Vitamin D is an essential nutrient of which many people struggle to obtain optimum levels. The benefits of vitamin D for bone health and immunity are well published and understood by the general population. However, the impacts of vitamin D on health are far reaching and more and more evidence is accumulating for the functions that it elicits across the body.
Vitamin D is considered to be a hormone itself, as it is synthesised in the skin by the presence of UV radiation and converted into its most active form by the liver and kidneys, where it elicits an effect on calcium regulation and bone density. No other vitamin has to go through this process:
When the skin is exposed to UVB radiation (from sunlight) a molecule known as 7-dehydrocholesterol (derived from cholesterol) is converted to cholecalciferol, also known as D3. Cholecalciferol can also be obtained from the diet or by supplementation (D3). Cholecalciferol travels to the liver where it is converted to 25-hydroxyvitamin D (25OHD). The kidney then converts 25OHD to 1,25-hydroxyvitamin D (1,25OHD), also known as calcitriol, which possesses hormonal properties and regulates calcium and phosphate balance. “D3 is the prohormone, 25(OH)D is the major circulating form, and 1,25(OH)2D is the hormonally active form.”1
However, although vitamin D is a hormone in its own right, it also elicits significant influence over other areas of the endocrine system, and therefore should be considered an important adjunct when determining appropriate interventions for hormone regulation. It has been shown to influence parathyroid hormone, testosterone and oestrogen, as well as dopamine and serotonin directly as well as influencing other indirectly through immune modulation.
Vitamin D and parathyroid hormone (PTH) are intimately involved in the regulation of calcium and bone modelling. Vitamin D increases calcium absorption form the small intestine, reduces calcium excretion in the kidneys and also inhibits PTH, and ultimately increases calcium concentration in the blood. This increased level of calcium allows for bone growth, formation, and maintenance, supporting bone density. It therefore works antagonistically to PTH which increases calcium release from bone into the blood stream to maintain a balance of blood pH as well as calcium levels required for normal tissue funciton, if and when required.
Vitamin D deficiency is associated with hyperparathyroidism, this drives the leaching of calcium from bone into blood and can be a major contributor to reduced bone density, osteoporosis and osteopenia. A 2017 study stated that; “The association between parathyroid hormone (PTH) and vitamin D may be an important determinant of bone remodeling, mainly in the elderly. A negative and significant correlation was found between PTH and 25(OH)D levels in the present study. Individuals with low vitamin D levels were those who had higher values of PTH, while individuals with high values of vitamin D showed low values of PTH.”2
Therefore, vitamin D not only affects bone modelling by increasing calcium retention and absorption but also by keeping PTH in check. If vitamin D deficiency occurs, this can lead to overactivity of PTH and hence calcium leaching from the bone, which will drive loss of bone density.
The presence of vitamin D receptors (VDR) in the ovary, uterus, placenta, and the testis suggest a regulatory role for vitamin D in reproductive physiology. Further research has demonstrated its importance in both male and female fertility, by influence over testosterone and oestrogen but also locally with gamete production and endometrial support. VDR knockout mice (cannot elicit a response to vitamin D effectively) have significant gonadal insufficiency, decreased sperm count and motility, and histological abnormalities of testis, ovary and uterus.
The mechanism of action of vitamin D on female fertility is not fully understood, however, both animal and epidemiological studies have demonstrated an association with vitamin D deficiency and reduced fertility as well as with female reproductive disorders such as PMS, endometriosis and polycystic ovary syndrome (PCOS). 4,5
Several studies have shown that vitamin D supplementation has improved in-vitro fertilisation outcomes. These finding have been associated with the effect of vitamin D on the endometrium. A randomised controlled trial also found increased endometrial thickness in women with PCOS receiving vitamin D during intrauterine insemination cycles. Vitamin D may also elicit a beneficial effect on serum lipids in PCOS women, therefore suggesting indirect benefits to conditions associated with hormone dysregulation. It was also favourably associated with primary dysmenorrhea, uterine leiomyoma (fibroids), and ovarian reserve in late reproductive aged women, suggesting uses for PMS, fibroids and menopause.
Animal models further support the influence of vitamin D on reproductive disorders – vitamin D treatment improved endometriosis in rat models and increased vitamin D intake was related to a decreased risk of endometriosis incident.
While mechanisms are far from understood, disrupted oestrogenic signalling is hypothesised to contribute to impaired reproductive physiology in vitamin D deficient females.
As mentioned, human and animal studies have demonstrated a high concentration of vitamin D in the testes, with evidence of local synthesis. Also, human studies have identified that vitamin D is positively associated with semen quality and androgen status in men.3 In vitamin D deficient men, perturbations in male behaviour, spermatogenesis and fertility are observed. Furthermore, inseminating wild-type females with sperm collected from diet-induced vitamin D deficient male rats resulted in 65% fewer sperm deposited in the genital tract, and 73% fewer pregnancies in vitamin D sufficient female rats. Therefore, highlighting the essential funciton of vitamin D in relation to sperm funciton and production.
Again, the exact mechanisms of action are not understood but as well as influencing local effect on both the endometrium and the testes, vitamin D also has an influence over steroid hormones, namely oestrogen and testosterone. Signalling via the VDR has additionally been linked to CYP19 (aromatase) gene expression, functionally linking vitamin D with the family of reproductive steroid hormones. Studies have supported the notion that vitamin D increases testosterone and oestrogen regulation.
Many epidemiological studies have demonstrated an association between vitamin D deficiency and depression, as well as other cognitive disorders including autism, ADHD, Alzheimer’s disease, and Parkinson’s. It appears that vitamin D elicits multiple influences on cognitive funciton but may also directly affect neurotransmitters.6 Most evidence shows the relationship between vitamin D status and dopamine but also there is further, although slightly less compelling evidence, that it also affects serotonin.
Studies have shown that vitamin D may be involved in neurodevelopment and may have a neuroprotective effect on dopaminergic pathways in the adult brain. It demonstrated that vitamin D increases the levels of tyrosine hydroxylase expression implying that vitamin D could modulate dopaminergic processes. Another study looking at children with ADHD showed that Vitamin D3 supplementation can increase serum dopamine levels.7
Vitamin D may influence serotonin levels. A suggested mechanism is that calcitriol (active vitamin D) activates the transcription of the serotonin-synthesising gene tryptophan hydroxylase 2 (TPH2) in the brain at a vitamin D response element (VDRE) and represses the transcription of TPH1 in tissues outside the blood-brain barrier at a distinct VDRE. This in part can explain abnormalities seen in conditions such as autism (associated with low vitamin D levels) where there are serotonin levels within the blood brain barrier but high concentration outside the BBB.8
Additionally, animal studies have shown that calcitriol can provide significant protection against the dopamine and serotonin depleting effects of neurotoxic doses of methamphetamine – a toxic drug, suggesting a potential for vitamin D to be protective against depletion of dopamine and serotonin.9,10
Additional evidence has strongly suggested that vitamin D plays an important role in modifying the risk of type 2 diabetes, an effect which is likely mediated by an effect of vitamin D on beta cell function, insulin sensitivity and systemic inflammation. Vitamin D has both direct and indirect effects, the latter via regulation of calcium effects on various mechanisms related to the pathophysiology of type 2 diabetes, including pancreatic beta cell dysfunction, impaired insulin action and systemic inflammation.11 Research has shown that:
- 1,25(OH)D appears to stimulate the expression of insulin receptors
- Calcium is essential for insulin-mediated intracellular processes in insulin-responsive tissues such as muscle and fat, with a narrow range of intracellular calcium needed for optimal insulin-mediated functions. The regulation of calcium by vitamin D indirectly assists with these processes
- Vitamin D supplementation seems to restore reduced glucose-stimulated insulin secretion
Hashimoto’s disease is a form of autoimmune hypothyroidism. T helper 1 (Th1) is essential for part of the innate immune system, particularly in response to infection. However, the balance of Th1 cells with Th2 cells needs to be tightly regulated. Excess Th1 compared with Th2 for prolonged periods of time, in the absence of acute infection, is known as Th1 dominance and is associated with tissue specific autoimmune disease such as Hashimoto’s. Vitamin D has been shown to help modulate T helper dominance and therefore, may indirectly influence the thyroid by helping to support a normal immune response.12
Vitamin D affects hormones both directly and indirectly. Epidemiological studies suggest that vitamin D deficiency is common in UK adults and the Government recommend everyone supplements a minimum of 10μg of vitaminD3 per day. It is therefore an important nutrient to consider when supporting clients with endocrine (and neurotransmitter) disorders.
- Vitamin D is considered to be a hormone as after synthesis via skin in the presence of UV radiation, or consumption, it is converted into the active form via the liver and kidneys
- It works antagonistically with parathyroid hormone to maintain calcium homeostasis. When vitamin D is deficient, parathyroid hormone is not inhibited and can continue to mobilise calcium from bone into the bloodstream
- On top of this vitamin D increases calcium absorption form the gut and reduces excretion form the kidney. Therefore, vitamin D deficiency creates a perfect storm for reduction of bone density and therefore risk of osteoporosis
- Vitamin D influences reproductive health of both males and female by affecting steroid hormones synthesis, particularly testosterone and oestrogen
- Vitamin D deficiency is associated with reduces sperm parameters in men and reduced fertility in both men and women as well as an increased risk of female reproductive dysfunction such as endometriosis, PCOS and PMS.
- Vitamin D has been shown to increase dopamine production within the brain and has shown promise in studies looking at ADHD, Autism and Parkinson’s disease.
- Vitamin D indirectly affects insulin and therefore is associated with a reduced risk of type 2 diabetes. It has been shown to to stimulate the expression of insulin receptors and supplementation seems to restore reduced glucose-stimulated insulin secretion.
- Vitamin D is important for modulating the balance of Th1 and Th2 cells. Dysregulation of Th cells is associated with autoimmunity. It therefore may indirectly influence thyroid function by helping to support normal immune function, and hence reduce risk of Hashimoto’s disease (an autoimmune thyroid condition).
If you have questions regarding the topics that have been raised, or any other health matters, please do contact me (Helen) by phone or email at any time.
Amanda Williams and the Cytoplan Editorial Team
- Juliana Sálvio Martins, Magda de Oliveira Palhares, Octávio Cury Mayrink Teixeira, Mariana Gontijo Ramos, “Vitamin D Status and Its Association with Parathyroid Hormone Concentration in Brazilians”, Journal of Nutrition and Metabolism, vol. 2017, Article ID 9056470, 5 pages, 2017.
- Lerchbaum E, Obermayer-Pietsch B. Vitamin D and fertility: a systematic review. Eur J Endocrinol. 2012 May;166(5):765-78. doi: 10.1530/EJE-11-0984. Epub 2012 Jan 24. PMID: 22275473.
- Anagnostis P, Karras S, Goulis DG. Vitamin D in human reproduction: a narrative review. Int J Clin Pract. 2013 Mar;67(3):225-35. doi: 10.1111/ijcp.12031. Epub 2013 Jan 7. PMID: 23294318.
- Harmon QE, Kissell K, Jukic AMZ, Kim K, Sjaarda L, Perkins NJ, Umbach DM, Schisterman EF, Baird DD, Mumford SL. Vitamin D and Reproductive Hormones Across the Menstrual Cycle. Hum Reprod. 2020 Feb 29;35(2):413-423. doi: 10.1093/humrep/dez283. PMID: 32068843; PMCID: PMC7986370.
- Kaviani M, Nikooyeh B, Zand H, Yaghmaei P, Neyestani TR. Effects of vitamin D supplementation on depression and some involved neurotransmitters. J Affect Disord. 2020 May 15;269:28-35. doi: 10.1016/j.jad.2020.03.029. Epub 2020 Mar 13. PMID: 32217340.
- Seyedi M, Gholami F, Samadi M, Djalali M, Effatpanah M, Yekaninejad MS, Hashemi R, Abdolahi M, Chamari M, Honarvar NM. The Effect of Vitamin D3 Supplementation on Serum BDNF, Dopamine, and Serotonin in Children with Attention-Deficit/Hyperactivity Disorder. CNS Neurol Disord Drug Targets. 2019;18(6):496-501.
- Patrick RP, Ames BN. Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. FASEB J. 2014 Jun;28(6):2398-413. doi: 10.1096/fj.13-246546. Epub 2014 Feb 20. PMID: 24558199.
- Jaqueline Kalleian Eserian, (2013) ‘Vitamin D as an effective treatment approach for drug abuse and addiction,’ Journal of Medical Hypotheses and Ideas, Volume 7, Issue 2, Pages 35-39
- Okasha, T.A., Sabry, W.M., Hashim, M.A. et al. Vitamin D serum level in major depressive disorder and schizophrenia. Middle East Curr Psychiatry 27, 34 (2020). https://doi.org/10.1186/s43045-020-00043-y
- Mitri j, pittas ag. Vitamin d and diabetes. Endocrinology and metabolism clinics of North America. 2014;43(1):205-232.
- Cantorna MT, Yu S, Bruce D. The paradoxical effects of vitamin D on type 1 mediated immunity. Mol Aspects Med. 2008;29(6):369-375. doi:10.1016/j.mam.2008.04.004