The Other Pill Research

“The long-term use of prescription and over-the-counter drugs can induce subclinical and clinically relevant micronutrient deficiencies, which may develop gradually over months or even years”

“Many health care providers are not knowledgeable about micronutrient deficiency or excess. This may lead to erroneous attribution of deficiency states to a disease state or the aging process itself [1] and may delay diagnosis. Drug-induced micronutrient depletion may be the origin of otherwise unexplained symptoms, some of which might influence medication compliance”

Emily S. Mohn et al. Evidence of Drug–Nutrient Interactions with Chronic Use of Commonly Prescribed Medications: An Update. Pharmaceutics 2018, 10(1), 36

 

Vitamin B6

“A report from the World Health Organization (WHO) points out that the influence of OCs on nutrient requirements is a topic of high clinical relevance and should, therefore, receive great attention. It has been shown that the key nutrient depletions concern folic acid, vitamins B2, B6, B12, vitamin C and E and the minerals magnesium, selenium and zinc.”
“The possibility to prevent vitamin and mineral deficiencies by taking appropriate dietary supplements should be considered a first-line approach by clinicians.”

Palmery M et al. Oral contraceptives and changes in nutritional requirements. Eur Rev Med Pharmacol Sci. 2013 Jul;17(13):1804-13.

“Oral contraceptive users were observed to have significantly lower PLP (vitamin B6) in both fasting and non-fasting plasma compared to nonusers.”

“Intervention studies with vitamin B6 supplementation have reported improvements in clinical symptoms of B6 deficiency and fewer side effects in OC users who may be deficient in this vitamin.”

Emily S. Mohn et al. Evidence of Drug–Nutrient Interactions with Chronic Use of Commonly Prescribed Medications: An Update. Pharmaceutics 2018, 10(1), 36

“Contraceptive steroid ingestion was shown to depress the physiologic levels of six nutrients (riboflavin, vitamin B6, folate, vitamin B12, vitamin C and zinc), elevate the levels of three others (vitamin K, iron and copper)

Most studies support the contention that OC usage leads to a deficiency of vitamin B6. Approximately 80% of all women using OCs for 6 or more months experience abnormal typtophan metabolism.

Webb JL.Nutritional effects of oral contraceptive use: a review. J Reprod Med. 1980 Oct;25(4):150-6.

“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. “

Veninga KS. Effects of oral contraceptives on vitamins B6, B12, C, and folacin. J Nurse Midwifery. 1984 Nov-Dec;29(6):386-90.

“Evidence of altered tryptophan metabolism and/or absolute vitamin-B6 deficiency has been found in emotionally depressed women taking oral contraceptives. Oral contraceptives, especially estrogens, produce tryptophan metabolism abnormalities in the great majority of users.” Anderson KE et al. Effects of oral contraceptives on vitamin metabolism. Adv Clin Chem. 1976;18:247-87.

These observations suggest a relatively deficient state with respect to vitamins B6 and folic acid in oral contraceptive users. Prasad AS, et al. Effect of oral contraceptives on nutrients. III. Vitamins B6, B12, and folic acid. Am J Obstet Gynecol. 1976 Aug 15;125(8):1063-9.

Vitamin B9 (folate)

“A report from the World Health Organization (WHO) points out that the influence of OCs on nutrient requirements is a topic of high clinical relevance and should, therefore, receive great attention. It has been shown that the key nutrient depletions concern folate, vitamins B2, B6, B12, vitamin C and E and the minerals magnesium, selenium and zinc.”
“The possibility to prevent vitamin and mineral deficiencies by taking appropriate dietary supplements should be considered a first-line approach by clinicians.”

Palmery M et al. Oral contraceptives and changes in nutritional requirements. Eur Rev Med Pharmacol Sci. 2013 Jul;17(13):1804-13.

The earliest evidence for a negative effect of OC use on folate status was reported in the 1960s and 70s.

In addition to several case studies in which folate deficiency and megaloblastic anemia were reported in OC users admitted to the hospital.

A cross sectional analysis of women taking OCs for two months to five years found significantly lower mean serum folate levels compared with controls that also appeared to be associated with duration of use.

A recent meta-analysis that included case–control, cohort studies, and clinical trials from 1970–2013 concluded that OC use is, indeed, associated with lower blood folate status.

Emily S. Mohn et al. Evidence of Drug–Nutrient Interactions with Chronic Use of Commonly Prescribed Medications: An Update. Pharmaceutics 2018, 10(1), 36

“Contraceptive steroid ingestion was shown to depress the physiologic levels of six nutrients (riboflavin, vitamin B6, folate, vitamin B12, vitamin C and zinc), elevate the levels of three others (vitamin K, iron and copper)

Webb JL.Nutritional effects of oral contraceptive use: a review. J Reprod Med. 1980 Oct;25(4):150-6.

“It has also been noted that OCs impair folate metabolism, as evidenced by folate deficiency in serum and an increase in urinary formiminoglutamic acid (FIGLU) secretion.

It is generally agreed that folate, which plays a critical role in fetal development, can become deficient in late pregnancy and in women who become pregnant shortly after discontinuing long term OC use.”

Veninga KS. Effects of oral contraceptives on vitamins B6, B12, C, and folacin. J Nurse Midwifery. 1984 Nov-Dec;29(6):386-90.

“Oral contraceptive users may develop megaloblastic anemia because of folate deficiency.”

Anderson KE et al. Effects of oral contraceptives on vitamin metabolism. Adv Clin Chem. 1976;18:247-87.

These observations suggest a relatively deficient state with respect to vitamins B6 and folate in oral contraceptive users.

Prasad AS, et al. Effect of oral contraceptives on nutrients. III. Vitamins B6, B12, and folic acid. Am J Obstet Gynecol. 1976 Aug 15;125(8):1063-9.

Magnesium

“A report from the World Health Organization (WHO) points out that the influence of OCs on nutrient requirements is a topic of high clinical relevance and should, therefore, receive great attention. It has been shown that the key nutrient depletions concern folic acid, vitamins B2, B6, B12, vitamin C and E and the minerals magnesium, selenium and zinc.”

“The possibility to prevent vitamin and mineral deficiencies by taking appropriate dietary supplements should be considered a first-line approach by clinicians.”

Palmery M et al. Oral contraceptives and changes in nutritional requirements. Eur Rev Med Pharmacol Sci. 2013 Jul;17(13):1804-13.

“Most cross-sectional studies have shown serum magnesium levels are lower in oral contraceptive users compared to both nonusers and women on other forms of contraception.”

“An increase in the blood calcium to magnesium ratio due to low magnesium levels can influence blood coagulation processes.”

Emily S. Mohnet al. Evidence of Drug–Nutrient Interactions with Chronic Use of Commonly Prescribed Medications: An Update. Pharmaceutics 2018, 10(1), 36

The effect of an oral contraceptive on serum magnesium was assessed in a group of 32 women, mean age 24.2 years, attending a family planning clinic. The pill contained ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg. As in pregnancy and during estrogen replacement in postmenopausal women, the contraceptive pill lowered serum magnesium (from a mean of 0.82 mmol/l, to 0.61 mmol/l in 6 months)

Blum M et al. Oral contraceptive lowers serum magnesium. Harefuah. 1991 Nov 15;121(10):363-4.

Catechol-O-methyltransferase (COMT) catalyzes the methylation of catechol estrogens to methoxy estrogens, with magnesium as an essential cofactor, which simultaneously lowers the potential for DNA damage.

Sheila Dawling et al. Catechol-O-Methyltransferase (COMT)-mediated Metabolism of Catechol Estrogens. Biochemistry and Biophysics. Sept. 2001.

Selenium

“A report from the World Health Organization (WHO) points out that the influence of OCs on nutrient requirements is a topic of high clinical relevance and should, therefore, receive great attention. It has been shown that the key nutrient depletions concern folic acid, vitamins B2, B6, B12, vitamin C and E and the minerals magnesium, selenium and zinc.”

“The possibility to prevent vitamin and mineral deficiencies by taking appropriate dietary supplements should be considered a first-line approach by clinicians.”

Palmery M et al. Oral contraceptives and changes in nutritional requirements. Eur Rev Med Pharmacol Sci. 2013 Jul;17(13):1804-13.

Several review studies have shown that blood folate, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin E, zinc, selenium, and magnesium was lower in OC users in comparison with non-users

Boyoung Park. Jeongseon Kim. Oral Contraceptive Use, Micronutrient Deficiency, and Obesity among Premenopausal Females in Korea: The Necessity of Dietary Supplements and Food Intake Improvement. PLOS One. June 2016.

B12

“A report from the World Health Organization (WHO) points out that the influence of OCs on nutrient requirements is a topic of high clinical relevance and should, therefore, receive great attention. It has been shown that the key nutrient depletions concern folic acid, vitamins B2, B6, B12, vitamin C and E and the minerals magnesium, selenium and zinc.”

“The possibility to prevent vitamin and mineral deficiencies by taking appropriate dietary supplements should be considered a first-line approach by clinicians.”

Palmery M et al. Oral contraceptives and changes in nutritional requirements. Eur Rev Med Pharmacol Sci. 2013 Jul;17(13):1804-13.

“Several studies have consistently reported serum B12 levels are lower in OC users compared to nonusers”

Emily S. Mohnet al. Evidence of Drug–Nutrient Interactions with Chronic Use of Commonly Prescribed Medications: An Update. Pharmaceutics 2018, 10(1), 36

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.

Hjelt K, et al. Oral contraceptives and the cobalamin (vitamin B12) metabolism. Acta Obstet Gynecol Scand. 1985;64(1):59-63.

“Contraceptive steroid ingestion was shown to depress the physiologic levels of six nutrients (riboflavin, vitamin B6, folate, vitamin B12, vitamin C and zinc), elevate the levels of three others (vitamin K, iron and copper)

Webb JL.Nutritional effects of oral contraceptive use: a review. J Reprod Med. 1980 Oct;25(4):150-6.

“OCs further influence serum B12 concentrations and the possibility of iron deficiency anemia.”

Veninga KS.Effects of oral contraceptives on vitamins B6, B12, C, and folacin. J Nurse Midwifery. 1984 Nov-Dec;29(6):386-90.

Zinc

“Serum zinc was significantly lower while serum copper was significantly higher for women taking the oral contraceptive agents.”
Dorea JG et al. Effects of anovulatory steroids on serum levels of zinc and copper]. Arch Latinoam Nutr. 1982 Mar;32(1):101-10.

“A report from the World Health Organization (WHO) points out that the influence of OCs on nutrient requirements is a topic of high clinical relevance and should, therefore, receive great attention. It has been shown that the key nutrient depletions concern folic acid, vitamins B2, B6, B12, vitamin C and E and the minerals magnesium, selenium and zinc.”

“The possibility to prevent vitamin and mineral deficiencies by taking appropriate dietary supplements should be considered a first-line approach by clinicians.”

Palmery M et al. Oral contraceptives and changes in nutritional requirements. Eur Rev Med Pharmacol Sci. 2013 Jul;17(13):1804-13.

“Contraceptive steroid ingestion was shown to depress the physiologic levels of six nutrients (riboflavin, vitamin B6, folate, vitamin B12, vitamin C and zinc), elevate the levels of three others (vitamin K, iron and copper)

Webb JL.Nutritional effects of oral contraceptive use: a review. J Reprod Med. 1980 Oct;25(4):150-6.

Riboflavin (B2)

“OCs may induce a thiamine deficiency and lower levels of vitamin-B2”
Anderson KE et al. Effects of oral contraceptives on vitamin metabolism. Adv Clin Chem. 1976;18:247-87.

“Our results clearly demonstrate that, of the vitamins tested, riboflavin and thiamine are essential in the metabolism of estradiol by liver slices. The inactivation of estradiol is dependent upon the concentration of these vitamins in the liver.”

“The presence of excess free estrogen may be associated with a number of clinical syndromes.” H. 0. Singher, The effect of thiamine deficiency on estradiol inactivation by the liver. March 1944.

“A report from the World Health Organization (WHO) points out that the influence of OCs on nutrient requirements is a topic of high clinical relevance and should, therefore, receive great attention. It has been shown that the key nutrient depletions concern folic acid, vitamins B2, B6, B12, vitamin C and E and the minerals magnesium, selenium and zinc.”

“The possibility to prevent vitamin and mineral deficiencies by taking appropriate dietary supplements should be considered a first-line approach by clinicians.”

Palmery M et al. Oral contraceptives and changes in nutritional requirements. Eur Rev Med Pharmacol Sci. 2013 Jul;17(13):1804-13.

“Contraceptive steroid ingestion was shown to depress the physiologic levels of six nutrients (riboflavin, vitamin B6, folate, vitamin B12, vitamin C and zinc), elevate the levels of three others (vitamin K, iron and copper)

Webb JL. Nutritional effects of oral contraceptive use: a review. J Reprod Med. 1980 Oct;25(4):150-6.

“Riboflavin seems to be a well-tolerated, effective, and low-cost prophylactic treatment in children and adolescents suffering from migraine.”

Condò M et al. Riboflavin prophylaxis in pediatric and adolescent migraine. J Headache Pain. 2009 Oct;10(5):361-5. doi: 10.1007/s10194-009-0142-2. Epub 2009 Aug 1.

Thiamine (B1)

“OCs may induce a thiamine deficiency and lower levels of vitamin-B2”
Anderson KE et al. Effects of oral contraceptives on vitamin metabolism. Adv Clin Chem. 1976;18:247-87.

“Our results clearly demonstrate that, of the vitamins tested, riboflavin and thiamine are essential in the metabolism of estradiol by liver slices. The inactivation of estradiol is dependent upon the concentration of these vitamins in the liver.”

“The presence of excess free estrogen may be associated with a number of clinical syndromes.” H. 0. Singher, The effect of thiamine deficiency on estradiol inactivation by the liver. March 1944.

“A report from the World Health Organization (WHO) points out that the influence of OCs on nutrient requirements is a topic of high clinical relevance and should, therefore, receive great attention. It has been shown that the key nutrient depletions concern folic acid, vitamins B2, B6, B12, vitamin C and E and the minerals magnesium, selenium and zinc.”

“The possibility to prevent vitamin and mineral deficiencies by taking appropriate dietary supplements should be considered a first-line approach by clinicians.”

Palmery M et al. Oral contraceptives and changes in nutritional requirements. Eur Rev Med Pharmacol Sci. 2013 Jul;17(13):1804-13.

“Contraceptive steroid ingestion was shown to depress the physiologic levels of six nutrients (riboflavin, vitamin B6, folate, vitamin B12, vitamin C and zinc), elevate the levels of three others (vitamin K, iron and copper)

Webb JL. Nutritional effects of oral contraceptive use: a review. J Reprod Med. 1980 Oct;25(4):150-6.

“Riboflavin seems to be a well-tolerated, effective, and low-cost prophylactic treatment in children and adolescents suffering from migraine.”

Condò M et al. Riboflavin prophylaxis in pediatric and adolescent migraine. J Headache Pain. 2009 Oct;10(5):361-5. doi: 10.1007/s10194-009-0142-2. Epub 2009 Aug 1.

Vitamin C

Studies in humans and animals suggest that the estrogen in oral contraceptives cause decreased plasma and tissue levels of vitamin C.
Increased use of vitamin C It is suggested that an increased catabolism of vitamin C accounts for the decreased plasma and tissue levels in humans and animals with estrogen or oral contraceptive steroids.

Rivers JM. Oral contraceptives and ascorbic acid. Am J Clin Nutr. 1975 May;28(5):550-4.

Studies indicate circulating vitamin C levels are lower in OC users compared to nonusers.

Several studies show chronic OC use leads to increased oxidative stress, in particular lipid peroxidation. Enhanced oxidative stress and lipid peroxidation may represent a potential risk for cardiovascular disease.

One study reported an increase in catalase and glutathione peroxidase activities, i.e., endogenous antioxidant defenses, in 19 young, healthy, non-smoking women after nine cycles of OC use when compared to baseline levels.

In a larger, controlled study of 120 healthy women, age 18–40 years, OC users were randomized to receive either supplements with 150 mg vitamin C and 200 IU vitamin E or no supplements, and compared with non-supplemented, non-OC users. After four weeks, increased plasma malondialdehyde levels, a marker of lipid peroxidation, and reduced glutathione peroxidase and reductase activities were reported in the non-supplemented OC users, while the directions of each were reversed in the supplemented OC users when compared with the control group.

Emily S. Mohnet al. Evidence of Drug–Nutrient Interactions with Chronic Use of Commonly Prescribed Medications: An Update. Pharmaceutics 2018, 10(1), 36

“A report from the World Health Organization (WHO) points out that the influence of OCs on nutrient requirements is a topic of high clinical relevance and should, therefore, receive great attention. It has been shown that the key nutrient depletions concern folic acid, vitamins B2, B6, B12, vitamin C and E and the minerals magnesium, selenium and zinc.”

“The possibility to prevent vitamin and mineral deficiencies by taking appropriate dietary supplements should be considered a first-line approach by clinicians.”

Palmery M et al. Oral contraceptives and changes in nutritional requirements. Eur Rev Med Pharmacol Sci. 2013 Jul;17(13):1804-13.

OC intake for 3 months or more increased the odds of being obese among those whose intakes of calcium, phosphorus, potassium, vitamin A, vitamin B1, vitamin B2, niacin, vitamin C, and folate were lower than the recommended levels

For those consuming more than the recommended levels of these nutrients, the duration of OC use was not associated with obesity

Boyoung Park. Jeongseon Kim. Oral Contraceptive Use, Micronutrient Deficiency, and Obesity among Premenopausal Females in Korea: The Necessity of Dietary Supplements and Food Intake Improvement. PLOS One. June 2016.

Vitamin E

Several studies show chronic OC use leads to increased oxidative stress, in particular lipid peroxidation, and lower circulating vitamin E.
Emily S. Mohnet al. Evidence of Drug–Nutrient Interactions with Chronic Use of Commonly Prescribed Medications: An Update. Pharmaceutics 2018, 10(1), 36

“A report from the World Health Organization (WHO) points out that the influence of OCs on nutrient requirements is a topic of high clinical relevance and should, therefore, receive great attention. It has been shown that the key nutrient depletions concern folic acid, vitamins B2, B6, B12, vitamin C and E and the minerals magnesium, selenium and zinc.”

“The possibility to prevent vitamin and mineral deficiencies by taking appropriate dietary supplements should be considered a first-line approach by clinicians.”

Palmery M et al. Oral contraceptives and changes in nutritional requirements. Eur Rev Med Pharmacol Sci. 2013 Jul;17(13):1804-13.

“Several review studies have shown that blood folate, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin E, zinc, selenium, and magnesium was lower in OC users in comparison with non-users.”

Boyoung Park. Jeongseon Kim. Oral Contraceptive Use, Micronutrient Deficiency, and Obesity among Premenopausal Females in Korea: The Necessity of Dietary Supplements and Food Intake Improvement. PLOS One. June 2016.

“The present study showed that pre-menopausal women with OCT had increased oxidative stress levels, as assessed by the d-ROMs test, and this increase was independent of traditional cardiovascular risk factors. These findings suggest that oxidative stress due to OCT may contribute to adverse vascular effects, and can provide new insights to the primary prevention of vascular complications in women with OCT.”

Jui Tung Chen. Oral Contraceptive Therapy Increases Oxidative Stress in Pre-Menopausal Women. Int J Prev Med. 2012 Dec; 3(12): 893–896.

The intake of OC significantly increases the lipid peroxidation

Plasma antioxidant defenses were significantly altered in OCU women as shown by lower levels of γ-tocopherol (decrease by 22%)

J. Pincemail S et al. Effect of different contraceptive methods on the oxidative stress status in women aged 40–48 years from the ELAN study in the province of Liège, Belgium. Human Reproduction, Volume 22, Issue 8, 1 August 2007, Pages 2335–2343

Pantothenic Acid

Oral contraceptives (birth control pills) containing estrogen and progestin may increase the requirement for pantothenic acid

Flodin N. Pharmacology of micronutrients. New York: Alan R. Liss, Inc.; 1988.

Calcium-d-glucarate

“Oral supplementation of calcium-D-glucarate has been shown to inhibit beta-glucuronidase, an enzyme produced by colonic microflora and involved in Phase II liver detoxification. Elevated beta-glucuronidase activity is associated with an increased risk for various cancers, particularly hormone-dependent cancers such as breast, prostate, and colon cancers. Other potential clinical applications of oral calcium-D-glucarate include regulation of estrogen metabolism and as a lipid-lowering agent.”
Altern Med Rev. Calcium-D-glucarate. 2002 Aug;7(4):336-9.

Broccoli sprout extract (sulforphane)

“Sulforaphane is found in cruciferous vegetables, such as broccoli and broccoli sprouts. It was first identified as a potent inducer of phase II detoxification enzymes”
Jia Chen, Xinran Xu, in Advances in Genetics, 2010

There is ample evidence that sulforaphane is a very potent inducer of Phase II enzymes and also raises cellular glutathione levels. It is well known that Phase II enzymes play an important role in protecting cells against the toxicities of electro- philes. But we show here that some Phase II enzymes also protect cells against a wide variety of oxidative stresses, and the induction of these enzymes contributes to the mechanisms by means of which cells guard against the toxicities of reactive oxygen species and other forms of oxidative toxicity. Indirect antioxidants such as sulforaphane and other Phase II enzyme inducers are actually very e􏰁cient and rather versatile antioxidants for the following reasons: (a) unlike direct antioxidants, they are not consumed stoichiometrically while exerting antioxidant functions; (b) they have a longer duration of action and high cellular concentrations need not be maintained continuously since the induced enzymes have half-lives measured in days; (c) they support the functions of important naturally-occurring, direct-acting antioxidants such as the tocopherols and coenzymes Q; (d) they enhance the synthesis of glutathione, one of the most abundant intracellular direct antioxidants; and (d) they elevate enzymes that can cope with a wide variety of types of oxidants. J. W. Fahey, P. Talalay. Antioxidant Functions of Sulforaphane: a Potent Inducer of Phase II Detoxication Enzymes. Food and Chemical Toxicology 37 (1999) 973-979

Birth control and weight gain

OC use duration of more than 3 months had a positive association with obesity. However, when stratified by micronutrient intake, OC use of more than 3 months had a positive association with obesity among females whose micronutrient intake was not sufficient. For those who took in more than recommended, the duration of OC use was not associated with being obese. Although this study design did not allow for causal inference, the findings suggested that consuming adequate levels of micronutrients may be necessary for OC users, who may also face higher odds of obesity.