.
Abstract: Metabolic effects of a long-acting low dose injectable contraceptive, norethisterone enanthate 20-mg, monthly injections (Neten-20), was tested in 13 women belonging to the low income groups over a period of 1 year. No change was observed in hemoglobin, hematocrit, glucose tolerance, plasma lipids, iron, calcium, or serum glutamate-oxaloacetate transaminase after treatment. Marginal rise in albumin and fall in some globulin fractions was observed. The slight fall seen in serum alkaline phosphatase could be attributed to a change in lactation status. Vitamin A, pyridoxine and riboflavin status were not altered. A peculiar aberration in the tryptophan-niacin pathway as indicated by rise in kynurenic acid excretion after tryptophan load was observed. This could be corrected by multivitamin therapy. These data suggest that the use of Neten-20 for one year does not lead to adverse metabolic effects analogous to those seen with combination type oral contraceptives.

Barinagarrementeria F, Gonzalez-Duarte A, Miranda L, Cantu C. Cerebral infarction in young women: analysis of 130 cases. Eur Neurol 1998 Nov;40(4):228-233.
Abstract: The aim of this study was to determine the risk factors and mechanism of cerebral infarction in young women. METHODS: We evaluated 130 consecutive women younger than 41 years of age with cerebral infarction and compared the risk factors with a control group of 122 healthy, age-matched women. RESULTS: The leading risk factors in patients with cerebral infarction were migraine (15%), tobacco use (15%), and oral contraceptive (OC) use (12%). Cerebral arteriograms were abnormal in 59% of patients (57 of 96). The causes of cerebral infarction were cardiac embolism in 36%, nonatherosclerotic vasculopathy in 25%, hematologic disorders in 8%, and migraine in 8%. The etiology could not be determined in 23% of patients. CONCLUSION: Migraine and OCs are independent risk factors for cerebral infarction in young women. The leading etiologies were rheumatic valve disease and nonatherosclerotic vasculopathy, hematologic disturbances, and migraine were responsible for a few cases.

Becker WJ. Migraine and oral contraceptives. Can J Neurol Sci 1997 Feb;24(1):16-21.
Abstract: Initiation of oral contraceptive (OC) therapy in migraine may worsen pre-existing migraine or change the pattern of the individual migraine attacks. Many women experience no change in their migraine and a few show improvement. Evidence is accumulating that migraine increases ischemic stroke risk and that this risk is higher in migraine with aura than in migraine without aura. OCs also increase stroke risk, and the increased stroke risk attributable to each of migraine and OC therapy may be additive. The risk of ischemic stroke in young women is very low and likely remains acceptably low in young women with migraine without aura and in those with a simple migraine aura when OCs are prescribed. However, the presence of a complex or prolonged migraine aura, or of additional stroke risk factors such as increased age, smoking, and hypertension likely increases the ischemic stroke risk further in patients with migraine when OCs are prescribed. Whether OCs can be prescribed safely for the patient with migraine depends upon many factors including patient age, type of migraine, and the presence or absence of other stroke risk factors.

Berg G, Kohlmeier L, Brenner H. Effect of oral contraceptive progestins on serum copper concentration. Eur J Clin Nutr 1998 Oct;52(10):711-715.
Abstract: OBJECTIVES: Recent epidemiologic studies have shown an increased mortality from cardiovascular diseases in people with higher serum copper levels. Even though higher serum copper concentration in women using oral contraceptives is well known, there is still uncertainty about the influence of newer progestin compounds in oral contraceptives on serum copper concentration. This issue is of particular interest in the light of recent findings of an increased risk of venous thromboembolism in users of oral contraceptives containing newer progestins like desogestrel compared to users of other oral contraceptives. DESIGN: Cross-sectional epidemiologic study. Examinations included a detailed questionnaire on medical history and lifestyle factors, a seven day food record, and blood samples. SETTING: National health and nutrition survey among healthy people living in private homes in West Germany in 1987-1988. SUBJECTS: Nonpregnant and nonlactating women aged 18-44 y (n = 610). RESULTS: Overall, the use of oral contraceptives was positively associated with serum copper concentration in by bi- and multivariable linear regression models with log-transformed values of serum copper concentration as dependend variable and oral contraceptive preparations and potential confounding variables as independent variables. Serum copper concentration in women using oral contraceptives varied more strongly by different progestin compounds than by estrogen contents. 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%). CONCLUSION: While elevated serum copper concentration was found in users of all types of oral contraceptives, elevation was more pronounced among women taking oral contraceptives with antiandrogen effective progestins like antiandrogens or third generation oral contraceptives containing desogestrel. Further investigation is required to shed light on the possible role of high serum copper concentration in increasing cardiovascular or thrombotic risk of women using oral contraceptives.

Brattstrom L, Israelsson B, Olsson A, Andersson A, Hultberg B. Plasma homocysteine in women on oral oestrogen-containing contraceptives and in men with oestrogen-treated prostatic carcinoma. Scand J Clin Lab Invest 1992 Jun;52(4):283-287.
Abstract: The mechanism by which oral oestrogen-containing contraceptives in women and oestrogen treatment of prostatic carcinoma in men increases the risk of vascular disease is unclear. These agents decrease serum concentrations of vitamin B12, pyridoxal 5-phosphate, and folate, all of which are essential for the metabolism of the atherogenic amino acid homocysteine. We found serum vitamin B12 concentrations to be lower in 17 women using oral contraceptives (219 +/- 84 pmol l-1) than in 13 age-matched female controls (385 +/- 129, p less than 0.001), but similar values were obtained in the two groups both for fasting plasma homocysteine concentrations (9.1 +/- 2.4 vs 9.2 +/- 3.6 mumol l-1) and for the increase in these concentrations after methionine loading (19.2 +/- 7.5 vs 17.8 +/- 5.2 mumol l-1). In five men with prostatic carcinoma, high-dose oestrogen treatment decreased serum vitamin B12 concentrations by a mean of 30% (p less than 0.05) within 4 weeks, during which fasting plasma homocysteine concentrations decreased (13.8 +/- 4.5 vs 10.5 +/- 2.8 mumol l-1) and response to methionine loading increased (12.4 +/- 3.4 vs 17.3 +/- 5.1 mumol l-1), though the latter changes were non-significant. Our findings do not support the hypothesis that hyperhomocysteinemia explains cardiovascular risk in women using oral oestrogen-containing contraceptives, or in oestrogen-treated men with prostatic carcinoma.

Briggs MH. Megadose vitamin C and metabolic effects of the pill. Br Med J (Clin Res Ed) 1981 Dec 5;283(6305):1547.

Briggs MH, Briggs M. Thiamine status and oral contraceptives. Contraception 1975 Feb;11(2):151-154.

Brown RR, Rose DP, Leklem JE, Linkswiler HM. Effects of oral contraceptives on tryptophan metabolism and vitamin B6 requirements in women. Acta Vitaminol Enzymol 1975;29(1-6):151-157.
Abstract: To evaluate the effect of oral contraceptive usage on the nutritional requirement for vitamin B6, control women and oral contraceptive users were depleted of vitamin B6 for 1 month followed by a month of repletion with 0.8, 2.0, or 20.0 mg of pyridoxine hydrochloride per day. At weekly intervals a number of indices of vitamin B6 nutrition were measured. Marked elevation in excretion of tryptophan metabolites occurred in oral contraceptive users after tryptophan loads. However, other indices of vitamin B6 nutritional state, including urinary 4-pyridoxic acid excretion, urinary cystathionine excretion, plasma pyridoxal phosphate concentrations, and erythrocyte aspartate and alanine aminotransferases were not different between controls and oral contraceptive users. The excretion of metabolites after oral loading doses of L-kynurenine (which bypasses tryptophan oxygenase) was elevated in oral contraceptive users indicating that abnormal metabolism of tryptophan was not due only to induced tryptophan oxygenase. The data indicate that use of oral contraceptives does not generally change the requirement for vitamin B6 but rather produces a specific change in activity of enzymes beyond kynurenine in the pathway of tryptophan metabolism.

Butterworth CE Jr, Hatch KD, Macaluso M, Cole P, Sauberlich HE, Soong SJ, Borst M, Baker VV. Folate deficiency and cervical dysplasia. JAMA 1992 Jan 22-29;267(4):528-533.
Abstract: OBJECTIVE--To test the hypothesis that nutritional deficiency affects the incidence of cervical dysplasia in young women. DESIGN AND SETTING--Case-control study. Participants were derived from community family-planning clinics and referrals to a colposcopy center. PARTICIPANTS--A total of 726 subjects were screened, yielding 294 cases of dysplasia and 170 controls defined by coexistent cytologic and colposcopic evidence. MAIN OUTCOME MEASURES--Planned prior to data collection. Odds ratios were computed using logistic regression models to evaluate association between cervical dysplasia and sociodemographic, sexual, and reproductive factors; smoking; oral contraceptive use; human papillomavirus (HPV) infection; and 12 nutritional indices determined by blind analysis of nonfasting blood specimens. RESULTS--The number of sexual partners, parity, oral contraceptive use, and HPV-16 infection were significantly associated with cervical dysplasia. Plasma nutrient levels were generally not associated with risk. However, red blood cell folate levels at or below 660 nmol/L interacted with HPV-16 infection. The adjusted odds ratio for HPV-16 was 1.1 among women with folate levels above 660 nmol/L but 5.1 (95% confidence interval, 2.3 to 11) among women with lower levels. Interactions of red blood cell folate levels with cigarette smoking and parity were also present but were not statistically significant. CONCLUSION--Low red blood cell folate levels enhance the effect of other risk factors for cervical dysplasia and, in particular, that of HPV-16 infection.

Butterworth CE, Hatch KD, Mueller H, Gore H. Folate-induced regression of cervical intraepithelial neoplasia (CIN) in users of oral contraceptive agents (OCA). Am J Clin Nutr 1980;33:926.

Butterworth CE Jr, Hatch KD, Gore H, Mueller H, Krumdieck CL. Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives. Am J Clin Nutr 1982 Jan;35(1):73-82.
Abstract: Forty-seven young women with mild or moderate dysplasia of the uterine cervix (cervical intraepithelial neoplasia) diagnosed by cervical smears, received oral supplements of folic acid, 10 mg, or a placebo (ascorbic acid, 10 mg) daily for 3 months under double-blind conditions. All had used a combination-type oral contraceptive agent for at least 6 months and continued it while returning monthly for follow-up examinations. All smears and a biopsy obtained at the end of the trial period were classified by a single observer without knowledge of treatment status using an arbitrary scoring system (1 normal, 2 mild, 3 moderate, 4 severe, 5 carcinoma in situe). Mean biopsy scores from folate supplemented subjects were significantly better than in folate-unsupplemented subjects (2.28 versus 2.92, respectively; p less than 0.05). Final versus initial cytology scores were also significantly better in supplemented subjects (1.95 versus 2.32, respectively; p less than 0.05), unchanged in patients receiving the placebo (2.27 versus 2.30, respectively). Before treatment the mean red cell folate concentration was lower among oral contraceptive agent users than nonusers (189 versus 269 ng/ml, respectively; p less than 0.01) and even lower among users with dysplasia (161 versus 269 ng/ml, respectively; p less than 0.001). Morphological features of megaloblastosis were associated with dysplasia and also improved in folate supplemented subjects. These studies indicate that either a reversible, localized derangement in folate metabolism may sometimes be misdiagnosed as cervical dysplasia, or else such a derangement is an integral component of the dysplastic process that may be arrested or in some cases reversed by oral folic acid supplementation.

Cumming FJ, Briggs MH. Changes in plasma vitamin A in lactating and non-lactating oral contraceptive users. Br J Obstet Gynaecol 1983 Jan;90(1):73-77.
Abstract: Plasma vitamin A and retinol-binding protein (RBP) concentrations have been studied in women using oral contraceptives (OC) for up to 4 years. In eight women taking an oestrogenic OC(1 mg of norethisterone acetate + 50 micrograms of ethinyloestradiol) values almost doubled within 6 months, but diminished somewhat after 4 years. Saturation of RBP with retinol remained fairly constant. Five lactating women who took progestogen-only OC (30 micrograms of levonorgestrel or 350 micrograms of norethisterone) showed no significant alteration in plasma vitamin A or RBP concentrations as compared with nine lactating non-OC users. All lactating women showed significant differences between the highest and lowest plasma vitamin A (P less than 0.005) and RBP (P less than 0.05) concentrations during the first 6 months of lactation. Highest values occurred 11-12 weeks postpartum and the lowest at 15-17 weeks. Percentage saturation of RBP with retinol was significantly higher (P less than 0.005) when vitamin A concentration was highest.

Durand P, Prost M, Blache D. Folic acid deficiency enhances oral contraceptive-induced platelet hyperactivity. Arterioscler Thromb Vasc Biol 1997 Oct;17(10):1939-1046.
Abstract: In previous studies conducted in female rats and in women, oral contraceptives (OC) were found to induce a platelet hyperactivity that was related to an oxidative stress. Because cases of megaloblastic anemia have been reported to occur in women taking OC, these treatments are suspected of depleting folate stores. In the study presented herein, which was conducted in rats, we sought to determine the influence of dietary folic acid deficiency (FD) on the thrombogenicity of OC. Animals were fed for 6 weeks with either a folic acid-deficient diet (250 micrograms/kg folic acid) or a control diet (750 micrograms/kg). One-half of the animals in each group were treated with OC (ethinyl estradiol plus lynestrenol). FD and OC individually potentiated platelet aggregation in response to thrombin and ADP and the release and metabolism of arachidonic acid, in particular, the biosynthesis of thromboxane. These platelet activities were further enhanced in animals given both the folic acid-deficient diet and the OC treatment. In addition, FD enhanced the pro-oxidant state in OC-treated rats characterized by (1) a fall in platelet and plasma n-3 fatty acids, (2) an increase in plasma lipid peroxidation products such as conjugated dienes, lipid peroxides, and thiobarbituric reactive substances, (3) a rise in ex vivo erythrocyte susceptibility to free radicals. Moreover, we found that OC treatment led to a reduction of plasma and erythrocyte folate concentrations associated with a moderate hyperhomocysteinemia. Under our experimental conditions, we did not find significant synergistic effects between OC and FD. We propose that, although the untoward effects associated with the OC treatment may not primarily be dependent on FD, the folic acid deficiency magnified OC-induced oxidative stress, which resulted in platelet hyperactivity by elevating the pro-oxidant homocysteine plasma concentration. Despite the limitations of this animal model, the data of the present study suggest that in addition to cigarette smoking, inadequate folic acid intake might predispose those taking OC to vascular thrombosis.

Egoramaiphol S, Migasena P, Supawan V. Effect of oral contraceptive agents on thiamine status. J Med Assoc Thai 1985 Jan;68(1):19-23.

Frassinelli-Gunderson EP, Margen S, Brown JR. Iron stores in users of oral contraceptive agents. Am J Clin Nutr 1985 Apr;41(4):703-712.
Abstract: A comparison of serum ferritin and other parameters of iron status was made between 46 women taking oral contraceptive agents (OCAs) for two or more years continuously and 71 women who never took OCAs. The mean serum ferritin level for the OCA users was 39.5 +/- 21.5 ng/ml and the control group mean level was 25.4 +/- 15.96 ng/ml, which is significantly different at p less than 0.001. Serum transferrin, serum iron, TIBC, MCH and MCHC levels were significantly greater for the OCA users group. Significantly lower RBC and hematocrit levels were found for OCA users while other parameters, hemoglobin, MCV and percent transferrin saturation, were not significantly different. No major differences in subject characteristics and dietary traits were evidenced, except a difference in reported menstrual cycle losses and a higher heme iron content in the diet of the OCA users.

Harper JM, Levine AJ, Rosenthal DL, Wiesmeier E, Hunt IF, Swendseid ME, Haile RW. Erythrocyte folate levels, oral contraceptive use and abnormal cervical cytology. Acta Cytol 1994 May-Jun;38(3):324-330.
Abstract: The initial hypothesis of this study was that folate depletion is a risk factor for human papillomavirus infection and cervical epithelial cell abnormalities, including dysplasia. The prevalences of low erythrocyte folate levels (defined as < 140 ng/mL erythrocytes and determined by the growth of Lactobacillus) were measured in 250 University of California at Los Angeles students. Among oral contraceptive users, low erythrocyte folate was a risk factor for an abnormal cytologic smear in both benign atypia and squamous intraepithelial lesions. Odds ratios were statistically significant for biopsied women who did not have condyloma and for those who did not have squamous intraepithelial lesions but not for those with histologically confirmed intraepithelial lesions. Low erythrocyte folate was a risk factor for a positive Virapap result in oral contraceptive users. If the folate effects are causal, the findings suggest that erythrocyte folate levels should be higher in oral contraceptive users than in nonusers to protect against an abnormal cytologic smear.

Hartard M, Bottermann P, Bartenstein P, Jeschke D, Schwaiger M. Effects on bone mineral density of low-dosed oral contraceptives compared to and combined with physical activity. Contraception 1997 Feb;55(2):87-90.
Abstract: A cross-sectional study was designed to examine the influence of exercise compared to and in combination with low-dosed oral contraceptives (OCs) on bone mineral density (BMD). One hundred twenty-eight women (20 to 35 years of age) were assigned to four groups with respect to the years of exercise and OC intake. Influence factors were determined by a detailed questionnaire and interview. BMD for L2-4 and the femoral neck was assessed by DXA. The highest BMD values were found in the group of women characterized by long-term exercise (9.45 +/- 4.32 yr) and short use of OC (1.6 +/- 1.69 yr). No beneficial effect of exercise on BMD was found in the group with a long exercise period (10.4 +/- 4.14 yr) and long-term intake of OC (8.2 +/- 4.14 yr). Differences in mean BMD values between the two groups were significant in all regions assessed (p < 0.05). No differences in mean BMD were found in the groups with short-term exercise but long or brief histories of OC. The question arises as to whether active women taking low-dosed OC at an earlier age will develop an adequate BMD.

Heese HD, Lawrence MA, Dempster WS, Pocock F. Reference concentrations of serum selenium and manganese in healthy nulliparas. S Afr Med J 1988 Feb 6;73(3):163-165.
Abstract: Reference serum selenium and manganese concentrations were established for healthy nulliparas aged 18-23 years resident in Cape Town. Measurements were determined for selenium in 100 female students who had been taking low-dosage triphasic contraceptive medication for a minimum of 3 months and in 100 female students who were not on contraceptive therapy. Manganese concentrations were determined for 25 female students from each group. The mean serum selenium concentrations were 0.988 +/- 0.189 micrograms/l (78 +/- 15 micrograms/dl) and 0.925 +/- 0.177 mumol/l (73 +/- 14 micrograms/l) respectively for females taking and not taking oral contraceptives. The corresponding concentrations for manganese were 21.84 +/- 9.82 nmol/l (1.20 +/- 0.54 micrograms/l) and 21.66 +/- 7.64 nmol/l (1.19 +/- 0.42 micrograms/l) respectively. The differences in selenium were statistically significant (P = 0.0231) but not for manganese (P = 0.910).

Hergenroeder AC, Smith EO, Shypailo R, Jones LA, Klish WJ, Ellis K. Bone mineral changes in young women with hypothalamic amenorrhea treated with oral contraceptives, medroxyprogesterone, or placebo over 12 months. Am J Obstet Gynecol 1997 May;176(5):1017-1025.
Abstract: OBJECTIVES: The objectives of this study were to assess (1) whether treatment with oral contraceptives, in comparison with medroxyprogesterone and placebo, improved bone mineral in women with hypothalamic amenorrhea and (2) whether treatment with medroxyprogesterone, in comparison with placebo, improved bone mineral in women with hypothalamic oligomenorrhea. STUDY DESIGN: The study was a randomized, controlled clinical trial. Twenty-four white women, aged 14 to 28 years, with hypothalamic amenorrhea or oligomenorrhea were prospectively enrolled for a 12-month intervention period. Amenorrheic subjects were randomized to receive oral contraceptives, medroxyprogesterone, or placebo. Oligomenorrheic subjects were randomized to receive medroxyprogesterone or placebo. Bone mineral was measured by dual-energy x-ray absorptiometry at baseline and at 6 and 12 months. RESULTS: In amenorrheic subjects spine and total body bone mineral measurements at 12 months were greater in the oral contraceptive group than in the medroxyprogesterone and placebo groups when baseline bone mineral measurements, body weight, and age were controlled for (p < or = 0.05). There were no differences in hip bone mineral calcium and bone mineral density measurements at 12 months among the three groups. In oligomenorrheic subjects there was no detectable improvement in bone mineral associated with medroxyprogesterone use. CONCLUSIONS: This study supports the hypothesis that oral contraceptive use in women with hypothalamic amenorrhea will improve lumbar spine and total body bone mineral.

Hjelt K, Brynskov J, Hippe E, Lundstrom P, Munck O. Oral contraceptives and the cobalamin (vitamin B12) metabolism. Acta Obstet Gynecol Scand 1985;64(1):59-63.
The mean concentrations of serum (S)-cobalamin (vitamin B12) and S-unsaturated B12 binding capacity (UBBC) were significantly decreased in 101 women (mean age: 30.4 years) taking oral contraceptives (OC) of the combination type, compared to 113 controls. OC users more frequently showed decreased concentrations of S-cobalamin (less than 200 pmol/l) than did their controls. However, the incidence of particularly low concentrations (less than 150 pmol/l) in OC users was not increased. To study a possible dose-dependent effect, 27 women (mean age: 50.5 years) given high-dose estrogen preparations (1-4 mg estrogen) were compared with 31 controls. The two groups showed no difference with regard to S-cobalamin, but the mean S- and plasma-UBBC levels were significantly decreased in the high-dose estrogen group. 12 OC users with decreased S-cobalamin (less than 200 pmol/l), 9 OC users with normal S-cobalamin and 10 controls were studied more intensively. The mean hemoglobin concentration was significantly decreased in those OC users having decreased S-cobalamin. On the contrary, the absorption and excretion of radiolabeled cobalamin and the concentrations of erythrocyte-folate, S-iron and -transferrin did not show any difference between the groups, and all results were normal, by and large. No characteristic changes in plasma volume were found. It is concluded that routine measurement of S-cobalamin in women taking OC is not justified.

Holt GA. Food and Drug Interactions.. Chicago: Precept Press, 1998, 197-198.

Horwitt MK, Harvey CC, Dahm CH Jr. Relationship between levels of blood lipids, vitamins C, A, and E, serum copper compounds, and urinary excretions of tryptophan metabolites in women taking oral contraceptive therapy. Am J Clin Nutr 1975 Apr;28(4):403-412.
Abstract: To evaluate which women using oral contraceptive agents might be at risk, biochemical indices known to be affected by the estrogens and progestogens were studied in women who take oral contraceptive agents, in women who do not use oral contraceptive agents, in women in third trimester of pregnancy and 6 weeks after parturition, and in men with normal and high blood lipid levels. The most consistent changes due to oral contraceptive agents were in serum levels of copper, triglycerides, and vitamin A and in the urinary excretion of xanthurenic acid and niacin derivatives before and after a tryptophan load test. There was only a slight suggestion, with no statistical significance, that serum vitamin C levels decreased when the serum levels of ceruloplasmin were high. The highest blood pressures and serum triglycerides and vitamin A levels were obtained in those women who ingested the highest level of estrogens. Pregnant women had the lowest levels of serum vitamin A. The oral contraceptive agents users had the lowest average levels of carotenoids corresponding to the highest average levels of vitamin A in the serum. Thus, estrogens not only increase the rate of change of tryptophan to niacin but may also increase the rate of conversion of carotene to vitamin A. Relative reactivity to oral contraceptive agents and possible risk to a patient might be evaluated by a profile of blood pressure and serum triglycerides, copper, and vitamin A.

King JC. Do women using oral contraceptive agents require extra zinc? J Nutr 1987 Jan;117(1):217-219.

Kornberg A, Segal R, Theitler J, Yona R, Kaufman S. Folic acid deficiency, megaloblastic anemia and peripheral polyneuropathy due to oral contraceptives. Isr J Med Sci 1989 Mar;25(3):142-145.
Abstract: A 34-year-old woman developed megaloblastic anemia and peripheral polyneuropathy following the use of oral contraceptives for 4 years. Low levels of folic acid and vitamin B12 were found. Both the complete recovery after therapy with the vitamins, and the absence of other causes of vitamin B12 and folate deficiency, suggest that the vitamin deficiencies were caused by the oral contraceptives and resulted in the rare combination of megaloblastic anemia and polyneuropathy. The poor response to vitamin B12 alone, and the development of anemia and polyneuropathy 4 months after cessation of vitamin B12 therapy suggest that folate deficiency was the primary problem.

Kuhnz W, Louton T, Humpel M, Back DJ, Zamah NM. Influence of high doses of vitamin C on the bioavailability and the serum protein binding of levonorgestrel in women using a combination oral contraceptive. Contraception 1995 Feb;51(2):111-116.
Abstract: The absence of an effect of high oral doses of vitamin C on the systemic availability of ethinylestradiol in women using a levonorgestrel-containing combination oral contraceptive (0.15 mg levonorgestrel and 0.03 mg ethinylestradiol) was demonstrated in a recent study. However, it is conceivable that the oral administration of gram quantities of vitamin C could also interfere with the sulfation of levonorgestrel (LNG) metabolites during phase II biotransformation, because sulfates represent a major part of the conjugated metabolites of LNG in the serum. This possible interaction was investigated in the aforementioned study, comparing Cmax and AUC(0-12h) values of LNG on the first and 15th day of two successive treatment cycles with and without co-medication of vitamin C. In addition, the serum protein binding of LNG and the concentration of the binding proteins SHBG and CBG were compared between both treatments. Corresponding parameters obtained during treatment with the oral contraceptive alone and during co-administration of vitamin C were evaluated statistically for possible differences. No effect of vitamin C was observed for any of the parameters investigated. Thus, the repeated oral administration of gram quantities of vitamin C does not impair the sulfation of hydroxylated metabolites of LNG. There was also no observable effect on the serum protein binding of LNG and the concentrations of SHBG and CBG in the serum. The results obtained in this study population (American women) for LNG are in good agreement with those obtained from a previous study in European women, who had taken a combination oral contraceptive containing the same doses of LNG and ethinylestradiol.

Kwasniewska A, Tukendorf A, Semczuk M. Folate deficiency and cervical intraepithelial neoplasia. Eur J Gynaecol Oncol 1997;18(6):526-530.
Abstract: The presence of HPV, using the Digene Hybrid Capture System, was identified in a group of 324 women with CIN and in 228 women with normal cytological smears. Risk of occurrence of CIN was 40 times higher for high risk HPV types. The serum folic acid level and the level of antioxidant compounds in plasma (retinol, alpha-tocopherol, vitamins C and E) in women of the studied and control group was determined by HPLC (high-performance liquid chromatography-reversed phase). Statistically lower levels of folic acid were found in the women with CIN-HPV (+) (OR: 7.5: 95% CI: 1.2-9.7). Studies have shown that lower levels of antioxidants coexisting with low levels of folic acid increases the risk of CIN development.

Leklem JE, Brown RR, Rose DP, Linkswiler H, Arend RA. Metabolism of tryptophan and niacin in oral contraceptives users receiving controlled intakes of vitamin B6. Am J Clin Nutr 1975 Feb;28(2):146-156.

Lewis CM, King JC. Effect of oral contraceptives agents on thiamin, riboflavin, and pantothenic acid status in young women. Am J Clin Nutr 1980 Apr;33(4):832-838.

Lewis DP, Van Dyke DC, Stumbo PJ, Berg MJ. Drug and environmental factors associated with adverse pregnancy outcomes. Part I: Antiepileptic drugs, contraceptives, smoking, and folate. Ann Pharmacother 1998 Jul-Aug;32(7-8):802-817. (Review)
Abstract: OBJECTIVE: Part I of this review examines the relationship between antiepileptic drugs (AEDs) and pregnancy outcomes. Drug-induced folate deficiency and the role of AED metabolism are emphasized. Part II will discuss periconceptional folate supplementation for prevention of birth defects. Part III will discuss the mechanism of folate's protective effect, therapeutic recommendations, compliance, and cost. DATA SOURCES: A MEDLINE search was conducted for journal articles published through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included phenytoin, carbamazepine, phenobarbital, primidone, valproic acid, oral contraceptives, clomiphene, drug-induced abnormalities, spina bifida, anencephaly, neural tube defect, folate, folic acid, and folic acid deficiency. STUDY SELECTION: Relevant animal and human studies examining the effects of AEDs, smoking, and oral contraceptives on folate status and pregnancy outcome are reviewed. DATA EXTRACTION: Studies and case reports were interpreted. Data extracted included dosing, serum and red blood cell folate concentrations, teratogenicity of anticonvulsant medications, metabolism of AEDs and folate, and genetic susceptibility to AED-induced teratogenicity. DATA SYNTHESIS: Low serum and red blood cell folate concentrations are associated with adverse pregnancy outcomes. Decreases in serum folate are seen with AEDs, oral contraceptives, and smoking. Since similar birth defects are observed with multiple AEDs, metabolism of aromatic AEDs to epoxide metabolites and genetic factors may play a role in teratogenesis. CONCLUSIONS: Adequate prepregnancy planning is essential for women who have epilepsy. Women receiving folate-lowering drugs may be at increased risk of adverse pregnancy outcomes. Therefore, epileptic women contemplating pregnancy should be treated with the minimum number of folate-lowering drugs possible and receive folic acid supplementation.

Lindenbaum J. Drugs and vitamin B12 and folate metabolism. Curr Concepts Nutr 1983;12:73-87. (Review)

Lindenbaum J, Whitehead N, Reyner F. Oral contraceptive hormones, folate metabolism, and the cervical epithelium. Am J Clin Nutr 1975 Apr;28(4):346-353. (Review)
Abstract: The currently available evidence concerning disorders of folate metabolism in women taking oral contraceptives has been reviewed. A disturbance in folate balance serious enough to cause symptoms (i.e., megaloblastic anemia) occurs very rarely. In some series, but not in others, serum and/or red cell folate concentrations have been reduced in oral contraceptive users. It is doubtful whether sex steroids affect polyglutamate folate absorption. About 20 percent of women taking contraceptive hormones manifest mild megaloblastic changes on Papanicolaou smears of the cervicovaginal epithelium which disappear after folic acid therapy. The current evidence, however, would not indicate that any significant benefit would ensue from routine folate supplementation in women on oral contraceptives.

Liu T, Soong SJ, Wilson NP, Craig CB, Cole P, Macaluso M, Butterworth CE Jr. A case control study of nutritional factors and cervical dysplasia. Cancer Epidemiol Biomarkers Prev 1993 Nov-Dec;2(6):525-530.
Abstract: The association of nutritional factors with cervical dysplasia was examined through a case-control study. Analysis was conducted in 257 cases and 133 controls confirmed both by cytological examination and colposcopic findings. A 24-h dietary recall questionnaire was used to assess nutritional intake. Various risk factors (including age at first intercourse, number of sexual partners, parity, cigarette smoking, oral contraceptive use, human papillomavirus type 16 infection, and age and race) were adjusted for their potential confounding effects. While analyses were also performed to adjust for total calories, results were not changed significantly. Among the nutrients examined, vitamin A intake showed a significantly increased risk at the lowest quartile compared to the highest quartile, with an odds ratio of 2.2 (95% confidence interval, 1.2-4.2). A significant trend of increasing risk was also observed with lower intake of vitamin A (P = 0.05). Riboflavin showed increased risk at the two lower quartiles of intake with a trend test P value of 0.04. Increased risk was also found for lower intakes of vitamin C compared to the highest intake level. For folate, increased risk was found in the second highest quartile compared with the highest quartile with an odds ratio of 2.0 (95% confidence interval, 1.0-3.8). The calcium:phosphorus ratio showed an increased risk at the lowest level (odds ratio, 2.0; 95% confidence interval, 1.0-4.3). Insufficient intake of vitamin A, riboflavin, ascorbate, and folate is associated with an increased risk of cervical dysplasia.

Liukko P, Erkkola R, Pakarinen P, Jarnstrom S, Nanto V, Gronroos M. Trace elements during 2 years' oral contraception with low-estrogen preparations. Gynecol Obstet Invest 1988;25(2):113-117.
Abstract: In 17 healthy women, taking either a combination of 0.030 mg of ethinyl estradiol and 0.150 mg of levonorgestrel (n = 9) or a combination of 0.030 mg of ethinyl estradiol and 0.150 mg of desogestrel (n = 8) for oral contraception, the profiles of iron, calcium, copper, and zinc levels were investigated. The blood samplings were performed prior to oral contraception and after 3, 12, and 24 months' contraception, as well as within 2 months after discontinuation of the pill. No changes occurred in iron, calcium, and zinc levels. On the other hand, the copper level was significantly increased during oral contraception, yet returned to the initial level after discontinuation of contraception. No differences occurred between the two preparations for oral contraception.

Masse PG, Roberge AG. Long-term effect of low-dose combined steroid contraceptives on body iron status. Contraception 1992 Sep;46(3):243-252.
Abstract: The present study was aimed to evaluate iron metabolism in active and healthy adult women having taken oral contraceptives (OC) long-term. Mean dietary iron intake in age-matched control and experimental groups was adequate. Serum ferritin used as a marker for body iron stores was marginal in both groups underlying a high prevalence of deficient-iron reserves among subjects. This parameter was not correlated to the iron content of the diet. The serum iron concentration was significantly higher in OC users than control subjects (p less than 0.001). Biochemical results commanded a discussion on the pertinence of evaluating the total dietary iron intake and on the sensitivity of biochemical methods used to assess the iron status.

Masse PG, Van den Berg H, Livingstone MM, Duguay C, Beaulieu G. Nutritional and psychological status of young women after a short-term use of a triphasic contraceptive steroid preparation. Int J Vitam Nutr Res 1998;68(3):203-207.
Abstract: The present study was aimed to assess the psychological status of young healthy women after the administration of a triphasic contraceptive steroid preparation for six complete menstrual cycles. Subjects had never used oral contraceptives (OC) and had neither a familial history of depression nor psychological disturbances. OC-induced psychological disturbances were interpreted for years as evidence of pyridoxine (vitamin B6) deficiency. Other nutritional deficiencies, namely in cobalamin, folate and iron, can disturb the functioning of the central nervous system. In addition, a deficiency of any of these nutrients can lead to several anemia-induced symptoms that are highly susceptible to influence the psychological status. For ample evidence, nutritional status was then evaluated in parallel to psychological testing. Blood iron and vitamin levels of interest were found to be adequate and could not have biased the response to a psychological test (MMPI). This study showed that a 6-month Triphasil treatment did not modify significantly the psychological status of subjects. To our knowledge, this is the first psychological study on young never OC-users taking an identical triphasic contraceptive steroid preparation to investigate early psychological side-effects due to OC, at a similar time of the menstrual cycle, when nutritional status was also evaluated.

Matsui MS, Rozovski SJ. Drug-nutrient interaction. Clin Ther 1982;4(6):423-440. (Review)
Abstract: The effect of certain drugs on nutrient metabolism is discussed. Antituberculotic drugs such as INH and cycloserine interfere with vitamin B6 metabolism and may produce a secondary niacin deficiency. Oral contraceptives interfere with the metabolism of folic acid and ascorbic acid, and in cases of deficient nutrition, they also seem to interfere with riboflavin. Anticonvulsants can act as folate antagonists and precipitate folic acid deficiency. Therefore, in some cases, supplementation with folate has been recommended simultaneously with anticonvulsant therapy. Cholestyramine therapy has been associated with malabsorption of vitamins; several reports suggest that cholestyramine affects absorption of the fat-soluble vitamins K and D and, in addition, may alter water-soluble vitamins, including folic acid. The study of the interaction of drugs and nutrients is an area that deserves a greater attention in the future, especially in groups where nutrient deficiencies may be prevalent.

Mooij PN, Thomas CM, Doesburg WH, Eskes TK. Multivitamin supplementation in oral contraceptive users. Contraception 1991 Sep;44(3):277-288.
Abstract: The effects of oral contraceptives (OC) containing 30 micrograms of ethinyl oestradiol and of subsequent multivitamin and folic acid supplementation on vitamin A, total B2 [including its three individual constituents, i.e. riboflavine, RB; flavine-mono-nucleotide, FMN; and flavine-adenine-dinucleotide, FAD], B12, C and folate concentration in serum and red blood cells have been studied in a group of 59 non-pregnant female volunteers. The group taking OC comprised 28 women while 31 women were included in the group of non-OC users serving as the controls. The women were studied for four cycles. Blood samples were taken on days 3 and 23 of the first cycle to obtain baseline values of each analyte. Multivitamin and folic acid supplementation started on day 1 of the second cycle and this was continued daily throughout three consecutive cycles until the end of the study. Vitamin A levels were significantly higher and vitamin B12 levels were significantly lower in the group using OC. Comparison of the baseline values of vitamin total B2, FAD, C, serum and red blood cell folate as determined on days 3 and 23 of the first cycle of the two groups compared revealed no significant differences. Multivitamin and folic acid supplementation did not affect the concentrations of vitamin A and vitamin B12 with either group, whereas all other vitamins increased significantly in both groups. The consistency of each effect of multivitamin supplementation between the two groups was also tested. The degree of these effects was not statistically different between both groups. The results suggest that the vitamin status is indeed affected by OC treatment, but the effects of multivitamin supplementation are not different in OC and non-OC users. Supplementation during OC use or just after discontinuing treatment cannot be justified for healthy young women. However, in the case of women with a critical vitamin balance or higher folate needs, multivitamin supplementation may be considered.

Mooij PN, Thomas CM, Doesburg WH, Eskes TK. The effects of oral contraceptives and multivitamin supplementation on serum ferritin and hematological parameters. Int J Clin Pharmacol Ther Toxicol 1992 Feb;30(2):57-62.
Abstract: We have studied the effects of oral contraceptive (OC) use and of subsequent multivitamin supplementation on several hematological parameters. Hemoglobin (Hb), hematocrit (Ht), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH), and serum iron status (serum iron, total iron binding capacity and ferritin) were tested in groups of women with and without OC in view of preconceptional status. The group taking sub-50 OC comprised 28 women while 31 women were included in the group of non-OC users. Blood samples were taken on days 3 and 23 of the first cycle to obtain baseline values of each analyte. Multivitamin supplementation started on day 1 of the second cycle and this was continued daily throughout three consecutive cycles until the end of the study. Comparison of the baseline values of each parameter as determined on days 3 and 23 of the first cycle of the two groups revealed no significant different hematological parameters due to OC-use unlike the parameters of serum iron status which were all significantly increased for the group of OC-users as compared to the group of non-OC users. The effects of multivitamin supplementation on the hematological and iron status parameters were studied within each group. The consistency of each effect of multivitamin supplementation between the two groups was also tested. A multivitamin supplementation significantly decreased MCHC within either group, and caused increases of MCV, whereas Ht and MCH remained unaltered. With respect to the iron balance, serum iron and total iron binding capacity significantly increased, whereas serum ferritin decreased during multivitamin supplementation.

Palomo I, Grebe G, Valladares G, Bustos P, Ferrada M. [Hemoglobin, serum iron and transferrin saturation among users of intrauterine devices and oral contraceptive agents]. Rev Med Chil 1990 May;118(5):506-511. [Article in Spanish]
Abstract: We studied 60 females using either intrauterine device or taking oral contraceptive pills. Hemoglobin, serum iron, total iron binding capacity and saturation of transferrin were determined before and 4 and 10 months after starting a responsible paternity program. Women with a basal hemoglobin level below 12 g/dl were excluded. Age, parity and hematologic parameters were similar for both groups. A significant decrease in hemoglobin level and saturation of transferrin was observed at 10 months in intrauterine device users (13.6 to 13.1 g/dl and 36.2 to 26.9%, respectively). Use of oral contraceptive pills was not associated to hemoglobin decrease but a significant rise in saturation of transferrin was observed (36.2 to 43.9%, p less than 0.05).

Pietarinen GJ, Leichter J, Pratt RF. Dietary folate intake and concentration of folate in serum and erythrocytes in women using oral contraceptives. Am J Clin Nutr 1977 Mar;30(3):375-380.
Abstract: Conflicting reports regarding the possible effect of oral contraceptives agents (OCA's) on folate status prompted us to evaluate the relationship between dietary folate intake and the concentration of folate in serum and erythrocytes among users and nonsuers of OCA's during two consecutive menstrual cycles. Twenty-two women (ages 19 to 28) had been on combination type OCA's for 4 months or more and a control group of 18 women (ages 18 to 29) had not used OCA's for at least 6 months prior to this study. The serum folate levels were lower in the OCA users than in the controls and the difference was statistically significant on day 5 of the menstrual cycle (P less t-an 0.05) but not on day 20. However, the differences in the erythrocyte folate levels and dietary folate intakes were not statistically significant between the two groups of subjects. There was a consistently higher degree of correlation between serum folate and folate intake among the control women than among the OCA users. Hematological parameters such as hemoglobin, hematocrit, mean corpuscular volume, mean corpusclar hemoglobin, mean corpuscular hemoglobin concentration and red cell count were similar in the two groups. It is concluded that the use of OCA's produces significantly lower serum folate levels during the first week of the menstrual cycle in spite of adequate folate intake.

Prasad AS, Oberleas D, Moghissi KS, Stryker JC, Lei KY. Effect of oral contraceptive agents on nutrients: II. Vitamins. Am J Clin Nutr 1975 Apr;28(4):385-391.
Abstract: Clinical, biochemical and nutritional data were collected from a large population of women using oral contraceptive agents. Higher incidence of abnormal clinical signs related to malnutrition were observed in the lower (B) as compared to the higher (A) socioeconomic groups, and also in the nonsupplemented groups as compared to the supplemented groups in the B subjects. As a rule the intake of oral contraceptive agent subjects of vitamin A, C, B6 and folic acid did not differ from that of the controls As expected, subjects from the supplemented groups had higher intake of vitamin A, C, B6, thiamin, riboflavin and folic acid, and A groups had higher intake of vitamin C, B6, riboflavin and folic acid. Increased plasma vitamin A and decreased carotene levels were observed in oral contraceptive agent users. In general oral contraceptive agents had little or no effect on plasma ascorbic acid. Urinary excretion of both thiamin and riboflavin in subjects using oral contraceptive agents were lower in A groups. Erythrocyte folate and plasma pyridoxal phosphate was decreased in A groups due to oral contraceptive agents. Subjects who took supplements had higher levels of plasma vitamin A, ascorbic acid and folate. But urinary thiamin and riboflavin were higher only in group A subjects who took supplements.

Prasad AS, Lei KY, Moghissi KS, Stryker JC, Oberleas D. Effect of oral contraceptives on nutrients. III. Vitamins B6, B12, and folic acid. Am J Obstet Gynecol 1976 Aug 15;125(8):1063-1069.
Abstract: The interactions of oral contraceptive agents (OCA's) with vitamins were studied in a large population of women. In the upper socioeconomic groups, higher incidences of abnormal clinical signs related to vitamin deficiencies were seen in OCA users than in the control subjects. Plasma pyridoxal phosphate and red cell and serum folate were lower in subjects using OCA's in the upper socioeconomic group as compared to levels in the control subjects. Reduction in erythrocyte glutamic oxalacetic transaminase (EGOT) activity and elevation in the EGOT-stimulation test were observed in subjects using OCA's in both upper and lower socioeconomic groups. These observations suggest a relatively deficient state with respect to vitamins B6 and folic acid in OCA users. No significant effect on serum vitamin B12 was observed as a result of OCA administration.

Rose DP, Adams PW. Oral contraceptives and tryptophan metabolism: effects of oestrogen in low dose combined with a progestagen and of a low-dose progestagen (megestrol acetate) given alone. J Clin Pathol 1972 Mar;25(3):252-258.

Rose DP, Leklem JE, Brown RR, Linkswiler HM. Effect of oral contraceptives and vitamin B6 deficiency on carbohydrate metabolism. Am J Clin Nutr 1975 Aug;28(8):872-878.
Abstract: Oral glucose tolerance, urinary xanthurenic acid excretion, and plasma pyridoxal phosphate concentrations were determined in nine women taking oral contraceptives and in four controls. The tests were repeated after 4 weeks ingestion of a vitamin B6-deficient diet, and again after pyridoxine supplementation. Vitamin B6 deficiency, as judged by an increased xanthurenic acid excretion and reduced plasma pyridoxal phosphate, was associated with a deterioration in the glucose tolerance of the contraceptive steroid-treated group despite normal or elevated plasma insulin levels. This abnormality was reversed by pyridoxine. There was no change in the glucose tolerance of the vitamin B6-deficient controls. The observed pyridoxine-responsive alteration in carbohydrate metabolism may involve the complexing of insulin with xanthurenic acid with a consequent loss of biological activity. In addition, oral contraceptives may enhance gluconeogensis.

Salmeron P, Molto-Jorda JM, Villaverde R, Morales-Ortiz A, Martinez-Garcia FA, Fernandez-Barreiro A. [Cerebrovascular disease in young women]. Rev Neurol 1997 Jul;25(143):1003-1007. [Article in Spanish]
Abstract: INTRODUCTION: Cerebrovascular disease is an important cause of morbi-mortality. Although its incidence is maximal in older groups, its incidence in young people cannot be forgotten, even more if we consider the socioeconomic and personal consequences derived from it. There are several works on this subject but few of them analyze the specific problem of stroke in women. There is some degree of controversy in this subject, specially about the role of several factors which are more prevalent or either exclusive for women. OBJECTIVES: We wanted to analyze the risk factors and clinical characteristics in a group of women under 45 who suffered a stroke and also to compare these risk factors between women under 35 and those from 35 to 45. MATERIAL AND METHODS: We have carried out a descriptive study, including 61 women under 45 admitted to our centre consecutively between January 1989 and October 1996. RESULTS: Among the most prevalent factors we have found hypertension (27.8%), tobacco consumption (24.5%) and the presence of cardiac abnormalities (22.9%), specially associated to valvular pathology, as well as a higher incidence of contraceptives consumption in women under 35 (80%). CONCLUSIONS: These factors are similar to those found in studies on the general population of young people. Our data indicate that the relevance of the main factors for stroke is common for both sexes and is also significant in young patients.

Shenfield GM. Oral contraceptives. Are drug interactions of clinical significance? Drug Saf 1993 Jul;9(1):21-37. (Review)
Abstract: There is a large quantity of literature on drug interactions with oral contraceptive (OC) steroids although their incidence is not known. The potential clinical significance of some interactions makes it important for all prescribing doctors and dentists to have some knowledge of the topic. Interactions may be divided into those in which OC effectiveness is impaired, causing breakthrough bleeding or pregnancy, those in which OC activity is enhanced by other drugs and those in which OCs interfere with the metabolism or activity of other therapeutic agents. Consideration of their pharmacology indicates that impairment of OC effect is most likely to be due to interference with ethinylestradiol. This is because this compound is sulphated in the gut wall, hydroxylated and glucuronidated in the liver, and undergoes enterohepatic recirculation. The progestogens are only metabolised in the liver and have no significant enterohepatic recirculation. Protein binding interactions are rarely of clinical importance. OC plasma concentrations may be reduced by induction of hepatic metabolism in the case of griseofulvin, rifampicin (rifampin) and several anticonvulsant drugs; valproic acid (sodium valproate) does not have this effect. Antibiotics may interfere with enterohepatic recirculation of ethinylestradiol and reduce plasma levels of active hormone. This is probably only of significance in a subgroup of women who may sometimes be suspected on history, but cannot be identified by any diagnostic test. Reasons for differences between case reports and formal studies of interactions with antibiotics are discussed. Plasma concentrations of ethinylestradiol may be increased by ascorbic acid (vitamin C) and paracetamol (acetaminophen) which compete with it for sulphation in the gut wall. Theoretically, problems may arise if these agents are stopped suddenly. Imidazole antifungal agents can inhibit ethinylestradiol metabolism and increase its plasma concentrations but the clinical significance of this is unknown. OCs have been shown to inhibit metabolism of many therapeutic drugs and increase their plasma concentrations. This may be of clinical significance in the case of benzodiazepines which are hydroxylated in the liver, but clinical effects are less certain with the other agents. OCs may induce metabolism of other drugs which are glucuronidated, including some benzodiazepines and analgesics. The clinical significance of this type of interaction is also unknown. It is suggested that all prescribers should remember to ask about OCs when taking a drug history and to consider the possibility of interactions with other drugs.

Shojania AM, Wylie B. The effect of oral contraceptives on vitamin B12 metabolism. Am J Obstet Gynecol 1979 Sep 1;135(1):129-134.
Abstract: Serum vitamin vitamin B12 levels were determined in 199 women who were on a regimen of oral contraceptives of either the combination or sequential type and in a control group of 196 women. The group using oral contraceptive agents (OCA) had significantly lower serum levels of vitamin B12 vitamin as compared to those of the control group. A total of 19 women using OCAs had serum vitamin B12 levels that were lower than normal values. However, the Schilling test and urinary methylmalonate excretion in this group were normal. The OCA group had a significantly lower total serum vitamin B12 binding capacity, a lower total transcobalamin I level, and a higher transcobalamin III level. Our study suggests that the fall of serum vitamin B12 in OCA users is due to the changes in vitamin B12 binders of serum and does not represent vitamin B12 deficiency. Therefore, according to our data, there is no justification for vitamin B12 supplementation in users of oral contraceptives.

Steegers-Theunissen RP, Van Rossum JM, Steegers EA, Thomas CM, Eskes TK. Sub-50 oral contraceptives affect folate kinetics. Gynecol Obstet Invest 1993;36(4):230-233.
Abstract: The effects of long-term use of oral contraceptives containing less than 50 micrograms of estrogen (sub-50 OCs) on the kinetics of folic acid monoglutamate, vitamin B12 levels, and iron status have been studied in 29 OC users (Marvelon) and in 13 women without OC use serving as controls. At 210 min after oral folate loading the median serum folate concentration was significantly lower in OC users when compared to the control group. OC users showed significantly higher total iron binding capacity and significantly lower serum vitamin B12 concentrations. This data demonstrates that sub-50 OCs significantly affect folate kinetics and vitamin B12 levels. However, the folate and vitamin B12 status does not seem to be at risk.

Thorp VJ. Effect of oral contraceptive agents on vitamin and mineral requirements. J Am Diet Assoc 1980 Jun;76(6):581-584.
Abstract: Oral contraceptive agents alter the metabolism of some nutrients, which could affect nutritional requirements. The effects of oral contraceptives on pyridoxine, folacin, thiamin, riboflavin, vitamin A, ascorbic acid, zinc, and copper as determined by studies done in the last five years are reviewed. Evidence for actual nutritional deficiencies due to the use of oral contraceptives is still insufficient, and more research is needed. Supplements are advised only for those women in whom other factors, such as disease, impair nutritional adequacy.

Threlkeld DS, ed. Hormones, Oral Contraceptives. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Jul 1994.

Vir SC, Love AH. Effect of oral contraceptive agents on thiamin status. Int J Vitam Nutr Res 1979;49(3):291-295.
Abstract: A cross-sectional and follow up study of oral contraceptive agent (OCA) users revealed no adverse effects of OCA on erythrocyte transketolase activity (ETK) or thiamin pyrophosphate effect (TPP effect). In the cross-sectional study group, thiamin intake was below the recommended in only 19.2 per cent subjects and thiamin intake/100 kcal/day revealed a significant negative correlation with TPP effect. Routine prophylactic administration of thiamin was not indicated in OCA users.

Werbach MR. Foundations of Nutritional Medicine. Tarzana, CA: Third Line Press, 1997, 210-211. (Review)

Wynn V, Adams PW, Folkard J, Seed M. Tryptophan, depression and steroidal contraception. J Steroid Biochem 1975 Jun;6(6):965-70.

Wynn V. Vitamins and oral contraceptive use. Lancet 1975 Mar 8;1(7906):561-564.
Abstract: Reports concerning the interaction between steroidal contraceptives (the combined pill) and vitamins indicate that in users the mean serum-vitamin-A level is raised and the mean serum-vitamin-B2 (riboflavine), vitamin-B6 (pyridoxine), vitamine-C, folic-acid, and vitamin-B12 levels are reduced. Other vitamins have been insufficiently studied for comment. Biochemical evidence of co-enzyme deficiency has been reported for vitamin B2, vitamin B6, and folic acid. Clinical effects due to vitamin deficiency have been described for vitamin B6--namely, depression and impaired glucose tolerance. Folic-acid deficiency with megaloblastic anaemia has been reported in only 21 cases.

Zamah NM, Humpel M, Kuhnz W, Louton T, Rafferty J, Back DJ. Absence of an effect of high vitamin C dosage on the systemic availability of ethinyl estradiol in women using a combination oral contraceptive. Contraception 1993 Oct;48(4):377-391.
Abstract: Previous studies in small numbers of women have suggested that the administration of gram quantities of ascorbic acid interferes with the conversion of ethinyl estradiol (EE2) to its sulfates, leading to higher blood levels of EE2. The possibility of such potentiation has been investigated in 37 women using a combination monophasic oral contraceptive (30 micrograms EE2 and 150 micrograms levonorgestrel) for two consecutive cycles. Concomitant daily administration of 1 g ascorbic acid taken 1/2 hour before OC intake, was randomly assigned to the first or second cycle of OC use. On the first and 15th day of OC intake, blood samples were drawn 11 times over a 12-hour interval and Cmax and AUC(0-12 h) calculated. On pill days 10 and 21, only 6-hour post-intake samples were obtained. Samples were analyzed for levels of ascorbic acid, free and sulfated ethinyl estradiol (and a number of other parameters). Cmax and AUC values for EE2 and EE2-sulfate in cycles with and without ascorbic acid were evaluated statistically by the Grizzle model for days 1 and 15 and the ratios of day 15/day 1 for each of the substances. No effect of ascorbic acid was observed (alpha = 0.05, 1-beta = 0.9). Only on day 15 was there a significantly lower AUC for EE2-sulfate in the presence of ascorbic acid intake. Thus, the competition between ascorbic acid and EE2 for sulfation does not lead to an increased systemic availability of EE2 and is, therefore, unlikely to be of any clinical importance. Ascorbic acid can, therefore, be removed from the list of drugs interfering with the pharmacokinetics of ethinyl estradiol.

Zarcone R, Bellini P, Carfora E, Vicinanza G, Raucci F. [Folic acid and cervix dysplasia.] Minerva Ginecol 1996 Oct;48(10):397-400. [Article in Italian]
Abstract: The localized folate deficiency, which is sometimes misdiagnosed as cervical dysplasia, because of morphological similarities between the cytologic features of megaloblastosis seen with folate deficiency and the changes associated with dysplasia, could be a component of the dysplastic process. In this study we attempted the effect of oral folic in women with cervical dysplasia. A total of 154 subjects with grade 1 or 2 CIN were randomly assigned either 10 mg of folic acid or a placebo daily for 6 months. Clinical status, human papillomavirus type 16 infection and blood folate levels were monitored at 2 month intervals. After 6-months no significant differences were observed between supplemented and unsupplemented subjects regarding dysplasia status, biopsy results, or prevalence of human papillomavirus type 16 infection. Folate deficiency the initiation of cervical dysplasia, but folic acid supplements do not alter the course of established disease.