Vitamin D and Human Reproduction—Evolving perspectives

We are all well versed with the role of Vitamin D in maintaining calcium and phosphorus homeostasis and promoting bone mineralization. Its deficiency is linked to many chronic diseases of the cardiovascular and metabolic systems.

Evidence from animal and human studies suggests that vitamin D plays a very important role in human fertility and neonatal development. This steroid hormone has Vitamin D receptors (VDR) at multiple sites in the body including ovary, particularly the granulosa cells, endometrium and placenta.

It plays a very important role in ovarian steroidogenesis. [1] It deficiency contribute to development of insulin resistance and impaired glucose metabolism in patients with Polycystic Ovary Syndrome (PCOS). Therapeutic efficacy of supplementation with Vitamin D to improve insulin resistance, bring about ovulation and regularize menstruation in PCOs patients have been documented.[2] [3]

Observations also shows that lower 25(OH)D levels put women at higher risk of developing uterine fibroids, both in black and white ethnicities. In these women, the growth and size of the fibroid is also directly related to decreased levels of Vitamin D. Animal studies and human in vitro studies have shown the beneficial effect Vitamin D supplementation in inhibition of development and/or growth of uterine fibroids.[4] [5]

A recent study by Harris HR et al demonstrated that women within the highest quintile of Vitamin D blood values have one fourth the risk of developing endometriosis as compared to those in lowest quintile.[6]

It also plays a role in Body Mass Index (BMI) as per a recent meta-analysis, every 10% increase in BMI leads to 4% decrees in Vitamin D concentration.[7]

It’s role in male reproductive physiology is well documented by the fact that it’s level directly correlate with sperm motility and morphology.

As per Hill’s criteria a causal relationship between Vitamin D deficiency and negative outcome in IVF is explained but further research into knowing the magnitude of association is needed.[8]

A systemic review and meta-analysis by Lerchbaum E and Obermayer-Pietsch B published in Eur J Endocrinol May 1, 2012 concludes that Vitamin D plays an important role in Human reproduction and advocates the need of further research in therapeutic benefits of Vitamin D supplementation in such patients.  

Another review by Vanni et al published in the Reproductive Biology and Endocrinology, 2014 emphasizes the importance of supplementation of Vitamin D in IVF settings because consisting evidence documenting the increase incidence of gestational diabetes, IUGR, pre-eclampsia and preterm births in patients deficient in Vitamin D.[9]

The authors opine that although drastic improvements in reproductive failure may not be achieved solely by supplementing Vitamin D, but its addition to any fertility regimen is cheap, effective and without any side effects. It is easily correctable by simple oral supplementation.

Dosage up to 4000 IU is safe, without any side effects and effectively improve maternal vitamin D status. [10]

Results of double blind randomized trial entitled “Vitamin D during IVF” is still awaited.[11]

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[1]Anagnostis P, Karras S, Goulis DG: Vitamin D in human reproduction: a narrative review. Int J Clin Pract. 2013, 67 (3): 225-235

[2] Selimoglu H, Duran C, Kiyici S, Ersoy C, Guclu M, Ozkaya G, Tuncel E, Erturk E, Imamoglu S: The effect of vitamin D replacement therapy on insulin resistance and androgen levels in women with polycystic ovary syndrome. J Endocrinol Invest. 2010, 33 (4): 234-238.

[3] Wehr E, Pieber TR, Obermayer-Pietsch B: Effect of vitamin D3 treatment on glucose metabolism and menstrual frequency in polycystic ovary syndrome women: a pilot study. J Endocrinol Invest. 2011, 34 (10): 757-63.

[4] Bläuer M, Rovio PH, Ylikomi T, Heinonen PK: Vitamin D inhibits myometrial and leiomyoma cell proliferation in vitro. Fertil Steril. 2009, 91 (5): 1919-1925.

[5] Halder SK, Osteen KG, Al-Hendy A: Vitamin D3 inhibits expression and activities of matrix metalloproteinase-2 and −9 in human uterine fibroid cells. Hum Reprod. 2013, 28 (9): 2407-2416.

[6]  Harris HR, Chavarro JE, Malspeis S, Willett WC, Missmer SA: Dairy-food, calcium, magnesium, and vitamin D intake and endometriosis: a prospective cohort study. Am J Epidemiol. 2013, 177 (5): 420-430.

[7] Vimaleswaran KS, Berry DJ, Lu C, Tikkanen E, Pilz S, Kiraki LT, Cooper JD, Dastani Z, Li R, Houston DK, Wood AR, Michaëlsson K, Vandenput L, Zgaga L, Yerges-Armstrong LM, McCarthy MI, Dupuis J, Kaakinen M, Kleber ME, Jameson K, Arden N, Raitakari O, Viikari J, Lohman KK, Ferrucci L, Melhus H, Ingelsson E, Byberg L, Lind L, Lorentzon M, et al: Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med. 2013, 10 (2): e1001383-

[8] Hill AB: The environment and disease: association or causation?. Proc R Soc Med. 1965, 58: 295-300.

[9] Aghajafari F, Nagulesapillai T, Ronksley PE, Tough SC, O’Beirne M, Rabi DM: Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies. BMJ. 2013, 26 (346): f1169-

[10] Wagner CL, McNeil R, Johnson DD, Husley TC, Ebeling M, Robinson C, Hamilton SA, Hollis BW: Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis. J Steroid Biochem Mol Biol. 2013, 136: 313-320.

[11] https://clinicaltrials.gov/ct2/show/NCT01019785

Preconception Cardiometabolic risk factors differs for preeclampsia and gestational hypertension.

It is estimated that ten million women develop preeclampsia each year around the world, with 76,000 deaths due preeclampsia and related hypertensive disorders.  It is also responsible for 50,000 stillbirths and early neonatal deaths in developing nations.

A woman in developing country is seven times more likely to develop preeclampsia than a woman in a developed country, contributing to 10-25% of all Maternal mortality.

In the United States it affects 5-8% of all pregnancies.

According to the World Health Organization, among women who have had preeclampsia, about 20% to 40% of their daughters and 11% to 37% of their sisters also will get the disorder.

Establishing casualty, early detection and prevention of preeclampsia along with identifying the women at risk has been the mainstay of preeclampsia research in the last decade.

Preconception maternal risks for cardiovascular disease, maternal insulin resistance and diabetes in their ability to predict preeclampsia have been the subject of speculation since long. Only two studies have so far evaluated these risk factors, but their small sample size lead to discrepancy.

A recent study published April 25, 2016 in Hypertension, by Norwegian researchers evaluated the extent of similarities and differences in preconception cardiometabolic risk factors associated with gestational hypertension, preeclampsia, and preterm preeclampsia. 

It was a prospective cohort study that followed participants by linking Cohort Norway (CONOR) health surveys (1994–2003) to the Medical Birth Registry of Norway for births subsequent to CONOR participation (through to December 31, 2012).

The study confirms that pregnancy is a stressor and unmasks predisposing familial and modifiable cardiometabolic risk factors. More risk factors predicted the development of preeclampsia than gestational hypertension. Study results show that:

• A family history of diabetes mellitus and women’s preconception diabetes mellitus predicted both gestational hypertension and preeclampsia.
• A family history of myocardial infarction before 60 years of age predicted preeclampsia, but not gestational hypertension.
• A family history of stroke predicted the combined outcome of gestational hypertension or preeclampsia.
• BMI and preexisting hypertension predicted both.
• A high total cholesterol/HDL cholesterol ratio predicted both gestational hypertension and preeclampsia. In contrast, an elevated triglyceride level only predicted preeclampsia.
• Alcohol once a week as compared to none or less than one serving per month was associated with lower risks of preeclampsia in contrast to binge drinking, a strong predisposing factor for preeclampsia.
• Physical exercise 3 hours a week or more was protective for preeclampsia, but not for gestational hypertension. The protective mechanism goes beyond simple weight management and also includes reduced inflammation and oxidative stress, improved endothelial function, placental growth and vascular development.

Odds of developing gestational HT and preeclampsia according to risk factors 

These findings have important implications in preventive medicine, as it is seen that if a woman can bring down her BMI pre pregnancy than she has pretty much good chances of being protected from preeclampsia and gestational hypertension.

These results are intriguing because it could help us preventing the long term cardiovascular morbidities of preeclampsia.

So,to conclude gestational hypertension and preeclampsia have several common baseline risk factors: a family history of diabetes mellitus, preconception diabetes mellitus, hypertension, obesity, a high total cholesterol/HDL cholesterol ratio, and a family history of stroke. But, preeclampsia additionally was also predicted by a family history of myocardial infarction before 60 years of age, physical inactivity, an elevated triglyceride level, and binge drinking.

References:

Grace Egeland, Kari Klungsoyr, Nina Oyen, et al. Preconception cardiovascular risk factor differences between gestational hypertension and preeclampsia. Cohort Norway Study. Hypertension 2016; DOI:10.1161/HYPERTENSIONAHA.116.07099.

http://www.acog.org/About-ACOG/News-Room/News-Releases/2013/Ob-Gyns-Issue-Task-Force-Report-on-Hypertension-in-Pregnancy

http://www.preeclampsia.org/health-information/149-advocacy-awareness/332-preeclampsia-and-maternal-mortality-a-global-burden

https://www.nichd.nih.gov/health/topics/preeclampsia/conditioninfo/Pages/risk.aspx#f5

World Health Organization Fact Sheet, May 2012

Lim, K.-H., & Ramus, R. M. (2011). Preeclampsia. Retrieved May 02, 2016, from http://emedicine.medscape.com/article/1476919-overview