One the potentially big problems with this study is that the researchers did not report the actual mortality rates. Instead they compared what is called "adjusted" mortality rates between supplement users and nonusers. This was done by adjusting for a wide range of factors including weight, intake of calories, cigarette smoking, blood pressure, educational level, diabetes, use of hormone-replacement therapy, physical exercise and fruit and vegetable intake. For each of these factors, those who took supplements were in the categories that would be considered healthier– for example— less diabetes, less obesity, more physically active, less smokers and more fruits and vegetables in their diet. These healthier people would be expected to have lower death rates than those individuals who did not take vitamins. What this does statistically is that the mortality rate of the supplement users would then be adjusted upward compared to the mortality rate of non supplement users. It is very possible that the researchers “over-adjusted” the collection of data, skewing the death rate among supplement users look higher than it really was. This conclusion is supported by the fact that when the researchers adjusted the data based only on age and intake of calories, there was in fact no statistically significant difference in mortality rate between supplement users and nonusers.

Studies that are observational, as this one was, are always weaker studies than randomized controlled trials. You can never prove cause and effect with observational studies, and it would be a mistake to make meaningful conclusions from this study due to its observational nature and possible over adjustment of the data. Another issue to ponder is that the individuals taking supplements were not more likely healthy, but perhaps less healthy. In other words… we might wonder why they were taking supplements to begin with. Perhaps they had a chronic health problem or a family health history that the researchers did not use as an identifier. What if they had a family history of heart disease for example and that is why they were taking supplements. These individuals could then easily have an increased mortality rate due to their family history.

The scientific literature is robust with randomized clinical trials demonstrating the diverse range of benefits of taking vitamins and minerals. It is always important to recognize the potential benefit and risk of any intervention whether it be over the counter or prescription drugs, vitamins, minerals or herbs. For now, women should not be discouraged to take vitamins and minerals, but individual assessment and need is best determined by a licensed practitioner trained in the use of these therapies. The medical degree that offers the most training in this area of medicine is a naturopathic doctor degree. Licensed graduates from the accredited naturopathic medical schools receive extensive training in nutrition and the use of vitamins and minerals for prevention and treatment.

Reference

Mursu J, Robien K, Harnack L, et al. Dietary supplements and mortality rate in older women. The Iowa Women’s Health Study. Arch Intern Med 2011;171(18): 1625-1633.

Commentary: While the percentage of women with tinnitus is less than men, women do experience unique influences that can cause or worsen their tinnitus which are not experienced by men. Hormonal influences such as puberty, the menstrual cycle, pregnancy, hormonal birth control, hormone replacement therapy and menopause are such influences. It appears that there is a link between the menstrual cycle and tinnitus and some women report that their tinnitus is worse during their premenstrual syndrome time. One survey found that 62% of women who had tinnitus before their pregnancies had it worsen during the pregnancy and 66% worsened after childbirth. Of course, hormonal changes are not the only thing going on during pregnancy and postpartum. Other changes that could influence and worsen tinnitus during these times could be lack of sleep, fatigue and stress.

Otosclerosis is a disease of bone growth where the small bones in the middle ear no longer are able to conduct signals to the inner ear, resulting in hearing loss. It affects both women and men but can become worse during pregnancy. Tinnitus is often associated with otosclerosis.

Hormone replacement therapy (HRT), specifically the synthetic progestin used in combination with estrogens can possibly exacerbate tinnitus. There have been case repots of onset of tinnitus shortly after starting HRT. Other theories postulate that side effects of HRT experienced by some women, such as fluid retention, depression, headache, dizziness, insomnia and blood pressure changes could be the cause of worsening of the tinnitus.

Tinnitus is also more common in the 40’s, 50’s and 60’s, which then may mean it is more age related than specifically perimenopause and menopause related. However, it is still possible that the fluctuations in estrogen/progesterone and/or the hot flashes and mood changes of this time of a woman’s life could affect tinnitus.

Whatever the cause, the use of melatonin 3 mg in the evening, is a reasonable and safe supplement to try for the challenging problem of tinnitus.

Reference

Hurtuk A, Dome C, Holloman C, et al. Melatonin: Can it stop the ringing? Annals of Otology, Rhinology and Laryngology 2011;120(7):433-440.

This study involved more than 61,000 women between the ages of 63 and 97. During the 19 year period of follow-up on these women, almost 15,000 of them, or about one-quarter, had some type of fracture for the first time. Among those, 3,871, or 6% of them, experienced a hip fracture. Among another subcohort of 5,000 women, 20% of them met the criteria for osteoporosis.

While perhaps surprising to some, the researchers found that the rates of fracture risk were not related to dietary calcium in a linear fashion. It’s true that those women who were in the lowest calcium intake quintile (less than 751 mg/day), had the highest risk for a first time hip fracture, but the group at the next highest risk for hip fracture was the fifth quintile (greater than 1,137 mg per day). A low vitamin D intake made the rate of hip fracture in the lowest calcium quintile group even more pronounced.

Commentary: This is yet one more study that teaches us that more is not always better. In fact in this case, the most was worse. While these results are inconsistent with current U.S. guidelines, I still think it would be a good opportunity to review those guidelines. For women ages 51-70, the Recommended Dietary Allowance (RDA), the intake that meets the needs of 97.5% of the North American population is 1,200 mg per day; the Estimated Average Requirement (EAR)- a number based on the intake that meets the needs of 50% of the North American population, is 1,000 mg per day for women ages 51-70.

Reference

Warensjo E, Byberg L, Melhus H, et al. Dietary calcium intake and risk of fracture and osteoporosis: prospective longitudinal cohort study. BMJ. 2011;342:d1473.

The JELIS (Japan EPA Lipid Intervention Study) trial [4] included a total of 18,645 subjects (men aged 40-75 and postmenopausal women aged > 75 and a mean age of 61 years and 31% men). Those with a serum total cholesterol level of > 250 mg/dL were eligible. About 36% were hypertensive, 15% had diabetes and 20% had coronary artery disease. Subjects were randomized to pravastatin 10mg/day or simvastatin 5mg/day or the same statin doses with 1,800 mg/day of EPA. After 5 years, those in the EPA group had a 19% reduction in major cardiac events.

These three trials indicated that omega-3 PUFAs lowered the risk of CV disease in both primary and secondary prevention. While not all studies have shown favorable results, the numbers of patients treated, the doses used, and the results of the DART, GISSI and JELIS study are strong motivations to increase dietary fish intake and especially fish oil supplementation. In order to test and remove heavy metals, pesticides, other environmental contaminants and microbes, look for products that can produce independent third part testing for each lot of supplements.

Recommended doses for primary and secondary prevention:

1,000 mg/day of combined EPA/DHA

References:

[1] Harris W, Poston W, Hadock C. Tissue n-3 and n-6 fatty acids and risk for coronary heart disease events. Atherosclerosis 2007;193:1-10.

[2] Burr M, Fehily A, Gilbert J, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and Reinfarction Trial (DART). Lancet 1989;2:757-761.

[3] Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI. Lancet 2001; 357;642 and Lancet 2007;369:106 and Lancet 1999;354;447-455.

[4] Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090-1098.

During the three months before pregnancy or the first month of pregnancy, mothers of children with autism were less likely than those of typically developing children to report having taken prenatal vitamins. In addition, there were greater risks for autism observed in some of the metabolic genetic variants, in those mothers who did not take prenatal vitamins preconception and/or in the first month. In short, the use of prenatal vitamins, taken preconception, may reduce the risk of having children with autism, especially for genetically susceptible mothers and children.

Commentary: Attention is being increasingly given to the preconception time period and the health and nutritional status of the mother in particular. This is distinct from the use of vitamins/minerals/herbs to enhance fertility in men and women. I’m encouraged to see research in this area, and to see positive results, in something as simple and affordable as prenatal vitamins is especially reassuring, and in something as daunting as autism, with the incidence increasing and as yet with an unclear cause. According to “Autism Speaks”, a leading science and advocacy organization, it is estimated that 1 in 110 children in US are diagnosed with autism. Government statistics suggest the prevalence rate of autism is increasing 10 to 17 percent annually. We clearly need to become more aggressive in understanding the potential causes and influences on autism, and be assertive in any prevention strategies that can reduce the incidence.

Reference

Schmidt R, Hansen R, Hartiala J, et al. Prenatal Vitamins, One-carbon Metabolism Gene Variants, and Risk for Autism. Epidemiology; July 2011 – Volume 22 – Issue 4 – pp 476-485

The list is long for the consequences of a magnesium deficiency. Magnesium deficiencies can result in hypokalemia (low potassium), alkalosis, hypertension, congestive heart failure, arrhythmia, myocardial infarction, angina pectoris, clotting, atherosclerosis, type 2 diabetes, preeclampsia and other electrolyte deficiencies. [2]

Magnesium deficiency can be acquired many ways. A decrease in dietary consumption of magnesium has gone from 500mg/day in 1900 to 215-283 mg/day in 1990.[3]^{, [4]} It is estimated that the typical dietary intake of magnesium today in the U.S. provides only 35-75% of the recommended daily amount.[5]

Many over the counter and prescription drugs can influence magnesium nutrient levels and depletion. The list is long, but includes loop and thiazide diuretics, digoxin, carboplatin and cisplatin, corticosteroids, estrogen and oral contraceptives, insulin, proton pump inhibitors, tetracyclines, cyclosporine, laxatives and more.1 Advanced age is also associated with decreased serum and tissue magnesium levels.

Perhaps one of the more common problems with magnesium results in the relationship of calcium and magnesium. High calcium diets or calcium supplementation without attention to magnesium supplementation has been shown to decrease tissue magnesium levels, [6] increase magnesium requirements[7] and decrease magnesium absorption.[8] In individuals with low or suboptimal magnesium status, administration of calcium without concomitant magnesium may further compromise their magnesium status, further increasing their risk of the many of the health risks associated with magnesium insufficiency/deficiency that we have mentioned earlier.

Convenient serum testing for magnesium is usually inadequate because it does not reflect magnesium stores. Less convenient but more accurate testing would include a magnesium-loading test looking at 24-hour urinary magnesium excretion after an infusion of magnesium. Magnesium can also be measured in red blood cells, white blood cells, mononuclear blood cells, and muscle. An intracellular mineral electrolyte panel using cell scrapings under the tongue with electronic photon bombardment technology is available as well.

Supplementing the body’s magnesium stores through oral supplementation takes about six weeks but may be up to six months or more. [9]^,[10] Many different magnesium salts are available as supplements. Magnesium oxide contains the largest amount of elemental magnesium. Magnesium chloride has high bioavailability. Magnesium may also be bound to aspartate, malate, succinate, fumarate, citrate, gluconate, sulfate and chloride. Some manufacturers assert that magnesium chelated to malate, succinate, fumarate or citrate are better absorbed, utilized and tolerated, but this is variable and not definitive.

Given the prevalence of hypertension, congestive heart failure, arrhythmias, ischemic heart disease, heart attacks and type 2 diabetes in the U.S., magnesium has emerged as a very critical supplement for prevention and management of these conditions. Intervention doses vary from 250 mg/day to 1,000 mg/day depending on the condition, body weight, age, and tolerability. Individuals with kidney disease or heart blocks should not take magnesium unless under a physician’s supervision. Magnesium is generally well tolerated, although there is often a dose limiting amount above which causes loose stool.

Magnesium is an essential mineral for normal body physiology. Deficiencies and insufficiencies are more common than is easily detected, and may lead to numerous cardiovascular disorders, type 2 diabetes, preeclampsia and eclampsia.

In most cases, I recommend that calcium supplementation should also include magnesium supplementation and a ration of approximate 2 parts calcium: 1 part magnesium. Current reference guidelines for daily intake for your age and gender can be obtained from the Institute of Medicine or from www.nutrition.gov. It is important to keep in mind the dietary supplement dosages are in addition to the average daily amount you are getting in your diet, to achieve the recommended daily amount.

References

[1] Dacey M. Hypomagnesemic disorders. Crit Care Clin. 2001;17:155-173.

[2] Gums J. Magnesium in cardiovascular and other disorders. Am J Health-Syst Pharm 2004;61:1569—76.

[3] Kawano Y, Matsuoka H, Takishita S, et al. Effects of magnesium supplementation of hypertensive patients: assessment by office, home, and ambulatory blood pressures. Hypertension. 1998;32:260-5.

[4] Arsenian M. Magnesium and cardiovascular disease. Prog Cardiovasc Dis. 1993; 35:271-310.

[5] Altura B, Altura B. Magnesium and cardiovascular biology: an important link between cardiovascular risk factors and atherogenesis. Cell Mol Biol Res. 1995;41:347-59.

[6] Smith K, Luhrsen K. Trace mineral interactions during elevated calcium consumption. Fed Proc 1986;45:374.

[7] O’Dell BL, Morris ER, Regan WO. Magnesium requirement of guinea pigs and rats. Effect of calcium and phosphorus and symptoms of magnesium deficiency. J Nutr 1960;70:103-111.

[8] Clarkson E, Warren L, McDonald S, de Wardener H. The effect of a high intake of calcium on magnesium metabolism in normal subjects and patients with chronic renal failure. Clin Sci 1967;32:11-18.

[9] Hollifield J. Thiazide treatment of hypertension: effects of thiazide diuretics on serum potassium, magnesium, and ventricular ectopy. AmJ Med. 1986;80 (suppl 4A): 8-12.

[10] Whang R, Ham;pton E, Whang D. Magnesium homeostasis and clinical disorders of magnesium deficiency. Ann Pharmacother. 1994;28:220-6.

Women who had the highest intake of thiamine were 25% less likely to develop PMS than those with the lowest intake. Women with the highest intake of riboflavin were 35% less likely to develop PMS. The intake of all B vitamins together in a B-complex supplement did not appear to lower the risk for PMS.

Comments: Vitamin B6 (pyridoxine) has shown benefits in treating PMS in most, but not all studies, and has shown a substantial and broad effect on the whole range of PMS symptoms in the positive studies. Doses have ranged from 50 gm to 500 mg per day. Given this body of research and information spanning since 1973, I’m not sure what compelled the investigators in this current study to track vitamins B1 and B2, rather than vitamin B6.

Reference: Chocano-Bedoya P, et al. Dietary B vitamin intake and incident premenstrual syndrome. Am J Clin Nutr 2011 May; 93:1080

In the last five years, some studies have suggested that high levels of unmetabolized folate may be associated with an increase in the risk for colorectal cancer. [ii]^{, [iii]}

In those individuals with premalignant colorectal lesions, excess folate, and in particular the thymidylate, a component of DNA that is synthesized from folate, could facilitate cell division of these premalignant lesions and lead to cancer. On the other hand, in those individuals without a premalignant lesion, folate may actually protect normal cells from becoming neoplastic. 3

Some evidence now exists for this “dual-modulator” effect of folate and colorectal neoplasia, whether dietary or supplemental. [iv],[v] This dual effect of folate, prevention vs. proliferative effect of premalignant lesions has been raised with prostate and breast cancer but recent studies have shown that appropriate folate intake does not significantly increase or decrease risks for breast[vi] and prostate cancer.[vii]

Adequate maternal intake of folic acid reduces the frequency of neural tube defects by up to 75%, and may also reduce the frequency of other birth defects such as ventricular septal defects, tetralogy of Fallot and transposition of the great vessels,[viii] urinary tract abnormalities [ix] and possibly even cleft lip and/or cleft palate.[x]

Currently, the average intake of folic acid from the diet of women of childbearing age is about 170mcg/day.[xi] A diet without folic acid fortified grains is typically 140 mcg/day. Clearly, too few women are achieving adequate serum folate levels through diet alone and do require supplementation. The RDA for folate in non-pregnant women is 400 mcg per day. [xii]The RDA for folate in pregnancy is 600 mcg per day[xiii] although the latest US Preventive Services Task Force recommendation is 400mcg-800 mcg per day for women of childbearing age.[xiv] The American College of Obstetricians and Gynecologists recommends that non pregnant women of childbearing aged consume 400 mcg/day. [xv] This variability reflects the uncertainty about the exact dose that is option for the prevention of neural tube defects. For women with a previous pregnancy resulting in a neural tube defect, 4,000 mcg is necessary to achieve these prevention benefits.15

While there is some concern about long term folic acid supplementation for a select number of individuals, the benefits for reproductive aged women, pre-pregnancy and pregnant, outweighs any concerns. A cautionary approach in terms of benefits and risks might be to meticulously track dietary intake to assure adequate levels, or to supplement with folic acid in combination with L-5-methyl-THF or L-5-methyl-THF alone.

[i] Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 1998.

[ii] Mason J, Dickstein A, Jacques P, et al. A temporal association between folic acid fortification and an increase in colorectal cancer rates myay be illuminating important biological principles : a hypothesis. Cancer Epidemiol Biomarkers Prev 2007;16(7):1325-1329

[iii] Sanjoaquin M, Allen N, Couto E, et al. Folate intake and colorectal cancer risk : a meta-analytical approach. Int J Cancer. 2005;113(5):825-828.

[iv] Mathers J. Folate intake and bowel cancer risk. Genes Nutr 2009;4(3)::173-178.

[v] Hubner R, Houlston R. Folate and colorectal cancer prevention. Br J Cancer. 2009;100(2):233-239.

[vi] Kim Y. Does a high folate intake increase rhe risk of breast cancer? Nutr Rev. 2006;64(10 pt 1):468-475

[vii] Figueiredo J, Grau M, Haile R, et al. Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst. 2009;101(6):432-435.

[viii] Botto L, Mulinare J, Erickson J. Do multivitamin or folic acid supplements reduce the risk for congenital heart defects? Evidence and gaps. Am J Med Genet. 2003;121A(2):95-101.

[ix] Czeizel A. Reduction of urinary tract and cardiovascular defects by periconceptional multivitamin supplementation. Am J Med Genet. 1996;62(2):179-183.

[x] Badovinac R, Werler M, Williams P, et al. Folic acid-containing supplement consumption during pregnancy and risk for oral clefts: a meta-analysis. Birth Defects Res A Clin Mol Teratol. 2007;79(1):8-15.

[xi] US Food and Drug Administration. Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Final rule. 212 CFR Parts 136, 137, 139. Fed Regist. 1996;61(44):8781-8797

[xii] Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington DC: National Academy Press; 1998.

[xiii] Simpson J, Bailey L, Pietrzik K, Shane B, Holzgreve . Micronutrients and women of reproductive potential: required dietary intake and consdquences of dietary deficiency or escess. Part !-Folate, Vitamin B12, Vitamin B6. J Matern Fetal Neonatal Med 2010.

[xiv] US Preventive Services Task Force. Folic acid for the prevention of neural tube defects: US preventive services task force recommendation statement. Ann Intern Med 2009;150(9):626-631

[xv] Cheschier N. ACOG Committee on Practice Bulletins-Obstetrics. ACOG practice bulletin. Neural tube defects. November 44, July 2003. Int J Gynecol Obstet 2003;83(1):123-133.

This study was a double blind clinical trial in 150 women in Iran. Two groups of 75 women each were evaluated for severity and duration of breast pain which was measured according to a breast pain chart and something called a Visual Analog Scale.

Chewable tablets of either vitamin E 200 mg tablets or a placebo were given twice a day for 4 months, and again, the severity and duration of breast pain was evaluated at the end of the second and fourth month. The results at two months for vitamin E were dramatically better than placebo in severity and duration, and appear to be achievable in about 70% of the women. The improvement was seen as soon as two months, and no continued improvement after 4 months.

Commentary: Other studies have been conducted in vitamin E and breast pain. In 1997, Khanna et al compared vitamin E with a drug called Danazol. Vitamin E reduced pain in 41% of the women in the studies and Danazol had similar pain reduction in 72% of the women. Clearly the drug helped more women, but the side effects of that drug are significant and one third of the women developed other side effects. Meyer et al did a study in 1990 but did not show any benefit from Vitamin E. Ernester in 1985 studied 201 women with mastalgia as it relates to fibrocystic breast disease. He concluded that vitamin E was not effective, but he was not evaluating breast pain as a distinct issue. In 2004, Bespalov et al studied 66 women with a combination of beta-carotene, vitamin E, vitamin C and garlic powder. There was a reduction in the severity of mastalgia, premenstrual syndrome, infrequent menses and menstrual cramping as well as a reduction in symptoms of fibromatosis in 75% of the women compared with 45% of women on placebo.

If vitamin E alone is not sufficiently helpful in reducing mastalgia, evening primrose or borage oil should be considered, as well as carotenoids, iodine, eliminating caffeine, lowering saturated fats in the diet and increasing fiber.

References

Parsay S, Olfati F, Nahidi S. Therapeutic effects of vitamin E on cyclic mastalgia. The Breast Journal 2009;15(5):510-514.

Commentary: We know that elevated homocysteine levels are associated with the risk for AMD and B vitamins lower homocysteine levels. The current study suggests that supplementation with these three B vitamins can lower the risk for AMD, although it is not clear if this result is indeed related to homocysteine lowering or some other mechanism.

References

Christen W,et al. Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: The women’s antioxidant and folic acid cardiovascular study. Arch Intern Med 2009. Feb 23;169:335