A 2020 study by Wise et al. found no association of UF incidence with dietary Vitamin A intake (i.e., salad greens, carrots, spinach, sweet potatoes, eggs, cheese, and cereal products) ^[1][12]. These results were generated within a particular racial group of women and as such might be worth exploring in the remaining population. Previously, in 2011, Wise et al. observed an inverse correlation between dietary intake of Vitamin A and the risk of UFs. They noted that it was predominantly conditioned by preformed Vitamin A derived from animal sources (i.e., liver and milk), but not by provitamin A from fruit and vegetable sources (i.e., carrots, sweet potatoes/yams, and collard greens) ^[2][16]. These findings may complement the molecular study of Heinonen et al. who showed that levels of vitamin A were specifically reduced in leiomyomas of the MED12 subtype ^[3][4], yet appeared to be contradictory to conclusions drawn by Martin et al. who noted positive, statistically significant, and dose-dependent association between vitamin A and uterine fibroid risk, except for the population of Hispanic women ^[4][18].

A possible explanation for the positive association between Vitamin A and the risk of UFs is that exposure to high levels of Vitamin A can activate peroxisome proliferator-activated receptors (PPARs). These nuclear receptors, in combination with retinoid X receptors, can activate gene expression, and thus simultaneously increase the risk of UFs in some women ^[4][18]. Retinoids are small molecule derivatives of Vitamin A. Studies have shown that the retinoid pathway is significantly altered in fibroids compared to normal myometrium. Retinol requires conversion to retinoic acid (RA), which requires the activity of specific enzymes. In fibroid fibroblasts, aldehyde dehydrogenase (ALDH1) has been specifically identified as one of them. Studies concluded that alterations in the retinoid pathway could lead to abnormal RA production and signaling, which might be important in fibroid development ^[5][6][7][8][38,39,43,44]. Zaitseva reports that transcription factor II (known as NR2F2) and CTNNB1(b-catenin) genes are potentially causal factors in the development of UFs ^[9][45]. According to her research, the combination of RA and progesterone regulates NR2F2 expression and thus affects fibroid growth. This suggests that retinoids, by causing these molecular alternations, may be useful in the treatment of UFs. In their in vitro studies, Ben-Sasson et al. and Malik et al. demonstrated decreased cell proliferation, ECM formation, RA metabolism, transforming growth factor beta (TGF- β) regulation, and increased apoptosis in human leiomyoma treated with retinoic acid (ATRA-all-trans-retinoic acid) ^[10][11][40,41]. Broaddus et al. showed, again in vitro, that treatment with 4-(N-hydroxyphenyl)-retinamide (4-HPR) or a-difluoromethylornithine (DFMO) resulted in growth inhibition of primary cultures of human uterine leiomyoma ^[12][37]. 4-HPR is a synthetic retinoid analog that, in comparison to other retinoids, has a reduced toxicity potential. It promotes apoptosis and induces growth inhibition through induction of p53, p21, and p16, and modulation of extracellular matrix in human uterine leiomyomas. It was noted that the mechanisms of growth inhibition and apoptosis induction could be independent of binding to nuclear retinoid receptors ^[12][37].

The above results suggest that a diet rich in Vitamin A and retinoids can prevent fibroids and inhibit tumor growth. Synthetic retinoid analogues can also be effective.

Vitamin E is a potent antioxidant that acts by scavenging lipid hydroperoxyl radicals and so can protect cells from the effects of free radicals ^[13][46]. Food sources of Vitamin E include canola oil, olive oil, almonds and peanuts, meat, dairy, leafy greens, and fortified cereals. It is also available in oral supplements. Little data is available on Vitamin E and its effects on UFs. Wise et al. found no associated risks with consumption of diet-derived Vitamin E ^[2][16]. Martin et al. highlighted a positive, dose-dependent link between vitamin E and the incidence of UFs; the findings were, however, not statistically significant ^[4][18]. Ciebiera et al. showed higher serum concentration levels of α-tocopherol (the most common form of vitamin E) in Caucasian women, which may be an important factor in fibroid development ^[14][47].

Vitamin E, despite its antioxidant properties, appears not to demonstrate proven beneficial effects in terms of leiomyoma prevention and management.

Vitamin D is obtained mainly from sun exposure (skin synthesis), food (oily fish such as trout, salmon, tuna, mackerel, and fish liver oils), and vitamin supplements. Prohormonal forms of vitamin D require hydroxylation in the liver to 25-hydroxyvitamin D (25(OH)D) and in the kidney to their active form, that is 1,25-dihydroxyvitamin D (1,25(OH)₂D₃). Vitamin D₃ exerts its biological functions by interacting with and activating the nuclear vitamin D receptor (VDR). In vitro studies point toward uterine myoma cells exhibiting lower levels of VDR expression ^[15][16][48,49]. In addition, a negative correlation between decreased levels of vitamin D receptor (VDR) and increased levels of estrogen and progesterone receptors (ER-α, PR-A, PR-B) was observed in myoma tumors ^[17][50]. It is estimated that Vitamin D deficiency affects 25–50% (possibly more) of patients ^[18][51]. Several studies found that insubstantial levels of Vitamin D can contribute to the development of UFs in African American, Caucasian, and Asian women alike ^{[19][20][21][22][23][24][25][26][27]}[52,53,54,55,56,57,58,59,60]. Vitamin D₃ deficiency activates fibroid cell growth, exacerbates DNA damage, and reduces DNA repairability; it promotes uncontrolled proliferation and fibrosis, and increases chronic inflammation. In combination, these processes are highly tumorogenic ^[28][29][61,62]. Othman et al. demonstrated that, in comparison to normal myometrium, myoma tissue contains significantly lower concentrations of 1,25(OH)₂D₃. Additionally, an overexpression of 24-hydroxylase was found in myoma, which may further suppress the anti-tumor effect of 1,25(OH)₂D₃ and exacerbate vitamin D deficiency in the tissue ^[30][63]. A recent study by Ciebiera et al. revealed an inverse correlation between lower 25(OH)D serum concentrations and increased serum transforming growth factor β3 (TGF-β3) concentrations in women affected by fibroids ^[31][64]. This growth factor can be associated with increased fibrosis and ECM accumulation in myoma ^[32][33][65,66]. Findings on inverse correlation between serum levels of 25(OH)D and fibroid volume vary, ranging from significant to insignificant association ^[19][34][35][52,67,68]. No correlation was however observed between 25(OH)D serum levels and number of fibroids ^[34][67]. Some data suggest that Vitamin D supplementation reduces leiomyoma cell proliferation and thus prevents leiomyoma growth ^{[23][36][37][38]}[56,69,70,71]. A significant downregulation of ER-α, PR-A, PR-B, and steroid receptor coactivators in human myoma cells may be one of the mechanisms—an effect similar to that observed during the course of hormone therapy with GnRH analogues and ulipristal acetate (UPA) ^[17][39][40][50,72,73]. Halder et al. and Li et al. point to the antifibrotic activity of Vitamin D ^[41][42][74,75]. Vitamin D₃ inhibited TGF-β3-induced protein expression and all TGF-β3-mediated effects involved in the fibrotic processes in leiomyoma. Other studies indicate that increasing Vitamin D levels by one unit can reduce the risk of developing UFs by 4–8% ^[26][31][59,64]. Hajhashemi et al. confirmed a significant decrease in leiomyoma size after 10 weeks of vitamin D administration ^[43][76]. A slight, statistically insignificant reduction in fibroid volume after a short-term Vitamin D supplementation was observed by Arjeh et al. ^[44][77], Davari Tanha et al. ^[45][78], and Suneja et al. ^[46][79] in patients with hypovitaminosis D (12, 16, and 8 weeks, respectively). Ciavattini et al. reported a similar effect after 12 months of Vitamin D₃ supplementation ^[34][67]. Vitamin D₃ supplementation may inhibit the growth of UFs, reduce fibroid-related symptoms, and reduce the need for surgical or medical treatment for progression of fibroids ^[34][45][46][67,78,79]. Especially, a long-term course of treatment can have antiproliferative, antifibrotic, and proapoptotic effects in leiomyoma, as demonstrated by Corachán et al. ^[47][80], a finding consistent with other studies in vitro ^[28][41][42][61,74,75]. Beside apoptosis induction, Vitamin D suppresses catechol-O-methyltransferase (COMT) expression and activity in myoma cells—an enzyme that plays a vital role in myoma formation ^[41][74]. In fact, physiological concentrations of vitamin D can effectively inhibit the growth of myoma cells ^[28][61]. 1,25(OH)₂D₃ can significantly reduce the expression of ECM-associated proteins and structural actin fibers in human leiomyoma cells, as observed by Halder et al. ^[15][48]. This effect was a consequence of previous significant induction of nuclear vitamin D receptor (VDR) expression by 1,25(OH)₂D₃ in a concentration-dependent manner. In another study, Halder et al. observed a significant reduction in MMP-2 and MMP-9 mRNA levels, as well as a reduction in MMP-2 and MMP-9 protein levels in uterine fibroid cells in a concentration-dependent manner and concluded that through this mechanism, 1,25(OH)₂D₃ might limit fibroid growth and ECM deposition ^[48][81]. Al-Hendy et al. observed that 1,25(OH)₂D₃ spontaneously induced its own VDR, while significantly downregulating the expression of sex steroid receptors (ERs and PRs) and receptor coactivators, which affected myoma formation and growth; hence, 1,25(OH)₂D₃ suppressed estrogen-induced proliferation in leiomyoma cells ^[17][50]. Cell proliferation and extracellular matrix production in myoma tumors can be affected by Vitamin D as it can suppress tumor-promoting Wnt4/β-catenin expression and reduce activation of mTOR signaling in human UF cells ^[49][82]. As observed by Corachán et al., Vitamin D inhibits the Wnt/β-catenin and TGFβ pathways, reducing proliferation and extracellular matrix formation, in different molecular subtypes of uterine myomas (MED12-mutated and wild-type human tumors) ^[50][83]. Ali et al. hypothesized that myoma tumor progression might be inhibited by recovering the damaged DNA repair system ^[51][84]. They showed in vitro that vitamin D₃ treatment significantly reduces DNA damage, restores the normal DNA damage response, and is accompanied by induction of VDR in fibroid cells ^[51][84]. DNA repair in cells exposed to classic DNA damage inducers in UF pathogenesis (endocrine-disrupting chemicals -EDCs) was achieved by a 1,25(OH)₂D₃ treatment of myoma cells in animal models ^[52][85]. Clinical trials show promising results in patients with UFs and hypovitaminosis D treated with Vitamin D₃ supplementation, revealing a significant decrease in tumor size and numbers ^[43][53][76,86]. At the time of the review, search results pointed to a randomized trial (RCT) being conducted in women at reproductive age affected with uterine myoma, aiming to evaluate whether supplementation with Vitamin D₃ could reduce the risk and inhibit the growth of fibroids ^[54][87]. Results of the evaluation of Vitamin D₃ effects in this particular group of women can be of value in everyday gynecological practice.

Paricalcitol, an analog of 1,25(OH)₂D₃, has less calcemic activity and, therefore, appears to be safer in long-term use than 1,25(OH)₂D₃. Halder et al. study indicates that treatment with paricalcitol has an inhibitory effect on uterine fibroid cell proliferation ^[36][69]. On a murine model, both paricalcitol and 1,25(OH)₂D₃ significantly reduced fibroid size, but paricalcitol was more potent. Porcaro et al. observed a significant reduction in myoma volume and overall improvement in quality of life in patients treated with a combination of Vitamin D, EGCG, and vitamin B6 ^[55][88]. This combined supplementation treatment presents as quite an innovative approach to treating leiomyoma with oral supplementation. Shen et al., on the other hand, arrived at contrary conclusions. In their study, Vitamin D supplementation had no effects on the risk of UFs ^[56][15].

A study by Güleç et al. determined the association between Vitamin D receptor polymorphisms and the occurrence of uterine myomas ^[57][89]. It shows that among the fok1 polymorphisms of the vitamin D receptor, the presence of the CC fok1 genotype may be a risk-reducing factor, and the T allele may increase the risk of uterine myomas. A recent study by Fazeli et al. evaluated CYP24A1 gene expression in uterine myoma tissue ^[58][90]. CYP24A1 is a mitochondrial enzyme that catalyzes the degradation of 1,25(OH)₂D₃ to its less active 25-D3 form and regulates the amount of active Vitamin D in tissues. The expression of CYP24A1 in leiomyoma suggests that local degradation of 1,25(OH)₂D₃ may also have a role in fibroma development.

Overall, Vitamin D₃ may be a promising option in prevention and treatment of UFs. The majority of presented studies consider treatment with Vitamin D₃ as safe and effective.