Vitamin D and Polycystic Ovary Syndrome (PCOS)

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,^11,12 cardiovascular 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-analyses^15,16 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

• Hypocaloric diet with balanced intake throughout the day.²¹ (Note that the authors acknowledge that the caloric restriction model has many flaws, and certainly is difficult for patients to sustain. We don’t have an equally proven replacement, though intermittent fasting and the ketogenic diet hold promise.)
• Small, frequent meals; avoid skipping meals in order to stabilize blood sugars and diminish extreme hunger^21,22
• Low glycemic index carbohydrates that are low in refined carbohydrates and high in fiber²²
• High-protein, low-glycemic-load hypocaloric diet improves weight loss and PCOS symptomology²³
• Emphasis on mono- and polyunsaturated fats, especially omega-3 fatty acids (e.g., consuming oily fish up to 4x/week)²²
• Mediterranean-inspired, low-glycemic-load, anti-inflammatory diet has shown good prognostic metabolic and reproductive responses to weight loss in PCOS²⁴
• Low carbohydrate (< 20 g) ketogenic diet is emerging area of research with promise and may be beneficial for certain patients, depending on adherence to diet restrictions^25-26
• Targeted supplementation; nutrients of concern include but are not limited to vitamin D₃, chromium, omega-3 fatty acids (EPA+DHA)²²

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

1. Thomson RL et al. Vitamin D in the aetiology and management of polycystic ovary syndrome. Clin Endocrinol (Oxf). 2012;77(3):343-350.
2. Hart R. Polycystic ovarian syndrome—prognosis and treatment outcomes. Curr Opin Obstet Gynecol. 2007;19(6):529–535.
3. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev. 1997;18(6):774-800.
4. Ding T et al. The prevalence of polycystic ovary syndrome in reproductive-aged women of different ethnicity: a systematic review and meta-analysis. Oncotarget. 2017;8(56):96351-96358.
5. McCartney CR et al. Polycystic ovary syndrome. N Engl J Med. 2016;375(1):54-64.
6. El Hayek S et al. Poly cystic ovarian syndrome: an updated overview. Front Physiol. 2016;7:124.
7. Teede HJ et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2018;110(3):364-79.
8. Gopalakrishnan S et al. Systematic reviews and meta-analysis: understanding the best evidence in primary healthcare. J Family Med Prim Care. 2013;2(1):9-14.
9. He C et al. Serum vitamin D levels and polycystic ovary syndrome: A systematic review and meta-analysis. Nutrients. 2015;7:4555-4577.
10. Holick MF et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911-1930.
11. Hahn S et al. Low serum 25-hydroxyvitamin D concentrations are associated with insulin resistance and obesity in women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes. 2006;114(10):577-583.
12. Yildizhan R et al. Serum 25-hydroxyvitamin D concentrations in obese and non-obese women with polycystic ovary syndrome. Arch Gynecol Obstet. 2009;280(4):559-563.
13. Talbott EO et al. Do women with polycystic ovary syndrome have an increased risk of cardiovascular disease? Review of the evidence. Minerva Ginecol. 2004;56(1):27-39.
14. Thomson RL et al. Seasonal effects on vitamin D status influence outcomes of lifestyle intervention in overweight and obese women with polycystic ovary syndrome. Fertil Steril. 2013;99(6):1779-1785.
15. Łagowska K et al. The role of vitamin D oral supplementation in insulin resistance in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials. Nutrients. 2018;10(11):E1637.
16. Akbari M et al. The effects of vitamin D supplementation on biomarkers of inflammation and oxidative stress among women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials. Horm Metab Res. 2018;50(5):271-279.
17. Jamilian M et al. Effect of two different doses of vitamin D supplementation on metabolic profiles of insulin-resistant patients with polycystic ovary syndrome. Nutrients. 2017;9(12):E1280.
18. Deswal R et al. Unveiling the association between vitamin D receptor and poly cystic ovary syndrome – a systematic review and meta-analysis. Int J Vitam Nutr Res. 2018:1-12.
19. Han FF et al. VDR gene variation and insulin resistance related diseases. Lipids Health Dis. 2017;16(1):157.
20. Moran LJ et al. Dietary composition in the treatment of polycystic ovary syndrome: a systematic review to inform evidence-based guidelines. J Acad Nutr Diet. 2013;113(4):520-545.
21. Faghfoori Z et al. Nutritional management in women with polycystic ovary syndrome: A review study. Diabetes Metab Syndr. 2017;11 Suppl 1:S429-432.
22. Rondanelli M et al. Focus on metabolic and nutritional correlates of polycystic ovary syndrome and update on nutritional management of these critical phenomena. Arch Gynecol Obstet. 2014;290(6):1079-1092.
23. Mehrabani HH et al. Beneficial effects of a high-protein, low-glycemic-load hypocaloric diet in overweight and obese women with polycystic ovary syndrome: a randomized controlled intervention study. J Am Coll Nutr. 2012;31(2):117-125.
24. Salama AA et al. Anti-inflammatory dietary combo in overweight and obese women with polycystic ovary syndrome. N Am J Med Sci. 2015;7(7):310-316.
25. Mavropoulos JC et al. The effects of a low-carbohydrate, ketogenic diet on the polycystic ovary syndrome: a pilot study. Nutr Metab (Lond). 2005;2:35.
26. Gupta L et al. Ketogenic diet in endocrine disorders: current perspectives. J Postgrad Med. 2017;63(4):242-251.
27. Ko H et al. Analysis of the barriers and enablers to implementing lifestyle management practices for women with PCOS in Singapore. BMC Res Notes. 2016;9:311.
28. Brennan L et al. Lifestyle and behavioral management of polycystic ovary syndrome. J Womens Health (Larchmt). 2017;26(8):836-848.

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 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.