 What we know for clinical practice and decision making
by Sara Gottfried, MD, and Kari Hamrick, PhD, RD Polycystic ovary syndrome (PCOS) is a problem of hormone dysregulation that can lead to irregular menstrual cycles, high androgens, and its downstream sequelae such as acne and hirsutism, infertility, weight gain, and cardiovascular disease. As practitioners and their affected female patients anguish over the root cause and solutions, one part is very clear: up to 85% of women with PCOS are insufficient in vitamin D.1 For our patients with PCOS, correcting low serum vitamin D levels can be a helpful lever in improving hormonal, metabolic, inflammatory, and possibly cardiovascular outcomes. Vitamin D is known as the “sunshine vitamin” because sunlight can trigger cutaneous synthesis of vitamin D. Previously, I reviewed the role of vitamin D in the body and the prevalence of vitamin D deficiency and insufficiency across populations. Vitamin D is a steroid hormone precursor that has hundreds of roles in the body beyond bone health. Having been interested in vitamin D deficiency and the connection with health issues, especially those impacting women, I wanted to delve into the link between vitamin D and PCOS. I will review the current literature to help inform clinical practice and decision making for this unique patient group. PCOS and women’s health PCOS is the most common endocrine disorder among women during reproductive years, with an estimated prevalence of 4-18% from puberty to perimenopause.2,3 Prevalence varies based on ethnicity (i.e., in descending order: Black > Middle Eastern > Caucasian > Chinese).4 Clinical presentation may include insulin resistance, obesity, hirsutism (excess male pattern hair growth), and chronic low-grade inflammation.5,6 PCOS has been linked to serious health concerns, including increased risk of breast and endometrial cancers, infertility, heart disease, stroke, dysglycemia, insulin resistance, gestational diabetes, and preeclampsia.5,6 Women experiencing hormonal imbalance at any age may feel out of control and even disempowered. Women seeking help for PCOS deserve compassionate healthcare providers who are able to diagnose, understand the root causes of their symptoms, and provide evidence-based guidelines for measurable and effective health improvement. Recently updated international PCOS guidelines have made diagnosis and care for patients more comprehensive, standardized, and evidence-based.7 In the summer of 2018, an international consortium of PCOS healthcare professionals, including 37 societies across 71 countries (spanning six continents), issued a guideline for the assessment and management of PCOS, with 31 evidence-based recommendations that help refine the therapeutic approach and increased the focus on the important role of education and lifestyle modification.7 I understand the desire to employ best practices with the most available research evidence in your clinic. But with patients coming and going all day, it is easy to become overwhelmed with journals piling up on your desk and not enough time in the day to do a targeted PubMed search, much less read all of the new hits. Along with key individuals clinical studies, the aforementioned international consensus guideline,7 as well as systematic reviews and meta-analyses, are a time-efficient way to help the clinician recognize patterns and synthesize evidence to identify answers or solutions to important research and clinical questions.8 Now, let’s explore the vitamin D-PCOS link further, from epidemiologic to intervention evidence. THE VITAMIN D-PCOS LINK Vitamin D status and PCOS Systematic review of vitamin D research indicates that hypovitaminosis D (low serum 25-hydroxvitamin D [25(OH)D]) is common in women with PCOS.9 In a review of PCOS etiology, average serum 25(OH)D levels ranged 11–31 ng/mL, but the majority of patients (67%–85%) had values < 20 ng/mL,1 which is the cutoff for deficiency according to a vitamin D clinical practice guideline from the US Endocrine Society.10 Serum vitamin D status is inversely associated with PCOS symptoms and pathology, including obesity,11,12cardiovascular disease risk,13 and insulin resistance.2,11 In a clinical study investigating the impact of lifestyle intervention on health outcomes in women with overweight or obesity and PCOS, higher 25(OH)D concentrations were significantly associated with lower waist circumference and total cholesterol among participants of both cohorts.14 Taken together, these findings suggest that vitamin D status is an important therapeutic consideration for women with PCOS. Vitamin D supplementation and PCOS Vitamin D supplementation studies show promising results for the potential impact of this essential micronutrient in PCOS symptomology. A 2018 systematic review and meta-analysis examined 11 randomized controlled trials (RCTs) including > 600 patients with PCOS; as expected, vitamin D deficiency and insufficiency were observed to be prevalent in this patient group, and vitamin D supplementation significantly improved 25(OH)D status.15 Analyses considered factors like dose frequency and whether vitamin D supplementation was provided alone or as a co-supplement. Major findings include: continuous daily supplementation (i.e., as opposed to weekly bolus dosing) with vitamin D (< 4,000 IU/day) alone reduced homeostatic model assessment of insulin resistance (HOMA-IR). Vitamin D provided as a co-supplement (i.e., in combination with other micronutrients – vitamin K, calcium, zinc, or magnesium) also reduced HOMA-IR and also decreased fasting glucose concentrations.15 In other words, vitamin D supplementation yielded improvements in insulin sensitivity in women with PCOS.15 Biomarkers of oxidative stress and inflammation among women with PCOS have also been examined in RCTs with vitamin D intervention; overall, higher dose groups experienced improvements in oxidative stress and inflammation.16 For example, one 3-month study included in both meta-analyses15,16 investigated the impact of vitamin D supplementation with or without with metformin on metabolic profiles of insulin resistant, Iranian women with PCOS.17 This RCT randomized patients into three groups: “high dose” vitamin D (4,000 IU/d) + metformin, “low dose” vitamin D (1,000 IU/d) + metformin, or placebo + metformin. Following intervention, metabolic profiles were significantly improved in the high dose vitamin D group compared to the low dose and placebo groups.17 Specifically, the high dose vitamin D group experienced significantly lower total testosterone, lower prevalence of hirsutism, and lower high-sensitivity C-reactive protein (hs-CRP), a marker of inflammatory response.17 Additionally, significant elevations in total antioxidant capacity (showing improved free radical fighters) and sex hormone binding globulin (SHBG) were observed in the high dose vitamin D group, indicating improved body regulation of circulating hormones.17 Female-centric considerations for vitamin D status There are many risk factors for vitamin D deficiency in women, which we have covered previously. One gender-based factor for some women, constructed by cultural and/or religious forces, may be partial or complete covering with clothing, and thus, limited exposure to sunlight and cutaneous synthesis of vitamin D. Additionally, with the increased prevalence and public health awareness of skin cancer, more women are using sunscreen and limiting time in the sun. Because of less opportunity to receive vitamin D through the skin, clinicians should discuss the implications of low vitamin D status with their patients and promote practical ways to achieve and maintain healthy serum 25(OH)D levels– namely, vitamin D supplementation. Genomic risk and PCOS The actions of the active, hormone form of vitamin D [1,25(OH)2D] are mediated by the vitamin D receptor (VDR). And over 3% of the human genome is regulated by the VDR gene.18 That may not sound like a lot, but it translates into hundreds of protein-coding genes. With advances in genetic testing for various diseases, many patients may want to know if there is a genetic component to PCOS. One meta-analysis found that VDR Fokl and Taql polymorphisms were associated with an increased risk of PCOS in certain populations (e.g., Asians).18 Another meta-analysis found that VDR variants, Apal, Bsml, and Fokl, were associated with heightened risk of diseases related to insulin resistance, particularly in Caucasians with darker skin (i.e., from Saudi Arabia, India, Egypt, and Iran) and Asian populations.19 The good news is that even if the patient carries a VDR variant linked to PCOS, improving vitamin D status via lifestyle modifications (e.g., achieving healthy weight, incorporating sun exposure in moderation, and incorporating vitamin D sources in the diet) along with intervention via routine vitamin D supplementation has more impact on PCOS outcomes than genetic variations. Dietary/nutrition considerations in PCOS It is well recognized that lifestyle intervention is the cornerstone of treatment for patients with PCOS.20 First line PCOS treatment should include targeted lifestyle modifications that focus on weight management, including optimizing dietary approach and increasing physical activity. In fact, the good news is that a relatively low reduction in weight (~ 5 percent) can improve insulin resistance, hyperandrogenism, menstrual function, and fertility.20,21 Clinical consensus for dietary recommendations from the international consortium have focused on overall reduction in calorie intake and general healthy eating principles, with no one particular diet reported to have more favorable outcomes over another. Dietary guidelines and lifestyle recommendations are centered on achieving a healthy weight and managing metabolic and reproductive functions. The following recommendations have been shown via research to be successful nutritional management approaches for PCOS:21-24
More on the ketogenic diet for PCOS—initial data are promising, but not quite ready for prime time according to PCOS guidelines, though it is an active area of investigation. Other areas of active research include intermittent fasting and the fasting-mimicking diet. Regardless of the dietary approach, “Weight loss should be targeted in all overweight women with PCOS through reducing caloric intake in the setting of adequate nutritional intake and healthy food choices irrespective of diet composition.”20 Improving vitamin D status in patients with PCOS Individual nutrients of interest in PCOS research, such as vitamin D, were not specifically addressed in the 2018 international PCOS guidelines.6 However, because the growing body of research on vitamin D status and supplementation interventions in patients with PCOS is compelling, it is prudent for practitioners to partner with patients to assess their vitamin D status (via serum 25(OH)D concentration; sufficiency is defined as ≥ 30 ng/mL) and help them achieve and maintain vitamin D sufficiency through supplementation.10 Supplementation recommendations can be personalized based on periodic serum 25(OH)D measurements (e.g., it can take 3-4 months for 25(OH)D to reach a new steady state), and dosing depends on whether you are repleting a deficient state (6,000 IU/day or 50,000 IU/week for 8 weeks) or maintaining a 25(OH)D level in the normal range (at least 1,500-2,000 IU/day).10 However, it is important to remember that patients with overweight and obesity (common in PCOS) may need 2-3 times more vitamin D daily than their normal-weight counterparts.10 Optimal healthcare approach for patients with PCOS A multidisciplinary, holistic, and personalized lifestyle medicine approach to care is the best practice for patients with PCOS. Collaboration and continuity of care with specialists across the PCOS spectrum has the greatest impact on outcomes and patient satisfaction.6,27 The evidence-based guidelines recommend lifestyle management as the first line therapy, with weight management being of utmost importance. Modest weight loss can net significant metabolic and hormonal improvements in patients with PCOS.20 Research indicates that weight management outcomes in women with PCOS are likely improved by the inclusion of the following factors: behavioral and psychological strategies, goal setting, self-monitoring, cognitive restructuring, problem solving, relapse prevention.28 Strategies that target improvements in motivation, social support, and psychological well-being are also key.28 Providing your patients with high-quality, multidisciplinary resources and referrals will improve their opportunity to receive support for the necessary lifestyle modifications.27 This may include consultations with fertility experts, endocrinologists, cardiologists, behavioral health specialists, registered dietitian nutritionists, or personal trainers, to name a few. Ask your patients what barriers to lifestyle management they may experience, and partner with them to champion key, gradual changes toward healing and wellness. Although vitamin D supplementation recommendations are not yet included in the latest international PCOS guidelines, the evidence to date indicates that assessment and treatment of vitamin D deficiency and insufficiency among PCOS patients is likely a critical piece of the PCOS management puzzle. Vitamin D supplementation is the most pragmatic, beneficial, and clinically necessary approach when serum 25(OH)D levels are low, a scenario that applies the majority of patients with PCOS. Citations
Sara Gottfried, MD is a board-certified gynecologist and physician scientist. She graduated from Harvard Medical School and the Massachusetts Institute of Technology and completed residency at the University of California at San Francisco. Over the past two decades, Dr. Gottfried has seen more than 25,000 patients and specializes in identifying the underlying cause of her patients’ conditions to achieve true and lasting health transformations, not just symptom management. Dr. Gottfried is the President of Metagenics Institute, which is dedicated to transforming healthcare by educating, inspiring, and mobilizing practitioners and patients to learn about and adopt personalized lifestyle medicine. Dr. Gottfried is a global keynote speaker who practices evidence-based integrative, precision, and Functional Medicine. She recently published a new book, Brain Body Diet, and has also authored three New York Times bestselling books: The Hormone Cure, The Hormone Reset Diet, and Younger. Kari Hamrick, PhD, RD is a registered dietitian with over 25 years of experience in nutrition and wellness and is the founder of Navigate Nutrition and Wellness, a private practice nutrition counseling center located in Gig Harbor, WA. Dr. Hamrick earned her PhD in nutritional sciences from Texas Woman’s University and received Adult Weight and Lifestyle Management certification from the Commission on Dietetic Registration. Kari has special training and experience in Mindfulness Based Eating Awareness Training (MB-EAT), women’s health issues, and the nutritional management of heart disease, eating disorders, and digestive health. Dr. Hamrick is currently completing a medical communication fellowship at Metagenics. Dr. Hamrick’s passion is helping individuals meet their nutrition and health goals with respect, open communication, and a sense of humor. She is also a yoga and dance instructor and enjoys learning and performing aerial acrobatic arts.
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 by Ashley Jordan Ferira, PhD, RDN
The importance of vitamin D in diverse organ systems and biochemical processes is ever-growing with novel research findings. From calcium absorption to extraskeletal health processes such as immune function- vitamin D is essential. The role of vitamin D in pain management is a newer area of investigation that has not been fully established. It is estimated that 25.3 million American adults experience pain every day, with nearly 40 million experiencing some form of extreme pain.1 Annual costs associated with treating pain and pain-related symptoms are estimated to be higher than cancer and diabetes combined, reaching upwards of $600 billion per year.2 The striking number of Americans experiencing pain, combined with the associated financial burdens, underscores the need for clinically efficacious pain management methods. Chronic non-specific widespread pain (CWP) including fibromyalgia (FMS) is associated with diffuse pain, reduced pain threshold, multiple points of tenderness, disability, and decreased quality of life. To better understand if vitamin D supplementation can significantly impact (CWP) including fibromyalgia (FMS), researchers, performed a systematic review and meta-analysis, the results of which were published in Clinical Rheumatology.3 Researchers comprehensively assessed databases for pertinent vitamin D trials. The authors focused on randomized controlled clinical trials evaluating the effects of vitamin D on CWP and FMS; 4 clinical trials met the inclusion criteria. After pooling the data from over 270 patients, regression, sensitivity and heterogeneity analyses were evaluated. Visual Analog Scale (VAS) of pain intensity was a major outcome measure. Pooled results revealed a significantly lower VAS of pain intensity in CWP patients who received vitamin D treatment vs. those who received a placebo control. The analysis concluded that vitamin D supplementation decreased pain scores and improved pain symptoms. Why is this Clinically Relevant?
Link to abstract Citations
 The female-centric 411 on this essential nutrient
by Ashley Jordan Ferira, PhD, RDN Overview Vitamin D research and daily news headlines are ubiquitous. PubMed’s search engine contains over 81,400 articles pertaining to vitamin D.1 Information abounds on vitamin D, but the vetting and translation of that information into pragmatic recommendations is harder to find. Evidence-based takeaways and female-centric recommendations are crucial for healthcare practitioners (HCPs), their female patients and consumers alike. Women are busy, multi-tasking pros, so practical, personalized takeaways are always appreciated. In other words, women need the “411” on vitamin D. Merriam-Webster defines “411” as “relevant information” or the “skinny”.2 So for all of you busy women, here’s the skinny on vitamin D. Let’s explore common questions about this popular micronutrient. Q: Is vitamin D more important for younger or older women? A: All of the above. Vitamin D plays a critical role in women’s health across all life stages, from fertility/conception, to in utero, childhood, adolescence, adulthood, older adulthood, and even in palliative care. Vitamin D is converted by the liver and kidneys into its active hormone form: 1,25-dihydroxyvitamin D. This dynamic hormone binds nuclear receptors in many different organs in order to modulate gene expression related to many crucial health areas across the lifecycle, including bone, muscle, immune, cardiometabolic, brain, and pregnancy to name a few.3 Q: I am a grandmother. Are my vitamin D needs different than my daughter and granddaughter? A: Yes, age-specific vitamin D recommendations exist. As an essential fat-soluble vitamin, women need to achieve adequate levels of vitamin D daily. Age-specific Recommended Dietary Allowances (RDA) from The Institute of Medicine (IOM),4 as well as newer clinical guidelines from The Endocrine Society,5 provide helpful clinical direction for daily vitamin D intake and/or supplementation goals. The IOM RDAs4 are considered by many vitamin D researchers to be a conservative, minimum daily vitamin D intake estimate to support the bone health of a healthy population (i.e. prevent the manifestation of frank vitamin D deficiency as bone softening: rickets and osteomalacia): Infants (0-1 year): 400 IU/day Children & Adolescents (1-18 years): 600 IU/day Adults (19-70 years): 600 IU/day Older Adults (>70 years): 800 IU/day The Endocrine Society’s clinical practice guidelines5 recommend higher daily vitamin D levels than the IOM, with a different end-goal: raising the serum biomarker for vitamin D status [serum 25-hydroxvitamin D: 25(OH)D] into the sufficient range (≥ 30 ng/ml) in the individual patient: Infants (0-1 year): At least 1,000 IU/day Children & Adolescents (1-18 years): At least 1,000 IU/day Adults (19+ years): At least 1,500 – 2,000 IU/day Q: I am a health-conscious woman who eats a nutritious, well-rounded diet. I should not need a vitamin D supplement, right? A: Not so fast. Daily micronutrient needs can be met via diet alone for many vitamins and minerals. Vitamin D is one of the exceptions, which is why an alarming number of Americans (93%) are failing to consume the recommended levels from their diet alone.6-7 Very few foods are endogenous sources of animal-derived vitamin D3 (cholecalciferol) or plant-derived vitamin D2 (ergocalciferol). Some natural vitamin D sources include certain fatty fish (e.g. salmon, mackerel, sardines, cod, halibut, and tuna), fish liver oils, eggs (yolk) and certain species of UV-irradiated mushrooms.8 In the early 20th century, the US began fortifying dairy and cereals with vitamin D to help combat rickets, which was widespread. For example, one cup (8 fluid ounces) of fortified milk will contain approximately 100 IU of vitamin D. Even though some food sources do exist, the amounts of these foods or beverages that an adult would need to consume daily in order to achieve healthy 25(OH)D levels (> 30 ng/ml) is quite unrealistic and even comical to consider. For example, you would need to toss back 20 glasses of milk daily or 50 eggs/day to achieve 2,000 IU of vitamin D! In contrast, daily vitamin D supplementation provides an easy and economical solution to consistently achieve 2,000 IU and any other specifically targeted levels. Q: I enjoy the outdoors and get out in the sun daily, so I should be getting all of the vitamin D that I need, correct? A: Vitamin D is a highly unique micronutrient due to its ability to be synthesized by our skin following sufficient ultraviolet (UV) B irradiation from the sun. Many factors can result in variable UV radiation exposure, including season, latitude, time of day, length of day, cloud cover, smog, skin’s melanin content, and sunscreen use. Furthermore, medical consensus advises limiting sun exposure due to its established carcinogenic effects. Interestingly, even when dietary and sun exposure are both considered, conservative estimates approximate that 1/3 of the US population still remains vitamin D insufficient or deficient.9 Q: What factors can increase my risk for being vitamin D deficient? Are there female-specific risk factors? A: Although the cutoff levels for vitamin D sufficiency vs. deficiency are still debated amongst vitamin D researchers and clinicians, insufficiency is considered a 25(OH)D of 21-29 ng/ml, while deficiency is < 20 ng/ml.5 Therefore, hypovitaminosis D (insufficiency and deficiency, collectively) occurs when a patient’s serum 25(OH)D falls below 30 ng/ml. The goal is 30 ng/ml or higher. Ideally, vitamin D intake recommendations4-5 and therapy are personalized by the HCP based on patient-specific information, such as baseline vitamin D status, vitamin D receptor single nucleotide polymorphisms and other pertinent risk factors. Common risk factors for vitamin D deficiency to look out for include: -> Overweight/obesity -> Older age -> Regular sunscreen use -> Winter season -> Frequent TV viewing -> Dairy product exclusion -> Darker skin (more melanin) -> Not using vitamin D supplements -> Malabsorption disorders (e.g. bariatric surgery, IBD, cystic fibrosis) -> Liver disease -> Renal insufficiency -> Certain drug classes: weight loss, fat substitutes, bile sequestrants, anti-convulsants, anti-retrovirals, anti-tuberculosis, anti-fungals, glucocorticoids -> Lastly, additional female-specific risk factors to look out for include exclusive breastfeeding while mother is vitamin D insufficient (can result in infant being vitamin D deficient) and certain cultural clothing that covers significant amounts of skin surface area (e.g. hijab, niqab). Key Takeaways
Ashley Jordan Ferira, PhD, RDN is Manager of Medical Affairs and the Metagenics Institute, where she specializes in nutrition and medical communications and education. Dr. Ferira’s previous industry and consulting experiences span nutrition product development, education, communications, and corporate wellness. Ashley completed her bachelor’s degree at the University of Pennsylvania and PhD in Foods & Nutrition at The University of Georgia, where she researched the role of vitamin D in pediatric cardiometabolic disease risk. Dr. Ferira is a Registered Dietitian Nutritionist (RDN) and has served in leadership roles across local and statewide dietetics, academic, industry, and nonprofit sectors. Food-Fortified Vitamin D3 More Effective than D2 at Raising Serum 25(OH)D Levels | Blog | Metagenics7/18/2019  by Ashley Jordan Ferira, PhD, RDN
A food fortification trial demonstrated that 600 IU of daily vitamin D3 had a significantly greater impact than 600 IU of daily vitamin D2 in elevating serum blood levels of 25-hydroxyvitamin D [25(OH)D].1-2 Vitamin D is essential for skeletal health and many emerging extraskeletal physiological processes, but remains one of the most common micronutrient dietary gaps, resulting in widespread hypovitaminosis D globally. Understanding how much vitamin D the body needs daily, in what form, and from what sources is still being discovered. There are two forms of vitamin D: plant-based ergocalciferol (vitamin D2) and animal-based cholecalciferol (vitamin D3). D2 can be found in UV-irradiated mushrooms, certain fortified foods (breakfast cereals, margarine, and milk), dietary supplements, and vitamin D prescription medications. D3 is found in oily fish, egg yolks, fortified milk, and dietary supplements.4 Chemically, D2 and D3 are almost identical except for key side chain differences, with D2 having an additional double bond. D3 has been shown to have a higher affinity to the vitamin D binding protein, hepatic 25-hydroxylase (enzyme that converts vitamin D to the circulating 25(OH)D form) and vitamin D receptor. Whether these chemical and cellular differences translate into differential abilities in raising serum 25(OH)D, the clinical measure of vitamin D status, has been a hotly debated topic since the early 20th century.5 Research literature to date demonstrates a robust case gaining momentum for vitamin D3 and against vitamin D2 for supplementation.4-5 In particular, a 2012 systematic review and meta-analysis by of randomized controlled vitamin D supplementation trials in humans explored a head-to-head comparison of vitamin D2 vs. D3 in raising serum 25(OH)D; vitamin D3 was clearly shown to be more efficacious at raising and maintaining serum 25(OH)D levels than vitamin D2.4 Authors concluded that vitamin D3 may be considered the preferred choice for supplementation.4 Since natural sources of vitamin D (dietary input and UVB exposure from the sun) are limited, and a daily vitamin D supplementation regimen is a personal health decision, vitamin D fortification of the food supply is an important, strategic public health measure to help increase dietary vitamin D intake and improve status in the general population.6 Clarity is needed to elucidate whether D2 and D3 are equally effective sources for food fortification, since both forms are currently utilized in the food supply.6 A study by Tripkovic et al. helps to shed light on key differences.1 Results were published in The American Journal of Clinical Nutrition by Dr. Laura Tripkovic and colleagues from a randomized, double-blind, placebo-controlled food fortification trial that included 335 healthy South Asian and white European women aged 20–64 years.1 Participants were randomized to one of five groups: 1) Placebo: Placebo juice with placebo biscuit 2) D2J: Juice supplemented with 15 mcg vitamin D2 with placebo biscuit 3) D2B: Placebo juice with biscuit supplemented with 15 mcg vitamin D2 4) D3J: Juice supplemented with 15 mcg vitamin D3 with placebo biscuit 5) D3B: Placebo juice with biscuit supplemented with 15 mcg vitamin D3 Fifteen mcg of vitamin D is equivalent to 600 IU of vitamin D, which is the US Recommended Daily Allowance (RDA) for ages 1-70 years.7 The daily food-fortified intervention was 12 weeks long during the winter, and serum total 25(OH)D levels were collected at baseline, week 6 and week 12. Data analysis combined ethnic groups. D3-fortified consumption was shown to be twice as effective as D2 in raising 25(OH)D serum levels in the body.1 While the placebo group experienced a 25% reduction in serum 25(OH)D levels over the course of the study, the D2J and D2B groups saw 25(OH)D increases of 33% and 34%, respectively. Most effective, however, were the D3 groups, with 25(OH)D increases in the D3J and D3B groups of 75% and 74%, respectively. The D3J group induced higher incremental increases in 25(OH)D levels: 16.9 nmol/L higher than the D2J group, 16.0 nmol/L higher than the D2B group, and 42.9 nmol/L higher than the placebo group.1 Both juice- and biscuit-supplemented vitamin D3 groups demonstrated similar results, with no statistical differences seen between D3J and D3B groups.1 Compared to white European women, the South Asian women demonstrated a greater increase in 25(OH)D levels in response to both D2 and D3, which was likely caused by their lower baseline vitamin D status.1 This study shows that modest supplementation levels (600 IU daily) of D3 in food and beverage sources twice as effective at raising serum levels of 25(OH)D than vitamin D2.1This study and previous supplementation studies may impact future policy and practice for vitamin D supplementation source. Additional research addressing dose response, bioactivity of D3 versus D2 and the impact of foods with high levels of vitamin D3 is needed.2 Why is this Clinically Relevant?
Citations
 by Ashley Jordan Ferira, PhD, RDN
Vitamin D is essential- it helps absorb calcium, supports nervous and muscle tissue, and the immune system. Compared to normal-weight counterparts, vitamin D deficiency is more prevalent in those with obesity. In the US over one-third of adults meet obesity criteria.1 A study in The Journal of Clinical Endocrinology and Metabolism2 examined cellular mechanisms of vitamin D trafficking in metabolically dysfunctional adipose tissue as compared to normal adipocytes in conjunction with a vitamin D supplementation intervention in a randomized, controlled trial. Ninety-seven male subjects completed the vitamin D intervention study. Fifty-four normal-weight and 67 obese males were initially randomized to receive either 50 mcg/week of 25-hydroxyvitamin-D3 [25(OH)D3] (2,000 IU/week equivalent) or 150 mcg/week of vitamin D3 (6,000 IU/week equivalent) for one year. Vitamin D sufficiency was defined as a 25(OH)D blood level > 20 ng/ml. This serum concentration is aligned with the National Academy of Medicine’s cutoff for vitamin D sufficiency.3 Vitamin D uptake, conversion and release were investigated in control (non-insulin-resistant) and insulin-resistant 3T3-L1 adipocytes, as well as in subcutaneous adipose tissue (SAT) samples from lean and obese participants. The release of vitamin D and its metabolites were induced with the addition of adrenaline. Expression of the vitamin D receptor and vitamin D conversion enzymes, 25-hyroxylase and 1α-hydroxylase, was also examined. The research team elucidated key differences in cellular vitamin D trafficking effects and supplementation effects:
Why is this Clinically Relevant?
Link to Abstract References
 by Ashley Jordan Ferira, PhD, RDN
Autism spectrum disorder (ASD) is a complex neurodevelopmental syndrome with significant social, communication and behavioral deficits and challenges.1 No cure exists for ASD, although early interventions (birth to 3 years) can yield developmental improvements.1 ASD impacts approximately 1 in 68 children in the US and is 4.5 times more common in boys (1 in 42) than girls (1 in 189).2 Vitamin D’s extraskeletal roles are numerous, including its role as a neurosteroid, impacting both brain development and connectivity, and likely synaptic plasticity as well.3 Vitamin D is also one of the most common micronutrient deficiencies. Previous research has revealed associations between gestational and early childhood vitamin D insufficiency and ASD.4 This suggests that hypovitaminosis D represents a modifiable risk factor for ASD.4Furthermore, preliminary evidence demonstrates that gene variants related to vitamin D metabolism play a role in the pathophysiology of ASD.5 Robustly designed intervention trials have been scant. The first double-blind randomized controlled trial (RCT) utilizing vitamin D3 supplementation in children with ASD was published in The Journal of Child Psychology and Psychiatry in 2018.6 The study included 109 Egyptian children (85 boys; 24 girls) 3-10 years of age with confirmed ASD diagnosis. The children were randomized to receive vitamin D3drops (300 IU D3/kg/day; not to exceed 5,000 IU/day) or matching placebo drops daily for 4 months.6 Serum 25-hydroxyvitamin D (25[OH]D) levels were measured at baseline and 4-months. For ethical reasons, children who were identified to have vitamin D deficiency (25[OH]D <20ng/mL) were excluded from the study and administered vitamin D supplementation by the study authors.6 Autism symptoms were assessed using validated measures completed by two different psychologists and a senior psychiatrist.6 Four months of daily vitamin D3 supplementation at 300 IU/kg/day:6
Following 4 months of vitamin D3 supplementation, improvements (all p <0.05, most p <0.01; as compared to placebo) were demonstrated in many core manifestations of ASD, including:6
This rigorously designed RCT is the first of its kind to demonstrate safety and efficacy of vitamin D3supplementation in children with ASD.6 Two previous open-label vitamin D3 supplementation studies also demonstrated improvements in ASD symptoms.7-8 Wide-scale studies are warranted to continue to critically ascertain the effects of vitamin D on ASD. Why is this Clinically Relevant?
Link to Article Citations
 Food first, but fill the gap: The case for vitamin D supplementation
Ashley Jordan Ferira, PhD, RDN If you can have a favorite nutrient, mine would be vitamin D. Historically famous for its essential, classical role in calcium and phosphorus homeostasis and bone physiology (think rickets prevention), the past few decades of research have unveiled diverse, extraskeletal health roles for vitamin D, including but not limited to the immune system, cardiometabolic pathophysiology, cancer, pregnancy, etc. Whether consuming vitamin D2 or D3 (FYI, the latter more potently impacts vitamin D status),1 vitamin D ultimately circulates in the 25-hydroxyvitamin D [25(OH)D] form (the clinical biomarker used to measure vitamin D status) and acts throughout the body as a pleiotropic hormone in its active form, 1,25-dihydroxyvitamin D [1,25(OH)2D]. Unlike other nutrients, this fat-soluble vitamin is obtainable via several unique routes: the skin with adequate UVB exposure, a handful of natural food sources, a few fortified foods, dietary supplements, and even prescription drugs. The problem is that few foods naturally contain vitamin D (e.g., egg yolk, certain fatty fish, fish liver oil, and certain species of UV-irradiated mushrooms), and fortified foods offer relatively small amounts (e.g., 100 IU vitamin D per 8 oz cup of fortified milk or orange juice),2 so vitamin D supplementation becomes a strategic solution. In the eloquent words of pediatrician and vitamin D researcher, Carol Wagner, MD: “Something so simple- vitamin D supplementation- could improve the health status of millions and so becomes an elegant solution to many of our health problems today.” If it’s possible to be defensive of a micronutrient, I am protective of vitamin D. Non-evidence-based rumors and negative media attention targeting vitamin D are common. Some of the misinformation is hype from anti-supplement camps who make broad, sweeping statements that lack scientific substantiation. But not all of the vitamin D myths originate from bias or lack of intellectual rigor. After all, who has time to keep up with the impressive, daily output of new vitamin D research? Clinicians certainly do not have the luxury of time, not in the current healthcare paradigm. Nevertheless, when inaccurate conclusions are propagated to patients about vitamin D and their health, that’s more harm than good. So, let me help out. This blog series explores some of the most common vitamin D myths. Let’s tackle just 1 myth today: Myth: I get enough vitamin D from food, so I don’t need a vitamin D supplement. Can you meet your vitamin D needs from food alone? Well, that depends on how you define “needs.” Let’s talk about the 2 major (and quite different) sets of vitamin D recommendations. First, the National Academy of Medicine (NAM), formerly known as the Institute of Medicine, provided vitamin D Recommended Dietary Allowances (RDAs) in 2010.3 Here’s how much vitamin D NAM says that we (Americans and Canadians) need based on bone health research (think rickets and osteomalacia prevention, calcium absorption, etc.):3
But I have a bone to pick (pun intended) with NAM’s vitamin D recommendations. I find them to be problematic, if not contradictory at times, for a few key reasons. To start with, the RDA is by definition “the average daily level of intake sufficient to meet the nutrient requirements of nearly all (97-98%) healthy people.”4 Well, that misses the unhealthy people. Since 2/3rd of the country are overweight or obese5 and heart disease and cancer are the #1 and #2 causes of mortality in the US, respectively,6 one can extrapolate that the vitamin D RDAs do not apply to a decent chunk of the gen pop. In fact, research indicates that overweight and obese individuals require more vitamin D than their lean counterparts,7 but the NAM recommendations fail to consider adiposity. Second, lumping a toddler and 68-year-old grandmother in the same RDA category (i.e., ages 1-70 years) seems to lack nuance. Skeletal health is critical throughout life, but you cannot tell me that the vitamin D needs for the rapidly accruing skeleton in childhood and adolescence are no different than an adult or older adult’s skeletal needs. Third, the RDAs for daily vitamin D intake are simply incongruent with the serum 25(OH)D cutoffs NAM also published in 2010. They provided the following 25(OH)D ranges:
The somewhat ironic problem is that the overly conservative vitamin D RDAs won’t get you into the 25(OH)D range that NAM defines for sufficiency. Regular UVB sun exposure (with adequate skin surface area, right latitude, right time of year, etc.) can raise serum D levels into sufficiency, except cutaneous vitamin D synthesis from sun is highly variable and limited for many. But 400-800 IU/day of vitamin D simply won’t do the trick. It’s like asking someone to fill up an 30-gallon fish tank and giving them a few cups of water to do the trick. In the sage words of the late Bob Heaney, MD: “We’ve been able to show that the (vitamin D) RDA barely budges the blood 25-hydroxyvitamin D level.”8 Thanks to Dr. Heaney, who made invaluable research contributions to the field of vitamin D, we know that 100 IU/day of vitamin D increases serum 25(OH)D concentrations by approximately 1 ng/mL.9That means that 1,000 IU/day of vitamin D would raise 25(OH)D by about 10 ng/mL. Although weight status, age, and the patient’s baseline vitamin D status can variably impact the supplementation response, this “rule of thumb” can be used to roughly calculate vitamin D supplementation needs. For example, let’s take a patient: me. I have limited UVB sun exposure and consume some foods that contain vitamin D (e.g., milk, eggs, salmon) but irregularly. My daily 5,000 IU vitamin D3 supplement has my serum 25(OH)D at 54 ng/mL. It stays between 50-60 ng/mL, which is in the sufficient range. But I’m an anomaly. Nationally representative research backs up the fact that Americans are not getting adequate vitamin D from their diets.10-11 First, 93% of Americans 2 years and older are failing to consume at least 400 IU/day of vitamin D from diet alone, and this estimate includes fortified food sources.10 Even when diet plus sun exposure are both thrown into the mix, about 1/3rd of the US population has serum 25(OH)D levels associated with vitamin D insufficiency or deficiency.11 For more details on vitamin D deficiency and why it persists, check out this blog. Dietitians (I am one) and other clinicians love to preach “food first.” That slogan is true but ignores research on key nutrient gaps. I prefer to say, “food first, then fill the gaps.” And in the case of vitamin D, the gap is practically guaranteed, except for the outlier patient who’s knocking back fish liver oils and irradiated mushrooms. Lastly, a more current and scientifically and clinically nuanced set of guidelines exist. One year after the NAM recommendations were released, several of the world’s leading vitamin D researchers convened to review the evidence to date, resulting in the 2011 publication: Evaluation, Treatment, and Prevention of Vitamin D Deficiency: An Endocrine Society Clinical Practice Guideline.12 The US Endocrine Society’s conclusions are harmonious with the mindset of a clinician, who is tasked with addressing the vitamin D needs of unique patients. The guideline recommends higher daily vitamin D levels than NAM, with a different and logical purpose in mind: Raising serum 25(OH)D levels into the sufficient range (≥ 30 ng/ml):12
The guidelines even differentiate vitamin D needs based on adiposity: Children and adults who are obese may need 2-3 times more vitamin D daily than normal-weight individuals.12 Finally, the US Endocrine Society provides clear guidance for correcting vitamin D deficiency in all age groups, with repletion and maintenance dosing information, which is a topic that I will cover in a future blog. Individual genetic differences for the vitamin D receptor (VDR) (i.e., gene polymorphisms like Cdx2, Apa1, Fok1, Taq1) are another important facet to weave into each patient’s unique vitamin D story, underscoring the prudence of a personalized lifestyle medicine approach to treat the individual. Takeaway: No, you cannot satisfy your vitamin D needs from food alone. If you plan to raise and maintain your serum 25(OH)D level (the biomarker that indicates vitamin D status) in the sufficient range for skeletal and extraskeletal health, that will require daily vitamin D supplementation. Remember, 30 ng/mL is not the goal. It’s the cutoff for insufficiency. Here’s a sneak peak at some of the additional vitamin D myths that will be covered in future blogs:
Do you have a question about the science and clinical application for vitamin D? Let me know by commenting below! Citations
Ashley Jordan Ferira, PhD, RDN is Manager of Medical Affairs and Metagenics Institute, where she specializes in nutrition and medical communications and education. Dr. Ferira’s previous industry and consulting experiences span nutrition product development, education, communications, and corporate wellness. Ashley completed her bachelor’s degree at the University of Pennsylvania and PhD in Foods & Nutrition at The University of Georgia, where she researched the role of vitamin D in pediatric cardiometabolic disease risk. Dr. Ferira is a Registered Dietitian Nutritionist (RDN) and has served in leadership roles across local and statewide dietetics, academic, industry, and nonprofit sectors.  Vitamin D deficiency and the need for practitioner intervention by Sara Gottfried, MD and Lewis Chang, PhD Introduction When I finished my medical training in 1998 at the University of California at San Francisco, I thought I knew everything about vitamin D, particularly vitamin D deficiency and insufficiency. I understood vitamin D was important for the efficient trafficking of calcium in the body, and that helps to keep bones strong, which was important for women’s health over the age of thirty when bone density begins to decline. What I learned in the subsequent twenty years is that vitamin D is both a hormone and a vitamin, and an essential nutrient for more than 400 biochemical jobs in the body. And I learned that what I knew in residency was the tip of the iceberg. Further, I discovered that I inherited a gene for a faulty vitamin D receptor (VDR), which means my body doesn’t absorb and transport vitamin D well, so I tend to have low levels of vitamin D in my blood. This potentially puts me at greater risk for accelerated bone loss, osteopenia, osteoporosis, multiple sclerosis, and certain malignancies such as colorectal cancer. I’m not that unique in carrying the risky gene, but I’m getting ahead of myself. More later on the gene/environment interactions as they relate to vitamin D status, and whether you should be checking your patients for them. As I continue to identify my own knowledge gaps regarding vitamin D, I have become obsessed with teaching other practitioners and my patients about how persistent vitamin D deficiency and insufficiency continue to be despite the public initiatives to raise awareness. In this series on vitamin D, I want to share with you the importance of vitamin D to your health and that of your patients, starting first in this article with how vitamin D status is determined, how prevalent vitamin D insufficiency and deficiency have been in our population, what factors can affect circulating vitamin D levels, recommendations for your female patients since they are at greater risk of problems, and what proven actions to take to help improve your patients’ vitamin D status. How is vitamin D deficiency defined? Serum 25-hydroxyvitamin D [25(OH)D] level is widely used as a bio marker of a person’s vitamin D status, for it is the main circulating form of vitamin D and the best estimator of both endogenous vitamin D synthesis in the skin upon exposure to UV-B light and dietary intake of foods and supplements containing vitamin D.1 Therefore, the diagnosis of vitamin D deficiency is based on the measurement of circulating 25(OH)D levels. However, there is no consensus among key opinion leaders for what is considered an appropriate cutoff for normal, desirable, and optimal serum 25(OH)D concentrations. As a result, different cut-off points have been used to define hypovitaminosis D (deficiency of vitamin D), ranging from 10 ng/mL (25 nmol/L) to 30 ng/mL (75 nmol/L).2-6 There is no consensus among professional societies, either. In 2010, Institute of Medicine (IOM)—renamed in 2016 as the National Academy of Medicine (NAM)—suggested that circulating 25(OH)D levels need to be at least 20 ng/mL (50 nmol/L) to prevent osteomalacia and maintain bone health in at least 97.5% of the population. Therefore, levels at or higher than 20 ng/mL (>50 nmol/L) are defined as vitamin D sufficient. Levels lower than 20 ng/mL (<50 nmol/L) but above 12 ng/mL (>30 nmol/L) are considered vitamin D insufficient and are inadequate for bone and overall health. Levels below 12 ng/mL (<30 nmol/L) are vitamin D deficient which can cause rickets in infants and children and osteomalacia in adults (Figure 1).7 Conversely, believing the IOM recommendations to be too conservative, the Endocrine Society released its clinical practice guidelines in 2011 in which vitamin D sufficiency, insufficiency and deficiency was defined as circulating 25(OH) levels above 30 ng/mL (>75 nmol/L), between 20-30 ng/mL (50-75 nmol/L), and below 20 ng/mL (<50 nmol/L), respectively (Figure 1).8 These recommended cut-off points are similar to the guidelines released by the Central European Scientific Committee on Vitamin D.9 The Endocrine Society also argued that, since any methodology for 25(OH)D measurement is subject to assay variability, targeting a higher 25(OH)D cut-off value may ensure that an individual meets the requirement for sufficient vitamin D levels with only minimal risk of vitamin D toxicity.8 These conflicting professional recommendations result in constant debate among researchers and confusion among clinicians about where the optimal 25(OH)D levels fall. Nevertheless, it is at least agreed upon that serum vitamin D levels less than 30 ng/mL are definitely insufficient and probably deficient for most people. I advise 50-75 ng/mL.  Figure 1. 25(OH)D recommendations by the Institute of Medicine (IOM) and the Endocrine Society. How prevalent is vitamin D insufficiency and deficiency? The prevalence varies depending on how vitamin D insufficiency and deficiency is defined. Another important factor that needs to be considered is how 25(OH)D is measured and how differences in the assay methodology (such as assay sensitivity and analytical variability) confound prevalence estimation.  Figure 2. Prevalence of vitamin D insufficiency and deficiency (%) from 1988 to 2010 in the U.S. using standardized serum concentrations of 25(OH)D.10Since 1988, the National Health and Nutrition Examination Surveys (NHANES) have periodically tracked nutrition status of adults and children in the U.S. via examining a nationally representative sample population. These estimates are highly valuable in assessing the trends of vitamin D status over time. However, different assays have been used to determine 25(OH)D levels between 1988 and 2010, from DiaSorin radioimmunoassay to reformulated radioimmunoassay to the more accurate chromatography-based assays. To minimize laboratory method bias and imprecision in these different assays, the Vitamin D Standardization Program—initiated by the US Office of Dietary Supplements in the National Institutes of Health in collaboration with the National Institute of Standards and Technology, Centers for Disease Control and Prevention, and Ghent University—was organized in 2010 to promote standardize 25(OH)D measurement using liquid chromatography-tandem mass spectrometry (LC-MS/MS).11 Also, equations were developed to help standardize data from older radioimmunoassays to LC-MS/MS-equivalent data. The first paper that reported the temporal trends of vitamin D status in the U.S. using standardized 25(OH)D measurement was published in American Journal of Clinical Nutrition (AJCN) in 2016. They found that the prevalence of IOM-defined vitamin D insufficiency and deficiency (together as one category) was 30-32 percent from 1988 to 2006 and 26 percent from 2007 to 2010 (Figure 2; left). The prevalence was even higher when the Endocrine Society recommended cut-off point was used: 70-77 percent from 1988 to 2006, dropping slightly to 64-65 percent from 2007 to 2010 (Figure 2; right). Also, non-Hispanic blacks and Mexican Americans had much higher prevalence of vitamin D insufficiency and deficiency than non-Hispanic whites.10 Prior to the development of standardizing 25(OH) measurements, an earlier study also had tracked the prevalence trend in the same NHANES cohort and found an increase in vitamin D deficiency over time.1 Now, from the standardized data, we know the prevalence of vitamin D insufficiency and deficiency has been relatively stable. This discrepancy illustrates the importance of method standardization and having data expressed in LC-MS/MS equivalents for the most accurate interpretation of the prevalence trends. This AJCN report also reported a small increase in vitamin D supplement use (≥ 600 IU/day) among women over time: 2.1% during 1998-1994, increasing to 19% during 2009-2010. Vitamin D supplement users tend to be older (≥40 y/o) and non-Hispanic whites, Still, the majority remained to be non-users; at 70% during 1988-1994 and at 57% during 2009-2010.10 What are the recommended dietary intakes of vitamin D for women? The recommended dietary intakes of vitamin D for women from the IOM and the Endocrine Society are compared in Table 1. IOM recommends 600 IU/day for those who are 9-70 y/o and 800 IU/day for those more than 70 y/o to maintain bone health in at least 97.5% of the population in those age groups. Pregnant and lactating women have the same requirement of 600 IU/day. The intake levels recommended by the Endocrine Society are higher than IOM’s. For those who are 9-18 y/o, at least 600 IU/day is needed. However, in order to consistently achieve 25(OH)D of 30 ng/mL (75 nmol/L) preferred by the Endocrine Society, 1000 IU/day may be required. For those who are 19 y/o and older, including pregnant and lactating women, at least 1500-2000 IU/day may be required to maintain the blood levels of 25(OH)D to above 30 ng/mL (75 nmol/L). Table 1. The recommended dietary intakes of vitamin D for women from IOM and the Endocrine Society.  *RDA (Recommended Dietary Allowance): the average daily dietary intake level that is sufficient to meet the nutrient requirement of 97.5% of healthy individuals in a group. **UL (Tolerable Upper Intake Level): the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects to almost all individuals in the general population. Are dietary intakes of vitamin D sufficient in women in the U.S.? Overall no. Even among supplement users, the majority of women have insufficient intakes of vitamin D. Read more in this additional article debunking the myths of vitamin D. The first study that presented national estimates of vitamin D intakes was conducted by the Office of Dietary Supplements and the National Institutes of Health based on NHANES 2005-2006 data. The average vitamin D intake from diet alone was low in every age group (Table 2); the lowest being those 19-30 y/o (144 IU/day) and the highest 9-13 y/o (212 IU/day). When including vitamin D-containing supplement, vitamin D intakes somewhat increased, particularly among those 51 y/o and older (to approximately 400 IU/day).12 Even so, the intake still fell short of the RDA (600-800 IU/day) and way below the levels recommended by the Endocrine Society (1,500-2,000 IU/day). Table 2. Mean vitamin D intake from the diet and from diet plus dietary supplements in women based on NHANES 2005-2006 data.12  *40 IU/day = 1 µg/day The low vitamin D intake seen during 2005-2006 was not a single event. A subsequent study that examined data from NHANES 2001-2002, 2003-2004, 2005-2006, and 2007-2008 confirmed the previous pattern: vitamin D intake from diet only remained extremely low across all populations and age groups, falling short of the RDA even when dietary supplement use was included.13
Further, this study identified certain sub populations that were at greater risks of insufficient vitamin D intakes. When comparing mean intakes by race, African Americans and Mexican Americans had even lower intakes than non-Hispanic whites. When stratifying by annual house income levels, low income was linked to lower vitamin D intakes. Further, those who were affected by obesity had the lowest intake levels compared with those who had normal body weight.13 What about dietary intakes of vitamin D in other countries? Insufficient intakes of vitamin D is not just a phenomenon in the U.S. In fact, it is a global issue. For example, a study involving populations in representative Western countries (Germany, U.K., and the Netherlands) concluded that vitamin D intakes are below recommendations in a significant part of the population in these countries.14 A more recent overview of vitamin D status globally found that vitamin D deficiency occurred all over the world such as in the Middle East, China, Mongolia, and India.15 How much vitamin D intake is needed to improve vitamin D status in women? The Women’s Health Initiative Observational Study (WHI-OS), one of the largest cohorts of postmenopausal women in the U.S., has detailed data on vitamin D intake and serum 25(OH)D level, which has allowed the investigators to address this question. Analysis of the data identified a more or less linear relationship between vitamin D intake and serum vitamin D status: every 100 IU increase in total vitamin D intake (diet and supplement combined) was associated with approximately 0.83 ng/mL (2.08 nmol/L) higher serum 25(OH)D levels. Also, total vitamin D intake was the main factor that determined vitamin D status.16 This dose-response observation is consistent with findings from VIDOS (Vitamin D Supplementation in Older Subjects) study, a 1-year randomized trial that investigated vitamin D intakes and serum 25(OH)D levels in healthy postmenopausal women.17 VIDOS study also found that vitamin D intake at 1,600 IU/day could achieve serum 25(OH)D of 30 ng/mL (75 nmol/L) in 97.5% of the participating women. This dosage level is in line with the recommendations from the Endocrine Society. Is increasing sun exposure alone able to optimize vitamin D status? Some insights can be gained from a study which investigated serum 25(OH)D levels in a group of healthy men who had just completed a summer season of extended outdoor activity such as landscaping, construction work, farming, or recreation. Compared with the general population, these were people who received some of the highest sun exposure—and with sufficient body surface area exposed and without sunscreen—during the season when UV-B radiation was the strongest. The study found that median serum 25(OH)D concentration in these subjects at late summer reached 48.8 ng/mL (122 nmol/L). However, even with ample summer sun exposure, the median serum 25(OH)D dropped to 29.6 ng/mL (74 nmol/L) by late winter, barely meeting vitamin D sufficiency (30 ng/mL) defined by the Endocrine Society.18 Latitude also determines whether one may obtain sufficient levels of vitamin D via sun exposure. One study compared sun exposure in two different cities, Miami (latitude 26 degrees N) and Boston (latitude 42 degrees N), and found that it’s possible to synthesize vitamin D via skin in all months in Miami but it’s very difficult to do so during winter in Boston.19 Therefore, for a very specific group of people such as landscapers, construction workers and farmers who don’t live in high latitude and don’t use sunscreen, their vitamin D level during summer would be sufficient even without dietary intakes of vitamin D. However, their healthy vitamin D status is not sustainable by end of winter if they don’t have additional sources of vitamin D. For the majority of the population—those who spend most of their daylight hours indoors (e.g., office workers), use sunscreen, have their body surface area covered up (e.g., hat, long-sleeve shirt and pants), or live a sedentary lifestyle, etc.—it is highly unlikely that sun exposure alone can increase serum 25(OH)D to sufficient levels even during summer, let alone the rest of the year. What are other important factors affecting vitamin D status? Key non-modifiable factors include age, sex, and race/ethnicity. Although the IOM, the Endocrine Society, and many other professional organizations around the world recommend intake levels based on age and sex, it does not mean that age and sex are the most impactful factors of vitamin D status. Race/ethnicity is another factor that one cannot change, either. However, many factors (besides vitamin D intake) that affect vitamin D status are behavior- and lifestyle-related and therefore modifiable. A 2018 analysis based on NHANES 2001-2010 data has identified several factors and calculated adjusted prevalence ratios of vitamin D deficiency (<20 ng/mL or 50 nmol/L) and insufficiency (20-30 ng/mL or 50-75 nmol/L) in the general population:20
The link between heavier body weight and poorer vitamin D status is a more recent discovery but from the public health viewpoint its impact can be significant, especially when the obesity epidemic has shown no sign of slowing. Due to higher fat mass, a larger individual may simply need more ingestion or internal synthesis of vitamin D to reach the same concentration as a smaller individual.21 This hypothesis is strengthened by findings from a weight loss intervention trial involving postmenopausal women which demonstrated an increase in serum 25(OH)D levels after weight loss.22 The link between physical activity and vitamin D status may be related to other factors. Decreased physical activity level, especially outdoor types, is associated with reduced sunlight exposure which limits vitamin D synthesis from the skin.8Lower physical activity may also contribute to weight gain leading to lower serum 25(OH)D levels due to the effect of dilution. Therefore, increasing outdoor physical activity can improve vitamin D status via increased sunlight exposure and improved body weight. Do genetic factors play an important role in determining vitamin D status? Several genes encode proteins and enzymes that are involved in vitamin D metabolism. Understandably, genetic variations such as single nucleotide polymorphisms (SNPs) of these genes may influence vitamin D status. The first genome-wide association study (GWAS) to identify common genetic variants that influence serum 25(OH)D levels was conducted in 2010 by the SUNLIGHT Consortium involving approximately 30,000 Caucasians from Europe, Canada and the U.S.23 This study identified four SNPs that were associated with lower 25(OH)D levels:
In 2018, the consortium was expanded to nearly 80,000 individuals (all Caucasians) from 31 epidemiological cohorts.28The study confirmed the previous four genetic loci and identified two novel loci for serum 25(OH)D levels:
However, this is an area of active research, and different genetic variations associated with vitamin D status are being discovered in other studies involving other study populations.32-36 Further, little is yet known on how genetic variants interact with other non-genetic factors. For example, one cohort study involving 1,200 postmenopausal women of European descent found that the association between 25(OH)D levels and certain SNPs in GC and CYP2R1 genes were stronger in summer months but not winter months, or in individuals with dietary intakes of vitamin D above 400 IU/day but not below.37 Also, a randomized controlled trial involving nearly 1,800 adults demonstrated that the increase in 25(OH)D after consumption of 1,000 IU/day vitamin D for 1 year was modified by certain SNPs in CYP2R1, CYP24A1, and VDRgene.38 These gene-environmental interactions and associations, once repeated in larger epidemiological studies and confirmed in large clinical trials, will have important public health implications. It will help determine whether individuals with certain genetic risk factors may indeed require higher amounts of vitamin D to achieve sufficient levels of 25(OH). Institute of Medicine miscalculation leads to the wrong recommendation of 600 IU/day As we wrap up, I would like to share with you an interesting article, published in 2014, which was titled “A Statistical Error in the Estimation of the Recommended Dietary Allowance for Vitamin D.” (I have included the hyperlink here in case you are interested in reading the whole open-access article.) In brief, researchers from School of Public Health, University of Alberta (Canada) described how IOM’s RDA for vitamin D was underestimated due to a calculation error. IOM estimated that 600 IU/day of vitamin D would achieve serum 25(OH)D above 20 ng/mL (50 nmol/L) for 97.5% of the population, but the authors re-examined the data and estimated that 600 IU/day of vitamin D would only achieve 10.7 ng/mL (26.8 nmol/L) in 97.5% of the population.39 This means that the dose needed to achieve 20 ng/mL (50 nmol/L) in the majority of the population would have been significantly much higher than 600 IU/day. Following the publication, another group of researchers verified in another publication that IOM indeed had made a calculation error.40 Miscalculated RDA for vitamin D can have serious public health and clinical implications as the true vitamin D insufficiency and deficiency would have been severely underestimated based on the IOM definition. Many researchers are now calling for the IOM and public health authorities to redefine RDA for vitamin D (closer to what the Endocrine Society has proposed) to allow for appropriate public health and clinical decision-making. In the meantime, I recommend dosing vitamin D to achieve serum sufficiency by starting with the Endocrine Society guidelines, not IOM. In the next series of articles, I will discuss how vitamin D status is related to women’s health, including current scientific data on the genetic influence of different disease outcomes, as well as common clinical issues we face as clinicians on the front lines. References
Sara Gottfried, MD is a board-certified gynecologist and physician scientist. She graduated from Harvard Medical School and the Massachusetts Institute of Technology and completed residency at the University of California at San Francisco. Over the past two decades, Dr. Gottfried has seen more than 25,000 patients and specializes in identifying the underlying cause of her patients’ conditions to achieve true and lasting health transformations, not just symptom management. Dr. Gottfried is the President of Metagenics Institute, which is dedicated to transforming healthcare by educating, inspiring, and mobilizing practitioners and patients to learn about and adopt personalized lifestyle medicine. Dr. Gottfried is a global keynote speaker who practices evidence-based integrative, precision, and Functional Medicine. She recently published a new book, Brain Body Diet and has also authored three New York Times bestselling books: The Hormone Cure, The Hormone Reset Diet, and Younger. Lewis Chang, PhD is Scientific Editorial Manager of R&D at Metagenics. Dr. Chang received his PhD in Nutritional Sciences at University of Washington, along with his MS in Nutrition and Public Health from Teachers College, Columbia University and BS in Pharmacy from National Taiwan University. Prior to joining Metagenics, he conducted dissertation research and completed a research assistantship and postdoctoral fellowship at the Fred Hutchinson Cancer Research Center in Seattle, WA. Dr. Chang has authored or co-authored and managed the publication of over 30 peer-reviewed journal articles and numerous scientific abstracts and posters. He has quite a green thumb, enjoys opera, theater and jazz, and loves cooking, collecting art, and learning to play gypsy jazz guitar.  Mental clarity, fitness, and good health are vital in racing, so a debilitating illness can threaten a professional race car driver’s career as well as his health. We sat down with seven-time professional sports car racing champion Lawson Aschenbach to learn how he used personalized lifestyle medicine to help manage his Crohn’s disease and return to the winner’s podium.
Let’s start with your professional background. How did you get into racing?I got into racing when I was 8 years old. My dad introduced my older brother and me to go-karting. It was a hobby at the time but quickly became my passion. What is your schedule like? How much are you home? How often do you travel?I’m on the road between 150 and 200 days a year. That could be for race weekends, testing, or PR events. It’s difficult to stick to a schedule when you’re always traveling, so preparation has become an essential aspect of my life. I have containers for all the supplements I’m taking, and everything is premeasured before I leave for every trip. When I’m racing, I’m either at the track or the hotel. I might be practicing, qualifying, or racing on those days, but I stick to a strict schedule. I go to bed at the same time every night; I wake up at the same time every morning. I make sure my health, focus levels, and body are in line to perform at a maximum level. When I’m home, it’s a straightforward routine. I wake up, get breakfast, and go work out. There are a variety of exercises I use to keep myself in shape during and after the racing season. My afternoons involve office work and family. I try to spend as much time as I can with my wife and daughter. I’m enjoying fatherhood. It was an incredible experience bringing a baby into the world, and my daughter just turned 2 in December. You were diagnosed with Crohn’s disease. How long were you having symptoms before you were diagnosed? How did your diagnosis come about?I initially started having digestive problems in middle school when I was 12 or 13 years old. After lunch, I would get embarrassing gas issues. It came out of nowhere and continued until I found the trigger, milk. Two cartons of milk were the daily lunch beverage at the time, and when I replaced it with something else, the issues stopped. It seemed strange to me that I could drink milk with no problems until that day. Fast-forward to 2012 when I was experiencing continued gas, horrible bathroom experiences, dizziness, lethargy, a B12 deficiency, and insomnia. I wasn’t recovering from workouts either. It got to the point where this was starting to affect my career. At one point I demanded a colonoscopy. I don’t know many people that would request one of those! But I had to get to the bottom of this, and sure enough, I immediately got a diagnosis of Crohn’s disease. How old were you when you were finally diagnosed?Twenty-eight. My disease progressed quickly until the diagnosis. And to make matters worse, that was a rough time in my life because the racing world had taken a considerable hit during the economic crash. Stress became a part of my issues, and I believe it advanced all my symptoms at a much faster rate. In some ways, I’m glad it happened because it forced me to figure out my health issues. Not only was it affecting my career, but also my life. How did your illness affect your racing? How did it affect your life outside of racing?The most critical attribute in a driver is focus, and fitness is a big player in that ability. When you start getting tired, you start losing attention, and at 170 miles an hour, that can lead to disastrous results. Not to mention the fact that we’re in close quarters. We’re battling, trying to go for fast laps, and continuously searching for a split-second opportunity to pass someone. When inflamed, I noticed my energy levels were declining. My workouts weren’t very promising, and the recovery times were slow. The combination of lack of sleep, lethargy, and consistent gastrointestinal issues created a lack of focus when I was in the car. When I was asked to do a two- or three-hour stint during an endurance race, I was having a hard time finishing it. When things start happening, people take notice. It was a scary time. I knew I couldn’t continue this way for another season or else my career could end. What was your experience with traditional medicine in treating Crohn’s disease?Immediately after my diagnosis in early 2012, I was prescribed an anti-inflammatory pharmaceutical drug. My doctor mentioned that we needed to get to the bottom of this, or I was on the path to resection surgery to remove part of my colon. Talk about scared straight! He said I was going to take a pharmaceutical for the rest of my life while throwing out some stat that 90% of all Crohn’s patients never get to complete remission. It was a frustrating thought, but anyone that knows me understands that I never back down from a challenge! How long was it before you were introduced to medical foods and personalized lifestyle medicine as a management option for Crohn’s?I did a significant amount of research after my diagnosis to try to figure out another way without taking pharmaceuticals. I was willing to do whatever it took. My symptoms were getting worse each day. I reached out to a friend who learned of alternative methods to manage his battle with colitis. A nutritionist helped him manage his symptoms using diet and supplementation. He went from yearly hospital visits to living a more happy, healthy life. I set up an appointment with the nutritionist, and that was my introduction to the world of lifestyle health plans and Functional Medicine. This was the turning point in my journey. What was your experience with UltraInflamX Plus 360® Medical Food?Within 24 hours of using the product, it was life-changing. Almost all of my gastrointestinal issues subsided, and I immediately felt like a different person. I had a new lease on life, and my mood changed accordingly. I felt that I could tackle any race in the world, and I had the health to back me up! I can say, without a doubt, that UltraInflamX Plus 360 changed my life! How have your life and your racing changed since you switched to a personalized lifestyle medicine approach to managing Crohn’s?First and foremost, I have more energy. I’m recovering faster from workouts and races. I’m sleeping better, my focus level is at an all-time high, and, most importantly, my driving ability has been raised to a new level. Driving three-hour stints is no problem anymore, and I’ve been very fortunate to win four championships since being introduced to lifestyle medicine. As a driver, we’re dealing with extreme temperatures-inside the car, it can be 130, 140 degrees. We don’t have a lot of driver comfort options, and our arms, legs, and head are constantly moving. It’s vital that you can zero in on what you’re doing, because you may only get one shot to pass someone during an entire race. Nowadays, if there’s an opportunity, I’m going to take it. I’ve been fortunate to win a lot of races because of that desire and dedication. I feel I’m driving better than ever, and it’s showing in the results. Lawson Aschenbach is a seven-time professional sports car racing champion. He started racing karts at the age of 8 and went on to win state, national, North American, and four Grand National Championships. In 2005, he finished on the podium in his first sports car race and then burst out onto the scene in 2006, winning the SPEED World Challenge GT Championship in his rookie year. Aschenbach has over 35 professional race wins and currently competes in the IMSA WeatherTech SportsCar Championship and Pirelli World Challenge Series.  “I’m addicted to sugar.” We’ve all heard or thought this before. Considering the American palate for highly processed, overly sweetened foods and the ubiquitous nature of sugar in advertising, we see evidence of a concerning shift. Sugar’s role in the American diet has moved beyond a character actor and into a starring role. Further, as discussed in the previous post, Sugar. How Much Is Too Much?, we consume far more sugar than is recommended for our health. But the question remains—are we addicted? More please: How sugar affects the brain While an ICD-10 code for “sugar addiction,” has yet to be established, an increasing body of research tells us that sugar has addictive effects on the brain.1,2 Like sex and drugs, consuming sugar stimulates the release of dopamine, a neurotransmitter that gives us a sense of euphoria and controls the reward and pleasure centers in the brain. But what may have evolved as a survival mechanism has gone rogue. The caveman sweet tooth From an anthropological perspective, we are hard-wired for sweetness. The pleasing taste of sweet foods was a conditioned reward, one which could increase early man’s survival odds. In times of food scarcity, a preference for more nutritionally dense foods might have provided the energy required to continue the hunt, outrun a predator, or simply avoid starvation. Flash forward a few hundred thousand years, and sugar is exponentially more abundant. Consistent intake of concentrated sugar can lead to changes in the brain’s dopamine receptors. Similar to increased drug or alcohol tolerance, over time, more sugar is needed for the same “high.” Cookies and cocaine So, the more you eat, the more you want. But, as for being “addictive” per se, animal studies have shown sugar consumption to have drug-like effects. These include sugar-related bingeing, craving, tolerance, and withdrawal. In fact, according to a Connecticut College study, Oreo cookies cause more neural activation in the brains of rats than cocaine.3 Taking control For many individuals, the only way to stop over consuming sugar is to stop the cravings. But the only way to end the cravings is to stop feeding them with sugar. So, in addition to cutting out the obvious forms of sugar—candy, baked goods, etc.—it is important to be aware of the less obvious forms of sugar in your diet. Over the course of a day, small quantities can add up, keep your cravings alive, and thwart your efforts to take control of sugar. So become a sugar sleuth. Here are five tips to get you started. 5 Tips for Identifying Added Sugars1. Beware of marketing geared toward dieters
2. Read ingredient labels, especially the first three ingredients
3. Beware of alternate forms and names for sugar
The journey to a healthy relationship with sugar starts with awareness. Watch for the next post in this series, which will feature strategies for taking control of sugar. References
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