The Relationship between Vitamin D and Estrogens: History
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Contributor:
Tiziana Ciarambino
,
Pietro Crispino
,
Giovanni Minervini
,
Mauro Giordano

Vitamin D has a potential role of regulating many cellular functions. The totality of vitamin D transport depends on the activity of vitamin D binding protein (DBP) and albumin in a measure of 85% and 15%, respectively. Vitamin D is found in the free circulating form in percentages ranging from 0.01% to 3%. Both DBP and albumin are synthesized by the liver, and their production is regulated by estrogens, glucocorticoids, and inflammatory cytokines.

  • vitamin D
  • estrogens

1. Introduction

It is customary to think that the biological role of vitamin D is particularly that of preventing and combating osteoporosis and sarcopenia, which are prevalent conditions in the general population and which, through a gradual process, tend to involve older people with complications ranging from the increased predisposition to bone fractures up to sarcopenia and immobilization syndrome [1]. However, it is useful to point out that vitamin D has a potential role of regulating many cellular functions. Considering its expression in many cell types and its common deficiency, it is linked to several health problems that go far beyond those related to the musculoskeletal system, including infections, autoimmune disorders, cardiovascular disease, metabolic syndrome, and related conditions to insulin resistance, and, last but not least, its deficiency is part of the genesis of some malignant tumors [1][2][3][4]. Furthermore, it has been reported that vitamin D can be a powerful mediator of inflammation and, therefore, it would be part of the genesis of some respiratory pathologies of the gastrointestinal and genitourinary tracts [5]. It is obvious to think that due to the importance of the role that vitamin D plays in our organism, it is necessary to have levels of vitamin D. It is equally necessary, however, to understand if, in addition to the daily intake of vitamin D, there are alterations that concern one’s own metabolism and that can modulate its bioavailability. The synthesis of vitamin D3 or cholecalciferol begins following exposure of the skin to ultraviolet radiation. 7-dehydrocholesterol or provitamin D is present in the basal layer and in the spinous layer of the epidermis and undergoes conversion into pre-vitamin D with exposure to ultraviolet B rays and is then subsequently isomerized into vitamin D. Vitamin D2, also called ergocalciferol, derives from food sources of a vegetable nature and is, therefore, absorbed in the intestine. Thus, most of the vitamin D originates from the heal and passes through the capillaries of the dermis carried mainly by vitamin D binding protein (DBP) and albumin to the liver, where vitamin D microsomal 25-hydroxylase converts it to 25-hydroxy vitamin D (1,25(OH)2D3) [6]. Vitamin D receptors, in particular, are found in various tissues of the human body; indeed, they are almost always expressed in all nucleated elements of our organism [5]. The bioactivity of vitamin D lies not only in the correct functioning of the kidneys, which, as known, convert vitamin D once absorbed by the skin and the gastrointestinal tract into its active form 1,25-dihydroxy vitamin D, due to the enzymatic activity of 1-alpha-hydroxylase, but since this enzyme has been detected in many other tissues, it is reasonable to think that the metabolism of the vitamin or its autocrine and paracrine effects in addition to its endocrine effects are present in various locations in our body [5]. The totality of vitamin D transport depends on the activity of vitamin D binding protein (DBP) and albumin in a measure of 85% and 15%, respectively. Vitamin D is found in the free circulating form in percentages ranging from 0.01% to 3% [5]. Both DBP and albumin are synthesized by the liver, and their production is regulated by estrogens, glucocorticoids, and inflammatory cytokines [5]. It has been observed that the levels of DBP can be lower according to the various breeds, and this is probably linked to the high genetic polymorphism, which determines a common genetic variant and other less common forms.

2. The Relationship between Vitamin D and Estrogens

As people have said, vitamin D performs multiple functions in our body and is involved in many diseases. Most of the actions performed by vitamin D are related to its intake and the affinity of its precursors with the vitamin D nuclear receptor (VDR) [7][8]. The VDR is expressed in organs, such as the gut, skeleton, and parathyroid gland in the ovaries and testicles; above all, the function of vitamin D at the level of both sexes is poorly understood [7][8]. It has been observed that vitamin D and estrogen have a double relationship in the sense that low levels of estrogen are associated with falls of osteopenia or rickets, while it has been seen that VDR at the level gonadal plays a role in the production of estrogen [7][8]. It has been showed that vitamin D regulates the biosynthesis of estrogens by means of calcitropic activity and by maintaining the homeostasis of intracellular and extracellular calcium in balance and by acting directly in the regulation of the expression of the aromatase gene [8]. The products of expression of the aromatase gene, such as Cytochrome P450 Family 19 Subfamily A Member 1 (CYP19A1) protein, an aromatase that plays a critical role in estrogen biosynthesis, thus, affects several organ-specific dysfunctions related to body fat distribution and to lipid metabolism regulations. In particular, the CYP19A1 rs10046 polymorphism is considered an important cardiovascular risk factor as it would seem to be associated with the increase in lipoproteins such as circulating apoB with high atherogenic potential, with insulin resistance as a metabolic condition for the onset of type 2 diabetes mellitus and arterial hypertension [9][10][11]. Some studies have observed that estrogens and, in particular, progesterone can reduce the risk of colorectal cancer and the hereditary variation in sex hormone genes may be a mechanism by which sex hormones influence the carcinogenesis of this tumor [12]. This aspect actively affects products that are derived from the aromatase gene. The biological activity of estrogens on the carcinogenic transformation of the colon still remains unclear. Studies on rodents have shown that estrogens, through their binding with the alpha receptor and/or the beta receptor, seem to inhibit the growth of neoplastic cells in the course of colon cancer, as well as the disappearance of both receptors in tissues taken after removal has also been found for colorectal cancer [13][14][15]. It has also been suggested that estrogens and, in particular, estradiol upregulate DNA repair genes in colon cells (mismatch repair) [16][17]. However, other studies have conversely suggested that estrogens stimulate cell proliferation in colon cancer [18][19].
The overexpression of aromatase is implicated not only in the pathogenesis of colorectal cancer but also participates in the pathogenesis and growth of those malignant tumors typical of the female gender, such as those of the breast, endometrium, and ovaries [20].
Several cognitive functions are influenced by concentrations of estradiol determined by the activity of the parts of the aromatase. This enzyme is highly expressed in various brain regions and appears to be implicated in potential cognitive deficits, including Alzheimer’s disease, and, in particular, those showing a polymorphism of the CYP19 gene may have prognostically more severe aging from a cognitive–functional point of view [21][22].
Also, in autoimmune pathology with rheumatoid arthritis, genes including IL-1, aromatase, and corticotropin-releasing hormone production are associated with hormonal and reproductive factors, affecting the susceptibility and severity of this disease. In fact, it is possible to observe that this disease is more common in women than men, especially before menopause [23][24].

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11061762

References

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  2. Xie, Z.; Wang, X.; Bikle, D.D. Editorial: Vitamin D Binding Protein, Total and Free Vitamin D Levels in Different Physiological and Pathophysiological Conditions. Front. Endocrinol. 2020, 11, 40.
  3. Ong, J.-S.; Gharahkhani, P.; An, J.; Law, M.H.; Whiteman, D.C.; E Neale, R.; MacGregor, S. Vitamin D and overall cancer risk and cancer mortality: A Mendelian randomization study. Hum. Mol. Genet. 2018, 27, 4315–4322.
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  7. Shimodaira, M.; Nakayama, T.; Sato, N.; Saito, K.; Morita, A.; Sato, I.; Takahashi, T.; Soma, M.; Izumi, Y. Association Study of Aromatase Gene (CYP19A1) in Essential Hypertension. Int. J. Med. Sci. 2008, 5, 29–35.
  8. Yang, Y.; Wang, P. Association of CYP19A1 and CYP1A2 genetic polymorphisms with type 2 diabetes mellitus risk in the Chinese Han population. Lipids Health Dis. 2020, 19, 187.
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  11. Qiu, Y.; E Waters, C.; E Lewis, A.; Langman, M.J.S.; Eggo, M.C. Oestrogen-induced apoptosis in colonocytes expressing oestrogen receptor beta. J. Endocrinol. 2002, 174, 369–377.
  12. Hartman, J.; Edvardsson, K.; Lindberg, K.; Zhao, C.; Williams, C.; Ström, A.; Gustafsson, J.-A. Tumor Repressive Functions of Estrogen Receptor β in SW480 Colon Cancer Cells. Cancer Res. 2009, 69, 6100–6106.
  13. Jin, P.; Lu, X.-J.; Sheng, J.-Q.; Fu, L.; Meng, X.-M.; Wang, X.; Shi, T.-P.; Li, S.-R.; Rao, J. Estrogen Stimulates the Expression of Mismatch Repair Gene hMLH1 in Colonic Epithelial Cells. Cancer Prev. Res. 2010, 3, 910–916.
  14. Slattery, M.L.; Potter, J.D.; Curtin, K.; Edwards, S.; Ma, K.N.; Anderson, K.; Schaffer, D.; Samowitz, W.S. Estrogens reduce and withdrawal of estrogens increase risk of microsatellite instability-positive colon cancer. Cancer Res. 2001, 61, 126–130.
  15. Honma, N.; Arai, T.; Matsuda, Y.; Fukunaga, Y.; Akishima-Fukasawa, Y.; Yamamoto, N.; Kawachi, H.; Ishikawa, Y.; Takeuchi, K.; Mikami, T. Estrogen concentration and estrogen receptor-β expression in postmenopausal colon cancer considering patient/tumor background. J. Cancer Res. Clin. Oncol. 2022, 148, 1063–1071.
  16. Schmuck, R.; Gerken, M.; Teegen, E.-M.; Krebs, I.; Klinkhammer-Schalke, M.; Aigner, F.; Pratschke, J.; Rau, B.; Benz, S. Gender comparison of clinical, histopathological, therapeutic and outcome factors in 185,967 colon cancer patients. Langenbeck’s Arch. Surg. 2020, 405, 71–80.
  17. Manna, P.; Molehin, D.; Ahmed, A. Dysregulation of Aromatase in Breast, Endometrial, and Ovarian Cancers. Prog. Mol. Biol. Transl. Sci. 2016, 144, 487–537.
  18. Rosenfeld, C.S.; Shay, D.A.; Vieira-Potter, V.J. Cognitive Effects of Aromatase and Possible Role in Memory Disorders. Front. Endocrinol. 2018, 9, 610.
  19. Song, Y.; Lu, Y.; Liang, Z.; Yang, Y.; Liu, X. Association between rs10046, rs1143704, rs767199, rs727479, rs1065778, rs1062033, rs1008805, and rs700519 polymorphisms in aromatase (CYP19A1) gene and Alzheimer’s disease risk: A systematic review and meta-analysis involving 11,051 subjects. Neurol. Sci. 2019, 40, 2515–2527.
  20. Ollier, W.E.; Harrison, B.; Symmons, D. What is the natural history of rheumatoid arthritis? Best Pract. Res. Clin. Rheumatol. 2001, 15, 27–48.
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  22. Viganò, P.; Lattuada, D.; Mangioni, S.; Ermellino, L.; Vignali, M.; Caporizzo, E.; Panina-Bordignon, P.; Besozzi, M.; Di Blasio, A.M. Cycling and early pregnant endometrium as a site of regulated expression of the vitamin D system. J. Mol. Endocrinol. 2006, 36, 415–424.
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  24. Ranjzad, F.; Mahmoudi, T.; Shemirani, A.I.; Mahban, A.; Nikzamir, A.; Vahedi, M.; Ashrafi, M.; Gourabi, H. A common variant in the adiponectin gene and polycystic ovary syndrome risk. Mol. Biol. Rep. 2012, 39, 2313–2319.
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