Dr. Daniella Perri, ND

 

Subheadline

From widespread deficiency to VDR signaling across tissues, this review synthesizes evidence on how vitamin D shapes immunity, infection severity (including COVID-19), tumor biology, uterine fibroids, metabolic syndrome, and PMOS—and outlines where supplementation may serve as a safe, adjunctive strategy.

Short Description

This article reviews vitamin D’s roles outside skeletal health, highlighting how deficiency and VDR-mediated pathways influence immune responses, viral infections, cancer mechanisms, uterine fibroids, metabolic syndrome, and PMOS. It summarizes key findings from in vitro, animal, and human studies to inform integrative, evidence-based care.

Abstract

Vitamin D supplementation is not strictly for healthy bone metabolism. This is mainly due to the high expression of vitamin D receptors (VDRs) in specific target cells and tissues. Vitamin D deficiency is very common around the world, being affected by latitude/winter season, melanin production, pharmaceutical side effects, obesity, and fat malabsorption disorders. Deficient serum vitamin D levels modulate VDR expression, which influences expression of downstream genes and induces protein cascades in different tissues to elicit disease symptoms. The common theme in all the studies reviewed is the role vitamin D has in the immune response. Vitamin D deficiency has been implicated in not only immune related conditions, but chronic medical conditions as well. While the mechanism of action of vitamin D in these conditions has not been fully elucidated, significant associations have been documented. This can pave the way for effective, non-invasive, and non-pharmaceutical interventions for treatment and prevention of many diseases. The present review will summarize key findings from various literature reviews and meta-analyses of in vitro studies, in vivo studies, as well as human clinical trials.

Introduction

Vitamin D is well known for its role in calcium and phosphorous homeostasis to maintain optimal mineralization of bones and teeth. It is not surprising that individuals with a vitamin D deficiency present with conditions such as osteomalacia, osteoporosis, and periodontitis. However, due to vitamin D’s various target tissues and cells, a deficiency can cause patients to present with symptoms that are beyond bone metabolism.

To understand the physiological activity of vitamin D, identification of its receptor in specific cells and tissues is crucial. The Vitamin D receptor (VDR) is located abundantly in small intestinal epithelium, large intestine, pancreatic beta islet cells, distal renal tubular epithelial cells, bronchial epithelial cells, epidermal epithelial cells, osteoblasts, T-lymphocytes, monocytes/macrophages, and parathyroid epithelial cells [Wang 2012]. VDR expression is lower, yet significant, in the center of efferent ducts in testes, the prostate gland, and in lobule and ductal epithelial cells in mammary glands [Wang 2012]. VDR was undetectable in hepatocytes, brain tissue, skeletal, smooth and cardiac muscle, thyroid, and adrenal gland. However, the antibodies used in the immunoassays were not one hundred percent VDR specific [Wang 2012]. Optimal functioning of these target tissues and cells depends on adequate serum vitamin D levels.

Vitamin D has two main forms: 25-hydroxyvitmain D (25(OH)D), which is produced in the liver, and 1,25-dihydroxyvitamin D (1,25(OH)D), which is the active form of vitamin D, that is produced in the kidneys. To determine an individual’s vitamin D status, serum 25(OH)D levels are measured [Holick 2011]. Vitamin D deficiency is defined as a serum level of 25(OH)D below 50nmol/L, while insufficiency is a serum level of 52.5-72.5 nmol/L [Holick 2011]. In order to consistently raise serum levels above 75nmol/L, at least 1000 IU per day of vitamin D is required in all age groups; however, various dosages above 1000 IU is required to correct the deficiency depending on age, pregnancy, and use of certain medications (anticonvulsants, glucocorticoids, and antifungals) [Charoenngam 2020, Hoick 2011]. The main cause for deficiency is the lack of exposure to sunlight due to sunscreen use, dark skin pigmentation, and the winter season [Charoenngam 2020]. Other significant factors that are associated with vitamin D deficiency are body mass index greater than 30, fat malabsorption disorders, such as Celiac disease, bile insufficiency, irritable bowel disease, and cystic fibrosis, liver and kidney failure, medications, such as anticonvulsants, drugs used to treat HIV/AIDS (HARRT), corticosteroids, and rifampicin, and primary hyperparathyroidism [Charoenngam 2020, Holick 2011]. One of the main target cells that are greatly affected by inadequate serum vitamin D levels are those of the immune system.

VITAMIN D AND THE IMMUNE SYSTEM

Over the last decade the immunological role of vitamin D has become more prominent. More recently, a deficiency of vitamin D has been associated with immune related conditions and diseases such as cancer, viral respiratory infections, and SARS-CoV-2 infection [Charoenngam 2020, Carlberg 2021, Costagliola 2021, Herr 2011, Ghasemian 2021]. However, vitamin D deficiency has also been implicated in many chronic medical conditions such as uterine fibroids, metabolic syndrome, cardiovascular disease, and polyendocrine metabolic ovarian syndrome (PMOS), all of which have some inflammatory component to disease progression [Ciebiera 2018, Cai 2021, Theik 2021, Gokosmanoglu 2020]. Awareness of the role that Vitamin D has in both the innate and adaptive immune responses can help to understand how and why vitamin D deficiency is associated with the aforementioned conditions.

The cells of the innate and adaptive immune system have the ability to convert 25(OH)D to its active form, 1,25(OH)D. They also express VDR, which is a nuclear receptor that can influence gene expression, so that the 1,25(OH)D can induce antimicrobial responses in those cells [Ismailova 2021]. During an infection, 1,25(OH)D is produced within monocytes and macrophages, which stimulates antimicrobial activities of these immune cells through an autocrine signaling cascade initiated by VDR binding and gene expression of cytokines, chemokines, pattern recognition receptors, and antimicrobial peptides [Charoengam 2020, Biriken 2020, Ismailova 2021]. It also influences the immune response of neighboring lymphocytes by upregulating TH2 and Treg cells and downregulating B, TH1 and TH17 cells, effectively suppressing the proinflammatory state [Cantorna 2015, Charoengam 2020, Holick 2007]. Vitamin D also downregulates B lymphocytes by suppressing immunoglobulin production; thus, reducing autoantibody production [Charoengam 2020]. The lack of vitamin D in target cells and tissues can help to explain the presence of disease symptoms and why supplementation may be used as an adjunct therapy for symptom relief and suppression of disease progression. Vitamin D and its effects can be clearly seen when studying viral infections.

VIRAL RESPIRATORY INFECTIONS: Special Focus on COVID-19

The course of a respiratory tract infection depends on the innate and adaptive immune response. Since vitamin D has demonstrated a strong influence on immune cell function [Charoengam 2020], it is clear that vitamin D levels can affect incidence and severity of a viral infection. At optimal levels, vitamin D causes enhancement of the lung epithelial cell barrier, stimulates maturation of type II pneumocytes, promotes surfactant production, and increases the innate immune response within the airways [Costagliola 2021]. Recent studies have shown that vitamin D deficiency status is associated with increased incidence and severity of viral respiratory infections [Martineau 2017, Lai 2017]. This association is stronger in patients with lung disease, such as asthma, COPD [Ginde 2009] and COVID-19 [Kazemi 2021].

A key theme that has emerged from observing and treating patients with SARS-COV-2 infection is immune hyperinflammation, making immunomodulation a possible treatment strategy [Tan 2020]. The cytokine storm that is created during this infection leads to acute respiratory syndrome, organ failure and, in many cases, death [Musavi 2020]. In a systematic review and meta-analysis of 15 recent studies, Kazemi ei al. revealed that there is an association between vitamin D deficient status and severity of COVID-19 disease [Kazemi 2021]. In other words, patients who are vitamin D deficient suffer from a more severe SARS-COV-2 infection [Alsafar 2021, Lau 2020]. The greater the cytokine storm, the more severe the infection is [Alsafar 2021, Mustavi 2020]. The role of vitamin D as a therapeutic agent comes into play here by inducing an anti-inflammatory response and suppressing the production of proinflammatory cytokines [Charoengam 2020]. A recent RCT studying patients with mild to moderate COVD-19 symptoms, demonstrated that supplementing patients with 5000 IU of vitamin D orally per day for two weeks significantly reduced the symptoms of cough and ageusia [Sabico 2021].

It has been posited that, in an effort to control (SARS-COV-2) viral replication, vitamin D induces numerous antimicrobial pathways, which reduces serum vitamin D levels quicker than the body can replenish them back to sufficiency. The antimicrobial response is then muted once vitamin D insufficiency is present [Lau 2020]. However, this effect does not last as the body is capable is recovering from the acute inflammatory response allowing vitamin D levels to rise again [Smolders 2021]. Unfortunately, this reaction was demonstrated in only 9 healthy male volunteers. While these volunteers had insufficient vitamin D levels, patients with severe COVID-19 disease had marked vitamin D deficiency [Karonova 2021], which could make recovery from the acute inflammatory response more difficult.

Current investigations have demonstrated the role of vitamin D in inducing an antiviral response and negatively regulating the renin-angiotensin-aldosterone system (RAS). [Costagliola 2021]. The RAS consists of 2 protein axes, which are ACE/Ang II/ATR and ACE2/Ang 1-7/MasR [Musavi 2020]. SARS-COV-2 infection disrupts this balance and causes lung damage, whereas, vitamin D upregulates ACE2 receptor expression providing a protective effect on lung tissue [Musavi 2020]. It is also through this mechanism that vitamin D protects against hypertension and inflammation by inhibiting RAS activity and suppressing renin synthesis [Musavi 2020]. While there is so much to learn from SARS-COV-2 infection and more large-scale studies are required, Vitamin D may be a possible adjunct treatment and prevention strategy for severe COVID-19 disease. Vitamin D not only affects the immune system in response to a microbial infection, but also its response to malignant cells.

ANTI- TUMOR

The human body is capable of searching for and destroying cancerous cells. Malignant tumor cell survival relies on genes and immune pathways, some of which are regulated by vitamin D [Carlberg 2021]. In addition, in vitro studies using human colon cancer cell lines, it has been demonstrated that vitamin D has direct effects on differentiation, proliferation, and apoptosis of neoplastic cells by altering specific gene expression [Carlberg 2021, Vaughan-Shaw 2021, Palmer 2003, Wood 2004]. Vitamin D also has indirect effects on tumor cell survival by regulating immune cells. [Carlberg 2021] Vitamin D induces autophagy of cancerous cells by genomic and non genomic pathways to regulate cell proliferation and differentiation [Bhutia 2021] Animal models as well as human and cancer cell lines have shown an antiproliferative effect by influencing specific genes involved in cancer cell growth [Bangeree 2003].

Many in vitro studies have shown that vitamin D demonstrated anti-tumor activity when it is used to treat several cancer cells lines. Recent work confirms the presence of VDR in glioma cells since stimulating glioma cells lines with vitamin D increased VDR expression and subsequence anti-tumor effects [Lo 2021]. Cell cycle arrest is the most well documented mechanism of how vitamin D exerts its anti-cancer effects in numerous glioblastoma cell lines [Lo 2021]. Vitamin D works synergistically with temozolomide to significantly increase apoptosis in the C6 rat glioblastoma cell line [Bak 2016]. Treating breast cancer cells with vitamin D and its analog, EB1089, also induces apoptosis through a VDR mediated signaling cascade that suppresses the anti-apoptotic protein, Beclin-2, which is normally overexpressed in tumors [Hoyer-Hansen 2005]. Downregulation of Beclin-2 was also demonstrated in prostate cancer cell lines [Gauzy 2002]. Vitamin D and its analogs have also been shown to have anti-invasive effects in glioma cell lines as well [Lo 2021]. An interesting new find is that VDR polymorphisms may be a genetic risk factor for several cancers; however, more large-scale association studies are required to confirm this in each individual cancer type [Lo 2021]. Human trials using vitamin D supplementation in patients with cancer, both invasive and in situ types, revealed that supplementation did not prevent cancer, reduce its risk, or affect cancer incidence [Avenell 2012 Scragg 2018]. It is suggested that humans may respond to vitamin D differently leading to the insignificant response in its supplementation [Carlberg 2021]. There are numerous factors that affect cancer progression in humans, so if Vitamin D demonstrates anti-proliferative effects in vitro, there may still be a therapeutic role for it in treatment strategies.

UTERINE FIBROIDS

Vitamin D has anti-tumor effects not only in cancerous cells, but also in benign tumor cells. One example is uterine fibroids or uterine leiomyomas. Uterine fibroids, derived from the myometrium of the uterus, are the most common benign tumor in women of reproductive age [Vergara 2021]. Many studies have demonstrated the association of vitamin D deficiency and the increased risk of developing uterine fibroids [Baird 2013, Li 2020, Mitro 2015, Paffoni 2021, Singh 2019]. In vitro studies demonstrated an anti-proliferative effect of vitamin D on human leiomyoma cells, in a concentration and time-dependent manner [Sharan 2011]. Proteins involved in tumor proliferation, such as cyclin-dependant kinase 1 (CDK-1), proliferating cell nuclear antigen (PCNA), catechol-O-methyltrasnferase (COMT), and proliferation marker protein KI-67 (MKI-67) were significantly reduced in the presence of vitamin D [Sharan 2011]. In addition, transforming growth factor beta (TGF-β), which is responsible for extracellular matrix regulation, was significantly inhibited by vitamin D, leading to decreased fibroid volume [Halder 2011]. It is well known that uterine fibroids are hormonally regulated. Increased extracellular vitamin D regulates the expression of nuclear estrogen and progesterone receptors in a dose dependent manner [Al-Hendy 2015]. In recent clinical trials, treating women with uterine fibroids who had a vitamin D deficiency demonstrated tumor growth inhibition [Arjeh 2020, Ciavattini 2016, Suneja 2021, Tanha 2020] as well as reduction in tumor volume [Hajhashemi 2019]. It has been suggested that uterine fibroids could be the result, in part, of a chronically inflammatory immune system that is governed predominantly by TH17 cytokines [Wengienka 2012]. Vitamin D can regulate the expression of TH17 cytokines through activation of its receptor and downstream genes [Charoengam 2020], This simple treatment may have beneficial implications in female health standards of care for dysmenorrhea and fertility. Uterine fibroids are but one of many conditions that are governed by inflammatory terrain.

METABOLIC SYNDROME

Chronic infection and system inflammation are major contributors to metabolic syndrome (MeS) and insulin resistance. Since vitamin D has the ability to modulate the adaptive and innate immune system, it is not surprising that a vitamin D deficiency has been associated with increased incidence for Type 2 Diabetes, increased risk for MeS, increased triglycerides, decreased high density lipoprotein levels, obesity, and metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD) [Barchetta 2011, Bea 2015, Ceglia 2017, Chon 2014, Zheng 2019]. An inflammatory terrain is associated with the health of the gastrointestinal tract. The small intestine is a major vitamin D targeting tissue, where VDR levels are abundantly expressed [Wang 2012, Zheng 2020]. VDR expression is greater in the distal small intestine, more specifically within Paneth cells, which are also more abundant than in proximal regions [Zheng 2020]. These intestinal cells are responsible for secreting antimicrobial agents, known as α-defensins, within the lumen of the small intestine modulating bacterial growth. In a narrative literature review of animal and human studies, vitamin D supplementation given to vitamin D deficient subjects, led to an increase in beneficial bacteria, including Ruminococcaceae, Akkermansia, Faecalibacterium, Lactococcus, and Coprococcus and a decrease in Firmicutes [Tangestani 2021]. Therefore, vitamin D signaling is crucial to maintaining the gut microbiome and a deficiency leads to dysbiosis and inflammation [Su 2016]. Conversely, a sufficient vitamin D can significantly suppress metabolic disorders by improving insulin resistance, reducing plasma triglycerides, and decreasing progression of hepatic steatosis. [Su 2016]. Targeting treatment plans to optimize gut health can have beneficial implications for many conditions characterized by inflammation.

POLYENDOCRINE METABOLIC OVARIAN SYNDROME (PMOS)

PMOS (formerly PCOS) is characterized by a polycystic ovarian morphology, hyperandrogenism, and ovulatory impairment, with insulin resistance as the main pathophysiological finding. As with uterine fibroids, there is an association of vitamin D deficiency with the development of PMOS in women of reproductive age [Gokosmangoglu 2020]. Furthermore, higher androgen levels were associated with vitamin D deficiency in women with PMOS [Gokosmangoglu 2020]. Supplementing women with vitamin D demonstrated a significant reduction in androgen levels and significant increase in insulin sensitivity post treatment [Karadag 2018]. While the pathophysiology of PMOS cannot be fully explained, vitamin D deficiency and its associations with androgen excess and insulin sensitivity sheds light on possible mechanisms. As suggested with uterine fibroids, vitamin D may modulate androgen production through activation of its receptor in ovarian cells.

CONCLUSION

A key element in all of the conditions and diseases discussed is inflammation. Whether it is acute or chronic, inflammation paves the way for disease progression. Fortunately, vitamin D can influence the inflammatory response in either case. How do we alleviate vitamin D deficiency? Current standards for treating vitamin D deficiency suggest testing only at-risk individuals. It makes sense that a patient who is likely to develop osteoporosis, based on age, diet, lifestyle and family history, is tested to confirm vitamin D status. However, patients with recurrent infections, cancer, metabolic syndrome, uterine fibroids, or PMOS may not show typical signs of vitamin D deficiency. Overall, recent scientific investigations have demonstrated that vitamin D has a strong impact in treating symptoms and preventing disease progression. It is time to change standards of care. Just as a CBC is run as a routine check, perhaps vitamin D levels should be included. Many more clinical trials are necessary to determine a therapeutic vitamin D dose that provides beneficial biological effects in each disease and condition. Having a non-invasive, non-pharmaceutical, and non-surgical treatment strategy can have a positive impact on today’s health care system and in people’s lives.

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Author Bio:

Dr. Daniella Perri, ND, CCCE, MSc, HBSc is a licensed naturopathic doctor, CAPPA Certified Childbirth Educator, and founder of MotherWell Academy. She specializes in postpartum care, maternal wellness, infant health, and family medicine, helping parents navigate pregnancy, birth, and the postpartum transition through an evidence-informed, holistic approach. Dr. Perri combines naturopathic medicine with childbirth education to support the physical, emotional, and nutritional health of mothers and babies. She is passionate about empowering families with practical, compassionate care and education that fosters lifelong wellness.

Acknowledgements

None

Conflicts of Interest

The author declares no conflicts of interest