Vitamin D3: Mechanism of Action and Role in Folliculogenesis Regulation

General Description

Vitamin D3, synthesized through skin exposure to UV-B radiation, undergoes hydroxylation to form the active metabolite calcitriol. Acting through the vitamin D receptor (VDR), calcitriol regulates gene expression, impacting various cellular processes. Alternative pathways involving membrane-associated proteins like MARRS offer additional signaling mechanisms. In female fertility, Vitamin D3 plays a crucial role in folliculogenesis regulation by influencing AMH secretion, ovarian morphology, and granulosa cell proliferation. Studies on knockout models and in vitro experiments highlight its significance in maintaining ovarian function and promoting successful oocyte maturation. Vitamin D3's multifaceted effects underscore its importance in cellular homeostasis and fertility-related processes.

Figure 1. Vitamin D3

Mechanism of Action

Synthesis and Circulation

Vitamin D3, or cholecalciferol, primarily originates from endogenous synthesis in the skin upon exposure to ultraviolet-B irradiation. This process involves the conversion of 7-dehydrocholesterol to previtamin D3, subsequently isomerizing to form biologically inactive vitamin D3. After release from keratinocytes, it enters the bloodstream bound to vitamin D binding proteins and undergoes hydroxylation in the liver and kidneys to form the active metabolite, 1α,25-dihydroxycholecalciferol or calcitriol. Despite variations in circulating calcitriol levels, calcidiol is considered a more reliable marker due to its stable concentration and lack of regulatory mechanisms.

Activation by VDR

The biological effects of calcitriol are exerted through the vitamin D receptor (VDR), a ligand-activated transcription factor belonging to the steroid receptor superfamily. Upon binding to calcitriol, VDR heterodimerizes with the retinoid X receptor and translocates to the nucleus to bind to vitamin D3 response elements, thereby regulating the expression of target genes. Various co-regulators participate in modulating transcription, while structural studies have identified distinct ligand binding sites in VDR, influencing genomic and non-genomic responses. Additionally, VDR localization within cellular compartments, such as caveolae, can lead to rapid cellular responses through interactions with G proteins, kinases, and ion channels.

Alternative Pathways of Signaling

Recent research has revealed alternative mechanisms of 1α,25-dihydroxycholecalciferol action involving membrane-associated proteins like MARRS (Membrane-Associated Rapid Response Steroid). These proteins, including GRP58, ERp57, and Pdia3, situated within caveolae, interact with VDR to initiate specific cellular responses beyond traditional genomic regulation. Understanding the diverse pathways of vitamin D3 signaling provides insights into its multifaceted roles in maintaining cellular homeostasis and influencing various physiological processes. ¹

Role in Folliculogenesis Regulation

Influence on Anti-Müllerian Hormone (AMH) and Ovarian Reserve

Vitamin D3 has emerged as a crucial regulator in female fertility through its impact on the ovarian reserve and the secretion of anti-Müllerian hormone (AMH). Studies demonstrate a positive correlation between plasma 25(OH)D3 levels and AMH concentration, implicating Vitamin D3 in maintaining the ovarian reserve by modulating follicular recruitment. Vitamin D3's influence on AMH gene expression, possibly mediated through the VDRE sequence in the AMH gene promoter, highlights its role in fine-tuning hormonal balance within follicular cells.

Effects on Ovarian Morphology and Development

Experimental models, particularly Vdr- and Cyp27b1-knockout mice, showcase Vitamin D3's pivotal role in follicular development and ovulation. Phenotypes like altered ovarian morphology, compromised follicular growth, and impaired ovulatory processes in these knockout models underscore Vitamin D3's significance in maintaining normal ovarian function. Furthermore, in vitro studies on primate follicles reveal dose-dependent effects of 1α,25(OH)2D3 on oocyte growth and differentiation, emphasizing Vitamin D3's dual influence on early and late stages of folliculogenesis.

Regulation of Granulosa Cell Proliferation and Differentiation

Vitamin D3's impact extends beyond hormonal regulation to the intricate mechanisms governing granulosa cell proliferation and differentiation. Evidence from studies on goat and hen granulosa cells signifies Vitamin D3's role in modulating oxidative stress, gene expression related to cell cycle regulation, and overall proliferation of granulosa cells. This intricate interplay suggests that Vitamin D3 exerts multifaceted effects on folliculogenesis, orchestrating a delicate balance in the ovarian microenvironment critical for successful oocyte maturation and fertility. ²

Reference

1. Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol. 2014; 21(3): 319-329.

2. Grzesiak M. Vitamin D3 action within the ovary - an updated review. Physiol Res. 2020; 69(3): 371-378.

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