The role of vitamin D in hormone balance

Vitamin D synthesis in humans
Vitamin D and Thyroid Hormones
Vitamin D and male hormones
Vitamin D and female hormones
References
References

Vitamin D3 is associated with a variety of functions including bone mineralization, regulating cell growth, immune and neuromuscular function, etc. This article focuses on the role of Vitamin D in hormone balance and how it impacts the development of many health issues, including infertility.

Vitamin D synthesis in humans

Vitamin D was first identified as a vitamin in the 20th century and is now recognized as a prohormone.¹ There are many different forms of vitamin D, including fat-soluble secosteroids, namely vitamins D1 to D5. In humans, vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) are the most important for biological function.² Vitamin D is primarily synthesized in the skin upon exposure to sunlight, but some forms, such as vitamins D2 and D3, are obtained from dietary sources.

When human skin is exposed to sunlight, 7-dehydrocholesterol is converted to D3, which is then converted to 25-hydroxyvitamin D (25(OH)D, also known as calcidiol or calcifediol) in the liver.³ The active form of vitamin D3, also called calcitriol, 1α,25-dihydroxyvitamin D3, or 1,25-dihydroxycholecalciferol, is synthesized in the kidneys in the presence of the 1α-hydroxylase enzyme. Vitamin D levels are determined by estimating serum 25(OH)D.^Four

Vitamin D regulates calcium phosphate metabolism and increases calcium concentrations through multiple pathways.² For example, it is associated with stimulation of calcium absorption in the intestine, resorption in renal tubules, and activation of the RANK/RANKL (receptor activator of nuclear factor kappaB/its ligand) pathway in osteoclasts.^Five

Vitamin D and Thyroid Hormones

The thyroid gland synthesizes hormones that control the functioning of physiological systems. The hypothalamic-pituitary-thyroid (HPT) axis controls the synthesis of thyroid hormones through feedback mechanisms.⁶ When thyroid hormone levels fall below a threshold level, the hypothalamus synthesizes thyrotropin-releasing hormone (TRH), which then stimulates thyroid cells to synthesize thyroid hormones.

Vitamin D and parathyroid hormone (PTH) are involved in regulating calcium and bone formation. Vitamin D increases calcium absorption from the small intestine, inhibits parathyroid hormone (PTH), and reduces calcium excretion by the kidneys, ultimately increasing calcium levels in the blood and promoting bone formation, growth, and maintenance.⁷

Autoimmune thyroid diseases, such as Hashimoto’s thyroiditis (hypothyroidism) and Graves’ disease (hyperthyroidism), are characterized by thyroid lymphocytic infiltration.⁸ A meta-analysis observed a significant decrease in 25(OH)D levels in patients with Hashimoto’s thyroiditis. Similarly, another study found that vitamin D deficiency is associated with the development of Graves’ disease in elderly people. Animal models of Graves’ disease and thyroiditis have shown that vitamin D supplementation is effective in alleviating these conditions.⁹

Vitamin D regulates the activity of many immune cells and is involved in immune cell regulation. Mechanistically, vitamin D receptor (VDR) and 1α-hydroxylase are expressed in immune cells, namely T and B lymphocytes, monocytes, dendritic cells, and neutrophils, and involve the production of calcitriol. Vitamin D promotes the production of anti-inflammatory cytokines (IL-4, IL-5, IL-10, etc.) and inhibits the production of pro-inflammatory cytokines (IL-6, IL-8, IL-9, IL-12, IFN-γ, TNF-α, etc.). Multiple In vitro and In vivo Studies have shown that vitamin D has a positive effect in treating thyroid cancer.^Ten

Vitamin D and male hormones

25(OH)D levels regulate several enzymes involved in the production of steroid hormones, including adrenal steroid hormones, sex hormones, and sex hormone signaling. Vitamin D metabolizes enzymes in the human testes and ejaculatory duct and is also associated with sperm maturation.

The experimental findings highlight the possibility that vitamin D may play a role in male fertility through the synthesis of male reproductive hormones.¹¹ Mendelian randomization analysis revealed a causal relationship between vitamin D deficiency and testosterone levels. In this study, genetically reduced 25(OH)D levels were associated with reduced testosterone levels. Another cross-sectional study confirmed this finding and highlighted a positive correlation between 25(OH)D levels and total/bioavailable testosterone levels. Men with low serum 25(OH)D levels, especially below 25 nmol/L, also had low testosterone levels.

Vitamin D and mental health

These observations have attracted a great deal of attention from the scientific community, which is seeking to better understand the potential impact of this vitamin on male reproductive function. Although further research is needed to understand how age, genetic variations, seasonal variations, and timing of measurements affect testosterone levels, recent studies have demonstrated that vitamin D supplementation boosts testosterone levels. Future studies should also focus on the therapeutic effects of vitamin D in alleviating problems related to male fertility.

Vitamin D and female hormones

Vitamin D influences estrogen and progesterone levels, which affect menstrual regularity, menopause, fertility, and pregnancy.¹² Animal studies have demonstrated that 25(OH)D deficiency reduces reproductive rates, impairs mating behavior, and stunts the growth of newborns.

Decreased maternal vitamin D levels are associated with poor maternal and fetal outcomes, including gestational diabetes, low birth weight, preeclampsia, and small-for-gestational-age fetuses. Many women experience polycystic ovary syndrome (PCOS), a heterogeneous endocrine disorder that causes female infertility and is associated with hyperandrogenism. Several studies have observed serum vitamin D deficiency in patients with PCOS. Mechanistically, vitamin D deficiency may affect insulin secretion and insulin resistance, leading to PCOS.

Studies have shown a link between Vitamin D and the biosynthesis of reproductive hormones. An inverse correlation between Vitamin D levels and androstenedione, anti-Mullerian hormone, and Follicle-stimulating hormone (FSH)/Luteinizing hormone (LH) has also been found. Recent studies have recommended that women with PCOS take 400 IU of Vitamin D supplements and 1000 mg of calcium daily for three months to improve fertility and other PCOS symptoms.

References

1. Institute of Medicine Committee to Review Dietary Reference Intakes for Vitamin D and Calcium, Ross AC, Taylor CL, Yaktin AL, et al. (eds.). Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press, 2011. 3. Vitamin D Overview. Available from: https://www.ncbi.nlm.nih.gov/books/NBK56061/.
2. Voltan G, Cannito M, Ferrarese M, Ceccato F, Camozzi V. Vitamin D: an overview of gene regulation from metabolism to genomic effects. gene. 2023;14(9):1691. https://doi.org/10.3390/genes14091691
3. Bikle DD. Vitamin D metabolism, mechanisms of action, and clinical applications. Chemistry and Biology. 2014;21(3):319-329. doi:10.1016/j.chembiol.2013.12.016 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968073/
4. Han, F., Wang, Y., Li, J., Li, Z., Mu, D., He, L., and Zhang, J. (2023). Hygiene Petrography = Hygiene Research Journal52(1), 129–135. https://doi.org/10.19813/j.cnki.weishengyanjiu.2023.01.022
5. Chacar FC, Kogika MM, Zafalon RVA, Brunetto MA. Vitamin D metabolism in chronic kidney disease and its role in mineral and bone diseases in humans, dogs, and cats. Metabolites. 2020;10(12):499. https://doi.org/10.3390/metabo10120499
6. Feldt-Rasmussen, U., Effraimidis, G., & Klose, M. (2021). The hypothalamic-pituitary-thyroid (HPT) axis and its role in the physiology and pathophysiology of other hypothalamic-pituitary functions. Molecular and Endocrinology, 525, 111173. https://doi.org/10.1016/j.mce.2021.111173
7. Khundmiri SJ, Murray RD, Lederer E. PTH and vitamin D. Physiology. 2016;6(2):561-601.. doi:10.1002/cphy.c140071
8. Vieira IH, Rodrigues D, Paiva I. Vitamin D and autoimmune thyroid disease – cause, effect or vicious circle? Nutrients. 2020;12(9):2791.. doi:10.3390/nu12092791
9. Babić Leko M, Jureško I, Rozić I, Pleić N, Gunjača I, Zemunik T. Vitamin D and the thyroid gland: a critical review of the current evidence. International Journal of Molecular Science. 2023;24(4):3586.. doi:10.3390/ijms24043586
10. Gallo D, Baci D, Kustrimovic N, et al. How does vitamin D affect immune cell crosstalk in autoimmune diseases? International Journal of Molecular Science2023;24(5):4689. doi:10.3390/ijms24054689
11. de Angelis C, Galdiero M, Pivonello C, et al. “The role of vitamin D in male fertility: focus on the testis” Rev Endocrine and metabolic disorders2017;18(3):285-305. doi:10.1007/s11154-017-9425-0
12. Kolcsár M, Berecki B, Gáll Z. Relationship between serum 25-hydroxyvitamin D levels and hormonal status in infertile women: a retrospective study. Diagnosis (Basel)2023;13(19):3024. doi:10.3390/diagnostics13193024

References