2.1. Literature Search/Data Source/Search Criteria

A narrative review of our literature search methodology, we conducted a review search using Ovid Medline, OVID EMBASE, OVID Cochrane Library, PubMed, Scopus, and Web of Science databases, focusing on studies published up to 2024. We employed a combination of keywords, including “Vitamin D,” “Women’s menstrual phases,” “Menstrual cycle,” “Hormonal regulation,” and “Reproductive health,” using Boolean operators (AND, OR) to refine our search strategy. Our eligibility criteria were stringent, including only peer-reviewed articles that specifically explored the relationship between vitamin D and menstrual phases in women, with studies available in English. Reviews, meta-analyses, and editorials were excluded to ensure the inclusion of primary research articles. The search process involved title and abstract screening, followed by a full-text review to assess eligibility. Key data points, such as study design, population characteristics, and main findings, were extracted.

2.2. Plan and Protocol

This review was planned by Dr. Rajeshkumar Shanmugam, and the study was protocolized by Dhanyaa Muthukumaran. The data extraction procedure was implemented by the authors. They employed the study’s objective, type, details, vitamin D, and reproductive health.

2.3. Review and Categorization

To ensure a thorough analysis of the literature, we conducted a narrative review and categorization of the identified studies. After the initial data extraction, studies were categorized based on key themes such as the impact of vitamin D on different menstrual phases, its role in hormonal regulation, and its overall effect on reproductive health. Each study was evaluated for its methodological quality, and studies with robust designs were prioritized in the synthesis of evidence. The categorization process also involved grouping studies according to the specific outcomes measured, such as changes in hormone levels, menstrual regularity, and reproductive health indicators. This approach allowed for a structured and narrative review, ensuring that the findings presented in our paper are well-organized and reflective of the current state of research on the relationship between vitamin D and menstrual phases in women.

3.1. Synthesis of Vitamin D

When the human body is exposed to UVR from the sun, it undergoes a process to synthesize vitamin D. This synthesis occurs precisely when the incoming UV radiation has wavelengths shorter than 315 nanometers (nm) [4]. On the other hand, Vitamin D₃, or cholecalciferol, is produced within the epidermis when 7-dehydrocholesterol is exposed to UVR [6]. Research indicates a complex interplay between skin color and vitamin D deficiency. Melanin, the pigment responsible for skin coloration, is a significant factor influencing vitamin D production. Melanin absorbs UVR, which is necessary for initiating vitamin D synthesis [19]. Consequently, individuals with darker skin, characterized by higher melanin levels, require increased sun exposure to generate equivalent vitamin D levels compared to those with lighter skin. This heightened reliance on sun exposure for adequate vitamin D synthesis contributes to a greater risk of deficiency in people with darker skin. However, skin pigmentation is just one facet of the intricate equation governing vitamin D levels [20]. Other variables such as available UVB radiation, exposure time, exposure pattern, skin area exposed, and age also impact vitamin D synthesis. Considering these factors is essential when determining the suitable amount of sun exposure or vitamin D supplementation needed to maintain optimal vitamin D levels [21]. Consulting a healthcare provider becomes crucial to navigating this complexity and ensuring personalized recommendations. For individuals with darker skin aiming to enhance their vitamin D levels, a multifaceted approach is recommended. Increasing sun exposure, especially during peak hours when the sun is at its peak, can be beneficial. However, caution is advised to avoid overexposure and mitigate the risk of skin cancer. Dietary adjustments, such as incorporating vitamin D-rich foods like fatty fish, egg yolks, and fortified items such as milk and cereal, can contribute to an improved vitamin D status [22].

Supplementation emerges as another viable option, with vitamin D supplements serving as a practical means to address deficiency. Nevertheless, the dosage should be determined in consultation with a healthcare provider, considering individual factors and requirements [23]. In summary, while skin pigmentation significantly influences vitamin D production, a comprehensive approach considering various factors and tailored guidance from healthcare professionals is imperative to effectively manage and prevent vitamin D deficiency, particularly in individuals with darker skin. The synthesis of vitamin D in the body involves a two-step process. Initially, vitamin D is hydroxylated in the liver, forming 25-hydroxy vitamin D₃, denoted as 25[OH]D₃ [24]. Subsequently, 25[OH]D₃ is further converted into its active form, 1,25-dihydroxy vitamin D₃, represented as 1,25[OH]₂D₃. The impact of latitude on vitamin D production is crucial in understanding the dynamics of maintaining optimal vitamin D levels. Latitude exerts a direct influence on the availability of UV radiation, a key factor in the synthesis of vitamin D. As one moves towards higher latitudes, there is a notable decrease in the amount of UV radiation, particularly during the winter months. This reduction in UV radiation poses a challenge for vitamin D synthesis in humans, necessitating a larger dose of UV relative to erythemal UV to produce an equivalent amount of vitamin D. Consequently, individuals residing at higher latitudes may encounter difficulties sustaining adequate vitamin D levels solely through sun exposure. Conversely, within the latitudinal range of 40° North to 40° South, there exists a relatively high and certainly sufficient presence of UVB radiation [25]. This signifies that sunlight exposure can serve as a primary and effective source of vitamin D production in tropical regions falling within this latitude belt. The consistent availability of UVB radiation in these areas supports the synthesis of vitamin D in the skin, reducing the reliance on alternative methods. The implications of latitude on vitamin D levels underscore the significance of geographical location in determining the effectiveness of sun exposure in obtaining this essential nutrient. Individuals residing at higher latitudes may find relying solely on sunlight to maintain adequate vitamin D levels challenging. In such cases, incorporating dietary sources rich in vitamin D and considering supplementation become crucial strategies to ensure a sufficient supply of this vital nutrient. The latitude-dependent variations in UV radiation thus highlight the need for tailored approaches to address vitamin D requirements, considering geographical considerations for individuals residing at different latitudes.

3.2. Food Sources

Fortified foods may contain either vitamin D₃ (cholecalciferol) or vitamin D₂ (ergocalciferol), both of which are forms of vitamin D. These vitamins are predominantly found in animal-derived products. Here are the approximate vitamin D content levels in various food sources (Table 2) [8, 31].

3.3. Vitamin D Safety Levels

Utilizing the optimal vitamin D supplement dosage is of paramount importance. Toxicity concerns typically arise when daily doses exceed 10,000 IU (International Unit) [32]. Conversely, the administration of dosages exceeding 50,000 IU per day over several weeks or months is frequently associated with severe adverse effects, notably confirmed hypercalcemia [3]. It is noteworthy that the majority of documented cases of vitamin D toxicity have involved daily intakes exceeding 40,000 IU [32].

The impact of vitamin D supplementation, either as a standalone treatment (with doses ranging from 1000 IU per day to 60,000 IU per week) or in conjunction with co-supplements, was examined in a recent comprehensive analysis published in 2018. The study compared the effects of these interventions to the use of placebos in a cohort of women diagnosed with polycystic ovary syndrome (PCOS) [33]. The study included 11 studies, including a sample of 601 women diagnosed with PCOS. The results indicated that the administration of vitamin D supplements substantially reduced fasting glucose levels and enhanced the HOMA-IR score within this particular group.

Evidence derived from randomized controlled trials indicates that continuous low doses of vitamin D at 4000 IU per day or the supplementation of vitamin D as a cotreatment for individuals with PCOS may lead to enhancements in insulin sensitivity. More precisely, there have been noticeable enhancements in fasting glucose levels (when vitamin D is added alongside other micronutrients) and HOMA-IR scores (when vitamin D is given in consistently low daily dosages or as a supplementary treatment) [2]. Furthermore, administering higher doses of vitamin D, exceeding 4000 IU per day, for at least 12 weeks has been associated with favorable outcomes. This dosage regimen has beneficial effects on glucose levels, insulin sensitivity, hyperlipidemia, and hormonal balance [34]. It is imperative to take into account various population parameters such as body mass index (BMI), ethnicity, as well as baseline levels of vitamin D and hormones when making decisions regarding the supplementation of vitamin D. These factors play a pivotal role in determining the appropriate and effective dosage for individuals with PCOS [35, 36].

4.1. Low Vitamin D Levels Affect the Menstrual Cycle

1,25[OH]₂D₃ also plays a crucial role in calcium metabolism. In females afflicted with PCOS, the combination of vitamin D insufficiency and disturbances in the body’s calcium regulation mechanisms contributes to the inhibition of ovarian follicular development [46]. There is compelling evidence indicating that vitamin D supplementation may offer potential benefits for individuals with PCOS in managing their menstrual cycles [47].

Furthermore, it is noteworthy that menstrual irregularities, even in women not diagnosed with PCOS, can be influenced by the actions of vitamin D₃ on the production of anti-Müllerian hormone (AMH), which serves as a marker for ovarian reserve [48]. Research findings suggest a correlation between low vitamin D levels and diminished AMH levels. Reduced AMH levels are, in turn, associated with a decline in ovarian reserve and an early-stage increase in follicle-stimulating hormone (FSH) during the menstrual cycle [49]. These interconnected factors can collectively result in a substantial reduction in fertility (Figure 3).

4.2. Stress Affecting Menstrual Health

In menstrual health, vitamin D has emerged as a pivotal player, exerting a significant influence on various aspects of women’s well-being. An extensive study has shed light on its profound impact on women attempting to conceive, especially those facing prolonged challenges in this endeavor [46]. The research indicates that women who have been engaged in the arduous journey of trying to conceive over an extended period tend to experience more pronounced adverse effects on their mental health when they encounter interruptions in their treatment regimen [50]. This highlights the delicate interplay between reproductive health and emotional well-being.

Notably, the number of confidants a woman has in her social circle does not appear to directly correlate with the extent of distress caused by treatment suspensions. Instead, what emerges as a crucial factor is the emotional support she receives, particularly from her partner and other individuals in her network [51]. Those who received more robust emotional support reported a mitigated negative impact on their mental health. This aligns seamlessly with prior research findings that emphasize the link between high-quality social support and reduced distress in the context of infertility [52].

It is worth highlighting that the study uncovered a relatively modest mean number of reported confidants within the surveyed group, with a mere 42% of respondents characterizing their confidants as even “somewhat” helpful in their coping efforts during fertility treatment suspensions. Interestingly, women found their partners to be somewhat more useful, with 58% rating them as at least “somewhat” useful. Additionally, a mere 22% of women reported seeking social support from friends and loved ones “often.” [46]. These statistics collectively point towards a scarcity of accessible, quality social support for the majority of women grappling with the complexities of infertility [53].

In summary, these findings highlight the pivotal role of high-quality social support in alleviating the burdens faced by women navigating the challenging terrain of infertility. However, they also shed light on the unfortunate reality that such support remains elusive for many of these women. This aligns with previous research, which consistently highlights the prevalence of unsupportive social interactions experienced by women contending with infertility and underscores their role in exacerbating distress in this vulnerable population.

4.3. Vitamin D in Behavioral Regulation

In the realm of brain health and function, vitamin D emerges as a multifaceted player, exerting its influence through diverse mechanisms. Critical to this involvement is the VDRs residing within the cellular nucleus, orchestrating the expression of target genes upon binding to the active form of vitamin D. Remarkably, VDRs find their expression in key cerebral regions integral to behavioral regulation, encompassing the cortex, cerebellum, and limbic system [54]. In illuminating animal models, genetically modified mice with impaired VDRs manifest striking anomalies in brain morphology, and reduced levels of neural growth factors exhibit behavioral deviations that include heightened anxiety, diminished grooming behaviors, and impaired social interactions [51]. In another context, a compelling observation emerges, a significant majority of women, specifically 82%, fall short of meeting the recommended dietary allowances (RDAs) for vitamin D [55]. Intriguingly, a discernible correlation comes to the fore, as the consumption of ≥400 IU of vitamin D per day aligns with superior mental health-related quality of life (QOL) scores in comparison to those who intake less than 400 IU daily [56]. This underscores the proposition that adhering to established dietary guidelines for vitamin D intake holds promise to enhance overall well-being, particularly in older women [51]. Furthermore, the intricate interplay between vitamin D and mental health extends to the modulation of brain-derived neurotrophic factor (BDNF), a pivotal protein encoded by the BDNF gene. Vitamin D emerges as a critical player in the intricate landscape of brain health, exerting influence through various mechanisms that impact neuronal growth, survival, and cognitive function. One of the pivotal aspects of vitamin D’s role in brain health is its involvement in the production of BDNF, a protein crucial for the growth and maintenance of neurons [57]. Studies have unveiled the presence of VDRs in the brain, emphasizing the direct regulatory role of vitamin D in the expression of genes associated with neuronal growth and differentiation, including those contributing to BDNF production [58]. The administration of vitamin D₃ has been linked to elevated BDNF levels, correlating with improved memory and reduced concentrations of Aβ (amyloid beta) in the hippocampus. This suggests a potential avenue for utilizing vitamin D as a modulator of cognitive function and memory [59]. Furthermore, vitamin D exhibits anti-inflammatory properties, which may contribute to BDNF production. Chronic inflammation has been associated with decreased BDNF levels, and the ability of vitamin D to mitigate inflammation may play a role in enhancing BDNF production [60]. However, the relationship between vitamin D and BDNF is intricate and context-dependent, as evidenced by contradictory findings in studies on depressed rats, where vitamin D did not consistently affect BDNF protein levels in the hippocampus [61]. Correlation studies in individuals with type 2 diabetes mellitus further complicate the understanding of the vitamin D–BDNF relationship [62]. While some studies indicate a positive effect of vitamin D on BDNF levels, others report contradictory or non-significant effects [61], highlighting the need for comprehensive exploration in diverse contexts.

In summary, the association between vitamin D and BDNF production is multifaceted, encompassing the regulation of gene expression, anti-inflammatory properties, and context-dependent effects. Although numerous studies demonstrate a positive correlation between vitamin D and BDNF levels, the intricacies of these interactions and the impact of various conditions on this relationship necessitate further investigation to comprehensively understand the role of vitamin D in brain health.

Empirical evidence accentuates the significance of BDNF, as deficiencies in this protein have been linked to age-related declines in spatial learning, neurodegenerative processes, cognitive impairment, and the emergence of depression [63]. Consequently, the profound implications of vitamin D resonate not only within the domain of menstrual health but also as a potential avenue for bolstering neurological and mental well-being. It underscores the critical importance of meeting dietary recommendations for vitamin D intake, especially for older women, as a means to promote holistic health [52].

Vitamin D’s potential to positively impact human mental health is postulated to be mediated through its regulatory influence on systemic inflammation [64]. An insightful review article, drawing from the insights of five extensive cross-sectional studies, has unearthed compelling evidence of significant inverse associations between 25(OH)D levels and markers of inflammation [65, 66]. These associations have been particularly pronounced in individuals with low 25(OH)D concentrations and adults characterized by elevated inflammation levels. A growing body of research has illuminated a strong nexus between vitamin D deficiency and a spectrum of mood disorders. Notable among these are major depressive disorder, seasonal affective disorder (SAD), and PMS. PMS, for instance, encompasses a cluster of distressing symptoms, with one prominent facet being a notably depressed mood during the final week of the luteal phase, occurring close to the onset of menses [67, 68]. The ample evidence suggests that optimizing 25(OH)D levels may contribute to alleviating the burdens of various mood-related conditions, including but not limited to depression, SAD, PMS, postpartum depression, perinatal depression, and depressive disorders, particularly in women of reproductive age. This underscores the potential therapeutic significance of 25(OH)D in managing mental health and highlights the relevance of vitamin D supplementation in promoting emotional well-being (Figure 2).

4.4. Vitamin D-Related Dysmenorrhea

Primary dysmenorrhea, characterized by menstrual pain in the absence of pelvic pathology, adversely impacts individuals’ daily lives, leading to work and school absenteeism, diminished QOL, and increased health and socioeconomic burdens. Its prevalence among menstruating women ranges from 20% to 90%, affecting up to 25% of this population [69]. Several studies have explored the potential of high-dose vitamin D administration in alleviating menstrual pain. Weekly intake of elevated vitamin D doses has demonstrated varying degrees of effectiveness. For instance, a single 300,000 IU dose was found to reduce dysmenorrhea severity in the initial month, while another regimen involving 300,000 IU vitamin D taken 5 days before each menstrual cycle for three consecutive cycles exhibited positive outcomes only in the second and third months post-intervention [70–73]. The biologically active form of vitamin D exerts its impact by diminishing prostaglandin production within the endometrium and influencing prostaglandin receptors, thereby limiting their biological activity [74]. Additionally, vitamin D exhibits anti-inflammatory effects through diverse pathways. Despite these mechanisms, the question remains whether vitamin D can effectively mitigate menstrual bleeding [3]. Some studies have indicated a reduction in the number of individuals experiencing heavy menstrual flow with vitamin D supplementation, although statistical significance was not achieved. Notably, this study’s findings indicate that high doses of vitamin D effectively alleviate menstrual pain but do not influence menstrual bleeding. It is speculated that vitamin D might exhibit more significant efficacy in individuals experiencing severe menstrual bleeding.

4.5. Vitamin D-Related Menorrhagia

Menorrhagia, characterized by a blood loss exceeding 80 mL per menstrual cycle, is a prevalent issue leading to considerable morbidity and diminished QOL among reproductive-aged women [9, 75, 76]. While its origins can be traced to pelvic or systemic pathologies, the etiology remains enigmatic in around half of the affected women. Emerging research underscores a significant interplay between Vitamin D and menstrual cycle disorders. Vitamin D plays a pivotal role in ovarian function and the regulation of the menstrual cycle [3]. Current knowledge firmly establishes that Vitamin D activates the VDR, thereby influencing the expression of approximately 3000 genes across diverse tissue types, including those in female reproductive tissues [10]. The amelioration of menorrhagia through vitamin D supplementation supports the notion that this condition may be mediated by dysregulation in the expression and signaling of endometrial mediators [77]. Notably, vitamin D supplementation has shown efficacy in addressing gynaecological issues such as irregular menstrual cycles and menorrhagia, particularly in women exhibiting low vitamin D levels. Consequently, its administration is recommended for individuals with vitamin D deficiency to harness its regulatory effects on menstrual disorders. It is crucial to recognize that vitamin D deficiency often goes unnoticed by a significant portion of the female population, highlighting the need for enhanced awareness and understanding of this medical condition within communities.

4.6. Other Medications Utilized in Menstrual Health

Menstrual dysfunction is an important symptom of PCOS and is a therapeutic strategy to restore regular menstrual cycles, focusing on ovulation induction and improving insulin sensitivity. Clomiphene citrate (CC) is commonly used as a first-line pharmacological agent to induce ovulation and regulate menstruation. However, in cases where women are resistant to CC, letrozole, an aromatase inhibitor, is more effective in increasing ovulation and menstrual regularity, particularly in women with a higher BMI. Additionally, insulin sensitizers like metformin are frequently employed to enhance menstrual cycle regularity, especially when combined with ovulation-inducing agents. Metformin’s ability to improve insulin sensitivity and reduce hyperinsulinemia has a positive impact on menstrual function, with studies reporting significant improvements in ovulatory cycles and overall reproductive outcomes in women with PCOS [78, 79]. Treatments like oral contraceptives are commonly used to regulate menstrual cycles, but they carry potential side effects, including weight gain and cardiovascular risks [80].