The relationship between fat-soluble vitamins and uterine fibroids: a systematic review

Abstract

Background

Uterine fibroids (UF) is a common gynecology tumor that in some cases may require hysterectomy. It is hypothesized that deficiency in fat-soluble vitamins might be a risk factor for UF. The aim of this systematic review was to evaluate the relationship between fat-soluble vitamins and UFs.

Methods

This systematic review was conducted on published articles in PubMed and Web of Science till Feb 2024 using a comprehensive search strategy.

Results

Of the initial 9161 identified articles, 31 (overall population of 55189 participants), including 17 case-control studies, 6 clinical trials, four cross-sectional studies, three cohort studies, and one Mendelian epidemiological study were reviewed. Majority of the studies evaluated the relationship between serum vitamin D and UF incidence and size. None of the reviewed studies evaluated the relationship between vitamin K and UF.

Conclusions

Vitamin D supplementation and intake of animal sources of vitamin A could reduce UF size. There is not enough evidence regarding the effect of vitamin K and E on UF size.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12905-025-04189-x.

Introduction

Uterine fibroids (UFs) are the most common benign tumors of the female reproductive tract and the leading cause of hysterectomy. The prevalence of UFs is between 30 and 70% in women of reproductive age [1]. The wide range of the prevalence of UFs is due to the differences in genetic and diagnosis criteria of UF. Although UFs are usually asymptomatic, 25 to 50% of the patients may present significant complications like menometrorrhagia, anemia, bladder pressure, digestive problems, and menstrual complications [2]. In addition, UFs are associated with multiple obstetric complications like infertility and early pregnancy loss. Various risk factors have been proposed for UFs [3].

The risk factors for UFs include genetic and familial factors; estrogen receptors and increased estrogen; occupational and environmental factors. The main endogenous factors (genetic factors and oxidative stress) for UFs includes factors that damage the DNA of the uterine tissue, which can trigger the formation, expansion, and increase in the size of UFs. Studies have shown that DNA damage is 15 times more common among women with UFs compared to healthy controls. Compensatory mechanisms exist for uterine cell DNA damage. UF growth can be influenced by the imbalance between DNA damage and repair [4, 5]. Recent studies have reported the role of oxidative stress in the formation of UFs [6, 7]. Oxidative stress can induce or accelerate the formation of UFs through genetic (induction of DNA damage in genetically predisposed individuals), epigenetic (induction of DNA damage in a non-genetically predisposed individual), or profibrotic (induction of cytokines secretion) mechanisms [8]. Therefore, the role of antioxidants have been focused in the prevention and management of UFs [1, 8, 9].

The mechanism of the effect of micronutrients and vitamins on UF growth has been studied in the past two decades. The antioxidant, anti-fibrotic and anti-inflammatory effects of water-soluble vitamins have hypothesized the link between these nutrients and the initiation of some diseases [10]. The low intake of fat-soluble vitamins has been considered to be more important than water soluble vitamins because the low intake of fat-soluble vitamins has been associated with more health complications, including reproductive complications, compared to low intake of water-soluble vitamins in diverse global populations [11]. Although fat-soluble vitamins involve in DNA repair, the effects of fat-soluble vitamins remain unclear and conflicting results have been stated in previous studies [4, 5, 12]. Among the fat-soluble vitamins, vitamin D deficiency has an important role in the initiation of uterine tissue DNA damage. Regardless of the extensive studies conducted in this regard, the exact mechanism of the initial damage has not been fully elucidated [13].

Due to the high prevalence of UFs in women of reproductive age and its importance in women’s reproductive health, this systematic review aims to evaluate the association between low intake of fat-soluble vitamins and the development of UFs in women of reproductive age.

Methods

In order to conduct this systematic review, medical databases PubMed and Web of Science were searched for English-language articles with no time restrictions through February 2024. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was used for the study. The PRISMA checklist guides researchers in organizing the steps of conducting the systematic review as well as data synthesis and interpretation and reporting the overall systematic review in a scientific and comprehensive way [14]. The search terms included “fat soluble vitamins”, “vitamin D”, “vitamin A”, “vitamin E”, “uterine fibroids”, “uterine fibroma”, and “uterine leiomyoma”. Search terms were built using Boolean operators were used to construct a search strategy in PubMed, which was then adapted for Web of Science (Supplementary File 1). Inclusion criteria were full-text articles published in English language that evaluated the relationship between UF characteristics and fat-soluble vitamins based on observational or interventional methods. Outcomes related to UF included size, location, recurrence or incidence and data related to fat-soluble vitamins included serum level or intake of fat-soluble vitamins (vitamin A, D, or E). Furthermore, the reference list of identified articles was hand-searched to increase sensitivity and find possible sources. Exclusion criteria were unavailable full texts and not presenting the required information in the manuscript.

Screening of the articles was performed by two researchers independently. In the first step, the titles and abstracts of the identified articles were screened for eligibility and in the second step, the full texts of the included articles were evaluated for quality, data extraction and synthesis. At the end of each step, the list of articles identified by the researchers was combined and in case of inconsistency, a team including the two researchers and the corresponding author evaluated the articles and made the final decision to include or exclude the article. The full text of the articles were evaluated for quality using the Joanna Briggs Institute (JBI) Critical Appraisal Checklists designed for the reviewed study types (cross-sectional, case-control cohort, and clinical trials). Based on the researchers consensus, Articles that met 75% of the criteria were included in the study.

A checklist was used to extract the data from the included articles (author, publication year, country, sample size, study design, type of vitamin (exposure or intervention), association with UF and general findings) after quality assessment. The findings of the articles were summarized in a Table 1 and were discussed afterwards. As shown in Fig. 1, the flow diagram illustrates the selection process.

Table 1.

Summary of the findings of the included studies

Author	Year	Country	Sample Size	Study Design	Vitamin D Assay Method	Vitamin Measured	Association with UF	Findings
Paffoni et al.[15]	2013	Italy	128/256	Case Control	Chemiluminescence	D	Inverse	Vitamin D deficiency was a predictor for UFs (OR = 2.4, 95% CI: 1.2–4.9, P = 0.016)
Sabry et al.[16]	2013	Egypt	140/50	Case Control	Radioimmunoassay	D	Inverse	Lower serum 25-(OH) Vit D levels were significantly associated with UFs (P = 0.01). Serum 25-(OH) Vit D was inversely correlated with total UF volume (r = − 0.31, P = 0.002)
Ciebiera et al.[17]	2016	Poland	105/83	Case Control	ELISA	D	Inverse	Higher serum 25-(OH) Vit D levels were preventive against UF (OR = 0.96; 95% CI: 0.93–0.99).
Ingala et al.[18]	2016	Congo	216/216	Case Control	Mmunoradiometric Assay (Radioimmunoassay)	D	Inverse (local criteria)	Vitamin D deficiency was significantly more prevalent in UF group compared to the control group when local criteria were used. Based on IOM criteria, vitamin D deficiency did not defer between groups.
Oskovi Kaplan et al.[19]	2018	Turkey	56/68	Case Control	Electrochemiluminescence Immunoassay (ECLIA)	D	Inverse (presence only)	While serum 25-(OH) Vit D levels were significantly lower in UF compared to the control group (p = 0.009), no significant correlation was found between 25-(OH) Vit D levels and size, volume, localization and number of UFs. No significant difference was found in serum 25-(OH) Vit D levels between participants with UF diameter < 40 mm and > 40 mm (p = 0.881), participants with single or multiple UFs (p = 0.962), participants with < 3 or > 3 UFs (p = 0.061).
Ajmani et al.[20]	2018	India	75/75	Case Control	Chemiluminescence Assay	D	Inverse	The mean serum 25-(OH) Vit D level was significantly lower in UF compared to the control group (p = 0.001). Vitamin D deficiency was significantly more prevalent in UF group (42.7%) compared to the control group (20%) (OR = 13.85, 95% CI: 4.82–39.86, p < 0.001). The prevalence of vitamin D insufficiency was significantly higher in the UF (49.3%) compared to the control group (28%) (OR = 11.45, 95% CI: 4.16–31.52, p = 0.001).
Singh et al.[21]	2019	India	72/72	Case Control	Chemiluminescence Immunoassay	D	Inverse	The mean serum 25-(OH) Vit D concentration was significantly lower in UF compared to control group (p < 0.001). The prevalence of severe vitamin D deficiency in the UF group (62.5%) compared to the control group (26.39%) (p < 0.001). Vitamin D sufficiency was significantly lower in the UF group (2.77%) compared to the control group (23.61%) (p = 0.0002). Serum 25-(OH) Vit D was a risk factor for UF (p < 0.001).
Srivastava et al.[22]	2020	India	45/45	Case Control	Chemiluminescence	D	Inverse with prevalence Direct with UF size	The mean serum 25-(OH) Vit D level was significantly lower in UF compared to the control group (p < 0.001). Vitamin D deficiency was significantly more prevalent in the UF compared to the control group (p < 0.001). There was a significant and direct correlation between serum 25-(OH) Vit D level and UF size (p = 0.014).
Farzaneh et al. [23]	2020	Iran	71/77	Case Control	Radioimmunoassay	D	Inverse	Serum levels of 25-(OH) Vit D were significantly lower in UF compared to the control group (p = 0.02). Vitamin D deficiency was significantly more prevalent in UF compared to the control group (p = 0.003).
Sarbhai et al. [24]	2021	India	75/75	Case Control	Chemiluminescence	D	Inverse	The mean serum 25-(OH) Vit D levels in was significantly lower in UF (12.58 + 4.09 ng/mL) compared to the control group (18.99 + 5.72 ng/mL, p < 0.001). There was a significant and inverse correlation between total UF volume (cm3) and serum vitamin D level (ng/mL) (r = − 0.292, p = 0.011).
Mortad A Ahmed et al.[25]	2022	Egypt	40/40	Case Control	Radioimmunoassay	D	Inverse	Serum vitamin D levels were significantly lower in UF (14.80 ± 5.87) compared to the control group (23.39 ± 9.11, P < 0.001).
Chen et al.[26]	2023	China	55/55	Case Control	Radioimmunoassay	D	Inverse	The mean serum 25-(OH) Vit D levels was significantly lower in UF (20.52 ± 6.17 ng/mL) compared to the control group (24.18 ± 6.88 ng/mL, p = 0.004). Vitamin D deficiency was significantly more prevalent in UF (50.91%) compared to the control group (23.64%, p = 0.001). There was a negative correlation between serum 25-(OH) Vit D level and UF volume (r = −0.18, p = 0.20). There was no significant correlation between serum 25-(OH) Vit D level and UF number (p = 0.038) or location (p = 0.89).
Dutta et al. [27]	2023	India	100/100	Case Control	Chemiluminescence Immunoassay	D	Inverse	The mean serum 25-(OH) Vit D levels were significantly lower in the UF (12.66 ± 5.42) compared to the control group (25.91 ± 14.18, p < 0.003). Serum 25-(OH) Vit D < 12 ng/dl was a risk factor for UF (OR = 5.38, 95% CI: 2.12–9.45, p < 0.001).
Ingala et al. [18]	2016	Congo	216/216	Case Control	Local Immunoradiometric Assay (IRMA)	D	Inverse	Vitamin D deficiency was significantly more prevalent in UF (17.7%) compared to the control group (10.2%) only if the local criteria were used for determining vitamin D deficiency (p = 0.028).
Xess et al. [28]	2020	India	60/50	Case Control	-	D	No association	No difference in the baseline vitamin D levels was seen between patients with or without “progression to extensive disease” (p = 0.44). Even in the “control group,” no difference in the baseline 25-(OH) Vit D levels was seen between patients with or without “progression to extensive disease” (p = 0.71).
Ahmed et al. [29]	2022	Egypt	50/40	Case Control	Elisa	D	Inverse	Serum 25-(OH) Vit D concentrations were significantly lower in the UF group compared to healthy controls (p < 0.001). There was a linear negative relationship between 25-(OH) Vit D level and UF size.
All Ansary et al. [30]	2019	Egypt	75/75	Case Control	Automated Electrochemilumecenc Immuno Assay ECLIA (Cobas _E_Immuno-Analyser)	D	Inverse	The mean 25-(OH) Vit D levels was significantly lower in the UF group compared to the control group (p = 0.001). There was no significant difference in UF size between low and normal vitamin D groups. Vitamin D deficiency was significantly more prevalent in UF group (80%) compared to the control group (14.7%) (OR = 7.75). The prevalence of vitamin D insufficiency was significantly higher in UF group compared to the control group (OR = 1.3, p = 0.001).
Rahmanian et al. [31]	2018	Iran	51	Double-Blind Clinical Trial	-	D	Beneficial	Four months of treatment with vitamin D, resulted in a significantly greater reduction in UF size and PBAC compared to the control group (p = 0.014 and p = 0.02, respectively).
Vahdat et al. [32]	2022	Iran	109	Double-Blind Clinical Trial	-	D	Beneficial	One year administration of vitamin D supplements reduced UF recurrence rates by 50% (p = 0.17). Vitamin D supplementation resulted in a significantly greater reduction in the size of recurrent UFs (−7.7 mm) compared to control group (p < 0.001).
Davari Tanha et al. [33]	2021	Iran	204	Double-Blind Clinical Trial	-	D	Beneficial	Eight weeks of vitamin D supplementation resulted in a significantly greater reduction in UF size (mm) (0.48 mm decrease) compared to the control group (5.83 mm increase, p < 0.001).
Hajhashemi et al. [34]	2017	Iran	70	Double-Blind Clinical Trial	-	D	Beneficial	Ten weeks of vitamin D supplementation resulted in a significantly greater reduction in the mean UF size (52.58 ± 14.4 mm) compared to the control group (61.11 ± 12.5 mm, P = 0.006).
Arjeh et al. [35]	2020	Iran	60	Clinical Trial	-	D	No effect	No statistically significant decrease in UF volume was observed in the vitamin D supplementation and [mean difference (MD): −0.71, 95% CI:−0.1-1.53, P = 0.085], while UF size significantly increased in the control group (MD: 2.53, 95% CI: 1.9–4.05, p = 0.001).
Guo et al. [36]	2022	China	441,291 (7,122/455,811)	Two-Sample Mendelian Randomization	-	D	Inverse (causal)	The inverse-variance weight (IVW) analysis found a causal association between genetically predicted vitamin D and the risk of UFs (OR = 0.995, 95% CI: 0.990–0.999, p = 0.024).
Nida et al. [37]	2023	Pakistan	113 Patients	Randomized Controlled Interventional Trial	-	D	Beneficial	The mean UF size decreased by 4.84 ± 1.55 cm following the intervention.
Baird, et al. [38]	2012	Usa	1036	Cross Sectional	-	D	Inverse	Vitamin D sufficiency was a preventive factor against UF (adjusted odds ratio (aOR) = 0.68, 95% CI: 0.48–0.96). This finding was consistent in both blacks and whites.
Rosen et al. [39]	2018	Usa	52	Cross Sectional	-	D	Inverse	Vitamin D deficiency was significantly more prevalent UF compared to the general population. Serum 25-(OH) Vit D levels < 23.3 ng/ml were considered as a potential risk factor for UF.
Harmon et al. [40]	2022	Usa	1610	Prospective Community Cohort	-	D	Inverse	Serum 25-(OH) Vit D > 20ng/mL was a preventive factor againts UF (95% CI: −17.3- −1.3%). Serum 25-(OH) Vit D < 30 ng/ml was a risk factor for UF (aHR = 0.78, 95% CI: 0.47–1.30). The probability of UF loss was 32% higher among women with serum 25-(OH) Vit D levels > 30 ng/ml (aHR = 1.32, 95% CI: 0.95–1.83).
Martin et al. [41]	2011	USA	887	Cross-Sectional	-	A	Inverse (dose-response)	A statistically significant dose-response relationship was observed between vitamin A and UFs.
Wise et al. [42]	2011	USA	22,583	Prospective Cohort	-	A	Inverse	Intake of fruits and sources of vitamin A was associated with reduced risk of UFs.
Ciebiera et al. [43]	2018	Polad	162	Retrospective Cohort	-	E	Positive	The mean alpha tocopherol concentration was significantly lower in Caucasian women with UFs compared to those without UFs.
Martin et al. [41]	2011	USA	887	Cross-Sectional	-	E	No association	No significant association was found between vitamin E and UF.

Fig. 1.

Flow diagram of the study

Results

The search identified 9161 studies; after removing duplicates, 9070 were included in the screening process. Of the 9070 studies, 31 met the inclusion criteria and were included in the final synthesis. In this systematic review, 31 studies, including 17 case-control studies, 6 clinical trial studies, 4 cross-sectional studies, 3 cohort studies, and one epidemiological two-sample Mendelian Randomization study, were analyzed.

The overall population of the studies was 55,189 participants. The 17 case-control studies consisted of 1579 cases and 1593 controls in, the clinical trials included 607 participants, the cross-sectional studies included 2862 participants, the cohort studies included 24,355 participants, and the Mendelian epidemiological study included 441,291 participants. Most studies assessed the association between vitamin D, uterine fibroids, while one study evaluated the role of vitamins A, one study evaluated the role of vitamin E, and one study evaluated the role of both vitamin A and E.

Summary of the reviewed studies are presented in Table 1.

Effects of vitamin D on UF

Findings of observational study findings

Pafoni et al., conducted a case-control study with the aim of investigating the vitamin D status in women with UF (n = 128) and without UF (n = 256) groups referred to 2 infertility units in Italy. The included participants had UF diameter of at least 10 mm. The study indicated significantly lower serum vitamin D in the UF group compared to the control group. This difference was also clinically significant as the prevalence of vitamin D deficiency was higher in the UF group compared to the control group. Therefore, vitamin D deficiency was associated with increased risk of UF (adjusted OR = 2.4, 95% CI = 1.2–4.9, P = 0.016). The study also indicated that the prevalence of three or more UFs was higher in the vitamin D deficient group (7, 37%) compared to the non-deficient group (21, 19%); however, this difference was not statistically significant (P = 0.08) [15].

Sabri et al., conducted a case-control study with the aim of investigating the serum level of 25-hydroxyvitamin D3 and the volume of UFs in different ethnic groups. Participants in the UF group had the minimum fibroid lesion size of 2 cm³ in transvaginal ultrasound. The study showed that Lower serum of vitamin D levels were significantly associated with the occurrence of UFs (P = 0.01) and Serum vitamin D levels were inversely correlated with UF size (r = − 0.31; P = 0.002). This inverse correlation was only significant among the black race (r = − 0.42; P = 0.001) [16].

Ciebiera et al., conducted a retrospective cohort study with the aim of investigating the effect of vitamin D3 on UF. Participants in the UP group had had at least one UF of at least 10 mm in size (submucous, intramural or subserosal) based on transvaginal or abdominal ultrasound. The Mean serum vitamin D concentrations were significantly lower in the UF group compared to the healthy control groups. The serum TGF-β3 concentrations were significantly higher in the UF (range: 1.20 to 436.15 pg/mL and median 16.25 pg/mL) compared to the control group (range: 0.96 to 49.08 pg/mL and median 11.80 pg/mL). Higher body mass index (BMI) and positive family history were also found to be among the risk factors for UF [17].

Ingola et al., conducted a case-control study with the aim of investigating the relationship between vitamin D deficiency and UF in women in six hospitals in Kinshasa, Democratic Republic of Congo from April 1 to October 31, 2014. Vitamin D deficiency was defined using local and IOM cut-off levels of serum vitamin D levels < 4 ng/mL and < 12 ng/mL, respectively. The prevalence of vitamin D deficiency using local and IOM criteria was 17.1% and 47.7%, respectively. The prevalence of vitamin D deficiency was significantly higher in the UF group compared to the healthy group based on local criteria (17.7% vs. 10.2%, p = 0.028). Family history of UF (aOR = 2.619, 95% CI: 1.376–4.986, p = 0,003), personal history of UF (OR = 3.776, 95% CI: 1.885–7.565, p = 0.001), non-menopause (OR = 5.502, 95% CI: 2.615–11.517, p = 0.001), high serum progesterone levels (aOR = 2.320, 95% CI: 1,136-4,711, p = 0.021), alcohol use (aOR = 0.295, 95% CI: 0.150–0.580, p = 0.001), and Vitamin D deficiency (aOR = 2.153, 95% CI: 1.035–4.517, p = 0.040) were related to UF [18].

Oskuy Kaplan et al., conducted a prospective observational cross-sectional study with the aim of investigating the relationship between serum levels of vitamin Dand the risk of UF in postmenopausal Turkish women. The serum level of vitamin D was measured by electrochemiluminescence immunoassay. The study showed no significant difference between the groups in terms of age, BMI, weight and parity. The mean serum vitamin D level was significantly lower in the UF group compared to the control group. Serum vitamin D level was not related to UF size, volume, location and number [19].

Ajmani et al., : A case-control study with the aim of determining the relationship between serum vitamin D level and UF on 150 women who referred to the outpatient department of Gynecology and Obstetrics at Kasturba Hospital. UF was diagnosed based on ultrasound and serum vitamin D level was measured using chemiluminescence method. The study showed no significant difference in mean age and age at menarche between groups (p >0.05). The mean serum vitamin D level in the UF group was significantly lower compared to the control group. This difference was also clinicalyy significant as the prevalence of vitamin D deficiency and insufficiency were significantly higher in the UF group compared to the control group (OR = 13.86, 95% CI: 4.82–39.86, p < 0.001 and OR = 11.45, 95% CI: 4.16–31.52, p = 0.001, respectively) [20].

Singh et al., conducted a cross-sectional observational study with the aim of determining the level of serum vitamin D levels in women with UF. The study showed that the mean serum vitamin D level was significantly lower in the UF group compared to control group. This difference was also clinically significant as the prevalence of severe vitamin D deficiency was significantly higher in the UF group compared to the control group and the prevalence of vitamin D sufficiency was significantly lower in the UF group compared to the control group. Severe vitamin D deficiency (serum vitamin D levels < 10 ng/mL) was significantly related to US (OR = 4.64, 95% CI: 2.28–9.44, p = 0.0001) [21].

Srivastava et al., conducted a cross-sectional study with the aim of evaluating the serum vitamin D level in patients with UF at Era’s Lucknow Medical College & Hospital, Lucknow. Participants with UFs larger than 10 mm in ultrasound evaluation were included in the study. The mean ± SD 25-hydroxyvitamin D3 concentration was Significantly lower in the UF group compared to the control group. This difference was also clinically significant as the prevalence of vitamin D deficiency was significantly higher in the UF group compared to the control group. There was a significant indirect correlation between UF size and serum vitamin D levels [22].

Farzaneh et al., conducted a cross-sectional study with the aim of investigating the relationship between serum vitamin D levels and UF in women referring to women’s outpatient clinic in Tehran, Iran in September 2017. Participants with at least one transvaginal or abdominal ultrasound-confirmed UF with the volume of at least 2 cm³ were included. The mean serum vitamin D level was significantly lower in the UF group compared to the control group. A modified odds ratio derived from a backward logistic regression model revealed that higher serum vitamin D levels were protective against UF controlling for family history, age, body mass index, bleeding volume, physical activity, sun exposure, and history of abortion (OR = 0.92, 95% CI: 0.88–0.98, p = 0.02) [23].

Sarbhai et al., conducted a case-control study with the aim of investigating the relationship between serum vitamin D level and UF size in a hospital in Delhi, India. UF was determined by pelvic ultrasound. Serum vitamin D was measured using chemiluminescence. The mean serum 25-hydroxyvitamin D3 levels was significantly lower in the UF group compared to the control group. This difference was also clinically significant as the prevalence of vitamin D deficiency was higher in the UF group compared to the control group. There was a significant and inverse correlation between serum vitamin D levels and UF size (r = − 0.292, p = 0.011) [24].

Mortada et al., conducted a case-control study with the aim of determining the relationship between the serum vitamin D level and the incidence of UF in Egyptian women from April to October 2021. UF was determined based on transvaginal ultrasound. The mean serum vitamin D levels were significantly lower in the UF group compared to the control group. This difference was also clinically significant as the prevalence of vitamin D deficiency (serum vitamin D < 20 ng/mL) was higher in the UF group compared to the control group. The prevalence of vitamin D insufficiency (serum vitamin D3 between 21 and 29 ng/mL) was significantly higher in the UF group compared to the control group, while the prevalence of vitamin D sufficiency (serum vitamin D between 30 and 100 ng/mL) was higher in the control group compared to the UF group. Although none of the participants in the case group had normal serum vitamin D. There was no significant relationship between vitamin D status (deficient and insufficient) and age, parity, hemoglobin, body mass index (BMI), UF size and number, complaints, previous intervention, family history, and associated gynecological diseases [25].

Chen et al., conducted a case-control study with the aim of comparing serum 25-hydroxyvitamin D3 levels in women with UF and healthy controls. The case group included women with UFs who underwent surgery. The UF number and volume were evaluated by transvaginal ultrasound. Serum vitamin D was measured using radioimmunoassay method. The mean serum vitamin D level was significantly lower in the UF group compared to the control group. This difference was also clinically significant as the prevalence of vitamin D deficiency (serum vitamin D < 20 ng/ml) was higher in the UF group compared to the control group. There was a negative correlation between serum vitamin D levels and UF volume (r=−0.18, p = 0.20), while no significant correlation was observed between serum vitamin D levels and UF number (p = 0.38) and UF location (p = 0.89) [26].

Dutta et al., conducted a cross-sectional observational study with the aim of investigating the serum vitamin D level in women with and without UF in India. UF was diagnosed using ultrasound. The mean serum vitamin D level was significantly lower in the UF group compared to the control group. This difference was also clinically significant as the prevalence of severe vitamin D deficiency (serum vitamin D < 9 ng/mL) was higher in the UF group compared to the control group [27].

Ingala et al., conducted a case-control study with the aim of investigating the relationship between vitamin D deficiency and UF on 216 women with UF diagnosed by ultrasound and 216 healthy controls. The prevalence of Vitamin D deficiency (serum vitamin D between 4 and 12 ng/ml) was significantly higher in the UF group compared to the control group [18].

Xess et al., conducted a case-control study with the aim of investigating the effect of vitamin D supplementation (60,000 IU for 12 weeks and maintenance of 2000 IU for one year) on UF in Participants with UF diameter of at least 10 mm and serum vitamin D levels below 29 ng/mL. Although the serum vitamin D level increased from 21 to 23 ng/mL, no significant change in UF size was observed in the intervention group. However, a non-significant increase in UF size was recorded in the control group [28].

Sayed Ahmed et al., conducted a case-control study with the aim of comparing serum vitamin D level in women with and without UF diagnosis based on ultrasound. Serum vitamin D level was measured by ELISA method. The study showed an inverse correlation between UF size and serum vitamin D level [29].

All Ansary et al., conducted a case-control study with the aim of investigating the relationship between serum vitamin D status and UF on women of reproductive age referring to a university Hospital. Participants with at least one UF by transvaginal evaluation were included in the case group. The sensitivity, specificity, and accuracy of serum vitamin D in detecting UF were 77.2%, 61.2%, and 71.6%, respectively (area under the curve was 0.754). The study showed that the risk of UF in women with vitamin D insufficiency was 1.3 times higher than women with sufficient vitamin D levels. Women who were exposed to sunlight for less than 1 h per day were 7.52 times more prone to UF compared to women who were exposed to sunlight equal to 1 h per day [30].

Baird et al., conducted a case-control study with the aim of investigating the prevalence of fibroids in premenopausal women from 1996 to 1999 on premenopausal women UFs at a large health program in Washington, USA. UF was evaluated using ultrasound. Serum vitamin D was measured using the radioimmunoassay method, while sun exposure was evaluated using questionnaire. The risk of UF was 32% lower among women with sufficient vitamin D (aOR = 0.68, 95% CI: 0.48–0.96), which was similar for blacks and whites. Sun exposure for at least 1 h per day was associated with reduced odds of UF (aOR = 06. [0.4–0.9]) [31].

Rosen et al., conducted a cross-sectional analytical study with the aim of estimating the prevalence of vitamin D deficiency (serum vitamin D less than 30 ng/mL) in women with UF compared to the general population in the United States from June 2012 to September 2012. UFs were diagnosed using ultrasound or MRI. The study showed that 86.5% of patients had vitamin D less than 30 ng/mL, including vitamin D deficiency (50%) and vitamin D insufficiency (36.5%). The mean serum vitamin D level was 23.3 ng/mL [32].

Harmon et al., conducted a cohort study with the aim of investigating the relationship between serum vitamin D and growth, incidence and loss of UFs. Inclusion criteria were 23–34 years of age and no prior diagnosis of UF at recruitment. The study included four visits 20 months apart. Serum vitamin D ≥ 20 ng/mL as associated 9.7% reduction in UF growth, similar to the minimally adjusted estimate − 8.4% compared to levels < 20ng/mL. Serum vitamin D was associated with 22% reduction in UF incidence, similar to the unadjusted estimate of 0.84 compared to serum vitamin D < 30 ng/mL. Serum vitamin D >30 ng/mL was associated with 32% increase in UF loss [33].

Findings of interventional studies

Rahmanian et al., conducted a double-blind study with the aim of investigating the effect of vitamin D supplementation (50000 IU per week for 16 weeks) on UFs in women vitamin D deficiency. The study showed that after four months of intervention resulted in a significantly greater reduction in UF volume compared to the control group [34].

Vahdat et al., conducted a double-blind placebo-controlled trial with the aim of investigating the effect of vitamin D supplementation (1000 IU for 12 months) on the recurrence of UFs (based on 3D transvaginal ultrasound examination) among women who underwent hysteroscopic myomectomy surgery from November 2017 to June 2020. Vitamin D supplementation for one year reduced the recurrence rate of UFs by 50%, and reduced the size of recurrent UFs by −7.7 mm with no adverse effects [35].

Davari Tanha et al., conducted a randomized blinded clinical trial with the aim of evaluating the effects of vitamin D supplementation (50000 IU for two months) on UF growth in a university-based hospital from August 2017 to September 2018. Participants with at least one UF larger than 10 mm on transvaginal ultrasound and serum vitamin D levels 20 and 30 ng/mL were included in the study. The intervention group experienced 0.48 mm reduction in UF size while UF size increased by 5.83 mm in the control group. The largest change in UF diameter was observed for the intramural followed by subserosal UFs in the intervention group, while the largest change in UF size was observed in submucosal followed by subserosal UFs in the control group [36].

Haj Hashemi et al., conducted a double-blind clinical trial with the aim of determining the effect of vitamin D supplementation (50000 IU every two weeks for 10 weeks) on UF size in women with UF and vitamin D deficiency. Vitamin D supplementation increased reduced UF size in the intervention group [37].

Arjeh et al., conducted a randomized double-blind clinical trial with the aim of investigating the effect of vitamin D supplementation (50000 IU for 12 weeks) on UFs from June to November 2018 in eligible women aged 22–40 years who referred to gynecologists in Bandar Abbas hospitals, Iran. Vitamin D supplementation had no effect on UF size [38].

Guo et al., conducted a randomized Mendelian study with the aim of investigating the causal relationship between genetically predicted serum vitamin D levels and the risk of UFs. Data were obtained from a genome-wide association study (GWAS) of 441,291 individuals from the UK Biobank, FinnGen Biobank and associated consortia datasets. The study showed that a one standard deviation increase in serum vitamin D level was associated with a decreased risk of UFs (OR = 0.995, 95% CI: 0.990–0.999, p = 0.024) in European population [39].

Nida Ayesha et al., conducted a randomized controlled trial with the aim of evaluating the effects of vitamin D supplementation (50000 IU vitamin D orally along with 500 mg tranexamic acid and 10 mg dydrogesterone) in patients with UF (3 to 13 cm) in Karachi, Pakistan. Participants were selected using stratified random sampling. The mean difference in UF size was − 4.84 ± 1.55 cm in the intervention group [40].

Effects of vitamin A and E on UF

Martin et al., conducted a population-based cross-sectional study with the aim of investigating the relationship between micronutrients and UFs in the 2003–2004 National Health and Nutrition Examination Survey (NHANES). Serum micronutrient levels were collected during health examinations and information about UFs was assessed in self-reported questionnaires. There was a statistically significant dose-response relationship between vitamin A and UFs, after adjustment for confounders including age, race, education, BMI, and oral contraceptive use (middle vs. low: OR = 2.43, 95% CI: 1.35–4.37, high vs. low: OR = 2.66, 95% CI: 1.16–6.10, p for trend = 0.02) [41].

Wise et al., conducted a prospective cohort study, with the aim of evaluating the relationship between dietary intake of fruits, vegetables, carotenoids, folate, fiber, and vitamins A, C, and E with UFs in the African-American Women’s Health Study from 1997 to 2009. Dietary intakes were estimated using food frequency questionnaires. Cox regression was used to derive incidence rate ratios (IRRs) and 95% CIs for the association between each dietary variable (in quintiles) and UL. The intake of preformed vitamin A from animal sources was found to be related to UF (upper compared with lower quintiles: IRR: 0.89; 95% CI: 0.83, 0.97; P-trend = 0.01). UF was not associated with dietary intake of vitamin E [42].

Ciebiera et al., conducted a cohort study with the aim of evaluating and comparing serum vitamin E concentration in patients with UFs and control group among Caucasian women in Warsaw, Poland from September 2014 to May 2015. The sample size included 162 women who were divided into 2 groups: women who were hospitalized for surgery due to clinical symptoms caused by UF, and the control group. Participants with at least 1 UF (at least 10 mm diameter) on transvaginal or transabdominal ultrasound examination were included in the study. After adjustment for age, BMI, medical history, fertility rate, women with serum vitamin E between 7.26 and 9.09 µg/mL had higher risk for UF compared with those with the serum lowest vitamin E quartile (OR = 2.91, 95% CI: 1.11–7.63). Among women in the highest quartile of serum vitamin E, the age-adjusted risk was higher compared with women in the lowest quartile (OR = 18.05, 95% CI: 4.81–67.79). The risk of UF increased with increased vitamin E quartile (p for trend = 0.004) in crude analysis, but not after adjusting for age (p for trend = 0.051) [43].

Discussion

Although UFs are among the most common uterine disorders that are easily diagnosed, their main pathogenesis remains unknown. The increasing knowledge on the function of oxidative stress mechanisms in cells has shed light on new aspects of the pathogenesis and risk factors for the growth of tumors, especially uterine tumors [44]. It has been determined that the change in the function of antioxidants and the inactivation of cellular lipid peroxidation reactions are the main triggers for the formation and progression of tumors. Fat-soluble antioxidants like vitamins A and D are important as they destroy cellular free radicals and can inhibit the primary tumor formation pathway [44, 45].

The current systematic review was conducted with the aim of evaluating the effect of fat-soluble vitamins on UFs. The overall findings of this study showed that low levels of fat-soluble vitamins, especially vitamin D3, can induce UFs, and that the incidence of UFs was inversely related to the serum level of vitamin D3.

Effects of vitamin D on UF

This systematic review evaluated the relationship between serum levels of vitamin D3 and UF incidence or growth in different races and nationalities. In this systematic review, the findings of majority of the observational studies indicated the possible preventive effect of sufficient serum vitamin D levels against the incidence of UF. Furthermore, the observational studies showed that the severity of vitamin D deficiency was associated with the incidence of UFs. However, two studies (Sabry et al. and Mortada Ahmed et al.), which were conducted on Egyptian participants stated that although the decrease in vitamin D3 levels was associated with the risk of UFs, severity of vitamin D3 deficiency was not related to neither the number of UFs, nor the size and volume of UFs [16, 25]. The reason for the observed findings in the two mentioned studies might be due to lack of participants with sufficient serum vitamin D in the control groups. The overall findings of the observational studies indicated no relationship between low serum vitamin D level and the volume, size, and the number of UFs.

Clinical trials provide stronger evidence for causal relationships, making them crucial for evaluating treatment effects on UFs. Therefore, the evaluation of this type of studies is of particular importance for reviewing the current research system [46]. The clinical trial studies included in this systematic review evaluated the role of vitamin D3, in the clinical symptoms of UFs, including the severity of bleeding, pelvic pains, and size, number, and recurrence of UFs.

Of the 6 double blind studies included in this systematic review, 5 studies were conducted in Iran and one study was conducted in Pakistan. One reason for conducting the studies in this region can be related to the high prevalence of vitamin D3 deficiency in these two countries [47, 48]. Contrary to case-control studies, clinical trial studies indicated an inverse relationship between vitamin D3 consumption and UF size. It is worth noting that these studies mainly reported changes in the size of the UFs and did not report the size of UFs like the case-control studies conducted by the Egyptians. The one-year follow-up of the patients of the study of Vahdat et al., also stated that the daily consumption of 1000 IU vitamin D3 for 12 months reduced the risk of relapse and recurrence in addition to reducing UF size. Therefore, the results of clinical trials showed a positive and safe effect for vitamin D3 on the volume and size; recurrence, and clinical symptoms caused by UFs [35].

One of the most important studies included in this systematic review was the Mendelian randomized study. Mendelian random studies operate based on Mendel’s genetic rule and evaluate causal relationship. Based on the biobank of more than 460,000 women living in the UK, a causal relationship was determined between low serum vitamin D3 levels and the incidence of UFs. The large sample size and the methodology of the Mendelian study was one of its main strengths, which can confirm the causal relationship between vitamin D3 and leiomyoma in European women [39].

Effects of vitamin A and E on UF

Unlike vitamin D the reviewed studies, no intervention study evaluated the effects of vitamin A and E on UF. Cross-sectional studies are the best types of studies to evaluate health and disease status in the population and the consequences of exposures. Therefore, we can rely on the dose response effect of fat-soluble vitamin A and UFs but with lower level of certainty [49].

The observational studies reported a dose-response relationship between vitamin A and UFs. Martin et al., reported that of the evaluated vitamins, only the serum level of vitamin A was significantly related to UFs [28]. A prospective cohort study evaluated the nutritional status of African-American women for 2 years reported an inverse relationship between the intake of fruit and the incidence of UFs, but this relationship was not significant. However, the intake of foods containing vitamin A, especially animal foods (like liver and dairy products), was associated with a decrease in the risk of UF [42]. The reason for this difference might be related to the difference in the methodology of the studies. While Martin et al., evaluated serum levels of vitamin A, the study by Wise et al., evaluated the dietary intake of the sources of vitamin A. Therefore, the difference between the findings of the studies could be due to the difference in the intake and type of provitamins and the serum level of vitamin A. This hypothesis could be proven by the observed superiority of animal sources of vitamin A, which have better bioavailability compared to plant sources, in reducing the risk of UFs [42].

The retrospective cohort by Ciebiera et al., showed that although vitamin E acts as a strong antioxidant, it had no effect on UFs. However, low serum alpha-tocopherol levels were associated with reduced size of UFs among black women [43]. In other words, high concentration of serum alpha-tocopherol was considered as a risk factor for UFs [43]. Although vitamin E has been used as a beneficial vitamin to improve reproductive health for many years, the results of this study raised doubts about the use of vitamin E in UFs. A reason for the contradictory finding of the study by Ciebiera et al., might be related to its design. This cohort study was conducted as a pilot and evaluated the results only among African-American women [43].

Although there was scarcity of data in terms of the effects of vitamin A and E on UF, the findings of the reviewed studies may indicate that vitamin A and E might not be ass effective as vitamin D in reducing the risk of UF. The reason for the different effects of vitamin E and A on UFs could be related to the cellular function of fat-soluble vitamins. Vitamin A and vitamin E are indirect antioxidants that can regulate the genetic functions in cell. However, vitamin E directly controls oxygen peroxidases and cellular pathways. Therefore, vitamin E deficiency can result in altered gene expression and cell function [50–52]. Due to the functional differences of vitamin E and A, some researchers do not classify vitamin A as an antioxidant because of its indirect cellular role [53]. Therefore, further observational and interventional studies are required to provide further evidence on the effect and mechanisms of action of these vitamins in relation to UF.

One of the limitations of this study is the heterogeneity of the studies included in this systematic review, which prevented its meta-analysis.

Conclusion

Of the fat-soluble vitamins, vitamin D3 can have a strong effect on UFs, and vitamin D3 supplementation in deficient populations may be a valuable adjunct to standard UF treatments to reduce symptoms and size. Vitamin A, especially from animal sources can also be effective in the prevention of UFs. Unlike vitamin D3 and A, the relationship between vitamin E and UFs has been determined only in the African-American race, where a direct relationship between the serum level of alpha-tocopherol and the incidence of UFs were reported.

Abbreviations

UF

Uterine fibroids

PRISMA

Preferred reporting items for systematic reviews and meta-analyses

JBI

Joanna briggs institute

25-(OH) Vit D

25-hydroxyvitamin D

IRMA

Immunoradiometric assay

Authors’ contributions

Study concept and design: S. D; analysis and interpretation of data: F. J., and N. J.; drafting of the manuscript: S. D., and T.FN and M. A.; critical revision of the manuscript for important intellectual content: S. D., T. FN.; All authors read and approved the final manuscript.

Funding

NONE.

Data availability

The data supporting this Systematic Review are from previously reported studies and datasets, which have been cited.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.