Diana Jędrzejuk1 , Andrzej Milewicz2 , Felicja Lwow2 and Anna Brona1
(1)
Department of Endocrinology, Diabetology and Isotope Therapy, Wrocław Medical University, Pasteura 4, 50-367 Wroclaw, Poland
(2)
Department of Health Promotion, Faculty of Physiotherapy, University School of Physical Education, Paderewskiego 35, 51-612 Wroclaw, Poland
Diana Jędrzejuk (Corresponding author)
Email: diana.jedrzejuk@gmail.com
Andrzej Milewicz
Email: andrzej.milewicz@umed.wroc.pl
Felicja Lwow
Email: felicitas1@wp.pl
Anna Brona
Email: abrona@mp.pl
Vitamin D has been well known for its function in calcium and phosphorus homeostasis and osteomalacia as well osteoporosis, because of promotion bone mineralisation. Vitamin D deficiency is highly prevalent in high-risk patient populations, but the prevalence among otherwise healthy adults is less well defined. This vitamin is produced in skin via UVB radiation, which induces conversion of 7-dehydrocholesterol to provitamin D3, which spontaneously isomerises to vitamin D3 (cholecalciferol). Vitamin D is released into circulation and transported by vitamin D binding protein. Approximately 80–90 % derives from sunlight induced production in the skin, small amount derived from diet and all supplements.
Biological actions of vitamin D3 are presented as: stimulation of reabsorption of calcium and phosphates in bones via increasing RANKL expression in osteoblasts and activation of RANK in precursors of osteoclasts. Vitamin D increases intestinal absorption of calcium and phosphates (stimulation of synthesis of calcium-binding protein) in intestinal system and increases reabsorption of calcium in kidney, if vitamin D3 level is high.
Recently, the pleiotropic actions of vitamin D is presented and discussed, because several papers show that vitamin D receptor (VDR) and hydroxylases activity enzymes are necessary to vitamin D metabolism in most tissues and immune cells. Its active metabolite 1,25 (OH)2 D modulates the immune response: T and B lymphocytes and production of cytokines and immunoglobulins.
It has been shown that vitamin D also has the influence on production and secretion of several hormones like parathormone, insulin, sex hormones as well has influence on regulation of cellular proliferation and differentiation.
6.1 What About the Metabolic Disorders and Vitamin D?
Several studies show presence of VDRs for 1,25-(OH)2-vitamin D and expression of 1α-hydroxylase in pancreatic beta cells [1, 2]. Vitamin D induces insulin sensitivity through stimulation of insulin receptors expression in peripheral tissues [3]. In other prospective study—The Medical Research Council Ely Prospective Study 1990–2000—inverse associations between baseline serum 25(OH) D and future glycaemia and insulin resistance were reported [4]. On the other hand, non-alcoholic fatty liver disease (NAFLD) is recommended as a sensitive risk marker for diabetes type 2 [5]. Vitamin D level was correlated with ALT (alanine transaminase) level—the marker of NAFLD [6]. Also, the patients with NAFLD had significantly lower vitamin D level and this was associated with severity of liver histology [7].
The other risk factor for diabetes type 2 and cardiovascular diseases is abdominal obesity with waist circumference over 80 cm in women and over 94 cm in men. The National Health and Nutrition Examination Survey (2001–2004) presented EBM data, which included 4,661 males and 5,108 females. The group of abdominal obese women and men separated from these population shows negative correlation between fasting glycaemia and CRP with serum vitamin D. The conclusion from that paper is that the abdominal obese persons should be additionally supplemented with vitamin D [8]. Negative linear correlations between serum vitamin D level and waist circumference, serum triglycerides, glucose levels and insulin resistance were shown [8].
6.2 What About the Diabetes Type 2 and Endogenous Vitamin D Levels?
National Health and Nutrition Examination Survey shows negative correlation between serum vitamin D and prevalence of diabetes type 2 [8]. This observation was supported by Finland observational study (17 years) [9], as well as for Nurse’s Health Study (83,779 persons—20 years observation) women received 800 IU vitamin D—shows significant reduction (33 %) of morbidity for diabetes type 2 in comparison to control [10].
6.3 What About Cardiovascular Disease and Vitamin D?
Pilz et al. [11] revealed in 3,299 patients after coronarography dependence between serum vitamin D deficiency and mortality caused by cardiac failure or sudden heart death during 7 years. The persons with vitamin D concentration <25 nmol/l = 10 ng/ml revealed three times higher mortality of heart failure and five times higher mortality of sudden heart death in comparison to patients with vitamin D concentration within normal ranges or above 75 nmol/l = 30 ng/ml. This mortality was higher in the group of patients with no history of circulatory diseases.
6.4 What About Mortality and Endogenous Vitamin D Levels?
EBM presented data in third National Health and Nutrition Examination Survey—NHANES III Study—evaluated mortality in 13,331 persons over 20 years of age during 7 years (1994–2000) shows higher mortality in patients with vitamin D deficiency. Vitamin D deficiency <17.8 ng/ml is an independent risk factor of general mortality. Vitamin D supplementation, physical activity and exposure to sunlight are correlated inversely with mortality. These data were supported by meta-analyses of 18 randomised clinical trials of vitamin D supplementation; significant reduction of all-cause mortality in group with vitamin D supplementation was observed [12].
In conclusions, the vitamin D deficiency is associated with several metabolic disorders: obesity, insulin resistance, metabolic syndrome, NAFLD, diabetes type 2 and is an independent risk factor of general mortality.
6.5 What About the Reproduction and Endogenous Vitamin D Levels?
In women, VDR mRNA has been shown to be expressed in the mixed ovarian cell and in purified granulosa cell culture indicating role in sex hormones production. VDR as well as the active form of 1α hydroxylase gene was expressed in human endometrium (13–15). In women with Premature Ovarian Failure, deficiency of serum vitamin D, zinc, and copper was shown and it was inversely correlated with serum FSH levels [16]. In pregnant women, 1,25(OH)2D3 regulates human chorionic gonadotropin expression and secretion in human syncytiotrophoblasts and increases placental sex steroid production [14]. Lower serum levels of 25(OH)D in pregnant women may result from enhanced maternal metabolism or increase the utilisation of vitamin D in foetus, elevated risk for preeclampsia and bacterial vaginosis [17, 18] and cause in early pregnancy are closely related to low birth weight [19]. The safety and effectiveness of vitamin D supplementation during pregnancy can be recommended 4,000 IU/day until delivery [20].
Vitamin D deficiency plays a role in pathogenesis of insulin resistance and metabolic syndrome in PCOS; however, association with hormonal disorders and infertility is not clear (insulin gene transcription in human is activated by 1,25 (OH)2D3). In our study included 202 women with PCOS in comparison to homogenous control (not published data), we found significant correlations between serum vitamin D levels negatively with: BMI, hip circumference, glucose at 0′ of OGTT, insulin at 0′ of OGTT, HOMA and positively with: serum HDL cholesterol levels. Our observations are supported by other study which show that vitamin D deficiency was found to be more common in PCOS women than in controls and there is some evidence that vitamin D deficiency may be involved in pathogenesis of insulin resistance and metabolic syndrome in PCOS [21–25].
VDR regulates more than 3 % human genome including genes that are crucial for glucose metabolism.
It has been shown that VDR-related polymorphisms (Cdx2, Bsm-I, Fok-I, Apa-I and Taq-I) are related to vitamin D metabolism and may contribute to PCOS susceptibility (women from Teheran) [26]. The role of genetic factor VDR was supported by other study which including 545 women with PCOS and 145 controls from Austria. They found association of VDR Cdx2 with insulin metabolism, whereas the VDR Apa-1 variant was associated with hyperandrogenemia [27].
In conclusion, vitamin D plays important role in regulation of sex hormones in women. Vitamin D supplementation (4,000 IU/day) during pregnancy can be recommended. Deficiency of endogenous vitamin D can play important role in ovary function disorders (PCOS and POF).
6.6 What Are the Most Common Reasons for Vitamin D Deficiency? How to Make Diagnosis and How to Treat it?
The most frequent reasons are disturbances of fat absorption in intestines, e.g. Whipple’s disease, cystic fibrosis, intestinal inflammations and hepatic diseases. Also, autoimmune diseases (psoriasis and rheumatoid arthritis) as well as drug like: glucocorticosteroids, antiepileptic drugs and antiretroviral. The other frequent reason is the body surface small exposition to sun light (cultural and civilisation regards) and last—but not least—is aging process. The clinical symptoms suggesting vitamin D are presented in Table 6.1.
Table. 6.1
Clinical symptoms suggesting vitamin D deficiency
|
Frequent muscular and osseous pains |
|
Parodontium diseases |
|
Lack of appetite |
|
Diarrhoea |
|
Insomnia |
|
Vision disturbances |
|
Bad taste and burning sensation in oral cavity and throat |
6.7 When We Can Recognised Vitamin D Deficiency and How Can We Prevent or Treat This Disease?
In Table 6.2, there are shown the serum levels of vitamin D to diagnose deficiency or hypovitaminosis. It is very important to remember the determination of serum PTH and calcium concentrations to excluded hyperparathyroidism as a cause.
Table 6.2
The disturbances in serum levels of vitamin D
|
Serum vitamin 25 (OH) D levels |
|
|
<20 ng/ml |
Deficiency |
|
20–30 ng/ml |
Hypovitaminosis |
|
>30 ng/ml |
Recommended level |
Remember!!! Only 15 min exposition to sunlight of 18 % of body surface (forearms and legs) without any filters from 10 a.m. to 3 p.m. is required to produce enough level of vitamin D.
According to the prevention—grown-ups—at insufficient exposition to sunlight from October till March and persons over 65 for the whole of the year, recommended daily dose is 800–1,000 IU of vitamin D3.
Administration of 1,000 IU of vitamin D3 daily cause the increase of vitamin D concentration by 1 ng/ml after 2–3 months in preventive measures, exceeding the dose of 2,000 IU is contraindicated in order to avoid side effects. Vitamin D should be administered along with a meal.
In vitamin D deficiency, the treated dose is usually 2,000 IU of vitamin D3 daily till attaining the serum level of vitamin D concentration >30 ng/ml.
Please remember that vitamin D3 activity (cholecalciferol) is higher than vitamin D2 (ergocalciferol) activity by 30 %. Also, very important is that calcitriol and alphacalcitriol are contraindicated in vitamin D deficiency supplementation in healthy population. Indication is only in disturbances of vitamin D hydroxylation in chronic disease of liver or kidneys [28].
6.8 What Side Effects Can We Expect if We Take Overdose of Vitamin D?
It is nausea and vomits, constipation, headaches, weakness, and drowsiness and only in extreme cases—toxic hypercalcaemia and hypercalciuria.
References
1.
Bland R, Markovic D, Hills CE, Hughes SV, Chan SL, Squires PE, Hewison M (2004) Expression of 25-hydroxyvitamin D3-1alpha-hydroxylase in pancreatic islets. J Steroid Biochem Mol Biol 89–90(1–5):121–125PubMedCrossRef
2.
Schuch NJ, Garcia VC, Martini LA (2009) Vitamin D and endocrine diseases. Arq Bras Endocrinol Metabol 53(5):625–633PubMedCrossRef
3.
Maestro B, Campión J, Dávila N, Calle C (2000) Stimulation by 1,25-dihydroxyvitamin D3 of insulin receptor expression and insulin responsiveness for glucose transport in U-937 human promonocytic cells. Endocr J 47(4):383–391PubMedCrossRef
4.
Forouhi NG, Luan J, Cooper A, Boucher BJ, Wareham NJ (2008) Baseline serum 25-hydroxy vitamin d is predictive of future glycemic status and insulin resistance: the Medical Research Council Ely Prospective Study 1990-2000. Diabetes 57(10):2619–2625PubMedCentralPubMedCrossRef
5.
Sung KC, Kim SH (2011) Interrelationship between fatty liver and insulin resistance in the development of type 2 diabetes. J Clin Endocrinol Metab 96(4):1093–1097PubMedCentralPubMedCrossRef
6.
Kayaniyil S, Vieth R, Harris SB, Retnakaran R, Knight JA, Gerstein HC, Perkins BA, Zinman B, Hanley AJ (2011) Association of 25(OH)D and PTH with metabolic syndrome and its traditional and nontraditional components. J Clin Endocrinol Metab 96(1):168–175PubMedCrossRef
7.
Targher G, Bertolini L, Scala L, Cigolini M, Zenari L, Falezza G, Arcaro G (2007) Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 17(7):517–524PubMedCrossRef
8.
Scragg R, Sowers M, Bell C, Third National Health and Nutrition Examination Survey (2004) Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the Third National Health and Nutrition Examination Survey. Diabetes Care 27(12):2813–2818PubMedCrossRef
9.
Mattila C, Knekt P, Männistö S, Rissanen H, Laaksonen MA, Montonen J, Reunanen A (2007) Serum 25-hydroxyvitamin D concentration and subsequent risk of type 2 diabetes. Diabetes Care 30(10):2569–2570PubMedCrossRef
10.
Pittas AG, Dawson-Hughes B, Li T, Van Dam RM, Willett WC, Manson JE, Hu FB (2006) Vitamin D and calcium intake in relation to type 2 diabetes in women. Diabetes Care 29(3):650–656PubMedCrossRef
11.
Pilz S, März W, Wellnitz B, Seelhorst U, Fahrleitner-Pammer A, Dimai HP, Boehm BO, Dobnig H (2008) Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography. J Clin Endocrinol Metab 93(10):3927–3935PubMedCrossRef
12.
Autier P, Gandini S (2007) Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med 167(16):1730–1737PubMedCrossRef
13.
Agic A, Xu H, Altgassen C, Noack F, Wolfler MM, Diedrich K, Friedrich M, Taylor RN, Hornung D (2007) Relative expression of 1,25-dihydroxyvitamin D3 receptor, vitamin D 1 alpha-hydroxylase, vitamin D 24-hydroxylase, and vitamin D 25-hydroxylase in endometriosis and gynecologic cancers. Reprod Sci 14(5):486–497PubMedCrossRef
14.
Parikh G, Varadinova M, Suwandhi P, Araki T, Rosenwaks Z, Poretsky L, Seto-Young D (2010) Vitamin D regulates steroidogenesis and insulin-like growth factor binding protein-1 (IGFBP-1) production in human ovarian cells. Horm Metab Res 42(10):754–757PubMedCrossRef
15.
Viganò P, Lattuada D, Mangioni S, Ermellino L, Vignali M, Caporizzo E, Panina-Bordignon P, Besozzi M, Di Blasio AM (2006) Cycling and early pregnant endometrium as a site of regulated expression of the vitamin D system. J Mol Endocrinol 36(3):415–424PubMedCrossRef
16.
Kebapcilar AG, Kulaksizoglu M, Kebapcilar L, Gonen MS, Unlü A, Topcu A, Demirci F, Taner CE (2013) Is there a link between premature ovarian failure and serum concentrations of vitamin D, zinc, and copper? Menopause 20(1):94–99PubMedCrossRef
17.
Haugen M, Brantsaeter AL, Trogstad L, Alexander J, Roth C, Magnus P, Meltzer HM (2009) Vitamin D supplementation and reduced risk of preeclampsia in nulliparous women. Epidemiology 20(5):720–726PubMedCrossRef
18.
Turton CW, Stanley P, Stamp TC, Maxwell JD (1977) Altered vitamin-D metabolism in pregnancy. Lancet 1(8005):222–225PubMedCrossRef
19.
Scholl TO, Chen X (2009) Vitamin D intake during pregnancy: association with maternal characteristics and infant birth weight. Early Hum Dev 85(4):231–234PubMedCrossRef
20.
Hollis BW, Wagner CL (2011) Vitamin D requirements and supplementation during pregnancy. Curr Opin Endocrinol Diabetes Obes 18(6):371–375PubMedCrossRef
21.
Mahmoudi T, Gourabi H, Ashrafi M, Yazdi RS, Ezabadi Z (2010) Calciotropic hormones, insulin resistance, and the polycystic ovary syndrome. Fertil Steril 93(4):1208–1214PubMedCrossRef
22.
Li HW, Brereton RE, Anderson RA, Wallace AM, Ho CK (2011) Vitamin D deficiency is common and associated with metabolic risk factors in patients with polycystic ovary syndrome. Metabolism 60(10):1475–1481PubMedCrossRef
23.
Ngo DT, Chan WP, Rajendran S, Heresztyn T, Amarasekera A, Sverdlov AL, O’Loughlin PD, Morris HA, Chirkov YY, Norman RJ, Horowitz JD (2011) Determinants of insulin responsiveness in young women: impact of polycystic ovarian syndrome, nitric oxide, and vitamin D. Nitric Oxide 25(3):326–330PubMedCrossRef
24.
Hahn S, Haselhorst U, Tan S, Quadbeck B, Schmidt M, Roesler S, Kimmig R, Mann K, Janssen OE (2006) Low serum 25-hydroxyvitamin D concentrations are associated with insulin resistance and obesity in women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes 114(10):577–583PubMedCrossRef
25.
Wehr E, Pilz S, Schweighofer N, Giuliani A, Kopera D, Pieber TR, Obermayer-Pietsch B (2009) Association of hypovitaminosis D with metabolic disturbances in polycystic ovary syndrome. Eur J Endocrinol 161(4):575–582PubMedCrossRef
26.
Mahmoudi T (2009) Genetic variation in the vitamin D receptor and polycystic ovary syndrome risk. Fertil Steril 92(4):1381–1383PubMedCrossRef
27.
Wehr E, Trummer O, Giuliani A, Gruber HJ, Pieber TR, Obermayer-Pietsch B (2011) Vitamin D-associated polymorphisms are related to insulin resistance and vitamin D deficiency in polycystic ovary syndrome. Eur J Endocrinol 164(5):741–749PubMedCrossRef
28.
(2010) Prophylaxis of vitamin D deficiency—Polish Recommendations 2009. Endokrynol Pol 61(2):228–32