Listing of References
Which Document the Adverse Effects of Birth Control Pill
by Jeffrey Dach MD
Br Med J. 1971 August 28; 3(5773): 495–500. Oral Contraceptives, Depression, and Libido Brenda N. Herzberg, Katharine C. Draper, Anthony L. Johnson, and Gillian C. Nicol Twenty-five per cent. stopped using oral- contraceptives because of side effects, the most common of which were headaches, depression, and loss of libido.The I.U.D. was acceptable to 74% of women, the only adverse affect being breakthrough bleeding. The improvement in mood and the increase in libido in the I.U.D. group suggest that this is a safe and acceptable method of contraception.
Common Nutrient Depletions Caused by Pharmaceuticals ALTERNATIVE & COMPLEMENTARY THERAPIES—FEBRUARY 2007 Chris D. Meletis, N.D., with Nieske Zabriskie, N.D. Estrogen and Progestins Hormone replacement therapy (HRT) is a common prescription for menopausal women. These estrogen/progestin combinations are used to decrease symptoms associated with menopause, such as hot flashes, vaginal dryness, sleep disturbances, and fatigue. In the United States, from 1999 to 2002, approximately 15 million women were on HRT, annually accounting for 90 million prescriptions per year.2 The Women’s Health Initiative study was widely publicized in 2002; this study demonstrated that HRT increases the risk of coronary heart disease, breast cancer, and strokes.3 Following the publication of the study, HRT prescriptions decreased by approximately 32 percent in 2003.4 Oral contraceptive pills (OCPs) also contain estrogen/progestin combinations. OCPs have been shown to increase the risk of cardiovascular events as well as breast, cervical, and liver cancer. 5,6 Estrogen/progestin hormones have been shown to deplete many nutrients. Research suggests that estrogens deplete several B vitamins significantly. Oral estradiol decreases pyridoxine (vitamin B6) and albumin in postmenopausal women.7 This vitamin B6 deficiency is believed to be associated with a disruption in tryptophan metabolism.8 Other research indicates that oral contraceptives deplete riboflavin (vitamin B2), folic acid, cobalamin (vitamin B12), ascorbic acid (vitamin C), and zinc.9 Other research indicates a decrease by 40 percent of both folic-acid and serum B12 levels with oral contraceptive use.10 Clinically, lower folic-acid levels appear to correlate with increased prevalence of abnormal Papanicolaou (Pap) smear results. In addition, studies have shown that estrogen supplementation increases magnesium uptake into bone and soft tissue, causing lowered blood magnesium levels. With low magnesium intake, this alters the calcium-to-magnesium ratio. This change in ratio can cause an increase in coagulation, which may lead to an increased risk of thrombosis that occurs with estrogen supplementation. 11
home.caregroup.org/clinical/altmed/interactions/Drug_Classes/Oral_Contracept.htm Oral Contraceptives drug class: Oral Contraceptives (Birth Control Pills) trade names: Brevicon®, Demulen®, Enovid®, Genora®, Levlen®, Loestrin®, Micronor®, Modicon®, Nordette®, Norinyl®, Ortho-Novum®, Ovcon®, Ovral®, Ovrette®, Triphasil®, etc. type of drug: Various combinations of artificial female hormones, specifically estrogens and progestins or only progestins. Note: hormone replacement therapy and oral contraceptives employ different forms of estrogen and/or progestin. used to treat: Pregnancy prevention; menstrual irregularities and endometriosis. overview of interactions: nice summary of various vitamin and mineral deficiencieds induced by OCs Vitamin A level decreased
Effects of oral contraceptives on vitamin A metabolism in the human and the rat’ David L. Yeung,2 Ph.D. ABSTRACT In this study, the effects of oral contraceptives (OC) on vitamin A metabolism in the human and rat were examined. Data obtained from the human study showed that the mean plasma vitamin A levels and basal body temperature of females taking OC were significantly higher than control subjects. However, there was no statistical correlation between the vitamin A levels and basal body temperature. The elevation of plasma vitamin A levels in the OC subjects was found not to be due to variation in dietary vitamin A intake or blood hematocrit values. The physiologic implication of the higher plasma vitamin A levels in the OC subjects is not clear. In the rat, Ovral, an OC agent, given as a saline suspension by stomach intubation daily for 4 weeks did not have any effect on plasma vitamin A. However, it markedly raised the liver vitamin A depletion rate and the rate of utilization of the vitamin. This indicated that rats given OC had a higher vitamin A requirement level. Whether oral contraceptives do alter vitamin A requirement in the human remains to be investigated. Am. J. Clin. Nutr. 27: 125-129, 1974. ascorbic acid decreased
Oral contraceptives and ascorbic acid’ Jen’y M. Rivers,2 Ph.D. ABSTRACF Plasma, heukocyte, and platelet ascorbic acid levels are decreased in women ingesting oral contraceptive steroids. Studies have shown that it is the estrogenic component of the oral contraceptive agents that is associated with the decreased ascorbic acid concentrations. Urinary excretion of ascorbic acid does not appear to be increased by the steroids. Although serum levels of copper are increased by estrogens and oral contraceptives, ascorbic acid catabolism does not appear to be increased (unpublished). Our preliminary data on tissue uptake of ascorbic acid suggest that changes in tissue distribution are one possible answer for the observed effects of the steroids on blood levels of ascorbic acid. Am. J. Clin. Nutr. 28: 550-554, 1975. Most Serotonin Metaboism in OCs
Contraception. 1982 Aug;26(2):193-204. Serotonin metabolism and depression in oral contraceptive users. Shaarawy M, Fayad M, Nagui AR, Abdel-Azim S. Abstract Serotonin and nicotinic acid ribonucleotide metabolic pathways of tryptophan metabolism were studied before and after tryptophan load test in thirty women using oral contraceptive steroids for a period of 2 to 5 years. Ten of them were suffering from depression. Another ten healthy women participated in this study as a control group. Twenty-four-hour urinary excretion of serotonin, 5-hydroxyindole acetic acid and total 5-hydroxyindoles were estimated as indices of serotonin pathway metabolites, while xanthrenate excretion was determined as an index of tryptophan oxygenase pathway. Plasma cortisol, urinary 17-oxosteroids and 17-hydroxycorticosteroids were determined to assess adrenal cortical function. Urinary creatinine output was assayed to check the adequacy of 24-hr urine collection. The changes induced by oral contraceptive steroids on tryptophan and corticosteroid metabolism were correlated with the associated depression. Changes in serotonin metabolism were demonstrated in the depression group before and after tryptophan load test, while in the non-depression group before and after tryptophan load test, while in the non-depression group, these changes were only demonstrated after tryptophan load test. Results indicated the alteration in tryptophan metabolism are usually well compensated in the non-depression group but may accentuate or precipitate the development of depression in susceptible women.
Compr Psychiatry. 1979 Jul-Aug;20(4):347-58. Oral contraceptives and depressive symptomatology: biologic mechanisms. Parry BL, Rush AJ. The biological mechanisms through which oral contraceptives influence the central nervous system and produce depression were examined. Oral contraceptives reduce the level of serotonin and norepinephrine available at the central adrenergic receptor sites, alter folate and B12 levels, and perhaps influence hypothalamic releasing hormone levels. The level of serotonin is influenced in the following manner. The estrogens in oral contraceptives increase tryptophan available for the brain to convert to serotonin and tryptamine. Depression is associated with lower levels of serotonin, tryptamine, and perhaps tryptophan in the brain. Estrogens in oral contraceptives may also alter pryridoxal phosphate which in turn affects the production of serotonin. Oral contraceptives possibly lower norepinephrine levels by 1) decreasing tyrosine; 2) influencing coenzymes necessary to norepinephrine production; and 3) increasing monoamine oxidase levels. Oral contraceptives apparently inhibit the metabolism of folate and B12, and lower levels of these substances are associated with depressive symptoms. Decreased norepinephrine and serotonin levels may inhibit the release of gonadotrophin-releasing hormones, and these hormones may in turn influence behavior. Recommendations to clinicians were: 1) patients should be screened for a history of depression prior to prescribing oral contraceptives; 2) pill users should be monitored for depression; and 3) 25 mg daily of pyxidoxine should be administered if a patient taking oral contraceptives is deficient in B6. Pyridoxine B6 deficiecy treate depression of BCP s
The Lancet Volume 301, Issue 7809, 28 April 1973, Pages 897-904
EFFECT OF PYRIDOXINE HYDROCHLORIDE (VITAMIN B6) UPON DEPRESSION ASSOCIATED WITH ORAL CONTRACEPTION
P. W. Adams, V. Wynn, D. P. Rose1, M. Seed, J. Folkard and R. Strong Abstract The known association between combined estrogen-progestagen oral contraceptive (o.c.) administration and abnormalities of tryptophan and vitamin-B6 metabolism has been investigated in a group of 22 depressed women whose symptoms were judged to be due to the effects of o.c. 11 of these women showed biochemical evidence of an absolute deficiency of vitamin B6. In a double-blind crossover trial this group of women responded clinically to the administration of pyridoxine hydrochloride. The remaining 11 women showed no such response. Placebo administration was without effect. Possible mechanisms for depression due to o.c. use and its treatment with pyridoxine hydrochloride are discussed. Tyrosine Metabolism in OCs
Effect of oral contraceptives on tryptophan and tyrosine availability: evidence for a possible contribution to mental depression. Møller SE. Abstract The plasma concentrations of branched-chain and aromatic amino acids, free tryptophan, and kynurenine have been determined in oral contraceptive users and comparable controls. There were no differences between progestogen users and controls in either of the biochemical measurements. The estrogen-progestogen users showed elevated plasma levels of total tryptophan and decreased levels of tyrosine. Mestranol was less potent than ethinylestradiol on the effect on plasma tyrosine. Mestranol was less potent than ethinylestradiol on the effect on plasma tyrosine. There was a clear trend that the incidence of adverse reactions was related to the decrease in tyrosine levels. The plasma ratio of tryptophan to competing amino acids was increased in the estrogen-progestogen users, whereas the ratio of tyrosine to competitors was severely decreased suggesting a decreased brain tyrosine concentration. It is suggested that a substrate-limited reduction in brain noradrenaline synthesis may contribute to the occurrence of depressive symptoms in susceptible individuals on estrogen-progestogen contraceptives.
Life Sci. 1995;56(9):687-95.
Tyrosine metabolism in users of oral contraceptives. Møller SE, Maach-Møller B, Olesen M, Madsen B, Madsen P, Fjalland B. Department of Clinical Pharmacology, St. Hans Psychiatric Hospital, Roskilde, Denmark. Abstract Brain noradrenaline takes part in the regulation of several brain functions. The formation of brain noradrenaline depends on brain tyrosine (Tyr) levels, which associates with the ratio in plasma of Tyr to other large, neutral amino acids (LNAA). Tyr metabolism has been studied in users of the new generation combined oral contraceptives (OC) and comparable controls at the follicular, mid-cycle, and luteal phases of the menstrual cycle. OC users showed significantly increased plasma Tyr transaminase activity, and significantly decreased plasma Tyr and Tyr/LNAA levels at mid-cycle and luteal phase, whereas plasma total 3-methoxy-4-hydroxyphenylglycol (MHPG) was not affected. Following an oral protein load, the area under the curve in plasma of Tyr and Tyr/LNAA in OC users at the luteal phase were 43% and 29%, respectively, of control levels. The results suggest that the decreased Tyr availability to the brain in OC users may result in a substrate-limited reduction of brain noradrenaline formation, which, secondarily, may contribute to disturbances of mood, coping mechanisms, and appetite in susceptible subjects. Psychosis from OCs
South Med J. 1969 Feb;62(2):190-2.
Psychosis associated with the use of oral contraceptive agents. Kane FJ Jr.
Am J Obstet Gynecol. 1971 Dec 15;111(8):1013-20.
Nervousness and depression attributed to oral contraceptives: a double-blind, placebo-controlled study. Goldzieher JW, Moses LE, Averkin E, Scheel C, Taber BZ. letter about depresion caused by OC's
www.ncbi.nlm.nih.gov/pmc/articles/PMC1129699/pdf/westjmed00295-0095b.pdf www.ncbi.nlm.nih.gov/pmc/articles/PMC1129699/?page=1 www.ncbi.nlm.nih.gov/pubmed/9076409 West J Med. 1975 March; 122(3): 255–256. Letter: more on oral contraceptives.D A Rockwell
Oral Contraceptives, Pyridoxine, and Depression
FRANK WINSTON M.B.B.S.1 Am J Psychiatry 130:1217-1221, November 1973 Taking steroid hormones for the control of ovulation may be associated with depressive mood changes in women who are predisposed to depression. The author postulates that such depression may in some cases be due to inhibition of the synthesis of biogenic amines in the central nervous system as the result of a functional pyridoxine deficiency caused by the estrogen in the oral contraceptives. It is suggested that this depression might be prevented or alleviated by the administration of supplementary vitamin B6. lower beta carotene Vitamin A in OC users Eur J Clin Nutr. 1997 Mar;51(3):181-7. Use of oral contraceptives and serum beta-carotene. Berg G, Kohlmeier L, Brenner H. Source Department of Epidemiology, University of Ulm, Germany. Abstract OBJECTIVE: Antioxidants, in particular carotenoids, may influence the risk for cardiovascular disease. This study investigates the influence of oral contraceptives (OC) on the serum concentration of beta-carotene, which may in turn affect the risk of cardiovascular diseases due to its antioxidative impact. DESIGN: Cross-sectional epidemiologic study. Examinations included a detailed questionnaire on medical history and lifestyle factors, a 7 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 (n = 610). RESULTS: Overall, the use of OC was negatively associated with serum beta-carotene concentration in bi- and multivariable analyses after adjustment for age, smoking, alcohol consumption, dietary intake of beta-carotene, use of vitamin supplements, body mass index, pregnancies, and serum concentrations of total triglyceride and cholesterol. A strong interaction between OC use and age on beta-carotene concentration was observed. While no relationship between OC use and serum beta-carotene was seen in the youngest age-group (18-24 y), there was a modest but significant negative association between OC use and beta-carotene levels among 25-34 y old women. The use of OC was associated with a strong decrease in beta-carotene levels among 35-44 y old women. The interaction between OC use and age could partly be explained by age dependent use of OC with higher estrogen content. CONCLUSIONS: OC use seems to be strongly related to serum beta-carotene levels, particularly among women above the age of 35. Further studies are needed to clarify the underlying mechanisms of this association and its implications for health risks of OC use. Beta-carotene, a provitamin with antioxidant effects, may substantially reduce the risk of coronary artery disease and acute myocardial infarction. A cross-sectional epidemiologic study involving 610 West German women 18-44 years of age indicates that oral contraceptive (OC) use has a negative impact on serum levels of beta-carotene. 195 respondents (32%) were current OC users, 322 (53%) were past users, and 91 (15%) had never used OCs. Median serum beta-carotene levels were significantly lower in current OC users (25.1 mcg/dl) than in past (32.5 mcg/dl) and never users (31.2 mcg/dl). The percentage of women with beta-carotene levels below the desirable value of 21.5 mcg/dl was significantly higher in the current OC use group (34%) than in the 2 other groups combined (21%), yielding an overall odds ratio (OR) of 1.9 (95% confidence interval, 1.3-2.8). The strength of the association between OC use and decreased beta-carotene increased with age (OR of 1.5 for women 18-24 years, 1.9 for those 25-34 years, and 3.4 for 35-44-year old women). In addition, the decrease of beta-carotene was larger for OCs containing 50 mcg of ethinyl estradiol than for low-dose formulations. Also observed were significant associations between serum beta-carotene levels and smoking, alcohol intake, body mass index, triglycerides, nutrient intake, and total cholesterol levels. Although further studies are required to identify the mechanisms underlying the OC-beta-carotene association and define its implications for women's health, OC users should be advised to consume vegetables rich in beta-carotene. Higher copper levels in OC users
Eur J Clin Nutr. 1998 Oct;52(10):711-5.
Effect of oral contraceptive progestins on serum copper concentration. Berg G, Kohlmeier L, Brenner H. Source Department of Epidemiology, University of Ulm, Germany. 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. High serum copper concentration--a well-known effect of oral contraceptive (OC) use--has been linked to increased mortality from cardiovascular disease. The influence of OCs containing newer progestins has not been investigated, however. This concern was addressed in a 1987-88 cross-sectional epidemiologic study of 610 nonpregnant, nonlactating West German women 18-44 years of age. 195 women (32.1%) were current OC users, but only 152 of these women were able to cite the name of the formulation they were taking. In 70% of cases, the OC contained less than 45 mcg of ethylestradiol (median dose, 32.4 mcg). The most common progestin components were desogestrel (41%) and levonorgestrel (30%). Mean serum copper concentration was higher among users of all types of OCs than among non-users, but this concentration varied more strongly according to the OC's progestin compound than its estrogen content. The greatest increase in serum copper (55% compared with non-users) was recorded in users of OCs containing anti-androgen progestins, followed by desogestrel (46%), norethisterone/lynestrenol (42%), and levonorgestrel (34%). The increase in serum copper was more pronounced in women taking OCs containing 45 mcg or less of ethylestradiol than in users of OCs with a high estrogen dose. In the regression models, the different progestin compounds alone explained 28% of the total variance in serum copper concentration. Further investigation of OC-induced increases in serum copper concentration and their impact on cardiovascular risk are warranted.
Am J Clin Nutr. 1981 Aug;34(8):1479-83.
Zinc and copper nutriture of women taking oral contraceptive agents. Vir SC, Love AH. Abstract A cross-sectional and follow-up study of young women taking oral contraceptive agents revealed a marked increase in serum copper levels. This increase was significant after the taking of oral contraceptive agents for 3 months. No significant effect of oral contraceptive agents on serum zinc and hair levels or copper were observed. There was no correlation between duration of oral contraceptive agent therapy and zinc or copper concentrations in serum or hair. Serum and hair concentration of zinc or copper were also not significantly correlated. It is well known that OC (oral contraception) may provoke changes in metal metabolism. This study examines the effects of OC use in serum and hair level of both zinc and copper. The study involved a control group of 24 women, aged 18-20, who had never been on OC; a cross-sectional experimental group of 33 women, aged 18-23, who had been using combined OC for at least 3 months; a follow-up experimental group of 12 women, aged 18-22, who were about to start OC treatment for the first time, and who were examined again at 3 and at 6 months. Blood samples and hair samples were collected and analyzed with the Vir and Love method. Mean serum copper concentration was significantly higher in OC users; hair copper values were also higher, but the difference was not a significant one. Mean serum zinc levels were slightly lower, and hair zinc levels slightly higher in OC users; differences between users and nonusers, however, were not significant. No significant correlation was found between duration of OC treatment and serum and hair metal values. In the follow-up experimental group mean serum copper level increased at 3 months of OC treatment, and mean hair copper values decreased; there were no significant differences at 3 and at 6 months. Mean serum zinc concentration and mean hair zinc concentration also decreased in the control group, but the decline was not significant. No significant correlation was found between serum and hair concentration of zinc or copper in the control or in the experimental group. These findings are consistent with others reported in the published literature. The biological significance of the rise in serum copper levels, and of the slight alteration in serum zinc level after OC use is still not known.
full text explains biochemicstry of B6 deficiency from BCPs
Am J Clin Nutr. 1971 Jun;24(6):684-93. Vitamin B 6 metabolism in users of oral contraceptive agents. I. Abnormal urinary xanthurenic acid excretion and its correction by pyridoxine. Luhby AL, Brin M, Gordon M, Davis P, Murphy M, Spiegel H
Am J Clin Nutr. 1972 May;25(5):494-8. Effects of dietary vitamin B 6 deficiency and oral contraceptives on the spontaneous urinary excretion of 3-hydroxyanthranilic acid. Price SA, Rose DP, Toseland PA.
Metabolism. 1973 Feb;22(2):165-71.
Urinary excretion of quinolinic acid and other tryptophan metabolites after deoxypyridoxine or oral contraceptive administration.
Rose DP, Toseland PA. Abstract The urinary excretion of quinolinic acid and some other tryptophan metabolites has been determined after a 2-g L-tryptophan load in a deoxypyridoxine-treated subject, in 20 women receiving estrogen-containing oral contraceptives, in and a control group of 12 women taking no steroids. In both situations there were increases in the excretion of quinolinic acid and 3-hydroxyanthanillic acid, as well as 3-hydroxykynurenine and xanthurenic acid. These changes were reversed by pyridoxine administration and are considered to reflect an inhibitory effect of estrogens and deoxypyridoxine on vitamin B6 dependent enzymes. Although the principal enzyme of the tryptophan-nicotinic acid ribonucleotide pathway affected by imparied pyridoxal phosphate function is kynureninase, the present results are consistent with the existence of an unidentified enzyme beyond the formation of 3 hydroxyanthranilic acid requires the coenzyme.
Increased typtophan maetbolites in urine suggesting B6 deficiency
Acta Vitaminol Enzymol. 1982;4(1-2):45-54.
Therapy of side effects of oral contraceptive agents with vitamin B6. Bermond P. Studies carried out in different countries during the last 15 years have provided evidence that supplementation with (or excess of) estro-progestational hormones may be accompanied by an increased urinary excretion of tryptophan metabolites, as happens in pyridoxine deficiency. Further methods of assessment of vitamin B6 in humans have confirmed an impaired status in women using hormonal contraception. Disturbances in the metabolism of tryptophan have been shown to be responsible for such symptoms as depression, anxiety, decrease of libido and impairment of glucose tolerance occurring in some of the OCA users. Administration of 40 mg of vitamin B6 daily not only restores normal biochemical values but also relieves the clinical symptoms in those vitamin B6 deficient women taking OCA's. Further studies are justified to clarify whether vitamin B6 supplementation may contribute to improving depression also in other situations with hyperoestrogenism (pregnancy, puerperium, estro-progestational treatments, etc.), as well as correcting metabolic impairments, such as a minor alteration of glucose tolerance.
British Journal of Nutrition (1986), 56, 363-367 363
The effect of oral contraceptives on the apparent vitamin B, status in some Sudanese women BY ELTAYEB Y. SALIH, ASMA A. ZEIN AND RIAD A. BAYOUMI Faculty of Medicine, University of Khartoum, PO Box 102, Khartoum, Sudan (Received 4 April 1986 - Accepted 23 April 1986)
Rose (1966) reported that oral contraceptive (OC) users frequently show signs of abnormal tryptophan metabolism which are similar to those observed in vitamin B, deficiency. Subsequently many workers have attempted to show vitamin B, deficiency among OC users (Rose et al. 1972, 1973a, b; Salkeld et al. 197.3; Adams et al. 1974; Miller et al. 1974; Prasad et al. 1975; Shane & Contractor, 1975; Pitkin, 1976; Rose, 1978). Women using OC are known to develop functional and apparent biochemical manifestations similar to those observed with vitamin B6 deficiency and our observations are in agreement with those earlier findings (Rose et al. 1973a, b; Adams et al. 1973; Nobbs, 1974), even though a low dose of OC was used by women in this study. The depression and other symptoms and signs usually associated with the use of OC were also observed in Sudanese women and the incidence of such symptoms and signs was more frequent in the OC users who had biochemical evidence of vitamin B, deficiency.
altered tryptophan metabolism
Acta Vitaminol Enzymol. 1975;29(1-6):151-7.
Effects of oral contraceptives on tryptophan metabolism and vitamin B6 requirements in women. Brown RR, Rose DP, Leklem JE, Linkswiler HM. 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. 10 healthy control women (mean age 22.3 years) and 15 women (23.2 years) who had used oral contraceptives (OCs) for at least 6 months were given a diet low in vitamin-B6 containing the equivalent of .19 mg of pyridoxine/day for 4 weeks. All subjects were started on the study at the same time in their menstrual cycle. After this depletion period, subjects continued to ingest the same diet but with daily supplements of .8, 2, or 20 mg of pyridoxine hydrochloride for another 4 weeks. Before starting the depletion diet, and at weekly intervals throughout the study, several indexes of vitamin-B6 nutrition were measured in each subject. Marked elevation in excretion of trytophan metabolites occurred in OC users after tryptophan loads. However, other indexes of vitamin-B6 nutritional state, including urinary 4-pyridoxic acid excretion, urinary cystathionine excretion, plasma pyridoxal phosphate concentrations, and erythrocyte asparate and alanine aminotransferases, were not different between controls and OC users. The excretion of metabolites after oral loading doses of L-kynurenine (which bypasses tryptophan oxygenase) was elevated in OC users, indicating that abnormal metabolism of tryptophan was not due only to induced tryptophan oxygenase. The data indicate that OC use 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.
J Nurse Midwifery. 1984 Nov-Dec;29(6):386-90.
Effects of oral contraceptives on vitamins B6, B12, C, and folacin. Veninga KS. Abstract This article examines the effects of oral contraceptives (OCs) on the metabolism of vitamin B6, folacin, vitamin B12, and vitamin C and outlines educational strategies through which nurse-midwives can improve their clients' nutritional health. Evidence of vitamin B6 deficiency has been found among combination OC users in numerous studies. Derangement of tryptophan metabolism occurs within 1 month of initiation of OC use. OCs also may cause a deficiency of pyridoxal phosphate, a coenzyme needed for the tryptophan-nicotinic acid pathway. It is recommended that OC users take 1-1.5 mg/day of supplemental vitamin B6; new OC users should take 5 mg/day until plasma levels of 1.5-2 mg have been achieved. It has also been noted that OCs impair folacin metabolism, as evidenced by folacin deficiency in serum and an increase in urinary formiminoglutamic acid secretion. It is generally ageed that folacin, which plays a critical role in fetal development, can become deficient in late pregnancy and in women who become pregnant shortly after discontinuing longterm OC use. OCs further influence serum B12 concentrations and the possiblity of iron deficiency anemia. Among patients who are well nourished and nonsmokers, OC use does not appear to jeopardize vitamin C levels. An assessment of a patient's nutritional health should begin with a demographic evaluation focused on her age, parity, alcohol and nicotine consumption, and use of medications and vitamins. Next, a dietary evaluation should be made by having the patient record everything she eats during the following week. It should be remembered that adolescents, lactating women, those with repeated pregnancies closely spaced, and women who are chemically dependent have greater nutritional needs than normal. Nutritional counseling is particularly needed by OC users, who may be deficient in 1 or more of the essential vitamins. Nutritional counseling should be an ongoing part of any comprehensive patient-teaching program.
Adv Clin Chem. 1976;18:247-87.
Effects of oral contraceptives on vitamin metabolism. Anderson KE, Bodansky O, Kappas A. Abstract Literature on the effects of oral contraceptives (OCs) on vitamin metabolism is reviewed. OCs have been reported to markedly increase serum levels of Vitamin-A. OCs may induce a thiamine deficiency and lower levels of Vitamin-B2. Concentrations of ascorbic acid in platelets, white cells, plasma, and urine are decreased by OCs. Decreased plasma and red blood cell concentrations of folic acid have been reported in OC users, though it does not appear that absorption of folate polyglutamate is affected. OC users may develop megaloblastic anemia because of folic acid deficiency. OCs have been reported to markedly reduce serum levels of Vitamin-B12. Some OC users who excrete abnormal amounts of tryptophan metabolites have some degree of true Vitamin-B6 deficiency. Evidence of altered tryptophan metabolism and/or absolute Vitamin-B6 deficiency has been found in emotionally depressed women taking OCs. OCs, especially estrogens, produce tryptophan metabolism abnormalities in the great majority of users. An effect of OCs on alpha-tocopherol plasma concentrations has yet to be demonstrated in humans.
Zhonghua Fu Chan Ke Za Zhi. 1995 Jul;30(7):410-3.
Megaloblastic changes in cervical epithelium associated with oral contraceptives and changes after treatment with folic acid]. [Article in Chinese] Li X, Ran J, Rao H. Source Second Affiliated Hospital of Shanxi Medical College, Taiyuan. Abstract OBJECTIVE: To study the influence of oral contraceptives on cervical epithelium, serum and red blood cell folate levels of users and to observe the changes after treatment with folic acid. METHODS: Morphology of cervical epithelium, serum folate and red blood cell folate levels were studied in 101 women who had used oral contraceptives for over 6 months and 33 intrauterine devices users served as controls, 29 women using oral contraceptives with cervical megaloblastic changes were treated with folic acid (5mg daily) for 3-4 weeks and followed up for observation on morphological changes of cervical epithelium. RESULTS: The mean nuclear diameter of cervical epithelial cells was larger in the oral contraceptive group than that in the control group (P < 0.001). Megaloblastic changes in cervical epithelium occurred in 29 women in the oral contraceptive group (28.7%). There was significant difference in the occurrence of cervical megaloblastic changes between the two groups (P < 0.01). The level of red blood cell folate was lower in the oral contraceptive group than that in the control group (P < 0.05). There was no difference in serum folate, hemoglobin and neutrophil nuclear index between the two groups (P > 0.05). The mean nuclear diameter of cervical epithelial cells decreased significantly (P < 0.001) and multinuclear and vacuolar changes disappeared after folic acid therapy in 26 women with megaloblastic changes. CONCLUSIONS: Oral contraceptives reduced folate storage in the body and resulted in megaloblastic changes in cervical epithelium. This condition was improved with folic acid therapy.
Lancet. 1975 Mar 8;1(7906):561-4.
Vitamins and oral contraceptive use. Wynn V. 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.
Ned Tijdschr Geneeskd. 1978 Feb 4;122(5):146-50.
[Folic acid deficiency, the "pill" and the withheld anamnesis]. [Article in Dutch] Mendes de Leon DE. Abstract 3 women, 25, 26, and 37 years of age, developed folic acid deficiencies during use of contraceptive agents. One patient used a depot preparation, while the other two used combination preparations. In addition, excessive alcohol use, smoking, malnutrition, and a latent case of sprue were involved in bringing about the folic acid deficiency.
Med Monatsschr Pharm. 1991 Aug;14(8):244-7.
[Folic acid and vitamin deficiency caused by oral contraceptives]. [Article in German] Bielenberg J. Abstract Recently there have been reports that long-term use of estrogen- containing oral contraceptives (OCs) can induce folic acid and vitamin B deficiency which can lead to hematopoiesis. The symptoms are paleness, forgetfulness, sleeplessness, and euphoric and depressive states. This deficiency occurs when serum folic content falls below 8 nmol/1 or 3 ng/ml. According to a nutrition group blood folic acid level declined up to 40% in patients taking OCs. In a Sri Lanka study of healthy women aged 20-45 taking Ovulen 50 (.05 mg of ethinyl estradiol and 1 mg of ethynodiol diacetate) folic acid level dropped in the 1st 6 months stabilizing at 2.2 ng/ml in those from the lowest social classes and at 2.9 ng/ml in those from privileged classes. Prophylactic substitution of folic acid in the diet was recommended by WHO, but it is less effective since it appears in the diet as polyglutamate that has to be broken down to absorbable monoglutamate. A US study found that taking OCs for 60 months resulted in a 40% reduction of the vitamin B12 serum level, while vitamin B12 concentrations in erythrocytes and peripheral blood stayed normal. Vitamin B12 helps recover tetrahydrofolic acid from N-methyltetrahydrofolic acid. Possibly this is another manifestation of OC-induced folic acid hypovitaminosis. OCs can also influence tryptophan metabolism reducing its blood concentration whereby less 5-hydroxytryptamine (serotonin) is produced. This results in headache, concentration decreases irritability, and sleep disturbances. In addition, lower riboflavin (vitamin B2) and thiamin concentration in erythrocytes was reported after using OCs. Counseling on the possible effect on vitamin stores and on proper nutrition including folic acid as monoglutamate is necessary for women who use OCs or estrogen substitution therapy for postmenopause or for osteoporosis prophylaxis.
Isr J Med Sci. 1989 Mar;25(3):142-5.
Folic acid deficiency, megaloblastic anemia and peripheral polyneuropathy due to oral contraceptives. Kornberg A, Segal R, Theitler J, Yona R, Kaufman S. Source Department of Hematology, Assaf Harofeh Medical Center, Zerifin, Israel. 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. A 34-year old woman developed megaloblastic anemia and peripheral polyneuropathy following the use of oral contraceptives (OCs) 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 these were caused by OCs 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
Curr Concepts Nutr. 1983;12:73-87.
Drugs and vitamin B12 and folate metabolism. Lindenbaum J.
Abstract Deficiency of either folic acid or vitamin B12 may interfere with DNA synthesis and result in megaloblastic anemia or other conditions. These 2 vitamins have dissimilar molecular structures and are present in different foods; they are also absorbed and metabolized differently. In 201 consecutive cases of megaloblastic anemia, for 90% the cause was alcoholism and poor diet; 0.5% (1 case) was related to oral contraceptives (OCs). Megaloblastic anemia due to folate deficiency has occasionally been reported in patients with inflammatory bowel disease and has been attributed to poor diet, impaired absorption, and increased tissue utilization of folate. Sulfasalazine, a compound containing a sulfa drug and a salicylate that is broken down to its active components by the gut flora, is widely used in the treatment of inflammatory bowel disease and has been shown to impair the absorption of folic acid, polyglutamyl folate, and methyl-tetrahydrofolic acid in patients with these disorders. There is also evidence suggesting an interaction between anticonvulsant drugs and folate balance. A number of cases of megaloblastic anemia due to folate deficiency have been reported in women taking OCs. While in some cases no apparent cause for the megaloblastic anemia other than contraceptive therapy was demonstrated, in many patients other underlying disorders that were likely to disturb folate balance such as celiac disease, decreased dietary vitamin intake, and the administration of other drugs known to affect folate status have also been present. There is no convincing evidence that sex steroids affect folate absorption; about 20% of women taking OCs were found to have mild megaloblastic changes on Papanicolaou smears. These changes disappered after folic acid therapy, suggesting that OCs may cause an increased demand for folate limited to the reproductive system. Another finding is of low serum cobalamin levels in women using OCs; this appears however to be a laboratory abnormality of uncertain cause and of no clinical significance.
Full text very good!!!!
Am J Obstet Gynecol. 1976 Aug 15;125(8):1063-9.
Effect of oral contraceptives on nutrients. III. Vitamins B6, B12, and folic acid.
Prasad AS, Lei KY, Moghissi KS, Stryker JC, Oberleas D.
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. The effect of oral contraceptives (OCs) on Vitamins-B6, -B12, and folic acid metabolism was studied in a large population of women. The OCs Norinyl (1 mg norethindrone plus 50 mcg mestranol) and Ovral (.5 mg norgestrel and 50 mcg ethinyl estradiol) were administered for 3 or more months. Higher incidences of abnormal clinical signs related to vitamin deficiency were seen in the upper socioeconomic OC users then in the control subjects. Plasma pyridoxal phosphate and red cell and serum folate were lower in OC users in the upper socioeconomic group as compared with levels in control subjects. A reduction in erythrocyte gl utamic oxalacetic transaminase (EGOT) activity and an elevation in the EGOT-stimulation test were observed in OC users in both upper and lower socioeconomic groups. These results suggest a relatively deficient state with respect to Vitamin-B6 and folic acid in OC users. No marked effects were seen with respect to Vitamin-B12 levels. These data are consistent with the hypothesis that the subjects in lower socioeconomic groups were already marginally deficient in Vitamin-B6 and folic acid and further reduction due to OCs could not be detected.
Haematologica. 1979 Apr;64(2):190-5.
Megaloblastic anemia due to folic acid deficiency after oral contraceptives. Barone C, Bartoloni C, Ghirlanda G, Gentiloni N.
Abstract A young patient was hospitalized for megaloblastic anemia due to folate deficiency. Laboratory exams and functional tests demonstrated that the deficiency was due to hormonal contraception treatment on which the woman had been for the last consecutive 11 months. The disease subsided completely following withdrawal of oral contraception (OC), and normal hematological values were maintained after that, suggesting that no malabsorption was present. Cases of megaloblastic anemia in women on OC are rare, and the phenomenon may be related to prolonged and uninterrupted drug assumption.
Eur J Obstet Gynecol Reprod Biol. 2003 Mar 26;107(1):57-61.
Acta Obstet Gynecol Scand. 1985;64(1):59-63.
Oral contraceptives and the cobalamin (vitamin B12) metabolism. Hjelt K, Brynskov J, Hippe E, Lundström P, Munck O.
Abstract 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. This study investigated the incidence and etiology of cobalamin (vitamin B12) deficiency in oral contraceptive (OC) users. Mean concentrations of serum (S)-cobalamin and S-unsaturated B12 binding capacity were significantly decreased in 101 women who had been taking combination OCs with an estrogen content of 50 mcg for at least the past 6 months compared to 113 controls who had not used OCs for at least the past 6 months. However, the incidence of particularly low concentrations of S-cobalamin (under 150 pmol/1) was not increased in OC users. To investigate the possibility of a dose-dependent effect, 27 women who wrere using high-dose estrogen OCs with an estrogen content of 1-4 mg were compared with 31 controls who had not used sex steroids. Although the group showed no difference in terms of S-cobalamin concentrations, mean serum and plasma-unsaturated B12 binding capacity levels were significantly decreased in the high-dose estrogen group. When 12 OC users with decreased S-cobalamin (under 200 pmol/1), 9 OC users with normal S-cobalamin, and 10 controls were studied more extensively, the mean hemoglobin concentration was found to be significantly decreased in OC users with decreased S-cobalamin levels. The absorption and excretion of radiolabeled cobalamin and concentrations of erythrocyte-folate, S-iron, and S-transferrin remained normal in all 3 groups and no changes in plasma volume were observed. it is concluded that the decreased S-cobalamin levels found in OC users are caused by a decreased S-unsaturated vitamin B12 binding capacity, possibly reflecting a lowering of the white blood cell count. Routine measurement of S-cobalamin in OC users is not recommended.
Serum folate and Vitamin B12 levels in women using modern oral contraceptives (OC) containing 20 microg ethinyl estradiol. Sütterlin MW, Bussen SS, Rieger L, Dietl J, Steck T. Source Department of Obstetrics and Gynecology, University of Würzburg, Josef-Schneider-Str 4, D-97080 Würzburg, Germany.
Abstract OBJECTIVE: The effects of modern oral contraceptives (OC) on serum concentrations of folate and cobalamin are controversial. STUDY DESIGN: Case-control study on the cobalamin and folate status of 71 healthy female nulligravidae using "low dose" OC for >or=3 months and 170 controls. Factors interfering with vitamin metabolism were thoroughly controlled. Serum concentrations were measured by commercial assays. The results were evaluated using Mann-Whitney's U-test and chi(2) analysis. RESULTS: OC-users showed significantly lower concentrations of cobalamin than controls. The rates of women with reduced, normal, and elevated levels differed significantly. Nine users but no control had frank cobalamin deficiency without clinical symptoms. Folate levels did not differ between the groups. Vegetarian diet, smoking or obesity did not have a significant influence. CONCLUSIONS: Routine measurement of cobalamin or folate in women using "low dose" OC is not warranted. Vitamin supplementation or different contraceptive methods should be considered in women with pre-existing cobalamin deficiency or restrictive dietary habits.
Effects of oral contraceptive steroids on vitamin and lipid levels in serum1 Jack L. Smith,2 Ph.D., Grace A. Goldsmith,3 M.D. and Jeffrey D. Lawrence,3 Sc.D.
ABSTRACT The results of a comprehensive study to determine the effects of oral contraceptive agents on nutrient metabolism have been reported. The group of women using oral contraceptive agents was found to have significantly higher levels of hemoglobin, packed cell volume, serum vitamin A, total lipids, triglycerides, vitamin E, and a1 -protein and significantly lower levels of serum and red cell folacin, vitamin B1 2 and albumin. The biological significance of many of these differences has not been elucidated satisfactorily. Am. J. Cli,. Nutr. 28: 371-376, 1975. Oral contraceptive agents (OCA) h
Can Med Assoc J. 1982 Feb 1;126(3):244-7. Oral contraceptives: effect of folate and vitamin B12 metabolism. Shojania AM.
Abstract Women who use oral contraceptives have impaired folate metabolism as shown by slightly but significantly lower levels of folate in the serum and the erythrocytes and an increased urinary excretion of formiminoglutamic acid. The vitamin B12 level in their serum is also significantly lower than that of control groups. However, there is no evidence of tissue depletion of vitamin B12 associated with the use of oral contraceptives. The causes and clinical significance of the impairment of folate and vitamin B12 metabolism in these women is discussed in this review of the literature. Clinicians are advised to ensure that women who shop taking "the pill" because they wish to conceive have adequate folate stores before becoming pregnant. The effects of oral contraception (OC) on folate and vitamin B12 metabolism are a subject of much controversy. Many studies indicate that OCs impair folate metabolsim and produce some degree of folate depletion, as demonstrated by slight but significant lower levels of folate in the serum and the erythrocytes, and by an increased urinary excretion of formiminoglutamic acid. These effects are unlikely to cause anemia or megalobastic changes in women who have a good dietary intake of folate. Since pregnant women are predisposed to the development of folate deficiency, it would be necessary when stopping the pill for desire of pregnancy to take folate supplements before becoming pregnant. OCs may also produce a low serum level of vitamin B12; this effect, however, is not associated with evidence of tissue depletion of vitamin B12, and does not have any great clinical significance; the effect may also be caused by vitamin B12 malabsorption rather than by OC treatment.
www.ditchthepill.org/ Ditch the Pill
Birth Control Pill Could Cause Long-Term Problems With Testosterone, New Research Indicates Main Category: Endocrinology Article Date: 04 Jan 2006 - 3:00 PDT Claudia Panzer,Dr. Andre Guay, study co-author and Director of the Center for Sexual Function/Endocrinology in Peabody, MA "This work is the culmination of 7 years of observational research in which we noted in our practice many women with sexual dysfunction who had used the oral contraceptive but whose sexual and hormonal problems persisted despite stopping the birth control pill," said Dr. Irwin Goldstein, a urologist and senior author of the research. "There are approximately 100 million women worldwide who currently use oral contraceptives, so it is obvious that more extensive research investigations are needed. The oral contraceptive has been around for over 40 years, but no one had previously looked at the long-term effects of SHBG in these women. The larger problem is that there have been limited research efforts in women's sexual health problems in contrast to investigatory efforts in other areas of women's health or even in male sexual dysfunction." Oral contraceptives decrease circulating levels of androgens by direct inhibition of androgen production in the ovaries and by a marked increase in the hepatic synthesis of sex-hormone binding globulin, the major binding protein for gonadal steroids in the circulation. The combination of these two mechanisms leads to low circulating levels of "unbound" or "free" testosterone.
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